Activity-driven synaptic and axonal degeneration in canine motor neuron disease

The role of neuronal activity in the pathogenesis of neurodegenerative disease is largely unknown. In this study, we examined the effects of increasing motor neuron activity on the pathogenesis of a canine version of inherited motor neuron disease (hereditary canine spinal muscular atrophy). Activity of motor neurons innervating the ankle extensor muscle medial gastrocnemius (MG) was increased by denervating close synergist muscles. In affected animals, 4 wk of synergist denervation accelerated loss of motor-unit function relative to control muscles and decreased motor axon conduction velocities. Slowing of axon conduction was greatest in the most distal portions of motor axons. Morphological analysis of neuromuscular junctions (NMJs) showed that these functional changes were associated with increased loss of intact innervation and with the appearance of significant motor axon and motor terminal sprouting. These effects were not observed in the MG muscles of age-matched, normal animals with synergist denervation for 5 wk. The results indicate that motor neuron action potential activity is a major contributing factor to the loss of motor-unit function and degeneration in inherited canine motor neuron disease.     

Immunization with Staphylococcus aureus iron regulated surface determinant B (IsdB) confers protection via Th17/IL17 pathway in a murine sepsis model

We have previously shown that IsdB, a conserved protein expressed by Staphylococcus aureus, induces a robust antibody response which correlates with protection in a murine challenge model. Here we investigate the role of cellular immunity in IsdB mediated protection using lymphocyte deficient SCID mice. As opposed to WT CB-17 mice the CB-17 SCID mice were not protected against a lethal challenge of S. aureus after active and passive immunizations with IsdB. Adoptive transfer of in vitro isolated lymphocyte subsets revealed that reconstituting mice with IsdB specific CD3+ or CD4+ T-cells conferred antigen specific protection while CD8 (+) T-cells, CD19 (+) B-cells and plasma cells (CD138 (high) B220 (int) CD19 (lo) ) alone were not protective. A combination of CD3 (+) T-cells plus CD19 (+) B-cells conferred protection in CB-17 SCID mice, whereas bovine serum albumin (BSA) immune lymphocytes did not confer protection. Active immunization experiments indicated that IsdB immunized Jh mice (B-cell deficient) were protected against lethal challenge, while nude (T-cell deficient) mice were not. In vitro assays indicated that isolated IsdB specific splenocytes from immunized mice produced abundant IL-17A, much less IFN-γ and no detectable IL-4. IL-23 deficient mice were not protected from a lethal challenge by IsdB vaccination, pointing to a critical role for CD4 (+) Th17 in IsdB-mediated vaccination. Neutralizing IL-17A, but not IL-22 in vivo significantly increased mortality in IsdB immunized mice; whereas, neutralizing IFN-γ did not alter IsdB-mediated protection. These findings suggest that IL-17A producing Th17 cells play an essential role in IsdB vaccine-mediated defense against invasive S. aureus infection in mice.     

Evaluating group visits in an uninsured or inadequately insured patient population with uncontrolled type 2 diabetes

PURPOSE: This study was conducted to evaluate the feasibility and acceptability of a managed-care approach (group visits) on delivering care to uninsured or inadequately insured patients with type 2 diabetes. METHODS: One hundred twenty patients with uncontrolled type 2 diabetes were randomly assigned to receive care in group visits or usual care for 6 months. At baseline, 3 months, and 6 months, the feasibility and acceptability of this model of healthcare delivery were assessed through the patients' responses to the Primary Care Assessment Tool and the Trust in Physician Scale. Attendance records were kept for each group. RESULTS: Patients who received care in group visits showed an improved sense of trust in their physician compared with patients who continued to receive usual care. There was a tendency for patients in groups to report better coordination of their care, better community orientation, and more culturally competent care. Patient attendance at the groups also indicated good acceptance of this form of healthcare delivery. CONCLUSIONS: Group visits were feasible and acceptable to these uninsured and inadequately insured patients with uncontrolled type 2 diabetes and fostered an improved sense of trust in their physician.     

Exploring the reciprocal relationship between immunity and inflammation in chronic inflammatory arthritis

Experimental models seeking to explore how susceptible individuals develop rheumatoid arthritis (RA) propose that genetic and environmental factors shape a complex series of molecular and cellular interactions leading to a chronic inflammatory response. T lymphocytes and MHC class II genes have featured prominently in these models. More recent studies have suggested that perpetuation of inflammation in a disease-susceptible host might occur through failure to down-regulate the inflammatory process. One prediction from this model is that effective mechanisms of immunoregulation might be most easily investigated in non-susceptible individuals. However, this has been difficult to study in man. Based on the observation that extended MHC haplotypes are strongly associated with RA in different ethnic groups, I have explored the function of human MHC-encoded genes in transgenic mice using two different experimental approaches. First, by comparing the molecular interactions between disease-associated or non-associated HLA-DR4 molecules and CD4+ T lymphocytes, it has been possible to gain insight into how immune responses in non-susceptible individuals might differ from T-cell responses observed in a susceptible host. This has been achieved using transgenic mice expressing RA disease-associated and non-associated human HLA class II molecules. Secondly, the effects of prolonged exposure of T cells to the proinflammatory cytokine tumour necrosis factor alpha (TNF) have been studied in vitro and in vivo, focusing on T-cell receptor (TCR) signalling and effector responses. In studies of HLA class II transgenic mice, the major differences between disease-associated and non-associated alleles in terms of T-cell responses occur at the level of presentation of antigenic peptides, and the sustained expression of inflammatory cytokines such as TNF. Chronic exposure of T cells to inflammatory cytokines such as TNF induces a phenotype which resembles RA synovial T cells, including the induction of non-deletional and reversible hyporesponsiveness to TCR ligation and uncoupling of proximal TCR signal transduction pathways. The experimental findings are consistent with a model in which HLA class II-driven inflammatory cytokine expression uncouples TCR signalling pathways in the susceptible host in such a way as to profoundly suppress proliferative and immunoregulatory cytokine responses, while at the same time promoting cell survival and effector responses.     

