Background] Since most genes are expressed in more than one tissue and engaged in many functions, some genetic variant could be associated with unpredicted diseases with or without interactions with other genetic variants or environmental factors.Recently Pembrey and Jones proposed a new method, 'phenome scan' (analogous to 'genome-wide scan', but in an opposite direction), in which dense phenotypic information in human cohorts is scanned for associations with individual genetic variants.We attempted to apply this method to our comprehensive clinicopathological database derived from large numbers of autopsy cases.[Subjects] The subjects of this database derived from more than 2,000 consecutive autopsies from the patients died in a community-based geriatric general hospital during recent 12 years.Most of the cases were registered in a SNP database named 'A Database of Japanese Single Nucleotide Polymorphism for Geriatric Research (JG-SNP)' and freely accessible on the Internet at http://www.tmgh.metro.tokyo.jp/jg-snp/english/E_top.html.[Results] The average age of the patients was 80 years and male to female ratio was 1.2.The autopsy rate has declined from 46 to 21% during this period.The database contained patient information, histories of smoking and drinking, clinical diagnosis including 26 geriatric diseases, serum lipid data, 750 pathological findings, 42 major pathological diagnoses, atherosclerotic degrees of 10 major arteries, emphysematous degrees, and so on.Twenty-six geriatric diseases included 6 cardiovascular diseases, 3 neurological diseases, 5 metabolic and skeletal disease, 3 respiratory diseases, 4 malignancies and so on.Forty-two major pathological diagnoses included an extended and partially overlapping list of geriatric diseases.Both clinical and subclinical findings were registered among 750 pathological findings.DNA was extracted from unfixed renal tissue in all cases and used for 123
Nerve growth factor (NGF) has been implicated as an effector of inflammatory pain because it sensitizes primary afferents to noxious thermal, mechanical, and chemical [e.g., capsaicin, a transient receptor potential vanilloid receptor 1 (TRPV1) agonist] stimuli and because NGF levels increase during inflammation. Here, we report the ability of glial cell line-derived neurotrophic factor (GDNF) family members artemin, neurturin and GDNF to potentiate TRPV1 signaling and to induce behavioral hyperalgesia. Analysis of capsaicin-evoked Ca2+ transients in dissociated mouse dorsal root ganglion (DRG) neurons revealed that a 7 min exposure to GDNF, neurturin, or artemin potentiated TRPV1 function at doses 10–100 times lower than NGF. Moreover, GDNF family members induced capsaicin responses in a subset of neurons that were previously insensitive to capsaicin. Using reverse transcriptase-PCR, we found that artemin mRNA was profoundly upregulated in response to inflammation induced by hindpaw injection of complete Freund's adjuvant (CFA): artemin expression increased 10-fold 1 d after CFA injection, whereas NGF expression doubled by day 7. No increase was seen in neurturin or GDNF. A corresponding increase in mRNA for the artemin coreceptor GFRα3 (for GDNF family receptor α) was seen in DRG, and GFRα3 immunoreactivity was widely colocalized with TRPV1 in epidermal afferents. Finally, hindpaw injection of artemin, neurturin, GDNF, or NGF produced acute thermal hyperalgesia that lasted up to 4 h; combined injection of artemin and NGF produced hyperalgesia that lasted for 6 d. These results indicate that GDNF family members regulate the sensitivity of thermal nociceptors and implicate artemin in particular as an important effector in inflammatory hyperalgesia.
Over 20 years ago, Watson described three families with a condition characterised by pulmonary valvular stenosis, café au lait patches, and dull intelligence. Short stature is an additional feature of this autosomal dominant condition. A fourth family with Watson syndrome has since been reported. We have had the opportunity to review members of three of these four families. The clinical phenotype of Watson syndrome has been expanded to include relative macrocephaly and Lisch nodules in the majority of affected subjects, and neurofibromas in one-third of family members. Because the additional clinical findings enhance the similarity between Watson syndrome and neurofibromatosis 1, molecular linkage studies have been performed using probes flanking the NF1 gene on chromosome 17. Probe HHH202 showed the tightest linkage to Watson syndrome with a maximum lod score of 3.59 at phi = 0.0 (95% confidence limits of phi = 0.0-0.15). This suggests either that Watson syndrome and neurofibromatosis 1 are allelic, or that there is a series of contiguous genes for pulmonary stenosis, neurocutaneous anomalies, short stature, and mental retardation on 17q.
Abstract A 10‐year follow‐up of a family with X‐linked cutaneous amyloidosis confirmed no more than streaks or spots of brown pigmentation of the skin in females but much more varied and severe manifestations in males. These included neonatal colitis, infantile diarrhea, recurrent respiratory infections, corneal dystrophy, photophobia, unruly hair with a frontal upsweep, dry skin, and mottled, muddy‐brown pigmentation seen first on the inner thighs and spreading diffusely to the buttocks, trunk, and arms. Amyloid was found in the pigmented skin of adults of both sexes but not in children. An autopsy of a 50‐year‐old man, subject to recurrent pneumonia, confirmed the presence of amyloid in the skin, but it was not found in other organs. Changes in the lungs were those of late‐stage diffuse pulmonary fibrosis. The pattern of inheritance is X‐linked, but the pathogenesis remains obscure.
In 3 families with the fragile-X [fra(X)] syndrome, we have identified a minimum of 4 recombinations in 9 meioses between the syndrome locus and the coagulation Factor IX gene. Two Factor IX intragenic restriction fragment length polymorphisms (RFLPs), produced with TaqI and XmnI, were used as markers. In lod score calculations, incomplete penetrance of the fra(X) mutation in males and females was taken into account by the computer program LIPED. The cumulative maximum lod score calculated from these data and from data previously reported was 2.75 at a recombination frequency of 20% (θ = 0.20). This indicates that the genetic distance between the Factor IX gene and the fra(X) locus is too great for Factor IX probes to be used alone for carrier detection in the fra(X) syndrome. Additional polymorphic loci more tightly linked to the fra(X) syndrome locus are required.
The early clinical histories of 36 patients with phenylketonuria were studied. It was found that more than half the patients had suffered from symptoms of one sort or another in the early weeks of life. These symptoms began months before any sign of mental defect was evident to the parents. The main symptoms found were vomiting (17 patients), irritability (12 patients) and infantile eczema (6 patients). Some patients had more than one symptom. Three children had pyloric stenosis. The findings are discussed. It is suggested that in these patients vomiting and irritability in early life may be due to a "toxic" effect of phenylalanine or its derivatives on the brain. It is recommended that all infants having these symptoms, as well as those with infantile eczema, a peculiar smell, seizures, suspected or actual mental retardation or a retarded (or phenylketonuric) sibling, should be tested for phenylketonuria.
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