Evolution and structure of drying material bridges of pharmaceutical excipients: studies on a microscope slide

An experimental procedure was developed to study directly the process by which liquid bridges between small particles in a granule form and solidify. The evolution of saturated solutions of such pharmaceutical excipients as lactose and mannitol in a liquid bridge was studied on a system situated on a microscope slide. Solidification and crystallization kinetics and phase composition during and immediately following bridge formation were observed directly. It was shown that bridges on the microscope slide and in the granule behave very much the same regardless of the different length and diffusion-scales of the two systems.We found that solid bridge formation takes place in several consecutive but distinct steps. In the case of lactose, considerable shrinkage of the initial liquid bridge takes place prior to the onset of crystallization. Further bridge solidification at ambient conditions occurs via simultaneous crystallization and vitrification within minutes. As a result, a “solid” bridge usually contains both a crystalline and a non-crystalline phase, the crystalline phase being predominately α-lactose monohydrate. Most of the non-crystalline phase eventually converts to crystalline β-lactose but the process may take many hours or even days. Results for this process are compared for samples obtained from different manufacturers of commercially available lactose. In the case of mannitol, different polymorphic forms crystallize as the drying/crystallization process progresses. A formed “solid” bridge usually contains several polymorphs of mannitol. The relevance of the behavior of the two model systems (pure lactose and pure mannitol) to a real granulation and tabletting process is discussed.     

STRL33, A novel chemokine receptor-like protein, functions as a fusion cofactor for both macrophage-tropic and T cell line-tropic HIV-1

The chemokine receptors CXCR4, CCR2B, CCR3, and CCR5 have recently been shown to serve along with CD4 as coreceptors for HIV-1. The tropisms of HIV-1 strains for subgroups of CD4(+) cells can be explained, at least partly, by the selective use of G protein-coupled receptors (GPCRs). We have identified a novel human gene, STRL33, located on chromosome 3 that encodes a GPCR with sequence similarity to chemokine receptors and to chemokine receptor-like orphan receptors. STRL33 is expressed in lymphoid tissues and activated T cells, and is induced in activated peripheral blood lymphocytes. When transfected into nonhuman NIH 3T3 cells expressing human CD4, the STRL33 cDNA rendered these cells competent to fuse with cells expressing HIV-1 envelope glycoproteins (Envs). Of greatest interest, STRL33, in contrast with CXCR4 or CCR5, was able to function as a cofactor for fusion mediated by Envs from both T cell line-tropic and macrophage-tropic HIV-1 strains. STRL33-transfected Jurkat cell lines also supported enhanced productive infection with HIV-1 compared with control Jurkat cells. Despite the sequence similarities between STRL33 and chemokine receptors, STRL33-transfected cell lines did not respond to any in a panel of chemokines. Based on the pattern of tissue expression of the STRL33 mRNA, and given the ability of STRL33 to function with Envs of differing tropisms, STRL33 may play a role in the establishment and/or progression of HIV-1 infection.     

Treatment of radiation-induced nervous system injury with heparin and warfarin

When radiation is used to treat nervous system cancer, exposure of adjacent normal nervous system tissue is unavoidable, and radiation-induced injury may occur. Acute injury is usually mild and transient, but late forms of radiation-induced nervous system injury are usually progressive and debilitating. Treatment with corticosteroids, surgery, and antioxidants is often ineffective. We treated 11 patients with late radiation-induced nervous system injuries (eight with cerebral radionecrosis, one with a myelopathy, and two with plexopathies, all unresponsive to dexamethasone and prednisone) with full anticoagulation. Some recovery of function occurred in five of the eight patients with cerebral radionecrosis, and all the patients with myelopathy or plexopathy. Anticoagulation was continued for 3 to 6 months. In one patient with cerebral radionecrosis, symptoms recurred after discontinuation of anticoagulation and disappeared again after reinstitution of treatment. We hypothesize that anticoagulation may arrest and reverse small-vessel endothelial injury--the fundamental lesion of radiation necrosis--and produce clinical improvement in some patients.     

Effects of single doses of irradiation on the expression of resistance-related proteins in murine NIH 3T3 and human lung carcinoma cells

In this report the effects of single doses of ionizing radiation on the mRNA expression of several proteins involved in multiple drug resistance were analyzed. Murine NIH 3T3 cells treated with single doses of 5, 10 and 20 Gy during the time interval from 1.5 to 72 h after irradiation were compared with their corresponding controls at the same points of time. The glutathione S-transferase-pi (GST pi) level was elevated in cells treated with 10 or 20 Gy from 24 to 72 h after irradiation compared with the control. Topoisomerase II alpha and thymidylate synthase were decreased in irradiated cells 24-72 h after exposure. These down-regulations were associated with cellular proliferation, determined by mRNA expression of the proliferation marker histone 3. Irradiated cells exhibited no alteration in the P-glycoprotein or glutathione peroxidase mRNA content. The finding that GST pi mRNA was overexpressed after irradiation was validated by investigations on a human lung carcinoma cell line (LXF 289) on the mRNA and protein level. Thus, our results indicate that irradiation alters the expression of proteins involved in multidrug resistance and may, therefore, play a role in clinical drug response.     

