Indirect induction of radiation lymphomas in mice. Evidence for a novel, transmissible leukemogen.

The transmission of a lymphomagenic agent(s) from the bone marrow of irradiated mice to thymic target cells has been demonstrated by: (a) the induction of T cell lymphomas in nonirradiated thymic grafts implanted in irradiated, Thy-l-congenic mice, (b) the induction of T cell lymphomas of host origin in mice infused with bone marrow from irradiated, Thy-l-congenic donors. The latter procedure also yields an appreciable number of pre-B cell lymphomas of uncertain origin. The results confirm Kaplan's theory that radiation induces thymic lymphomas in mice by an indirect mechanism. However, the previously described radiation leukemia virus is clearly not involved in the majority of transferred lymphomas. We propose that the mediating agent in radiation lymphomagenesis is a novel, transmissible agent induced in the bone marrow, but exerting its transforming activity on cells in the thymus. The nature and mode of action of the agent are under investigation

Appetite suppressants and valvular heart disease - a systematic review

Background Although appetite suppressants have been implicated in the development of valvular heart disease, the exact level of risk is still uncertain. Initial studies suggested that as many as 1 in 3 exposed patients were affected, but subsequent research has yielded substantially different figures. Our objective was to systematically assess the risk of valvular heart disease with appetite suppressants. Methods We accepted studies involving obese patients treated with any of the following appetite suppressants: fenfluramine, dexfenfluramine, and phentermine. Three types of studies were reviewed: controlled and uncontrolled observational studies, and randomized controlled trials. Outcomes of interest were echocardiographically detectable aortic regurgitation of mild or greater severity, or mitral regurgitation of moderate or greater severity. Results Of the 1279 patients evaluated in seven uncontrolled cohort studies, 236 (18%) and 60 (5%) were found to have aortic and mitral regurgitation, respectively. Pooled data from six controlled cohort studies yielded, for aortic regurgitation, a relative risk ratio of 2.32 (95% confidence intervals 1.79 to 3.01, p < 0.00001) and an attributable rate of 4.9%, and for mitral regurgitation, a relative risk ratio of 1.55 (95% confidence intervals 1.06 to 2.25, p = 0.02) with an attributable rate of 1.0%. Only one case of valvular heart disease was detected in 57 randomized controlled trials, but this was judged unrelated to drug therapy. Conclusions The risk of valvular heart disease is significantly increased by the appetite suppressants reviewed here. Nevertheless, when considering all the evidence, valvulopathy is much less common than suggested by the initial, less methodologically rigorous studies

Risk of valvular heart disease associated with use of fenfluramine

BACKGROUND: Estimates of excess risk of valvular heart disease among prior users of fenfluramine and dexfenfluramine have varied widely. Two major forms of bias appear to contribute to this variability and also result in a systematic under-estimation of risk. The first, a form of nondifferential misclassification, is the result of including background, prevalent cases among both exposed and unexposed persons in calculations of risk. The second bias results from not considering the relatively short duration of exposure to drugs. METHODS: We examined data from all available echocardiographic studies reporting the prevalence of aortic regurgitation (AR) and mitral regurgitation (MR) among persons exposed to fenfluramine or dexfenfluramine and a suitable control group. We also included one study in which previously existing AR or MR had been excluded. We corrected for background prevalent cases, estimated incidence rates in unexposed persons, and performed a person-years analysis of apparent incidence rates based on exposure time to provide an unbiased estimate of relative risk. RESULTS: Appearance of new AR was strongly related to duration of exposure (R(2 )= 0.75, p < 0.0001). The summary relative risk for mild or greater AR was 19.6 (95% CI 16.3 – 23.5, p < 0.00001); for moderate or greater MR it was 5.9 (95% CI 4.0 – 8.6, p < 0.00001). CONCLUSION: These findings provide strong support for the view that fenfluramine and dexfenfluramine are potent causal factors in the development of both aortic and mitral valvular heart disease

