A clinical study of schistosomiasis in the European resident in Southern Rhodesia: with particular reference to new methods of diagnosis and treatment

In series A, 2 children were examined wiith urine and stool examination, Eosinophil. Counts, and Cercarial Skin Test Antigen.15 cases with ova demonstrable, gave raised Eosinophil Counts and + positive Skin Tests. In series B, 30 adult male Railway employees were similarly investigated. 8 cases has ova demonstrable in either urine or stool. All gave a + positive skin test, but Eosinophil :Dounts did not snow a consistent rise. Cases Nos. 11, 12 and 19 alone had percentage counts above normal limits. In -series C, 33 adult male private patients were similarly investigated. Only one case was found to nave demonstrable ova, the case gave a positive skin test and the Eosinophil count was normal.In series D 18 adult private patients were similarly investigated. None showed demonstrable ova in urine or stool. One case (No. 18) with a previous history of S. mansoni infestation was found to have a very high Eosinophilia and a doubtful skin test reaction. This case was further investigated by crystoscopy and sigmoidoscopy with negative findings and a diagnosis of Tropical Eosinophilia was finally mace.In the cases where ova were present in urine and stool: - In series A, three children gave positive skin test, Eosinophilia and history of risk of infestation. Two children gave doubtful skin test, normal Eosinophilia Counts and risk of infestation, and nine children gave negative skin test, normal Eosinophil Counts and possible risk.In series B, seven cases of Railwaymen gave positive skin test, and normal Eosinophil Counts, except in 2 cases where Eosinophilia was present. Three cases of Railwaymen gave doubtful skin test - one only had an Eosinophilia, and eleven cases of Railwaymen gave negative skin test - two only had an Eosinophilia. All these cases ran an occupational risk of infestation. In series C, two cases gave a positive skin test, normal Eosinophil Counts and risk of infestation. Five cases gave a doubtful skin test, normal Eosinophil Counts and risk of Infestation, and twenty-five cases gave a negative skin test, Eosinophilia was present in 4 cases only, and risk of infestation was doubtful. In series D, two cases gave a positive skin test, both had Eosinophilia and risk of infestation was unlikely. One case gave a doubtful skin test, a very high Eosinophilia, and a history of old S. mansoni infestation of 4 years duration, and fourteen cases gave a negative skin test, five of whom has an Eosinophilia. The risk of infestation in all these cases was very improbable.In a review of the cases in the series A, B, C, and D, it is apparent that: - 1. The demonstration of ova in urine and stool is positive evidence of the disease; that in such cases the Cercarial Skin Test Antigen gives a positive reaction in every case, and that the Eosinophil Percentage Count is not a completely reliable test in such cases. • 2. Absence of ova in urine and stool in a case does not necessarily imply freedom from the disease as such cases do not. always give a negative Cercarial Skin Test Antigen Reaction, nor is the Eosinophil Percentage Count always within normal limits. Should, however, the Cercarial Skin Test Reaction be a negative one, and the Eosinophil Count is normal, then it is practically certain the case is not one suffering from Schistosomiasis. • 3. Absence of ova in urine and stool in a case giving a positive Cercarial Skin Test Antigen may or may not mean the presence of Schistosomiasis, even with an Eosinophilia. • 4. The absence of ova in urine and stool in a case giving a doubtful Cercarial Skin Test Antigen Reaction may or may not mean the presence of Schistosomiasis, and that, with or without an Eosinophilia. In cases complying with categories 3 and 4, further intensive investigations are called for by cystoscopic and sigmoidoscopic examinations as well as further examinations of urine and stool specimens, etc. From this examination and analysis the author concludes that; - The children in S. Rhodesia are very liable to infestation by Schistosomiasis. The employees on the Rhodesian Railways in tn.e course of their occupation run a very grave risk of becoming infested, and The men and women engaged in their ordinary pursuits of life in cities of S. Rhodesia are the least likely subjects to fall victim to the disease

Is it possible to estimate the minimal clinically important treatment effect needed to change practice in preterm birth prevention? Results of an obstetrician survey used to support the design of a trial

