title stringlengths 0 1.13k | abstract stringlengths 1 15.7k | PMID int64 22 36.5M |
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The potential of nano-structured silicon oxide type coatings deposited by PACVD for control of aquatic biofouling. | SiO(x)-like coatings were deposited on glass slides from a hexamethylsiloxane precursor by plasma-assisted CVD (PACVD). Surface energies (23.1-45.7 mJ m(-1)) were correlated with the degree of surface oxidation and hydrocarbon contents. Tapping mode AFM revealed a range of surface topologies with Ra values 1.55-3.16 nm and RMS roughness 1.96-4.11 nm. Settlement of spores of the green alga Ulva was significantly less, and detachment under shear significantly more on the lowest surface energy coatings. Removal of young plants (sporelings) of Ulva under shear was positively correlated with reducing the surface energy of the coatings. The most hydrophobic coatings also showed good performance against a freshwater bacterium, Pseudomonas fluorescens, significantly reducing initial attachment and biofilm formation, and reducing the adhesion strength of attached bacterial cells under shear. Taken together the results indicate potential for further investigation of these coatings for applications such as heat exchangers and optical instruments. | 18,855,197 |
Prevalence and risk factors of nasal colonization with Staphylococcus aureus - association with HIV infection in older patients. | Nasal S. aureus colonization was detected in 62/127 patients (49%) at a German infectious diseases clinic; MRSA colonization was infrequent at 2.4%. Male gender (OR=2.71, p=0.04), antimicrobial therapy in hospitalized patients (OR=20.1, p=0.02), and HIV infection in patients>42 y of age (OR=7.74, p=0.02) were independent risk factors for S. aureus colonization. | 18,855,226 |
Assessing change in clinical teaching skills: are we up for the challenge? | The faculty development community has been challenged to more rigorously assess program impact and move beyond traditional outcomes of knowledge tests and self ratings. The purpose was to (a) assess our ability to measure supervisors' feedback skills as demonstrated in a clinical setting and (b) compare the results with traditional outcome measures of faculty development interventions. A pre-post study design was used. Resident and expert ratings of supervisors' demonstrated feedback skills were compared with traditional outcomes, including a knowledge test and participant self-evaluation. Pre-post knowledge increased significantly (pre = 61%, post = 85%; p < .001) as did participant's self-evaluation scores (pre = 4.13, post = 4.79; p < .001). Participants' self-evaluations were moderately to poorly correlated with resident (pre r = .20, post r = .08) and expert ratings (pre r = .43, post r = -.52). Residents and experts would need to evaluate 110 and 200 participants, respectively, to reach significance. It is possible to measure feedback skills in a clinical setting. Although traditional outcome measures show a significant effect, demonstrating change in teaching behaviors used in practice will require larger scale studies than typically undertaken currently. | 18,855,231 |
Molecular cloning and expression analysis of CD82 in pig. | CD82, which was originally referred to as KAI1 (kangai 1), is a member of the tetraspanin protein family, which contains four transmembrane domains. CD82 is implicated in a variety of biological processes, including apoptosis, cell adhesion, and cell migration. In this study, the full-length cDNA of pig CD82 was cloned and sequenced. Pig Cd82 cDNA contains an open reading frame (801 bp) encoding 266 amino acids. Sequence alignment results indicated that pig CD82 cDNA evidenced 85.45%, 85.63%, 77.03%, and 77.78% identity with human, cattle, rat, and mouse, respectively. In the expression study, the constitutive expression of swine Cd82 mRNA was detected in a variety of tissues, including lymphoid tissues as well as nonlymphoid tissues. Future studies will be focused on the functional role of CD82 during the course of pig infectious diseases or tumor development. | 18,855,249 |
Vascular endothelial growth factor attenuates Nomega-nitro-L-arginine methyl ester-induced preeclampsia-like manifestations in rats. | To verify the hypothesis that vascular endothelial growth factor (VEGF) attenuates Nomega-Nitro-L-arginine Methyl Ester (L-NAME)-induced preeclampsia-like manifestations in rats. Forty pregnant Wistar rats were randomly divided into four groups: control, preeclampsia model, VEGF treatment, and VEGF prophylactic. On day 5 of gestation, L-NAME was injected subcutaneously in rats of the preeclampsia model, VEGF treatment, and VEGF prophylactic groups. VEGF was given after the occurrence of hypertension and proteinuria in the VEGF treatment group and from day 5 in the VEGF prophylactic group. Blood pressure was monitored and urine protein was assayed. Blood platelet was counted, and serum nitric oxide metabolites, endothelin-1, 6-keto-PGF-1alpha, and TXB2 were determined. Blood pressure increased significantly on day 8 of gestation in the preeclampsia model and VEGF treatment groups compared with control (p < 0.05 for both) and remained elevated through the pregnancy in the preeclampsia model group. Blood pressure was significantly decreased after the administration of VEGF in the VEGF treatment group (p < 0.05). There was no significant difference in blood pressure between the VEGF prophylactic group and control (p > 0.05). Urine protein, platelet count, serum nitric oxide metabolites, endothelin-1, 6-keto-PGF-1alpha, and TXB2 were significantly different between control and the preeclampsia model group (p < 0.05), but not between control and the VEGF treatment or VEGF prophylactic groups (p > 0.05 for all). VEGF attenuates L-NAME-induced preeclampsia-like manifestations in rats, suggesting the important role of VEGF in preeclampsia and providing a potential strategy for the prevention and treatment of preeclampsia. | 18,855,264 |
[Cost-efficacy analysis of fixed combinations of prostaglandin/prostamide for treating glaucoma]. | To assess the cost-efficacy of three fixed-combination glaucoma treatments currently available in Spain [bimatoprost with timolol (BT)- Ganfort, latanoprost with timolol (LT)- Xalacom, and travoprost with timolol (TT)- DuoTrav]. Because no studies are available that give a direct comparison of these drugs, a systematic review was carried out to assess their efficacy. Resource consumption and costs were estimated using a model of usual local practice. For each of the three drugs, average and incremental cost-efficacy ratios were determined in terms of euros per percentage point of reduction of intraocular pressure (IOP) over a three-month period. BT reduced IOP by 35.1%, LT by 35.0% and TT by 34.7%. Average cost-efficacy was estimated to be euro 5.34 per percentage point of IOP reduction with BT, euro 5.40 with LT, and euro 5.45 with TT. Incremental cost-efficacy (incremental cost per incremental percentage point of IOP reduction) was estimated to be euro 94.65 for LT vs. TT, and was negative for BT vs. TT and BT vs. LT, since in both cases BT was more efficacious and less expensive. Compared to travoprost/timolol and latanoprost/timolol, bimatoprost/timolol appears to be the most economic alternative, with equal or better efficacy and safety results. | 18,855,279 |
[Optical coherence tomography study in tamoxifen maculopathy]. | We describe the case of a patient who presented with progressive and bilateral loss of vision. She had been treated with tamoxifen for 13 years. We performed fluorescein angiography and optical coherence tomography in order to study the macula. Loss of visual acuity related to tamoxifen maculopathy may be caused either by retinal nerve fibre atrophy or macular oedema. Macular findings obtained by fluorescein angiography and optical coherence tomography are complementary. | 18,855,282 |
[Intracranial hypertension and cranial sinus stenosis]. | Craneal sinuses stenosis can appear in patients with idiopathic intracranial hypertension. Neuroimaging techniques revealed a right transverse sinus stenosis. As the pressure gradient between both sides of the stenosis was small and response to conservative treatment good, angioplasty was not indicated. Lateral sinus stenosis in patients with idiopathic intracranial hypertension is prevalent. It is not clear whether these stenoses are the origin of, or secondary to, cerebrospinal fluid pressure increases. Some cases refractory to conservative treatment may respond to angioplasty with stent placement. | 18,855,283 |
Pre-coronal, paramedian minicraniotomy: a minimal access approach for microsurgical, transcallosal, transforaminal removal of colloid cysts of the third ventricle. | Microsurgical excision of colloid cysts of the third ventricle is accomplished along the transcallosal or the transfrontal routes. In the transcallosal approach, venous tributaries of the superior sagittal sinus can often act as an impediment to entry into the interhemispheric fissure for accessing the corpus callosum. We propose a paramedian minicraniotomy anterior to the coronal suture for removing colloid cysts via the transcallosal approach as veins are relatively rare in this area. A triangular minicraniotomy was designed with each side measuring 3 cm based on the midline in the pre-coronal area of the frontal bone on the right side. Nineteen cases of symptomatic colloid cysts of the third ventricle whose diagnoses were proven by CT and/or MRI were subjected to microsurgery in the period from June 2004 to May 2007. Following the minicraniotomy the cysts were removed utilizing the transcallosal transforaminal route. Venous tributaries crossing the interhemispheric fissure were seen in 2 patients and these could be avoided to access the corpus callosum. Complete excision could be achieved in all cases. All patients had a good outcome although one patient had transient left lower limb weakness. The mean operating time was 163 minutes, while the mean duration of stay in the intensive care unit and hospitalization were 1.35 days and 3.73 days, respectively. The pre-coronal, paramedian minicraniotomy is safe and effective for the total excision of colloid cysts of the third ventricle. As a minimal access approach, it needs only a short duration of postoperative hospitalized care. | 18,855,287 |
Minimally invasive vertebroplasty in the treatment of pain induced by spinal metastatic tumor. | Spinal metastatic tumor is a common problem and represents a challenging problem in oncology practice. Patients with osteolytic metastases often suffer from intractable local and/or radicular pain. Percutaneous vertebroplasty is a minimally invasive, radiologically guided procedure whereby bone cement is injected into structurally weakened vertebrae to provide immediate biomechanical stability. Vertebroplasty is also used to relieve pain by stabilizing metastatically compromised vertebrae that are at risk of pathological burst fracture. In this retrospective study, a total of 57 patients (78 vertebrae) with spinal metastatic tumor were treated with PMMA vertebroplasty. The mean value of the visual analogue scale (VAS) was 8.1 +/- 0.67 preoperatively, and significantly decreased to 3.8 +/- 1.9 (1-8, p < 0.015) one day after vertebroplasty. The mean VAS value 6 months after vertebroplsty was 2.8 +/- 2.0 (p < 0.001). Mean injected bone cement amount in our study is 5.16 +/- 1.6 mL. The complication rate is about 21.8%, bone cement extravasation without neurological deficit is the most common complication. No new or adjacent vertebral fracture has occurred in more than 2 years follow-up. Percutaneous vertebroplasty is a minimally invasive procedure that offers a remarkable advantage of effective and immediate pain relief with few complications. | 18,855,293 |
De novo sequencing of peptides secreted by the skin glands of the Caucasian Green Frog Rana ridibunda. | Amphibian skin glands are known to secrete various types of bioactive peptides. The array of these peptides is specific for every frog species. The present research deals with the identification of peptides isolated from the skin secretion of the Marsh frog R. ridibunda inhabiting the Kolkhida Canyon of the Caucasian region. The research is based on comprehensive high-performance liquid chromatography/tandem mass spectrometry (HPLC/MS/MS) analysis of intact and chemically modified peptides. In particular, an oxidation procedure was applied directly to the crude skin secretion to open S--S loops whereas N-terminal acetylation was additionally carried out for one individual peptide. Sequences were determined by manual interpretation of electron capture dissociation (ECD) and collisionally induced dissociation (CID) tandem mass spectra. A total of 29 peptides were identified in the skin secretion of the Caucasian Marsh frog. The peptide profile is represented with disulfide-containing peptides belonging to the brevinin, esculentin and ranatuerin families, neuropeptides of the bradykinin and bombesin families. Two identified peptides belonging to the ranatuerins are the first peptides of this family discovered in the skin secretions of European frogs. Ten of the identified peptides coincide with those reported earlier for the European Edible frog. Another ten are identical to those found in R. ridubunda from the Moscow region. This fact verifies the described method as being an efficient analytical tool to compare intra- and interspecific variabilities. | 18,855,342 |
Ionization energies of the nucleotides. | The vertical ionization energies of the four nucleotides have been computed. Geometries have been chosen to mimic orientations as they appear in B-DNA. The negative charge on the phosphate was neutralized by protonation, and also by the inclusion of counterions. Calculations have been performed with electron propagator methods (P3), Møller-Plesset second-order perturbation theory, and density functional theory to determine the nature of the orbitals associated with the highest lying ionization energies. Calculations at the MP2/6-311G(d,p)//P3/6-311G(d,p) level of theory yield vertical ionization energies for 5'-dTMP 9.05 eV, for 5'-dCMP 8.40 eV, for 5'-dAMP 8.16 eV and for 5'-dGMP 7.96 eV. In all cases the highest occupied molecular orbital resides on the base moieties. | 18,855,364 |
An arene-stabilized cobalt(I) aryl: reactions with CO and NO. | The half-sandwich cobalt(I) complex (eta (6)-C 7H 8)CoAr*-3,5- ( i )Pr 2 (Ar*-3,5- ( i )Pr 2 = -C 6H-2,6-(C 6H 2-2,4,6- ( i )Pr 3) 2-3,5- ( i )Pr 2) was synthesized by reduction of [3,5- ( i )Pr 2Ar*Co(mu-Cl)] 2 in toluene. It reacts with CO or NO to afford the unusual complexes [3,5- ( i )Pr 2Ar*C(O)Co(CO)] or [3,5- ( i )Pr 2Ar*N(NO)OCo(NO) 2]. | 18,855,383 |
Identification of conical structures in small aluminum oxide clusters: infrared spectroscopy of (Al2O3)1-4(AlO)+. | The vibrational spectroscopy of the electronically closed-shell (Al 2O 3) n (AlO) (+) cations with n = 1-4 is studied in the 530-1200 cm (-1) range by infrared predissociation spectroscopy of the corresponding ion-He atom complexes in combination with quantum chemical calculations. In all cases we find, assisted by a genetic algorithm, global minimum structures that differ considerably from those derived from known modifications of bulk alumina. The n = 1 and n = 4 clusters exhibit an exceptionally stable conical structure of C 3 v symmetry, whereas for n = 2 and n = 3, multiple isomers of lower symmetry and similar energy may contribute to the recorded spectra. A blue shift of the highest energy absorption band is observed with increasing cluster size and attributed to a shortening of Al-O bonds in the larger clusters. This intense band is assigned to vibrational modes localized on the rim of the conical structures for n = 1 and n = 4 and may aid in identifying similar, highly symmetric structures in larger ions. | 18,855,393 |
