The teratogenic Veratrum alkaloid cyclopamine inhibits sonic hedgehog signal transduction

The steroidal alkaloid cyclopamine produces cyclopia and holoprosencephaly when administered to gastrulation-stage amniote embryos. Cyclopamine-induced malformations in chick embryos are associated with interruption of Sonic hedgehog (Shh)-mediated dorsoventral patterning of the neural tube and somites. Cell types normally induced in the ventral neural tube by Shh are either absent or appear aberrantly at the ventral midline after cyclopamine treatment, while dorsal cell types normally repressed by Shh appear ventrally. Somites in cyclopamine-treated embryos show Pax7 expression throughout, indicating failure of sclerotome induction. Cyclopamine at concentrations of 20-100 nM blocks the response of neural plate explants to recombinant Shh-N in a dose-dependent manner. Similar concentrations have no effect on the post-translational modification of Shh by cholesterol in transfected COS-1 cells. Comparison of the effects of cyclopamine to those of the holoprosencephaly-inducing cholesterol synthesis inhibitor AY-9944 shows that cyclopamine does not induce malformations by interfering with cholesterol metabolism. Although AY-9944 does not interrupt Shh signaling in ovo, it blocks the response to Shh-N in explants cultured without an exogenous cholesterol source. As predicted by current models of the regulation of cholesterol metabolism, the response to Shh-N in AY-9944-treated explants is restored by providing exogenous cholesterol. However, exogenous cholesterol does not restore Shh signaling in cyclopamine-treated explants. These findings suggest that cyclopamine-induced teratogenesis is due to a more direct antagonism of Shh signal transduction.     

Group homes for the mentally ill I. A description of access and residents

In a cross-sectional study, we assessed social and psychiatric characteristics of 71 residents in the group home programme for the mentally ill in Copenhagen. The majority suffered from long-term functional or organic psychosis, dominated by anxiety and residual symptoms of schizophrenia. Social functioning was impaired to a moderate degree. Emotional and social support were among the main functions of the staff. More than 60% regarded the group home as a temporary residence, but the length of stay varied between a few months and 5.7 years. All residents were treated in the local outpatient psychiatric service. This type of housing support should be regarded as an important part of a comprehensive community care service.     

Membrane-induced secondary structures of neuropeptides: a comparison of the solution conformations adopted by agonists and antagonists of the mammalian tachykinin NK1 receptor

We present what we believe to be the first documented example of an inducement of distinctly different secondary structure types onto agonists and antagonists selective for the same G-coupled protein receptor using the same membrane-model matrix wherein the induced structures are consistent with those suggested to be biologically active by extensive analogue studies and conventional binding assays. 1H NMR chemical shift assignments for the mammalian NK1 receptor-selective agonists alpha-neurokinin (NKA) and beta-neurokinin (NKB) as well as the mammalian NK1 receptor-selective antagonists [d-Pro2,d-Phe7,d-Trp9]SP and [d-Arg1, d-Pro2,d-Phe7,d-His9]SP have been determined at 600 MHz in sodium dodecyl sulfate (SDS) micelles. The SDS micelle system simulates the membrane-interface environment the peptide experiences when in the proximity of the membrane-embedded receptor, allowing for conformational studies that are a rough approximation of in vivo conditions. Two-dimensional NMR techniques were used to assign proton resonances, and interproton distances were estimated from the observed nuclear Overhauser effects (NOEs). The experimental distances were used as constraints in a molecular dynamics and simulated annealing protocol using the modeling package DISCOVER to generate three-dimensional structures of the two agonists and two antagonists when present in a membrane-model environment to determine possible prebinding ligand conformations. It was determined that (1) NKA is helical from residues 6 to 9, with an extended N-terminus; (2) NKB is helical from residues 4 to 10, with an extended N-terminus; (3) [d-Pro2,d-Phe7,d-Trp9]SP has poorly defined helical properties in the midregion and a beta-turn structure in the C-terminus (residues 6-9); and (4) [d-Arg1,d-Pro2, d-Phe7,d-His9]SP has a helical structure in the midregion (residues 4-6) and a well-defined beta-turn structure in the C-terminus (residues 6-10). Attempts have been made to correlate the observed conformational differences between the agonists and antagonists to their binding potencies and biological activity.     

"The demographics of trauma in 1995" revisited: an assessment of the accuracy and utility of trauma predictions

Syndromes of risk factor disturbance may contribute to the development of coronary heart disease and non-insulin-dependent diabetes mellitus, but their definition and quantification remain problematic. Using factor analysis, constellations of risk factor variables that could indicate distinct syndromes of metabolic disturbance were explored in the baseline data of the first follow-up cohort of 742 men from the Heart Disease and Diabetes Risk Indicators in a Screened Cohort (HDDRISC) study. The primary analysis considered 16 intercorrelated variables measured in more than 90% of cohort participants. A missing-values estimation routine was used to ensure inclusion of all participants in the analysis. Subanalyses were undertaken, including a repeat of the primary analysis on the 522 individuals who had received measurement of HDL cholesterol, an oblique rather than orthogonal factor rotation procedure performed on primary and HDL subset analyses, a repeat of these two primary and HDL subset analyses using only those participants with complete measurements, and a repeat of these six analyses including only the seven variables conventionally associated with the metabolic syndrome. The principal factor that emerged in all analyses undertaken comprised oral glucose tolerance test insulin and glucose response, serum uric acid, and body mass index. Fasting serum triglyceride concentration was included in this factor in 11 of the 12 analyses undertaken, fasting plasma insulin in 8, fasting plasma glucose in 5, and mean arterial pressure in 3. HDL cholesterol factored in isolation from insulin in all analyses undertaken. These findings provide strong support for a core metabolic cluster, which is unlikely to include blood pressure and does not include HDL. The factor scores relating to this cluster will provide a means of assessing its quantitative importance in prospective analysis of the development of CHD and diabetes in this cohort.     

