EFFECT OF SPLENECTOMY ON THE SUSCEPTIBILITY OF MICE INOCULATED WITH DIPLOCOCCUS PNEUMONIAE

An experimental model is described which demonstrated increased susceptibility of mice to infection with D. pneumoniae following splenectomy. It was necessary to use small numbers of a particular strain of pneumococcus (D. pneumoniae type 6), intravenous infection and a particular strain of mouse (pathogen-free NCS strain). The increase in susceptibility persisted for at least 4 months after splenectomy. With modifications in experimental design such as use of large numbers of organisms, a different strain of pneumococcus, the intraperitoneal route of infection or a different mouse strain no increase or a much less impressive increase in susceptibility was demonstrated. Following intravenous injection of small numbers of D. pneumoniae Type 6 bacteremia tended to persist in all NCS mice. Multiplication of pneumococci subsequently occurred in a higher proportion of mice with splenectomy and at a more rapid rate than in control animals. Mice with splenectomy usually had more D. pneumoniae per ml of blood than per gram of any tissue. This suggested that in these mice multiplication of microorganisms occurs primarily in blood. In control mice higher concentrations of bacteria were present in spleen than in blood, and higher concentrations were found in blood than in other tissues. These results suggested that in normal mice infected intravenously with small numbers of D. pneumoniae Type 6, the spleen protects by removing and killing small but critical numbers of D. pneumoniae which are circulating in the blood. No evidence was found to suggest that the altered susceptibility is mediated by an effect of splenectomy on numbers of circulating leukocytes or on the antibacterial activity of mouse blood

Atmospheric neutrino induced muons in the MACRO detector

A measurement of the flux of neutrino-induced muons using the MACRO detector is presented. Different event topologies, corresponding to different neutrino parent energies can be detected. The upward throughgoing muon sample is the larger event sample. The observed upward-throughgoing muons are 26% fewer than expected and the zenith angle distribution does not fit with the expected one. Assuming neutrino oscillations, both measurements suggest maximum mixing and Dm2 of a few times 10-3 eV2. The other samples are due to the internally produced events and to upward-going stopping muons. These data show a regular deficit of observed events in each angular bin, as expected assuming neutrino oscillations with maximum mixing, in agreement with the analysis of the upward-throughgoing muon sample.Comment: 7 pages 6 figures to appear in the proceedings of XVIII International Conference on Neutrino Physics and Astrophysics (Neutrino'98), Takayama, Japan 4-9 June, 199

Energy Flow in the Hadronic Final State of Diffractive and Non-Diffractive Deep-Inelastic Scattering at HERA

An investigation of the hadronic final state in diffractive and non--diffractive deep--inelastic electron--proton scattering at HERA is presented, where diffractive data are selected experimentally by demanding a large gap in pseudo --rapidity around the proton remnant direction. The transverse energy flow in the hadronic final state is evaluated using a set of estimators which quantify topological properties. Using available Monte Carlo QCD calculations, it is demonstrated that the final state in diffractive DIS exhibits the features expected if the interaction is interpreted as the scattering of an electron off a current quark with associated effects of perturbative QCD. A model in which deep--inelastic diffraction is taken to be the exchange of a pomeron with partonic structure is found to reproduce the measurements well. Models for deep--inelastic $ep$ scattering, in which a sizeable diffractive contribution is present because of non--perturbative effects in the production of the hadronic final state, reproduce the general tendencies of the data but in all give a worse description.Comment: 22 pages, latex, 6 Figures appended as uuencoded fil

Hydroxyurea and sickle cell anemia: effect on quality of life

BACKGROUND: The Multicenter Study of Hydroxyurea (HU) in Sickle Cell Anemia (MSH) previously showed that daily oral HU reduces painful sickle cell (SS) crises by 50% in patients with moderate to severe disease. The morbidity associated with this disease is known to have serious negative impact on the overall quality of life(QOL) of affected individuals. METHODS: The data in this report were collected from the 299 patients enrolled in the MSH. Health quality of llife (HQOL) measures were assessed in the MSH as a secondary endpoint to determine if the clinical benefit of HU could translate into a measurable benefit perceptible to the patients. HQOL was assessed with the Profile of Mood States, the Health Status Short Form 36 (SF-36), including 4-week pain recall, and the Ladder of Life, self-administered twice 2-weeks apart pre-treatment and every 6 months during the two-year, randomized, double-blind, treatment phase. The effects of factors including randomized treatment, age, gender, pre-treatment crises frequency, Hb-F level mean, daily pain from 4-week pre-treatment diaries, and 2-year Hb-F response level (low or high) were investigated. RESULTS: Over two years of treatment, the benefit of HU treatment on QOL, other than pain scales, was limited to those patients taking HU who maintained a high HbF response, compared to those with low HbF response or on placebo. These restricted benefits occurred in social function, pain recall and general health perception. Stratification according to average daily pain prior to treatment showed that responders to HU whose average daily pain score was 5–9 (substantial pain) achieved significant reduction in the tension scale compared to the placebo group and to non-responders. HU had no apparent effect on other QOL measures. CONCLUSION: Treatment of SS with HU improves some aspects of QOL in adult patients who already suffer from moderate-to-severe SS

Effects of an Alpha-4 Integrin Inhibitor on Restenosis in a New Porcine Model Combining Endothelial Denudation and Stent Placement

