Bleomycin in the Reticuloses

Bleomycin alone was used in the treatment of 54 patients with Hodgkin''s disease in its later stages, 17 with generalized lymphosarcoma, 22 with reticulum cell sarcoma, and 7 with mycosis fungoides. The patients had had radiotherapy and full courses of conventional chemotherapy. Bleomycin was given in doses of 30 mg weekly to an average total dosage of 200 mg, though up to 800 mg could be given because of its marrow-sparing properties. Sixteen (29%) of the patients with Hodgkin''s disease remitted, most of them achieving only a partial remission, and similar results were obtained in the other three reticuloses. Bleomycin would seem to have some beneficial action in the late stages of Hodgkin''s disease, though it is less effective than some drug regimens recently introduced. Nevertheless it may be useful when there is diminished bone marrow reserve. It would be a suitable drug to use in combination therapy of these four reticuloses.     

Triacylglycerol fatty acid composition in diet-induced weight loss in subjects with abnormal glucose metabolism--the GENOBIN study

Background

The effect of weight loss on different plasma lipid subclasses at the molecular level is unknown. The aim of this study was to examine whether a diet-induced weight reduction result in changes in the extended plasma lipid profiles (lipidome) in subjects with features of metabolic syndrome in a 33-week intervention.

Methodology/Principal Findings

Plasma samples of 9 subjects in the weight reduction group and 10 subjects in the control group were analyzed using mass spectrometry based lipidomic and fatty acid analyses. Body weight decreased in the weight reduction group by 7.8±2.9% (p<0.01). Most of the serum triacylglycerols and phosphatidylcholines were reduced. The decrease in triacylglycerols affected predominantly the saturated short chain fatty acids. This decrease of saturated short chain fatty acid containing triacylglycerols correlated with the increase of insulin sensitivity. However, levels of several longer chain fatty acids, including arachidonic and docosahexanoic acid, were not affected by weight loss. Levels of other lipids known to be associated with obesity such as sphingolipids and lysophosphatidylcholines were not altered by weight reduction.

Conclusions/Significance

Diet-induced weight loss caused significant changes in global lipid profiles in subjects with abnormal glucose metabolism. The observed changes may affect insulin sensitivity and glucose metabolism in these subjects.

Trial Registration

ClinicalTrials.gov {"type":"clinical-trial","attrs":{"text":"NCT00621205","term_id":"NCT00621205"}}NCT00621205     

Negative associations between corpus callosum midsagittal area and IQ in a representative sample of healthy children and adolescents

Documented associations between corpus callosum size and cognitive ability have heretofore been inconsistent potentially owing to differences in sample characteristics, differing methodologies in measuring CC size, or the use of absolute versus relative measures. We investigated the relationship between CC size and intelligence quotient (IQ) in the NIH MRI Study of Normal Brain Development sample, a large cohort of healthy children and adolescents (aged six to 18, n = 198) recruited to be representative of the US population. CC midsagittal area was measured using an automated system that partitioned the CC into 25 subregions. IQ was measured using the Wechsler Abbreviated Scale of Intelligence (WASI). After correcting for total brain volume and age, a significant negative correlation was found between total CC midsagittal area and IQ (r = −0.147; p = 0.040). Post hoc analyses revealed a significant negative correlation in children (age<12) (r = −0.279; p = 0.004) but not in adolescents (age≥12) (r = −0.005; p = 0.962). Partitioning the subjects by gender revealed a negative correlation in males (r = −0.231; p = 0.034) but not in females (r = 0.083; p = 0.389). Results suggest that the association between CC and intelligence is mostly driven by male children. In children, a significant gender difference was observed for FSIQ and PIQ, and in males, a significant age-group difference was observed for FSIQ and PIQ. These findings suggest that the correlation between CC midsagittal area and IQ may be related to age and gender.     