Gender comparison of peak oxygen uptake: repetitive box lifting versus treadmill running

The gender differences in peak oxygen uptake (VO2peak) for various modes of exercise have been examined previously; however, no direct gender comparisons have been made during repetitive lifting (RL). In the present study the VO2peak between RL and treadmill running (TR) was compared between 20 men [mean (SD) age, height, body mass and body fat: 21 (3) years, 1.79 (0.06) m, 81 (9) kg, 19 (6)%, respectively] and 20 women [mean (SD) age, height, body mass and body fat: 21 (3) years, 1.63 (0.05) m, 60 (7) kg, 27 (6)%, respectively]. VO2peak (l x min[-1]), defined as the highest value obtained during exercise to volitional fatigue, was determined using discontinuous protocols with treadmill grade or box mass incremented to increase exercise intensity. For RL VO2peak, a pneumatically driven shelf was used to lower a loaded box to the floor, and subjects then lifted the box, at a rate of 15 lifts x min(-1). VO2peak (l x min(-1) and ml x kg(-1) x min[-1]) and minute ventilation (VE, l x min[-1]) were determined using an on-line gas analysis system. A two-way repeated measures analysis of variance revealed significant gender effects, with men having higher values for VO2peak (l x min(-1) and ml x kg(-1) x min[-1]) and VE, but women having higher values of the ventilatory equivalent for oxygen (VE/VO2). There were also mode of exercise effects, with TR values being higher for VO2peak (l x min(-1) and ml x kg(-1) x min[-1]) and VE and an interaction effect for VO2peak (l x min(-1) and ml x kg(-1) x min[-1]) and VE/VO2. The women obtained a greater percentage (approximately 84%) of their TR VO2peak during RL than did the men (approximately 79%). There was a marginal tendency for women to decrease and men to increase their VE/VO2 when comparing TR with RL. The magnitude of the gender differences between the two exercise modalities appeared to be similar for heart rate, VE and R, but differed for VO2peak (l x min(-1) and ml x kg(-1) x min[-1]). Lifting to an absolute height (1.32 m for the RL protocol) may present a different physical challenge to men and women with respect to the degree of involvement of the muscle groups used during lifting and ventilation.     

Dwindling supplies of anti-D

We report on two patients with truncal rigidity and agoraphobia. The fear of crossing open places had been judged as psychogenic in both cases. The detection of positive GAD-antibodies led to our final diagnosis. Treatment with liquorphoresis and clonazepam or diazepam alone resulted in a prompt amelioration of the rigidity and, to a lesser extent, of the agoraphobia as well. The stiff-man syndrome has neurological and psychological aspects and shows one more facet of the syndrome of agoraphobia first described by Westphal.     

Cerebrovascular muscle atrophy is a feature of Alzheimer's disease

We examined vascular amyloid-beta deposition and other abnormalities in the posterior cerebral artery of consecutive cases of Alzheimer's disease (AD) compared to controls. Smooth muscle atrophy was a consistent feature in the cases of AD examined (p<0.01) and was surprisingly independent of adjacent amyloid-beta deposition. These findings suggest that vascular abnormalities are a consistent feature in AD and may be an important contributor to the pathogenesis and complications of AD.     

Regulation of prolactin secretion by adrenal steroids in oestrogen-treated ovariectomized rats: participation of endogenous opioid peptides

The purpose of the present study was to determine whether glucocorticoid inhibition of prolactin (PRL) release in oestrogen-treated ovariectomized (OVX) rats is mediated by endogenous opioid peptides (EOPs). All the animals were OVX and given oestradiol benzoate (OB, 20 microg/rat, s.c.) 2 weeks later (day 0). On day 3 they received vehicle, mifepristone (MIF, 10 mg/kg, s.c.) or hydrocortisone (HYD, 2 mg/rat, s.c.), in combination with the opioid antagonist naloxone (NAL, 2 mg/kg, i.p.) or vehicle. Serum PRL concentration was then measured by RIA at 13.00 and 18.00 hr, to include assessment of diurnal variation of PRL secretion. At 13.00 hr either MIF or NAL alone increased PRL secretion with no additional effect when NAL was combined with MIF. HYD had no significant inhibitory effect, but NAL with HYD increased PRL secretion. At 18.00 hr serum PRL concentration was higher than at 13.00 hr, and not affected significantly by MIF or NAL alone, although PRL secretion was increased by treatment with both. HYD inhibited PRL secretion and this inhibition was prevented by NAL. In a second experiment to distinguish antiglucocorticoid and antiprogesterone effects of MIF, we administered progesterone (2 mg/rat, s.c.) or a specific progesterone antiserum. In contrast with MIF, the progesterone antibody had no effect on PRL secretion at 13.00 hr, nor on the stimulation by NAL, while progesterone (unlike HYD) increased PRL secretion and NAL attenuated this response; this was opposite to the effect of NAL with HYD. Similarly, at 18.00 hr the interaction of MIF and NAL was not explained by antagonism of progesterone. Together, these results indicate inhibition of PRL by glucocorticoids but not progesterone, mediated in part by EOPs. At 18.00 hr endogenous glucocorticoids do not regulate oestrogen-stimulated PRL release, although HYD is inhibitory through EOPs.