The asymmetric synthesis and in vitro characterization of succinyl mercaptoalcohol and mercaptoketone inhibitors of matrix metalloproteinases

A series of succinyl based mercaptoketones and diastereomeric mercaptoalcohols were prepared and evaluated in vitro as inhibitors of the matrix metalloproteinases collagenase-1 (MMP-1), stromelysin (MMP-3), and gelatinase-B (MMP-9).     

Differential regulation of discrete apoptotic pathways by Ras

The products of the ras genes are known to regulate cell proliferation and differentiation; recently, they have been found to play a role in apoptosis. The expression of oncogenic p21(ras) in a number of cell types, including Jurkat (a human T lymphoblastoid cell line) and murine fibroblasts, makes the cells susceptible to apoptosis following suppression of protein kinase C (PKC) activity (PKC/Ras-mediated apoptosis). Engagement of Fas antigen, a potent effector of apoptosis, activates cellular p21(ras), which may be required for completion of the cell death program. To further investigate the role of p21(ras) in the regulation of apoptosis, the cellular mechanisms employed in these two apoptotic processes in which Ras activity is involved (PKC/Ras-related and Fas-triggered apoptosis), was explored. Increasing p21(ras) activity by expressing v-ras or by treatment with an antisense oligonucleotide to the GTPase-activating protein was found to accelerate the Fas-mediated apoptotic process in Jurkat and mouse LF cells. PKC/Ras-related apoptosis was associated with, and required, cell cycle progression, accompanied by the expression of the G1/S cyclins. In contrast, Fas engagement, although inducing a vigorous and PKC-independent activation of endogenous p21(ras), did not alter cell cycle progression, nor did it require such progression for apoptosis. Both the protein synthesis inhibitor cycloheximide and cyclin E antisense oligonucleotides partially abolished PKC/Ras-mediated apoptosis but had only a moderate effect on Fas-induced apoptosis. In contrast, the CED-3/interleukin-1beta-converting enzyme (ICE) protease inhibitor Z-VADfmk efficiently suppressed Fas-induced apoptosis and only marginally inhibited PKC/Ras-mediated apoptosis. Induction of both pathways resulted in activation of the Jun NH2-terminal kinase/JUN signaling system. These results suggest that different cell death programs, such as PKC/Ras-mediated and Fas-mediated apoptosis, may be interconnected via p21(ras) and perhaps Jun NH2-terminal kinase/JUN. In response to various death stimuli, p21(ras) may act as a common intermediate regulator in the transduction of apoptotic signals.     

Asymptomatic myocardial ischemia before and after surgical revascularization in patients with multivessel occlusive coronary disease

INTRODUCTION: The objective of this study was to examine the occurrence of asymptomatic myocardial ischemia prior to and after myocardial revascularization in patients with multivessel occlusive coronary disease. Asymptomatic ischemia can be described as real ischemia without anginal pain or other ischemic symptoms in patients with coronary disease or coronary artery spasm. Our study examined silent ischemia after myocardial revascularization. Early detection of silent ischemia is important for prevention of cardiac incidents. MATERIAL AND METHODS: We have examined patients with multivessel coronary disease with occurrence of continued preoperative silent ischemia. All patients have undergone ECG examination, exercise stress test and Holter-monitoring prior to and after myocardial revascularization. RESULTS: The investigation comprised 27 patients and their average age was 54.5 years. All patients with silent ischemia had a multivessel occlusive coronary disease and have undergone myocardial revascularization managed with triple or quadruple aortocoronary bypass surgery. Exercise stress test was performed postoperatively in elder patients, as well as ECG and Holter-monitoring. Silent ischemia was established in 21.6% of patients, while in 87.5% untreated diabetes mellitus was diagnosed. Silent ischemia most often occurred in the early morning hours and it was frequently associated with heart rhythm disturbances (VES) whereas these rhythm disturbances depended on the length of the ischemic episode. Intermittent 2nd degree atrioventricular block was found in one patient. CONCLUSION: Silent myocardial ischemia occurred in 21% of patients after myocardial revascularization. It is most often detected in the early morning hours and is associated with ventricular rhythm disorders. Silent ischemia is easily detected by simple examination procedures providing adequate therapy and prevention of cardiac incidents.     

The clinical complexity of splenic vein thrombosis

Upper gastrointestinal hemorrhage secondary to splenic vein thrombosis is a curable form of localized portal hypertension when treated with splenectomy. A high index of suspicion is necessary in order to promptly diagnose and treat this underrecognized condition that is most commonly caused by inflammation or neoplasm of the pancreas. The triad of isolated gastric varices, splenomegaly, and normal hepatic function is classic; it is not uncommon, however, for patients to have only some or even none of these conditions. Mesenteric angiography with venous phase imaging is the gold standard of diagnosis. Ultrasound and CT may identify splenic vein thrombosis, but are most helpful in delineating concomitant upper abdominal pathology. Early recognition and intervention allow associated underlying conditions to be treated under the same anesthetic with minimal morbidity and mortality.     