Selective stabilization of natively folded RNA structure by DNA constraints. | Learning how native RNA conformations can be stabilized relative to unfolded states is an important objective, for both understanding natural RNAs and improving the design of artificial functional RNAs. Here we show that covalently attached double-stranded DNA constraints (ca. 14 base pairs in length) can significantly stabilize the native conformation of an RNA molecule. Using the P4-P6 domain of the Tetrahymena group I intron as the test system, we identified pairs of RNA sites where attaching a DNA duplex is predicted to be structurally compatible with only the folded state of the RNA. The DNA-constrained RNAs were synthesized and shown by nondenaturing polyacrylamide gel electrophoresis (native PAGE) to have substantial decreases in their Mg2+ midpoints ([Mg2+]1/2 values). These changes are equivalent to free energy stabilizations as large as DeltaDeltaGdegrees = -2.5 kcal/mol, which is approximately 14% of the total tertiary folding energy. For comparison, the sole modification of P4-P6 previously reported to stabilize this RNA is a single-nucleotide deletion (DeltaC209) that provides only 1.1 kcal/mol of stabilization. Our findings indicate that nature has not completely optimized P4-P6 RNA folding. Furthermore, the DNA constraints are designed not to interact directly and extensively with the RNA, but rather more indirectly to modulate the relative stabilities of folded and unfolded RNA states. The successful implementation of this strategy to further stabilize a natively folded RNA conformation suggests an important element of modularity in stabilization of RNA structure, with implications for how nature might use other molecules such as proteins to stabilize specific RNA conformations. | 18,855,395 |
A new one-pot, four-component synthesis of 1,2-amino alcohols: TiCl3/t-BuOOH-mediated radical hydroxymethylation of imines. | An amine, an aldehyde, and methanol can be readily assembled in one pot under very mild conditions through a free-radical multicomponent reaction by using an aqueous acidic TiCl3/t-BuOOH system to afford 1,2-amino alcohols in fair to excellent yields. | 18,855,404 |
Synergistic effects on enantioselectivity of zwitterionic chiral stationary phases for separations of chiral acids, bases, and amino acids by HPLC. | In an attempt to overcome the limited applicability scope of earlier proposed Cinchona alkaloid-based chiral weak anion exchangers (WAX) and recently reported aminosulfonic acid-based chiral strong cation exchangers (SCX), which are conceptionally restricted to oppositely charged solutes, their individual chiral selector (SO) subunits have been fused in a combinatorial synthesis approach into single, now zwitterionic, chiral SO motifs. The corresponding zwitterionic ion-exchange-type chiral stationary phases (CSPs) in fact combined the applicability spectra of the parent chiral ion exchangers allowing for enantioseparations of chiral acids and amine-type solutes in liquid chromatography using polar organic mode with largely rivaling separation factors as compared to the parent WAX and SCX CSPs. Furthermore, the application spectrum could be remarkably expanded to various zwitterionic analytes such as alpha- and beta-amino acids and peptides. A set of structurally related yet different CSPs consisting of either a quinine or quinidine alkaloid moiety as anion-exchange subunit and various chiral or achiral amino acids as cation-exchange subunits enabled us to derive structure-enantioselectivity relationships, which clearly provided strong unequivocal evidence for synergistic effects of the two oppositely charged ion-exchange subunits being involved in molecular recognition of zwitterionic analytes by zwitterionic SOs driven by double ionic coordination. | 18,855,417 |
Off-line coupling of capillary electrophoresis to substrate-assisted laser desorption inductively coupled plasma mass spectrometry. | A novel off-line coupling of capillary electrophoresis (CE) and inductively coupled plasma mass spectrometry (ICPMS) is reported here. The coupling interface is based on the connection of a separation capillary to a deposition capillary via a liquid junction maintaining high separation efficiency and sample utilization due to the self-focusing effect and lack of pressure-induced flow in comparison with nebulizer-like interfaces. The separation is recorded in the form of droplets of CE effluent on a suitable substrate--a poly(ethylene terephthalate) glycol (PETG) sample plate placed inside a partially evacuated chamber. Substrate-assisted laser desorption (SALD) is used to vaporize the sample fractions and to enable further transfer to the ICPMS. The mechanism of SALD is examined using model samples deposited on a variety of substrates. The highest response is obtained for a PETG substrate; sample desorption due to ablation of PETG is found to outweigh direct ablation of sample. Detection limits are given for several metal elements. Finally, a rapid (2.5-min), high-resolution separation of Cr(III)/Cr(VI) species injected in subpicomolar quantity is shown. | 18,855,419 |
Kinetic and spectroscopic analysis of the catalytic role of H79 in the methionine aminopeptidase from Escherichia coli. | To gain insight into the role of the strictly conserved histidine residue, H79, in the reaction mechanism of the methionyl aminopeptidase from Escherichia coli ( EcMetAP-I), the H79A mutated enzyme was prepared. Co(II)-loaded H79A exhibits an overall >7000-fold decrease in specific activity. The almost complete loss of activity is primarily due to a >6000-fold decrease in k cat. Interestingly, the K m value obtained for Co(II)-loaded H79A was approximately half the value observed for wild-type (WT) EcMetAP-I. Consequently, k cat/ K m values decreased only 3000-fold. On the other hand, the observed specific activity of Mn(II)-loaded H79A EcMetAP-I decreased by approximately 2.6-fold while k cat decreased by approximately 3.5-fold. The observed K m value for Mn(II)-loaded H79A EcMetAP-I was approximately 1.4-fold larger than that observed for WT EcMetAP-I, resulting in a k cat/ K m value that is lower by approximately 3.4-fold. Metal binding, UV-vis, and EPR data indicate that the active site is unperturbed by mutation of H79, as suggested by X-ray crystallographic data. Kinetic isotope data indicate that H79 does not transfer a proton to the newly forming amine since a single proton is transferred in the transition state for both the WT and H79A EcMetAP-I enzymes. Therefore, H79 functions to position the substrate by hydrogen bonding to either the amine group of the peptide linkage or a backbone carbonyl group. Together, these data provide new insight into the catalytic mechanism of EcMetAP-I. | 18,855,426 |
Enzyme-catalyzed formation and structure characteristics of a protein-based hydrogel. | A protein-based hydrogel with tunable gelation time and mechanical strength was obtained by the hydrogelation of soy protein isolate (SPI) in the presence of microbial transglutaminase (MTGase). In order to control the gelation process and understand the relationship between the property and network structure of the formed SPI hydrogel, the changes of viscoelastic properties with time during the gelation process were monitored by the use of dynamic rheometry. The measurements were carried out at different protein concentrations, enzyme amounts, and reaction temperatures to clarify their effects on the gelation kinetics. In particular, the fractal characteristics of the SPI hydrogels formed in the presence and absence of MTGase were examined by relating the rheological data to a scaling model. In addition, the resultant SPI hydrogel matrix was investigated for the controlled release of 5-aminosalicylic acid as the model drug. | 18,855,437 |
Extensional properties of hydroxypropyl ether guar gum solutions. | The extensional properties of 2-hydroxypropyl ether guar gum solutions were investigated using a capillary breakup extensional rheometer (CaBER). Optimization of the geometric parameters of this device allowed for the measurement of the characteristic relaxation times and the apparent extensional viscosities of a series of dilute to semidilute guar gum solutions. The measured relaxation times were compared with predicted Zimm relaxation times, assuming that the hydrophobically modified guar was in a good solvent. Good agreement was found at low concentrations (0.01 wt % approximately 0.17 c*, where c* is the polymer overlap concentration), and this technique allowed for relaxation times on the order of 1 ms to be measured for solutions with shear viscosities of 2 mPa.s. Both the shear and (apparent) steady-state extensional viscosities of this set of industrially relevant fluids exhibited two regions of dependency on polymer concentration: linear up to concentrations of 0.2 wt % ( c/ c* approximately 3) and power law thereafter, where interchain interactions became significant. The extracted relaxation times followed the same trend (i.e., having a near linear dependency on concentration up to 0.2 wt % and a power-law dependency on concentration up to 9 c*). The results indicate that the transition from dilute to semidilute behavior occurs at a nominal concentration of approximately 3 c* instead of c*. The results presented suggest that interchain interactions for this modified guar are weak overall, and the solutions investigated are absent of entanglements over the whole range of frequencies and concentrations explored ((0.17-9) c*). | 18,855,439 |
Catalytic asymmetric intramolecular hydroamination of alkynes in the presence of a catalyst system consisting of Pd(0)-methyl Norphos (or tolyl Renorphos)-benzoic acid. | Enantiomerically pure methyl Norphos (A), tolyl Norphos (B), CF(3) Norphos (C), methyl Renorphos (D), and tolyl Renorphos (E) were synthesized and used as chiral bisphosphine ligands for the catalyst system, Pd(2)(dba)(3) x CHCl(3)/PhCOOH, in an intramolecular hydroamination of aminoalkynes 15. Among the Norphos series, methyl Norphos (A) was the best ligand for the hydroamination, and the corresponding five- and six-membered nitrogen heterocycles 16 were obtained in high yields with high enantioselectivities. Among the Renorphos series, tolyl Renorphos (E) gave the best result; both methyl Norphos (A) and tolyl Renorphos (E) afforded high yields and high enantioselectivities. NMR investigation using Me-Norphos revealed that this ligand was oxidized gradually in the presence of Pd(2)(dba)(3).CHCl(3) in C(6)D(6) even under the conditions using Ar atmosphere to give Me-Norphos oxide, which prevented the intramolecular hydroamination. On the other hand, Me-Norphos was rather stable in C(6)D(6) in the absence of the palladium catalyst under Ar atmosphere and was not converted to its oxide even after 3 days. The gradual oxidation of ligands (A and E) in the presence of the Pd catalyst is perhaps a reason why 20 mol % of A or E was needed to obtain high yields and high ee's of 16. | 18,855,453 |
A model for self-diffusion of guanidinium-based ionic liquids: a molecular simulation study. | We propose a novel self-diffusion model for ionic liquids on an atomic level of detail. The model is derived from molecular dynamics simulations of guanidinium-based ionic liquids (GILs) as a model case. The simulations are based on an empirical molecular mechanical force field, which has been developed in our preceding work, and it relies on the charge distribution in the actual liquid. The simulated GILs consist of acyclic and cyclic cations that were paired with nitrate and perchlorate anions. Self-diffusion coefficients are calculated at different temperatures from which diffusive activation energies between 32-40 kJ/mol are derived. Vaporization enthalpies between 174-212 kJ/mol are calculated, and their strong connection with diffusive activation energies is demonstrated. An observed formation of cavities in GILs of up to 6.5% of the total volume does not facilitate self-diffusion. Instead, the diffusion of ions is found to be determined primarily by interactions with their immediate environment via electrostatic attraction between cation hydrogen and anion oxygen atoms. The calculated average time between single diffusive transitions varies between 58-107 ps and determines the speed of diffusion, in contrast to diffusive displacement distances, which were found to be similar in all simulated GILs. All simulations indicate that ions diffuse by using a brachiation type of movement: a diffusive transition is initiated by cleaving close contacts to a coordinated counterion, after which the ion diffuses only about 2 A until new close contacts are formed with another counterion in its vicinity. The proposed diffusion model links all calculated energetic and dynamic properties of GILs consistently and explains their molecular origin. The validity of the model is confirmed by providing an explanation for the variation of measured ratios of self-diffusion coefficients of cations and paired anions over a wide range of values, encompassing various ionic liquid classes as well as the simulated GILs. The proposed diffusion model facilitates the qualitative a priori prediction of the impact of ion modifications on the diffusive characteristics of new ionic liquids. | 18,855,466 |
Change in relationship quality for partners from lesbian, gay male, and heterosexual couples. | Growth curves for relationship quality over the first 10 years of cohabitation, controlling for separation, were estimated on the basis of survey data obtained over part or all of this time interval. Participants were both partners from 95 lesbian, 92 gay male, and 226 heterosexual couples living without children, and both partners from 312 heterosexual couples living with children. Relative to other partners, those from lesbian couples showed the highest levels of relationship quality averaged over all assessments. Pattern of change in relationship quality varied by type of couple. Partners from lesbian and gay male couples showed no change, those from heterosexual couples without children showed an early phase of accelerated decline followed by a leveling off, and those from heterosexual couples with children showed an early phase of accelerated decline followed by a 2nd phase of accelerated decline. | 18,855,506 |
Pharmacogenetics of apolipoprotein E gene during lipid-lowering therapy: lipid levels and prevention of coronary heart disease. | A non-optimal plasma concentration of lipids is among the major modifiable risk factors of atherosclerosis. Therefore, the prevention of cardiovascular disease by means of lipid-lowering therapy with statins and other agents is of great importance for patient groups where a lifestyle change, for example, diet modification, does not lead to adequately reduced lipid levels. The response of low-density-lipoprotein cholesterol (LDL-C) levels to statin therapy is highly variable. This is partly attributed to hereditary variation in genes involved in pharmacokinetics, pharmacodynamics and lipid metabolism. The pharmacogenetics of lipid-lowering therapy have been investigated for more than 40 different genes. The gene for apolipoprotein E (APOE) has been the most frequently studied, particularly regarding the epsilon2/epsilon3/epsilon4 polymorphism. Those with the epsilon4 allele seem to have the poorest and those with the epsilon2 allele the strongest response to statins with regards to LDL-C levels. In addition, the epsilon2 carriers may reach the LDL-C treatment goals more frequently than epsilon4 carriers. Few studies have investigated the interaction of the APOE epsilon2/epsilon3/epsilon4 polymorphism and lipid-lowering therapy in relation to the course of coronary heart disease; the results are contradictory and so far inconclusive. This review summarizes the pharmacogenetic findings related to the influence of APOE gene variation on lipid responses and the prevention of coronary heart disease during lipid-lowering therapy. | 18,855,536 |
