Input: Calcium sensing receptor protects high glucose - induced energy metabolism disorder via blocking gp78 - ubiquitin proteasome pathway . Diabetic cardiomyopathy ( DCM ) is a major complication and fatal cause of the patients with diabetes . The calcium sensing receptor ( CaSR ) is a G protein - coupled receptor , which is involved in maintaining calcium homeostasis , regulating cell proliferation and apoptosis , and so on . In our previous study , we found that CaSR expression , intracellular calcium levels and cardiac function were all significantly decreased in DCM rats ; however , the exact mechanism are not clear yet . The present study revealed the protective role of CaSR in myocardial energy metabolism disorder induced by high glucose ( HG ) as well as the underlying mechanism . Here , we demonstrated that HG decreased the expression of CaSR , mitochondrial fusion proteins ( Mfn1 , Mfn2 ) , cell gap junction related proteins ( Cx43 , beta - catenin , N - cadherin ) , and intracellular ATP concentration . In contrast , HG increased extracellular ATP concentration , the expression of gp78 , mitochondrial fission proteins ( Fis1 , Drp1 ) , and the ubiquitination levels of Mfn1 , Mfn2 and Cx43 . Moreover , CaSR agonist and gp78 - siRNA significantly reduced the above changes . Taken together , these results suggest that HG induces myocardial energy metabolism disorder via decrease of CaSR expression , and activation of gp78 - ubiquitin proteasome system . In turn , these effects disrupt the structure and function of the mitochondria and the cell gap junction , result in the reduced ATP synthesis and the increased ATP leakage . Stimulation of CaSR significantly attenuates HG - induced abnormal myocardial energy metabolism , suggesting CaSR would be a promising potential therapeutic target for DCM .

Calcium sensing receptor

calcium sensing receptor

CaSR

G protein - coupled receptor

CaSR

CaSR

CaSR

beta - catenin

N - cadherin

CaSR

CaSR

CaSR

CaSR

glucose

calcium

calcium

glucose

ATP

ATP

ATP

ATP

metabolism disorder

Diabetic cardiomyopathy

DCM

diabetes

DCM

myocardial energy metabolism disorder

myocardial energy metabolism disorder

abnormal myocardial energy metabolism

DCM

patients

rats

ATP

ATP

ATP

ATP

ATP

ATP

ATP

ATP

ATP

ATP

ATP

ATP

ATP

ATP

ATP

ATP

myocardial energy metabolism disorder

myocardial energy metabolism disorder

abnormal myocardial energy metabolism

myocardial energy metabolism disorder

myocardial energy metabolism disorder

abnormal myocardial energy metabolism

myocardial energy metabolism disorder

myocardial energy metabolism disorder

abnormal myocardial energy metabolism

myocardial energy metabolism disorder

myocardial energy metabolism disorder

abnormal myocardial energy metabolism

ATP

myocardial energy metabolism disorder

ATP

myocardial energy metabolism disorder

ATP

abnormal myocardial energy metabolism

ATP

myocardial energy metabolism disorder

ATP

myocardial energy metabolism disorder

ATP

abnormal myocardial energy metabolism

ATP

myocardial energy metabolism disorder

ATP

myocardial energy metabolism disorder

ATP

abnormal myocardial energy metabolism

ATP

myocardial energy metabolism disorder

ATP

myocardial energy metabolism disorder

ATP

abnormal myocardial energy metabolism

glucose

ATP

glucose

ATP

glucose

ATP

glucose

ATP

glucose

ATP

glucose

ATP

glucose

ATP

glucose

ATP

Calcium sensing receptor

calcium sensing receptor

CaSR

G protein - coupled receptor

CaSR

CaSR

CaSR

CaSR

CaSR

CaSR

CaSR

Calcium sensing receptor

calcium sensing receptor

CaSR

G protein - coupled receptor

CaSR

CaSR

CaSR

CaSR

CaSR

CaSR

CaSR

Calcium sensing receptor

ATP

Calcium sensing receptor

ATP

Calcium sensing receptor

ATP

Calcium sensing receptor

ATP

calcium sensing receptor

ATP

calcium sensing receptor

ATP

calcium sensing receptor

ATP

calcium sensing receptor

ATP

CaSR

ATP

CaSR

ATP

CaSR

ATP

CaSR

ATP

G protein - coupled receptor

ATP

G protein - coupled receptor

ATP

G protein - coupled receptor

ATP

G protein - coupled receptor

ATP

CaSR

ATP

CaSR

ATP

CaSR

ATP

CaSR

ATP

CaSR

ATP

CaSR

ATP

CaSR

ATP

CaSR

ATP

CaSR

ATP

CaSR

ATP

CaSR

ATP

CaSR

ATP

CaSR

ATP

CaSR

ATP

CaSR

ATP

CaSR

ATP

CaSR

ATP

CaSR

ATP

CaSR

ATP

CaSR

ATP

CaSR

ATP

CaSR

ATP

CaSR

ATP

CaSR

ATP

CaSR

ATP

CaSR

ATP

CaSR

ATP

CaSR

ATP

Calcium sensing receptor

Calcium sensing receptor

calcium sensing receptor

calcium sensing receptor

CaSR

CaSR

G protein - coupled receptor

G protein - coupled receptor

CaSR

CaSR

CaSR

CaSR

CaSR

CaSR

CaSR

CaSR

CaSR

CaSR

CaSR

CaSR

CaSR

CaSR

Calcium sensing receptor

Calcium sensing receptor

calcium sensing receptor

calcium sensing receptor

CaSR

CaSR

G protein - coupled receptor

G protein - coupled receptor

CaSR

CaSR

CaSR

CaSR

CaSR

CaSR

CaSR

CaSR

CaSR

CaSR

CaSR

CaSR

CaSR

CaSR

Calcium sensing receptor

Calcium sensing receptor

calcium sensing receptor

calcium sensing receptor

CaSR

CaSR

G protein - coupled receptor

G protein - coupled receptor

CaSR

CaSR

CaSR

CaSR

CaSR

CaSR

CaSR

CaSR

CaSR

CaSR

CaSR

CaSR

CaSR

CaSR

Calcium sensing receptor

myocardial energy metabolism disorder

Calcium sensing receptor

myocardial energy metabolism disorder

Calcium sensing receptor

abnormal myocardial energy metabolism

calcium sensing receptor

myocardial energy metabolism disorder

calcium sensing receptor

myocardial energy metabolism disorder

calcium sensing receptor

abnormal myocardial energy metabolism

CaSR

myocardial energy metabolism disorder

CaSR

myocardial energy metabolism disorder

CaSR

abnormal myocardial energy metabolism

G protein - coupled receptor

myocardial energy metabolism disorder

G protein - coupled receptor

myocardial energy metabolism disorder

G protein - coupled receptor

abnormal myocardial energy metabolism

CaSR

myocardial energy metabolism disorder

CaSR

myocardial energy metabolism disorder

CaSR

abnormal myocardial energy metabolism

CaSR

myocardial energy metabolism disorder

CaSR

myocardial energy metabolism disorder

CaSR

abnormal myocardial energy metabolism

CaSR

myocardial energy metabolism disorder

CaSR

myocardial energy metabolism disorder

CaSR

abnormal myocardial energy metabolism

CaSR

myocardial energy metabolism disorder

CaSR

myocardial energy metabolism disorder

CaSR

abnormal myocardial energy metabolism

CaSR

myocardial energy metabolism disorder

CaSR

myocardial energy metabolism disorder

CaSR

abnormal myocardial energy metabolism

CaSR

myocardial energy metabolism disorder

CaSR

myocardial energy metabolism disorder

CaSR

abnormal myocardial energy metabolism

CaSR

myocardial energy metabolism disorder

CaSR

myocardial energy metabolism disorder

CaSR

abnormal myocardial energy metabolism

Calcium sensing receptor

calcium

Calcium sensing receptor

calcium

calcium sensing receptor

calcium

calcium sensing receptor

calcium

CaSR

calcium

CaSR

calcium

G protein - coupled receptor

calcium

G protein - coupled receptor

calcium

CaSR

calcium

CaSR

calcium

CaSR

calcium

CaSR

calcium

CaSR

calcium

CaSR

calcium

CaSR

calcium

CaSR

calcium

CaSR

calcium

CaSR

calcium

CaSR

calcium

CaSR

calcium

CaSR

calcium

CaSR

calcium

Calcium sensing receptor

metabolism disorder

calcium sensing receptor

metabolism disorder

CaSR

metabolism disorder

G protein - coupled receptor

metabolism disorder

CaSR

metabolism disorder

CaSR

metabolism disorder

CaSR

metabolism disorder

CaSR

metabolism disorder

CaSR

metabolism disorder

CaSR

metabolism disorder

CaSR

metabolism disorder

calcium

DCM

calcium

DCM

calcium

DCM

calcium

DCM

calcium

DCM

calcium

DCM

glucose

N - cadherin

glucose

N - cadherin

glucose

beta - catenin

glucose

beta - catenin

glucose

glucose

glucose

glucose

glucose

glucose

glucose

glucose

glucose

glucose

glucose

glucose

Calcium sensing receptor

DCM

Calcium sensing receptor

DCM

Calcium sensing receptor

DCM

calcium sensing receptor

DCM

calcium sensing receptor

DCM

calcium sensing receptor

DCM

CaSR

DCM

CaSR

DCM

CaSR

DCM

G protein - coupled receptor

DCM

G protein - coupled receptor

DCM

G protein - coupled receptor

DCM

CaSR

DCM

CaSR

DCM

CaSR

DCM

CaSR

DCM

CaSR

DCM

CaSR

DCM

CaSR

DCM

CaSR

DCM

CaSR

DCM

CaSR

DCM

CaSR

DCM

CaSR

DCM

CaSR

DCM

CaSR

DCM

CaSR

DCM

CaSR

DCM

CaSR

DCM

CaSR

DCM

CaSR

DCM

CaSR

DCM

CaSR

DCM

Calcium sensing receptor

glucose

Calcium sensing receptor

glucose

calcium sensing receptor

glucose

calcium sensing receptor

glucose

CaSR

glucose

CaSR

glucose

G protein - coupled receptor

glucose

G protein - coupled receptor

glucose

CaSR

glucose

CaSR

glucose

CaSR

glucose

CaSR

glucose

CaSR

glucose

CaSR

glucose

CaSR

glucose

CaSR

glucose

CaSR

glucose

CaSR

glucose

CaSR

glucose

CaSR

glucose

CaSR

glucose

CaSR

glucose

glucose

glucose

glucose

glucose

glucose

glucose

glucose

glucose

glucose

glucose

glucose

glucose

glucose

myocardial energy metabolism disorder

glucose

myocardial energy metabolism disorder

glucose

abnormal myocardial energy metabolism

glucose

myocardial energy metabolism disorder

glucose

myocardial energy metabolism disorder

glucose

abnormal myocardial energy metabolism

glucose

metabolism disorder

glucose

metabolism disorder


Input: A novel compound , maltolyl p - coumarate , attenuates cognitive deficits and shows neuroprotective effects in vitro and in vivo dementia models . To develop a novel and effective drug that could enhance cognitive function and neuroprotection , we newly synthesized maltolyl p - coumarate by the esterification of maltol and p - coumaric acid . In the present study , we investigated whether maltolyl p - coumarate could improve cognitive decline in scopolamine - injected rats and in amyloid beta peptide ( 1 - 42 ) - infused rats . Maltolyl p - coumarate was found to attenuate cognitive deficits in both rat models using passive avoidance test and to reduce apoptotic cell death observed in the hippocampus of the amyloid beta peptide ( 1 - 42 ) - infused rats . We also examined the neuroprotective effects of maltolyl p - coumarate in vitro using SH - SY5Y cells . Cells were pretreated with maltolyl p - coumarate , before exposed to amyloid beta peptide ( 1 - 42 ) , glutamate or H2O2 . We found that maltolyl p - coumarate significantly decreased apoptotic cell death and reduced reactive oxygen species , cytochrome c release , and caspase 3 activation . Taking these in vitro and in vivo results together , our study suggests that maltolyl p - coumarate is a potentially effective candidate against Alzheimer ' s disease that is characterized by wide spread neuronal death and progressive decline of cognitive function .

maltolyl p - coumarate

maltolyl p - coumarate

maltol

p - coumaric acid

maltolyl p - coumarate

scopolamine

amyloid beta peptide ( 1 - 42 )

Maltolyl p - coumarate

amyloid beta peptide ( 1 - 42 )

maltolyl p - coumarate

maltolyl p - coumarate

amyloid beta peptide ( 1 - 42 )

glutamate

maltolyl p - coumarate

reactive oxygen species

cytochrome c

maltolyl p - coumarate

cognitive deficits

dementia

cognitive decline

cognitive deficits

Alzheimer ' s disease

neuronal death

decline of cognitive function

rats

rats

rat

rats

SH - SY5Y

caspase 3

maltol

p - coumaric acid

maltolyl p - coumarate

p - coumaric acid

maltolyl p - coumarate

p - coumaric acid

maltolyl p - coumarate

p - coumaric acid

Maltolyl p - coumarate

p - coumaric acid

maltolyl p - coumarate

p - coumaric acid

maltolyl p - coumarate

p - coumaric acid

maltolyl p - coumarate

p - coumaric acid

maltolyl p - coumarate

p - coumaric acid

maltolyl p - coumarate

maltol

maltolyl p - coumarate

maltol

maltolyl p - coumarate

maltol

Maltolyl p - coumarate

maltol

maltolyl p - coumarate

maltol

maltolyl p - coumarate

maltol

maltolyl p - coumarate

maltol

maltolyl p - coumarate

maltol

maltolyl p - coumarate

amyloid beta peptide ( 1 - 42 )

maltolyl p - coumarate

amyloid beta peptide ( 1 - 42 )

maltolyl p - coumarate

amyloid beta peptide ( 1 - 42 )

maltolyl p - coumarate

amyloid beta peptide ( 1 - 42 )

maltolyl p - coumarate

amyloid beta peptide ( 1 - 42 )

maltolyl p - coumarate

amyloid beta peptide ( 1 - 42 )

maltolyl p - coumarate

amyloid beta peptide ( 1 - 42 )

maltolyl p - coumarate

amyloid beta peptide ( 1 - 42 )

maltolyl p - coumarate

amyloid beta peptide ( 1 - 42 )