Lung transplant reperfusion injury involves pulmonary macrophages and circulating leukocytes in a biphasic response

OBJECTIVE: Both donor pulmonary macrophages and recipient circulating leukocytes may be involved in reperfusion injury after lung transplantation. By using the macrophage inhibitor gadolinium chloride and leukocyte filters, we attempted to identify the roles of these two populations of cells in lung transplant reperfusion injury. METHODS: With our isolated, ventilated, blood-perfused rabbit lung model, all groups underwent lung harvest followed by 18-hour cold storage and 2-hour blood reperfusion. Measurements of pulmonary artery pressure, lung compliance, and arterial oxygenation were obtained. Group I (n = 8) served as a control. Group II (n = 8) received gadolinium chloride at 14 mg/kg 24 hours before lung harvest. Group III (n = 8) received leukocyte-depleted blood reperfusion by means of a leukocyte filter. RESULTS: The gadolinium chloride group had significantly improved arterial oxygenation and pulmonary artery pressure measurements compared with control subjects and an improved arterial oxygenation compared with the filter group after 30 minutes of reperfusion. After 120 minutes of reperfusion, however, the filter group had significantly improved arterial oxygenation and pulmonary artery pressure measurements compared with the control group and an improved arterial oxygenation compared with the gadolinium chloride group. CONCLUSIONS: Lung transplant reperfusion injury occurs in two phases. The early phase is mediated by donor pulmonary macrophages and is followed by a late injury induced by recipient circulating leukocytes.     

Host feeding of mosquitoes (Diptera: Culicidae) associated with the recurrence of Rift Valley fever in Egypt

In 1993, Rift Valley fever (RVF) virus reappeared in Egypt. We determined the prevalence and feeding patterns of mosquitoes in 5 villages where the virus was active. Of 10 species recovered, Aedes caspius (Pallas), Culex pipiens L., Cx. antennatus (Becker), and Cx. perexiguus Theobald constituted 99% of > 35,000 mosquitoes captured in dry ice-baited CDC light traps. Ae. caspius was most prevalent, except at Nag' El Hagar where it was replaced by Cx. perexiguus. Cx. pipiens ranked 2nd, except at Nag' El Ghuneimiya, where it was replaced by Cx. antennatus. Most blood meals analyzed by an enzyme-linked immunosorbent assay reacted to > or = 1 antiserum. Cx. pipiens was mainly anthropophagic, and therefore may have been the main vector of RVF virus among humans. Ae. caspius feeds were chiefly from humans, bovines, and equines. Cx. antennatus and Cx. perexiguus fed generally on bovines. Mixed blood meals from humans and RVF virus susceptible animals were identified in the predominant mosquitoes. Prevalence and host selection, as well as predicted probability for a blood meal being interrupted, indicated that Ae. caspius may have served as a bridge vector between humans and bovines in 4 of the villages. Cx. perexiguus may have played this role at Nag' El Hagar. Because potential vectors are abundant, susceptible domestic animals are associated closely with humans, and surveillance of imported livestock is not systematic, we conclude that RVF virus sporadically will recur in Egypt.     

Influence of synaptic identity on single-Ia-afferent connectivity and EPSP amplitude in the adult cat: homonymous versus heteronymous connections.

1. This study makes use of the pattern of synaptic connections between motoneurons and Ia afferents of triceps surae muscles in the cat to test the relative importance of synaptic identity, neuronal size, and neuronal topography as determinants of Ia-afferent connectivity and excitatory postsynaptic potential (EPSP) amplitude. 2. The synaptic actions of single-Ia medial gastrocnemius (MG) afferents were measured by intracellular recording in MG and lateral gastrocnemius (LG) motoneurons. The spike-triggered averaging technique was used to measure EPSPs generated by homonymous or heteronymous Ia afferents and motoneurons, i.e., neurons supplying the same or different muscles, respectively. In agreement with earlier studies, the pooled sample showed that the number of functional connections and the size of EPSPs were both significantly greater for homonymous than for heteronymous neurons. 3. Afferent conduction velocity, motoneuron conduction velocity, rheobase current, and position of the motoneuron relative to the spinal cord afferent entry were all correlated with EPSP amplitude, but the amplitude difference between homonymous and heteronymous connections remained significant after the statistical removal analysis of covariance (ANCOVA) of the contribution of these variables. Stepwise multiple-regression analysis showed that synaptic identity explained the greatest fraction of the variance in EPSP amplitude (9%), with significant but smaller fractions accounted for by rheobase current or motoneuron conduction velocity. 4. In a separate experiment, the monosynaptic affects from both homonymous and heteronymous single-Ia afferents were examined in each of 88 MG or LG motoneurons. The single-Ia afferents used in this portion of the study were sampled from both MG and LG muscles and selected for similar conduction velocities and spinal cord entry points.(ABSTRACT TRUNCATED AT 250 WORDS)