Publications

A 12.6-year-old girl presented with a 2-month history of headache, recurrent vomiting and 5 kg weight loss. She had been receiving recombinant human growth hormone (rhGH) replacement therapy at a dose of 0.035 mg/kg for the past 10 months, due to short stature. Investigations before initiating rhGH, including brain MRI, had been normal. Physical examination revealed a nystagmus and a mildly elevated arterial blood pressure. Brain MRI revealed a lesion in the posterior aspect of the medulla oblongata, adjacent to the foramen of Magendie. rhGH therapy was discontinued, followed by a gradual resolution of the symptoms. At follow-up 3 months later, she was asymptomatic and physical examination was unremarkable. A subsequent repeat brain MRI showed complete resolution of the lesion, supporting the diagnosis of a variant of reversible posterior leucoencephalopathy syndrome. This is the first case report of a reversible brain lesion linked to rhGH replacement therapy.

The ovine CRH (oCRH) stimulation test is useful in distinguishing Cushing's disease from the syndrome of ectopic ACTH secretion. Most patients with Cushing's disease have increased plasma ACTH and cortisol responses to oCRH, while patients with the ectopic ACTH syndrome do not. We predicted that the homologous hormone human CRH (hCRH) might be an equally useful diagnostic agent, with the theoretic advantage of being less immunogenic. This study compared the responses to hCRH and oCRH (1 μg/kg, iv) in 15 patients with Cushing's disease. Plasma ACTH and cortisol levels increased in most patients during the first hour after administration of either hCRH or oCRH. However, the peak and time-integrated hormonal responses to hCRH were smaller than the responses to oCRH. All but 1 patient had an ACTH and/or cortisol response to oCRH that exceeded 4 times the intraassay coefficient of variation. Three patients had neither an ACTH nor a cortisol response to hCRH by the same criterion. Thus, when administered at equivalent doses, hCRH is a less effective stimulus of ACTH and cortisol secretion in patients with Cushing's disease. Based upon the observation that the oCRH stimulation test has greater sensitivity than the hCRH stimulation test for the diagnosis of Cushing's disease, we conclude that oCRH is the preferred analog to use for CRH testing in patients with Cushing's syndrome.

Chronic fatigue syndrome (CFS) is a serious health concern affecting over 800,000 Americans of all ages, races and socioeconomic groups and both genders. The etiology and pathophysiology of CFS are unknown, yet studies have suggested an involvement of the autonomic nervous system (ANS). A symposium was organized in December 2000 to explore the possibility of an association between ANS dysfunction and CFS, with special emphasis on the interactions between ANS dysfunction and other abnormalities noted in the immune and endocrine systems of individuals with CFS. This paper represents the consensus of the panel of experts who participated in this meeting.

Data from recent studies suggest a possibly increased risk of cardiovascular disease in women with polycystic ovary syndrome (PCOS), but the state of endothelial function in these women remains uncertain. Two recent studies indicate impaired endothelial function and vascular structure in relatively young, nonobese women with PCOS. The present study compared endothelial function in 62 women with PCOS, whose mean age was 22.7 years, and 17 control women matched with the affected women for age and body mass index. Eighteen of the women with PCOS were obese and 21 others were overweight. Endothelium-dependent and endothelium-independent vascular function was evaluated by measuring, respectively, flow-mediated dilation (FMD) and nitrate-mediated dilation (NMD) in the brachial artery. The former was estimated by the change in vascular diameter during hyperemia of the hand and the latter by administering sublingual glyceryl trinitrate sublingually. Both FMD and NMD were significantly lower in women with PCOS than in matched control women. The decrements approximated 50% and 25%, respectively. Both differences were statistically significant (P < .0005). Insulin resistance, total testosterone, and total cholesterol were all independent predictors of FMD; they accounted, respectively, for 21%, 10%, and 9% of the variance. FMD tended to deteriorate as body mass index increased, but not to a significant degree. In obese women with PCOS, factors correlating with FMD included body mass index, waist circumference, fasting insulin level, and the level of low-density lipoprotein cholesterol. In these women, total cholesterol and waist circumference accounted for 31% and 22%, respectively, of the variance in FMD. In this study, asymptomatic, relatively young women with PCOS exhibited impaired endothelial function and may be at increased risk of early-onset cardiovascular disease for this reason. Obesity is not a precondition for endothelial dysfunction in this context. It may well be appropriate to assess younger women with PCOS for cardiovascular risk factors and, when indicated, to take cardioprotective measures aimed at improving endothelial function. Possibilities include dietary modification, physical exercise and, possibly, administering an insulin sensitizer or an androgen-lowering drug.