Maltolyl p - coumarate

amyloid beta peptide ( 1 - 42 )

Maltolyl p - coumarate

amyloid beta peptide ( 1 - 42 )

Maltolyl p - coumarate

amyloid beta peptide ( 1 - 42 )

maltolyl p - coumarate

amyloid beta peptide ( 1 - 42 )

maltolyl p - coumarate

amyloid beta peptide ( 1 - 42 )

maltolyl p - coumarate

amyloid beta peptide ( 1 - 42 )

maltolyl p - coumarate

amyloid beta peptide ( 1 - 42 )

maltolyl p - coumarate

amyloid beta peptide ( 1 - 42 )

maltolyl p - coumarate

amyloid beta peptide ( 1 - 42 )

maltolyl p - coumarate

amyloid beta peptide ( 1 - 42 )

maltolyl p - coumarate

amyloid beta peptide ( 1 - 42 )

maltolyl p - coumarate

amyloid beta peptide ( 1 - 42 )

maltolyl p - coumarate

amyloid beta peptide ( 1 - 42 )

maltolyl p - coumarate

amyloid beta peptide ( 1 - 42 )

maltolyl p - coumarate

amyloid beta peptide ( 1 - 42 )

maltolyl p - coumarate

dementia

maltolyl p - coumarate

dementia

maltolyl p - coumarate

dementia

Maltolyl p - coumarate

dementia

maltolyl p - coumarate

dementia

maltolyl p - coumarate

dementia

maltolyl p - coumarate

dementia

maltolyl p - coumarate

dementia

cognitive deficits

scopolamine

cognitive decline

scopolamine

cognitive deficits

scopolamine

decline of cognitive function

scopolamine

cognitive deficits

amyloid beta peptide ( 1 - 42 )

cognitive deficits

amyloid beta peptide ( 1 - 42 )

cognitive deficits

amyloid beta peptide ( 1 - 42 )

cognitive decline

amyloid beta peptide ( 1 - 42 )

cognitive decline

amyloid beta peptide ( 1 - 42 )

cognitive decline

amyloid beta peptide ( 1 - 42 )

cognitive deficits

amyloid beta peptide ( 1 - 42 )

cognitive deficits

amyloid beta peptide ( 1 - 42 )

cognitive deficits

amyloid beta peptide ( 1 - 42 )

decline of cognitive function

amyloid beta peptide ( 1 - 42 )

decline of cognitive function

amyloid beta peptide ( 1 - 42 )

decline of cognitive function

amyloid beta peptide ( 1 - 42 )

maltolyl p - coumarate

neuronal death

maltolyl p - coumarate

neuronal death

maltolyl p - coumarate

neuronal death

Maltolyl p - coumarate

neuronal death

maltolyl p - coumarate

neuronal death

maltolyl p - coumarate

neuronal death

maltolyl p - coumarate

neuronal death

maltolyl p - coumarate

neuronal death

maltolyl p - coumarate

Alzheimer ' s disease

maltolyl p - coumarate

Alzheimer ' s disease

maltolyl p - coumarate

Alzheimer ' s disease

Maltolyl p - coumarate

Alzheimer ' s disease

maltolyl p - coumarate

Alzheimer ' s disease

maltolyl p - coumarate

Alzheimer ' s disease

maltolyl p - coumarate

Alzheimer ' s disease

maltolyl p - coumarate

Alzheimer ' s disease

maltolyl p - coumarate

cytochrome c

maltolyl p - coumarate

cytochrome c

maltolyl p - coumarate

cytochrome c

Maltolyl p - coumarate

cytochrome c

maltolyl p - coumarate

cytochrome c

maltolyl p - coumarate

cytochrome c

maltolyl p - coumarate

cytochrome c

maltolyl p - coumarate

cytochrome c

maltolyl p - coumarate

caspase 3

maltolyl p - coumarate

caspase 3

maltolyl p - coumarate

caspase 3

Maltolyl p - coumarate

caspase 3

maltolyl p - coumarate

caspase 3

maltolyl p - coumarate

caspase 3

maltolyl p - coumarate

caspase 3

maltolyl p - coumarate

caspase 3

maltolyl p - coumarate

reactive oxygen species

maltolyl p - coumarate

reactive oxygen species

maltolyl p - coumarate

reactive oxygen species

Maltolyl p - coumarate

reactive oxygen species

maltolyl p - coumarate

reactive oxygen species

maltolyl p - coumarate

reactive oxygen species

maltolyl p - coumarate

reactive oxygen species

maltolyl p - coumarate

reactive oxygen species

maltolyl p - coumarate

cognitive deficits

maltolyl p - coumarate

cognitive decline

maltolyl p - coumarate

cognitive deficits

maltolyl p - coumarate

decline of cognitive function

maltolyl p - coumarate

cognitive deficits

maltolyl p - coumarate

cognitive decline

maltolyl p - coumarate

cognitive deficits

maltolyl p - coumarate

decline of cognitive function

maltolyl p - coumarate

cognitive deficits

maltolyl p - coumarate

cognitive decline

maltolyl p - coumarate

cognitive deficits

maltolyl p - coumarate

decline of cognitive function

Maltolyl p - coumarate

cognitive deficits

Maltolyl p - coumarate

cognitive decline

Maltolyl p - coumarate

cognitive deficits

Maltolyl p - coumarate

decline of cognitive function

maltolyl p - coumarate

cognitive deficits

maltolyl p - coumarate

cognitive decline

maltolyl p - coumarate

cognitive deficits

maltolyl p - coumarate

decline of cognitive function

maltolyl p - coumarate

cognitive deficits

maltolyl p - coumarate

cognitive decline

maltolyl p - coumarate

cognitive deficits

maltolyl p - coumarate

decline of cognitive function

maltolyl p - coumarate

cognitive deficits

maltolyl p - coumarate

cognitive decline

maltolyl p - coumarate

cognitive deficits

maltolyl p - coumarate

decline of cognitive function

maltolyl p - coumarate

cognitive deficits

maltolyl p - coumarate

cognitive decline

maltolyl p - coumarate

cognitive deficits

maltolyl p - coumarate

decline of cognitive function


Input: Mono - allelic POLG expression resulting from nonsense - mediated decay and alternative splicing in a patient with Alpers syndrome . Alpers syndrome is an autosomal recessive mitochondrial DNA depletion disorder that affects children and young adults . It is characterized by a progressive , fatal brain and liver disease . This syndrome has been associated with mutations in POLG , the gene encoding the mitochondrial DNA polymerase ( pol gamma ) . Most patients with Alpers syndrome have been found to be compound heterozygotes , carrying two pathogenic mutations in trans at the POLG locus . POLG is a nuclear - encoded gene whose protein product is imported into mitochondria , where it is essential for mtDNA replication and repair . We studied the skin fibroblasts of a patient with Alpers syndrome having the genotype E873stop / A467T . The E873stop mutation produces a premature termination codon ( TAG ) in exon 17 . The A467T mutation produces a threonine to alanine substitution at a highly conserved site in exon 7 . The allele bearing the stop codon ( E873 - TAG ) is predicted to produce a truncated , catalytically inactive polymerase . However , only full - length pol gamma protein was detected by Western blot analysis . Here , we show that transcripts containing this stop codon undergo nonsense - associated alternative splicing and nonsense - mediated decay . More than 95 % of the functional POLG mRNA was derived from the allele bearing the A467T mutation and less than 5 % contained the E873stop mutation . These events ensured that virtually all POLG protein in the cell was expressed from the A467T allele . Therefore , the Alpers phenotype in this patient was a consequence of a single - copy gene dose of the A467T allele , and selective elimination of transcripts bearing the E873stop mutation .

POLG

POLG

pol gamma

POLG

POLG

pol gamma

POLG

POLG

patient

patients

patient

patient

Alpers syndrome

Alpers syndrome

mitochondrial DNA depletion

liver disease

Alpers syndrome

Alpers syndrome

threonine to alanine

E873 - TAG

Alpers syndrome

Alpers syndrome

Alpers syndrome

threonine to alanine

Alpers syndrome

Alpers syndrome

Alpers syndrome

Alpers syndrome

Alpers syndrome

Alpers syndrome

threonine to alanine

Alpers syndrome

Alpers syndrome

Alpers syndrome

Alpers syndrome

Alpers syndrome

Alpers syndrome

threonine to alanine

Alpers syndrome

Alpers syndrome

Alpers syndrome

Alpers syndrome

Alpers syndrome

Alpers syndrome

threonine to alanine

Alpers syndrome

Alpers syndrome

Alpers syndrome

Alpers syndrome

Alpers syndrome

Alpers syndrome

E873 - TAG

Alpers syndrome

Alpers syndrome

Alpers syndrome

Alpers syndrome

Alpers syndrome

E873 - TAG

Alpers syndrome

Alpers syndrome

Alpers syndrome

Alpers syndrome

Alpers syndrome

E873 - TAG

Alpers syndrome

Alpers syndrome

Alpers syndrome

Alpers syndrome

Alpers syndrome

E873 - TAG

Alpers syndrome

Alpers syndrome

Alpers syndrome

POLG

Alpers syndrome

POLG

Alpers syndrome

pol gamma

Alpers syndrome

POLG

Alpers syndrome

POLG

Alpers syndrome

pol gamma

Alpers syndrome

POLG

Alpers syndrome

POLG

Alpers syndrome

POLG

Alpers syndrome

POLG

Alpers syndrome

pol gamma

Alpers syndrome

POLG

Alpers syndrome

POLG

Alpers syndrome

pol gamma

Alpers syndrome

POLG

Alpers syndrome

POLG

Alpers syndrome

POLG

Alpers syndrome

POLG

Alpers syndrome

pol gamma

Alpers syndrome

POLG

Alpers syndrome

POLG

Alpers syndrome

pol gamma

Alpers syndrome

POLG

Alpers syndrome

POLG

Alpers syndrome

POLG

Alpers syndrome

POLG

Alpers syndrome

pol gamma

Alpers syndrome

POLG

Alpers syndrome

POLG

Alpers syndrome

pol gamma

Alpers syndrome

POLG

Alpers syndrome

POLG


Input: Large deletion involving exon 5 of the arylsulfatase B gene caused apparent homozygosity in a mucopolysaccharidosis type VI patient . Apparent homozygosity for the mutation p . R315X present on exon 5 of the arylsulfatase B ( ARSB ) gene in a mucopolysaccharidosis type VI patient was solved in this study by further testing for a second mutation . Patient cDNA analysis revealed that the entire exon 5 of the ARSB gene was lacking ; this new mutation was identified as c . 899 - 1142del . As the genomic DNA sequencing excluded the presence of splicing mutations , polymerase chain reaction analysis was performed for polymorphisms listed in the NCBI SNP database for the ARSB gene . This allowed the mutation at the genomic DNA level to be identified as g . 99367 - 102002del ; this gross deletion , involving the entire exon 5 of the gene and parts of introns 4 and 5 led to a frameshift starting at amino acid 300 and resulting in a protein with 39 % amino acids different from the normal enzyme . We stress that extensive DNA analysis needs to be performed in case of apparent homozygosity to avoid potential errors in genetic counseling .

arylsulfatase B

arylsulfatase B

ARSB

ARSB

ARSB

mucopolysaccharidosis type VI

mucopolysaccharidosis type VI

patient

patient

Patient

p . R315X

c . 899 - 1142del

g . 99367 - 102002del

g . 99367 - 102002del

mucopolysaccharidosis type VI

g . 99367 - 102002del

mucopolysaccharidosis type VI

mucopolysaccharidosis type VI

arylsulfatase B

mucopolysaccharidosis type VI

arylsulfatase B

mucopolysaccharidosis type VI

ARSB

mucopolysaccharidosis type VI

ARSB

mucopolysaccharidosis type VI

ARSB

mucopolysaccharidosis type VI

arylsulfatase B

mucopolysaccharidosis type VI

arylsulfatase B

mucopolysaccharidosis type VI

ARSB

mucopolysaccharidosis type VI

ARSB

mucopolysaccharidosis type VI

ARSB

mucopolysaccharidosis type VI

p . R315X

mucopolysaccharidosis type VI

p . R315X

mucopolysaccharidosis type VI

c . 899 - 1142del

mucopolysaccharidosis type VI

c . 899 - 1142del


Input: Hypoxia in renal disease with proteinuria and / or glomerular hypertension . Despite the increasing need to identify and quantify tissue oxygenation at the cellular level , relatively few methods have been available . In this study , we developed a new hypoxia - responsive reporter vector using a hypoxia - responsive element of the 5 ' vascular endothelial growth factor untranslated region and generated a novel hypoxia - sensing transgenic rat . We then applied this animal model to the detection of tubulointerstitial hypoxia in the diseased kidney . With this model , we were able to identify diffuse cortical hypoxia in the puromycin aminonucleoside - induced nephrotic syndrome and focal and segmental hypoxia in the remnant kidney model . Expression of the hypoxia - responsive transgene increased throughout the observation period , reaching 2 . 2 - fold at 2 weeks in the puromycin aminonucleoside model and 2 . 6 - fold at 4 weeks in the remnant kidney model , whereas that of vascular endothelial growth factor showed a mild decrease , reflecting distinct behaviors of the two genes . The degree of hypoxia showed a positive correlation with microscopic tubulointerstitial injury in both models . Finally , we identified the localization of proliferating cell nuclear antigen - positive , ED - 1 - positive , and terminal dUTP nick - end labeled - positive cells in the hypoxic cortical area in the remnant kidney model . We propose here a possible pathological tie between chronic tubulointerstitial hypoxia and progressive glomerular diseases .