A topological approach to chemical organizations. | Large chemical reaction networks often exhibit distinctive features that can be interpreted as higher-level structures. Prime examples are metabolic pathways in a biochemical context. We review mathematical approaches that exploit the stoichiometric structure, which can be seen as a particular directed hypergraph, to derive an algebraic picture of chemical organizations. We then give an alternative interpretation in terms of set-valued set functions that encapsulate the production rules of the individual reactions. From the mathematical point of view, these functions define generalized topological spaces on the set of chemical species. We show that organization-theoretic concepts also appear in a natural way in the topological language. This abstract representation in turn suggests the exploration of the chemical meaning of well-established topological concepts. As an example, we consider connectedness in some detail. | 18,855,563 |
Dimeric approaches to anti-cancer chemotherapeutics. | Numerous proteins responsible for cell proliferation and differentiation exist either as hetero or homodimers or become activated through dimerization as a key step in their respective signaling cascade. Many of these proteins have been identified as major components in oncogenic signaling pathways and have become popular targets for the development of anti-tumor agents. For this reason, bivalent anti-cancer drugs that could potentially interact with each monomer of a dimeric protein target have been developed. This review provides a brief background on prevalent dimeric drug targets within the anti-cancer field and focuses mainly on dimeric natural product and synthetic cancer chemotherapeutics. | 18,855,582 |
Mitochondria, mitochondrial DNA and Alzheimer's disease. What comes first? | To date, the beta amyloid (Abeta) cascade hypothesis remains the main pathogenetic model of Alzheimer's disease (AD), but its role in the majority of sporadic AD cases is unclear. The mitochondria play central role in the bioenergetics of the cell and apoptotic cell death. In the past 20 years research has been directed at clarifying the involvement of mitochondria and defects in mitochondrial oxidative phosphorylation in late-onset neurodegenerative disorders, including AD. Morphological, biochemical and genetic abnormalities of the mitochondria in several AD tissues have been reported. Impaired mitochondrial respiration, particularly COX deficiency, has been observed in brain, platelets and fibroblasts of AD patients. The "mitochondrial cascade hypothesis" could explain many of the biochemical, genetic and pathological features of sporadic AD. Somatic mutations in mitochondrial DNA (mtDNA) could cause energy failure, increased oxidative stress and accumulation of Abeta, which in a vicious cycle reinforces the mtDNA damage and the oxidative stress. Despite the evidence of mitochondrial dysfunction in AD, no causative mutations in the mtDNA have been detected so far. Indeed, results of studies on the role of mtDNA haplogroups in AD are controversial. In this review we discuss the role of the mitochondria in the cascade of events leading to AD, and we will try to provide an answer to the question "what comes first". | 18,855,587 |
CD47 in the immune response: role of thrombospondin and SIRP-alpha reverse signaling. | The past decades have been marked by spectacular progress towards understanding how dendritic cells (DCs) interact with T cells to elicit protective immune responses to fight infectious diseases and cancer. DCs that are lying at the interface between innate and adaptive immunity, are educated in peripheral tissues prior to their journey to the secondary lymphoid organs (SLO) whereby they dictate different classes of T cell responses. Uncontrolled or unwanted inflammatory responses are the price to pay to eliminate pathogens. However, if not self-limited, they may induce collateral damages that result in chronic inflammation often associated with autoimmune disorders. CD47 and its two ligands, i.e. thrombospondin 1 (TSP-1) and SIRP-alpha, were identified as a previously unappreciated inhibitory axis of DC and T cell functions. TSP-1 is predominantly a negative regulator of DC and T cell function while basal SIRP-alpha ligation on APC by CD47 enforces tolerance. Yet, CD47/SIRP-alpha interaction positively controls DC and innate cell transendothelial migration. Due to the promiscuity of the protein interactions for CD47 and its ligands, it is quite interesting to note that deletion of the CD47 gene in mice largely agrees with the in vitro data with human cells. In fact, the well-conserved tissue distribution of CD47 and SIRP-alpha across species may facilitate the transition from bench to bedside. We thus propose CD47/TSP-1/SIRP-alpha axis as an important sensor to maintain homeostasis and regulate innate and adaptive immune responses. | 18,855,618 |
The role of cartilage oligomeric matrix protein (COMP) in skeletal disease. | Cartilage oligomeric matrix protein is a non-collagenous extracellular matrix protein expressed primarily in cartilage, ligament, and tendon. Cartilage oligomeric matrix protein has been studied extensively because mutations in the gene cause two skeletal dysplasias, pseudoachondroplasia and multiple epiphyseal dysplasia. Pseudoachondroplasia is a disproportionate dwarfing condition associated with joint abnormalities, while multiple epiphyseal dysplasia is less severe. Both of these skeletal dysplasias have a characteristic chondrocyte pathology that consists of intracellular retention of cartilage oligomeric matrix protein and other extracellular matrix proteins in an enlarged rough endoplasmic reticulum. This toxic intracellular retention of extracellular matrix proteins causes chondrocyte cell death thereby decreasing linear bone growth. Additionally, when cartilage oligomeric matrix protein and the other co-retained proteins are not exported to the extracellular matrix, the resulting matrix is abnormal and easily erodes with normal physical activity. Cartilage oligomeric matrix protein is also a marker for joint destruction associated osteoarthritis, rheumatoid arthritis, joint trauma, and intense activity. Serum cartilage oligomeric matrix protein levels are higher in aggressive cases of arthritis and levels are used to predict future disease progression. Recent studies have identified molecular functions of cartilage oligomeric matrix protein that may contribute to its role in skeletal disease. These molecular functions include: binding other ECM proteins, catalyzing polymerization of type II collagen fibrils, and regulation of chondrocyte proliferation. Here, we review cartilage oligomeric matrix protein's role in skeletal disease and potential molecular mechanisms. | 18,855,621 |
Physicochemical parameters of non-viral vectors that govern transfection efficiency. | Gene therapy is based on the vectorization of nucleic acids to target cells and their subsequent expression. Cationic lipids and polymers are the most widely used vectors for the delivery of DNA into cultured cells. Nowadays, numerous reagents made of these cationic molecules are commercially available and used by researchers from the academic and industrial field. By contrast their evaluations in preclinical programs have revealed that their use for in vivo applications will be more problematic than their massive use in vitro. This is mostly due to the physicochemical properties of cationic vectors/DNA complexes, which are the result of their mode of interaction. Indeed, these cationic vectors interact through electrostatic forces with negatively charged DNA. This results in the formation of highly organized positively charged supramolecular structures where DNA molecules are condensed. Association of DNA with cationic lipids under a micellar or liposomal form leads to lamellar organization with DNA molecules sandwiched between lipid bilayers. Although the lamellar phase is the common described structure, as evidenced by small-angle X-ray scattering and electron microscopy, some cationic lipid combined with a hexagonal forming lipid could also result with DNA in an inverted hexagonal structure. Despite a lot of effort, the precise mechanism of gene transfer with cationic vector is still ill-defined. Here, our objective was to overview the main relationships between the physico chemical properties of cationic lipid/DNA complexes and their transfection efficiency. An overview of a new class of vectors consisting of amphiphilic block copolymers designed for in vivo delivery is also presented and discussed. | 18,855,629 |
Clopidogrel and aspirin in cardiovascular medicine: responders or not--current best available evidence. | Dual antiplatelet therapy represents an important advance for patients with established coronary artery disease. It is an important strategy for patients with acute coronary syndromes and those undergoing percutaneous transcatheter coronary interventions. Clopidogrel effectively inhibits ADP-induced platelet activation and aggregation by selectively and irreversibly blocking the P2Y(12) receptor on the platelet membrane. Aspirin works by irreversibly acetylating the cyclooxygenase (COX-1) enzyme, thus suppressing the production of thromboxane A(2) (TxA(2)) and inhibiting platelet activation and aggregation. Variable platelet response and potential resistance to therapy has emerged with aspirin and clopidogrel. The definitions of antiplatelet agents variability in responsiveness and nonresponsiveness are discussed. Clopidogrel and aspirin responsiveness as they are measured in the laboratory by various techniques (platelet aggregometry and point-of-care assays such as platelet function analyzer [PFA-100] and rapid platelet function assay [RPFA]) are evaluated. The mechanisms responsible for variations in responsiveness to antiplatelet agents such as clinical, cellular and genetic factors are defined. Aspirin and clopidogrel resistance are emerging clinical entities with potentially severe consequences such as myocardial infarction, stroke or death. The therapeutic interventions to deal with nonresponsiveness are reported, although specific recommendations are not clearly established. In the future, routine measurement of platelet function in patients with cardiovascular disease may become the standard of care. Personalized antithrombotic treatment strategies may be determined by ex-vivo measurements that identify critical pathways influencing thrombotic risk in the individual patient. | 18,855,644 |
HHV-6 is frequently detected in dried cord blood spots from babies born to HIV-positive mothers. | Intrauterine transmission of HHV-6 is well established in immunocompetent women while few data are available on infections in babies born to HIV-positive mothers. To assess the rate of HHV-6 vertical transmission in comparison to CMV, we analyzed cord blood spots dried on cards (Dried Blood Spots, DBS) collected during a multi-center study on HIV congenital infections in Italy. DBS were tested by PCR for HHV-6 and CMV footprints. HHV-6 amplimers were sequenced and characterized. As control group, cards taken from babies born to HIV-negative mothers were analyzed. DBS of 187 babies born to HIV-positive and 372 to HIV-negative mothers were analyzed. The prevalence of HHV-6 was 3.2% in babies born to HIV-positive mothers. CMV was found in the HIV-positive group with a prevalence rate of 1.6%. In newborns of control pregnant women, HHV-6 prevalence rate was 1.1% (p=0.09), while CMV was not detected (p=0.04). Sequence analysis could distinguish between HHV-6 A and B variant in both groups and one A/B coinfection was found in a baby born to a HIV-positive mother. HIV-infected mothers transmit HHV-6 and CMV viruses to their babies more frequently than uninfected women. | 18,855,654 |
Better CD4+ T cell recovery in Brazilian HIV-infected individuals under HAART due to cumulative carriage of SDF-1-3'A, CCR2-V64I, CCR5-D32 and CCR5-promoter 59029A/G polymorphisms. | Polymorphisms of chemokines and chemokine-receptors genes have been shown to influence the rate of progression to AIDS; however, their influence on response to HAART remains unclear. We investigated the frequency of the SDF-1-3'A, CCR2-64I, CCR5-D32 and CCR5-Promoter-59029-A/G polymorphisms in Brazilian HIV-1-infected and uninfected individuals and their influence on CD4+ T-cell evolution HIV-1 infected individuals before and during HAART. Polymorphism detection was done in a transversal study of 200 HIV-1-infected and 82 uninfected individuals. The rate of CD4+ T cell increase or decrease was studied in a cohort of 155 HIV-1 infected individuals on pre and post-HAART. Polymorphisms were determined by PCR associated with RFLP. The rate of CD4+ T-cell decline or increase was also determined. HIV-1 infected and uninfected subjects showed, respectively, frequencies of 0.193 and 0.220 for SDF-1-3'A, of 0.140 and 0.110 for CCR2-V64I, of 0.038 and 0.055 for CCR5-D32, and of 0.442 and 0.390 for CCR5-P-59029-A/G. HIV-1-infected subjects carrying one, two or three of these four polymorphisms showed better CD4+ T-cell recovery than HIV-1-infected subjects carrying the four wild-type alleles (+2.7, +1.6, +3.5, and -0.9 lymphocytes/microl/month, respectively). Regression logistic analysis showed that the CCR5-D32/CCR2-V64I association was predictor of positive CD4+ T cell slope after HAART. The distribution of polymorphisms did not differ between HIV-1-infected and uninfected individuals, but differed from more homogenous ethnic groups probably reflecting the miscegenation of the Brazilian population. We add further evidence of the role of these polymorphisms by showing that the CD4 gain was influenced by carriage of one or more of the polymorphisms studied here. These results highlight the possibility that these genetic traits can be useful to identify patients at risk for faster progression to AIDS or therapeutic failure. | 18,855,658 |
Cytochrome P450-activated prodrugs: targeted drug delivery. | Cytochrome P450 (CYP) enzymes are a superfamily of heme containing proteins that catalyze xenobiotic metabolism phase I reactions. Oxidation reactions are the most common CYP-catalyzed reactions for both endogenous substrates and exogenous compounds, including drugs, although CYP enzymes are capable also to catalyze reduction reactions. Whereas the majority of clinically used drugs are inactivated by CYPs, several prodrugs are bioconverted to their active species by these enzymes. Therefore, this mechanism could be exploited to a greater extend, e.g. by taking advantage of the different CYP enzymes to achieve targeted drug delivery, to improve efficacy or to decrease the unwanted adverse effects of existing and novel drug molecules. This review describes the potential of CYP enzymes in prodrug design and summarizes a wide variety of CYP-activated prodrug structures, which are on the market or under the development. The bioactivation mechanisms of each CYP-activated prodrug structure are described and the specificity for the different forms of CYP enzymes is discussed. | 18,855,665 |
The cell cycle molecules behind neurodegeneration in Alzheimer's disease: perspectives for drug development. | Alzheimer's disease (AD), the leading cause of senile dementia, has become a considerable social and economical problem. Current AD therapeutics provide mainly symptomatic short-term benefit, rather than targeting disease mechanisms. The hallmarks for AD are beta-amyloid plaques, neurofibrillary tangles, and regionalized neuronal loss. Additional neuropathological features have been described that may provide some clues to the mechanism by which neurons die in AD. Specifically, the aberrant expression of cell cycle proteins and the presence of de novo-replicated DNA in neurons have been described both in AD brain and in culture models of the disease. The unscheduled cell cycle events are deleterious to neurons, which undergo death rather than complete the cell cycle. Although our understanding of the neuronal cell cycle is not complete, experimental evidence suggests that compounds able of arresting the aberrant cell cycle will yield neuroprotection. This review focuses on drug development centered on the cell cycle hypothesis of AD. | 18,855,671 |
