Nonbacterial thrombotic endocarditis clinically mimicking veno-occlusive disease of the liver complicating autologous bone marrow transplantation.

Nonbacterial thrombotic endocarditis is an uncommon, but well-described, complication of bone marrow transplantation. We describe a case of nonbacterial thrombotic endocarditis following autologous bone marrow transplantation that was marked by weight gain, hepatomegaly, ascites, and extreme hyperbilirubinemia leading to a clinical diagnosis of hepatic veno-occlusive disease. Autopsy revealed nonbacterial thrombotic endocarditis of the tricuspid and pulmonic valves, and passive congestion of the liver, but there was no evidence of veno-occlusive disease. We discuss the pathophysiology and clinical features of nonbacterial thrombotic endocarditis and review its occurrence in association with bone marrow transplantation. Nonbacterial thrombotic endocarditis is often difficult to detect clinically and should be a diagnostic consideration in patients who develop systemic emboli or congestive heart failure after bone marrow transplantation.     

Extremely complex repeat shuffling during germline mutation at human minisatellite B6.7

Human minisatellite B6.7 is a highly variable locus showing extensive heterozygosity with alleles ranging from six to >500 repeat units. Paternal and maternal mutation rates to new length alleles were estimated from pedigrees at 7.0 and 3.9% per gamete, respectively, indicating that B6.7 is one of the most unstable minisatellites isolated to date. Mutation at this locus was also analysed by small pool PCR of sperm and blood DNA. Male germline instability varied from <0.8 to 14% per allele and increased with tandem array size. In contrast, the frequency of mutants in somatic (blood) DNA was far lower (<0.5%), consistent with a meiotic origin of germline mutants. Sperm mutants were further characterized by minisatellite variant repeat mapping using four major polymorphic sites within the B6.7 repeats. This highly informative system revealed a wide variety of changes in allele structure, including simple intra-allelic duplications and deletions and more complicated inter- and intra-allelic transfers of repeat blocks, as seen at other human minisatellites. The main mode of sperm mutation, however, resulted in extremely complex allele reorganization with evidence of inter-allelic transfer plus the generation of novel repeats by rearrangement at the sub-repeat level, suggesting that recombinational instability at B6.7 is a complex multistep process.     

Somatic mutation processes at a human minisatellite

Germline instability at human minisatellites frequently involves complex inter-allelic transfers of repeat units usually restricted to one end of the repeat array and apparently regulated by flanking DNA. In contrast, nothing is known about the structural basis of somatic instability at minisatellites. An electrophoretic size-enrichment strategy was therefore developed at minisatellite MS32 (D1S8) to enable rare abnormal-length mutants to be detected, validated and quantitated in blood DNA by single molecule PCR. Structural analysis of rare mutant alleles in blood revealed simple deletions/duplications of repeat unit blocks located at random along the tandem repeat array, a mode of mutation completely different from that seen in sperm. Furthermore, allele-specific suppression of sperm instability at MS32 did not affect somatic instability. These data suggest that conversion-based minisatellite mutation in sperm is completely germline-specific and most likely meiotic in origin. Somatic instability appears to occur by a separate pathway involving replication slippage or, more likely, intra-allelic unequal crossing over.      

Increased mucosal inflammatory cytokines in children with Helicobacter pylori-associated gastritis

The concentrations of tumour necrosis factor-alpha (TNF-α), interleukin-6 (IL-6) and IL-1-β in tissue homogenates of gastric mucosal biopsy specimens, and in gastric juice samples from Helicobacter pylori-positive and -negative children, were determined. The study population comprised 30 children with recurrent abdominal pain attending upper gastrointestinal endoscopy. Of these patients 18 were infected with H. pylori. Cytokine concentrations in gastric biopsy homogenate supernatants and in gastric juice were measured by enzyme-linked immunosorbent assay (ELISA). TNF-α levels in gastric juice and in gastric biopsy homogenate supernatants in patients with H. pylori-positive gastritis were found to be significantly higher than those in children without H. pylori infection. IL-6 levels were also higher in H. pylori -infected subjects, but the difference in IL-6 concentrations measured in gastric juice and biopsy homogenate supernatants did not reach statistical significance. IL-1-β concentrations in both specimens showed no significant difference between the two groups of children. It was suggested that increased levels of inflammatory cytokines, especially TNF-α and IL-6 generated locally within the gastric mucosa might be implicated in the pathogenesis of H. pylori-associated gastritis in childhood.     

Demographic and Clinical Factors Associated With Nonsurgical Osteoarthritis Treatment Among Patients in Outpatient Clinics

Objective

To identify patient demographic and clinical characteristics associated with osteoarthritis (OA) treatment use.

Methods

This was a secondary data analysis of 3 clinical trials among patients with hip or knee OA conducted in Duke Primary Care practices, the Durham Veterans Affairs (VA) Health Care System, and the University of North Carolina–Chapel Hill (UNC). At baseline, participants reported sociodemographic characteristics, OA‐related pain and function, and OA treatment use, including oral analgesics, topical creams, joint injections, and physical therapy. Separate, multivariable logistic models (adjusted for clustering of clinics and providers for the Duke and VA cohorts) were used to estimate odds ratios (ORs) and 95% confidence intervals (95% CIs) for the associations between participant characteristics and each type of OA treatment.

Results

Oral analgesic use was reported by 70–82% of participants across the 3 cohorts. Physical therapy, knee injections, and topical creams were used by 39–52%, 55–60%, and 25–39% of Duke, VA, and UNC participants, respectively. In multivariable models, worse pain, stiffness, and function, per 5‐unit increase, were associated with greater odds of using any oral analgesic for the cohorts from Duke (OR 1.18 [95% CI 1.08–1.28]) and UNC (OR 1.14 [95% CI 1.05–1.24]), but not for the VA cohort (OR 1.04 [95% CI 0.95–1.14]). For all 3 cohorts, nonwhites had higher odds of using topical creams compared to whites.

Conclusion

Results suggest potential underutilization of therapies other than oral analgesics. Patient characteristics may affect OA treatment use, and understanding the relationship between these factors and OA treatment preferences may improve adherence to OA treatment guidelines.     

Human monoclonal thyroid stimulating autoantibody

A monoclonal autoantibody (MAb) with powerful thyroid stimulating activity has been produced from lymphocytes from a patient with Graves' disease. The autoantibody and its Fab fragment bind to the thyroid stimulating hormone (TSH) receptor (TSHR) with high affinity, inhibit labelled TSH binding to the receptor and stimulate cyclic AMP production in Chinese hamster ovary cells transfected with TSHR. TSHR autoantibodies with TSH agonist or antagonist activities from patients' serum samples are effective inhibitors of labelled monoclonal autoantibody binding to TSHR. Thus, the human monoclonal autoantibody has all the characteristics of serum TSHR autoantibodies. Its availability has important implications for new studies on the pathogenesis of Graves' disease.