Hypoxia

renal disease

proteinuria

hypertension

hypoxia

hypoxia

hypoxia

hypoxia

diseased kidney

hypoxia

nephrotic syndrome

hypoxia

hypoxia

hypoxia

tubulointerstitial injury

hypoxic

hypoxia

glomerular diseases

vascular endothelial growth factor

vascular endothelial growth factor

ED - 1

rat

puromycin aminonucleoside

puromycin aminonucleoside

dUTP

ED - 1

Hypoxia

ED - 1

hypoxia

ED - 1

hypoxia

ED - 1

hypoxia

ED - 1

hypoxia

ED - 1

hypoxia

ED - 1

hypoxia

ED - 1

hypoxia

ED - 1

hypoxia

ED - 1

hypoxic

ED - 1

hypoxia

dUTP

Hypoxia

dUTP

hypoxia

dUTP

hypoxia

dUTP

hypoxia

dUTP

hypoxia

dUTP

hypoxia

dUTP

hypoxia

dUTP

hypoxia

dUTP

hypoxia

dUTP

hypoxic

dUTP

hypoxia

Hypoxia

vascular endothelial growth factor

Hypoxia

vascular endothelial growth factor

hypoxia

vascular endothelial growth factor

hypoxia

vascular endothelial growth factor

hypoxia

vascular endothelial growth factor

hypoxia

vascular endothelial growth factor

hypoxia

vascular endothelial growth factor

hypoxia

vascular endothelial growth factor

hypoxia

vascular endothelial growth factor

hypoxia

vascular endothelial growth factor

hypoxia

vascular endothelial growth factor

hypoxia

vascular endothelial growth factor

hypoxia

vascular endothelial growth factor

hypoxia

vascular endothelial growth factor

hypoxia

vascular endothelial growth factor

hypoxia

vascular endothelial growth factor

hypoxia

vascular endothelial growth factor

hypoxia

vascular endothelial growth factor

hypoxic

vascular endothelial growth factor

hypoxic

vascular endothelial growth factor

hypoxia

vascular endothelial growth factor

hypoxia

vascular endothelial growth factor

Hypoxia

puromycin aminonucleoside

Hypoxia

puromycin aminonucleoside

hypoxia

puromycin aminonucleoside

hypoxia

puromycin aminonucleoside

hypoxia

puromycin aminonucleoside

hypoxia

puromycin aminonucleoside

hypoxia

puromycin aminonucleoside

hypoxia

puromycin aminonucleoside

hypoxia

puromycin aminonucleoside

hypoxia

puromycin aminonucleoside

hypoxia

puromycin aminonucleoside

hypoxia

puromycin aminonucleoside

hypoxia

puromycin aminonucleoside

hypoxia

puromycin aminonucleoside

hypoxia

puromycin aminonucleoside

hypoxia

puromycin aminonucleoside

hypoxia

puromycin aminonucleoside

hypoxia

puromycin aminonucleoside

hypoxic

puromycin aminonucleoside

hypoxic

puromycin aminonucleoside

hypoxia

puromycin aminonucleoside

hypoxia

puromycin aminonucleoside

puromycin aminonucleoside

nephrotic syndrome

puromycin aminonucleoside

nephrotic syndrome


Input: Novel somatic MEN1 gene alterations in sporadic primary hyperparathyroidism and correlation with clinical characteristics . Primary hyperparathyroidism ( pHPT ) is a common endocrine disease that in more than 95 % of cases is sporadic and only in some cases is caused by inherited disorders , isolated or as part of multiple endocrine neoplasia ( MEN1 and 2 ) . Somatic mutations of MEN1 gene have also been described in sporadic parathyroid tumors . In our study , we examined the presence of alterations in MEN1 gene in a series of 39 patients who had undergone surgery for sporadic pHPT ( 35 with parathyroid adenoma or hyperplasia , 4 with a carcinoma ) . A genotype - phenotype correlation was also analysed . After DNA extraction from paraffin - embedded tissues , we amplified by PCR and sequenced the exons 2 - 10 of the MEN1 gene . Somatic MEN1 mutations were detected in 6 of the 35 patients with a benign parathyroid lesion examined ( 17 . 1 % ) , whereas no alterations were found in the carcinomas . Four novel MEN1 gene mutations were identified as follows : one frameshift mutation ( 222insT , exon 2 ) , one frameshift deletion ( 912delTA , exon 5 ) , one in - frame deletion ( 835del18 , exon 4 ) and one missense mutation ( P291A , exon 6 ) . In addition , one missense mutation ( L89R , exon 2 ) and one nonsense mutation ( Q536X , exon 10 ) were previously reported . Moreover , two polymorphisms were also found : one allele carried a R171Q polymorphism ( 1 / 39 tumors ) , while a D418D polymorphism ( GAC / GAT ) was found in 15 and 8 tumors in hetero ( CT ) and homozygosity ( TT ) , respectively . In no case ( mutations and / or polymorphisms ) did we find a genotype - phenotype correlation . In conclusion , our data demonstrate the presence of somatic alterations of the MEN1 tumor suppressor gene in about one fifth of benign sporadic parathyroid tumors . The absence of a genotype - phenotype correlation , however , suggests the involvement of other genetic / epigenetic factors for the full expression of the disease .

primary hyperparathyroidism

Primary hyperparathyroidism

pHPT

endocrine disease

inherited disorders

multiple endocrine neoplasia

MEN1 and 2

parathyroid tumors

pHPT

parathyroid adenoma or hyperplasia

carcinoma

benign parathyroid lesion

carcinomas

tumors

tumors

tumor

parathyroid tumors

patients

patients

paraffin

GAC / GAT

tumors

tumors

tumor

GAC / GAT

tumors

GAC / GAT

tumors

GAC / GAT

tumor

tumors

tumors

tumor

parathyroid tumors

parathyroid adenoma or hyperplasia

parathyroid tumors

benign parathyroid lesion

parathyroid tumors

parathyroid adenoma or hyperplasia

parathyroid tumors

benign parathyroid lesion

parathyroid tumors

parathyroid adenoma or hyperplasia

parathyroid tumors

benign parathyroid lesion

parathyroid tumors

parathyroid adenoma or hyperplasia

parathyroid tumors

benign parathyroid lesion

parathyroid tumors

parathyroid adenoma or hyperplasia

parathyroid tumors

benign parathyroid lesion

parathyroid tumors

parathyroid adenoma or hyperplasia

parathyroid tumors

benign parathyroid lesion

carcinoma

carcinoma

carcinoma

carcinoma

carcinoma

carcinoma

carcinoma

carcinomas

carcinomas

carcinomas

carcinomas

carcinomas

carcinomas

carcinomas

primary hyperparathyroidism

primary hyperparathyroidism

GAC / GAT

Primary hyperparathyroidism

Primary hyperparathyroidism

GAC / GAT

pHPT

pHPT

GAC / GAT

pHPT

pHPT

GAC / GAT

primary hyperparathyroidism

Primary hyperparathyroidism

pHPT

pHPT

primary hyperparathyroidism

Primary hyperparathyroidism

pHPT

pHPT

primary hyperparathyroidism

Primary hyperparathyroidism

pHPT

pHPT

primary hyperparathyroidism

Primary hyperparathyroidism

pHPT

pHPT

primary hyperparathyroidism

Primary hyperparathyroidism

pHPT

pHPT

primary hyperparathyroidism

Primary hyperparathyroidism

pHPT

pHPT

primary hyperparathyroidism

Primary hyperparathyroidism

pHPT

pHPT

tumors

tumors

tumor

tumors

tumors

tumor

tumors

tumors

tumor

tumors

tumors

tumor

tumors

tumors

tumor

tumors

tumors

tumor

tumors

tumors

tumor

parathyroid tumors

parathyroid adenoma or hyperplasia

parathyroid tumors

parathyroid tumors

parathyroid adenoma or hyperplasia

parathyroid tumors

parathyroid tumors

parathyroid adenoma or hyperplasia

parathyroid tumors

parathyroid tumors

parathyroid adenoma or hyperplasia

parathyroid tumors

parathyroid tumors

parathyroid adenoma or hyperplasia

parathyroid tumors

parathyroid tumors

parathyroid adenoma or hyperplasia

parathyroid tumors

parathyroid tumors

parathyroid adenoma or hyperplasia

parathyroid tumors

benign parathyroid lesion

benign parathyroid lesion

benign parathyroid lesion

benign parathyroid lesion

benign parathyroid lesion

benign parathyroid lesion

benign parathyroid lesion

primary hyperparathyroidism

Primary hyperparathyroidism

pHPT

pHPT

primary hyperparathyroidism

Primary hyperparathyroidism

pHPT

pHPT

primary hyperparathyroidism

Primary hyperparathyroidism

pHPT

pHPT

primary hyperparathyroidism

Primary hyperparathyroidism

pHPT

pHPT

primary hyperparathyroidism

Primary hyperparathyroidism

pHPT

pHPT

primary hyperparathyroidism

Primary hyperparathyroidism

pHPT

pHPT

primary hyperparathyroidism

Primary hyperparathyroidism

pHPT

pHPT


Input: Identification of novel mutations and sequence variants in the SOX2 and CHX10 genes in patients with anophthalmia / microphthalmia . PURPOSE : Mutations in the SOX2 and CHX10 genes have been reported in patients with anophthalmia and / or microphthalmia . In this study , we evaluated 34 anophthalmic / microphthalmic patient DNA samples ( two sets of siblings included ) for mutations and sequence variants in SOX2 and CHX10 . METHODS : Conformational sensitive gel electrophoresis ( CSGE ) was used for the initial SOX2 and CHX10 screening of 34 affected individuals ( two sets of siblings ) , five unaffected family members , and 80 healthy controls . Patient samples containing heteroduplexes were selected for sequence analysis . Base pair changes in SOX2 and CHX10 were confirmed by sequencing bidirectionally in patient samples . RESULTS : Two novel heterozygous mutations and two sequence variants ( one known ) in SOX2 were identified in this cohort . Mutation c . 310 G > T ( p . Glu104X ) , found in one patient , was in the region encoding the high mobility group ( HMG ) DNA - binding domain and resulted in a change from glutamic acid to a stop codon . The second mutation , noted in two affected siblings , was a single nucleotide deletion c . 549delC ( p . Pro184ArgfsX19 ) in the region encoding the activation domain , resulting in a frameshift and premature termination of the coding sequence . The shortened protein products may result in the loss of function . In addition , a novel nucleotide substitution c . * 557G > A was identified in the 3 ' - untranslated region in one patient . The relationship between the nucleotide change and the protein function is indeterminate . A known single nucleotide polymorphism ( c . * 469 C > A , SNP rs11915160 ) was also detected in 2 of the 34 patients . Screening of CHX10 identified two synonymous sequence variants , c . 471 C > T ( p . Ser157Ser , rs35435463 ) and c . 579 G > A ( p . Gln193Gln , novel SNP ) , and one non - synonymous sequence variant , c . 871 G > A ( p . Asp291Asn , novel SNP ) . The non - synonymous polymorphism was also present in healthy controls , suggesting non - causality . CONCLUSIONS : These results support the role of SOX2 in ocular development . Loss of SOX2 function results in severe eye malformation . CHX10 was not implicated with microphthalmia / anophthalmia in our patient cohort .

