Beta2-adrenoceptor-mediated prejunctional facilitation and postjunctional inhibition of sympathetic neuroeffector transmission in the guinea pig vas deferens.

This study examines the role of prejunctional and postjunctional beta-adrenoceptors in the modulation of sympathetic cotransmission in the guinea pig vas deferens. The prejunctional involvement of beta-adrenoceptors was evaluated by testing the effects of several agonists and antagonists on the nerve stimulation-evoked overflow of ATP and norepinephrine (NE) from the "in vitro" vas deferens. The nonsubtype-selective beta-adrenoceptor agonist isoproterenol and the beta2-subtype-selective agonist clenbuterol increased, to a similar degree, the overflow of ATP and NE, while the beta1-subtype-selective agonist xamoterol and the beta3-subtype-selective agonist BRL 37 344 had no effect. Pretreatment with ICI 118, 551, a beta2-subtype-selective antagonist, abolished the facilitation of cotransmitter release by isoproterenol and clenbuterol, while the beta1-subtype-selective antagonist atenolol had no effect. Activation of beta-adrenoceptors by either isoproterenol or clenbuterol, but not by xamoterol and BRL 37 344, reduced the amplitude of contractions evoked by exogenously applied ATP. Pretreatment with propranolol or ICI 118, 551, but not atenolol, prevented these inhibitory effects. Isoproterenol in lower concentrations produced dose-dependent reduction of the purinergic but not the adrenergic phase of nerve stimulation-induced contraction of the guinea pig vas deferens. When applied in concentrations greater than 1 microM, isoproterenol, but not clenbuterol, actually produced a concentration-dependent facilitation of contractions evoked by both nerve stimulation and exogenously applied ATP. Antagonists of alpha-adrenoceptors blocked these facilitatory effects. Together, these results demonstrate that beta2-adrenoceptors can influence sympathetic neuroeffector transmission both prejunctionally, where they facilitate equally well the release of sympathetic cotransmitters and postjunctionally, where they inhibit smooth muscle contractions evoked by ATP.     

Contributions of parental alcoholism, prenatal substance exposure, and genetic transmission to child ADHD risk: a female twin study

BACKGROUND: Genetic influences have been shown to play a major role in determining the risk of attention-deficit hyperactivity disorder (ADHD). In addition, prenatal exposure to nicotine and/or alcohol has also been suggested to increase risk of the disorder. Little attention, however, has been directed to investigating the roles of genetic transmission and prenatal exposure simultaneously. METHOD: Diagnostic telephone interview data from parents of Missouri adolescent female twin pairs born during 1975-1985 were analyzed. Logistic regression models were fitted to interview data from a total of 1936 twin pairs (1091 MZ and 845 DZ pairs) to determine the relative contributions of parental smoking and drinking behavior (both during and outside of pregnancy) as risk factors for DSM-IV ADHD. Structural equation models were fitted to determine the extent of residual genetic and environmental influences on ADHD risk while controlling for effects of prenatal and parental predictors on risk. RESULTS: ADHD was more likely to be diagnosed in girls whose mothers or fathers were alcohol dependent, whose mothers reported heavy alcohol use during pregnancy, and in those with low birth weight. Controlling for other risk factors, risk was not significantly increased in those whose mothers smoked during pregnancy. After allowing for effects of prenatal and childhood predictors, 86% of the residual variance in ADHD risk was attributable to genetic effects and 14% to non-shared environmental influences. CONCLUSIONS: Prenatal and parental risk factors may not be important mediators of influences on risk with much of the association between these variables and ADHD appearing to be indirect.     

Selective silencing of DNA-specific B lymphocytes delays lupus activity in MRL/lpr mice

The pathological DNA-specific B lymphocytes in lupus are logical targets for a selected therapeutic intervention. We have hypothesized that it should be possible to suppress selectively the activity of these B cells in lupus mice by administering to them an artificial molecule that cross-links their surface immunoglobulins with the inhibitory FcgammaIIb surface receptors. A hybrid molecule was constructed by coupling the DNA-mimicking DWEYSVWLSN peptide to a monoclonal anti-mouse FcgammaRIIb antibody. This chimeric antibody was added to cultured spleen cells from sick MRL/lpr mice, immunized with diphtheria toxoid, resulting in reduction of the numbers of anti-DNA but not of anti-diphtheria IgG antibody-producing cells. Intravenous infusions with the DNA-peptide antibody chimera to 7-wk-old animals prevented the appearance of IgG anti-DNA antibodies and of albuminuria in the next 2 months. The administration of the DNA-peptide chimeric antibody to 18 wk-old mice with full-blown disease resulted in the maintenance of a flat level of IgG anti-DNA antibodies and in delay of the aggravation of the lupus glomerulonephritis. The use of chimeric antibodies targeting inhibitory B lymphocyte receptors represents a novel approach for the selective suppression of autoreactive disease-associated B cells in autoimmune diseases.     

