Analysis of Xq27-28 linkage in the international consortium for prostate cancer genetics (ICPCG) families

ABSTRACT: BACKGROUND: Genetic variants are likely to contribute to a portion of prostate cancer risk. Full elucidation of the genetic etiology of prostate cancer is difficult because of incomplete penetrance and genetic and phenotypic heterogeneity. Current evidence suggests that genetic linkage to prostate cancer has been found on several chromosomes including the X; however, identification of causative genes has been elusive. METHODS: Parametric and non-parametric linkage analyses were performed using 26 microsatellite markers in each of 11 groups of multiple-case prostate cancer families from the International Consortium for Prostate Cancer Genetics (ICPCG). Meta-analyses of the resultant familyspecific linkage statistics across the entire 1,323 families and in several predefined subsets were then performed. RESULTS: Meta-analyses of linkage statistics resulted in a maximum parametric heterogeneity lod score (HLOD) of 1.28, and an allele-sharing lod score (LOD) of 2.0 in favor of linkage to Xq27- q28 at 138 cM. In subset analyses, families with average age at onset less than 65 years exhibited a maximum HLOD of 1.8 (at 138 cM) versus a maximum regional HLOD of only 0.32 in families with average age at onset of 65 years or older. Surprisingly, the subset of families with only 2-3 affected men and some evidence of male-to-male transmission of prostate cancer gave the strongest evidence of linkage to the region (HLOD = 3.24, 134 cM). For this subset, the HLOD was slightly increased (HLOD = 3.47 at 134 cM) when families used in the original published report of linkage to Xq27-28 were excluded. CONCLUSIONS: Although there was not strong support for linkage to the Xq27-28 region in the complete set of families, the subset of families with earlier age at onset exhibited more evidence of linkage than families with later onset of disease. A subset of families with 2-3 affected individuals and with some evidence of male to male disease transmission showed stronger linkage signals. Our results suggest that the genetic basis for prostate cancer in our families is much more complex than a single susceptibility locus on the X chromosome, and that future explorations of the Xq27-28 region should focus on the subset of families identified here with the strongest evidence of linkage to this region.     

Safety and efficacy of alemtuzumab in the treatment of late acute renal allograft rejection

Safety and efficacy of alemtuzumab in the treatment of AR in children after renal transplantation is unknown. Five episodes of refractory late AR in three children (three episodes in patient 1 and a single episode in patients 2 and 3 occurring after 7-23 months of transplantation) were treated with one dose of alemtuzumab as a rescue therapy. Four episodes (Banff IA-IB) in patients 1 and 2 reversed fully or partially with alemtuzumab, whereas patient 3 with Banff IB-IIA AR failed to respond. Patient 1 had recurrent AR 5, 13, and 15 months later; first two episodes responded to retreatment with alemtuzumab, and the last episode was not treated causing allograft failure. Patient 2 had steroid-responsive AR after two months and had a functioning allograft 25 months later. A transient reduction in all lymphocyte subsets except natural killer cells occurred in all patients. Patient 3 (treated with steroids, Thymoglobulin(R) , intravenous immunoglobulin, and rituximab prior to alemtuzumab) suffered many bacterial infections during one-yr period after therapy. However, symptomatic viral infections were not observed in any of the children. Treatment with alemtuzumab may prolong allograft survival in multidrug-resistant AR but may not prevent recurrent AR in non-adherent children.     

Ofatumumab for a rituximab-allergic child with chronic-relapsing paraneoplastic opsoclonus-myoclonus

Ofatumumab is a fully human anti‐CD20 monoclonal antibody in phase II–III trials for various autoimmune and lymphoreticular diseases. We used it to treat a rituximab‐allergic child with severe, chronic‐relapsing, opsoclonus–myoclonus syndrome (OMS), characterized by persistent cerebrospinal fluid (CSF) B‐cell expansion and T‐cell dysregulation. He had relapsed despite chemotherapy, plasma exchange with immunoadsorption, and resection of ganglioneuroblastoma, detected 3 years after OMS onset. The four ofatumumab infusions (1,195 mg/m² total dose) were well tolerated, and CSF B‐cell expansion was eliminated. No further relapses have occurred in 3 years, but he remains on low‐dose ACTH with neuropsychiatric residuals of OMS. Pediatr Blood Cancer 2012; 58: 988–991. © 2011 Wiley Periodicals, Inc.     

The Chymase Mouse Mast Cell Protease 4 Degrades TNF, Limits Inflammation, and Promotes Survival in a Model of Sepsis

Mouse mast cell protease 4 (mMCP-4), the mouse counterpart of human mast cell chymase, is thought to have proinflammatory effects in innate or adaptive immune responses associated with mast cell activation. However, human chymase can degrade the proinflammatory cytokine TNF, a mediator that can be produced by mast cells and many other cell types. We found that mMCP-4 can reduce levels of mouse mast cell-derived TNF in vitro through degradation of transmembrane and soluble TNF. We assessed the effects of interactions between mMCP-4 and TNF in vivo by analyzing the features of a classic model of polymicrobial sepsis, cecal ligation and puncture (CLP), in C57BL/6J-mMCP-4-deficient mice versus C57BL/6J wild-type mice, and in C57BL/6J-Kit(W-sh/W-sh) mice containing adoptively transferred mast cells that were either wild type or lacked mMCP-4, TNF, or both mediators. The mMCP-4-deficient mice exhibited increased levels of intraperitoneal TNF, higher numbers of peritoneal neutrophils, and increased acute kidney injury after CLP, and also had significantly higher mortality after this procedure. Our findings support the conclusion that mMCP-4 can enhance survival after CLP at least in part by limiting detrimental effects of TNF, and suggest that mast cell chymase may represent an important negative regulator of TNF in vivo.     

