Structure–Function Analysis of Liver Flavin Monooxygenase 3 that Drives Trimethylaminuria in Humans

Proceedings of the National Academy of Sciences, India Section B: Biological Sciences - Mutations in human flavin monooxygenase-3 (hFMO3) enzyme have been implicated in the rare autosomal recessive...     

Lipid abnormalities in coronary heart disease: a population-based case-control study

BACKGROUND: We performed a case-control study to estimate lipid-cholesterol fractions in patients with coronary heart disease and compared them with population-based controls. METHODS AND RESULTS: A total of 635 newly diagnosed patients with coronary heart disease (518 males and 117 females) and 632 subjects (346 males and 286 females) obtained from an ongoing urban coronary heart disease risk factor epidemiological study were evaluated. Age-specific lipid values (total cholesterol, low-density lipoprotein, high-density lipoprotein, triglycerides, and total:high-density lipoprotein cholesterol ratio) were compared using the t-test. Age-adjusted prevalence of dyslipidemia as defined by the US National Cholesterol Education Program was compared using the Chi-square test. In all the age groups, and in both males and females, levels of total and low-density lipoprotein cholesterol were not significantly different. In males, the high-density lipoprotein cholesterol (mg/dl) was significantly lower in patients with coronary heart disease as compared to controls in the age groups 30-39 years (35.1+/-11 v. 43.7+/-9), 40-49 years (39.0+/-10 v. 47.1+/-8), 50-59 years (38.9+/-11 v. 43.8+/-9) and 60-69 years (38.6+/-11, v. 42.8+/-7) (p<0.05). In females, high-density lipoprotein cholesterol was less in the age groups 30-39 years (30.2+/-9 v. 40.7+/-9), 50-59 years (39.7+/-12 v. 44.7+/-8) and 60-69 years (35.6+/-11 v. 42.2+/-9). The level of triglycerides was significantly higher in male patients in the age groups 40-49 years (195.3+/-96 v. 152.8+/-78), 50-59 years (176.7+/-76 v. 162.9+/-97), 60-69 years (175.5+/-93 v. 148.1+/-65) and >70 years (159.8+/-62 v. 100.0+/-22); and in female patients in the age group 30-39 years (170.8+/-20 v. 149.9+/-9) (p<0.05). The total:high-density lipoprotein cholesterol ratio was significantly higher in all age groups in male as well as female patients with coronary heart disease (p<0.05). CONCLUSIONS: An age-adjusted case-control comparison showed that the prevalence of hypertension, diabetes, high total cholesterol (> or =200 mg/dl) (males 48.8% v. 20.2%; females 59.8% v. 33.4%) and high low-density lipoprotein cholesterol (> or =130 mg/dl) (males 42.1% v. 15.0%; females 52.1% v. 31.0%) was significantly more in cases than in controls. The prevalence of low high-density lipoprotein cholesterol (<35 mg/dl) (males 39.6% v. 6.2%; females 39.3% iv 9.5%), high total:high-density lipoprotein ratio (> or = 5.0) and high triglycerides (> or =200 mg/ dl: males 39.6%, v. 10.2%; females 17.1% v. 11.9%) was also significantly higher in cases (p<0.05).     

Thalidomide after allogeneic haematopoietic stem cell transplantation: activity in chronic but not in acute graft-versus-host disease

Thalidomide was used to treat acute (n=21) or chronic (n=59) graft-vs-host disease (GVHD) in 80 haematopoietic stem cell allograft recipients after failure to respond to the combination of cyclosporine and corticosteroids with or without other agents. The median time to onset of acute GVHD was 11 days, and thalidomide was started at a median of 48 days post transplant. In addition to corticosteroids and cyclosporine, 13 patients had also received other agents before thalidomide. None of the patients responded and all died of acute GVHD. For chronic GVHD (limited in 13, extensive in 46), thalidomide was started at a median of 385 days post transplant. In addition to corticosteroids and cyclosporine, 34 patients received azathioprine concomitantly. In all patients, thalidomide was added to the ongoing immunosuppressive regimen. The median duration of therapy with thalidomide was 60 days (range, 11-1210; <2 weeks in 11). In total, 13 patients (22%) had complete response, eight (14%) partial response and 38 (64%) no response. Response rates were comparable for limited (39%) and extensive (33%) chronic GVHD. At a median of 53 months, 19 patients are alive, 13 without evidence of chronic GVHD. Survival was significantly better in patients who responded to thalidomide. The principal causes of death were progressive chronic GVHD (n=29) and relapsed leukaemia (n=7). In conclusion, thalidomide has no activity in acute GVHD, but has some activity in chronic GVHD in combination with other agents.     