The development and morphofunctional characteristics of the human lateral pterygoid muscle

Peculiarities of the development of superior and inferior heads of lateral pterygoid muscle (LPM) as well as their micro- and ultramicroscopic structure were studied as related to the temporomandibular joint elements in human fetuses and newborns. As a result, heterogeneity and asynchronism of the development of myogenic elements of certain LPM heads were demonstrated. The process of muscle fibres differentiation in LPM superior head leads to more mature structural organization and runs faster than in the inferior head. By the moment of birth average section area of superior head muscle fibres is significantly higher than the inferior head similar parameter.     

Superiority of blood over saline resuscitation from hemorrhagic shock: a 31P magnetic resonance spectroscopy study

OBJECTIVE: To study the relation between blood and saline administration, postresuscitation hematocrit (Hct) level, and metabolic recovery after hemorrhagic shock. SUMMARY BACKGROUND DATA: It is generally believed that crystalloid can be substituted, in whole or in part, for blood during resuscitation of hemorrhagic shock. This is based on the belief that Hct can be safely reduced but should not fall below a critical level. METHODS: Male rats weighing 200 g were subjected to an isobaric hemorrhagic shock at a mean arterial pressure of 30 mmHg for 14 minutes, after which they were randomized to one of three resuscitation regimens. Control group (n = 36) were resuscitated by return of all shed blood. Mid-Hct (n = 39) and low-Hct (n = 60) groups were depleted of one third and one half of their circulating blood volumes, respectively, and were resuscitated with three times that volume of normal saline. Skeletal muscle intracellular energetics and pH were measured serially using 31P magnetic resonance spectroscopy at baseline, during shock, and after resuscitation. Arterial blood was sampled at the same time points. The number of surviving animals in each group at 24 hours was recorded. RESULTS: After resuscitation, surviving rats in the low-Hct group demonstrated a greater consumption of high-energy phosphocreatine stores than did the other groups (control = 0.479 +/- 0.003, mid-Hct = 0.465 +/- 0.004, low-Hct = 0.457 +/- 0.007, mean +/- standard error of the mean; p < 0.01 low-Hct vs. other groups by analysis of variance). The rats that received saline resuscitation developed a relative intracellular acidosis (control = 7.29 +/- 0.02, mid-Hct = 7.25 +/- 0.02, low-Hct = 7.23 +/- 0.02; p < 0.05 controls vs. other groups by analysis of variance). At 24 hours, the death rates were significantly different among the groups: control = 1 of 36 rats (2.8%), mid-Hct = 6 of 39 (15.4%), and low-Hct = 14 of 60 (23.3%) (p < 0.05 by chi square analysis). CONCLUSION: The oxygen-carrying capacity of resuscitation fluid has an important impact on intracellular metabolism and outcome.     

A high deuterium abundance at redshift z = 0.7

Of the light elements, the primordial abundance of deuterium relative to hydrogen, (D/H)p, provides the most sensitive diagnostic for the cosmological mass density parameter, omegaB. Recent high-redshift D/H measurements are highly discrepant, although this may reflect observational uncertainties. The larger primordial D/H values imply a low omegaB (requiring the Universe to be dominated by non-baryonic matter), and cause problems for galactic chemical evolution models, which have difficulty in reproducing the steep decline in D/H to the present-day values. Conversely, the lower D/H values measured at high redshift imply an omegaB greater than that derived from 7Li and 4He abundance measurements, and may require a deuterium-abundance evolution that is too low to easily explain. Here we report the first measurement of D/H at intermediate redshift (z = 0.7010), in a gas cloud selected to minimize observational uncertainties. Our analysis yields a value of D/H ((2.0 +/- 0.5) x 10[-4]) which is at the upper end of the range of values measured at high redshifts. This finding, together with other independent observations, suggests that there may be inhomogeneity in (D/H)p of at least a factor of ten.     

Influence of energy supplementation on grazing ruminants: requirements and responses

Energy requirements of grazing livestock seem to be poorly defined. Requirements generated from measurements in pen-fed animals present both theoretical and practical concerns when they are applied to grazing situations. In mature ruminants a majority of energy used for maintenance seems to be consumed by visceral tissues. Moreover, factors that affect visceral energy use are poorly understood. Energy supplementation to meet requirements and production demands is often practiced during periods of summer dormancy and in winter months. Source of supplemental energy varies widely and includes grains, readily digestible fiber sources, and high-quality forages. Intake and digestibility can be reduced or unaffected by energy supplementation. In some cases, lower levels of energy supplementation have been shown to increase utilization of grazed forage. Reductions in ruminal pH, often cited as the major cause of reduced fiber digestion, may not always explain reductions in intake and digestibility associated with energy supplementation. Livestock production is usually either enhanced or unaffected by energy supplementation. Additional research regarding energy requirements of grazing ruminants, visceral energy use, and mechanisms associated with reductions in intake and digestibility of grazed forage resulting from energy supplementation is warranted.