Karen Tordjman

Corticotropin tests for hypothalamic-pituitary- adrenal insufficiency: a metaanalysis.

CONTEXTnThe diagnostic value of tests for detecting hypothalamic-pituitary adrenal insufficiency (HPAI) is controversial.nnnOBJECTIVEnOur objective was to compare standard-dose and low-dose corticotropin tests for diagnosing HPAI.nnnDATA SOURCESnWe searched the PubMed database from 1966-2006 for studies reporting diagnostic value of standard-dose or low-dose corticotropin tests, with patient-level data obtained from original investigators.nnnSTUDY SELECTIONnEligible studies had more than 10 patients. All subjects were evaluated because of suspicion for chronic HPAI, and patient-level data were available. We excluded studies with no accepted reference standard for HPAI (insulin hypoglycemia or metyrapone test) if test subjects were in the intensive care unit or if only normal healthy subjects were used as controls.nnnDATA EXTRACTIONnWe constructed receiver operator characteristic (ROC) curves using patient-level data from each study and then merged results to create summary ROC curves, adjusting for study size and cortisol assay method. Diagnostic value of tests was measured by calculating area under the ROC curve (AUC) and likelihood ratios.nnnDATA SYNTHESISnPatient-level data from 13 of 23 studies (57%; 679 subjects) were included in the metaanalysis. The AUC were as follows: low-dose corticotropin test, 0.92 (95% confidence interval 0.89-0.94), and standard-dose corticotropin test, 0.79 (95% confidence interval 0.74-0.84). Among patients with paired data (seven studies, 254 subjects), diagnostic value of low-dose corticotropin test was superior to standard-dose test (AUC 0.94 and 0.85, respectively; P<0.001).nnnCONCLUSIONSnLow-dose corticotropin test was superior to standard-dose test for diagnosing chronic HPAI, although it has technical limitations.

Low-dose (1 μg) adrenocorticotrophin (ACTH) stimulation as a screening test for impaired hypothalamo-pituitary-adrenal axis function : sensitivity, specificity and accuracy in comparison with the high-dose (250 μg) test

We have shown previously that in contrast to the standard high‐dose 250‐μg ACTH test, a low‐dose 1‐μg ACTH stimulation test correctly identified all patients with pituitary disease who had impaired hypothalamo–pituitary–adrenal (HPA) function. In this study we further compared the performances of these two tests as screening procedures for possible HPA impairment.

The 5 lipoxygenase system in the vasculature: Emerging role in health and disease

Activation of the 5 lipoygenase (5LO) system within the vascular bed requires the presence of several cell types with distinct transcellular cross-talk mechanisms, resulting in the generation of 5LO produced metabolites and increased expression of receptors for these metabolites in vascular cells. The key products in this system, the leukotriens LTB4, LTC4 and LTD4, are potent mediators of vascular inflammation initiated by white blood cells and sustained or propagated thereafter through amplified metabolite generation and direct effects in endothelial and vascular smooth muscle cells. Leukotrienes act to enhance cell permeability and increase oxidative stress, vascular smooth muscle cell migration and arterial tone. 5LO activation is highly regulated, and is apparently both model/species-specific and region-specific. 5LO activation is also linked to plaque progression, plaque stability, activation of matrix metalloproteinases, propensity to coronary and cerebrovascular events and the evolution of aortic aneurysms. Genetic variants in the 5LO activating protein are strongly linked to increased cardiovascular risk and may serve as useful markers for future therapy targeting down regulation of 5LO expression and activity as a means to combat cardiovascular disease.

The use of β‐subunits of gonadotrophin hormones in the follow‐up of clinically non‐functioning pituitary tumours

Clinically nonfunctioning pituitary adenomas (NFA) are mostly of gonadotroph origin. However, increased levels of circulating hormones or subunits in patients with NFA usually do not cause clinical symptoms, nor are they used as biological tumour markers. In this study we assessed the value of measuring β subunits of gonadotrophin hormones in the post‐operative follow‐up of patients bearing these tumours.