Use of total leukocyte and platelet counts to guide stem cell apheresis in healthy allogeneic donors treated with G-CSF

Healthy stem cell donors start leukapheresis 4-5 days after starting G-CSF based on the peripheral blood CD34+ cell count (PBCD34). Data from 137 harvests (68 donors) were analyzed to determine correlation between pre-apheresis leukocytes (11.0-94.8x10(9)/l; median 38.8) and platelets (49-374x10(9)/l; median 180), and PBCD34 (3-276/microl; median 40). PBCD34 correlated positively with leukocytes (r=0.48; P<0.0001) and platelets (r=0.40; P<0.0001). When pre-apheresis leukocytes were >or=25 and platelets were >or=100, PBCD34 and CD34+ collection were 5-276/microl (median 57) and 0.5-27.6x10(6)/kg (median 4.7), respectively; significantly higher than PBCD34 of 3-74/microl (median 17) and CD34+ collection of 0.2-8.9 x 10(6)/kg (median 2.2) when leukocytes were <25 and/or platelets were <100. With leukocytes >or=25 and platelets >or=100, PBCD34 was low (<20/microl) 8% of the time, compared to 57% of the time with leukocytes <25 and/or platelets <100 (P<0.0001). Our data suggest that it is not always necessary to measure PBCD34 to guide leukapheresis in healthy donors because pre-apheresis leukocytes and platelets >or=25 and >or=100, respectively, are associated with excellent mobilization. When blood counts do not meet these criteria, PBCD34 should be determined prior to initiation of apheresis.     

Proton pump inhibitor use and risk for recurrent Clostridioides difficile infection: a systematic review and meta-analysis

ObjectivesProton pump inhibitor (PPI) therapy is a potentially modifiable risk factor for recurrent Clostridioides difficile infection (CDI). Citing an absence of clinical trials, many guidelines do not provide recommendations for addressing PPI management. Our aim was to perform an updated systematic review and meta-analysis evaluating the association between PPI use and recurrent CDI addressing prior methodological limitations.MethodsData sources were MEDLINE and EMBASE. Eligible studies were cohort and case–control studies; there were no restrictions on study setting or duration of follow-up. Participants were adults with prior CDI who did or did not receive PPI therapy and were assessed for recurrent CDI. Summary (unadjusted) odds ratios (ORs) and 95% confidence intervals (CIs) were calculated using a random effects model. Prespecified subgroup analyses were performed to explore heterogeneity including study design, study quality, duration of follow-up, adjustment for confounders, and outcome definition.ResultsSixteen studies were included in the meta-analysis, comprising 57 477 patients with CDI, of whom 6870 (12%) received PPIs. The rate of recurrent CDI was 24% in patients treated with PPIs versus 18% in those who were not. A meta-analysis that pooled unadjusted odds ratios demonstrated higher odds of recurrent CDI in patients who received PPIs (OR 1.69, 95%CI 1.46–1.96) versus those who did not. There was moderate heterogeneity between studies (I² 56%); however, a sensitivity analysis restricted to studies with 56 days of follow-up substantially reduced the heterogeneity (OR 1.59, 95%CI 1.36–1.85; I² 12%). An analysis restricted to multivariate studies that combined adjusted ORs also demonstrated higher odds of recurrent CDI in patients who received PPIs (OR 1.49, 95%CI 1.12–2.00). No publication bias was identified.ConclusionsWe found significantly higher odds of recurrent CDI among users of PPIs that persisted across multiple sensitivity analyses. These results support stronger recommendations for PPI stewardship at CDI diagnosis.