Incidence and functional consequences of hMLH1 promoter hypermethylation in colorectal carcinoma

Inactivation of the genes involved in DNA mismatch repair is associated with microsatellite instability (MSI) in colorectal cancer. We report that hypermethylation of the 5′ CpG island of hMLH1 is found in the majority of sporadic primary colorectal cancers with MSI, and that this methylation was often, but not invariably, associated with loss of hMLH1 protein expression. Such methylation also occurred, but was less common, in MSI− tumors, as well as in MSI+ tumors with known mutations of a mismatch repair gene (MMR). No hypermethylation of hMSH2 was found. Hypermethylation of colorectal cancer cell lines with MSI also was frequently observed, and in such cases, reversal of the methylation with 5-aza-2′-deoxycytidine not only resulted in reexpression of hMLH1 protein, but also in restoration of the MMR capacity in MMR-deficient cell lines. Our results suggest that microsatellite instability in sporadic colorectal cancer often results from epigenetic inactivation of hMLH1 in association with DNA methylation.     

Impacts of metformin and aspirin on life history features and longevity of crickets: trade-offs versus cost-free life extension?

We examined the impacts of aspirin and metformin on the life history of the cricket Acheta domesticus (growth rate, maturation time, mature body size, survivorship, and maximal longevity). Both drugs significantly increased survivorship and maximal life span. Maximal longevity was 136 days for controls, 188 days (138 % of controls) for metformin, and 194 days (143 % of controls) for aspirin. Metformin and aspirin in combination extended longevity to a lesser degree (163 days, 120 % of controls). Increases in general survivorship were even more pronounced, with low-dose aspirin yielding mean longevity 234 % of controls (i.e., health span). Metformin strongly reduced growth rates of both genders (<60 % of controls), whereas aspirin only slightly reduced the growth rate of females and slightly increased that of males. Both drugs delayed maturation age relative to controls, but metformin had a much greater impact (>140 % of controls) than aspirin (~118 % of controls). Crickets maturing on low aspirin showed no evidence of a trade-off between maturation mass and life extension. Remarkably, by 100 days of age, aspirin-treated females were significantly larger than controls (largely reflecting egg complement). Unlike the reigning dietary restriction paradigm, low aspirin conformed to a paradigm of “eat more, live longer.” In contrast, metformin-treated females were only ~67 % of the mass of controls. Our results suggest that hormetic agents like metformin may derive significant trade-offs with life extension, whereas health and longevity benefits may be obtained with less cost by agents like aspirin that regulate geroprotective pathways.     

Comparison of graft-versus-host-disease and survival after HLA-identical sibling bone marrow transplantation in ethnic populations

The association of ethnicity with the incidence of graft-versus-host disease (GVHD) and other clinical outcomes after transplantation is controversial. We compared the results of HLA-identical sibling bone marrow transplantations for leukemia, performed between 1990 and 1999, among different ethnic populations, including 562 Japanese, 829 white Americans, 71 African Americans, 195 Scandinavians, and 95 Irish. Results for adults and children were analyzed separately. Multivariate analyses of adult patients showed that white Americans, African Americans, and Irish cohorts were at significantly higher risk for acute GVHD than Japanese or Scandinavian cohorts (relative risk [RR] = 1.77, P < .001; RR = 1.84, P < .006; RR = 2.22, P < .001, respectively). White Americans, African Americans, and Irish, but not Scandinavians, were at significantly higher risk for early (within 3 months of transplantation) transplant-related mortality (TRM) compared with Japanese (RR = 2.99, P < .001; RR = 5.88, P < .001; RR = 2.66, P < .009, respectively). No differences in the risk for chronic GVHD, relapse, and overall survival were noted. In the pediatric cohort (limited to Japanese and white Americans), white Americans were at significantly higher risk for acute (RR = 1.93; P = .04) and chronic (RR = 3.16; P = .002) GVHD. No differences in other clinical outcomes were noted. Our findings suggest that ethnicity may influence the risk for GVHD, though overall survival rates after transplantation remain similar.     