Strategy for a genetic assessment of antipsychotic and antidepressant-related proarrhythmia. | Antidepressants and antipsychotics may affect several ion channels involved in the control of cardiac action potential and be proarrhythmic. In this field, accurate understanding of genetics, which per se is a non-controllable risk factor, may help clinicians to prevent life-threatening side effects. So far, a number of genes have been associated with arrhythmia: SCN5A, SCN4B, CACNL1AC, KCNH2, KCNQ1, KCNE1, ANK2, ALG10, KCNJ2, KCNE2, RYR2, KCND3, KCND2, ACE, NOS1AP, CASQ2 and Rad. These genes represent good candidates for the definition of a genetic pro-arrhythmic profile. A genetic analysis of these targets is provided and their possible pathophysiological role in arrhythmias is discussed. Special attention is devoted to the interactions between these genes and new generation antidepressants and antipsychotics. A list of relevant rare mutations within the selected genes is presented, together with a complete list of Tag SNPs covering the whole genetic sequence. The aim of this paper is to define a part of the genetic framework responsible for the proarrhythmic effects of antidepressants and antipsychotics. The selected variants, both mutations and polymorphisms, may help in defining a next-to-come genetic assessment to be performed before drug prescription in order to improve drug safety. | 18,855,674 |
Screening aortic drug treatments through arterial compliance measurements. | Abdominal aortic aneurysm (AAA) is a common and deadly problem. The aortic diameter increases in association with a complex remodeling process that includes changes in the structure and content of key proteins, elastin and collagen. As these changes occur, the tissue mechanical properties also change. The natural history of AAA is progressive enlargement to a point of mechanical tissue failure typically followed by death. Currently, the marker used to predict the risk of impending rupture is the largest transverse diameter. After reaching a diameter threshold of 5.5 cm the AAA needs to be surgically repaired. This criterion does not consider any patient-specific information or heterogeneity of the AAA that may, in some cases, lead to rupture before the AAA reaches the standard intervention threshold. Conversely, in many patients, continued observation beyond this threshold is safe. While no medical treatment is yet approved, doxycycline (Doxy) has been shown to greatly reduce AAA growth in animal models and has been shown to slow growth in 1 small clinical trial. While larger prospective randomized trials are needed, one unknown is what effect Doxy has on the structural integrity of the aortic wall. That is, does slowed AAA growth, by Doxy treatment, prevent rupture, or does the wall continue to weaken and the AAA instead ruptures at a smaller diameter? Using an established animal model of AAA, we begun to determine the changes in tissue mechanics compliance of the aorta as the AAA develops. Our current research is focused on verifying that these changes mimic the observed changes seen in the human population as reported by other researchers, so that we can confidently study how potential drug therapies may affect wall strength and compliance in the human population. The long-term objectives are to understand better factors related to progression of AAA and help verify that drug therapy with Doxy will decrease the chance of rupture by preventing wall weakening and maintaining function of the aorta. | 18,855,713 |
The crosstalk between insulin and renin-angiotensin-aldosterone signaling systems and its effect on glucose metabolism and diabetes prevention. | Essential hypertension is an insulin resistant state. Early insulin signaling steps are impaired in essential hypertension and a large body of data suggests that there is a crosstalk at multiple levels between the signal transduction pathways that mediate insulin and angiotensin II actions. At the extracellular level the angiotensin converting enzyme (ACE) regulates the synthesis of angiotensin II and bradykinin that is a powerful vasodilator. At early intracellular level angiotensin II acts on JAK-2/IRS1-IRS2/PI3-kinase, JNK and ERK to phosphorylate serine residues of key elements of insulin signaling pathway therefore inhibiting signaling by the insulin receptor. On another level angiotensin II inhibits the insulin signaling inducing the regulatory protein SOCS 3. Angiotensin II acting through the AT1 receptor can inhibit insulin-induced nitric oxide (NO) production by activating ERK 1/2 and JNK and enhances the activity of NADPH oxidase that leads to an increased reactive oxygen species generation. From the clinical standpoint, the inhibition of the renin angiotensin system improves insulin sensitivity and decreases the incidence of Type 2 Diabetes Mellitus (T2DM). This might represent an alternative approach to prevent type 2 diabetes in patients with hypertension and metabolic syndrome, (i.e. insulin resistant patients). This review will discuss: a) the molecular mechanisms of the crosstalk between the insulin and angiotensin II signaling systems b) the results of clinical studies employing drugs targeting the renin-angiotensin II-aldosterone systems and their role in glucose metabolism and diabetes prevention. | 18,855,718 |
Occurrence and clinical impact of microembolic signals (MES) in patients with chronic cardiac diseases and atheroaortic plaques--a systematic review. | In various cardiac diseases, thrombembolism constitutes a major risk, and in these patients clinically silent microembolic signals (MES) are detectable within the transcranial Doppler frequency spectrum (TCD) of the major brain arteries. MES are already an accepted surrogate parameter of the future risk of stroke in patients with carotid artery stenosis. The aim of this review is to summarize and evaluate the data about occurence and clinical impact of MES in patients with chronic cardiac diseases and to clarify whether cardiogenic MES can serve as a surrogate parameter of the heart's future thrombembolic risk as well. We performed a systematic MEDLINE search and reviewed the currently available literature about chronic cardiac diseases and atheroaortic plaques leading to MES apart from cardiosurgical procedures. The cardiac conditions producing MES are heterogenous and therefore the prevalence of MES is highly variable. The data in patients with acute or after myocardial infarction, endocarditis, patent foramen ovale, mitral valve prolapse, dilatative cardiomyopathy and intracardiac thrombus is promising but only small patient cohorts have been investigated by means of TCD in these categories. MES in atrial fibrillation, or derived from atheroaortic plaques, have been investigated more intensively, but again larger cohorts need to be explored to draw firm conclusions. In all cardiac diseases there is a lack of large prospective studies allowing to reliably correlating MES with clinical events. Compared to carotid artery disease, the current knowledge about the impact of cardiogenic MES on the patient's risk is sparse. This should encourage the clinical research in this promising field. | 18,855,720 |
Chemistry and pharmacology of collinin, active principle of Zanthoxylum spp. | Collinin is a geranyloxycoumarins isolated in small amounts from plants of the Rutaceae family. Synthetic schemes were recently developed allowing to handle collinin in sufficient quantities to put in evidence valuable biological effects. The aim of this review is to examine the phytochemical and pharmacological properties of this compound. | 18,855,734 |
Protein-based voltammetric biosensors fabricated with nanomaterials. | Protein-based voltammetric biosensors are sensors based on the electric communication between proteins and electrodes. Recently, more and more nanomaterials are utilized to assist the fabrication of such kind of biosensors. In this review, we mainly detail the biosensors constructed with different kinds of nanomaterials depending on their categories in the past two years. | 18,855,746 |
Classification of amine type G-protein coupled receptors with feature selection. | G-protein coupled receptors (GPCRs) are involved in various physiological processes. Therefore, classification of amine type GPCRs is important for proper understanding of their functions. Though some effective methods have been developed, it still remains unknown how many and which features are essential for this task. Empirical studies show that feature selection might address this problem and provide us with some biologically useful knowledge. In this paper, a feature selection technique is introduced to identify those relevant features of proteins which are potentially important for the prediction of amine type GPCRs. The selected features are finally accepted to characterize proteins in a more compact form. High prediction accuracy is observed on two data sets with different sequence similarity by 5-fold cross-validation test. The comparison with a previous method demonstrates the efficiency and effectiveness of the proposed method. | 18,855,757 |
From the bakery to the brain business: developing inducible yeast models of human neurodegenerative disorders. | In the last decade, the budding yeast Saccharomyces cerevisiae has been used as a model system to study the mechanisms of the human aging process and of age-associated neurodegenerative disorders such as Parkinson's, Huntington's, Alzheimer's, and amyotrophic lateral sclerosis. S. cerevisiae is a facultative aerobic, unicellular yeast, and despite their simplicity, yeast cells possess most of the same basic cellular machinery as neurons in the brain, including pathways required for protein homeostasis and energy metabolism. The power of yeast genetics and the use of high-throughput screening technologies have provided important clues concerning the pathophysiology of these disorders and the identification of candidate therapeutic targets and drugs. The yeast models are based on the expression of human disease proteins in yeast and recapitulate some of the cytotoxic features observed in patients. However, the currently available models mostly suffer from high-level protein expression that results in acute cytotoxicity, and from metabolic constraints when the models are based on extensively used, strong, galactose-inducible promoters. The models would increase their significance if they were based on continuous and tightly regulated gene expression systems for both activation and levels of expression. This would allow for more chronic cytotoxicity that better simulates the timing of events that occur during disease progression. Additionally, the use of metabolism-independent inducers would allow for the study of cell toxicities under conditions where the cells are forced to exclusively respire, thus more reliably modeling the highly oxidative neuronal metabolism. Here we have constructed yeast models of Huntington's disease based on the expression, under the control of different promoters, of the first exon of the huntingtin-containing polyglutamine tracts of both wild-type and mutant lengths. The different models are compared and evaluated. | 18,855,765 |
Generation of a tightly regulated all-cis beta cell-specific tetracycline-inducible vector. | Ability to induce protein expression at will in a cell is a powerful strategy used by scientists to better understand the function of a protein of interest. Various inducible systems have been designed in eukaryotic cells to achieve this goal. Most of them rely on two distinct vectors, one encoding a protein that can regulate transcription by binding a compound X, and one hosting the cDNA encoding the protein of interest placed downstream of promoter sequences that can bind the protein regulated by compound X (e.g., tetracycline, ecdysone). The commercially available systems are not designed to allow cell- or tissue-specific regulated expression. Additionally, although these systems can be used to generate stable clones that can be induced to express a given protein, extensive screening is often required to eliminate the clones that display poor induction or high basal levels. In the present report, we aimed to design a pancreatic beta cell-specific tetracycline-inducible system. Since the classical two-vector based tetracycline-inducible system proved to be unsatisfactory in our hands, a single vector was eventually designed that allowed tight beta cell-specific tetracycline induction in unselected cell populations. | 18,855,768 |
Evaluating statistics in clinical trials: making the unintelligible intelligible. | Medical practitioners should be familiar with the basic principles of statistical testing and analysis, as the critical evaluation of clinical trials is an essential component to the effective practise of evidence-based medicine. Practitioners also need to be able to identify unethical trial design. The aim of this review is to facilitate an understanding of inferential methodology by introducing some of the basic principles involved in the critical analysis of trial design and interpretation. | 18,855,776 |
Treatment of lentigo maligna with total circumferential margin control using vertical and horizontal permanent sections: a retrospective study. | This retrospective study assesses the long-term cure rate for the treatment of lentigo maligna using total circumferential margin control with vertical and horizontal permanent sections using life-table analysis. A cohort of 31 patients in Sydney with lentigo maligna treated with total circumferential margin control with vertical and horizontal permanent sections over a 6-year period were followed up. Follow up to determine recurrence was obtained by direct examination, by contact with the referring dermatologist, general practitioner, or by telephone interview with the patient's relative if the patient was deceased. Following our total circumferential margin control technique, of the 16 primary tumours, only one recurred (a cure rate of 94%). Of the 15 recurrent tumours, two had recurred. The mean follow-up time in this study was 42 months (range 12-89 months). Kaplan-Meier analysis estimated that at 5 years, 87% of patients would be free from disease (95% confidence interval 70-100%). Seventy-five per cent of the population can be expected to be disease-free for 6 years (lower 95% confidence limit 4 years). We describe the use of total circumferential margin control with vertical and horizontal permanent sections for the treatment of lentigo maligna that we believe is simple, effective and reproducible. | 18,855,780 |
Annular lesions in Kawasaki disease: a cause of confusion. | We present three cases of Kawasaki disease in which an annular eruption was the predominant cutaneous finding. The provisional diagnosis was Stevens-Johnson syndrome. However, the annular lesions were not typical of Stevens-Johnson syndrome: the lips were crusted without mucosal ulceration and the conjunctivitis was non-purulent without corneal erosions. Dermatologists are often involved in the initial assessment of this multisystem disease and should be aware of the variety of cutaneous manifestations, as rapid treatment is known to decrease morbidity and mortality. | 18,855,782 |
Hyperpigmentation, nail dystrophy and alopecia with generalised intestinal polyposis: Cronkhite-Canada syndrome. | A 62-year-old Malaysian woman presented with a constellation of skin signs including alopecia, hyperpigmentation and nail dystrophy. On questioning, a history of diarrhoea, taste disturbance and weight loss was found. The onset of these changes coincided with the administration of thyroxine prescribed for a benign multinodular goitre. Hormonal investigations showed no abnormality and no underlying malignancy was found. Investigation of the diarrhoea showed a protein-losing enteropathy with generalized intestinal polyposis and non-specific histology. A diagnosis of Cronkhite-Canada syndrome was made. Treatment with prednisone and nutritional support has been partially effective. | 18,855,786 |
