DRB1*0402 may influence arthritis by promoting naive CD4+ T‐cell differentiation in to regulatory T cells

HLA‐DRB1*0401 expression in humans has been associated with a predisposition to developing rheumatoid arthritis (RA) and collagen‐induced arthritis (CIA), while HLA‐DRB1*0402 is not associated with susceptibility. Here, we determined if mice transgenic (Tg) for human *0401 have a CD4⁺ T‐cell repertoire that predetermines proinflammatory cytokine production. The data show that both *0401 and *0402 Tg mice can produce TH1/TH17 cytokines, although the kinetics of response may be different. However, in the context of antigen‐specific responses in a CIA model, *0402 Tg mice generate a TH2 response that may explain their resistance to developing arthritis. In addition, a significant subset of naïve CD4⁺ T cells from *0402 Tg mice can be activated in polarizing conditions to differentiate into Treg cells that produce IFN‐γ. *0401 Tg mice harbor memory CD4⁺ T cells that differentiate into IL‐17⁺ cells in various polarizing conditions. Our data suggest that *0401 Tg mice generate a strong immune response to lipopolysaccharide and may be efficient in clearing infection, and may *0401 have been evolutionarily selected for this ability. Autoimmunity, such as RA, could likely be a bystander effect of the cytokine storm that, along with the presence of low Treg‐cell numbers in *0401 Tg mice, causes immune dysregulation.     

Double-blind randomized crossover trial of luteal phase estrogens (premarin®) in the premenstrual syndrome (PMS)

Eleven patients with moderate to severe premenstrual syndrome were given Premarin® during the latter half of the menstrual cycle for at least two cycles, and a placebo for at least two cycles. Mental and physical symptoms were monitored daily with a self-rating scale. Premarin® was significantly less effective than placebo in relieving the severity of both mental (p<0.02) and physical (p<0.02) symptoms of PMS (combined data p<0.01). It is concluded that luteal phase Premarin® is ineffective as a treatment for PMS, and may actually aggravate the symptoms.     

Soluble type II transforming growth factor-beta receptor inhibits established murine malignant mesothelioma tumor growth by augmenting host antitumor immunity.

PURPOSE: Transforming growth factor (TGF)-beta blockade has been proposed as an anticancer therapy; however, understanding which tumor patients might benefit most from such therapy is crucial. An ideal target of such inhibitory therapy might be malignant mesothelioma (MM), a highly lethal, treatment-resistant malignancy of mesothelial cells of the pleura and peritoneum that produces large amounts of TGF-beta. The purpose of this study was to explore the possible therapeutic utility of TGF-beta blockade on MM. EXPERIMENTAL DESIGN: To evaluate this hypothesis, we tested the effects of a soluble TGF-beta type II receptor (sTGF-beta R) that specifically inhibits TGF-beta1 and TGF-beta 3 in three different murine MM tumor models, AB12 and AC29 (which produce large amounts of TGF-beta) and AB1 (which does not produce TGF-beta). RESULTS: Tumor growth of both established AB12 and AC29 tumors was inhibited by sTGF-beta R. In contrast, AB1 tumors showed little response to sTGF-beta R. The mechanism of these antitumor effects was evaluated and determined to be primarily dependent on immune-mediated responses because (a) the antitumor effects were markedly diminished in severe combined immunodeficient mice or mice depleted of CD8(+) T cells and (b) CD8(+) T cells isolated from spleens of mice treated with sTGF-beta R showed strong antitumor cytolytic effects, whereas CD8(+) T cells isolated from spleens of tumor-bearing mice treated with of control IgG2a showed no antitumor cytolytic effects. CONCLUSIONS: Our data suggest that TGF-beta blockade of established TGF-beta-secreting MM should be explored as a promising strategy to treat patients with MM and other tumors that produce TGF-beta.     

Perinatal and postneonatal mortality in England and Wales among immigrants from the Indian subcontinent

Perinatal and postneonatal mortality among immigrants to England and Wales from India, Pakistan and Bangladesh (Asians) for the years 1982–85 showed significant differences not only between the immigrant and indigenous populations, but also among the different groups from the Indian subcontinent. Compared with the perinatal mortality rate of 10.1 per 1000 total births in UK born mothers, rates in infants of mothers born in India, Bangladesh, and Pakistan were 12.5, 14.3 and 18.8 respectively. In contrast, postneonatal mortality in infants of Indian and Bangladeshi origin (3.9 and 2.8 per 1000 live births respectively) was lower than in the indigenous population (4.1), with Pakistani infants experiencing the highest rate (6.4). Excess perinatal mortality in infants of Asian origin was apparent at most maternal ages and parities. Pakistani infants had the highest rates of perinatal and postneonatal mortality in all age, parity and birth weight groups. The Asian groups showed higher mortality from congenital anomalies in both the perinatal and the postneonatal period, the rates in Pakistani infants being almost double those in Indian and Bangaladeshi infants. A significant finding was the lower rates of sudden infant death in all the groups of Asian origin.     