patients

patients

patient

Patient

patient

patient

patient

patients

patient

anophthalmia

microphthalmia

anophthalmia

microphthalmia

anophthalmic

microphthalmic

eye malformation

microphthalmia

anophthalmia

c . 310 G > T

p . Glu104X

glutamic acid to a stop codon

c . 549delC

p . Pro184ArgfsX19

c . * 557G > A

c . * 469 C > A

c . 471 C > T

p . Ser157Ser

c . 579 G > A

p . Gln193Gln

c . 871 G > A

p . Asp291Asn

microphthalmia

microphthalmia

microphthalmic

microphthalmia

microphthalmia

microphthalmia

microphthalmic

microphthalmia

microphthalmia

microphthalmia

microphthalmic

microphthalmia

microphthalmia

microphthalmia

microphthalmic

microphthalmia

microphthalmia

microphthalmia

microphthalmic

microphthalmia

microphthalmia

microphthalmia

microphthalmic

microphthalmia

microphthalmia

microphthalmia

microphthalmic

microphthalmia

anophthalmia

anophthalmia

anophthalmic

anophthalmia

anophthalmia

anophthalmia

anophthalmic

anophthalmia

anophthalmia

anophthalmia

anophthalmic

anophthalmia

anophthalmia

anophthalmia

anophthalmic

anophthalmia

anophthalmia

anophthalmia

anophthalmic

anophthalmia

anophthalmia

anophthalmia

anophthalmic

anophthalmia

anophthalmia

anophthalmia

anophthalmic

anophthalmia

microphthalmia

microphthalmia

microphthalmic

microphthalmia

microphthalmia

microphthalmia

microphthalmic

microphthalmia

microphthalmia

microphthalmia

microphthalmic

microphthalmia

microphthalmia

microphthalmia

microphthalmic

microphthalmia

microphthalmia

microphthalmia

microphthalmic

microphthalmia

microphthalmia

microphthalmia

microphthalmic

microphthalmia

microphthalmia

microphthalmia

microphthalmic

microphthalmia

microphthalmia

microphthalmia

microphthalmic

microphthalmia

anophthalmia

anophthalmia

anophthalmic

anophthalmia

anophthalmia

anophthalmia

anophthalmic

anophthalmia

anophthalmia

anophthalmia

anophthalmic

anophthalmia

anophthalmia

anophthalmia

anophthalmic

anophthalmia

anophthalmia

anophthalmia

anophthalmic

anophthalmia

anophthalmia

anophthalmia

anophthalmic

anophthalmia

anophthalmia

anophthalmia

anophthalmic

anophthalmia

anophthalmia

anophthalmia

anophthalmic

anophthalmia

c . * 469 C > A

microphthalmia

c . * 469 C > A

microphthalmia

c . * 469 C > A

microphthalmic

c . * 469 C > A

microphthalmia

microphthalmia

microphthalmia

microphthalmic

microphthalmia

c . * 469 C > A

anophthalmia

c . * 469 C > A

anophthalmia

c . * 469 C > A

anophthalmic

c . * 469 C > A

anophthalmia

anophthalmia

anophthalmia

anophthalmic

anophthalmia

c . * 469 C > A

eye malformation

eye malformation

c . * 557G > A

anophthalmia

c . * 557G > A

anophthalmia

c . * 557G > A

anophthalmic

c . * 557G > A

anophthalmia

c . * 557G > A

eye malformation

c . 549delC

microphthalmia

c . 549delC

microphthalmia

c . 549delC

microphthalmic

c . 549delC

microphthalmia

p . Pro184ArgfsX19

microphthalmia

p . Pro184ArgfsX19

microphthalmia

p . Pro184ArgfsX19

microphthalmic

p . Pro184ArgfsX19

microphthalmia

c . 549delC

anophthalmia

c . 549delC

anophthalmia

c . 549delC

anophthalmic

c . 549delC

anophthalmia

p . Pro184ArgfsX19

anophthalmia

p . Pro184ArgfsX19

anophthalmia

p . Pro184ArgfsX19

anophthalmic

p . Pro184ArgfsX19

anophthalmia

glutamic acid to a stop codon

microphthalmia

glutamic acid to a stop codon

microphthalmia

glutamic acid to a stop codon

microphthalmic

glutamic acid to a stop codon

microphthalmia

glutamic acid to a stop codon

anophthalmia

glutamic acid to a stop codon

anophthalmia

glutamic acid to a stop codon

anophthalmic

glutamic acid to a stop codon

anophthalmia

p . Glu104X

microphthalmia

p . Glu104X

microphthalmia

p . Glu104X

microphthalmic

p . Glu104X

microphthalmia

p . Glu104X

anophthalmia

p . Glu104X

anophthalmia

p . Glu104X

anophthalmic

p . Glu104X

anophthalmia

microphthalmia

c . * 557G > A

microphthalmia

c . * 557G > A

microphthalmic

c . * 557G > A

microphthalmia

c . * 557G > A

c . 310 G > T

microphthalmia

c . 310 G > T

microphthalmia

c . 310 G > T

microphthalmic

c . 310 G > T

microphthalmia

c . 310 G > T

anophthalmia

c . 310 G > T

anophthalmia

c . 310 G > T

anophthalmic

c . 310 G > T

anophthalmia

eye malformation

eye malformation

eye malformation

eye malformation

eye malformation

eye malformation

eye malformation

eye malformation

c . 549delC

eye malformation

p . Pro184ArgfsX19

eye malformation

glutamic acid to a stop codon

eye malformation

p . Glu104X

eye malformation

c . 310 G > T

eye malformation


Input: Pharmacogenetic Analysis of INT 0144 Trial : Association of Polymorphisms with Survival and Toxicity in Rectal Cancer Patients Treated with 5 - FU and Radiation . PURPOSE : We tested whether 18 polymorphisms in 16 genes ( GSTP1 , COX2 , IL10 , EGFR , EGF , FGFR4 , CCDN1 , VEGFR2 , VEGF , CXCR2 , IL8 , MMP3 , ICAM1 , ERCC1 , RAD51 , and XRCC3 ) would predict disease - free survival ( DFS ) , overall survival ( OS ) , and toxicity in the INT0144 trial , which was designed to investigate different postoperative regimens of 5 - fluorouracil ( 5 - FU ) - based chemoradiation ( CRT ) in locally advanced rectal cancers : Arm 1 consisted of bolus 5 - FU followed by 5 - FU protracted venous infusion ( PVI ) with radiotherapy ; arm 2 was induction and concomitant PVI 5 - FU with radiotherapy and arm 3 was induction and concomitant bolus 5 - FU with radiotherapy . EXPERIMENTAL DESIGN : DNA from 746 stage II / III rectal patients enrolled in the Southwest Oncology Group ( SWOG ) S9304 phase III trial was analyzed . Genomic DNA was extracted from formalin - fixed , paraffin - embedded ( FFPE ) tumor tissue . The polymorphisms were analyzed using direct DNA - sequencing or polymerase chain reaction - restriction fragment length polymorphism ( PCR - RFLP ) . RESULTS : GSTP1 - Ile105Val ( rs1695 ) was significantly associated with DFS and OS and its effect did not vary by treatment arm . The five - year DFS and OS were 53 % and 58 % , respectively , for G / G , 66 % and 72 % for G / A , and 57 % and 66 % for A / A patients . In arm 2 , IL8 - 251A / A genotype ( rs4073 ) was associated with a lower risk of toxicities ( P = 0 . 04 ) . The VEGFR2 H472Q Q / Q genotype ( rs1870377 ) was associated with a higher risk of grade 3 - 5 proximal upper gastrointestinal tract ( PUGIT ) mucositis ( P = 0 . 04 ) in arm 2 . However , in arm 1 , this genotype was associated with a lower risk of PUGIT mucositis ( P = 0 . 004 ) . CONCLUSION : rs1695 may be prognostic in patients with rectal cancer treated with adjuvant CRT . rs4073 and rs1870377 may exhibit different associations with toxicity , according to the 5 - FU schedule .

Toxicity

Rectal Cancer

toxicity

rectal cancers

tumor

toxicities

mucositis

mucositis

rectal cancer

toxicity

Patients

patients

patients

patients

5 - FU

5 - fluorouracil

5 - FU

5 - FU

5 - FU

5 - FU

5 - FU

formalin

paraffin

5 - FU

EGFR

EGF

VEGF

- 251A / A

- 251A / A

5 - FU

- 251A / A

5 - fluorouracil

- 251A / A

5 - FU

- 251A / A

5 - FU

- 251A / A

5 - FU

- 251A / A

5 - FU

- 251A / A

5 - FU

- 251A / A

5 - FU

5 - FU

5 - fluorouracil

5 - FU

5 - FU

5 - FU

5 - FU

5 - FU

5 - FU

5 - FU

5 - fluorouracil

5 - FU

5 - FU

5 - FU

5 - FU

5 - FU

5 - FU

Rectal Cancer

rectal cancers

rectal cancer

Rectal Cancer

rectal cancers

rectal cancer

Rectal Cancer

rectal cancers

rectal cancer

5 - FU

5 - fluorouracil

5 - FU

5 - FU

5 - FU

5 - FU

5 - FU

5 - FU

5 - FU

5 - fluorouracil

5 - FU

5 - FU

5 - FU

5 - FU

5 - FU

5 - FU

5 - FU

5 - fluorouracil

5 - FU

5 - FU

5 - FU

5 - FU

5 - FU

5 - FU

mucositis

mucositis

mucositis

mucositis

5 - FU

5 - fluorouracil

5 - FU

5 - FU

5 - FU

5 - FU

5 - FU

5 - FU

5 - FU

5 - fluorouracil

5 - FU

5 - FU

5 - FU

5 - FU

5 - FU

5 - FU

5 - FU

5 - fluorouracil

5 - FU

5 - FU

5 - FU

5 - FU

5 - FU

5 - FU

5 - FU

5 - fluorouracil

5 - FU

5 - FU

5 - FU

5 - FU

5 - FU

5 - FU

Rectal Cancer

Rectal Cancer

rectal cancers

rectal cancers

rectal cancer

rectal cancer

mucositis

mucositis

mucositis

mucositis

mucositis

mucositis

5 - FU

Rectal Cancer

5 - FU

rectal cancers

5 - FU

rectal cancer

5 - fluorouracil

Rectal Cancer

5 - fluorouracil

rectal cancers

5 - fluorouracil

rectal cancer

5 - FU

Rectal Cancer

5 - FU

rectal cancers

5 - FU

rectal cancer

5 - FU

Rectal Cancer

5 - FU

rectal cancers

5 - FU

rectal cancer

5 - FU

Rectal Cancer

5 - FU

rectal cancers

5 - FU

rectal cancer

5 - FU

Rectal Cancer

5 - FU

rectal cancers

5 - FU

rectal cancer

5 - FU

Rectal Cancer

5 - FU

rectal cancers

5 - FU

rectal cancer

5 - FU

Rectal Cancer

5 - FU

rectal cancers

5 - FU

rectal cancer


Input: Identification of three F5 gene mutations associated with inherited coagulation factor V deficiency in two Chinese pedigrees . To investigate the molecular defects in two Chinese pedigrees with inherited factor V ( FV ) deficiency . A 37 - year - old male ( proband 1 ) and an 18 - month - old boy ( proband 2 ) were diagnosed as inherited coagulation FV deficiency by severely reduced plasma levels of FV activity and antigen . All 25 exons and their flanking sequence of F5 gene were amplified by polymerase chain reaction ( PCR ) for both probands and the PCR products were directly sequenced . Total RNA was extracted from the peripheral lymphocytes of proband 1 for detecting the changes at mRNA level . The homozygous deletion IVS8 - 2A > G was identified in the F5 gene of proband 1 and complementary DNA ( cDNA ) analysis revealed the abolishment of the canonical splicing site by the mutation and the activation of the cryptic acceptor site 24 bp upstream instead . The insertion introduced eight additional amino acids ( AA ) into the FV protein . Two heterozygous mutations of F5 gene were discovered in proband 2 . The 2238 - 9del AG in exon 13 introduced a premature termination code at 689 AA and the substitution of G6410 by T in exon 23 lead to the missense mutation Gly2079Val . Three F5 gene mutations , IVS8 - 2A > G , 2238 - 9del AG and G6410T , have been identified in two Chinese pedigree with congenital FV deficiency , respectively .

FV

FV

inherited coagulation factor V deficiency

inherited factor V ( FV ) deficiency

inherited coagulation FV deficiency

congenital FV deficiency

IVS8 - 2A > G

insertion introduced eight additional amino acids

2238 - 9del AG

689 AA

G6410 by T

IVS8 - 2A > G

2238 - 9del AG

G6410 by T

inherited coagulation factor V deficiency

G6410 by T

inherited factor V ( FV ) deficiency

G6410 by T

inherited coagulation FV deficiency

G6410 by T

congenital FV deficiency

inherited coagulation factor V deficiency

inherited factor V ( FV ) deficiency

inherited coagulation FV deficiency

congenital FV deficiency

2238 - 9del AG

inherited coagulation factor V deficiency

2238 - 9del AG

inherited factor V ( FV ) deficiency

2238 - 9del AG

inherited coagulation FV deficiency

2238 - 9del AG

congenital FV deficiency

2238 - 9del AG

inherited coagulation factor V deficiency

2238 - 9del AG

inherited factor V ( FV ) deficiency

2238 - 9del AG

inherited coagulation FV deficiency

2238 - 9del AG

congenital FV deficiency

IVS8 - 2A > G

inherited coagulation factor V deficiency

IVS8 - 2A > G

inherited factor V ( FV ) deficiency

IVS8 - 2A > G

inherited coagulation FV deficiency

IVS8 - 2A > G

congenital FV deficiency

IVS8 - 2A > G

inherited coagulation factor V deficiency

IVS8 - 2A > G

inherited factor V ( FV ) deficiency

IVS8 - 2A > G

inherited coagulation FV deficiency

IVS8 - 2A > G

congenital FV deficiency

inherited coagulation factor V deficiency

insertion introduced eight additional amino acids

inherited factor V ( FV ) deficiency

insertion introduced eight additional amino acids

inherited coagulation FV deficiency

insertion introduced eight additional amino acids

congenital FV deficiency

insertion introduced eight additional amino acids

inherited coagulation factor V deficiency

689 AA

inherited factor V ( FV ) deficiency

689 AA

inherited coagulation FV deficiency

689 AA

congenital FV deficiency

689 AA

inherited coagulation factor V deficiency

inherited factor V ( FV ) deficiency

inherited coagulation FV deficiency

congenital FV deficiency

inherited coagulation factor V deficiency

inherited factor V ( FV ) deficiency

inherited coagulation FV deficiency

congenital FV deficiency

FV

inherited coagulation factor V deficiency

FV

inherited factor V ( FV ) deficiency

FV

inherited coagulation FV deficiency

FV

congenital FV deficiency

inherited coagulation factor V deficiency

inherited factor V ( FV ) deficiency

inherited coagulation FV deficiency

congenital FV deficiency

inherited coagulation factor V deficiency

inherited factor V ( FV ) deficiency

inherited coagulation FV deficiency

congenital FV deficiency

FV

inherited coagulation factor V deficiency

FV

inherited factor V ( FV ) deficiency

FV

inherited coagulation FV deficiency

FV

congenital FV deficiency

inherited coagulation factor V deficiency

inherited factor V ( FV ) deficiency

inherited coagulation FV deficiency

congenital FV deficiency

inherited coagulation factor V deficiency

inherited factor V ( FV ) deficiency

inherited coagulation FV deficiency

congenital FV deficiency


Input: Bradykinin receptors antagonists and nitric oxide synthase inhibitors in vincristine and streptozotocin induced hyperalgesia in chemotherapy and diabetic neuropathy rat model . PURPOSE : The influence of an irreversible inhibitor of constitutive NO synthase ( L - NOArg ; 1 . 0 mg / kg ip ) , a relatively selective inhibitor of inducible NO synthase ( L - NIL ; 1 . 0 mg / kg ip ) and a relatively specific inhibitor of neuronal NO synthase ( 7 - NI ; 0 . 1 mg / kg ip ) , on antihyperalgesic action of selective antagonists of B2 and B1 receptors : D - Arg - [ Hyp3 , Thi5 , D - Tic7 , Oic8 ] bradykinin ( HOE 140 ; 70 nmol / kg ip ) or des Arg10 HOE 140 ( 70 nmol / kg ip ) respectively , in model of diabetic ( streptozotocin - induced ) and toxic ( vincristine - induced ) neuropathy was investigated . METHODS : The changes in pain thresholds were determined using mechanical stimuli - - the modification of the classic paw withdrawal test described by Randall - Selitto . RESULTS : The results of this paper confirm that inhibition of bradykinin receptors and inducible NO synthase but not neuronal NO synthase activity reduces diabetic hyperalgesia . Pretreatment with L - NOArg and L - NIL but not 7 - NI , significantly increases antihyperalgesic activity both HOE 140 and des Arg10 HOE 140 . It was also shown that both products of inducible NO synthase and neuronal NO synthase activation as well as bradykinin are involved in hyperalgesia produced by vincristine . Moreover , L - NOArg and 7 - NI but not L - NIL intensify antihyperalgesic activity of HOE 140 or des - Arg10HOE 140 in toxic neuropathy . CONCLUSIONS : Results of these studies suggest that B1 and B2 receptors are engaged in transmission of nociceptive stimuli in both diabetic and toxic neuropathy . In streptozotocin - induced hyperalgesia , inducible NO synthase participates in pronociceptive activity of bradykinin , whereas in vincristine - induced hyperalgesia bradykinin seemed to activate neuronal NO synthase pathway . Therefore , concomitant administration of small doses of bradykinin receptor antagonists and NO synthase inhibitors can be effective in alleviation of neuropathic pain , even in hospital care .

