Alterations to Placental Glucocorticoid Receptor Expression with Alcohol Consumption.

Maternal alcohol consumption during pregnancy results in elevated vulnerability to intrauterine growth restriction, preterm birth, miscarriage, and stillbirth. Many of the detrimental effects of fetal alcohol exposure may be mediated through placental dysfunction; however, the exact mechanisms remain unknown. Here, we aimed to determine the effect of maternal alcohol exposure prior to and during early pregnancy on placental glucocorticoid receptor (GR) isoforms, associated GR regulated genes, and infant outcomes. Participants carrying singleton fetuses (n = 113) were recruited during early pregnancy. Amount and type of alcohol consumed over the last 12 months were obtained at 18 weeks of gestation. The level of drinking was separated into none (0 g/day), low (< 10 g/day), moderate (10-100 g/day), and heavy (> 100 g/day). At delivery, placental weight, infant sex, birthweight, and head circumference were recorded. Placental GR isoforms and genes involved in downstream signalling pathways were quantified. The majority of women (70.8%) consumed alcohol. Of these, most consumed low (48.8%) or moderate (37.5%) amounts. Placental weight was unaffected by alcohol consumption, but infants born to heavy drinkers tended to be lighter at birth. In female, but not male, placentae, maternal alcohol consumption resulted in increased GRαC and decreased GRαD1 cytoplasmic expression. In both female and male placentae, a dampened inflammatory response was evident with maternal alcohol consumption, involving downregulated IL6R and upregulated POU2F2 gene expression, respectively. Maternal alcohol consumption in the months prior to, and/or during early, pregnancy alters placental GR isoform and expression of some inflammatory genes in a sex-specific manner.

Vasopeptidase inhibitors: incorporation of geminal and spirocyclic substituted azepinones in mercaptoacyl dipeptides.

A series of 7-(di)alkyl and spirocyclic substituted azepinones were generated and incorporated as conformationally restricted dipeptide surrogates in mercaptoacyl dipeptides. Clear structure-activity relationships with respect to both angiotensin-converting enzyme (ACE) and neutral endopeptidase (NEP) activity in vitro were observed. The best in this series, compound 1g, a geminally dimethylated C-7-substituted azepinone, demonstrated excellent blood pressure lowering in animal models. Compound 1g (BMS-189921) is characterized by a good duration of activity and excellent oral efficacy in models relevant to ACE or NEP inhibition, and its activity is comparable to that of the clinically efficacious agent omapatrilat. Consequently this inhibitor has been advanced clinically for the treatment of hypertension and congestive heart failure.

A pseudopeptide incorporating the tetrahydrophthalazine nucleus, a constrained aza analog of phenylalanine.

Replacement of the alpha-carbon with a nitrogen in alpha-amino acids gives rise to azaamino acids. Most examples of azaamino acids that have been incorporated into peptides are linear analogs, in which conformational effects are restricted to the immediate vicinity of the urea bond. In contrast to the linear azaamino acids, the heterocyclic analogs might be expected to exhibit stronger conformational preferences, but examples of this class of azaamino acids are very limited. We synthesized tetrahydrophthalazine (THPhth) as a constrained phenylalanine analog and elaborated it into the model pseudotripeptide N-¿([N-alanyl]-1,2,3,4-tetrahydro-2-phthalazinyl)carbonyl)¿-L-alan ine (1). As shown by NMR studies, tetrahydrophthalazine 1A has a secondary structure in which psi THphth is fixed at 16-18 degrees and there are two equal populations of cis and trans amide bonds from the N-terminal alanine.

Evidence for light-induced lysine conformational changes during the primary event of the bacteriorhodopsin photocycle.

Fourier transform infrared difference spectroscopy is used to examine the role of lysine in the primary event of the bacteriorhodopsin photocycle. Isotopically labeled lysine is used to tentatively assign the lysine modes in the BR and K species. The results suggest that the lysine side-chain undergoes conformational changes in concert with the known light-induced chromophore structural alterations.

Myoglobin in the very early phase of acute myocardial infarction.

In this study of 35 patients with a definite or possible myocardial infarction seen within the first 5 h of the onset of symptoms and who could clearly define the onset of symptoms, the serum myoglobin was raised in 20% of those in whom blood was sampled within 1 h of the acute event. In 11 of the 35 (31%) patients the serum myoglobin was normal in the first blood sample. Of the nine patients seen within the first 2 h of the onset of symptoms who had frequent samples taken, the first raised serum myoglobin was recorded from 45 min to 3 h 15 min after the onset of symptoms. The serum levels started to rise 15-20 min before levels greater than 85 ng/mL were reached. In the absence of further chest pain more than one peak in serum myoglobin was recorded in 58% of the patients with acute myocardial infarction. The serum myoglobin level returned to normal within 24 h of the onset of symptoms in 44% of patients and within 36 h in 67%.

Myoglobin and creatine kinase in acute myocardial infarction.

Serum myoglobin concentration and creatine kinase activity were measured serially in 70 consecutive patients presenting within four hours of the onset of symptoms of suspected acute myocardial infarction. Of 36 patients with definite or possible myocardial infarction (WHO criteria), the serum myoglobin concentration was raised (greater than 85 micrograms/l) one hour after the onset of symptoms in 25% and at four hours in 89%. Creatine kinase activity was raised (greater than 140 U/l) one hour after the onset in 25% and at four hours in only 56%. Within 12 hours of the onset of symptoms the myoglobin concentration reached a peak in 83% and the creatine kinase a peak in only 14%. Within 36 hours the myoglobin concentration fell to normal values in 67% while creatine kinase activity fell to normal values in only 3%. Four hours after the onset of symptoms the serum myoglobin concentration distinguished easily those patients with myocardial infarction from those without, whereas when creatine kinase values were used the sensitivity was poor but the specificity high. From the combined results of the two studies and using a single measurement of serum myoglobin concentration at six hours from the onset of symptoms to predict the diagnosis in 114 patients with suspected infarction, the sensitivity was 93% and specificity 89%.

Serum myoglobin after cardiac catheterisation.

Study of 80 consecutive patients undergoing elective diagnostic cardiac catheterisation showed that after the procedure 25 (31%) developed myoglobinaemia. This was attributed to complications of the catheterisation in two. The remaining 23 had received premedication by intramuscular injection. In patients without intramuscular injections myoglobinaemia did not occur after uncomplicated cardiac catheterisation. The study did not support the proposition that cardiac catheterisation results in myocardial damage which can be detected by abnormalities of myoglobin but not by conventional indications of myocardial necrosis.