Linkage heterogeneity of end-stage renal disease on human chromosome 10

BACKGROUND: The human syntenic region of the rodent renal failure-1 gene (Rf1), an attractive candidate region for end-stage renal disease (ESRD) susceptibility, is located on chromosome 10q24-q26. In an attempt to assess for linkage between markers on human chromosome 10 and ESRD, we performed a linkage analysis in 356 African American sib pairs concordant for ESRD [199 sib pairs concordant for non-diabetic etiologies (hypertension-associated, chronic glomerulonephritis and unknown) and 157 sib pairs concordant for diabetic ESRD]. METHODS: Linkage was tested between 30 polymorphic markers spanning chromosome 10 and ESRD using GeneHunter software. RESULTS: In all 356 sib pairs, the maximum likelihood ratio z-score (Zlr) occurred near locus D10S677 (Zlr = 3.33, P = 0.0004, lod = 3.40), with a lesser peak near D10S1435 (Zlr = 1.77, P = 0.04, lod = 1.42). The locus at D10S677 contributed significantly to both diabetic ESRD (Zlr = 2.39, P = 0.008, lod = 2.08) and non-diabetic ESRD (Zlr = 2.35, P = 0.009, lod = 2.03). Additionally, the D10S677 peak was observed in both early onset (< or =50 years) and late onset (>50 years) ESRD (Zlr = 2.96, P = 0.002, lod = 2.82 in early onset and Zlr = 1.96, P = 0.03, lod = 1.60 in late onset ESRD families, respectively). The lesser peak at D10S1435 was observed in families with non-diabetic etiologies of ESRD (Zlr = 1.94, P = 0.02, lod = 1.58) and in those with early onset ESRD (Zlr = 1.89, P = 0.03, lod = 1.53). CONCLUSIONS: These results suggest that the region near D10S677, adjacent to the human homolog of the Rf1 gene, contributes to ESRD susceptibility in African Americans. They confirm that the region on 10p, near D10S1435, appears to be involved in early onset, non-diabetic etiologies of ESRD in African Americans.     

Microbicides--evaluating multiple formulations of C31G

The purpose of the study was to evaluate semen quality in young Chinese men and to establish reference values. Normal healthy young men from seven geographical areas were enrolled. The study showed that the mean sperm volume was 2.61 mL, and mean percent of sperm with forward progression was 59.89, while median of semen viability was 79.0%, and geometric mean of semen density was 55.45 x 10(6)/mL. Proportion of routine semen indexes that met World Health Organization (WHO) criteria were as follows: 81.9% for semen volume, 91.1% for liquefaction time, 93.4% for viscosity, 90.8% for pH, 81.3% for sperm with forward progression, 65.3% for sperm viability, 93.8% for semen density, 98.8% for normal sperm morphology, and 89.1% for total sperm count. Participants whose sperm met all WHO standard parameters accounted for 42.3%. Because the infertility rate in China is about 10-15%, the fifteenth percentile of semen parameters might be used as the lower limit of reference values, which may be more appropriate for young Chinese men. The fifteenth percentiles of parameters in this study were as follows: 1.5 mL for semen volume, 7.2 for pH value, 45% for proportion of sperm with forward progression, 68% for sperm viability, 30 x 10(6)/mL for semen density, 68% for proportion of sperm with normal morphology, and 50 x 10(6) for total sperm count.     

The role of PI 3-kinase in the UVB-induced expression of c-fos

The role of the PI 3-kinase signaling pathway in UVB-induced c-fos gene expression was investigated in a human keratinocyte cell line, HaCaT. The enzymatic activity of PI 3-kinase was increased threefold by 250 J/m(2) UVB. Inhibition of PI 3-kinase activity, via expression of a mutant p85 subunit or treatment with wortmannin, resulted in decreased levels of c-fos promoter activity and c-fos protein. Two members of the PI 3-kinase signaling pathway, Akt and GSK-3beta, were also found to affect c-fos transactivation. Expression of dominant negative Akt or wild-type GSK-3beta significantly inhibited UVB-induced c-fos promoter activity. In addition, when GSK-3beta activity was inhibited by lithium chloride, both c-fos promoter activity and protein levels increased. These results demonstrate that both Akt activation and GSK-3beta inactivation are required in the UVB-induction of c-fos. Our results demonstrate for the first time that UVB induction of c-fos is in part mediated by the PI 3-kinase signaling pathway in the HaCaT cell line. By identifying the multiple signaling pathways that are induced by UVB and contribute to the induction of c-fos expression, more drug targets may be identified to aid attempts to prevent and treat skin cancer.     

