ACTH-producing carcinoma of the pituitary with haematogenic metastases

Two laboratories equipped with CAS 200 (Becton Dickinson Image Cytometry Systems, San Jose, CA) instruments participated in this study of variability of DNA analysis of bladder tumor specimens. Formalin fixed paraffin embedded specimens were disaggregated and centrifuged onto microscope slides from ten bladder tumor specimens and two specimens of normal urothelium. Sources of variability considered were Specimen, Slide, Run, Laboratory, and Error. Slides were systematically scanned and 200 cells measured followed by the operator selecting 100 nuclei with abnormal morphology. DNA index (DI) and hyperdiploid fraction (HDF) were calculated from the DNA frequency distributions. For systematic sampling, 92% of the variability was due to Specimen indicating that differences in HDF values between specimens reflect biological differences. With selective sampling, only 67% of the variability in HDF is due to Specimen differences. Other factors, Laboratory, Error, and Laboratory x Specimen interaction each accounted for approximately 10% of the variability. Similarly variability of DI with selective sampling was also higher, and less specimen dependent than systematic sampling. It is important that sampling schemes and selection criteria be carefully documented in order to control variability. Enriched (or selective) sampling for abnormal cells has the potential to increase sensitivity but specimen classification based on these measurements must depend on determination of the frequency of such cells in the total population.     

Consistency in structural energetics of protein folding and peptide recognition

We report a new free energy decomposition that includes structure-derived atomic contact energies for the desolvation component, and show that it applies equally well to the analysis of single-domain protein folding and to the binding of flexible peptides to proteins. Specifically, we selected the 17 single-domain proteins for which the three-dimensional structures and thermodynamic unfolding free energies are available. By calculating all terms except the backbone conformational entropy change and comparing the result to the experimentally measured free energy, we estimated that the mean entropy gain by the backbone chain upon unfolding (delta Sbb) is 5.3 cal/K per mole of residue, and that the average backbone entropy for glycine is 6.7 cal/K. Both numbers are in close agreement with recent estimates made by entirely different methods, suggesting a promising degree of consistency between data obtained from disparate sources. In addition, a quantitative analysis of the folding free energy indicates that the unfavorable backbone entropy for each of the proteins is balanced predominantly by favorable backbone interactions. Finally, because the binding of flexible peptides to receptors is physically similar to folding, the free energy function should, in principle, be equally applicable to flexible docking. By combining atomic contact energies, electrostatics, and sequence-dependent backbone entropy, we calculated a priori the free energy changes associated with the binding of four different peptides to HLA-A2, 1 MHC molecule and found agreement with experiment to within 10% without parameter adjustment.     

Androgenetic alopecia in men and women: an overview of cause and treatment

Hair loss is a cause of anxiety and distress in both men and women. New understanding of the causes of androgenetic alopecia is leading to potential new medical therapies. Pathophysiology, clinical presentations, diagnosis, current and future treatments are discussed.     

Clustering sodium channels at the node of Ranvier: close encounters of the axon-glia kind

VIP-PACAP receptors were characterized in a human airway epithelial-like cell line (Calu-3), Pituitary adenylate cyclase activating polypeptide (PACAP) 1-27, PACAP 1-38, vasoactive intestinal polypeptide (VIP) and the beta 1- and beta 2-adrenoceptor agonist isoproterenol (3 nM-1 microM) increased cAMP concentration dependently. The peptides and isoproterenol displayed similar potencies (range of means pEC50[M]: 6.5-7.1). The maximum increase in cAMP (Emax in % of basal cAMP level) was similar for the peptides (range of means Emax: 2500-5100%). Pretreatment with the peptidase inhibitors captopril (10 microM) and phosphoramidon (1 microM) significantly increased the cAMP response to PACAP 1-38 (to 480% of control) only.     

Metabolic responses of postmenopausal women to supplemental dietary boron and aluminum during usual and low magnesium intake: boron, calcium, and magnesium absorption and retention and blood mineral concentrations

