Trypanosoma brucei gambiense group 1 is distinguished by a unique amino acid substitution in the HpHb receptor implicated in human serum resistance

Trypanosoma brucei rhodesiense (Tbr) and T. b. gambiense (Tbg), causative agents of Human African Trypanosomiasis (sleeping sickness) in Africa, have evolved alternative mechanisms of resisting the activity of trypanosome lytic factors (TLFs), components of innate immunity in human serum that protect against infection by other African trypanosomes. In Tbr, lytic activity is suppressed by the Tbr-specific serum-resistance associated (SRA) protein. The mechanism in Tbg is less well understood but has been hypothesized to involve altered activity and expression of haptoglobin haemoglobin receptor (HpHbR). HpHbR has been shown to facilitate internalization of TLF-1 in T.b. brucei (Tbb), a member of the T. brucei species complex that is susceptible to human serum. By evaluating the genetic variability of HpHbR in a comprehensive geographical and taxonomic context, we show that a single substitution that replaces leucine with serine at position 210 is conserved in the most widespread form of Tbg (Tbg group 1) and not found in related taxa, which are either human serum susceptible (Tbb) or known to resist lysis via an alternative mechanism (Tbr and Tbg group 2). We hypothesize that this single substitution contributes to reduced uptake of TLF and thus may play a key role in conferring serum resistance to Tbg group 1. In contrast, similarity in HpHbR sequence among isolates of Tbg group 2 and Tbb/Tbr provides further evidence that human serum resistance in Tbg group 2 is likely independent of HpHbR functio

Dysplastic Ichthyosis Uteri-like changes of the entire endometrium associated with a squamous cell carcinoma of the uterine cervix

Ichthyosis uteri is an exceedingly rare condition in which the entire surface of the endometrium is replaced by stratified squamous epithelium. Originally described as an endometrial response to iatrogenically-introduced caustic substances, similar changes have since been described in association with a variety of inflammatory conditions of the endometrium. We describe herein a heretofore undescribed example of a moderately differentiated squamous cell carcinoma of the uterine cervix associated with extensive ichthyosis uteri-like changes of the entire adjacent endometrium. Additionally, the squamous epithelium of the latter also showed multifocal changes diagnostic of a low-grade squamous intraepithelial lesion. The potential genesis of this composite of findings is discussed, as is the neoplastic potential of ichthyosis uteri. It is concluded that a squamous cell carcinoma of the cervix extended proximally into the endometrium, and that there was a colonization of a pre-existing ichthyosis uteri by associated human papillomavirus. The possibility of significant cervical pathology should be considered when plaques of squamous epithelium with low grade dysplastic changes are identified in an endometrial biopsy or curettage

Preliminary Results on Evaluation of Chickpea, Cicer arietinum, Genotypes for Resistance to the Pulse Beetle, Callosobruchus maculatus

The chickpea, Cicer arietinum L. (Fabales: Fabaceae), seeds are vulnerable, both in the field and in storage, to attack by seed-beetles. Beetles of the genus Callosobruchus are major storage pests of chickpea crops and cause considerable economic losses. In the present study, a total of 11 chickpea genotypes including five ‘kabuli’ (Mexican white, Diyar, CA 2969, ILC 8617 and ACC 245) and six ‘desi’ chickpeas (ICC 1069, ICC 12422, ICC 14336, ICC 4957, ICC 4969 and ICC 7509) were evaluated for resistance to the pulse beetle Callosobruchus maculatus F. (Coleoptera: Bruchidae). Resistance was evaluated by measuring percent damage to seeds. Damage to seeds by C. maculatus was manifested by the round exit holes with the ‘flap’ of seed coat made by emerging adults. Of the 11 genotypes tested, only one (ICC 4969) exhibited a complete resistance to C. maculatus in both free-choice and no-choice tests; no seed damage was found over the test period. In general, the ‘desi’ chickpeas were more resistant to C. maculatus than the ‘kabuli’ chickpeas. Among the tested chickpea genotypes, only ICC 4969 can be used as a source of C. maculatus resistance in breeding programmes that could then be grown in organic cultivation free from pesticides