Restenosis remains the main complication of balloon angioplasty and/or stent implantation. Preclinical testing of new pharmacologic agents preventing restenosis largely rely on porcine models, where restenosis is assessed after endothelial abrasion of the arterial wall or stent implantation. We combined endothelial cell denudation and implantation of stents to develop a new clinically relevant porcine model of restenosis, and used this model to determine the effects of an α4 integrin inhibitor, ELN 457946, on restenosis. Balloon-angioplasty endothelial cell denudation and subsequent implantation of bare metal stents in the left anterior descending coronary, iliac, and left common carotid arteries was performed in domestic pigs, treated with vehicle or ELN 457946, once weekly via subcutaneous injections, for four weeks. After 1 month, histopathology and morphometric analyses of the arteries showed complete healing and robust, consistent restenotic response in stented arteries. Treatment with ELN 457946 resulted in a reduction in the neointimal response, with decreases in area percent stenosis between 12% in coronary arteries and 30% in peripheral vessels. This is the first description of a successful pig model combining endothelial cell denudation and bare metal stent implantation. This new double injury model may prove particularly useful to assess pharmacological effects of drug candidates on restenosis, in coronary and/or peripheral arteries. Furthermore, the ELN 457946 α4 integrin inhibitor, administered subcutaneously, reduced inflammation and restenosis in stented coronary and peripheral arteries in pigs, therefore representing a promising systemic therapeutic approach in reducing restenosis in patients undergoing angioplasty and/or stent implantation

De novo single-nucleotide and copy number variation in discordant monozygotic twins reveals disease-related genes

Recent studies have demonstrated genetic differences between monozygotic (MZ) twins. To test the hypothesis that early post-twinning mutational events associate with phenotypic discordance, we investigated a cohort of 13 twin pairs (n = 26) discordant for various clinical phenotypes using whole-exome sequencing and screened for copy number variation (CNV). We identified a de novo variant in PLCB1, a gene involved in the hydrolysis of lipid phosphorus in milk from dairy cows, associated with lactase non-persistence, and a variant in the mitochondrial complex I gene MT-ND5 associated with amyotrophic lateral sclerosis (ALS). We also found somatic variants in multiple genes (TMEM225B, KBTBD3, TUBGCP4, TFIP11) in another MZ twin pair discordant for ALS. Based on the assumption that discordance between twins could be explained by a common variant with variable penetrance or expressivity, we screened the twin samples for known pathogenic variants that are shared and identified a rare deletion overlapping ARHGAP11B, in the twin pair manifesting with either schizotypal personality disorder or schizophrenia. Parent-offspring trio analysis was implemented for two twin pairs to assess potential association of variants of parental origin with susceptibility to disease. We identified a de novo variant in RASD2 shared by 8-year-old male twins with a suspected diagnosis of autism spectrum disorder (ASD) manifesting as different traits. A de novo CNV duplication was also identified in these twins overlapping CD38, a gene previously implicated in ASD. In twins discordant for Tourette's syndrome, a paternally inherited stop loss variant was detected in AADAC, a known candidate gene for the disorder

Comparison of acute and chronic lithium treatment on 3 H-norepinephrine uptake by rat brain slices

The effects of lithium chloride, given IP in high (2.5–15 mEq/kg) and low (1.25 mEq/kg) doses twice daily, upon 3 H-norepinephrine uptake and retention were examined with slices from four regions of the rat brain, namely brain stem, hypothalamus, parietal cortex, and caudate nucleus. Control uptake was significantly higher in slices from the caudate nucleus and lower in brain stem slices than in slices from hypothalamus or parietal cortex. With the higher doses, uptake increased significantly in all regions after 2 days of treatment and returned to normal by 7 days. With the lowest dose, uptake was increased after 7 days but normal at 14 days. Only in caudate slices was there a second elevation of 3 H-norepinephrine uptake after 21 days of treatment, which returned to normal by 42 days. No other effects were observed during 70 days of treatment with lithium. The correlation between changes in 3 H-norepinephrine uptake and plasma lithium levels was studied.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/46411/1/213_2004_Article_BF00427599.pd

Civil society leadership in the struggle for AIDS treatment in South Africa and Uganda

Includes abstract.Includes bibliographical references.This thesis is an attempt to theorise and operationalise empirically the notion of ‘civil society leadership’ in Sub-Saharan Africa. ‘AIDS leadership,’ which is associated with the intergovernmental institutions charged with coordinating the global response to HIV/AIDS, is both under-theorised and highly context-specific. In this study I therefore opt for an inclusive framework that draws on a range of approaches, including the literature on ‘leadership’, institutions, social movements and the ‘network’ perspective on civil society mobilisation. This framework is employed in rich and detailed empirical descriptions (‘thick description’) of civil society mobilisation around AIDS, including contentious AIDS activism, in the key case studies of South Africa and Uganda. South Africa and Uganda are widely considered key examples of poor and good leadership (from national political leaders) respectively, while the Treatment Action Campaign (TAC) and The AIDS Support Organisation (TASO) are both seen as highly effective civil society movements. These descriptions emphasise ‘transnational networks of influence’ in which civil society leaders participated (and at times actively constructed) in order to mobilise both symbolic and material resources aimed at exerting influence at the transnational, national and local levels