Determinant spreading associated with demyelination in a nonhuman primate model of multiple sclerosis

Definition of the immune process that causes demyelination in multiple sclerosis is essential to determine the feasibility of Ag-directed immunotherapy. Using the nonhuman primate, Callithrix jacchus jacchus (common marmoset), we show that immunization with myelin basic protein and proteolipid protein determinants results in clinical disease with significant demyelination. Demyelination was associated with spreading to myelin oligodendrocyte glycoprotein (MOG) determinants that generated anti-MOG serum Abs and Ig deposition in central nervous system white matter lesions. These data associate intermolecular "determinant spreading" with clinical autoimmune disease in primates and raise important issues for the pathogenesis and treatment of multiple sclerosis.     

Thin-film interference effects on the efficiency of a normal-incidence grating in the 100-350-A wavelength region

Thin-film interference effects were observed in the normal-incidence efficiency of a 2400-groove/mm replica grating. The efficiency was measured in the 100-350-A wavelength range and had an oscillatory behavior that resulted from the presence of a thin SiO(2) coating. The thicknesses of the SiO(2) and the underlying oxidized aluminum layers were inferred from computer modeling of the zero-order efficiency. The efficiencies in the diffracted orders were calculated with the modified integral approach and accounting for the multilayer coating and the groove profile derived from atomic force microscopy. The calculated and measured efficiencies were in good agreement.     

"Milk makes me sick but my body needs it": conflict and contradiction in the establishment of authoritative knowledge

This article takes lactose intolerance as a topic for exploring clashes of power, authority, and knowledge in clinical interactions and interpretations of laywomen. In clinics providing maternal and child care, staff and clients jointly produced authoritative knowledge, most often a version of biomedicine. The Euroamerican staff tended to give advice that was biologically appropriate for them but not for many of their patients, a process reflecting what we refer to as biocentrism. Resulting information given to pregnant and lactating women and diagnoses of children's growth patterns were inappropriate in some cases, with potentially serious legal and health implications. Clinic staff often unwittingly ignored the efforts of their clients to begin a discussion of discrepancies between their bodily knowledge and clinic advice. Some women created their own syntheses, which supported the ascendancy of biomedical knowledge but were not in the interests of their own health.     

Mapping sky and surface luminance distribution using a flux mapper

A prototype, all-sky flux mapper has been developed at the Solar Energy Research Institute (SERI). The flux mapper is a video system which provides a rapid, real time processing of daylightning luminance data. The system uses an orthographic-projection fish-eye lens to project the entire image of a 180° field onto a vidicon target. The signal is then digitized and may be plotted as equal brightness comtours or recorded on tape for later analysis. The system has great potential for use in delineating illuminance distribution of the sky and of interior spaces.     

A randomized phase-II study of BB-10010 (macrophage inflammatory protein- 1alpha) in patients with advanced breast cancer receiving 5-fluorouracil, adriamycin, and cyclophosphamide chemotherapy

BB-10010 is a variant of the human form of macrophage inflammatory protein-1alpha (MIP-1alpha), which has been shown in mice to block the entry of hematopoietic stem cells into S-phase and to increase their self-renewal capacity during recovery from cytotoxic damage. Its use may constitute a novel approach for protecting the quality of the stem cell population and its capacity to regenerate after periods of cytotoxic treatment. Thirty patients with locally advanced or metastatic breast cancer were entered into the first randomized, parallel group controlled phase II study. This was designed to evaluate the potential myeloprotective effects of a 7-day regimen of BB-10010 administered to patients receiving six cycles of 5-fluorouracil (5-FU), adriamycin, and cyclophosphamide (FAC) chemotherapy. Patients were randomized, 10 receiving 100 microgram/kg BB-10010, 11 receiving 30 microgram/kg BB-10010, and nine control patients receiving no BB-10010. BB-10010 was well-tolerated in all patients with no severe adverse events related to the drug. Episodes of febrile neutropenia complicated only 4% of the treatment cycles and there was no difference in incidence between the treated and nontreated groups. Studies to assess the generation of progenitor cells in long-term bone marrow cultures were performed immediately preceding chemotherapy and at the end of six dosing cycles in 18 patients. Circulating neutrophils, platelets, CD 34(+) cells, and granulocyte/macrophage colony-forming cell (GM-CFC) levels were determined at serial time points in cycles 1, 3, and 6. The results showed similar hemoglobin and platelet kinetics in all three groups. On completion of the six treatment cycles, the average pretreatment neutrophil levels were reduced from 5.3 to 1.7 x 10(9)/L in the control patients and from 4.3 to 1.9 and 4.5 to 2.5 x 10(9)/L in the 30/100 microgram/kg BB-10010 groups, respectively. Relative to their pretreatment values, 50% of the patients receiving BB-10010 completed the treatment with neutrophil values significantly higher than any of the controls (P = .02). Mobilization of GM-CFC was enhanced by BB-10010 with an additional fivefold increase over that generated by chemotherapy alone, giving a maximal 25-fold increase over pretreatment values. Bone marrow progenitor assays before and after this standard regimen of chemotherapy indicated little long-term cumulative impairment to recovery from chemotherapy. Despite the limited cumulative damage to the bone marrow, which may have minimized the protective value of BB-10010 during this regimen of chemotherapy, better recovery of neutrophils in the later treatment cycles with BB-10010 was indicated in a number of patients.     