Human cytomegalovirus DNA detection in a recurrent glioblastoma multiforme tumour,but not in whole blood: a case report and discussion about the HCMV latency and therapy perspectives

Journal of NeuroVirology - In the current study, a 58-year-old male patient presented with recurrent glioblastoma multiforme (GBM). The patient underwent surgical resection, 4 months...     

Induction of mixed chimerism with MHC-mismatched but not matched bone marrow transplants results in thymic deletion of host-type autoreactive T-cells in NOD mice

OBJECTIVE

Induction of mixed or complete chimerism via hematopoietic cell transplantation (HCT) from nonautoimmune donors could prevent or reverse type 1 diabetes (T1D). In clinical settings, HLA-matched HCT is preferred to facilitate engraftment and reduce the risk for graft versus host disease (GVHD). Yet autoimmune T1D susceptibility is associated with certain HLA types. Therefore, we tested whether induction of mixed chimerism with major histocompatibility complex (MHC)-matched donors could reverse autoimmunity in the NOD mouse model of T1D.

RESEARCH DESIGN AND METHODS

Prediabetic wild-type or transgenic BDC2.5 NOD mice were conditioned with a radiation-free GVHD preventative anti-CD3/CD8 conditioning regimen and transplanted with bone marrow (BM) from MHC-matched or mismatched donors to induce mixed or complete chimerism. T1D development and thymic deletion of host-type autoreactive T-cells in the chimeric recipients were evaluated.

RESULTS

Induction of mixed chimerism with MHC-matched nonautoimmune donor BM transplants did not prevent T1D in wild-type NOD mice, although induction of complete chimerism did prevent the disease. However, induction of either mixed or complete chimerism with MHC-mismatched BM transplants prevented T1D in such mice. Furthermore, induction of mixed chimerism in transgenic BDC2.5-NOD mice with MHC-matched or -mismatched MHC II^−/− BM transplants failed to induce thymic deletion of de novo developed host-type autoreactive T-cells, whereas induction of mixed chimerism with mismatched BM transplants did.

CONCLUSIONS

Induction of mixed chimerism with MHC-mismatched, but not matched, donor BM transplants re-establishes thymic deletion of host-type autoreactive T-cells and prevents T1D, with donor antigen-presenting cell expression of mismatched MHC II molecules being required.Type 1 diabetes (T1D) is an autoimmune disease in which autoreactive T-cells attack the insulin-secreting islet β-cells and result in insulin deficiency and hyperglycemia (1–3). NOD mouse is still the best animal model for T1D, although the autoimmune abnormality in NOD mice does not totally reflect the abnormality in T1D patients (4–6). The autoimmunity in NOD mice and T1D patients is associated with particular major histocompatibility complex (MHC) or HLA loci such as IAβ^g7 or HLA-DR (7–9). This particular genetic background is associated with central tolerance defects, in which autoreactive thymocytes are resistant to negative selection (10–12), as well as peripheral tolerance defects (13–17).Transgenic expression of protective MHC II molecules in the thymus has been shown to prevent T1D development in mice (18–20). However, this approach cannot readily be translated to humans. Immunomodulation therapies such as administration of anti-CD3 have been shown to reverse new-onset T1D in mouse or ameliorate new-onset T1D in patients via induction of regulatory T-cells (21–25). However, the therapeutic benefit in patients appears to be limited in terms of duration (25). This indicates modulation of peripheral tolerance may not be sufficient for stable re-establishment of immune tolerance in T1D patients, because the defective thymus may constantly export autoreactive T-cells, which can overwhelm peripheral tolerance mechanisms. Therefore, a therapy that can re-establish both central and peripheral tolerance in T1D patients would appear optimal as a means to reverse the autoimmunity associated with T1D.Indeed, autoimmune diseases such as T1D arise from abnormality in the immuno-hematological compartment, and a replacement of the system from a nonautoimmune individual can cure autoimmune T1D or vice versa (26). Therefore, previous studies have proposed that induction of mixed chimerism via hematopoietic cell transplantation (HCT) may provide a curative therapy for autoimmune diseases such as T1D (27). Although it was reported induction of mixed chimerism with bone marrow (BM) transplants from MHC-mismatched or MHC-matched nonautoimmune donors was able to prevent T1D development in NOD recipients conditioned with myelo- or nonmyeloablative total body irradiation (TBI) (28–32), as well as in recipients conditioned with a radiation-free anti-CD3-based regimen (33,34), the mechanisms whereby mixed chimerism reverses such autoimmunity remain largely unknown. So-called mixed chimerism has been defined by the coexistence of donor- and host-type lymphocytes in the periphery such as in the blood or spleen, but it remains unclear whether the host-type cells in the mixed chimeric recipients are de novo developed after HCT or residual mature lymphocytes developed before HCT. In other words, it is not clear whether mixed chimerism can mediate deletion of de novo developed autoreactive T-cells. In addition, although MHC-matched HCT is preferred in clinical settings, it is not yet clear whether induction of mixed chimerism with MHC-matched donor transplants can mediate thymic deletion of de novo developed host-type autoreactive T-cells, because the defect in negative selection is associated with particular MHC II loci (7–9).In the current study, we identified true mixed chimeras by measuring the donor and host-type T-cell precursors in the thymus as well as immature B and myeloid cells in the BM and we evaluated the impact of mixed and complete chimerism with MHC-matched or mismatched donor BM transplants.     