The Eurocode 8—Part 4 approaches, per their December 2022 update, are presented for the design of acceleration-sensitive industrial ancillary components. The seismic performance of such nested and/or supported ancillary elements, namely mechanical and electrical equipment, machinery, vessels, etc. is critical for the safety and operability of an industrial facility in the aftermath of an earthquake. Of primary importance are the structural characteristics of the supporting structure and the supported component, pertaining to resonance, strength, and ductility, and whether these are known (and to what degree) during initial design and/or subsequent modifications and upgrades. Depending on the availability and reliability of information on the overall system, the Eurocode methods comprise (a) a detailed component/structure-specific design accounting for all pertinent component and building characteristics, equivalent to typical building design per Eurocode 8—Part 1–2, (b) a conservative approach where a blanket safety factor is applied when little or no such data is available, and (c) a ductile design founded on the novel concept of inserting a fuse of verified ductility and strength in the load path between the supporting structure and the ancillary element. All three methods are evaluated and compared on the basis of a case-study industrial structure, showing how an engineer can achieve economy without compromising safety under different levels of uncertainty.

Absence of leptin secretion compromises reproductive function and fertility in the ob/ob mouse which, when given leptin, shows a rise in serum LH levels and becomes fertile. Recently, the long and active isoform of the leptin receptor was detected in the ovary, indicating that leptin may also show direct gonad-related activity. To examine this, we studied the effect of graded doses of human leptin on estradiol (E2) and progesterone (P4) concentrations in the culture media of human granulosa-lutein cells obtained from follicular fluid of women undergoing in vitro fertilization. We also evaluated the mRNA expression of steroidogenic acute regulatory protein (StAR), aromatase, and cytochrome P450 17alpha (CYP17) in these cells at baseline and after exposure to leptin. Estradiol levels were significantly decreased in the media 24 hours after incubation of the cells with increasing hLeptin concentrations (10(-11) - 10(-7) mol/l). The maximal 30% decrease in E2 production was caused by the 10(-9) mol/l hLeptin concentration; however, P4 levels in the media were not influenced by leptin. Exposure of granulosa-lutein cells to 10(-9) mol/l hLeptin did not produce any measurable changes on StAR, aromatase, or CYP17 mRNA expression. When hLeptin (10(-9) mol/l) was co-incubated with increasing concentrations of hCG (1.25 - 10 mlU/ml), IGF-II (15-60 ng/ml) or 1-6 desaminated IGF-II (deslGF-II; 15-60 ng/ml), it did not modify the elevation of E2 concentrations caused by each of the different stimuli. We conclude that leptin suppresses E2 secretion by human granulosa-lutein cells but does not impair the stimulatory effects of hCG and IGFs on these cells. Leptin may play a minor, but direct regulatory role on unstimulated human ovarian steroidogenesis by interfering with either the translational or post-translational steps of the baseline CYP17 and/or aromatase synthesis and/or the activation of the enzymes.

The hypothalamo-pituitary-adrenal axis and sympathetic nervous system (SNS) interact to maintain cardiovascular and metabolic homeostasis, especially during stress. Pima Indians have a low SNS activity, which may contribute to both their increased risk of obesity and reduced risk of hypertension. Although glucocorticoids inhibit SNS activity, Pima Indians are not hypercortisolemic compared with Caucasians. This does not exclude the possibility that the SNS is more responsive to an inhibitory effect of cortisol in the former than in the latter group. We measured fasting plasma ACTH and cortisol and muscle SNS activity [muscle sympathetic nervous system activity (MSNA), microneurography] in 58 males [27 Pimas/31 Caucasians]. Seven Pimas and 12 Caucasians were randomized to a double-blind, placebo-controlled, cross-over study to examine the effect of overnight partial chemical adrenalectomy (metyrapone) followed by cortisol replacement (hydrocortisone) on plasma ACTH, cortisol, and MSNA. There were no ethnic differences in fasting plasma ACTH or cortisol, but MSNA adjusted for percent body fat was lower in Pimas than in Caucasians (P < 0.006). No correlation was found between fasting cortisol and basal MSNA. Administration of metyrapone did not lead to significant changes in MSNA. In response to a hydrocortisone infusion, MSNA decreased in Pima Indians (P = 0.03) but not in Caucasians (P = 0.7). Our data indicate that the low SNS activity that predisposes Pima Indians to obesity is not due to a tonic inhibitory effect of cortisol. However, an acute release of cortisol is likely to more effectively contain sympathoexcitation during stress in Pima Indians than in Caucasians, which may be an important mechanism of cardioprotection in this Native American population.