Stress, alcohol and drug interaction: an update of human research. | A challenging question that continues unanswered in the field of addiction is why some individuals are more vulnerable to substance use disorders than others. Numerous risk factors for alcohol and other drugs of abuse, including exposure to various forms of stress, have been identified in clinical studies. However, the neurobiological mechanisms that underlie this relationship remain unclear. Critical neurotransmitters, hormones and neurobiological sites have been recognized, which may provide the substrates that convey individual differences in vulnerability to addiction. With the advent of more sophisticated measures of brain function in humans, such as functional imaging technology, the mechanisms and neural pathways involved in the interactions between drugs of abuse, the mesocorticolimbic dopamine system and stress systems are beginning to be characterized. This review provides a neuroadaptive perspective regarding the role of the hormonal and brain stress systems in drug addiction with a focus on the changes that occur during the transition from occasional drug use to drug dependence. We also review factors that contribute to different levels of hormonal/brain stress activation, which has implications for understanding individual vulnerability to drug dependence. Ultimately, these efforts may improve our chances of designing treatment strategies that target addiction at the core of the disorder. | 18,855,803 |
Guidelines for research on drugged driving. | A major problem in assessing the true public health impact of drug-use on driving and overall traffic safety is that the variables being measured across studies vary significantly. In studies reported in a growing global literature, basic parameters assessed, analytical techniques and drugs tested are simply not comparable due to lack of standardization in the field. These shortcomings severely limit the value of this research to add knowledge to the field. A set of standards to harmonize research findings is sorely needed. This project was initiated by several international organizations to develop guidelines for research on drugged driving. A September 2006 meeting of international experts discussed the harmonization of protocols for future research on drugged driving. The principal objective of the meeting was to develop a consensus report setting guidelines, standards, core data variables and other controls that would form the basis for future international research. A modified Delphi method was utilized to develop draft guidelines. Subsequently, these draft guidelines were posted on the internet for global review, and comments received were integrated into the final document. The Guidelines Document is divided into three major sections, each focusing upon different aspects of drugged driving research (e.g. roadside surveys, prevalence studies, hospital studies, fatality and crash investigations, etc.) within the critical issue areas of 'behavior', 'epidemiology' and 'toxicology'. The behavioral section contains 32 specific recommendations; (2) epidemiology 40 recommendations; and (3) toxicology 64 recommendations. It is anticipated that these guidelines will improve significantly the overall quality of drugged driving research and facilitate future cross-study comparisons nationally and globally. | 18,855,814 |
Pulmonary mucormycosis with cervical lymph node involvement in a patient with acute myeloid leukaemia: a case report. | Here we describe a rare case of pulmonary mucormycosis and simultaneous cervical lymphadenitis in a patient with acute myeloid leukaemia. The patient was successfully treated with liposomal amphotericin B. The diagnosis of Mucor is very difficult, especially in severely immunocompromised patients. This report seems to be the first case about documented lymph node involvement by mucormycosis in humans. | 18,855,847 |
Epithelial stem cells in corneal regeneration and epidermal gene therapy. | Regenerative medicine refers to innovative therapies aimed at the permanent restoration of diseased tissues and organs. Regeneration of self-renewing tissues requires specific adult stem cells, which need to be genetically modified to correct inherited genetic diseases. Cultures of epithelial stem cells permanently restore severe skin and mucosal defects, and genetically corrected epidermal stem cells regenerate a normal epidermis in patients carrying junctional epidermolysis bullosa. The keratinocyte stem cell is therefore the only cultured stem cell used both in cell therapy and gene therapy clinical protocols. Epithelial stem cell identification, fate and molecular phenotype have been extensively reviewed, but not in relation to tissue regeneration. In this paper we focus on the localization and molecular characterization of human limbal stem cells in relation to corneal regeneration, and the gene therapy of genetic skin diseases by means of genetically modified epidermal stem cells. | 18,855,878 |
BAL in the diagnosis of smoking-related interstitial lung diseases: review of literature and analysis of our experience. | The group of interstitial lung diseases (ILDs) is formed by respiratory tract disorders, whose aetiology is unknown in the majority of cases, the clinical course differs and the prognosis is generally serious. Some of the ILDs have a potential relation to tobacco smoking and are known as smoking-related ILDs (sr-ILD). Bronchoalveolar lavage fluid (BALF) examination is one of the initial procedures in the diagnosis of ILD. Despite the fact that histological confirmation is the gold standard in ILD diagnosis in many studies, the number of reported biopsies was low. In this review we present the results of BALF examinations of patients with sr-ILD and discuss their value in the differential diagnosis with other types of ILD. An extremely high total cell count (about 50 x 10(6) cells) with significant predominance of pigmented alveolar macrophages is a characteristic pattern of BALF in sr-ILD. The greatest challenge in BALF cytology interpretation is to distinguish sr-ILD and idiopathic pulmonary fibrosis (IPF). IPF is characterised by an elevated proportion and absolute count of lymphocytes and neutrophils; in addition, BALF lymphocytosis is higher in non-specific interstitial pneumonia than in usual interstitial pneumonia (UIP). The population of alveolar macrophage of patients with sr-ILD differs markedly from the foamy and vacuolated cells that predominate in IPF/UIP. Thus, the absence of pigmented cells rather excludes sr-ILD and indicates other types of ILD. To summarise, the place of BALF in the diagnosis of sr-ILD seems to be established. | 18,855,907 |
Methodology for development of a physiological model incorporating CYP3A and P-glycoprotein for the prediction of intestinal drug absorption. | The small intestine poses a major barrier to the efficient absorption of orally administered therapeutics. Intestinal epithelial cells are an extremely important site for extrahepatic clearance, primarily due to prominent P-glycoprotein-mediated active efflux and the presence of cytochrome P450s. We describe a physiologically based pharmacokinetic model which incorporates geometric variations, pH alterations and descriptions of the abundance and distribution of cytochrome 3A and P-glycoprotein along the length of the small intestine. Simulations using preclinical in vitro data for model drugs were performed to establish the influence of P-glycoprotein efflux, cytochrome 3A metabolism and passive permeability on drug available for absorption within the enterocytes. The fraction of drug escaping the enterocyte (F(G)) for 10 cytochrome 3A substrates with a range of intrinsic metabolic clearances were simulated. Following incorporation of P-glycoprotein in vitro efflux ratios all predicted F(G) values were within 20% of observed in vivo F(G). The presence of P-glycoprotein increased the level of cytochrome 3A drug metabolism by up to 12-fold in the distal intestine. F(G) was highly sensitive to changes in intrinsic metabolic clearance but less sensitive to changes in intestinal drug permeability. The model will be valuable for quantifying aspects of intestinal drug absorption and distribution. | 18,855,913 |
Extended testing across, not within, tasks raises diagnostic accuracy of smell testing in Parkinson's disease. | The aim of this study was to determine whether extended olfactory testing within a single olfactory task and/or across olfactory tasks increases diagnostic accuracy of olfactory testing in Parkinson's disease (PD). Olfactory function was assessed using an extended version of the "Sniffin' Sticks", comprising 32-item odor identification and discrimination tasks, and a detection threshold task in 52 PD patients and 50 controls, all aged between 49 and 78 years. ROC curves based on sensitivity and specificity estimates were used to compare the diagnostic accuracy of extended and combined olfactory testing. There was no significant difference in diagnostic accuracy between the 16-item and the 32-item versions of the odor identification or discrimination test. The single olfactory test that was best in discriminating between PD patients and controls was a 16-item odor identification test. A combination of the 16-item identification test and the detection threshold task had a significantly higher area under the curve than the 16-item odor identification test alone. In conclusion, extended testing across, and not within, olfactory tasks increases diagnostic accuracy of olfactory testing in PD. A combination of an odor detection threshold task and a 16-item odor identification test had the highest sensitivity and specificity in distinguishing between PD patients and controls. | 18,855,928 |
Mechanisms underlying Li+ effects in glutamatergic and GABAergic neurotransmissions in the adult rat brain and in primary cultures of neural cells as revealed by 13C NMR. | We investigated by (13)C nuclear magnetic resonance (NMR) the mechanisms underlying Li(+) effects on glutamatergic and GABAergic neurotransmission systems in the adult rat brain and in primary cultures of cortical neurons and astrocytes during the metabolism of (1-(13)C) glucose or (2-(13)C) acetate. Adult male rats receiving a single dose of Li(+) intraperitoneally (7 mmol/kg) were infused 2 hr later, for 60 min, with (1-(13)C) glucose (80 mumol/min/kg) or (2-(13)C) acetate (240 micromol/min/kg). High-resolution (13)C NMR spectra of brain extracts prepared after the infusion revealed that Li(+) significantly decreased the incorporation of (13)C in glutamate and GABA (gamma-aminobutyric acid) carbons from (1-(13)C) glucose, but not from (2-(13)C) acetate. To complement the in vivo approach, primary cultures of cortical neurons or astrocytes were incubated with 1 mM uniformly (13)C-labeled glucose or 5 mM (2-(13)C) acetate, in the absence and presence of increasing Li(+) concentrations up to 15 mM. Under these conditions, Li(+) significantly decreased neuronal glucose uptake in a concentration-dependent manner without apparent effects on astrocytic acetate uptake. Extracts prepared at the end of the incubations showed that Li(+) significantly decreased the incorporation of (13)C labeling into GABA carbons from its precursor glutamate in neurons, but such a decrease into glutamine carbons in astrocytes was not statistically significant. Our results indicate that the effects of Li(+) are mediated through a reduction of neuronal glucose uptake, resulting in a decrease of glutamatergic and GABAergic neurotransmission without apparent effects on astrocytic metabolism. | 18,855,940 |
Fluoxetine affords robust neuroprotection in the postischemic brain via its anti-inflammatory effect. | Fluoxetine is a selective serotonin reuptake inhibitor that is widely used in the treatment of major depression including after stroke. In this study, we tested whether fluoxetine protects neuronal death in a rat cerebral ischemia model of middle cerebral artery occlusion (MCAO). The administration of fluoxetine intravenously (10 mg/kg) at 30 min, 3 hr, or 6 hr after MCAO reduced infarct volumes to 21.2+/-6.7%, 14.5+/-3.0%, and 22.8+/-2.9%, respectively, of that of the untreated control. Moreover, the neuroprotective effect of fluoxetine was evident when it was administered as late as 9 hr after MCAO/reperfusion. These neuroprotective effects were accompanied by improvement of motor impairment and neurological deficits. The fluoxetine-treated brain was found to show marked repressions of microglia activation, neutrophil infiltration, and proinflammatory marker expressions. Moreover, fluoxetine suppressed NF-kappaB activity dose-dependently in the postischemic brain and also in lipopolysaccharide-treated primary microglia and neutrophil cultures, suggesting that NF-kappaB activity inhibition explains in part its anti-inflammatory effect. These results demonstrate that curative treatment of fluoxetine affords strong protection against delayed cerebral ischemic injury, and that these neuroprotective effects might be associated with its anti-inflammatory effects. | 18,855,941 |
Up-regulation of P-glycoprotein by HIV protease inhibitors in a human brain microvessel endothelial cell line. | A major concern regarding the chronic administration of antiretroviral drugs is the potential for induction of drug efflux transporter expression (i.e., P-glycoprotein, P-gp) at tissue sites that can significantly affect drug distribution and treatment efficacy. Previous data have shown that the inductive effect of human immunodeficiency virus protease inhibitors (PIs) is mediated through the human orphan nuclear receptor, steroid xenobiotic receptor (SXR or hPXR). The objectives of this study were to investigate transport and inductive properties on efflux drug transporters of two PIs, atazanavir and ritonavir, at the blood-brain barrier by using a human brain microvessel endothelial cell line, hCMEC/D3. Transport properties of PIs by the drug efflux transporters P-gp and multidrug resistance protein 1 (MRP1) were assessed by measuring the cellular uptake of (3)H-atazanavir or (3)H-ritonavir in P-gp and MRP1 overexpressing cells as well as hCMEC/D3. Whereas the P-gp inhibitor, PSC833, increased atazanavir and ritonavir accumulation in hCMEC/D3 cells by 2-fold, the MRP inhibitor MK571 had no effect. P-gp, MRP1, and hPXR expression and localization were examined by Western blot analysis and immunogold cytochemistry at the electron microscope level. Treatment of hCMEC/D3 cells for 72 hr with rifampin or SR12813 (two well-established hPXR ligands) or PIs (atazanavir or ritonavir) resulted in an increase in P-gp expression by 1.8-, 6-, and 2-fold, respectively, with no effect observed for MRP1 expression. In hCMEC/D3 cells, cellular accumulation of these PIs appears to be primarily limited by P-gp efflux activity. Long-term exposure of atazanavir or ritonavir to brain microvessel endothelium may result in further limitations in brain drug permeability as a result of the up-regulation of P-gp expression and function. | 18,855,943 |
A facile route for regioselective conjugation of organo-soluble polymers onto chitosan. | A facile route is described for the regioselective conjugation of organo-soluble polymers onto chitosan under very mild conditions, using SCC as intermediates. SCC could be prepared simply by mixing chitosan acidic aqueous solution with SDS. PEG or PCL were then grafted to SCC using the NHS/DCC coupling method. In addition, the polymers were found to be linked to chitosan through the hydroxyl groups of chitosan when stoichiometric SCC was used as a precursor. SDS could be removed simply by either precipitating the solution of SCC-graft-polymer in DMSO into Tris aqueous solution or dialyzing against Tris solution. | 18,855,945 |