In vitro and in vivo antileishmanial efficacy of a combination therapy of diminazene and artesunate against Leishmania donovani in BALB /c mice

The in vitro and in vivo activity of diminazene (Dim), artesunate (Art) and combination of Dim and Art (Dim-Art) against Leishmania donovani was compared to reference drug; amphotericin B. IC50 of Dim-Art was found to be $2.28 \pm 0.24 \mu$ g/mL while those of Dim and Art were $9.16 \pm 0.3 \mu$ g/mL and $4.64 \pm 0.48 \mu$ g/mL respectively. The IC50 for Amphot B was $0.16 \pm 0.32 \mu$ g/mL against stationary-phase promastigotes. In vivo evaluation in the L. donovani BALB/c mice model indicated that treatments with the combined drug therapy at doses of 12.5 mg/kg for 28 consecutive days significantly ($p < 0.001$) reduced parasite burden in the spleen as compared to the single drug treatments given at the same dosages. Although parasite burden was slightly lower ($p < 0.05$) in the Amphot B group than in the Dim-Art treatment group, the present study demonstrates the positive advantage and the potential use of the combined therapy of Dim-Art over the constituent drugs, Dim or Art when used alone. Further evaluation is recommended to determine the most efficacious combination ratio of the two compounds.Comment: 4 Pages, 3 Figure

Mixed-methods evaluation of the NHS Genomic Medicine Service for paediatric rare diseases: study protocol [version 1; peer review: awaiting peer review]

Background: A new nationally commissioned NHS England Genomic Medicine Service (GMS) was recently established to deliver genomic testing with equity of access for patients affected by rare diseases and cancer. The overarching aim of this research is to evaluate the implementation of the GMS during its early years, identify barriers and enablers to successful implementation, and provide recommendations for practice. The focus will be on the use of genomic testing for paediatric rare diseases. / Methods: This will be a four-year mixed-methods research programme using clinic observations, interviews and surveys. Study 1 consists of qualitative interviews with designers/implementers of the GMS in Year 1 of the research programme, along with documentary analysis to understand the intended outcomes for the Service. These will be revisited in Year 4 to compare intended outcomes with what happened in practice, and to identify barriers and facilitators that were encountered along the way. Study 2 consists of clinic observations (pre-test counselling and results disclosure) to examine the interaction between health professionals and parents, along with follow-up interviews with both after each observation. Study 3 consists of a longitudinal survey with parents at two timepoints (time of testing and 12 months post-results) along with follow-up interviews, to examine parent-reported experiences and outcomes. Study 4 consists of qualitative interviews and a cross-sectional survey with medical specialists to identify preparedness, facilitators and challenges to mainstreaming genomic testing. The use of theory-based and pre-specified constructs will help generalise the findings and enable integration across the various sub-studies. / Dissemination: We will disseminate our results to policymakers as findings emerge, so any suggested changes to service provision can be considered in a timely manner. A workshop with key stakeholders will be held in Year 4 to develop and agree a set of recommendations for practice

Cross-cultural adaptation of the VISA-A questionnaire, an index of clinical severity for patients with Achilles tendinopathy, with reliability, validity and structure evaluations