Lipoxygenase metabolites are mediators of PTH-dependent human osteoblast growth

PTH-induced osteoblast proliferation may contribute to its anabolic effects in bone. Since PTH-dependent osteoblast-like cell (Ob) growth is mediated via protein kinase C (PKC) and MAP kinase-kinase (MEK) and since lipoxygenase (LO) products activate PKC in a number of cell types, we assessed the expression of LO pathways in primary human cultured Ob. Ob from pre- or post-menopausal women were cultured and were treated with PTH and assayed for the expression of 12-LO and both type I and type II 15-LO mRNA and for the release their enzymatic products, 12- and 15-hydroxyeicosatetraenoic acid (HETE). Cells were also treated with PTH for stimulation DNA synthesis. First, Ob express platelet type- 12-LO and both type I and type II 15-LO mRNA and release their enzymatic products, 12- and 15-hydroxyeicosatetraenoic acid (HETE). Second, in female Ob, PTH induced a rapid increase in 12-HETE (50 fold increase) and 15-HETE (80 fold increase) and increased the expression of 12-LO mRNA but not of the two isoforms of 15-LO. PTH as well as 12 and 15-HETE stimulated DNA synthesis in Ob. The LO inhibitor baicalein inhibited PTH-stimulated DNA synthesis, which was reversed in the presence of either 12- or 15-HETE. A PKC inhibitor (bisindolylmaleimide I) as well as a MEK inhibitor (PD 98059) completely inhibited the stimulation of DNA synthesis by PTH, 12-HETE and the combination of PTH and 12-HETE. In contrast, 15-HETE-induced DNA synthesis was not abolished by these inhibitors. Further, 15-HETE partially restored the stimulatory effect of PTH on DNA synthesis in cells treated with PKC or MEK inhibitors. Finally, PTH- induced ERK1/2 phosphorylation, was blocked by a MEK inhibitor. These results demonstrate a novel mechanism of PTH-induced human bone cell proliferation operating through LO enzymes.

Serum free cortisol as an ancillary tool in the interpretation of the low‐dose 1‐μg ACTH test

Objectiveu2002 Serum free cortisol, rather than serum total cortisol (TC), determines glucocorticoid activity in vivo, but how the considerable inter‐subject variation in ambient serum free cortisol affects the outcome of dynamic hypothalamic–pituitary–adrenal (HPA) assessment in noncritically ill subjects is unknown.

Urinary concentrations of organophosphate and carbamate pesticides in residents of a vegetarian community.

Few population studies have measured urinary levels of pesticides in individuals with vegan, vegetarian, or organic diets. The objectives of this study were to evaluate whether a vegan/vegetarian diet was associated with increased exposure to organophosphate and carbamate pesticides, and to evaluate the impact of organic consumption on pesticide exposure in vegans and vegetarians. In the current pilot study conducted in 2013-2014, we collected spot urine samples and detailed 24h recall dietary data in 42 adult residents of Amirim, a vegetarian community in Northern Israel. We measured urinary levels of non-specific organophosphate pesticide metabolites (dialkylphosphates, (DAPs)) and specific metabolites of the current-use pesticides chlorpyrifos (3,5,6-trichloro-2-pyridinol (TCPy)), propoxur (-isopropoxyphenol (IPPX)), and carbaryl (1-naphthol). Six DAP metabolites were detected in between 67 and 100% of urine samples, with highest geometric mean concentrations for dimethylphosphate (19.2μg/g). Creatinine-adjusted median concentrations of total DAPs and of TCPy were significantly higher in Amirim residents compared to the general Jewish population in Israel (0.29μmol/g compared to 0.16, p<0.05 for DAPs and 4.32μg/g compared to 2.34μg/g, p<0.05 for TCPy). Within Amirim residents, we observed a positive association between vegetable intake and urinary TCPy levels (rho=0.47, p<0.05) and lower median total dimethyl phosphate levels in individuals reporting that >25% of the produce they consume is organic (0.065μmol/L compared to 0.22, p<0.05). Results from this pilot study indicate relatively high levels of urinary organophosphate pesticide metabolite concentrations in residents of a vegetarian community, a positive association between vegetable intake and urinary levels of a chlorpyrifos specific metabolite, and lower levels of total dimethyl phosphate in individuals reporting higher intake of organic produce. Results suggest that consumption of organic produce may offer some protection from increased exposure to organophosphate pesticide residues in vegetarians.