The regulation by neuropeptide Y of alpha2-adrenoceptors in the nucleus tractus solitarii was evaluated in the adult normotensive Wistar Kyoto rat and the adult spontaneously hypertensive rat. The microinjection of a submaximal dose of l-noradrenaline (800 pmol in 50 nl) alone into the nucleus tractus solitarii produced a significant reduction in the mean arterial blood pressure in either strain. The threshold dose (1 pmol in 50 nl) of neuropeptide Y(1-36) for the vasodepressor response in the Wistar Kyoto rat was five times higher than that (0.2 pmol in 50 nl) in the spontaneously hypertensive rat. Furthermore, neuropeptide Y(1-36) at 0.2 pmol in 50 nl could significantly counteract the vasodepressor response to l-noradrenaline (800 pmol in 50 nl) in the spontaneously hypertensive rat, but not in the Wistar Kyoto rat, in which 1 pmol in 50 nl of neuropeptide Y(1-36) must be employed to counteract the vasodepressor response to l-noradrenaline (800 pmol in 50 nl), although the vasodepressor responses are of a similar magnitude. The in situ hybridization and quantitative receptor autoradiographical experiments showed that the alpha2A-adrenoceptor messenger RNA levels and the B(max) value of the alpha2-adrenoceptor agonist [3H]p-aminoclonidine binding sites measured in the nucleus tractus solitarii of the spontaneously hypertensive rat were substantially lower than those in the Wistar Kyoto rat. The quantitative receptor autoradiographical results were consistent with the cardiovascular results and showed that in the spontaneously hypertensive rat, neuropeptide Y(1-36) at 1 nM led to a significant increase in the K(d) value of [3H]p-aminoclonidine binding sites. In the Wistar Kyoto rat, neuropeptide Y(1-36) produced this effect only at 10 nM. The present study provides evidence for an increase of the potency of neuropeptide Y(1-36) to antagonistically modulate alpha2-adrenoceptors in the nucleus tractus solitarii of the spontaneously hypertensive rat. This enhanced antagonistic action may partly be related to a reduction in the number of alpha2A-adrenoceptors in the nucleus tractus solitarii of the spontaneously hypertensive rat, since a decrease has been observed in the alpha2A-adrenoceptor messenger RNA levels and the alpha2-adrenoceptor binding sites in the spontaneously hypertensive rat. This increased potency of neuropeptide Y(1-36) to antagonize alpha2-adrenoceptor function in the nucleus tractus solitarii of the spontaneously hypertensive rat may contribute to the development of high blood pressure in this hypertensive strain.     

Effects of somatotropin and salbutamol in three genotypes of finishing barrows: blood hormones and metabolites and muscle characteristics

We evaluated the effects of recombinant porcine somatotropin (pST) and the beta-adrenergic agonist salbutamol on plasam endocrine and metabolite profiles and muscle chemistry in three genotypes of growing barrows (n = 96, 139 d old). Treatments were in a 2 x 2 x 3 factorial arrangement, and main effects were pST (0 or 4 mg/d) and salbutamol (0 or 2.75 ppm); the three genotypes including purebred Meishan (M), 1/4 Duroc, 3/4 White composite (D x Wc), and 1/4 Meishan, 3/4 White composite (M x Wc). Individual pigs were injected daily with buffer or pST at 0700 and allowed ad libitum access to a corn-soybean meal diet (1.2% lysine) and water for 33 d. Plasma was obtained 4 h after injection and 3 h postprandially on d 0, 14, and 28 for determination of growth hormone (GH), insulin, IGF-I, glucose, urea N (PUN), NEFA, triglycerides, and cholesterol. Longissimus and semitendinosus samples were obtained, and protein, RNA, and DNA were quantified and loin chop shear force was measured. In general, plasma hormones and metabolites on d 14 and 28 were not affected by salbutamol in the absence of pST, although salbutamol tended to increase d 14 and 28 GH concentrations. Salbutamol lowered plasma IGF-I (d 14 and 28, P < .05), insulin (d 14, P < .01), and NEFA (d 28, P = .07) when pST was administered, although concentrations still exceeded those for control pigs. Salbutamol reduced (P < .05) IGF-I in M and M x Wc pigs, and GH was not changed in M pigs. Meishan pigs had a greater increase in glucose with pST than M x Wc or D x Wc pigs, although the effect was not consistent over time. Individual treatment with pST caused GH, insulin, IGF-I, glucose, NEFA, and triglycerides to be increased and PUN to be decreased on d 14 and 28. Cholesterol on d 14 and 28 was decreased by pST in M pigs, whereas no effects were found in the other genotypes. Muscle protein and RNA were increased by salbutamol and were consistently lowest for M pigs. Furthermore, pST did not affect muscle protein, but it increased RNA more in M pigs than in the others. Overall, pST and salbutamol seemed to act separately and by different mechanisms to alter muscle composition, but blood criteria generally representing fat metabolism (insulin, glucose, NEFA, triglycerides) were interactively affected. Meishan pigs tended to have greater changes in muscle and plasma composition with pST treatment than did M x Wc or D x Wc pigs.