Surgical management of contiguous multilevel thoracolumbar tuberculous spondylitis

Introduction

Tuberculous spondylitis (TBS) is the most common form of extra-pulmonary tuberculosis. The mainstay of TBS management is anti-tuberculous chemotherapy. Most of the patients with TBS are treated conservatively; however in some patients surgery is indicated. Most common indications for surgery include neurological deficit, deformity, instability, large abscesses and necrotic tissue mass or inadequate response to anti-tuberculous chemotherapy. The most common form of TBS involves a single motion segment of spine (two adjoining vertebrae and their intervening disc). Sometimes TBS involves more than two adjoining vertebrae, when it is called multilevel TBS. Indications for correct surgical management of multilevel TBS is not clear from literature.

Materials and methods

We have retrospectively reviewed 87 patients operated in 10 years for multilevel TBS involving the thoracolumbar spine at our spine unit. Two types of surgeries were performed on these patients. In 57 patients, modified Hong Kong operation was performed with radical debridement, strut grafting and anterior instrumentation. In 30 patients this operation was combined with pedicle screw fixation with or without correction of kyphosis by osteotomy. Patients were followed up for correction of kyphosis, improvement in neurological deficit, pain and function. Complications were noted. On long-term follow-up (average 64 months), there was 9.34 % improvement in kyphosis angle in the modified Hong Kong group and 47.58 % improvement in the group with pedicle screw fixation and osteotomy in addition to anterior surgery (p < 0.001). Seven patients had implant failures and revision surgeries in the modified Hong Kong group. Neurological improvement, pain relief and functional outcome were the same in both groups.

Conclusion

We conclude that pedicle screw fixation with or without a correcting osteotomy should be added in all patients with multilevel thoracolumbar tuberculous spondylitis undergoing radical debridement and anterior column reconstruction.

     

Apolipoprotein E genotypes of fertile and infertile men

Lipid components of spermatozoa have an important role in the functional activity of this cell. The protein, apolipoprotein E (apoE), has a central role in lipid transport. The aim of this study was to investigate the distribution of APOE genotypes, ?3?3, ?3?4, and ?2?3, and the corresponding alleles in fertile and infertile males, and to assess the semen parameters from the patients carrying the different alleles. In addition, the levels of cholesterol, phospholipid, and triacylglycerol in spermatozoa, isolated by PureSperm gradient and from seminal plasma in samples from infertile males was compared with respect to the APOE genotype. APOE genotypes were determined by PCR-RFLP on DNA extracted from peripheral blood leucocytes in 108 fertile and 107 infertile men. There was a significant difference between the distribution of APOE genotypes in fertile as compared to infertile males (χ(2)?=?9.1, df?=?2, p?=?0.011). The presence of genotype ?3?4 conferred a 3.82 risk factor for male infertility {Odds ratio?=?3.82 (1.46-10, p?=?0.006)}. Our findings showed that the distribution of APOE genotypes and alleles differed between fertile and infertile individuals and may be a risk factor for male infertility. We suggest that the effects of APOE genotypes may be linked to differences in the efficacy of the expressed apoE isoforms in promoting sperm maturation during epididymal transit.     

Use of the national electronic maternal and child health registry (MCH eRegistry) in primary care clinics in occupied Palestinian territory: a pilot time-motion study

Background

In primary care maternal and child health clinics in occupied Palestinian territory, documentation and reporting consume considerable time for care providers. An electronic maternal and child health registry (MCH eRegistry), with point-of-care clinical decision support, is being implemented nationally in governmental clinics. We conducted a pilot study of time spent by care providers on important tasks, in preparation for a trial to compare eRegistry and non-eRegistry clinics.

Late onset immune pancytopenia following bone marrow transplantation

A 17-year-old boy developed autoimmune pancytopenia in the absence of chronic graft-versus-host disease 170 d after allogeneic bone marrow transplantation (BMT) from his HLA identical brother. The anaemia and thrombocytopenia responded to conventional immunosuppressive treatment, but the neutropenia was refractory to this and to splenectomy and subsequent removal of splenic remnant. Following total lymphoid irradiation the neutrophil count rose to low normal levels but thrombocytopenia and anaemia secondary to marrow hypoplasia required transfusion support. Bone marrow function was finally normalized by an additional transfusion of donor marrow without prior immunosuppressive therapy. We conclude that late onset immune pancytopenia post BMT caused by antibodies of probable donor origin may be life threatening in the absence of chronic graft-versus-host disease.