JunB negatively regulates AP-1 activity and cell proliferation of malignant mouse keratinocytes

OBJECTIVE: Previously we have shown that a malignant mouse keratinocyte cell line, 10Gy5, has elevated AP-1 transactivation and reduced JunB protein levels compared to its parental benign cell line, 308, and that the tumorigenicity in the 10Gy5 cells could be blocked by a dominant negative c-Jun mutant protein. We wished to determine whether the change in JunB protein levels could account for the elevated AP-1 activity and whether re-expression of JunB in malignant 10Gy5 cells altered their proliferative capacity. DESIGN: In the current study, we reduced JunB expression in benign 308 cells with antisense oligonucleotides and increased JunB expression in malignant 10Gy5 cells by stable transfection of a JunB expression vector. RESULTS: Increased AP-1 activity was detected after treatment of the benign 308 cell line with JunB antisense oligonucleotides that reduced JunB protein levels. Stably JunB-transfected clones of malignant 10Gy5 cells showed decreased AP-1 activity, slowed in vitro cell proliferation and reduced tumor growth when xenografted to athymic nude mice. CONCLUSION: These findings suggest that expression of JunB protein has a negative effect on malignant tumor cell proliferation in part through its ability to inhibit AP-1 transactivation.     

Homocysteine and vascular access thrombosis in end-stage renal disease patients: a retrospective study

BACKGROUND: Though pathology in end-stage renal disease (ESRD) patients with high total homocysteine (tHcy) can be established, the research findings with vascular access thrombosis (VAT) and tHcy are equivocal. Investigators have found significantly higher homocysteine levels in patients with recurrent VAT compared with one or less episodes of thrombosis. Initial prospective evidence supports an independent association between tHcy levels and access thrombosis. METHODS: One hundred and four patients undergoing dialysis were selected. The experimental group participants were identified as those having one or more vascular access thromboses (VAT) during the previous 14-month period (November 2000 to January 2002) and the control group participants were those with no VAT during the same period. Additional sub-group analyses included the following: a) hypertensive vs. normotensive; b) diabetes mellitus, Type I, Type II, and none; c) gender; d) age. RESULTS: The Mann-Whitney U test for variance revealed no significant difference in tHcy values between VAT groups (U = 1580.5, p = 0.075), no significant differences in VAT and hypertension (U = 1009.0, p = 0.70), and no significant differences in VAT and Diabetes Mellitus (U = 1254.5, p = 0.67). A two-sample t-Test revealed no significant differences in tHcy and age (F-ratio = 1.26, p = 0.47). A Kolmogorov Smirnov test for normality revealed insufficient evidence that the tHcy distribution is not normal. Spearman Rank Correlations were calculated revealing low to moderate associations among variables. CONCLUSIONS: While some studies have demonstrated a relationship between tHcy and VAT, this study found chronically high homocysteine levels in patients with ESRD were not associated with incidence of VAT. There were no significant differences in the number of VAT's across additional variables of age, gender, and previous morbidity. No significant interactions were discovered.     

Infectious diseases. 6: Sexually transmitted infections: new diagnostic approaches and treatments

1. Commercially available nucleic acid amplification assays (eg, polymerase or ligase chain reaction) are now the "gold standard" tests for genital chlamydial infection and also have a role in screening for gonococcal infection. 2. Single-dose oral antibiotics are available for treatment of Chlamydia trachomatis, Neisseria gonorrhoeae and Trichomonas vaginalis infections. 3. Strains of N. gonorrhoeae in urban Australia are often penicillin resistant, while strains from South East Asia and those in homosexually active men may show high-level resistance to quinolones. 4. Imiquimod, a novel immune-response modifier, is now available for effective, safe, self-administered treatment of genital warts. 5. The Pap smear remains the cornerstone of screening for precursor lesions of cervical cancer, but human papillomavirus genotyping may have a role in clinical decision-making for women with equivocal or early precancerous lesions. 6. Treatment of primary genital herpes changes the clinical course, and long-term suppressive therapy is effective for those with multiple recurrences. New technologies have made diagnosis and screening easier for patients and clinicians     

Identification and use of biomarkers in Gaucher disease and other lysosomal storage diseases

The value of biomarkers in the clinical management of lysosomal storage diseases is best illustrated by the present use of plasma chitotriosidase levels in the diagnosis and monitoring of Gaucher disease. The enzyme chitotriosidase is specifically produced and secreted by the pathological storage macrophages (Gaucher cells). Plasma chitotriosidase levels are elevated on average 1000-fold in symptomatic patients with Gaucher disease and reflect the body burden on storage cells. Changes in plasma chitotriosidase reflect changes in clinical symptoms. Monitoring of plasma chitotriosidase levels is nowadays commonly used in decision making regarding initiation and optimization of costly therapeutic interventions (enzyme replacement therapy or substrate reduction therapy). A novel substrate has been developed that further facilitates the measurement of chitotriosidase in plasma samples. Moreover, an alternative Gaucher-cell marker, CCL18, has been very recently identified and can also be employed to monitor the disease, particularly in those patients lacking chitotriosidase due to a genetic mutation. There is a need for comparable surrogate markers for other lysosomal storage diseases and the search for such molecules is an area of intense investigation.
Conclusion: The use of biomarkers can provide valuable insight into the molecular pathogenesis of LSDs, such as Gaucher disease and Fabry disease.