BACKGROUND: Achilles tendinopathy is considered to be one of the most common overuse injuries in elite and recreational athletes and the recommended treatment varies. One factor that has been stressed in the literature is the lack of standardized outcome measures that can be used in all countries. One such standardized outcome measure is the Victorian Institute of Sports Assessment – Achilles (VISA-A) questionnaire, which is designed to evaluate the clinical severity for patients with Achilles tendinopathy. The purpose of this study was to cross-culturally adapt the VISA-A questionnaire to Swedish, and to perform reliability, validity and structure evaluations. METHODS: Cross-cultural adaptation was performed in several steps including translations, synthesis of translations, back translations, expert committee review and pre-testing. The final Swedish version, the VISA-A Swedish version (VISA-A-S) was tested for reliability on healthy individuals (n = 15), and patients (n = 22). Tests for internal consistency, validity and structure were performed on 51 patients. RESULTS: The VISA-A-S had good reliability for patients (r = 0.89, ICC = 0.89) and healthy individuals (r = 0.89–0.99, ICC = 0.88–0.99). The internal consistency was 0.77 (Cronbach's alpha). The mean [95% confidence interval] VISA-A-S score in the 51 patients (50 [44–56]) was significantly lower than in the healthy individuals (96 [94–99]). The VISA-A-S score correlated significantly (Spearman's r = -0.68) with another tendon grading system. Criterion validity was considered good when comparing the scores of the Swedish version with the English version in both healthy individuals and patients. The factor analysis gave the factors pain/symptoms and physical activity CONCLUSION: The VISA-A-S questionnaire is a reliable and valid instrument and comparable to the original version. It measures two factors: pain/symptoms and physical activity, and can be used in both research and the clinical setting

Is bisphosphonate therapy for benign bone disease associated with impaired dental healing? A case-controlled study

<p>Abstract</p> <p>Background</p> <p>Bisphosphonates are common first line medications used for the management of benign bone disease. One of the most devastating complications associated with bisphosphonate use is osteonecrosis of the jaws which may be related to duration of exposure and hence cumulative dose, dental interventions, medical co-morbidities or in some circumstances with no identifiable aggravating factor. While jaw osteonecrosis is a devastating outcome which is currently difficult to manage, various forms of delayed dental healing may be a less dramatic and, therefore, poorly-recognised complications of bisphosphonate use for the treatment of osteoporosis. It is hypothesised that long-term (more than 1 year's duration) bisphosphonate use for the treatment of post-menopausal osteoporosis or other benign bone disease is associated with impaired dental healing.</p> <p>Methods/Design</p> <p>A case-control study has been chosen to test the hypothesis as the outcome event rate is likely to be very low. A total of 54 cases will be recruited into the study following review of all dental files from oral and maxillofacial surgeons and special needs dentists in Victoria where potential cases of delayed dental healing will be identified. Potential cases will be presented to an independent case adjudication panel to determine if they are definitive delayed dental healing cases. Two hundred and fifteen controls (1:4 cases:controls), matched for age and visit window period, will be selected from those who have attended local community based referring dental practices. The primary outcome will be the incidence of delayed dental healing that occurs either spontaneously or following dental treatment such as extractions, implant placement, or denture use.</p> <p>Discussion</p> <p>This study is the largest case-controlled study assessing the link between bisphosphonate use and delayed dental healing in Australia. It will provide invaluable data on the potential link between bisphosphonate use and osteonecrosis of the jaws.</p

Comparative effectiveness of dipeptidyl peptidase-4 (DPP-4) inhibitors and human glucagon-like peptide-1 (GLP-1) analogue as add-on therapies to sulphonylurea among diabetes patients in the Asia-Pacific region: a systematic review

