Potent and selective bicyclic lactam inhibitors of thrombin: Part 2: P1 modifications

The synthesis and antithrombotic activity of a series of nonpeptide bicyclic thrombin inhibitors is described. We have explored the SAR with modifications to the P1 site. The introduction of arginine mimetics at the P1 site led to potent and selective thrombin inhibitors.     

1998 William J. Stickel Bronze Award. Antifungal activity of Melaleuca alternifolia (tea-tree) oil against various pathogenic organisms

Tea-tree oil (oil of Melaleuca alternifolia) has recently received much attention as a natural remedy for bacterial and fungal infections of the skin and mucosa. As with most naturally occurring agents, claims of effectiveness have been only anecdotal; however, several published studies have recently demonstrated tea-tree oil's antibacterial activity. This study was conducted to determine the activity of tea-tree oil against 58 clinical isolates: Candida albicans (n = 10), Trichophyton rubrum (n = 8), Trichophyton mentagrophytes (n = 9), Trichophyton tonsurans (n = 10), Aspergillus niger (n = 9), Penicillium species (n = 9), Epidermophyton floccosum (n = 2), and Microsporum gypsum (n = 1). Tea-tree oil showed inhibitory activity against all isolates tested except one strain of E floccosum. These in vitro results suggest that tea-tree oil may be useful in the treatment of yeast and fungal mucosal and skin infections.     

Depressive symptom reversal for women in a primary care setting: a pilot study

Our goal is to assess the viability of an in vitro preparation of bovine ciliary body/epithelium (CBE) in a small volume Ussing-type chamber. A new small volume Ussing-type chamber with continuous perfusion was developed for bovine CBE. The trans-CBE electrical parameters were monitored and the electrical responses of the CBE to ouabain (1 and 0.01 mM) were recorded. The trans-CBE fluxes of [14C]-L-ascorbate and [3H]-L-glucose were also studied. The bovine CBE preparation was stable inside the chamber in terms of its potential difference (PD), short circuit current (SCC) and trans-CBE resistance. They were -0.51+/-0.05 mV (aqueous side negative), -5.43+/-0.04 microAcm-2 and 94+/-2 Q.cm2 (mean s.e.m., n=35), respectively. The preparation hyperpolarised when 0.01 mM ouabain was administered to the aqueous side, depolarised when ouabain was applied to the stromal side. [3H]-L-glucose diffusion was about 74 nEq h(-1)cm(-2) in either direction (n=12). Taking the area magnification factor of the CBE into consideration, the diffusional L-glucose flux across the bovine CBE was comparable to other tight epithelia. A significant net ascorbate flux (0.26+/-0.05 nEq h(-1)cm(-2), n=4, p<0.01) was found in the stroma to aqueous direction. We have developed a viable in vitro bovine CBE preparation which was (1) electrically stable, (2) responsive to ouabain, (3) tight to L-glucose diffusion, and (4) capable of actively secreting ascorbate. A net trans-CBE chloride transport (0.81+/-0.30 microEq h(-1)cm(-2), n=12, p=0.01) from stromal to aqueous side was found in the present in vitro model under short-circuited conditions.     

Lysophosphatidylcholine is involved in the antigenicity of oxidized LDL

Lysophosphatidylcholine (LPC) is formed by hydrolysis of PC in low density lipoprotein (LDL) and cell membranes by phospholipase A2 or by oxidation. Oxidized (ox) LDL activates endothelial cells, an effect mimicked by LPC. oxLDL also has the capacity to activate T and B cells, and antibody titers to oxLDL are related to the degree of atherosclerosis. The antigen in oxLDL responsible for its immune-stimulatory capacity is not well characterized, and we hypothesized that LPC was involved. We demonstrate herein the presence of antibodies against LPC, both of the IgG and IgM isotype, in 210 healthy individuals. This antibody reactivity was not specifically related to oxidation of the fatty acid moiety in LPC, since LPC containing only palmitic acid showed antibody titers equivalent to those of LPC containing unsaturated fatty acids. Antibody titers to PC were low compared with LPC, and hydrolysis of PC at the sn-2 position is thus essential for immune reactivity. There was a close correlation between anti-oxLDL and anti-LPC antibodies. Furthermore, LPC competitively inhibited anti-oxLDL reactivity, which indicates that LPC may explain a significant part of the immune-stimulatory properties of oxLDL. LPC, being a lipid, is not likely to be an antigen itself. Instead, LPC could form immunogenic complexes with peptides, which may induce and potentiate immune reactions in the vessel wall. This study adds to the evidence that LPC is an important component of oxLDL and emphasizes the potential role of phospholipase A2 in atherosclerosis.     