The relationship of structural alterations to cognitive deficits in schizophrenia: a voxel-based morphometry study.

BACKGROUND: Region of interest studies have identified a number of structure-cognition associations in schizophrenia and revealed alterations in structure-cognition relationship in this population. METHODS: We examined the relationship of structural brain alterations, identified using voxel-based morphometry, to cognitive deficits in 45 schizophrenia patients relative to 43 healthy control subjects and tested the hypothesis that structure-cognition relationship is altered in schizophrenia. RESULTS: Patients had smaller total brain, gray matter, and white matter volumes. Regional alterations were left-hemisphere specific, including: gray matter reduction of inferior frontal, lingual, and anterior superior temporal gyri; white matter reduction of posterior and occipital lobes; and gray matter increase of the putamen and the precuneus. Smaller whole brain and gray matter volumes were associated with lower premorbid intelligence quotient (IQ) and poorer performance on IQ-dependent cognitive measures in patients and to a similar extent in control subjects. Larger precuneus was associated with better immediate verbal memory in patients, whereas verbal and nonverbal memory were positively associated with inferior frontal gyrus volume in control subjects. Smaller occipital white matter volume was associated with slower information processing speed in patients but not in control subjects. CONCLUSIONS: Regional volume alterations are associated with specific cognitive deficits in schizophrenia. Some structure-cognition relationships differentiate this population from healthy control subjects.     

Modification of radioresponse of sublethally irradiated mouse jejunum by misonidazole.

The radiation-induced changes in a critically radiosensitive tissue, jejunum of BALB/c mice and their modification by a hypoxic cell sensitizer, misonidazole (MISO), were studied. Adult mice were exposed to 1.5, 3.0 and 5.0 Gy of 60Co gamma radiation 30 min after MISO injection and quantitative studies in jejunal cross sections were carried out at different post-treatment times from 3 h to 28 d. Radiation-induced damage to the jejunal mucosa was dose-dependent and reached a maximum on day 1 post-treatment in all the groups. MISO pretreated animals did not exhibit any change in the crypt survival or crypt and villous cellularity compared to the radiation alone group. However, there was a significant suppression of mitotic activity by MISO at early intervals after irradiation. This reduction in mitosis in the drug pretreated animals appeared to affect the rate of recovery from radiation damage, which was slower and prolonged compared with that in the radiation alone group.     

Writer's cramp in an Australian pedigree with DYT1 dystonia.

Oppenheim's or DYT1 dystonia is a primary dystonia typically presenting in a limb at an early age and usually becoming generalised within 5 years. Over the last decade research into this debilitating disorder has progressed considerably, enabling the identification of a genetic lesion (a 3bp deletion in the DYT1 gene) now widely accepted as the cause of a majority of cases. This case report presents the first molecularly diagnosed pedigree of an Australian family with DYT1 dystonia, which presented as writer's cramp in the 15-year-old proband and two of his cousins.     

High-performance liquid chromatography separation of aminopterin-polyglutamates within red blood cells of children treated for acute lymphoblastic leukemia

Aminopterin (AMT), like the related compound methotrexate (MTX), is a drug with anticancer and antiinflammatory efficacy that works by interfering with synthetic reactions dependent on the vitamin folic acid. Red blood cell (RBC) precursors will accumulate antifolates like AMT and MTX through the same mechanism by which they take up folate. Intracellular folate and antifolates are then metabolized to polyglutamates that remain within the mature RBCs. RBC MTX has been correlated with toxicity and/or treatment efficacy among patients with acute lymphoblastic leukemia (ALL) or rheumatoid arthritis. Because AMT may offer clinically relevant advantages over MTX, we are testing whether it can be administered safely in multiagent therapy to children with ALL. Total RBC AMT was measured to monitor compliance with this oral, outpatient regimen, and to estimate AMT exposure to the bone marrow. Here we describe methods for quantifying each AMT-polyglutamate species within the RBCs of patients. The assay was linear over a concentration range of 62.5-500 nmol/L. Recovery of individual AMT-polyglutamates ranged from 85% to 92%, and the intraday coefficients of variation were 1.3% to 3.6%. Long-chain AMT-polyglutamates (triglutamate and tetraglutamate forms) accounted for over 40% of intracellular AMT within the RBCs of patients. Patients with long-chain AMT polyglutamate concentrations above the median tended to have lower mean neutrophil counts during weekly AMT therapy, which suggests that RBC AMT polyglutamate accumulation may correlate with hematologic toxicity. As AMT continues to be tested in clinical trials, the methods described here will be useful to define relationships between clinical response to AMT and RBC accumulation of AMT-polyglutamates.