Bradykinin receptors antagonists

nitric oxide synthase inhibitors

vincristine

streptozotocin

L - NOArg

L - NIL

7 - NI

D - Arg - [ Hyp3 , Thi5 , D - Tic7 , Oic8 ] bradykinin

HOE 140

des Arg10 HOE 140

L - NOArg

L - NIL

7 - NI

HOE 140

des Arg10 HOE 140

vincristine

L - NOArg

7 - NI

L - NIL

HOE 140

des - Arg10HOE 140

streptozotocin

vincristine

bradykinin receptor antagonists

NO synthase inhibitors

hyperalgesia

diabetic neuropathy

diabetic ( streptozotocin - induced ) and toxic ( vincristine - induced ) neuropathy

pain

diabetic hyperalgesia

hyperalgesia

toxic neuropathy

diabetic and toxic neuropathy

hyperalgesia

hyperalgesia

neuropathic pain

rat

constitutive NO synthase

inducible NO synthase

neuronal NO synthase

B2 and B1 receptors

bradykinin receptors

inducible NO synthase

neuronal NO synthase

inducible NO synthase

neuronal NO synthase

bradykinin

B1 and B2 receptors

inducible NO synthase

bradykinin

bradykinin

neuronal NO synthase

constitutive NO synthase

nitric oxide synthase inhibitors

constitutive NO synthase

L - NOArg

constitutive NO synthase

L - NOArg

constitutive NO synthase

L - NOArg

constitutive NO synthase

NO synthase inhibitors

Bradykinin receptors antagonists

neuropathic pain

bradykinin receptor antagonists

neuropathic pain

nitric oxide synthase inhibitors

neuropathic pain

L - NOArg

neuropathic pain

L - NOArg

neuropathic pain

L - NOArg

neuropathic pain

NO synthase inhibitors

neuropathic pain

B2 and B1 receptors

des Arg10 HOE 140

B2 and B1 receptors

des Arg10 HOE 140

B2 and B1 receptors

des - Arg10HOE 140

bradykinin receptors

des Arg10 HOE 140

bradykinin receptors

des Arg10 HOE 140

bradykinin receptors

des - Arg10HOE 140

B1 and B2 receptors

des Arg10 HOE 140

B1 and B2 receptors

des Arg10 HOE 140

B1 and B2 receptors

des - Arg10HOE 140

B2 and B1 receptors

D - Arg - [ Hyp3 , Thi5 , D - Tic7 , Oic8 ] bradykinin

B2 and B1 receptors

HOE 140

B2 and B1 receptors

HOE 140

B2 and B1 receptors

HOE 140

bradykinin receptors

D - Arg - [ Hyp3 , Thi5 , D - Tic7 , Oic8 ] bradykinin

bradykinin receptors

HOE 140

bradykinin receptors

HOE 140

bradykinin receptors

HOE 140

B1 and B2 receptors

D - Arg - [ Hyp3 , Thi5 , D - Tic7 , Oic8 ] bradykinin

B1 and B2 receptors

HOE 140

B1 and B2 receptors

HOE 140

B1 and B2 receptors

HOE 140

7 - NI

neuropathic pain

7 - NI

neuropathic pain

7 - NI

neuropathic pain

neuronal NO synthase

nitric oxide synthase inhibitors

neuronal NO synthase

7 - NI

neuronal NO synthase

7 - NI

neuronal NO synthase

7 - NI

neuronal NO synthase

NO synthase inhibitors

neuronal NO synthase

nitric oxide synthase inhibitors

neuronal NO synthase

7 - NI

neuronal NO synthase

7 - NI

neuronal NO synthase

7 - NI

neuronal NO synthase

NO synthase inhibitors

neuronal NO synthase

nitric oxide synthase inhibitors

neuronal NO synthase

7 - NI

neuronal NO synthase

7 - NI

neuronal NO synthase

7 - NI

neuronal NO synthase

NO synthase inhibitors

neuronal NO synthase

nitric oxide synthase inhibitors

neuronal NO synthase

7 - NI

neuronal NO synthase

7 - NI

neuronal NO synthase

7 - NI

neuronal NO synthase

NO synthase inhibitors

L - NIL

neuropathic pain

L - NIL

neuropathic pain

L - NIL

neuropathic pain

inducible NO synthase

nitric oxide synthase inhibitors

inducible NO synthase

L - NIL

inducible NO synthase

L - NIL

inducible NO synthase

L - NIL

inducible NO synthase

NO synthase inhibitors

inducible NO synthase

nitric oxide synthase inhibitors

inducible NO synthase

L - NIL

inducible NO synthase

L - NIL

inducible NO synthase

L - NIL

inducible NO synthase

NO synthase inhibitors

inducible NO synthase

nitric oxide synthase inhibitors

inducible NO synthase

L - NIL

inducible NO synthase

L - NIL

inducible NO synthase

L - NIL

inducible NO synthase

NO synthase inhibitors

inducible NO synthase

nitric oxide synthase inhibitors

inducible NO synthase

L - NIL

inducible NO synthase

L - NIL

inducible NO synthase

L - NIL

inducible NO synthase

NO synthase inhibitors

bradykinin

hyperalgesia

bradykinin

diabetic hyperalgesia

bradykinin

hyperalgesia

bradykinin

hyperalgesia

bradykinin

hyperalgesia

bradykinin

hyperalgesia

bradykinin

diabetic hyperalgesia

bradykinin

hyperalgesia

bradykinin

hyperalgesia

bradykinin

hyperalgesia

bradykinin

hyperalgesia

bradykinin

diabetic hyperalgesia

bradykinin

hyperalgesia

bradykinin

hyperalgesia

bradykinin

hyperalgesia

nitric oxide synthase inhibitors

diabetic ( streptozotocin - induced ) and toxic ( vincristine - induced ) neuropathy

nitric oxide synthase inhibitors

toxic neuropathy

nitric oxide synthase inhibitors

diabetic and toxic neuropathy

L - NOArg

diabetic ( streptozotocin - induced ) and toxic ( vincristine - induced ) neuropathy

L - NOArg

toxic neuropathy

L - NOArg

diabetic and toxic neuropathy

L - NOArg

diabetic ( streptozotocin - induced ) and toxic ( vincristine - induced ) neuropathy

L - NOArg

toxic neuropathy

L - NOArg

diabetic and toxic neuropathy

L - NOArg

diabetic ( streptozotocin - induced ) and toxic ( vincristine - induced ) neuropathy

L - NOArg

toxic neuropathy

L - NOArg

diabetic and toxic neuropathy

NO synthase inhibitors

diabetic ( streptozotocin - induced ) and toxic ( vincristine - induced ) neuropathy

NO synthase inhibitors

toxic neuropathy

NO synthase inhibitors

diabetic and toxic neuropathy

diabetic hyperalgesia

B2 and B1 receptors

diabetic hyperalgesia

bradykinin receptors

diabetic hyperalgesia

B1 and B2 receptors

des Arg10 HOE 140

diabetic ( streptozotocin - induced ) and toxic ( vincristine - induced ) neuropathy

des Arg10 HOE 140

toxic neuropathy

des Arg10 HOE 140

diabetic and toxic neuropathy

des Arg10 HOE 140

diabetic ( streptozotocin - induced ) and toxic ( vincristine - induced ) neuropathy

des Arg10 HOE 140

toxic neuropathy

des Arg10 HOE 140

diabetic and toxic neuropathy

des - Arg10HOE 140

diabetic ( streptozotocin - induced ) and toxic ( vincristine - induced ) neuropathy

des - Arg10HOE 140

toxic neuropathy

des - Arg10HOE 140

diabetic and toxic neuropathy

B2 and B1 receptors

diabetic neuropathy

B2 and B1 receptors

diabetic ( streptozotocin - induced ) and toxic ( vincristine - induced ) neuropathy

B2 and B1 receptors

diabetic and toxic neuropathy

bradykinin receptors

diabetic neuropathy

bradykinin receptors

diabetic ( streptozotocin - induced ) and toxic ( vincristine - induced ) neuropathy

bradykinin receptors

diabetic and toxic neuropathy

B1 and B2 receptors

diabetic neuropathy

B1 and B2 receptors

diabetic ( streptozotocin - induced ) and toxic ( vincristine - induced ) neuropathy

B1 and B2 receptors

diabetic and toxic neuropathy

B2 and B1 receptors

toxic neuropathy

bradykinin receptors

toxic neuropathy

B1 and B2 receptors

toxic neuropathy

D - Arg - [ Hyp3 , Thi5 , D - Tic7 , Oic8 ] bradykinin

diabetic ( streptozotocin - induced ) and toxic ( vincristine - induced ) neuropathy

D - Arg - [ Hyp3 , Thi5 , D - Tic7 , Oic8 ] bradykinin

toxic neuropathy

D - Arg - [ Hyp3 , Thi5 , D - Tic7 , Oic8 ] bradykinin

diabetic and toxic neuropathy

HOE 140

diabetic ( streptozotocin - induced ) and toxic ( vincristine - induced ) neuropathy

HOE 140

toxic neuropathy

HOE 140

diabetic and toxic neuropathy

HOE 140

diabetic ( streptozotocin - induced ) and toxic ( vincristine - induced ) neuropathy

HOE 140

toxic neuropathy

HOE 140

diabetic and toxic neuropathy

HOE 140

diabetic ( streptozotocin - induced ) and toxic ( vincristine - induced ) neuropathy

HOE 140

toxic neuropathy

HOE 140

diabetic and toxic neuropathy

7 - NI

diabetic ( streptozotocin - induced ) and toxic ( vincristine - induced ) neuropathy

7 - NI

toxic neuropathy

7 - NI

diabetic and toxic neuropathy

7 - NI

diabetic ( streptozotocin - induced ) and toxic ( vincristine - induced ) neuropathy

7 - NI

toxic neuropathy

7 - NI

diabetic and toxic neuropathy

7 - NI

diabetic ( streptozotocin - induced ) and toxic ( vincristine - induced ) neuropathy