Clinical Significance of IgG Antibody Titer against Helicobacter pylori

Background: We clarified the clinical significance of measurement of IgG antibody titers against Helicobacter pylori using data from a nested case–control study from a large-scale cohort study in Japan.
Method: Participants included 36,745 subjects from the Japan Health Center-based Prospective Study who responded to the baseline questionnaire and provided a blood sample. Subjects were aged 40–69 years and were followed over 15 years after initial sampling. Controls were matched to 511 gastric cancer patients. Plasma surface antigen (Hp)-IgG titer was measured using ELISA, and mucosal atrophy was determined by measuring pepsinogen I and II levels.
Results: Seropositive subjects with low Hp-IgG titer and mucosal atrophy showed a higher risk for gastric cancer than high-titer subjects. Odds ratio (OR) referred to cases with true negative IgG titers and no mucosal atrophy. In moderately atrophic subjects, the low titer OR was 19.0, with a 95% confidence interval (CI) of 7.7–46.9, and 12.5 for high titer, with a 95% CI of 5.2–30.0. In severely atrophic subjects, the low titer OR was almost double that of high-titer subjects (OR = 30.2, 95% CI = 12.4–73.7 and OR = 15.9, 95% CI = 6.3–40.3, respectively). These associations were observed more frequently for differentiated than undifferentiated gastric cancer.
Conclusion: Combination assay with Hp-IgG titer and pepsinogens may help identify groups at high risk for gastric cancer. Subjects with low Hp-IgG titer and mucosal atrophy were at extremely high risk for gastric cancer, particularly differentiated cancer. Subjects with this background may require ongoing observation and periodic endoscopic examination for early cancer detection.     

Excess of de novo deleterious mutations in genes associated with glutamatergic systems in nonsyndromic intellectual disability

Little is known about the genetics of nonsyndromic intellectual disability (NSID). We hypothesized that de novo mutations (DNMs) in synaptic genes explain an important fraction of sporadic NSID cases. In order to investigate this possibility, we sequenced 197 genes encoding glutamate receptors and a large subset of their known interacting proteins in 95 sporadic cases of NSID. We found 11 DNMs, including ten potentially deleterious mutations (three nonsense, two splicing, one frameshift, four missense) and one neutral mutation (silent) in eight different genes. Calculation of point-substitution DNM rates per functional and neutral site showed significant excess of functional DNMs compared to neutral ones. De novo truncating and/or splicing mutations in SYNGAP1, STXBP1, and SHANK3 were found in six patients and are likely to be pathogenic. De novo missense mutations were found in KIF1A, GRIN1, CACNG2, and EPB41L1. Functional studies showed that all these missense mutations affect protein function in cell culture systems, suggesting that they may be pathogenic. Sequencing these four genes in 50 additional sporadic cases of NSID identified a second DNM in GRIN1 (c.1679_1681dup/p.Ser560dup). This mutation also affects protein function, consistent with structural predictions. None of these mutations or any other DNMs were identified in these genes in 285 healthy controls. This study highlights the importance of the glutamate receptor complexes in NSID and further supports the role of DNMs in this disorder.     

Fanconi anemia: contribution of molecular analyses to the identification of bone marrow graft donors and the study of chimerism in grafted patients

We report on the effectiveness of molecular studies regarding Fanconi anemia (FA) for a better selection of bone marrow graft donors and for post-transplant follow up. Ten unrelated FA patients and their families were analyzed by microsatellite markers. In 9 cases, the cytogenetic investigation of potential human leukocyte antigen (HLA)-identical related donors was normal, and the molecular analyses confirmed that they were also either normal or heterozygous carriers. For 1 patient, cytogenetic analysis of an HLA-identical sibling donor yielded ambiguous results with a relatively high number of chromosomal breakages using cross-linking agents. However, genotyping of this potential donor demonstrated his heterozygous state. Nine patients have received allogeneic bone marrow transplantation from HLA-matched related donors. Microsatellite analysis showed complete chimerism (CC) in all cases. The median follow up was 54 months (range 8-144 months). One patient out of 9 with CC rejected her graft without prior detection of a transitional mixed chimerism. Among these patients, 1 died 25 months after the transplantation of a chronic graft-versus-host-disease (GVHD). We conclude that, when the cytogenetic studies are not conclusive, molecular analyses are crucial to distinguish heterozygous carriers from asymptomatic FA Tunisian patients. Molecular analyses also allowed the evaluation of hematopoietic chimerism after allogeneic bone marrow transplantation and might be of value to identify patients with a high risk for graft rejection.