<p>Abstract</p> <p>Background</p> <p>Sample sizes for obstetrical trials are often based on the opinion of investigators about clinically important effect size. We surveyed Canadian obstetricians to investigate clinically important effect sizes required before introducing new treatments into practice to prevent preterm birth.</p> <p>Methods</p> <p>Questionnaires were mailed to practicing obstetricians, asking the magnitude of pregnancy prolongation required to introduce treatments into practice. The three prophylactic treatments were of increasing invasiveness: vaginal progesterone, intramuscular progesterone, and cervical cerclage. We also asked about the perceived most relevant outcome measures for obstetrical trials and current obstetrical practice in preterm birth prevention.</p> <p>Results</p> <p>544/1293(42.1%) completed questionnaires were received. The majority of respondents required one or two weeks' increase in length of gestation before introducing vaginal (372,77.1%), and intramuscular progesterone(354,67.9%). At least three weeks increase was required before introducing prophylactic cervical cerclage(326,62.8%). Clinicians who already used a treatment required a smaller difference before introducing it into practice. Decreasing neonatal morbidity was cited as the most important outcome for obstetrical trials (349,72.2%).</p> <p>Conclusion</p> <p>Obstetricians would require a larger increase in treatment effect before introducing more invasive treatments into practice. Although infant morbidity was perceived as a more important outcome, clinicians appeared willing to change practice on the basis of prolongation of pregnancy, a surrogate outcome. We found that there is not a single minimum clinically important treatment effect that will influence all practising clinicians: rather the effect size that will influence physicians is affected by the nature of the treatment, the reported outcome measure and the clinician's own current clinical practice.</p

Binding characteristics of a panel of monoclonal antibodies against the ligand binding domain of the human LDLr

To obtain a panel of monoclonal antibodies (MAbs) to study the folding and conformation of the low density lipoprotein receptor (LDLr), we have generated hybridomas from LDLr-deficient mice that had been immunized with the extracellular domain of the human LDLr. The 12 MAbs were specific for the ligand binding domain of the LDLr, with individual MAbs recognizing epitopes in ligand binding repeats 1, 2, 3, 5, and 7. A subset of the MAbs failed to react with the LDLr when disulfide bonds were reduced, and one MAb, specific for an epitope that spans ligand binding repeats 1 and 2, recognized two conformational forms of the LDLr with different affinities. Antibodies specific for ligand binding repeats 3, 5, and 7 completely blocked the binding of LDL particles to the LDLr on cultured human fibroblasts, whereas MAbs with epitopes in ligand binding repeats 1 and 2 partially blocked the binding of LDL to the LDLr. These anti-LDLr MAbs will serve as useful probes for further analysis of LDLr conformation and LDLr-mediated lipoprotein binding

Suppressor of cytokine signaling 2 (SOCS2) deletion protects bone health of mice with DSS induced inflammatory bowel disease.

Individuals with inflammatory bowel disease (IBD) often present with poor bone health. The development of targeted therapies for this bone loss requires a fuller understanding of the underlying cellular mechanisms. Although bone loss in IBD is multifactorial the altered sensitivity and secretion of growth hormone (GH) and insulin-like growth factor-1 (IGF-1) in IBD is understood to be a critical contributing mechanism. The expression of suppressor of cytokine signaling 2 (SOCS2), a well-established negative regulator of GH signaling, is stimulated by pro-inflammatory cytokines. Therefore, it is likely that SOCS2 expression represents a critical mediator through which pro-inflammatory cytokines inhibit GH/IGF-1 signaling and decrease bone quality in IBD. Utilising the DSS model of colitis we have revealed that endogenously elevated GH function in the Socs2−/− mouse protects the skeleton from osteopenia. Micro-computed tomography assessment of DSS treated wild-type mice revealed a worsened trabecular architecture compared to control mice. Specifically, DSS treated WT mice had significantly decreased bone volume (BV/TV) (41%; p&#60;0.05), trabecular thickness (16%; p&#60;0.05), trabecular number (30%; p&#60;0.05), and a resulting increase in trabecular separation (19%; &#60;0.05). In comparison, the trabecular bone of Socs2 deficient mice was partially protected from the adverse effects of DSS. The reduction in a number of parameters including BV/TV (21%; p&#60;0.05) was less, and no changes were observed in trabecular thickness or separation. This protected phenotype was unlikely to be a consequence of improved mucosal health in the DSS treated Socs2−/− mice but rather a result of unregulated GH signaling directly on bone. These studies indicate that the absence of SOCS2 is protective against bone loss typical of IBD. This study also provides an improved understanding of the relative effects of GH/IGF-1 on bone health in experimental colitis, information that is essential before these drugs are explored as bone protective agents in children and adults with IBD