Transcriptional activation of hypoxia-inducible factor-1 (HIF-1) in myeloid cells promotes angiogenesis through VEGF and S100A8

Emerging evidence indicates that myeloid cells are essential for promoting new blood vessel formation by secreting various angiogenic factors. Given that hypoxia-inducible factor (HIF) is a critical regulator for angiogenesis, we questioned whether HIF in myeloid cells also plays a role in promoting angiogenesis. To address this question, we generated a unique strain of myeloid-specific knockout mice targeting HIF pathways using human S100A8 as a myeloid-specific promoter. We observed that mutant mice where HIF-1 is transcriptionally activated in myeloid cells (by deletion of the von Hippel-Lindau gene) resulted in erythema, enhanced neovascularization in matrigel plugs, and increased production of vascular endothelial growth factor (VEGF) in the bone marrow, all of which were completely abrogated by either genetic or pharmacological inactivation of HIF-1. We further found that monocytes were the major effector producing VEGF and S100A8 proteins driving neovascularization in matrigel. Moreover, by using a mouse model of hindlimb ischemia we observed significantly improved blood flow in mice intramuscularly injected with HIF-1-activated monocytes. This study therefore demonstrates that HIF-1 activation in myeloid cells promotes angiogenesis through VEGF and S100A8 and that this may become an attractive therapeutic strategy to treat diseases with vascular defects.X1137Ysciescopu

Inter- and intra-observer variability in Sonographic measurements of the cross-sectional diameters and area of the umbilical cord and its vessels during pregnancy

Background. The purpose of the study was to evaluate inter- and intra-observer variability in sonographic measurements of the cross-sectional area of the umbilical cord and the diameters of its vessels in low-risk pregnancies of 12 to 40 weeks of gestation. Methods. A prospective cross sectional study was performed in 221 pregnant women at different gestational ages. Measurements were carried out also by a second observer to evaluate inter-observer variability and repeated once again by the first observer to assess intra-observer variability. The linear correlation between the measurements (Spearman's coefficient of correlation) and their reliability through the intraclass correlation coefficient (ICC), the Cronbach's alpha coefficient and the limits of agreement proposed by Bland and Altman were evaluated. Results. The results showed that inter-observer and intra-observer variability did not show any significant difference between examiners. A good linear correlation between the measurements and reliability was obtained, with values of R, ICC and Cronbach's alpha all above the standard limits. Conclusion. It is possible to conclude that inter- and intra-observer variability in the measurements of the umbilical cord and its vessels was small; their reliability and agreement were good. © 2008 Barbieri et al; licensee BioMed Central Ltd

Valvular regurgitation and surgery associated with fenfluramine use: an analysis of 5743 individuals

<p>Abstract</p> <p>Background</p> <p>Use of fenfluramines for weight loss has been associated with the development of characteristic plaques on cardiac valves causing regurgitation. However, previously published studies of exposure to fenfluramines have been limited by relatively small sample size, short duration of follow-up, and the lack of any estimate of the frequency of subsequent valvular surgery. We performed an observational study of 5743 users of fenfluramines examined by echocardiography between July 1997 and February 2004 in a single large cardiology clinic.</p> <p>Results</p> <p>The prevalence of at least mild aortic regurgitation (AR) or moderate mitral regurgitation (MR) was 19.6% in women and 11.8% in men (<it>p </it>< 0.0001 for gender difference). Duration of use was strongly predictive of mild or greater AR (<it>p </it>< 0.0001 for trend), MR (<it>p </it>= 0.002), and tricuspid regurgitation (TR) (<it>p </it>< 0.0001), as was earlier scan date (<it>p </it>< 0.0001 for those scanned prior to 1 January 2000 versus later). Increasing age was also independently associated with increased risk of AR and MR (both <it>p </it>< 0.0001). With mean follow-up of 30.3 months, AR worsened in 15.2%, remained the same in 63.1%, and improved in 21.7%. Corresponding values for MR were 24.8%, 47.4% and 27.9%. Pulmonary hypertension was strongly associated with MR but not AR. Valve surgery was performed on 38 patients (0.66% of 5743), 25 (0.44%) with clear evidence of fenfluramine-related etiology.</p> <p>Conclusion</p> <p>Regurgitant valvulopathy was common in individuals exposed to fenfluramines, more frequent in females, and associated with duration of use in all valves assessed. Valve surgery was performed as frequently for aortic as mitral valves and some tricuspid valve surgeries were also performed. The incidence of surgery appeared to be substantially increased compared with limited general population data.</p