Bias in proxies' reports of disability: data from the National Health Interview Survey on disability

OBJECTIVES: These studies examined whether differences between self-reports and proxy reports of disabilities reflect proxy response biases or only respondent selection factors. METHODS: The data were from the National Health Interview Survey on Disability (1994-1995, phases 1 and 2). In study 1, reports of disabilities were regressed on respondent status, self vs proxy, and demographic factors. In study 2, the ratios of the proportions of self-reports and proxy reports of disabilities were regressed on independent lay ratings of observability of these disabilities and their "interactional" nature. In study 3, the disability reports for people who differed in respondent status in one phase but self-reported the same disability in the other phase were compared. RESULTS: In study 1, proxies under-reported disabilities for people aged 18 to 64 years but overreported for people 65 years or older. In study 2, the observability and interactional scores accounted for more than 60% of the variance of self and proxy differences in an inverse relationship, study 3 confirmed the basic findings of study 1. CONCLUSIONS: Use of proxies in representative surveys on disability introduces systematic biases, affecting national disability estimates.     

Effect of the water extract of Galega officinalis L. on human platelet aggregation in vitro

Galega officinalis L. is a traditional medicinal plant from Bulgaria. It was found that the aqueous extract of Herba Galegae suppressed platelet aggregation in vitro induced by adenosine diphosphate, epinephrine, thrombin and collagen. The compounds with antiaggregating action have not as yet been isolated from Galega officinalis.     

Effect of a fluorinated pyrimidine on cachexia and tumour growth in murine cachexia models: relationship with a proteolysis inducing factor

The fluorinated pyrimidine nucleoside, 5'-deoxy-5-fluorouridine (5'-dFUrd) has been shown to effectively attenuate the progress of cachexia in the murine adenocarcinomas MAC16 and colon 26 as well as in the human uterine cervical carcinoma xenograft, Yumoto. Although concomitant inhibition of tumour growth was observed in all three models this was not sufficient to account for the preservation of body weight. An attempt has been made to correlate the anti-cachectic activity of 5'-dFUrd with the presence of a tumour produced proteolysis-inducing factor (PIF), thought to be responsible for the development of cachexia in the MAC16 model. Two variants of colon 26 adenocarcinoma were employed, clone 20 which produces profound cachexia, and clone 5 which produces no change in body weight in recipient animals. Mice bearing the colon 26, clone 20 variant showed evidence for the presence of PIF in tumour, serum and urine, while there was no evidence for the presence of PIF in tumour or body fluids of mice bearing the clone 5 tumours. Treatment of animals bearing the clone 20 variant with 5'-dF Urd led to the disappearance of PIF from the tumour, serum and urine concomitant with the attenuation of the development of cachexia. The human cervical carcinoma, Yumoto, which also induced cachexia in recipiant animals, showed expression of PIF in tumour, serum and urine in control and vehicle-treated mice, but was absent in mice treated with 5'-dFUrd. Thus in these experimental models cachexia appears to be correlated with the presence of PIF.