Suppression of gastric cancer growth by baculovirus vector-mediated transfer of normal epithelial cell specific-1 gene. | To study the inhibitory effect of baculovirus-mediated normal epithelial cell specific-1 (NES1) gene therapy on gastric cancer (GC) in vitro and in vivo. We first constructed recombinant baculovirus vectors and then transfected them into gastric cancer cells (SGC-7901). Efficiency of the baculovirus for gene transfer into SGC-7901 cells and cell growth curves were detected by fluorescence microscopy, Western blot and 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay in vitro, respectively. The therapeutic effect of this gene therapy on GC was confirmed in xenografted nude mice. Tumor growth was determined by tumor volume, and expression of NES1 in tumor was analyzed by immunohistochemistry. Baculovirus vectors were successfully transfected into SGC-7901 cells. SGC-7901 cells transfected with the NES1 gene inhibited cell growth. In the Bac-NES1 treated group, tumor growth was significantly reduced with a high level of NES1 expression Baculovirus-mediated NES1 gene can be used in gene therapy for GC. | 18,855,978 |
Health improvement through dietary management of type 2 diabetes. | Diabetes is found to be one of the fastest growing chronic diseases with a high incidence among older people, and in residential care homes the prevalence of diabetes can be as high as 25% percent. A range of complications can develop following the onset of the disease. The prevention of these complications is in line with the emphasis that is being placed on health promotion and the prevention of ill health in current health strategies. This article will discuss a district nurse's approach to health improvement through dietary management of diabetes for elderly residents with type 2 diabetes living in a care home. The PRECEDE-PROCEED health promotion model chosen to assess the learning needs of the residents and to structure the implementation and evaluation of the health promotion project was good guidance and will form the structure for this article. | 18,856,019 |
[Diagnostic image (390). A man with hepatic and mesenterial gas]. | A 78-year-old man presented with pneumatosis intestinalis and hepatic portal venous gas. | 18,856,028 |
[Differences between hospitals in outcome after a stroke are only partially explained by differences in the quality of care]. | To determine the extent to which the outcome of stroke patients stroke is correlated with patient characteristics and care process parameters, and to determine whether outcome measures can be used to measure the quality of hospital care provided for these patients. Descriptive cohort study. At 10 hospitals in the Netherlands, in the period October 2002-April 2003, patients with acute stroke were included in the study. Poor outcome was defined as dead or disabled at 1 year (a score on the modified Rankin scale > or = 3). Quality of the care was assessed by relating diagnostic, therapeutic and preventive procedures to indication. Multiple logistic regression models were used to compare observed numbers of patients with a poor outcome with expected numbers per hospital, after adjustment for patient characteristics and quality of care parameters. In total, 579 patients were included in the study, of which 271 (47%) were dead or disabled at 1 year. Poor outcome varied across the hospitals from 29 to 78%. The mean age was 70 years. There were large differences between hospitals with respect to patient characteristics and quality of care. Most of the differences in outcome between hospitals were explained by the differences in patient characteristics (Akaike's information criterion (AIC) = 134). Quality of care parameters explained just a small additional part of the variation in patient outcome (AIC = 5.5). Large differences between Dutch hospitals in the patient outcome after stroke could mostly be explained by differences in patient characteristics. Only a small part of the hospital variation in patient outcome was related to differences in quality of care. Therefore, outcome indicators cannot be regarded as valid performance indicators for care following a stroke. | 18,856,030 |
Prevalence of quinolone-resistant urinary tract infections in Comanche County Memorial Hospital. | Urinary tract infection (UTI) is not only a common outpatient but also the most frequently occurring nosocomial infection. The most common causative organisms of UTI remain Escherichia coli, nosocomial gram-negative bacilli, enteroccoci and candida. Many physicians use quinolones as the agent of choice for treatment of UTI. As calculated by the drug utilization data of 2007, the rate of quinolone use by physicians for UTI is 48%. This study was performed to determine the prevalence of quinolone-resistant UTI in our hospital and community. All patients admitted to Comanche County Memorial Hospital (CCMH) from Jan 2004 to July 2007 with documented positive urine cultures, as well as patients with hospital-acquired UTI's were included in this study. Pertinent data was collected by a retrospective review of medical records. Resistance of E. coli in urine to ciprofloxacin in total number of patients, divided in two age groups, was studied. X2 and P-value were calculated. Data was stratified for age and stratum specific resistance rate of different drugs (% and 95% CI) were calculated. 2000 cases of positive urine cultures were reviewed. The most common organism causing UTI was E. coli in 1225 (61%). Susceptibility reports showed that only 900 of 1225 E. coli (73.5%) were sensitive to quinolones and crude resistance rate to E. coli in older age group was as high as 26.5%. X2 = 200.922 and p-value < 0.001. Resistance was lowest in younger group (18-50), 3.2%, 95% CI of 1.6-4.7 and approached 41% in patients aged 51-90, (95% CI of 37-45). The sensitivity of E. coli to third generation cephalosporins was 100% and to 1st and 2nd generation was 90% and 98% respectively. Klebsiella was sensitive to both quinolones and third generation cephalosporins in 98% and 100% respectively. Other gram negative organisms (Proteus, Pseudomonas) were sensitive to quinolones in only 69% and 57% of cases respectively while being sensitive to cephalosporins (cefepime and ceftazidime in case of pseudomonas) in more than 99% cases. Prevalence of quinolone-resistance to most common organisms causing urinary tract infections is significantly high in this community. (26.5% for E. coli). Therefore, in Comanche County Memorial Hospital and community, cephalosporins, preferably third generation, intravenous and oral preparations, rather than quinolones should be the first line of treatment, specially for elderly patients who are started on empirical therapy for UTI. | 18,856,050 |
[Association between the Val66Met polymorphism of brain-derived neurotrophic factor gene and schizophrenia in Russians]. | Recent studies have demonstrated a role of the brain-derived neurotrophic factor (BDNF) in schizophrenia. An association between the Val66Met BDNF polymorphism has been reported but the results of different studies are inconsistent. An aim of the present article is to study the allele and genotype distribution in patients with schizophrenia (783) and mentally healthy controls (633). No statistically significant between-group differences have been found. When the group of patients has been stratified by sex and form of schizophrenia, the higher frequency of the Val/Val genotype is observed in the subgroup of men with continuous (chronic) schizophrenia as compared to men with attack-like form (p = 0.047). Clinical symptoms assessed with the PANSS were more severe in male patients with the Val/Val genotype. The Val66Met polymorphism was not associated with forms of schizophrenia or clinical symptoms in female patients. The results obtained suggest that the association between the BDNF gene and schizophrenia may be related to sex and clinical heterogeneity of disease. The Val/Val genotype is associated with severer form of schizophrenia in men. | 18,856,059 |
[Increase of BIRC5 gene expression in non-small cell lung cancer and esophageal squamous cell carcinoma does not correlate with expression of genes SMAC/DIABLO and PML encoding its inhibitors]. | Survivin (BIRC5) is one of the members of IAP-family apoptosis inhibitors. The BIRCS gene is expressed in most human embryonic tissues and malignant tumors but not in normal differentiated tissues of adult human. It was suggested that BIRC5 proteins inhibit apoptosis and play an essential role in tumorigenesis, makings surviving an attractive target for anticancer therapy. The mechanisms regulating level of survivin are not completely understood. It was supposed that natural inhibitors of survivin, namely SMAC and PML, play an important role in these processes. Using RT-PCR and immunoblotting we analyzed the transcription level of BIRC5, SMAC and PML genes and content of corresponding proteins in normal and tumor human tissues in non-small cell lung cancer and esophageal squamous cell carcinoma. It was demonstrated that BIRC5 is transcribed only in tumor tissues, whereas expression levels of SMAC and PML are the same in normal and tumor tissues. The contents of proteins correspond to levels of mRNA of the respective genes. Thus the increase of level of survivin in tumor tissues is not the result of decrease in content of its inhibitors SMAC and PML, as their content in tumor and normal cells is the same. | 18,856,066 |
[Intramolecular G-quadruplexes from microsatellite d(GT)12 sequence in the presence of K+]. | Polymorphic d(GT)n microsatellite sequences are known to drastically affect genes expression. By use of CD spectroscopy, UV melting, fluorescence polarization of EtBr probe and FRET, we detected formation of a new fold with three G-quartets by d(GT)12 oligonucleotide in 0.01 M Na phosphate buffer, pH 8.0, in the presence 0.1 M KCl. Monomolecular type of the structure was verified with measurements of rotational relaxation time (p = 28 +/- 0.5 ns) of EtBr:d(GT)12 complex. CD spectra supported G-quartets formation. A distance between FITC, covalently attached to 5'-end of d(GT)12, and intercalated EtBr molecule was estimated using FRET (R < or =17 A). These data are in agreement with the proposed self folding of d(GT)12. | 18,856,070 |
Pharmacotherapy of hepatitis B infection: a brief review. | Chronic infection with hepatitis B virus can lead to liver disease, cirrhosis, and hepatocellular carcinoma. Treatment options include interferons and antiviral drugs. The interferons have immunomodulatory, antiproliferative, and antiviral effects. Nucleoside analogs, such as entecavir, lamivudine and telbivudine, and neucleotide analogs, such as adefovir and tenofovir, exhibit antiviral effects by inhibiting viral replication. Treatment is directed at suppressing viral replication and halting the progression of disease. | 18,856,082 |
[Risk factors for non-compliance to treatment with highly effective antiretroviral therapy]. | The purpose of the study was: to measure the prevalence of non-compliance to highly active antiretroviral therapy (HAART) by AIDS patients; to identify whether some of the factors listed in health literature were associated with non-compliance; to establish the predictive values of non-compliance to HAART-related factors. An analytic prevalence study (N = 60) was performed, in which the three days prior to the interview were considered. Those classified as compliant were the patients who ingested 95% or over of the total amount of pills prescribed a day. Compliance appeared as 73.3%. The multivariate logistic regression analysis indicated that the black subjects presented 6.48 times higher risk for non-compliance. Those who did not present side effects showed 7.6 times higher risk, and a risk of 1.12 for each pill taken. The compliance observed in the study proved to be higher than in literature. The sociodemographic and cultural factors may interfere in the compliance with HAART. | 18,856,116 |
[Cardiopulmonary resuscitation with semi-automated external defibrillator: assessment of the teaching-learning process]. | Studies demonstrate that, for every minute delayed on defibrillating a heart arrest patient, survival chances decrease by 10%, and that the same chances of survival are 98% effective when it is employed within 30 seconds. While attending a heart arrest patient, it is crucial that the use of external semi-automated defibrillator (AED) is included in the training. The purpose of the present study is to compare Psychomotor Ability and the Theoretical Knowledge of lay people on cardiopulmonary resuscitation (CPR) using AED, before and after training. This sample was composed of 40 administrative workers of a public institution that were trained on CPR technique using EAD, as an experiment. The significantly higher scores in the assessment instrument items of Psychomotor Ability and Theoretical Knowledge, after training, indicates that the participants have presented improvements in their performances. | 18,856,122 |
Acute nursing care and management of patients with sickle cell. | The information provided in this article has been developed to coincide with the recent findings from a National Confidential Enquiry into Patient Outcome and Death (2008) report, 'A Sickle Cell Crisis', which calls for nurses to learn more about the disorder in order to better support patients in their care. This article reiterates much of the previous written literature, which has made reference to compromised patient care due to the ongoing unfamiliarity surrounding sickle cell disorders among healthcare professionals in Western societies. Readers will be given an overview of the condition and general clinical guidance on the management of care for patients when they are experiencing a state of'crisis'. Readers should note that the term 'painful episodes' is sometimes used in preference to sickle cell 'crises'. | 18,856,142 |
Pressure ulcer prevention and pressure-relieving surfaces. | Although rarely subject to media attention, political interest or research funding, pressure ulcers, and their almost inevitable increase in incidence, detrimentally affect the quality of life of thousands of patients, both in the hospital and community setting. In addition, the costs to the NHS of pressure-ulcer-related care in hospitals is estimated to be pounds sterling 1.8-pounds sterling 2.5 billion annually. Many pressure ulcers that develop could have been prevented, and there are several up-to-date, easily-accessible sources of evidence to guide decision-making regarding appropriate interventions in pressure care. Consideration and assessment of the patient holistically, followed by appropriate intervention and evaluation, is the key to any prevention strategy. | 18,856,145 |
Iatrogenic lip and facial burns caused by an overheated surgical instrument. | An unusual case of an iatrogenic superficial burn of the lip and face during third molar surgery is presented. The burn was caused by a heated surgical instrument after sterilization. Although completely healed within three weeks, the burn had a negative influence on the patient-doctor trust. The surgical team must avoid using recently sterilized instruments in an unsafe manner. | 18,856,171 |
Finger and toe temperatures on exposure to cold water and cold air. | Subjects with a weak cold-induced vasodilatation response (CIVD) to experimental cold-water immersion of the fingers in a laboratory setting have been shown to have a higher risk for local cold injuries when exposed to cold in real life. Most of the cold injuries in real life, however, occur in the foot in cold air rather than in the hand in cold water. Therefore, an experiment was conducted to investigate the within-subject relation between CIVD in the fingers and toes exposed to cold water and cold air. In 4 experimental sessions, 11 healthy male subjects immersed their toes and fingers in 5 degrees C water and exposed the fingers and toes to -18 degrees C cold air for 30 min. The pad temperature of the middle three digits was measured. CIVD in water was more pronounced in the fingers (onset time 5.1 +/- 1.8 min; amplitude 5.0 +/- 2.1 degrees C) than in the toes (onset time 10.6 +/- 6.0 min; amplitude 3.0 +/- 1.0 degrees C). Out of 22 skin temperature responses to cold air, 13 were not identifiable as CIVD. The mean skin temperatures for fingers and toes during the last 20 min of cold exposure were 25.6 +/- 7.1 degrees C and 20.9 +/- 6.8 degrees C, respectively, for air and 9.3 +/- 1.9 degrees C and 7.1 +/- 1.3 degrees C for water immersion. There was a strong relation between the mean temperature of the fingers during cold-water immersion and toes during cold air exposure (r = 0.83, P < 0.01), showing that a weak CIVD response in the hand is related to a weak response in the foot. We conclude that the cold-water finger immersion test is related to the temperature response in the toes and may thus continue to serve as a valid indicator for the risk of local cold injuries. | 18,856,183 |