Feasibility, safety and tolerability of accelerated dobutamine stress echocardiography

A continuous infusion of a single high dose of dobutamine has been, recently, suggested as a simple and effective protocol of stress echocardiography. The present study assesses the feasibility, safety, and tolerability of an accelerated dobutamine stress protocol performed in patients with suspected or known coronary artery disease. Two hundred sixty five consecutive patients underwent accelerated dobutamine stress echocardiography: the dobutamine was administered at a constant dose of 50 μg/kg/min for up to 10 minutes. The mean weight-adjusted cumulative dose of dobutamine used was 330 ± 105.24 μg/kg. Total duration of dobutamine infusion was 6.6 ± 2.1 min. Heart rate rose from 69.9 ± 12.1 to 123.1 ± 22.1 beats/min at peak with a concomitant change in systolic blood pressure (127.6 ± 18.1 vs. 167.6 ± 45.0 mmHg). Dobutamine administration produced a rapid increase in heart rate (9.4 ± 5.9 beats/min2). The side effects were similar to those described with the standard protocol; the most common were frequent premature ventricular complexes (21.5%), frequent premature atrial complexes (1.5%) and non sustained ventricular tachycardia (1.5%); among non cardiac symptoms the most frequent were nausea (3.4%), headache (1.1%) and symptomatic hypotension (1.1%). No major side effects were observed during the test. Our data demonstrate that a continous infusion of a single high dose of dobutamine is a safe and well tolerated method of performing stress echocardiography in patients with suspected or known coronary artery disease. This new protocol requires the administration of lower cumulative dobutamine dose than standard protocol and results in a significant reduction in test time

Does hypoglycemia following a glucose challenge test identify a high risk pregnancy?

<p>Abstract</p> <p>Objective</p> <p>An association between maternal hypoglycemia during pregnancy with fetal growth restriction and overall perinatal mortality has been reported. In a retrospective pilot study we found that hypoglycemia was linked with a greater number of special care/neonatal intensive care unit admissions and approached significance in the number of women who developed preeclampsia. That study was limited by its retrospective design, a narrow patient population and the inability to perform multivariate analysis because of the limitations in the data points collected. This study was undertaken to compare the perinatal outcome in pregnancies with hyoglycemia following a glucose challenge test (GCT) to pregnancies with a normal GCT.</p> <p>Methods</p> <p>Obstetric patients (not pre-gestational diabetics or gestational diabetes before 24 weeks were eligible. Women with a 1 hour glucose ≤ 88 mg/dL (4.8 m/mol) following a 50-gram oral GCT were matched with the next patient with a 1 hour glucose of 89–139 mg/dL. Pregnancy outcomes were evaluated.</p> <p>Results</p> <p>Over 22 months, 436 hypoglycemic patients and 434 normal subjects were identified. Hypoglycemia was increased in women < 25 (p = 0.003) and with pre-existing medical conditions (p < 0.001). Hypoglycemia was decreased if pre-pregnancy BMI ≥ 30 (p = 0.008).</p> <p>Preeclampsia/eclampsia was more common in hypoglycemic women. (OR = 3.13, 95% CI 1.51 – 6.51, p = 0.002) but not other intrapartum and perinatal outcomes.</p> <p>Conclusion</p> <p>Hypoglycemic patients are younger, have reduced pre-pregnancy weight, lower BMIs, and are more likely to develop preeclampsia than normoglycemic women.</p