Risk factors for cognitive impairment in epilepsy.

The literature suggests that seizure disorders are associated with an increased likelihood of intellectual problems, prompting researchers to investigate risk factors of cognitive impairment in epileptic patients. This study examined the contribution of certain variables (age of seizure onset, duration, etiology, seizure location and laterality, sex, handedness, and cerebral speech pattern) to cognitive outcome in patients with medically refractory seizures. Seizure location (temporal or extratemporal), age of onset of seizures, and handedness proved to be the best indicators of general intellectual ability. There was a relatively diverse pattern of relationships when neuropsychological tests of language, visuospatial ability, and memory were considered individually. However, a factor analytic approach revealed a simpler pattern in which location of dysfunction, age at seizure onset, hand preference, cerebral speech dominance, and gender were relevant and independent indicators of verbal and nonverbal ability. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Role of endoproteolytic dibasic proprotein processing in maturation of secretory proteins in Trichoderma reesei

Cell extracts of Trichoderma reesei exhibited dibasic endopeptidase activity toward the carboxylic side of KR, RR, and PR sequences. This activity was stimulated by the presence of Ca2+ ions and localized in vesicles of low bouyant density; it therefore exhibited some similarity to yeast Kex2. Analytical chromatofocusing revealed a single peak of activity. The dibasic endopeptidase activity was strongly and irreversibly inhibited in vitro as well as in vivo by 1 mM p-amidinophenylmethylsulfonyl fluoride (pAPMSF) but not by PMSF at concentrations up to 5 mM. We therefore used pAPMSF to study the role of the dibasic endopeptidase in the secretion of protein by T. reesei. Secretion of xylanase I (proprotein processing sequence -R-R- downward arrow-R- downward arrow-A-) and xylanase II (-K-R- downward arrow-Q-) was strongly inhibited by 1 mM pAPMSF, and a larger, unprocessed enzyme form was detected intracellularly under these conditions. Secretion of cellobiohydrolase II (CBH II; -E-R- downward arrow-Q-) was only slightly inhibited by pAPMSF, and no accumulation of unprocessed precursors was detected. In contrast, secretion of CBH I (-R-A- downward arrow-Q-) was stimulated by pAPMSF addition, and a simultaneous decrease in the concentration of intracellular CBH I was detected. Similar experiments were also carried out with a single heterologous protein, ShBLE, the phleomycin-binding protein from Streptoalloteichus hindustanus, fused to a series of model proprotein-processing sequences downstream of the expression signals of the Aspergillus nidulans gpdA promoter. Consistent with the results obtained with homologous proteins, pAPMSF inhibited the secretion of ShBLE with fusions containing dibasic (RK and KR) target sequences, but it even stimulated secretion in fusions to LR, NHA, and EHA target sequences. Addition of 5 mM PMSF, a nonspecific inhibitor of serine protease, nonspecifically inhibited the secretion of heterologous proteins from fusions bearing the NHA and LR targets. These data point to the existence of different endoproteolytic proprotein processing enzymes in T. reesei and demonstrate that dibasic processing is obligatory for the secretion of the proproteins containing this target.