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Hypocalcemia is a common finding in critically ill equine patients. Parathyroid hormone (PTH) helps to maintain calcium homeostasis in hypocalcemic patients by promoting renal calcium reabsorption and bone resorption. Increased serum PTH concentrations have been reported in critically ill people and animals, including horses and foals. It is unknown whether increased secretion of PTH is associated with markers of bone turnover in hospitalized foals. The goals of this study were to measure markers of bone resorption (C-terminal telopeptide of type I collagen [CTX-I]) and bone formation (osteocalcin [OCN]; alkaline phosphatase [ALP]) and to determine their association with PTH concentrations, disease severity, and mortality in hospitalized foals. This prospective, multicenter, cross-sectional study was conducted on 75 newborn foals ≤3 d old divided into hospitalized (n = 65; 41 septic; 24 sick nonseptic) and healthy (n = 10) groups. Blood samples were collected on admission to measure serum CTX-I, OCN, and PTH concentrations and ALP activity. Data were analyzed by nonparametric methods and univariate logistic regression. Serum CTX-I and PTH concentrations were significantly higher, whereas OCN concentrations were lower, in septic compared with healthy foals (P < 0.05). Serum ALP activity was not different between groups; however, it was lower in hospitalized and septic foals with low OCN concentrations (P < 0.05). In hospitalized foals, PTH concentrations were positively correlated with CTX-I concentrations and inversely associated with ALP activity (P < 0.05). High CTX-I and low OCN concentrations were associated with disease severity (P < 0.05). Hospitalized nonsurviving foals had significantly lower OCN concentrations compared with survivors (P < 0.05), but CTX-I concentrations were not associated with survival. Hospitalized foals with PTH concentrations >12.4 pmol/L were more likely to die (OR = 1.5; 95% CI = 1.1-4.16; P < 0.05). Elevated PTH and CTX-I together with reduced OCN concentrations and ALP activity in sick foals indicates that bone resorption is increased during critical illness, which may be a compensatory mechanism to correct hypocalcemia or reflect a response to systemic inflammation and metabolic imbalances. Bone resorption could negatively impact skeletal development in the growing foal. Low OCN and high PTH concentrations were predictors of nonsurvival in hospitalized foals.

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BACKGROUND: Congenital hypothyroidism (CH) has an incidence of approximately 1:3000, but only 15% have mutations in the thyroid hormone synthesis pathways. Genetic analysis allows for the precise diagnosis. CASE PRESENTATION: A 3-week old girl presented with a large goiter, serum TSH > 100 mIU/L (reference range: 0.7-5.9 mIU/L); free T4 < 3.2 pmol/L (reference range: 8.7-16 pmol/L); thyroglobulin (TG) 101 µg/L. Thyroid Tc-99 m scan showed increased radiotracer uptake. One brother had CH and both affected siblings have been clinically and biochemically euthyroid on levothyroxine replacement. Another sibling had normal thyroid function. Both Sudanese parents reported non-consanguinity. Peripheral blood DNA from the proposita was subjected to whole exome sequencing (WES). WES identified a novel homozygous missense mutation of the TG gene: c.7021G > A, p.Gly2322Ser, which was subsequently confirmed by Sanger sequencing and present in one allele of both parents. DNA samples from 354 alleles in four Sudanese ethnic groups (Nilotes, Darfurians, Nuba, and Halfawien) failed to demonstrate the presence of the mutant allele. Haplotyping showed a 1.71 centiMorgans stretch of homozygosity in the TG locus suggesting that this mutation occurred identical by descent and the possibility of common ancestry of the parents. The mutation is located in the cholinesterase-like (ChEL) domain of TG. CONCLUSIONS: A novel rare missense mutation in the TG gene was identified. The ChEL domain is critical for protein folding and patients with CH due to misfolded TG may present without low serum TG despite the TG gene mutations.

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Di- and tripeptide analogues containing alpha-ketoamide as a new core structure and incorporating allophenylnorstatine (Apns) as a transition state mimic, were designed and synthesized in the hope of obtaining a novel structural type of HIV-1 protease inhibitors. The immediate precursor, Apns-Thz-NHBu(t) was prepared by coupling of Boc-Apns with N-tert x butyl Thz-4-carboxamide hydrochloride. Removal of Boc group followed by coupling with the respective alpha-ketoacid residue (P2) gave the desired dipeptides (8-12) in almost quantitative yields. The alpha-keto tripeptides (18-21) were obtained by oxidation of the hydroxyl group of Apns (PI) in the appropriate tripeptide, iQOA-Val-Apns-(un)substituted Thz(Oxa)-NHBu(t) with DMSO/DCC. Preliminary evaluation of the activity of the synthesized derivatives was determined as percentage of enzyme inhibition at 5 microM and 50 nM levels of the di- and tripeptides respectively. The alpha-ketoamides displayed a significant enhanced potency relative to their parent isosteres as inhibitors of HIV-1 protease and are shown to be a promising new core structure for the development of enzyme inhibitors. A quantitative approach was attempted, using an LFE model, correlating the effect of structural modification and HIV-1 protease inhibition activity of the prepared dipeptides. The result indicates the contribution of the torsion angle by 84% to the activity of the inhibitors.

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Two series of new pyridines bearing thiazoline (3a--n) and thiazolidinone (5a--e) moieties were prepared via the cyclization of the corresponding substituted pyridyl thiourea (2a--g) with an appropriately substituted phenacyl bromide or chloroacetic acid, respectively. The antimicrobial activity was determined for representative compounds and most of them showed moderate activity against Gram-positive bacteria.

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A simple and rapid spectrophotometric procedure has been developed for the determination of four local anaesthetics containing a free primary amine moiety and of procainamide hydrochloride as the drug substances and in dosage forms. The method is based on the reaction of the drug with 7,7,8,8-tetracyanoquinodimethane in alkaline solution to produce yellow products. The chromogen was measured at 473 nm. The effects of several variables on colour development were established. Job's plots of absorbance versus molar ratio of drug to reagent indicated a 1:1 ratio for all the drugs studied. Results of the analysis of drug substances and their dosage forms by the proposed method are in good agreement with those obtained by the USP XX method.

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A simple and sensitive spectrophotometric method has been developed for the determination of some dibenzazepines, based on reaction with picryl chloride in chloroform medium and measurement at 395 nm. Beer's law is obeyed in concentration ranges 0.1-1.0 microg/ml for imipramine hydrochloride, trimipramine maleate and opipramol dihydrochloride, 0.16-1.6 microg/ml for desipramine hydrochloride and 0.4-2.4 microg/ml for clomipramine hydrochloride. The method was applied successfully to the determination of dibenzazepines in tablets and the results were comparable to those obtained by official procedures.

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Two sensitive spectrophotometric methods for the determination of imipramine hydrochloride, clomipramine hydrochloride, desipramine hydrochloride, and trimipramine maleate in bulk and in dosage forms are described. The first method is based on the interaction of diazotized p-nitroaniline (DPNA) with the dibenzazepine drug in 5M hydrochloric acid. The second is based on the oxidative coupling of the dibenzazepine drug with 3-methylbenzothiazolin-2-one hydrazone (MBTH) in the presence of ammonium iron(III) sulphate in 0.1M hydrochloric acid. The resulting chromophores are measured at 575 nm (for the DPNA method) or at 620-630 nm (for the MBTH method), and are stable for at least 24 hr. The commonly encountered excipients and additives do not interfere with the determinations. Results from the analysis of pure drugs, commercial tablets and laboratory-prepared tablets by these methods agree well with those of official methods.