Attempted Forced Titration of Blood Pressure to <130/85 mm Hg in Type 2 Diabetic Hypertensive Patients in Clinical Practice: The Diastolic Cost

The authors assessed the practicality and results of forced titrating of blood pressure to <130/85 mm Hg based on guidelines of the sixth Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure in the setting of a clinical practice in 257 diabetic, hypertensive patients. Goal diastolic pressure was achieved in 90% of the patients, but goal systolic pressure was achieved in only 33%. In 57% of the patients, the attained diastolic pressure was ≤70 mm Hg, and in 20% of the cohort diastolic pressure was reduced to <70 mm Hg (mean, 60±1 mm Hg). Patients with final diastolic pressure <70 mm Hg were older, had a higher prevalence of coronary artery disease, and higher initial systolic and pulse pressures compared with patients with final diastolic pressure of 71–85 mm Hg. Thus, attempted lowering of blood pressure to <130/85 mm Hg is associated with excessive lowering of diastolic pressure in a significant number of patients. Whether the benefits of tight systolic control out‐weigh the risks of excessive diastolic reduction requires further prospective assessment.

Exposure to endocrine disrupting chemicals among residents of a rural vegetarian/vegan community

BACKGROUND & AIMSnEndocrine-disrupting chemicals (EDCs) are increasingly thought to be involved in the rising prevalence of disorders such as obesity, diabetes, and some hormone-dependent cancers. Several lines of evidence have indicated that vegetarian and vegan diets may offer some protection from such diseases. We hypothesized that exposure to selected EDCs among residents of the unique vegetarian/vegan community of Amirim would be lower than what has recently been reported for the omnivorous population in the first Israel Biomonitoring Study (IBMS).nnnMETHODSnWe studied 42 Amirim residents (29 vegetarians/13 vegans; 24 women/18men, aged 50.7±13.7y). Subjects answered detailed lifestyle, and multipass, memory-based 24-hr dietary recall questionnaires. Concentrations of bisphenol A (BPA), 11 phthalate metabolites, and the isoflavone phytoestrogens (genistein and daidzein) were determined by GC or LC tandem mass-spectrometry on a spot urine sample. The results were compared to those obtained following the same methodology in the Jewish subgroup of the IBMS (n=184).nnnRESULTSnWhile a vegetarian/vegan nutritional pattern had no effect on exposure to BPA, it seemed to confer a modest protection (~21%) from exposure to high molecular weight phthalates. Furthermore, the summed metabolites of the high molecular weight phthalate DiNP were 36% lower in vegans compared to vegetarians (P<0.05). In contrast, Amirim residents exhibited a level of exposure to isoflavone phytoestrogens about an order of magnitude higher than in the IBMS (P<0.001).nnnCONCLUSIONSnIn Israel, a country whose inhabitants demonstrate exposure to EDCs comparable to that of the US and Canada, a voluntary lifestyle of vegetarianism and preference for organic food has a modest, but possibly valuable, impact on exposure to phthalates, while it is associated with a very steep increase in the exposure to phytoestrogens. Major reduction in exposure to EDCs will require regulatory actions.

The Proatherogenic Effect of Chronic Nitric Oxide Synthesis Inhibition in ApoE-Null Mice Is Dependent on the Presence of PPARα

Inhibition of endothelial nitric oxide synthase (eNOS) accelerates atherosclerosis in ApoE-null mice by impairing the balance between angiotensin II (AII) and NO. Our previous data suggested a role for PPARα in the deleterious effect of the renin-angiotensin system (RAS). We tested the hypothesis that ApoE-null mice lacking PPARα (DKO mice) would be resistant to the proatherogenic effect of NOS inhibition. DKO mice fed a Western diet were immune to the 23% worsening in aortic sinus plaque area seen in the ApoE-null animals under 12 weeks of NOS inhibition with a subpressor dose of L-NAME, P = 0.002. This was accompanied by a doubling of reactive oxygen species (ROS-) generating aortic NADPH oxidase activity (a target of AII, which paralleled Nox1 expression) and by a 10-fold excess of the proatherogenic iNOS, P < 0.01. L-NAME also caused a doubling of aortic renin and angiotensinogen mRNA level in the ApoE-null mice but not in the DKO, and it upregulated eNOS in the DKO mice only. These data suggest that, in the ApoE-null mouse, PPARα contributes to the proatherogenic effect of unopposed RAS/AII action induced by L-NAME, an effect which is associated with Nox1 and iNOS induction, and is independent of blood pressure and serum lipids.