Alfalfa yield response to inoculation with recombinant strains of Rhizobium meliloti with an extra copy of dctABD and/or modified nifA expression

The construction of rhizobial strains which increase plant biomass under controlled conditions has been previously reported. However, there is no evidence that these newly constructed strains increase legume yield under agricultural conditions. This work tested the hypothesis that carefully manipulating expression of additional copies of nifA and dctABD in strains of Rhizobium meliloti would increase alfalfa yield in the field. The rationale for this hypothesis is based on the positive regulatory role that nifA plays in the expression of the nif regulon and the fact that a supply of dicarboxylic acids from the plant is required as a carbon and energy source for nitrogen fixation by the Rhizobium bacteroids in the nodule. These recombinant strains, as well as the wild-type strains from which they were derived, are ideal tools to examine the effects of modifying or increasing the expression of these genes on alfalfa biomass. The experimental design comprised seven recombinant strains, two wild-type strains, and an uninoculated control. Each treatment was replicated eight times and was conducted at four field sites in Wisconsin. Recombinant strain RMBPC-2, which has an additional copy of both nifA and dctABD, increased alfalfa biomass by 12.9% compared with the yield with the wild-type strain RMBPC and 17.9% over that in the uninoculated control plot at the site where soil nitrogen and organic matter content was lowest. These increases were statistically significant at the 5% confidence interval for each of the three harvests made during the growing season. Strain RMBPC-2 did increase alfalfa biomass at the Hancock site; however, no other significant increases or decreases in alfalfa biomass were observed with the seven other recombinant strains at that site. At three sites where this experiment was conducted, either native rhizobial populations or soil nitrogen concentrations were high. At these sites, none of the recombinant strains affected yield. We conclude that RMBPC -2 can increase alfalfa yields under field conditions of nitrogen limitation, low endogenous rhizobial competitors, and sufficient moisture.     

Inclusion body fibromatosis of the breast. Two cases with immunohistochemical and ultrastructural findings

Two cases of fibromatosis of the breast, characterized by a proliferation of spindle cells containing intracytoplasmic, spherical, eosinophilic inclusion bodies, are reported. The light and electron microscopic features, as well as the immunohistochemical features, are indistinguishable from those found in infantile digital fibromatosis. The proliferating spindle cells are characterized as myofibroblasts, whereas the inclusion bodies show an immunohistochemically nonreactive, hollow-like pattern with peripheral reactivity for actin filaments. This lesion, observed for the first time in the breast, expands the number of extradigital inclusion body fibromatoses.     

Ovarian aging and hormone replacement therapy. Hormonal levels, symptoms, and attitudes of African-American and white women

The purpose of the study was to identify psychiatric symptoms, neurological impairments, and situational factors associated with the emergence of violence and with its persistence. Psychiatric symptoms were assessed in newly admitted physically assaultive psychiatric patients and nonviolent controls. Patients were than evaluated for 4 weeks to determine the persistence or resolution of these physical assaults. Patients who showed marked resolution of assaults were classified as transiently violent (n = 41), and those who remained assaultive throughout were categorized as persistently violent (n = 34). At the end of 4 weeks, all patients received a comprehensive psychiatric and neurological assessment. Physical assaults were associated initially with prominent positive psychotic symptoms. Both transiently and persistently violent patients were more psychotic than the nonviolent controls; however transiently violent patients showed better resolution of these symptoms over the 4 weeks. They also evidenced less frontal lobe impairment on the neurological examination than the persistently violent patients. The two violent groups differed in their susceptibility to environmental influences: the surrounding ward agitation fostered physical assaults in transiently but not in persistently violent patients. This differentiation between transiently and persistently violent patients has major implications for the comprehensive treatment of violent behavior.     

Kinetics of decomposition of undercooled austenite formed in the critical range of temperatures

Using dilatometric and microstructural methods, the thermokinetic diagrams of decomposition of undercooled austenite formed upon heating in the intercritical temperature range have been constructed for a group of steels with 0.05–0.10% C, 0.15–1.63% Mn, 0.17–1.18% Si, and 0.003% B. The effect of the compositions of the steels, temperature of heating in the two-phase region, and rate of subsequent cooling on the kinetics of the formation of austenite and products of its decomposition has been considered. The carbon content in austenite at different temperatures of its formation has been estimated from the position of the temperature of the onset of the martensitic transformation.