Lilienthal's fatal glider crash in 1896: evidence regarding the cause of death. | Otto Lilienthal's pioneering work on gliders helped form the basis for development of powered aircraft. His death following a glider crash in 1896 was officially ascribed to fracture of the cervical spine. However, the clinical details assembled here make it more likely that he died from head trauma with resulting complications, possibly including intracranial hematoma. | 18,856,192 |
Adaptation of the cardiovascular system to postinfarction cardiosclerosis in rats with congenital adrenoreactivity of the myocardium. | Three months after myocardial infarction the severity of heart failure and size of postinfarction scars in August rats with inherently reduced adrenoreactivity of the myocardium were similar to those in Wistar rats. The mortality rate in August rats was 2.5-fold lower than in Wistar rats. During the postinfarction period, myocardial adrenoreactivity in August rats remained lower, while the efficiency of cardiac function was 62% higher than in Wistar rats. The incidence of epinephrine-induced arrhythmias in August rats was much lower than in Wistar rats. | 18,856,199 |
Effect of silimarin, succinic acid, and their combination on bioenergetics of the brain in experimental encephalopathy. | In rats with experimental encephalopathy caused by intoxication with 4-pentenoic acid inhibiting beta-oxidation of medium- and long-chain fatty acids, hepatoprotector silimarin inhibited LPO, prevented deenergization and maintained high respiratory activity of brain mitochondria, and increased the rate and coupling of oxidation and phosphorylation. Succinic acid improved oxidation of substrates in motochondria and promoted activation of succinate-dependent ATP generation. Silimarin and succinic acid used together produced a synergistic protective effect on brain mitochondria surpassing the protective effects of individual preparations and prevented LPO activation. | 18,856,206 |
Comparison of the toric implantable collamer lens and custom ablation LASIK for myopic astigmatism. | To compare the results of wavefront-guided custom LASIK and the Toric Implantable Collamer Lens (TICL) in the correction of myopic astigmatism. This observational, non-randomized study compared clinical efficacy results from the TICL's US Food and Drug Administration Clinical Trial and published Summaries of Safety and Effectiveness of two wavefront-guided lasers: STAR S4 CustomVue excimer laser system (VISX Inc) and LADARVision4000 CustomCornea excimer laser system (Alcon Laboratories Inc). Preoperative myopic refractive error was divided into two groups: -3.00 to -7.00 diopters (D) and -7.00 to -11.00 D. The percentage of eyes with uncorrected visual acuity (UCVA) of 20/20 and 20/40 and predictability of manifest refraction spherical equivalent within +/- 0.50 and +/- 1.00 D in the three groups was similar with only one statistically significant difference (TICL versus Alcon within +/- 1.00 D: 97% versus 82%; P = .008). The TICL had significantly better postoperative best spectacle-corrected visual acuity (BSCVA) compared to preoperative BSCVA than both the VISX CustomVue and Alcon CustomCornea (P < .001). The TICL postoperative UCVA outcomes compared to preoperative BSCVA were significantly better than Alcon CustomCornea outcomes (P < .001). Additionally, almost half (48%) of the TICL cases had improvement in postoperative UCVA compared to preoperative BSCVA, whereas only 23% of the Alcon CustomCornea eyes showed improvement. Although comparable in clinical efficacy outcomes, the TICL had a significantly better postoperative improvement in BSCVA and significantly better postoperative UCVA than preoperative BSCVA. The TICL can be considered as an alternative to LASIK through the full range of use. | 18,856,230 |
Phakic toric Implantable Collamer Lens implantation for the correction of high myopic astigmatism in eyes with keratoconus. | To present two patients in whom phakic toric Implantable Collamer Lenses (toric ICL, STAAR Surgical) have been effective for the correction of high myopic astigmatism with stable keratoconus. Both patients had a history of contact lens intolerance, and refraction and corneal topography were stable for 3 to 4 years. Preoperatively, the manifest refraction was -10.00 -6.00 x 100 in case 1 and -8.00 -2.75 x 100 in case 2. Postoperatively, the manifest refraction was +0.50 -1.00 x 90 in case 1 and -0.25 -1.25 x 100 in case 2. Uncorrected visual acuity and best spectacle-corrected visual acuity were markedly improved after implantation in both patients. No progressive sign of keratoconus was seen during 1-year follow-up. Phakic toric ICL implantation may be an alternative for the correction of high myopic astigmatism in eyes with stable keratoconus. | 18,856,240 |
A study of the relationship between the fever caused by bacterial pyrogens and the fever accompanying acute infections. | The relationship between the fever of acute infection and that following injection of bacterial pyrogen was studied by administering pyrogens to animals convalescent from acute infections. Rabbits surviving dermal pneumococcal infections or peritonitis due to Escherichia coli were given intravenous injections of typhoid or E. coli vaccine. They showed no evidence of tolerance to the fever-promoting effect of these pyrogenic materials. Tolerance did develop in infected animals given daily pyrogen injections during the course of the infection. Certain previous observations upon the ability of rabbits to develop tolerance to pyrogens, the broad nature of the tolerance, and its duration were confirmed. It is concluded that the pyrogen produced by certain bacteria plays little or no rôle in the production of the fever of infection. These findings are compatible with the hypothesis that there is a common factor, perhaps a product of cell injury, underlying the fever accompanying diseases of various types. | 18,881,485 |
Production of atheromatosis in the aorta of the bird by the administration of diethylstilbestrol. | A new experimental procedure for the production of arteriosclerosis in the bird is described. The subcutaneous implantation of diethylstilbestrol by means of which a sustained increase in the concentration of cholesterol, phospholipid, and neutral fat can be readily established, is shown to induce atherosclerosis of the aorta. The atherosclerosis has been compared with that artificially induced in the bird by the prolonged feeding of cholesterol and also with that occurring spontaneously. The stilbestrol-induced lesion more closely resembled the spontaneously occurring one in the bird than did that produced by cholesterol feeding. But all 3 lesions were fundamentally similar, differing only in the amounts and proportions of the various lipid constituents present. The concentrations of cholesterol in plasma of the stilbestrol-treated and cholesterol-fed birds were of the same order. Yet cholesterol constituted a greater proportion of the lipids deposited in the arterial wall of the cholesterol-fed than in that of the stilbestrol-treated birds. This finding suggests that the cholesterol content of the vascular lesion depends not only on the absolute concentration of cholesterol in plasma, but also on the proportion of cholesterol to other lipid constituents in plasma. | 18,881,496 |
Hypertension in the systemic blood of animals with experimental renal hypertension. | 1. A method has been developed which makes possible the demonstration of a pressor substance in the circulating systemic blood of dogs with experimental renal hypertension. 2. After the intravenous injection of renin into normal dogs, it was possible to detect a pressor substance formed in the systemic blood. After the intravenous injection of 1 unit of renin, as much as 1 unit of the pressor substance was detected in the plasma from 200 cc. of systemic blood. 3. Large amounts of systemic blood pooled from several normal dogs did not contain detectable amounts of pressor substance. 4. In experimental renal hypertension due to unilateral or bilateral constriction of the main renal arteries, a pressor substance was demonstrated in large amounts of systemic blood, corresponding to from one-fifth to one-third of the total blood volume. This was accomplished without the addition of hypertensinogen to enhance the action of the renin in the blood. In an animal weighing about 15 kilos, with benign hypertension up to 3 months' duration, about 3 to 5 units of this pressor substance are probably constantly circulating in the entire systemic blood. 5. The pressor substance was also detected in a relatively small amount of renal vein blood from an ischemic kidney. 6. In the systemic blood of dogs weighing about 15 kilos, with malignant experimental renal hypertension, from 15 to 25 units, or more, of the pressor substance are present in the entire circulating blood. 7. The pressor substance which appears in the systemic blood of dogs with experimental renal hypertension, and of normal dogs after intravenous injection of renin, is destroyed by hypertensinase. 8. The pressor substance obtained from the systemic blood of dogs with experimental renal hypertension has the same physiological and chemical properties as hypertensin produced in vitro. It is therefore suggested that the name hypertensin be adopted for the pressor substance which causes experimental renal hypertension. 9. In this study the animals in the benign phase of hypertension were almost all in the early stage (3 months or less). Whether the humoral mechanism obtains in animals in the late stage, after years of hypertension, or in any form of human hypertension is being investigated. | 18,884,899 |
Regulatory mechanisms of cellular respiration; the role of cell membranes; uranium inhibition of cellular respiration. | Uranium as UO(2)(NO(3))(2) combines reversibly with proteins. The degree of dissociation of this combination depends, among other factors, on the H(+) concentration. At pH 7.3 the U-albumin complex was easily dissociated on addition of citrate, while at pH 3.8 it was not. Uranium inhibited reversibly a number of enzyme systems. Uranium enzyme inhibitions could be reversed on addition of certain hydroxypolycarboxylic acids (citric acid, alpha-hydroxyaspartic acid, malic acid); in no case, however, did phosphate have any effect. In cell-free yeast juice, the fermentation of glucose-hexosediphosphate was inhibited by UO(2)(NO(3))(2). Slight reactivation occurred on addition of phosphate. In living yeast cells, the fermentation and oxidation of glucose was inhibited by small amounts of UO(2)(NO(3))(2) (7,7 micrograms per mg. dry weight), while the oxidation of acetic acid, ethyl alcohol, malic and citric acids, was not affected at all. U inhibition in living yeast cells at pH 7.3 was completely released on addition of small amounts of phosphate, adenosinetriphosphate, and citrate, while at pH 3.8 U inhibition was not released by phosphate and citrate. At saturation, one yeast cell contained 7.06 x 10(6) molecules of uranium. Lactic dehydrogenase was not inhibited by U while the oxidation of lactic acid by gonococci was inhibited. Addition of phosphate released this inhibition. The U inhibition of liver succinoxidase was unaffected by phosphate, while the U inhibition of the oxidation of succinate by E. coli was released by phosphate. It has been concluded from these experiments that U inhibition of cell metabolism is due to combination of the metal with the protein portion of the cell membrane. Uranium is presented as an example of surface inhibition. | 18,891,143 |
Regulatory mechanisms of cellular respiration; the role of soluble sulfhydryl groups as shown by the effect of sulfhydryl reagents on the respiration of sea urchin sperm. | Oxidizing agents of sulfhydryl groups such as iodosobenzoate, alkylating agents such as iodoacetamide, and mercaptide-forming agents such as cadmium chloride, mercuric chloride, p-chloromercuribenzoate, sodium arsenite, and p-carboxyphenylarsine oxide, added in small concentrations to a suspension of sea urchin sperm produced an increase in respiration. When the concentration was increased there was an inhibition. These effects are explained by postulating the presence in the cells of two kinds of sulfhydryl groups: soluble sulfhydryl groups, which regulate cellular respiration, and fixed sulfhydryl groups, present in the protein moiety of enzymes. Small concentrations of sulfhydryl reagents combine only with the first, thus producing an increase in respiration; when the concentration is increased, the fixed sulfhydryl groups are also attacked and inhibition of respiration is the consequence. Other inhibitors of cell respiration, such as cyanide and urethanes, which do not combine with -SH groups, did not stimulate respiration in small concentration. | 18,891,144 |
Phage formation in Staphylococcus muscae cultures; the competition between host and virus for a nutrient. | 1. Experiments carried out in Fildes' synthetic medium show that there is a competition between the host and virus for a substance present in acid-hydrolyzed casein. This substance appears to be essential for the multiplication of the virus but not for the host. | 18,891,147 |
Immunochemical studies on blood groups; the cross reaction between type XIV antipneumococcal horse serum and purified blood group A, B, and O substances from hog and human sources. | Purified blood group A, B, and O substances from hog and human sources precipitate with Type XIV antipneumococcal horse serum and provide an explanation for the observation that Type XIV antibody agglutinates human erythrocytes of all four major blood groups. Individual preparations of A substance or O substance from either species vary in their capacity to precipitate Type XIV antibody although the hog A substances did not differ in potency toward anti-A. Similarly, no correlation between A activity and reactivity with Type XIV antibody could be found among the human A substances. | 18,904,215 |
Food protein effect on plasma specific gravity, plasma protein, and hematocrit value. | When the protein consumption of normal human individuals is increased from 0.5, to 1.5, to 2.5 gm. of protein per kilo body weight, the specific gravity of the plasma rises and the hematocrit value falls. The analysis of variance demonstrates that the change in protein consumption is a significant but minor factor in determining the total variability of the observations. When albino rats were given diets containing a small, a moderate, and a large amount of protein, there was an increase in serum protein concentration but no change in hematocrit value. During the period over which the most rapid changes in rate of urea excretion and serum urea concentration occurred as normal human individuals passed from a 2.5 to an 0.1 gm. of protein per kilo body weight consumption, there was no change in serum protein concentration. Over a 5 day period during which a diet that was adequate in calories but almost wholly devoid of protein was taken, the serum protein concentration of normal individuals steadily rose. This was associated with a slight increase in hematocrit value but no change in blood or plasma volume. The protein effect is one of the minor factors that contribute to the variability of serum protein and hematocrit measurements in normal individuals. The general conclusion is reached that we shall have to measure the rate at which red cells and protein enter and leave the circulating blood stream before we can hope to comprehend the mechanism of the protein effect. | 18,904,220 |