The prevalence of diabetes mellitus is rising globally, and it induces a substantial public health burden to the healthcare systems. Its optimal control is one of the most significant challenges faced by physicians and policy-makers. Whereas some of the established oral hypoglycaemic drug classes like biguanide, sulphonylureas, thiazolidinediones have been extensively used, the newer agents like dipeptidyl peptidase-4 (DPP-4) inhibitors and the human glucagon-like peptide-1 (GLP-1) analogues have recently emerged as suitable options due to their similar efficacy and favorable side effect profiles. These agents are widely recognized alternatives to the traditional oral hypoglycaemic agents or insulin, especially in conditions where they are contraindicated or unacceptable to patients. Many studies which evaluated their clinical effects, either alone or as add-on agents, were conducted in Western countries. There exist few reviews on their effectiveness in the Asia-Pacific region. The purpose of this systematic review is to address the comparative effectiveness of these new classes of medications as add-on therapies to sulphonylurea drugs among diabetic patients in the Asia-Pacific countries. We conducted a thorough literature search of the MEDLINE and EMBASE from the inception of these databases to August 2013, supplemented by an additional manual search using reference lists from research studies, meta-analyses and review articles as retrieved by the electronic databases. A total of nine randomized controlled trials were identified and described in this article. It was found that DPP-4 inhibitors and GLP-1 analogues were in general effective as add-on therapies to existing sulphonylurea therapies, achieving HbA1c reductions by a magnitude of 0.59–0.90% and 0.77–1.62%, respectively. Few adverse events including hypoglycaemic attacks were reported. Therefore, these two new drug classes represent novel therapies with great potential to be major therapeutic options. Future larger-scale research should be conducted among other Asia-Pacific region to evaluate their efficacy in other ethnic groups

Augmented Lung Inflammation Protects against Influenza A Pneumonia

Influenza pneumonia causes high mortality every year, and pandemic episodes kill millions of people. Influenza-related mortality has been variously ascribed to an ineffective host response that fails to limit viral replication, an excessive host inflammatory response that results in lung injury and impairment of gas exchange, or to bacterial superinfection. We sought to determine whether lung inflammation promoted or impaired host survival in influenza pneumonia.To distinguish among these possible causes of influenza-related death, we induced robust lung inflammation by exposing mice to an aerosolized bacterial lysate prior to challenge with live virus. The treatment induced expression of the inflammatory cytokines IL-6 and TNF in bronchoalveolar lavage fluid 8- and 40-fold greater, respectively, than that caused by lethal influenza infection. Yet, this augmented inflammation was associated with striking resistance to host mortality (0% vs 90% survival, p = 0.0001) and reduced viral titers (p = 0.004). Bacterial superinfection of virus infected lungs was not observed. When mice were repeatedly exposed to the bacterial lysate, as would be clinically desirable during an influenza epidemic, there was no tachyphylaxis of the induced viral resistance. When the bacterial lysate was administered after the viral challenge, there was still some mortality benefit, and when ribavirin was added to the aerosolized bacterial lysate, host survival was synergistically improved (0% vs 93.3% survival, p<0.0001).Together, these data indicate that innate immune resistance to influenza can be effectively stimulated, and suggest that ineffective rather than excessive inflammation is the major cause of mortality in influenza pneumonia

H5N1 Influenza Vaccine Formulated with AS03A Induces Strong Cross-Reactive and Polyfunctional CD4 T-Cell Responses

Objective Adjuvantation of an H5N1 split-virion influenza vaccine with AS03(A) substantially reduces the antigen dose required to produce a putatively protective humoral response and promotes cross-clade neutralizing responses. We determined the effect of adjuvantation on antibody persistence and B- and T-cell-mediated immune responses. Methods Two vaccinations with a split-virion A/Vietnam/1194/2004 (H5N1, clade 1) vaccine containing 3.75-30 mu g hemagglutinin and formulated with or without adjuvant were administered to groups of 50 volunteers aged 18-60 years. Results Adjuvantation of the vaccine led to better persistence of neutralizing and hemagglutination-inhibiting antibodies and higher frequencies of antigen-specific memory B cells. Cross-reactive and polyfunctional H5N1-specific CD4 T cells were detected at baseline and were amplified by vaccination. Expansion of CD4 T cells was enhanced by adjuvantation. Conclusion Formulation of the H5N1 vaccine with AS03(A) enhances antibody persistence and induces stronger T- and B-cell responses. The cross-clade T-cell immunity indicates that the adjuvanted vaccine primes individuals to respond to either infection and/or subsequent vaccination with strains drifted from the primary vaccine strain