Clinically useful calcitonin assays.

Calcitonin assays are essential tools for research into calcitonin (CT) and C-cell physiology and pathophysiology. Several existing radio immunoassays for CT, based on polyclonal antisera, are generally reliable for detection and follow-up of patients having medullary thyroid carcinoma. Occasionally, however, these assays suffer from problems of specificity and sensitivity. Two-site immunometric techniques for CT offer potential for great improvement in sensitivity, specificity, and turnaround time over those based on classical competitive-binding radioimmunoassays.     

Slow moving proteinase. Isolation, characterization, and immunohistochemical localization in gastric mucosa

Human gastric mucosa contains three immunochemically distinguishable aspartic proteinases, pepsinogen I (pepsinogen A), pepsinogen II (pepsinogen C, progastricsin), and a nonpepsinogen proteinase also termed slow moving proteinase (SMP). The properties of SMP, and in particular its relationship to another aspartic proteinase, cathepsin D, were examined in this study. Slow moving proteinase and cathepsin D were isolated, respectively, from gastric mucosa and human spleen. Antiserum specific to each proteinase was prepared in rabbits. Rabbit anti-SMP did not recognize cathepsin D, and conversely, anticathepsin D did not react with SMP. Immunohistochemical studies localized SMP to surface epithelial cells in both the fundic and pyloric gland areas of the stomach. In contrast, cathepsin D was found mainly in mononuclear cells in the lamina propria and in parietal cells. Slow moving proteinase exhibited considerably lower Km values for its interaction with two chromogenic substrates than did cathepsin D. An even greater distinction between the two enzymes was found with the protein inhibitor from Ascaris lumbricoides; the activity of SMP was inhibited very strongly, whereas that of cathepsin D was not affected. By sodium dodecyl sulfate-polyacrylamide gel electrophoresis under denaturing conditions, SMP consisted of two subunits with apparent molecular weights of 42,500 and 41,000. The last two properties characterize a less-well-known aspartic proteinase, cathepsin E. We conclude that SMP is not cathepsin D, but that it may be cathepsin E.     

Different degrees of risk of high-frequency atrial fibrillation in symptomatic and asymptomatic WPW syndrome. Electrophysiologic evaluation

Sudden death in WPW pattern can occur when atrial fibrillation (a.f.) with rapid ventricular response develops. This event seems to be the final result of three concomitant conditions: the appearance of an orthodromic atrio-ventricular reciprocating tachycardia, the most common form of tachycardia in these patients; a high atrial vulnerability, which makes possible that reciprocating tachycardia degenerates into atrial fibrillation and a short anterograde refractory period of the Kent bundle. With the purpose of evaluating the risk to develop high frequency a.f., 36 WPW subjects were electrophysiologically studied. 22 were symptomatic for palpitations (Group I) and 14 were totally asymptomatic (Group II). 3/22 patients of Group I had experienced clinical atrial fibrillation (Subgroup I A), which was never documented in the remaining 19/22 (Subgroup I B). In all cases the following parameters were analyzed: the presence or absence of the retrograde conduction of the anomalous pathway, essential for the occurrence of orthodromic reciprocating atrio-ventricular tachycardia; the presence or absence of a high atrial vulnerability and the presence of RR intervals between pre-excited complexes during induced a.f. less than 250 msec. As an index of atrial vulnerability were considered the spontaneous degeneration into atrial fibrillation of an electrophysiologically induced reciprocating tachycardia and/or the induction of a sustained a.f. by programmed right atrial stimulation during sinus rhythm and/or during 600 and 400 ms atrial driving and/or by 160-250/m' atrial bursts. Results--Retrograde conduction of Kent bundle was documented in 100% of Gr. I vs 22% of Gr. II (p less than 0.001).(ABSTRACT TRUNCATED AT 250 WORDS)     

Identification of somatic JAK1 mutations in patients with acute myeloid leukemia

Somatic mutations in JAK2 are frequently found in myeloproliferative diseases, and gain-of-function JAK3 alleles have been identified in M7 acute myeloid leukemia (AML), but a role for JAK1 in AML has not been described. We screened the entire coding region of JAK1 by total exonic resequencing of bone marrow DNA samples from 94 patients with de novo AML. We identified 2 novel somatic mutations in highly conserved residues of the JAK1 gene (T478S, V623A), in 2 separate patients and confirmed these by resequencing germ line DNA samples from the same patients. Overexpression of mutant JAK1 did not transform primary murine cells in standard assays, but compared with wild-type JAK1, JAK1^T478S, and JAK1^V623A expression was associated with increased STAT1 activation in response to type I interferon and activation of multiple downstream signaling pathways. This is the first report to demonstrate somatic JAK1 mutations in AML and suggests that JAK1 mutations may function as disease-modifying mutations in AML pathogenesis.     

Folding of a donor-acceptor polyrotaxane by using noncovalent bonding interactions

Mechanically interlocked compounds, such as bistable catenanes and bistable rotaxanes, have been used to bring about actuation in nanoelectromechanical systems (NEMS) and molecular electronic devices (MEDs). The elaboration of the structural features of such rotaxanes into macromolecular materials might allow the utilization of molecular motion to impact their bulk properties. We report here the synthesis and characterization of polymers that contain pi electron-donating 1,5-dioxynaphthalene (DNP) units encircled by cyclobis(paraquat-p-phenylene) (CBPQT(4+)), a pi electron-accepting tetracationic cyclophane, synthesized by using the copper(I)-catalyzed azide-alkyne cycloaddition (CuAAC). The polyrotaxanes adopt a well defined "folded" secondary structure by virtue of the judicious design of two DNP-containing monomers with different binding affinities for CBPQT(4+). This efficient approach to the preparation of polyrotaxanes, taken alongside the initial investigations of their chemical properties, sets the stage for the preparation of a previously undescribed class of macromolecular architectures.     