Benign nonpeptic esophageal strictures. Diagnosis and treatment

This article studies the causes and treatment of benign nonpeptic esophageal strictures. The authors also discuss various therapeutic techniques for esophageal strictures, including esophageal dilatation with various dilators and balloons. Although the goals of stricture therapy are to relieve dysphagia and prevent stricture reoccurrence, only the first of these goals (effective dilatation with bougienage or balloon dilatation) has been achieved. The prevention of stricture reoccurrence remains to be achieved.     

Low prevalence of the ret/PTC3r1 rearrangement in a series of papillary thyroid carcinomas presenting in Belarus ten years post-Chernobyl

Many neurosurgeons prefer to use intraoperative computed tomographic (CT) scanning, when possible, to check whether there is residual lesion or unexpected bleeding. We report a practical intraoperative CT imaging system using a high-speed CT scanner installed in the operating room along with a digitally controlled neurosurgical operating table. We designed a rail-track system to mobilize the CT gantry. The gantry is fixed onto a motorized carrier that can be moved smoothly on a rail-track embedded in the floor and with a maximum reach of 2.85 m from the room's wall to the operating table. The longitudinal motion of the operating table is easily adjusted by a foot switch from manual control to automatic control directly from the CT scanner's computer like an ordinary CT scanner bed in increments of 2, 5 or 10 mm during CT scanning. Either a carbon-made radiolucent head frame or carbon-made head plate is used as a headrest. Using this CT scanner system, pre- and intraoperative CT scannings were performed on 46 patients with brain tumors, cervical lesions or other intracranial lesions. We could operate on the patient with enough working space between the mobile CT gantry and the operating table for microneurosurgery. We could obtain intraoperative CT imaging of a patient on the operating table while the surgical wound remained open, the surgical drapes kept in place, and the surgical position unchanged, saving time in intraoperative CT scanning and preparation for further surgery when needed. This intraoperative CT imaging system installed in the operating room should be useful for neurosurgery.     

Sports and peripheral nerve injuries: report of 190 injuries evaluated in a single electromyography laboratory

We retrospectively reviewed electrodiagnostic studies performed on 169 athletes with 190 sports injuries to nerve fibers. Eighty-eight percent of the injuries were to the upper extremity. Athletes participated in 27 sports, but over one third of injuries were sustained playing football. The most common injuries were burners (n = 38) and cervical radiculopathies (n = 18), followed by median (n = 28), axillary (n = 22), ulnar (n = 19), suprascapular (n = 14), and peroneal (n = 11) mononeuropathies. This is the largest reported series of sports-related nerve injuries.     

A primary care nurse clinic

A nurse-driven clinic that uses a client-centered approach evolved from an independent ambulatory care program. The clinic operates 4 to 5 hours per day and provides patient counseling, health care maintenance, primary care, patient education, and therapeutic care.     

Mycobacterium tuberculosis and the complement system

Accumulated evidence to date confirms the importance of the C3-CR pathway in the phagocytosis of pathogenic mycobacteria. Detailed receptor-ligand studies for phagocytosis are creating the framework to test the hypothesis that the entry pathway for these bacteria influences the immediate host cell response and their intracellular fate. These types of study are particularly important for improving our understanding of the outcome of primary infection in humans, where the number of bacilli is presumed to be very low.     

Radiation doses in the population of the coastal area of the Kakhovsk Water Reservoir

Central and cerebral hemodynamics was studied using echocardiography and transcranial dopplerography in 200 poststroke patients over 60 in the course of 5-year follow-up. It was established that cardiac hypodynamic syndrome, i.e. continuous or paroxysmal fall of minute blood volume below 3 l, is the most significant contributing factor in the onset of cerebral ischemia. Drugs are recommended for prevention of ischemic stroke. Those lowering cardiac hemodynamic reserve should be excluded in patients at high risk of acute failure of cerebral circulation.