Hepatitis B virus subgenotype A1 predominates in liver disease patients from Kerala,India

AIM:To molecularly characterize hepatitis B virus(HBV)isolates from Kerala and to relate them to the clinical manifestation of infection.METHODS:Sera and clinical data were collected from91 patients diagnosed with chronic HBV infection and HBV-related hepatocellular carcinoma(HCC).HBV from44 HCC,22 cirrhotic and 25 chronic hepatitis patients were genotyped by sequencing of the complete S region or by restriction fragment length polymorphism assays.The basic core promoter/precore region was sequenced.The complete surface DNA sequences were assembled and aligned manually,and then compared with the sequences of HBV of genotypes(A-J)from GenBank.The evolutionary history was inferred using the Neighbor-Joining method and the evolutionary distances computed using the Kimura 2-parameter method.Bootstrapping was performed using 1000 replicates.The TaqMan BS-1 probe was used to quantify HBV DNA at a lower detection limit of approximately20 IU/mL.Continuous variables were compared using an independent Student’s t test.Theχ2test or Fisher’s exact test was used to compare categorical variables.The differences were considered statistically significant at P<0.05.RESULTS:Irrespective of disease status,the predominant genotype was A(72%);95%belonging to subgenotype A1,followed by genotypes D(27%)and C(1%).HCC patients infected with subgenotype A1were significantly younger than those infected with D.Mutation A1762T/G1764A was significantly associated with HCC in both genotypes A and D.Mutation G1862T was more frequent in subgenotype A1(P<0.0001),and in combination with A1762T/G1764A,it was significantly associated with HBV from HCC patients.Mutation C1766T/T1768A was significantly associated with genotype A(P=0.05)and HCC(P=0.03).The preS2start codon M1T/I mutation was unique to genotype A strains(15.6%)from all disease groups and occurred at a higher frequency in isolates from HCC patients(P=0.076).A higher frequency of preS deletion mutants(33.3%)was observed in genotype A from HCC compared with non-HCC patients,but     

46XY girls: the importance of careful newborn examination

Study ObjectiveTo understand the timing and factors affecting diagnosis of phenotypically female 46XY children.Design, Setting, and ParticipantsWe studied all phenotypically female 46XY children who attended our multidisciplinary disorders of sexual differentiation (DSD) clinic in Nottingham England in a 3-year period since its inception. Case notes from a prospectively maintained database were reviewed and data were analyzed on the age at presentation, family history, findings on genital examination, and underlying endocrine abnormality.ResultsEleven children were studied, all of whom were being raised as girls. The median age of presentation was 18 months (range birth-15 years). Although the newborn examination detected the possibility of DSD in only 3 cases; 10 of 11 children had at least one significant abnormality in their external genitalia at presentation.ConclusionCareful neonatal genital examination can identify children with DSD. However, not all children with these conditions are identified early. Early diagnosis, when possible, is important, as it has the potential to make the management of this difficult condition more straightforward.     

Normal and delayed wound healing is improved by sesamol, an active constituent of Sesamum indicum (L.) in albino rats

Ethno-pharmacological relevance

The seeds of Sesamum indicum Linn. (Pedaliaceae) has been used traditionally for the treatment of wounds in Buldhana district of Maharashtra state. Sesamol is the main anti-oxidative constituent contained mainly in the processed sesame seed oil which has not been explored scientifically for its wound healing activity.

Aim of the study

To investigate the influence of sesamol (SM) on wound repair, both in normal and dexamethasone (DM) delayed healing processes in albino rats.

Materials and methods

Incision, excision and dead space wounds were inflicted on albino rats (180-220 g) of either sex, under ketamine anaesthesia. Group I served as control, group II received SM 50 mg/kg i.p., group III was treated with dexamethasone (DM) i.m. (0.17 mg/kg) and SM + DM was given to group IV. The tensile strength, wound contraction, hydroxyproline, lysyl oxidase and total RNA and DNA levels (in granulation tissue) were measured.

Results

The tensile strength significantly (p < 0.05) increased with SM at 471.40 ± 14.66 g when compared to control at 300.60 ± 9.16 g in normal and DM suppressed healing. No significant change was observed in duration of wound contraction and lysyl oxidase when compared to control at 2.98 ± 0.10 mg. SM treated rats showed a significant (p < 0.05) rise in hydroxyproline levels at 6.45 ± 0.45 mg when compared to control at 1.75 ± 0.20 mg.

Conclusion

These results indicate that sesamol could be a promising drug in normal as well as delayed wound healing processes.