Studies in biochemical genetics in Drosophila. | The metabolism of the imaginal discs of wild type, miniature, vestigial, and four-jointed varieties of Drosophila was investigated using the Cartesian diver ultramicrorespirometer. Wild type and vestigial wing disc respiration is inhibited by cyanide and azide and thus is mediated by an iron or copper porphyrin system, presumable cytochrome-cytochrome oxidase. Respiration is also inhibited by certain hydroxynaphthoquinones, believed to inactivate some enzyme between cytochromes b and c. The respiration of the vestigial and miniature wing discs is increased to normal by the addition of ascorbic acid and to a lesser extent by p-phenylenediamine and hydroquinone, hence the cytochrome oxidase and cytochrome c systems of vestigial and miniature wing discs are normal and the effects of these genes are on enzymes below cytochrome c in the respiratory chain. The respiratory enzymes of the developing imaginal discs of insects are similar to those of a wide variety of cells from bacteria to mammals. The correlation of these biochemical findings with embryological studies of the discs is discussed. | 18,904,757 |
Studies on the intermediary carbohydrate metabolism of aquatic animals; the distribution of acid-soluble phosphorus and certain enzymes in dolphin tissues. | 1. Liver, kidney, brain, skeletal muscle, and cardiac muscle from one newborn and three adult long-snouted dolphins (Stenella plagiodon) were obtained for enzyme studies. 2. All of the dolphin tissues exhibited cytochrome oxidase, succinic dehydrogenase, and malic dehydrogenase activity. Considerable differences in the enzyme activities of the various tissues were noted, with cardiac muscle exhibiting the highest respiratory enzyme activity. The enzyme activities of dolphin tissues were lower than those of the corresponding rat tissues. 3. All of the dolphin tissues exhibited adenosine triphosphatase activity which was accelerated by magnesium and manganese but, in contrast to rat tissues, was only slightly activated by calcium. 4. Measurements of the distribution of acid-soluble phosphorus in dolphin tissues indicated that glycolysis in all of the tissues examined proceeded through the Emden-Meyerhof phosphorylation scheme. 5. The average glycogen content of dolphin skeletal muscle was 0.98 per cent as compared with 0.16 to 0.20 per cent for rat skeletal muscle. The high glycogen content of dolphin skeletal muscle indicates a ready source of substrate for glycolysis even during submergence when the blood supply may be differentially shunted to other organs. 6. Measurements of the organ weights of dolphins showed that the lungs occupy over three times and the liver one-half as much of the total body weight as do these organs in the rat. The heart and the thyroid gland of the dolphin are also larger in proportion to the total body weight than in the rat while the relative weights of the other tissues in the two species are about the same. | 18,904,758 |
The reaction between actomyosin and adenosine triphosphate. | 1. A study is made of the effect of adenosine triphosphate (ATP) upon the viscosity of solutions of actomyosin in 0.5 M KCl. 2. The observed effects are discussed in terms of an initial drop of the viscosity (viscosity response) and its subsequent slow reversal (recovery effect). The latter is ascribed to a decrease in the ATP concentration through enzymatic hydrolysis. 3. The recovery effect is inhibited by Mg, activated by Ca, in accordance with the effect of these ions on the activity of myosin-ATPase. 4. The viscosity response is not inhibited, probably promoted by Mg. It is not promoted, probably inhibited by Ca. 5. The viscosity response is induced not only by ATP, but to a certain extent also by inosinetriphosphate, inorganic triphosphate, and inorganic pyrophosphate, not by adenosine diphosphate or monophosphate. 6. The viscosity response could be obtained with enzymatically inactive myosin. 7. It is concluded that the effect of ATP upon myosin does not depend on its enzymatic hydrolysis. | 18,904,759 |
Effect of enzyme inhibitors and activators on the multiplication of typhus rickettsiae; correlation of effects of PABA and KCN with oxygen consumption in embryonate eggs. | A technique is described for measuring the oxygen uptake of embryonate eggs. Statistical analysis has shown that the method is reliable and accurate. Determinations were made on groups of 15 to 20 eggs, in order to average out individual biological variations. Reduction of the CO(2) tension and relative humidity to approximately zero previous to analysis has been found to be desirable. The oxygen consumption of normal and typhus-infected eggs, untreated and treated with agents previously found to inhibit or enhance rickettsial growth has been studied. Rickettsial infection caused a slight but significant increase in the rate of oxygen consumption on the 4th day after inoculation, followed by a rapid drop in the rate as the infection developed. The evidence suggests that low concentrations of rickettsial toxins may stimulate respiration, while higher concentrations depress respiration and lead eventually to embryonic death. PABA, which is rickettsiostatic, markedly increased the oxygen uptake of normal eggs, the effect appearing 4 days after injection and lasting for about 4 days. Thereafter, the rate fell below that of the untreated eggs. In typhus-infected eggs, PABA had similar effects, but the oxygen consumption reached much higher levels. A possible explanation of this fact is suggested. MABA and OABA, which are not rickettsiostatic, did not increase oxygen uptake; in fact they depressed cellular respiration moderately, OABA being more active in this way than MABA. These two compounds may compete with PABA for a position in some respiratory enzyme system. Potassium cyanide, which enhances rickettsial growth, caused, in concentrations not lethal to the embryos, a moderate drop in the oxygen consumption of normal eggs, the effect starting almost immediately after injection and lasting usually for 9 days. In infected eggs, its effect was more striking. It is probable that rickettsial toxins and KCN act synergistically to depress cellular respiration. When PABA and KCN were injected simultaneously, the stimulating effect of PABA on respiration predominated. The resulting level of oxygen consumption, though lower than that resulting from PABA alone, was still high enough to inhibit rickettsial growth. As far as our results go, they support the hypothesis that, within certain limits, rickettsial growth is inversely proportional to the respiratory rate of the host cells, regardless of the factors which determine that rate. It is not yet clear that PABA owes its rickettsiostatic action to its ability to increase cellular respiration, but this assumption seems reasonable as a working hypothesis. The respiratory mechanism in which PABA participates is not as yet known. Although PABA forms part of the folic acid molecule, folic acid itself, in concentrations corresponding to effective doses of PABA, did not increase cellular respiration or show rickettsiostatic action. | 18,908,221 |
The proteins in unheated culture filtrates of human tubercle bacilli; fractionation and determination of physical-chemical properties. | Concentrated culture filtrates of two strains of human tubercle bacilli, a virulent and a slightly virulent one, have been fractionated to give fourteen fractions in each case. Chemical determinations and sedimentation velocity measurements have been carried out on those fractions for which significant results could be obtained. The evidence is that two distinct proteins are present, in addition to a polysaccharide and nucleic acid. The physical measurements have not demonstrated the presence of any other proteins. One of the proteins has been isolated in pure form, and found to have a molecular weight of 44,000 +/- 5,000, based on measurements of partial specific volume, sedimentation velocity, and diffusion rate. This protein is believed to be the same as one previously isolated by Seibert et al. (6), who assigned it a molecular weight of 32,000. The other protein was not obtained sufficiently free from polysaccharide so that its molecular weight could be determined, but it is believed to have a sedimentation constant of about 2 S. Sedimentation and diffusion constants have been obtained for the polysaccharide, which appears to be a homogeneous molecular species with a molecular weight of about 20,000. The source in unheated tuberculin of the proteins obtained from heated preparations is discussed. | 18,908,224 |
The proteins in unheated culture filtrates of human tubercle bacilli; determination of serological properties. | 1. Only two serologically different proteins were found in the unheated culture filtrates of both virulent and slightly virulent tubercle bacilli. One of them was the protein which had a sedimentation constant of 3.4 S, and the other was in filtrate fractions with a constant of 2 S. 2. That these proteins were distinct was demonstrated by three methods: quantitative precipitin and precipitin absorption tests with rabbit antisera, skin tests in guinea pigs actively sensitized with the culture filtrate fractions, and skin tests in passively sensitized guinea pigs. 3. A third antigen of unknown nature was found by means of the precipitin tests, but only in certain fractions from the virulent culture filtrate. 4. The protein with the constant of 3.4 S could not be demonstrated serologically in an O.T. made from the same culture filtrate as the unheated preparation from the virulent organism. | 18,908,225 |
Phage formation in Staphylococcus muscae cultures; a factor necessary for phage formation. | 1. A factor necessary for the formation, of Staphylococcus muscae phage was found in acid digests of many highly purified proteins. 2. The factor is released from egg albumen and pepsin by peptic digestion. 3. No amino acids tried could replace the acid digests of proteins as a source of the factor. 4. The factor, when added to a multiplying bacteria-phage system, cannot be found in purified phage or in the lysate after complete lysis of the system has taken place. | 18,920,610 |
Two different proteases from Streptomyces hygroscopicus are involved in transglutaminase activation. | Transglutaminase (TGase), the only commercial enzyme in the food industry capable of introducing covalent bonds to proteins, is secreted as a zymogen (Pro-TGase) in several Streptomyces species. In previous studies, only a metalloprotease has been isolated from Streptomyces mobaraensis as an endogenous TGase-activating protease (TAP). In this study, not only an endogenous metalloprotease but also an endogenous serine protease is found to be involved in TGase activation in Streptomyces hygroscopicus. In a cell-free system, the TAP inhibitor was first precipitated with cetyltrimethyl ammonium bromide (CTAB) to maintain TAP activity. Subsequently, different types of protease inhibitors were added to identify the TAP involved in TGase activation in S. hygroscopicus. TGase activation was inhibited by 1 mM phenylmethanesulfonyl fluoride (PMSF) and 10 mM ethylenediaminetetraacetic acid (EDTA), indicating the involvement of serine protease and metalloprotease in the TGase activation process. Furthermore, the TAP purified from a liquid culture of S. hygroscopicus was identified as a serine protease, which is different from the TAP isolated from S. mobaraensis. In addition, Streptomyces Pro-TGases were found to have a conserved amino acid sequence preceding the N-terminal of TGase, which contained cleavage sites for both serine protease and metalloprotease. These results indicate that endogenous serine and metalloproteases are both involved in TGase activation in S. hygroscopicus. To the authors' knowledge, this is the first report that an endogenous serine protease is involved in Streptomyces TGase activation. | 18,921,967 |
Alkylresorcinols in wheat varieties in the HEALTHGRAIN Diversity Screen. | The contents of alkylresorcinols (AR) were analyzed in 131 winter wheats, 20 spring wheats, 10 durum wheats, 5 spelt wheats, and 10 early cultivated forms of wheat (5 diploid einkorn and 5 tetraploid emmer), which are part of the HEALTHGRAIN diversity screen. AR were analyzed by gas chromatography (GC), which provides both total contents and relative homologue compositions, as well as with a Fast Blue colorimetric method that provides only total contents but which is fast and easily screens a large number of samples. There was considerable variation in the total AR content analyzed with GC: winter wheat (220-652 microg/g of dm), spring wheat (254-537 microg/g of dm), durum wheat (194-531 microg/g of dm), spelt (490-741 microg/g of dm), einkorn (545-654 microg/g of dm), and emmer wheat (531-714 microg/g of dm). The relative AR homologue composition was different for different types of wheat, with a C17:0 to C21:0 ratio of 0.1 for winter, spring, and spelt wheats, 0.04 for einkorn and emmer wheat, and 0.01 for durum wheat. The total AR content analyzed with the Fast Blue method was lower than that analyzed with GC but there was a good correlation between the two methods (R(2) = 0.76). | 18,921,971 |
Topological analysis of the reaction of uranium ions (U+, U2+) with N2O in the gas phase. | Density functional theory calculations were performed to study the ability of uranium cations, U(+) and U(2+), to activate the N-N and N-O bonds of N(2)O. A close description of the reaction pathways leading to different reaction products is presented. The obtained results are compared with previous experimental works. The nature of the bonding of all the involved species and the bonding evolution along the reaction pathways was studied by means of the topological analysis of the ELF function. | 18,921,990 |
Relative and absolute stereochemistry of quinadoline B, an inhibitor of lipid droplet synthesis in macrophages. | New fungal metabolites, designated quinadolines A (1) and B (2), were isolated from culture broth of Aspergillus sp. FKI-1746, and their structures were elucidated by NMR spectroscopy. The complete relative and absolute stereochemistry of 2 was determined by X-ray crystallography and amino acid analysis using a chiral column. Quinadolines moderately inhibited lipid droplet synthesis in mouse macrophages. | 18,922,003 |
The efficacy of topoisomerase II-targeted anticancer agents reflects the persistence of drug-induced cleavage complexes in cells. | Genistein, a widely consumed bioflavonoid with chemopreventative properties in adults, and etoposide, a commonly prescribed anticancer drug, are well-characterized topoisomerase II poisons. Although both compounds display similar potencies against human topoisomerase IIalpha and IIbeta in vitro and induce comparable levels of DNA cleavage complexes in cultured human cells, their cytotoxic and genotoxic effects differ significantly. As determined by assays that monitored cell viability or the phosphorylation of histone H2AX, etoposide was much more toxic in CEM cells than genistein. Further studies that characterized the simultaneous treatment of cells with genistein and etoposide indicate that the differential actions of the two compounds are not related to the effects of genistein on cellular processes outside of its activity against topoisomerase II. Rather, they appear to result from a longer persistence of cleavage complexes induced by etoposide as compared to genistein. Parallel in vitro studies with purified type II enzymes led to similar conclusions regarding cleavage complex persistence. Isoform-specific differences were observed in vitro and in cells treated with etoposide. To this point, the t 1/2 of etoposide-induced DNA cleavage complexes formed with topoisomerase IIalpha in CEM cells was approximately 5 times longer than those formed with topoisomerase IIbeta. The cytotoxicity of etoposide following four treatment-recovery cycles was similar to that induced by continuous exposure to the drug over an equivalent time period. Taken together, these findings suggest that it may be possible to preferentially target topoisomerase IIalpha with etoposide by employing a schedule that utilizes pulsed drug treatment-recovery cycles. | 18,922,022 |
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