7 - NI

toxic neuropathy

7 - NI

diabetic and toxic neuropathy

nitric oxide synthase inhibitors

des Arg10 HOE 140

nitric oxide synthase inhibitors

des Arg10 HOE 140

nitric oxide synthase inhibitors

des - Arg10HOE 140

7 - NI

des Arg10 HOE 140

7 - NI

des Arg10 HOE 140

7 - NI

des - Arg10HOE 140

7 - NI

des Arg10 HOE 140

7 - NI

des Arg10 HOE 140

7 - NI

des - Arg10HOE 140

7 - NI

des Arg10 HOE 140

7 - NI

des Arg10 HOE 140

7 - NI

des - Arg10HOE 140

NO synthase inhibitors

des Arg10 HOE 140

NO synthase inhibitors

des Arg10 HOE 140

NO synthase inhibitors

des - Arg10HOE 140

nitric oxide synthase inhibitors

D - Arg - [ Hyp3 , Thi5 , D - Tic7 , Oic8 ] bradykinin

nitric oxide synthase inhibitors

HOE 140

nitric oxide synthase inhibitors

HOE 140

nitric oxide synthase inhibitors

HOE 140

7 - NI

D - Arg - [ Hyp3 , Thi5 , D - Tic7 , Oic8 ] bradykinin

7 - NI

HOE 140

7 - NI

HOE 140

7 - NI

HOE 140

7 - NI

D - Arg - [ Hyp3 , Thi5 , D - Tic7 , Oic8 ] bradykinin

7 - NI

HOE 140

7 - NI

HOE 140

7 - NI

HOE 140

7 - NI

D - Arg - [ Hyp3 , Thi5 , D - Tic7 , Oic8 ] bradykinin

7 - NI

HOE 140

7 - NI

HOE 140

7 - NI

HOE 140

NO synthase inhibitors

D - Arg - [ Hyp3 , Thi5 , D - Tic7 , Oic8 ] bradykinin

NO synthase inhibitors

HOE 140

NO synthase inhibitors

HOE 140

NO synthase inhibitors

HOE 140

neuronal NO synthase

hyperalgesia

neuronal NO synthase

diabetic hyperalgesia

neuronal NO synthase

hyperalgesia

neuronal NO synthase

hyperalgesia

neuronal NO synthase

hyperalgesia

neuronal NO synthase

hyperalgesia

neuronal NO synthase

diabetic hyperalgesia

neuronal NO synthase

hyperalgesia

neuronal NO synthase

hyperalgesia

neuronal NO synthase

hyperalgesia

neuronal NO synthase

hyperalgesia

neuronal NO synthase

diabetic hyperalgesia

neuronal NO synthase

hyperalgesia

neuronal NO synthase

hyperalgesia

neuronal NO synthase

hyperalgesia

neuronal NO synthase

hyperalgesia

neuronal NO synthase

diabetic hyperalgesia

neuronal NO synthase

hyperalgesia

neuronal NO synthase

hyperalgesia

neuronal NO synthase

hyperalgesia

inducible NO synthase

bradykinin

inducible NO synthase

bradykinin

inducible NO synthase

bradykinin

inducible NO synthase

bradykinin

inducible NO synthase

bradykinin

inducible NO synthase

bradykinin

inducible NO synthase

bradykinin

inducible NO synthase

bradykinin

inducible NO synthase

bradykinin

inducible NO synthase

bradykinin

inducible NO synthase

bradykinin

inducible NO synthase

bradykinin

inducible NO synthase

diabetic hyperalgesia

inducible NO synthase

diabetic hyperalgesia

inducible NO synthase

diabetic hyperalgesia

inducible NO synthase

diabetic hyperalgesia

inducible NO synthase

hyperalgesia

inducible NO synthase

hyperalgesia

inducible NO synthase

hyperalgesia

inducible NO synthase

hyperalgesia

inducible NO synthase

hyperalgesia

inducible NO synthase

hyperalgesia

inducible NO synthase

hyperalgesia

inducible NO synthase

hyperalgesia

inducible NO synthase

hyperalgesia

inducible NO synthase

hyperalgesia

inducible NO synthase

hyperalgesia

inducible NO synthase

hyperalgesia

inducible NO synthase

hyperalgesia

inducible NO synthase

hyperalgesia

inducible NO synthase

hyperalgesia

inducible NO synthase

hyperalgesia

hyperalgesia

B2 and B1 receptors

hyperalgesia

bradykinin receptors

hyperalgesia

B1 and B2 receptors

hyperalgesia

B2 and B1 receptors

hyperalgesia

bradykinin receptors

hyperalgesia

B1 and B2 receptors

hyperalgesia

B2 and B1 receptors

hyperalgesia

bradykinin receptors

hyperalgesia

B1 and B2 receptors

hyperalgesia

B2 and B1 receptors

hyperalgesia

bradykinin receptors

hyperalgesia

B1 and B2 receptors

nitric oxide synthase inhibitors

des Arg10 HOE 140

nitric oxide synthase inhibitors

des Arg10 HOE 140

nitric oxide synthase inhibitors

des - Arg10HOE 140

L - NOArg

des Arg10 HOE 140

L - NOArg

des Arg10 HOE 140

L - NOArg

des - Arg10HOE 140

L - NOArg

des Arg10 HOE 140

L - NOArg

des Arg10 HOE 140

L - NOArg

des - Arg10HOE 140

L - NOArg

des Arg10 HOE 140

L - NOArg

des Arg10 HOE 140

L - NOArg

des - Arg10HOE 140

NO synthase inhibitors

des Arg10 HOE 140

NO synthase inhibitors

des Arg10 HOE 140

NO synthase inhibitors

des - Arg10HOE 140

nitric oxide synthase inhibitors

D - Arg - [ Hyp3 , Thi5 , D - Tic7 , Oic8 ] bradykinin

nitric oxide synthase inhibitors

HOE 140

nitric oxide synthase inhibitors

HOE 140

nitric oxide synthase inhibitors

HOE 140

L - NOArg

D - Arg - [ Hyp3 , Thi5 , D - Tic7 , Oic8 ] bradykinin

L - NOArg

HOE 140

L - NOArg

HOE 140

L - NOArg

HOE 140

L - NOArg

D - Arg - [ Hyp3 , Thi5 , D - Tic7 , Oic8 ] bradykinin

L - NOArg

HOE 140

L - NOArg

HOE 140

L - NOArg

HOE 140

L - NOArg

D - Arg - [ Hyp3 , Thi5 , D - Tic7 , Oic8 ] bradykinin

L - NOArg

HOE 140

L - NOArg

HOE 140

L - NOArg

HOE 140

NO synthase inhibitors

D - Arg - [ Hyp3 , Thi5 , D - Tic7 , Oic8 ] bradykinin

NO synthase inhibitors

HOE 140

NO synthase inhibitors

HOE 140

NO synthase inhibitors

HOE 140

L - NIL

des Arg10 HOE 140

L - NIL

des Arg10 HOE 140

L - NIL

des - Arg10HOE 140

L - NIL

des Arg10 HOE 140

L - NIL

des Arg10 HOE 140

L - NIL

des - Arg10HOE 140

L - NIL

des Arg10 HOE 140

L - NIL

des Arg10 HOE 140

L - NIL

des - Arg10HOE 140

L - NIL

D - Arg - [ Hyp3 , Thi5 , D - Tic7 , Oic8 ] bradykinin

L - NIL

HOE 140

L - NIL

HOE 140

L - NIL

HOE 140

L - NIL

D - Arg - [ Hyp3 , Thi5 , D - Tic7 , Oic8 ] bradykinin

L - NIL

HOE 140

L - NIL

HOE 140

L - NIL

HOE 140

L - NIL

D - Arg - [ Hyp3 , Thi5 , D - Tic7 , Oic8 ] bradykinin

L - NIL

HOE 140

L - NIL

HOE 140

L - NIL

HOE 140

streptozotocin

hyperalgesia

streptozotocin

diabetic hyperalgesia

streptozotocin

hyperalgesia

streptozotocin

hyperalgesia

streptozotocin

hyperalgesia

streptozotocin

hyperalgesia

streptozotocin

diabetic hyperalgesia

streptozotocin

hyperalgesia

streptozotocin

hyperalgesia

streptozotocin

hyperalgesia

vincristine

hyperalgesia

vincristine

diabetic hyperalgesia

vincristine

hyperalgesia

vincristine

hyperalgesia

vincristine

hyperalgesia

vincristine

hyperalgesia

vincristine

diabetic hyperalgesia

vincristine

hyperalgesia

vincristine

hyperalgesia

vincristine

hyperalgesia

vincristine

hyperalgesia

vincristine

diabetic hyperalgesia

vincristine

hyperalgesia

vincristine

hyperalgesia

vincristine

hyperalgesia


Input: Association of a FGFR - 4 gene polymorphism with bronchopulmonary dysplasia and neonatal respiratory distress . BACKGROUND : Bronchopulmonary dysplasia ( BPD ) is the most common chronic lung disease of premature birth , characterized by impaired alveolar development and inflammation . Pathomechanisms contributing to BPD are poorly understood . However , it is assumed that genetic factors predispose to BPD and other pulmonary diseases of preterm neonates , such as neonatal respiratory distress syndrome ( RDS ) . For association studies , genes upregulated during alveolarization are major candidates for genetic analysis , for example , matrix metalloproteinases ( MMPs ) and fibroblast growth factors ( FGFs ) and their receptors ( FGFR ) . OBJECTIVE : Determining genetic risk variants in a Caucasian population of premature neonates with BPD and RDS . Methods . We genotyped 27 polymorphisms within 14 candidate genes via restriction fragment length polymorphism ( RFLP ) : MMP - 1 , - 2 , - 9 , and - 12 , - 16 , FGF receptors 2 and 4 , FGF - 2 , - 3 , - 4 , - 7 , and - 18 , Signal - Regulatory Protein a ( SIRPA ) and Thyroid Transcription Factor - 1 ( TTF - 1 ) . RESULTS : Five single nucleotide polymorphisms ( SNPs ) in MMP - 9 , MMP - 12 , FGFR - 4 , FGF - 3 , and FGF - 7 are associated ( P < 0 . 05 ) with RDS , defined as surfactant application within the first 24 hours after birth . One of them , in FGFR - 4 ( rs1966265 ) , is associated with both RDS ( P = 0 . 003 ) and BPD ( P = 0 . 023 ) . CONCLUSION : rs1966265 in FGF receptor 4 is a possible genetic key variant in alveolar diseases of preterm newborns .