Lipodystrophy-associated morphological, cholesterol and triglyceride abnormalities in a population-based HIV/AIDS treatment database

OBJECTIVE: To provide population-based estimates of the prevalence of lipodystrophy syndrome and constituent symptoms and to identify correlates of prevalent symptomology. METHODS: Participants in a province-wide HIV/AIDS treatment programme reported morphological and metabolic abnormalities. Probable lipodystrophy was defined as self-report of at least one morphological abnormality or both high cholesterol and triglyceride levels. Explanatory variables investigated included: age; sex; ethnicity; transmission risk group; CD4 cell count; plasma viral load; AIDS diagnosis; duration of infection; alternative therapy use; past, current and duration of use of antiretroviral therapy (ART) by class and specific drug; total duration of ART; and current adherence. Stepwise logistic regression identified possible determinates of lipodystrophy. RESULTS: Of 1035 participants, 50% appeared to have probable lipodystrophy, with 36% reporting peripheral wasting, 33% abdominal weight gain, 6% buffalo hump, and 10 and 12% increased triglyceride or cholesterol levels, respectively. In multivariate analysis, lipodystrophy was associated with older age (per year) (AOR 1.03; 95% CI 1.01, 1.04), the use of ingested alternative therapies (AOR 1.46; 95% CI 1.06, 2.01), having ever used protease inhibitors (PI) (AOR 2.63; 95% CI 1.89, 3.66), and duration of stavudine treatment (per year) (AOR 1.35; 95% CI 1.15, 1.58). In analysis limited to participants exposed to PI, after similar adjustment, the duration of lamivudine rather than stavudine treatment was associated with lipodystrophy (AOR 1.32; 95% CI 1.13, 1.53). CONCLUSION: Increased risk of abnormalities is associated with the use of PI, and the duration of stavudine and lamivudine treatment after adjustment for personal characteristics, clinical disease stage, duration of infection and detailed treatment history.     

Growth and paracrine factors regulating follicular formation and cellular function

The purpose of this paper is to review, using fetal sheep as the animal model, aspects of ovarian development related to follicular formation and to report on the identity of growth and paracrine factors which might be involved in this process. Before follicular formation there is a massive and sustained colonisation of the fetal ovary by mesonephric cells, which become a precursor source of follicular cells. From within the ovarian medulla, somatic 'cell-streams' branch into the cortex around nests of oogonia and oocytes. These 'cell-streams', which contain elongated cells with either flattened or cuboidal shaped nuclei, express steroidogenic factor-1 (SF-1), steroid acute regulatory protein (StAR), 3beta-hydroxysteroid dehydrogenase (3beta-HSD), cytochrome P450(scc), and P450(aromatase) mRNA and/or protein. Follicles form from the association of an oocyte with the 'cell-stream' with either a single layer of flattened cells (i.e. type 1 follicle) or with a mixture of flattened and cuboidal cells (i.e. type 1a follicle). These newly-formed follicles have between 3 and 57 somatic cells (i.e. granulosa cells) and contain oocytes which vary in diameter between 23 and 52 microm. Newly formed and early growing follicles have been identified with growth factors or growth factor receptors in either the oocytes or granulosa cells. Many of the growth factors are from the TGFbeta superfamily and are expressed in a cell- and stage-specific manner.     

Bioactive and immunoreactive FSH and immunoreactive inhibin concentrations in the ovine fetus.

The bioactive (B) and immunoreactive (I) pituitary contents/concentrations of FSH, together with the plasma concentrations of B-FSH, I-FSH and I-inhibin were determined in ovine fetuses at days 55, 75, 90 and 135 of gestation (day 145 = term). The pituitary contents and concentrations of B-FSH and I-FSH increased in both sexes with gestational age. The female fetuses had significantly (P < 0.01) higher pituitary contents/concentrations of B-FSH and I-FSH than the male fetuses at days 75 and 135. The pituitary B/I ratios of FSH were not significantly different with age or sex. The plasma concentrations of B-FSH remained relatively constant from days 75 to 135, with no significant differences between sexes or with age. In contrast, the plasma concentrations of I-FSH reached a peak at day 90 and then declined towards term in both sexes. At all gestational ages except day 55, the female fetuses had significantly (P < 0.05) higher plasma concentrations of I-FSH than the males. In both sexes, the plasma B/I ratios of FSH were lowest at day 90 and had increased again by day 135, with the male fetuses having significantly (P < 0.05) higher B/I ratios compared with the female group at days 75 and 135 but not at day 90. At all gestational ages, the plasma concentrations of I-inhibin declined throughout gestation in the female fetuses, whereas in the males they reached a nadir at day 75 and then increased towards term. The concentrations of I-inhibin were significantly (P < 0.01) higher in the male fetuses compared with the females.(ABSTRACT TRUNCATED AT 250 WORDS)     

Correction to: Effect of Opioid Use on Immune Activation and HIV Persistence on ART

Journal of Neuroimmune Pharmacology - The original version of this article unfortunately contained mistakes.