The Cyclical Variation of Wage Premiums in the Canadian Manufacturing Industries

The Cyclical Variation of Wage Premiums in the Canadian Manufacturing Industrie

Binding of an antibody mimetic of the human low density lipoprotein receptor to apolipoprotein E is governed through electrostatic forces. Studies using site-directed mutagenesis and molecular modeling.

Monoclonal antibody 2E8 is specific for an epitope that coincides with the binding site of the low density lipoprotein receptor (LDLR) on human apoE. Its reactivity with apoE variants resembles that of the LDLR: it binds well with apoE3 and poorly with apoE2. The heavy chain complementarity-determining region (CDRH) 2 of 2E8 shows homology to the ligand-binding domain of the LDLR. To define better the structural basis of the 2E8/apoE interaction and particularly the role of electrostatic interactions, we generated and characterized a panel of 2E8 variants. Replacement of acidic residues in the 2E8 CDRHs showed that Asp52, Glu53, and Asp56 are essential for high-affinity binding. Although Asp31 (CDRH1), Glu58 (CDRH2), and Asp97 (CDRH3) did not appear to be critical, the Asp97 → Ala variant acquired reactivity with apoE2. A Thr57 → Glu substitution increased affinity for both apoE3 and apoE2. The affinities of wild-type 2E8 and variants for apoE varied inversely with ionic strength, suggesting that electrostatic forces contribute to both antigen binding and isoform specificity. We propose a model of the 2E8·apoE immune complex that is based on the 2E8 and apoE crystal structures and that is consistent with the apoE-binding properties of wild-type 2E8 and its variants. Given the similarity between the LDLR and 2E8 in terms of specificity, the LDLR/ligand interaction may also have an important electrostatic component

Effect of increasing fruit and vegetable intake by dietary intervention on nutritional biomarkers and attitudes to dietary change : a randomised trial

This work was funded by The Scottish Government Rural and Environmental Science and Analytical Sciences Division (RESAS) and supported by the Rank Prize Funds.Peer reviewedPublisher PD

Apolipoprotein E mediates evasion from hepatitis C virus−neutralizing antibodies

Background &#38; Aims Efforts to develop an effective vaccine against hepatitis C virus (HCV) have been hindered by the propensity of the virus to evade host immune responses. HCV particles in serum and in cell culture associate with lipoproteins, which contribute to viral entry. Lipoprotein association has also been proposed to mediate viral evasion of the humoral immune response, though the mechanisms are poorly defined. Methods We used small interfering RNAs to reduce levels of apolipoprotein E (apoE) in cell culture−derived HCV−producing Huh7.5-derived hepatoma cells and confirmed its depletion by immunoblot analyses of purified viral particles. Before infection of naïve hepatoma cells, we exposed cell culture−derived HCV strains of different genotypes, subtypes, and variants to serum and polyclonal and monoclonal antibodies isolated from patients with chronic HCV infection. We analyzed the interaction of apoE with viral envelope glycoprotein E2 and HCV virions by immunoprecipitation. Results Through loss-of-function studies on patient-derived HCV variants of several genotypes and subtypes, we found that the HCV particle apoE allows the virus to avoid neutralization by patient-derived antibodies. Functional studies with human monoclonal antiviral antibodies showed that conformational epitopes of envelope glycoprotein E2 domains B and C were exposed after depletion of apoE. The level and conformation of virion-associated apoE affected the ability of the virus to escape neutralization by antibodies. Conclusions In cell-infection studies, we found that HCV-associated apoE helps the virus avoid neutralization by antibodies against HCV isolated from chronically infected patients. This method of immune evasion poses a challenge for the development of HCV vaccines