FGFR - 4

matrix metalloproteinases

MMPs

fibroblast growth factors

FGFs

FGFR

MMP - 1 , - 2 , - 9 , and - 12 , - 16

FGF receptors 2 and 4

FGF - 2 , - 3 , - 4 , - 7 , and - 18

Signal - Regulatory Protein a

SIRPA

Thyroid Transcription Factor - 1

TTF - 1

MMP - 9

MMP - 12

FGFR - 4

FGF - 3

FGF - 7

FGFR - 4

FGF receptor 4

bronchopulmonary dysplasia

neonatal respiratory distress

Bronchopulmonary dysplasia

BPD

lung disease

premature birth

impaired alveolar development

inflammation

BPD

BPD

pulmonary diseases

neonatal respiratory distress syndrome

RDS

BPD

RDS

RDS

RDS

BPD

alveolar diseases

alveolar diseases

alveolar diseases

bronchopulmonary dysplasia

Bronchopulmonary dysplasia

BPD

BPD

BPD

BPD

BPD

bronchopulmonary dysplasia

Bronchopulmonary dysplasia

BPD

BPD

BPD

BPD

BPD

neonatal respiratory distress

neonatal respiratory distress syndrome

RDS

RDS

RDS

RDS

neonatal respiratory distress

neonatal respiratory distress syndrome

RDS

RDS

RDS

RDS

matrix metalloproteinases

neonatal respiratory distress

matrix metalloproteinases

neonatal respiratory distress syndrome

matrix metalloproteinases

RDS

matrix metalloproteinases

RDS

matrix metalloproteinases

RDS

matrix metalloproteinases

RDS

MMPs

neonatal respiratory distress

MMPs

neonatal respiratory distress syndrome

MMPs

RDS

MMPs

RDS

MMPs

RDS

MMPs

RDS

MMP - 1 , - 2 , - 9 , and - 12 , - 16

neonatal respiratory distress

MMP - 1 , - 2 , - 9 , and - 12 , - 16

neonatal respiratory distress syndrome

MMP - 1 , - 2 , - 9 , and - 12 , - 16

RDS

MMP - 1 , - 2 , - 9 , and - 12 , - 16

RDS

MMP - 1 , - 2 , - 9 , and - 12 , - 16

RDS

MMP - 1 , - 2 , - 9 , and - 12 , - 16

RDS

MMP - 12

neonatal respiratory distress

MMP - 12

neonatal respiratory distress syndrome

MMP - 12

RDS

MMP - 12

RDS

MMP - 12

RDS

MMP - 12

RDS

MMP - 9

neonatal respiratory distress

MMP - 9

neonatal respiratory distress syndrome

MMP - 9

RDS

MMP - 9

RDS

MMP - 9

RDS

MMP - 9

RDS

fibroblast growth factors

neonatal respiratory distress

fibroblast growth factors

neonatal respiratory distress syndrome

fibroblast growth factors

RDS

fibroblast growth factors

RDS

fibroblast growth factors

RDS

fibroblast growth factors

RDS

FGFs

neonatal respiratory distress

FGFs

neonatal respiratory distress syndrome

FGFs

RDS

FGFs

RDS

FGFs

RDS

FGFs

RDS

FGF - 2 , - 3 , - 4 , - 7 , and - 18

neonatal respiratory distress

FGF - 2 , - 3 , - 4 , - 7 , and - 18

neonatal respiratory distress syndrome

FGF - 2 , - 3 , - 4 , - 7 , and - 18

RDS

FGF - 2 , - 3 , - 4 , - 7 , and - 18

RDS

FGF - 2 , - 3 , - 4 , - 7 , and - 18

RDS

FGF - 2 , - 3 , - 4 , - 7 , and - 18

RDS

FGF - 7

neonatal respiratory distress

FGF - 7

neonatal respiratory distress syndrome

FGF - 7

RDS

FGF - 7

RDS

FGF - 7

RDS

FGF - 7

RDS

FGF - 3

neonatal respiratory distress

FGF - 3

neonatal respiratory distress syndrome

FGF - 3

RDS

FGF - 3

RDS

FGF - 3

RDS

FGF - 3

RDS

FGFR - 4

alveolar diseases

FGFR

alveolar diseases

FGF receptors 2 and 4

alveolar diseases

FGFR - 4

alveolar diseases

FGFR - 4

alveolar diseases

FGF receptor 4

alveolar diseases

FGFR - 4

bronchopulmonary dysplasia

FGFR - 4

Bronchopulmonary dysplasia

FGFR - 4

BPD

FGFR - 4

BPD

FGFR - 4

BPD

FGFR - 4

BPD

FGFR - 4

BPD

FGFR

bronchopulmonary dysplasia

FGFR

Bronchopulmonary dysplasia

FGFR

BPD

FGFR

BPD

FGFR

BPD

FGFR

BPD

FGFR

BPD

FGF receptors 2 and 4

bronchopulmonary dysplasia

FGF receptors 2 and 4

Bronchopulmonary dysplasia

FGF receptors 2 and 4

BPD

FGF receptors 2 and 4

BPD

FGF receptors 2 and 4

BPD

FGF receptors 2 and 4

BPD

FGF receptors 2 and 4

BPD

FGFR - 4

bronchopulmonary dysplasia

FGFR - 4

Bronchopulmonary dysplasia

FGFR - 4

BPD

FGFR - 4

BPD

FGFR - 4

BPD

FGFR - 4

BPD

FGFR - 4

BPD

FGFR - 4

bronchopulmonary dysplasia

FGFR - 4

Bronchopulmonary dysplasia

FGFR - 4

BPD

FGFR - 4

BPD

FGFR - 4

BPD

FGFR - 4

BPD

FGFR - 4

BPD

FGF receptor 4

bronchopulmonary dysplasia

FGF receptor 4

Bronchopulmonary dysplasia

FGF receptor 4

BPD

FGF receptor 4

BPD

FGF receptor 4

BPD

FGF receptor 4

BPD

FGF receptor 4

BPD

FGFR - 4

neonatal respiratory distress

FGFR - 4

neonatal respiratory distress syndrome

FGFR - 4

RDS

FGFR - 4

RDS

FGFR - 4

RDS

FGFR - 4

RDS

FGFR

neonatal respiratory distress

FGFR

neonatal respiratory distress syndrome

FGFR

RDS

FGFR

RDS

FGFR

RDS

FGFR

RDS

FGF receptors 2 and 4

neonatal respiratory distress

FGF receptors 2 and 4

neonatal respiratory distress syndrome

FGF receptors 2 and 4

RDS

FGF receptors 2 and 4

RDS

FGF receptors 2 and 4

RDS

FGF receptors 2 and 4

RDS

FGFR - 4

neonatal respiratory distress

FGFR - 4

neonatal respiratory distress syndrome

FGFR - 4

RDS

FGFR - 4

RDS

FGFR - 4

RDS

FGFR - 4

RDS

FGFR - 4

neonatal respiratory distress

FGFR - 4

neonatal respiratory distress syndrome

FGFR - 4

RDS

FGFR - 4

RDS

FGFR - 4

RDS

FGFR - 4

RDS

FGF receptor 4

neonatal respiratory distress

FGF receptor 4

neonatal respiratory distress syndrome

FGF receptor 4

RDS

FGF receptor 4

RDS

FGF receptor 4

RDS

FGF receptor 4

RDS

fibroblast growth factors

FGFR

fibroblast growth factors

FGF receptors 2 and 4

FGFs

FGFR

FGFs

FGF receptors 2 and 4

FGF - 2 , - 3 , - 4 , - 7 , and - 18

FGFR

FGF - 2 , - 3 , - 4 , - 7 , and - 18

FGF receptors 2 and 4

fibroblast growth factors

FGFR - 4

fibroblast growth factors

FGFR - 4

fibroblast growth factors

FGFR - 4

fibroblast growth factors

FGF receptor 4

FGFs

FGFR - 4

FGFs

FGFR - 4

FGFs

FGFR - 4

FGFs

FGF receptor 4

FGF - 2 , - 3 , - 4 , - 7 , and - 18

FGFR - 4

FGF - 2 , - 3 , - 4 , - 7 , and - 18

FGFR - 4

FGF - 2 , - 3 , - 4 , - 7 , and - 18

FGFR - 4

FGF - 2 , - 3 , - 4 , - 7 , and - 18

FGF receptor 4

FGF - 7

FGFR

FGF - 7

FGF receptors 2 and 4

FGF - 7

FGFR - 4

FGF - 7

FGFR - 4

FGF - 7

FGFR - 4

FGF - 7

FGF receptor 4

FGF - 3

FGFR

FGF - 3

FGF receptors 2 and 4

FGF - 3

FGFR - 4

FGF - 3

FGFR - 4

FGF - 3

FGFR - 4

FGF - 3

FGF receptor 4


Input: Pleomorphic adenoma gene like - 2 induces epithelial - mesenchymal transition via Wnt / b - catenin signaling pathway in human colorectal adenocarcinoma . Epithelial - mesenchymal transition ( EMT ) is a critical step in the acquisition of metastatic and invasive power for tumor cells . Colorectal adenocarcinoma ( CRC ) is a common cancer where metastasis is directly linked to patient survival . Recent studies show that pleomorphic adenoma gene like - 2 ( PLAGL2 ) could induce tumor EMT and is an independent predictive factor associated with poor prognosis in cancer . In the present study , we confirmed the role of PLAGL2 in the prognosis of CRC patients and provide molecular evidence of PLAGL2 promoted EMT in CRC cell line SW480 . We found that PLAGL2 expression was upregulated in the paraffin - embedded CRC tissues compared to borderline or benign tissues . Experimental EMT induced by PLAGL2 plasmid transfection proved PLAGL2 protein overexpression could enhance the cell scratch wound - healing and transwell ability and significantly upregulated mesenchymal marker proteins , N - cadherin and vimentin and concurrently downregulated epithelial marker of E - cadherin . Subsequently , through western blot assay , we found that PLAGL2 could activate the wnt - signaling component b - catenin in the nuclei . More CRC cell metastasis to the lungs was observed when the PLAGL2 overexpressing SW480 cells were injected into the tail vein of rats , compared with the cell control and PLAGL2 silence group . Our findings indicated that PLAGL2 might be a very upstream key molecule regulating EMT involved in Wnt / b - catenin signaling pathway .

Pleomorphic adenoma gene like - 2

Wnt

b - catenin

pleomorphic adenoma gene like - 2

N - cadherin

vimentin

E - cadherin

wnt

b - catenin

Wnt

b - catenin

human

patient

patients

rats

colorectal adenocarcinoma

tumor

Colorectal adenocarcinoma

CRC

cancer

metastasis

tumor

cancer

CRC

CRC

CRC

CRC

metastasis

paraffin

paraffin

colorectal adenocarcinoma

paraffin

Colorectal adenocarcinoma

paraffin

CRC

paraffin

CRC

paraffin

CRC

paraffin

CRC

paraffin

CRC

b - catenin

colorectal adenocarcinoma

b - catenin

Colorectal adenocarcinoma

b - catenin

CRC

b - catenin

CRC

b - catenin

CRC

b - catenin

CRC

b - catenin

CRC

b - catenin

colorectal adenocarcinoma

b - catenin

Colorectal adenocarcinoma

b - catenin

CRC

b - catenin

CRC

b - catenin

CRC

b - catenin

CRC

b - catenin

CRC

b - catenin

colorectal adenocarcinoma

b - catenin

Colorectal adenocarcinoma

b - catenin

CRC

b - catenin

CRC

b - catenin

CRC

b - catenin

CRC

b - catenin

CRC

Wnt

colorectal adenocarcinoma

Wnt

Colorectal adenocarcinoma

Wnt

CRC

Wnt

CRC

Wnt

CRC

Wnt

CRC

Wnt

CRC

wnt

colorectal adenocarcinoma

wnt

Colorectal adenocarcinoma

wnt

CRC

wnt

CRC

wnt

CRC

wnt

CRC

wnt

CRC

Wnt

colorectal adenocarcinoma

Wnt

Colorectal adenocarcinoma

Wnt

CRC

Wnt

CRC

Wnt

CRC

Wnt

CRC

Wnt

CRC

Wnt

b - catenin

Wnt

b - catenin

Wnt

b - catenin

wnt

b - catenin

wnt

b - catenin

wnt

b - catenin

Wnt

b - catenin

Wnt

b - catenin

Wnt

b - catenin

Pleomorphic adenoma gene like - 2

paraffin

pleomorphic adenoma gene like - 2

paraffin

paraffin

paraffin

paraffin

paraffin

paraffin

paraffin

paraffin

paraffin

paraffin

paraffin

Pleomorphic adenoma gene like - 2

tumor

Pleomorphic adenoma gene like - 2

cancer

Pleomorphic adenoma gene like - 2

tumor

Pleomorphic adenoma gene like - 2

cancer

pleomorphic adenoma gene like - 2

tumor

pleomorphic adenoma gene like - 2

cancer

pleomorphic adenoma gene like - 2

tumor

pleomorphic adenoma gene like - 2

cancer

tumor

cancer

tumor

cancer

tumor

cancer

tumor

cancer

tumor

cancer

tumor

cancer

tumor

cancer

tumor

cancer

tumor

cancer

tumor

cancer

tumor

cancer

tumor

cancer

tumor

cancer

tumor

cancer

tumor

cancer

tumor

cancer

tumor

cancer

tumor

cancer

tumor

cancer

tumor

cancer

Pleomorphic adenoma gene like - 2

colorectal adenocarcinoma

Pleomorphic adenoma gene like - 2

Colorectal adenocarcinoma

Pleomorphic adenoma gene like - 2

CRC

Pleomorphic adenoma gene like - 2

CRC

Pleomorphic adenoma gene like - 2

CRC

Pleomorphic adenoma gene like - 2

CRC

Pleomorphic adenoma gene like - 2

CRC

pleomorphic adenoma gene like - 2

colorectal adenocarcinoma

pleomorphic adenoma gene like - 2

Colorectal adenocarcinoma

pleomorphic adenoma gene like - 2

CRC

pleomorphic adenoma gene like - 2

CRC

pleomorphic adenoma gene like - 2

CRC

pleomorphic adenoma gene like - 2

CRC

pleomorphic adenoma gene like - 2

CRC

colorectal adenocarcinoma

Colorectal adenocarcinoma

CRC

CRC

CRC

CRC

CRC

colorectal adenocarcinoma

Colorectal adenocarcinoma

CRC

CRC

CRC

CRC

CRC

colorectal adenocarcinoma

Colorectal adenocarcinoma

CRC

CRC

CRC

CRC

CRC

colorectal adenocarcinoma

Colorectal adenocarcinoma

CRC

CRC

CRC

CRC

CRC

colorectal adenocarcinoma

Colorectal adenocarcinoma

CRC

CRC

CRC

CRC

CRC

colorectal adenocarcinoma

Colorectal adenocarcinoma

CRC

CRC

CRC

CRC

CRC

colorectal adenocarcinoma

Colorectal adenocarcinoma

CRC

CRC

CRC

CRC

CRC

colorectal adenocarcinoma

Colorectal adenocarcinoma

CRC

CRC

CRC

CRC

CRC

colorectal adenocarcinoma

Colorectal adenocarcinoma

CRC

CRC

CRC

CRC

CRC

colorectal adenocarcinoma

Colorectal adenocarcinoma

CRC

CRC

CRC

CRC

CRC

Pleomorphic adenoma gene like - 2

Wnt

Pleomorphic adenoma gene like - 2

wnt

Pleomorphic adenoma gene like - 2

Wnt

pleomorphic adenoma gene like - 2

Wnt

pleomorphic adenoma gene like - 2

wnt

pleomorphic adenoma gene like - 2

Wnt

Wnt

wnt

Wnt

Wnt

wnt

Wnt

Wnt

wnt

Wnt

Wnt

wnt

Wnt

Wnt

wnt

Wnt

Wnt

wnt

Wnt

Wnt

wnt

Wnt

Wnt

wnt

Wnt

Wnt

wnt

Wnt

Wnt

wnt

Wnt

Pleomorphic adenoma gene like - 2

E - cadherin

pleomorphic adenoma gene like - 2

E - cadherin

E - cadherin

E - cadherin

E - cadherin

E - cadherin

E - cadherin

E - cadherin

E - cadherin

E - cadherin

E - cadherin

E - cadherin

Pleomorphic adenoma gene like - 2

vimentin

pleomorphic adenoma gene like - 2

vimentin

vimentin

vimentin

vimentin

vimentin

vimentin

vimentin

vimentin

vimentin

vimentin

vimentin

Pleomorphic adenoma gene like - 2

N - cadherin

pleomorphic adenoma gene like - 2

N - cadherin

N - cadherin

N - cadherin

N - cadherin

N - cadherin

N - cadherin

N - cadherin

N - cadherin

N - cadherin

N - cadherin

N - cadherin

Pleomorphic adenoma gene like - 2

b - catenin

Pleomorphic adenoma gene like - 2

b - catenin

Pleomorphic adenoma gene like - 2

b - catenin

pleomorphic adenoma gene like - 2

b - catenin

pleomorphic adenoma gene like - 2

b - catenin

pleomorphic adenoma gene like - 2

b - catenin

b - catenin

b - catenin

b - catenin

b - catenin

b - catenin

b - catenin

b - catenin

b - catenin

b - catenin

b - catenin

b - catenin

b - catenin

b - catenin

b - catenin

b - catenin

b - catenin

b - catenin

b - catenin

b - catenin

b - catenin

b - catenin

b - catenin

b - catenin

b - catenin

b - catenin

b - catenin

b - catenin

b - catenin

b - catenin

b - catenin


Input: Successful therapy with argatroban for superior mesenteric vein thrombosis in a patient with congenital antithrombin deficiency . A 38 - year - old woman was admitted with superior mesenteric vein ( SMV ) thrombosis , which was refractory to anticoagulation therapy . The plasma antithrombin activity was decreased and hardly compensated by concentrated antithrombin preparation due to high consumption rate . However , successful anticoagulation was achieved by administration of direct thrombin inhibitor , argatroban . Family studies of antithrombin activity revealed that she had type I congenital antithrombin deficiency . A novel heterozygous mutation in the gene for antithrombin ( single nucleotide T insertion at 7916 and 7917 , Glu 272 to stop in exon 4 ) was identified . Argatroban administration would be effective in the treatment of congenital antithrombin deficiency with SMV thrombosis .

argatroban

argatroban

Argatroban

vein thrombosis

congenital antithrombin deficiency

superior mesenteric vein ( SMV ) thrombosis

type I congenital antithrombin deficiency

congenital antithrombin deficiency

SMV thrombosis

patient

woman

antithrombin

antithrombin

thrombin

antithrombin

antithrombin

nucleotide T insertion at 7916 and 7917

Glu 272 to stop

thrombin

argatroban

thrombin

argatroban

thrombin

Argatroban

argatroban

vein thrombosis

argatroban

superior mesenteric vein ( SMV ) thrombosis

argatroban

SMV thrombosis

argatroban

vein thrombosis

argatroban

superior mesenteric vein ( SMV ) thrombosis

argatroban

SMV thrombosis

Argatroban

vein thrombosis

Argatroban

superior mesenteric vein ( SMV ) thrombosis

Argatroban

SMV thrombosis

argatroban

congenital antithrombin deficiency

argatroban

congenital antithrombin deficiency

argatroban

congenital antithrombin deficiency

argatroban

congenital antithrombin deficiency

Argatroban

congenital antithrombin deficiency

Argatroban

congenital antithrombin deficiency

vein thrombosis

antithrombin

vein thrombosis

antithrombin

vein thrombosis

antithrombin

vein thrombosis

antithrombin

superior mesenteric vein ( SMV ) thrombosis

antithrombin

superior mesenteric vein ( SMV ) thrombosis

antithrombin

superior mesenteric vein ( SMV ) thrombosis

antithrombin

superior mesenteric vein ( SMV ) thrombosis

antithrombin

SMV thrombosis

antithrombin

SMV thrombosis

antithrombin

SMV thrombosis

antithrombin

SMV thrombosis

antithrombin

type I congenital antithrombin deficiency

Glu 272 to stop

type I congenital antithrombin deficiency

nucleotide T insertion at 7916 and 7917

antithrombin

type I congenital antithrombin deficiency

antithrombin

type I congenital antithrombin deficiency

antithrombin

type I congenital antithrombin deficiency

antithrombin

type I congenital antithrombin deficiency


Input: Amisulpride related tic - like symptoms in an adolescent schizophrenic . Tic disorders can be effectively treated by atypical antipsychotics such as risperidone , olanzapine and ziprasidone . However , there are two case reports that show tic - like symptoms , including motor and phonic variants , occurring during treatment with quetiapine or clozapine . We present a 15 - year - old girl schizophrenic who developed frequent involuntary eye - blinking movements after 5 months of amisulpride treatment ( 1000 mg per day ) . The tic - like symptoms resolved completely after we reduced the dose of amisulpride down to 800 mg per day . However , her psychosis recurred after the dose reduction . We then placed her on an additional 100 mg per day of quetiapine . She has been in complete remission under the combined medications for more than one year and maintains a fair role function . No more tic - like symptoms or other side effects have been reported . Together with previously reported cases , our patient suggests that tic - like symptoms might occur in certain vulnerable individuals during treatment with atypical antipsychotics such as quetiapine , clozapine , or amisulpride .

Amisulpride

antipsychotics

risperidone

olanzapine

ziprasidone

quetiapine

clozapine

amisulpride

amisulpride

quetiapine

antipsychotics

quetiapine

clozapine

amisulpride

tic - like symptoms

schizophrenic

Tic disorders

tic - like symptoms

schizophrenic

involuntary eye - blinking movements

tic - like symptoms

psychosis

tic - like symptoms

tic - like symptoms

patient

Tic disorders

ziprasidone

Tic disorders

olanzapine

Tic disorders

risperidone

Tic disorders

antipsychotics

Tic disorders

antipsychotics

psychosis

quetiapine

psychosis

quetiapine

psychosis

quetiapine

Amisulpride

psychosis

amisulpride

psychosis

amisulpride

psychosis

amisulpride

psychosis

Amisulpride

schizophrenic

Amisulpride

schizophrenic

amisulpride

schizophrenic

amisulpride

schizophrenic

amisulpride

schizophrenic

amisulpride

schizophrenic

amisulpride

schizophrenic

amisulpride

schizophrenic

involuntary eye - blinking movements

Amisulpride

involuntary eye - blinking movements

amisulpride

involuntary eye - blinking movements

amisulpride

involuntary eye - blinking movements

amisulpride

Amisulpride

quetiapine

Amisulpride

quetiapine

Amisulpride

quetiapine

amisulpride

quetiapine

amisulpride

quetiapine

amisulpride

quetiapine

amisulpride

quetiapine

amisulpride

quetiapine

amisulpride

quetiapine

amisulpride

quetiapine

amisulpride

quetiapine

amisulpride

quetiapine


Input: Syncope caused by hyperkalemia during use of a combined therapy with the angiotensin - converting enzyme inhibitor and spironolactone . A 76 year - old woman with a history of coronary artery bypass grafting and prior myocardial infarction was transferred to the emergency room with loss of consciousness due to marked bradycardia caused by hyperkalemia . The concentration of serum potassium was high , and normal sinus rhythm was restored after correction of the serum potassium level . The cause of hyperkalemia was considered to be several doses of spiranolactone , an aldosterone antagonist , in addition to the long - term intake of ramipril , an ACE inhibitor . This case is a good example of electrolyte imbalance causing acute life - threatening cardiac events . Clinicians should be alert to the possibility of hyperkalemia , especially in elderly patients using ACE / ARB in combination with potassium sparing agents and who have mild renal disturbance .

Syncope

hyperkalemia

myocardial infarction

loss of consciousness

bradycardia

hyperkalemia

hyperkalemia

hyperkalemia

renal disturbance

angiotensin - converting enzyme inhibitor

spironolactone

potassium

potassium

spiranolactone

aldosterone

ramipril

ARB

potassium

woman

patients

ACE

ACE

ARB

renal disturbance

ARB

hyperkalemia

ARB

hyperkalemia

ARB

hyperkalemia

ARB

hyperkalemia

potassium

renal disturbance

potassium

renal disturbance

potassium

renal disturbance

ACE

renal disturbance

ACE

renal disturbance

ACE

hyperkalemia

ACE

hyperkalemia

ACE

hyperkalemia

ACE

hyperkalemia

ACE

hyperkalemia

ACE

hyperkalemia

ACE

hyperkalemia

ACE

hyperkalemia

ARB

potassium

ARB

potassium

ARB

potassium

ACE

ARB

ACE

ARB

ACE

potassium

ACE

potassium

ACE

potassium

ACE

potassium

ACE

potassium

ACE

potassium

angiotensin - converting enzyme inhibitor

spironolactone

angiotensin - converting enzyme inhibitor

spiranolactone

potassium

hyperkalemia

potassium

hyperkalemia

potassium

hyperkalemia

potassium

hyperkalemia

potassium

hyperkalemia

potassium

hyperkalemia

potassium

hyperkalemia

potassium

hyperkalemia

potassium

hyperkalemia

potassium

hyperkalemia

potassium

hyperkalemia

potassium

hyperkalemia

hyperkalemia

ramipril

hyperkalemia

ramipril

hyperkalemia

ramipril

hyperkalemia

ramipril

Syncope

spironolactone

Syncope

spiranolactone

Syncope

angiotensin - converting enzyme inhibitor

aldosterone

spironolactone

aldosterone

spiranolactone

ramipril

ACE

ramipril

ACE

hyperkalemia

spironolactone

hyperkalemia

spiranolactone

hyperkalemia

spironolactone

hyperkalemia

spiranolactone

hyperkalemia

spironolactone

hyperkalemia

spiranolactone

hyperkalemia

spironolactone

hyperkalemia

spiranolactone

hyperkalemia

angiotensin - converting enzyme inhibitor

hyperkalemia

angiotensin - converting enzyme inhibitor

hyperkalemia

angiotensin - converting enzyme inhibitor

hyperkalemia

angiotensin - converting enzyme inhibitor


Input: A first Taiwanese Chinese family of type 2B von Willebrand disease with R1306W mutation . Clinical , laboratory and genetic defect of a Taiwanese family with type 2B von Willebrand disease ( VWD ) were studied . The proband was a 55 - year - old woman who gave birth to two daughters and one son aged 30 , 29 and 27 , respectively . All had abnormal mucocutaneous bleedings since their childhood . In proband , PT , PTT and platelet count were normal ; template bleeding time was 14 min ; VIII : C was 51 % , von Willebrand factor antigen ( VWF : Ag ) , 42 % and von Willerand factor ristocetin - cofactor ( VWF : RCo , 15 % ) ; ristocetin - induced platelet aggregation ( RIPA ) at 0 . 3 and 0 . 6 mg / ml of ristocetin was 16 % and 68 % , respectively . The enhanced response to ristocetin was identified to be in plasma , not in platelet itself , by mixing studies . Analysis of von Willebrand factor ( VWF ) multimer of plasma but not of platelets showed absence of high - molecular weight ( HMW ) multimer . All three children had similar laboratory findings . Exon 28 of VWF gene was amplified using polymerase chain reaction ( PCR ) and sequenced . The proband and three children were all found to be heterozygous for C to T transition at nucleotide 3916 resulting in Arg 1306 Trp ( R1306W ) substitution . This mutation in the glycoprotein Ib ( GPIb ) - binding site has been found to increase the affinity of plasma VWF for platelets , and thus cause loss of HMW multimers and often thrombocytopenia . In conclusion , a first report of type 2B VWD in a Taiwanese Chinese family who show R1306W mutation in VWF gene was described .

type 2B von Willebrand disease

genetic defect

type 2B von Willebrand disease

VWD

bleedings

bleeding

ristocetin - induced platelet aggregation

RIPA

thrombocytopenia

type 2B VWD

C to T transition at nucleotide 3916

Arg 1306 Trp

woman

VIII

von Willebrand factor

VWF

von Willerand factor

VWF

von Willebrand factor

VWF

VWF

glycoprotein Ib

GPIb

VWF

VWF

ristocetin

ristocetin

ristocetin

type 2B von Willebrand disease

type 2B von Willebrand disease

C to T transition at nucleotide 3916

type 2B von Willebrand disease

Arg 1306 Trp

type 2B von Willebrand disease

type 2B von Willebrand disease

type 2B von Willebrand disease

type 2B von Willebrand disease

C to T transition at nucleotide 3916

type 2B von Willebrand disease

Arg 1306 Trp

type 2B von Willebrand disease

type 2B von Willebrand disease

type 2B VWD

type 2B VWD

C to T transition at nucleotide 3916

type 2B VWD

Arg 1306 Trp

type 2B VWD

type 2B VWD

type 2B von Willebrand disease

von Willebrand factor

type 2B von Willebrand disease

VWF

type 2B von Willebrand disease

von Willerand factor

type 2B von Willebrand disease

VWF

type 2B von Willebrand disease

von Willebrand factor

type 2B von Willebrand disease

VWF

type 2B von Willebrand disease

VWF

type 2B von Willebrand disease

VWF

type 2B von Willebrand disease

VWF

type 2B von Willebrand disease

von Willebrand factor

type 2B von Willebrand disease

VWF

type 2B von Willebrand disease

von Willerand factor

type 2B von Willebrand disease

VWF

type 2B von Willebrand disease

von Willebrand factor

type 2B von Willebrand disease

VWF

type 2B von Willebrand disease

VWF

type 2B von Willebrand disease

VWF

type 2B von Willebrand disease

VWF

type 2B VWD

von Willebrand factor

type 2B VWD

VWF

type 2B VWD

von Willerand factor

type 2B VWD

VWF

type 2B VWD

von Willebrand factor

type 2B VWD

VWF

type 2B VWD

VWF

type 2B VWD

VWF

type 2B VWD

VWF

glycoprotein Ib

thrombocytopenia

GPIb

thrombocytopenia

glycoprotein Ib

von Willebrand factor

glycoprotein Ib

VWF

glycoprotein Ib

von Willerand factor

glycoprotein Ib

VWF

glycoprotein Ib

von Willebrand factor

glycoprotein Ib

VWF

glycoprotein Ib

VWF

glycoprotein Ib

VWF

glycoprotein Ib

VWF

GPIb

von Willebrand factor

GPIb

VWF

GPIb

von Willerand factor

GPIb

VWF

GPIb

von Willebrand factor

GPIb

VWF

GPIb

VWF

GPIb

VWF

GPIb

VWF

von Willebrand factor

thrombocytopenia

VWF

thrombocytopenia

von Willerand factor

thrombocytopenia

VWF

thrombocytopenia

von Willebrand factor

thrombocytopenia

VWF

thrombocytopenia

VWF

thrombocytopenia

VWF

thrombocytopenia

VWF

thrombocytopenia

von Willebrand factor

ristocetin

von Willebrand factor

ristocetin

von Willebrand factor

ristocetin

VWF

ristocetin

VWF

ristocetin

VWF

ristocetin

von Willerand factor

ristocetin

von Willerand factor

ristocetin

von Willerand factor

ristocetin

VWF

ristocetin

VWF

ristocetin

VWF

ristocetin

von Willebrand factor

ristocetin

von Willebrand factor

ristocetin

von Willebrand factor

ristocetin

VWF

ristocetin

VWF

ristocetin

VWF

ristocetin

VWF

ristocetin

VWF

ristocetin

VWF

ristocetin

VWF

ristocetin

VWF

ristocetin

VWF

ristocetin

VWF

ristocetin

VWF

ristocetin

VWF

ristocetin

thrombocytopenia

C to T transition at nucleotide 3916

thrombocytopenia

Arg 1306 Trp

thrombocytopenia

thrombocytopenia

thrombocytopenia

ristocetin - induced platelet aggregation

ristocetin

ristocetin - induced platelet aggregation

ristocetin

ristocetin - induced platelet aggregation

ristocetin

RIPA

ristocetin

RIPA

ristocetin

RIPA

ristocetin


Input: Identification of PVT1 as a candidate gene for end - stage renal disease in type 2 diabetes using a pooling - based genome - wide single nucleotide polymorphism association study . To identify genetic variants contributing to end - stage renal disease ( ESRD ) in type 2 diabetes , we performed a genome - wide analysis of 115 , 352 single nucleotide polymorphisms ( SNPs ) in pools of 105 unrelated case subjects with ESRD and 102 unrelated control subjects who have had type 2 diabetes for > or = 10 years without macroalbuminuria . Using a sliding window statistic of ranked SNPs , we identified a 200 - kb region on 8q24 harboring three SNPs showing substantial differences in allelic frequency between case and control pools . These SNPs were genotyped in individuals comprising each pool , and strong evidence for association was found with rs2720709 ( P = 0 . 000021 ; odds ratio 2 . 57 [ 95 % CI 1 . 66 - 3 . 96 ] ) , which is located in the plasmacytoma variant translocation gene PVT1 . We sequenced all exons , exon - intron boundaries , and the promoter of PVT1 and identified 47 variants , 11 of which represented nonredundant markers with minor allele frequency > or = 0 . 05 . We subsequently genotyped these 11 variants and an additional 87 SNPs identified through public databases in 319 - kb flanking rs2720709 ( approximately 1 SNP / 3 . 5 kb ) ; 23 markers were associated with ESRD at P < 0 . 01 . The strongest evidence for association was found for rs2648875 ( P = 0 . 0000018 ; 2 . 97 [ 1 . 90 - 4 . 65 ] ) , which maps to intron 8 of PVT1 . Together , these results suggest that PVT1 may contribute to ESRD susceptibility in diabetes .

end - stage renal disease

type 2 diabetes

end - stage renal disease

ESRD

type 2 diabetes

ESRD

type 2 diabetes

ESRD

ESRD

diabetes

end - stage renal disease

end - stage renal disease

ESRD

ESRD

ESRD

ESRD

end - stage renal disease

end - stage renal disease

ESRD

ESRD

ESRD

ESRD

end - stage renal disease

end - stage renal disease

ESRD

ESRD

ESRD

ESRD

type 2 diabetes

type 2 diabetes

type 2 diabetes

type 2 diabetes

type 2 diabetes

type 2 diabetes

type 2 diabetes

type 2 diabetes

type 2 diabetes

diabetes

diabetes

diabetes

diabetes

diabetes

type 2 diabetes

type 2 diabetes

type 2 diabetes

type 2 diabetes

type 2 diabetes

type 2 diabetes

type 2 diabetes

type 2 diabetes

type 2 diabetes

type 2 diabetes

type 2 diabetes

type 2 diabetes

type 2 diabetes

type 2 diabetes

type 2 diabetes

end - stage renal disease

end - stage renal disease

ESRD

ESRD

ESRD

ESRD

end - stage renal disease

end - stage renal disease

ESRD

ESRD

ESRD

ESRD

end - stage renal disease

end - stage renal disease

ESRD

ESRD

ESRD

ESRD

end - stage renal disease

end - stage renal disease

ESRD

ESRD

ESRD

ESRD

end - stage renal disease

end - stage renal disease

ESRD

ESRD

ESRD

ESRD