Antibiotic resistance in invasive Streptococcus pneumoniae isolates identified in Scotland between 1999 and 2007

Data from 4727 invasive isolates of Streptococcus pneumoniae submitted to the Scottish Haemophilus, Legionella, Meningococcus and Pneumococcus Reference Laboratory between 1999 and 2007 were analysed to establish susceptibility profiles to penicillin, erythromycin and cefotaxime. Pneumococcal resistance to penicillin over the study period remained low, with only 0.2 % (n=7/4727) of isolates falling into this category (MIC ≥2 mg l−1). These isolates have been sporadic, and have mainly represented serogroup 14 (ST9) and 9 (ST156). In comparison, the ‘intermediate sensitivity’ group (MIC 0.12–1 mg l−1) ranged between 2 and 6 % per year, the majority from serogroup 9 (ST156). Over the study period, we found that 12 % (n=585/4727) of isolates were erythromycin-resistant (MIC >0.5 mg l−1), with the majority (n=467; 80 %) of these isolates identified as serogroup 14 (ST9). Cephalosporin resistance (cefotaxime MIC >1 mg l−1) was found in only 0.06 % (n=2/3135) of isolates. Internationally recognized clones (Pneumococcal Molecular Epidemiology Network) accounted for 35 % (n=28/81) of the penicillin non-susceptible isolates and 75 % (n=248/330) of the macrolide-resistant isolates, with ST9 and ST306 predominating. Between 1999 and 2007 we found that 11.6 % (n=18/155) of the penicillin non-susceptible isolates and 4.8 % (n=28/585) of the macrolide-resistant isolates were from serogroups not covered by the 7-valent conjugate pneumococcal vaccine in use in the UK since 2006. Susceptibility to first-line antimicrobial agents for invasive pneumococcal disease in Scotland remained high over the period 1999–2007.

Forgotten but not gone - Scrofuloderma in a migrant student from India

A 34-year-old Indian student who immigrated to Australia five years ago presented with a four-week history of neck pain. Physical examination revealed two firm fixed cervical lymph nodes in the anterior triangle and midline region which were tender on palpation and erythematous on inspection. Cording phenomenon was found on ZN staining of FNA sample and mycobacterium tuberculosis (M.tb) PCR confirmed the diagnosis with incomplete resistance to isoniazid. Patient was treated with other three first line antituberculosis medications for nine months with an excellent outcome. Prednisolone was also used as adjunctive therapy and tapered during the course of treatment.

Effect of diet versus diet and exercise on weight loss and body composition in class II and III obesity: A systematic review

Class II and III obesity (BMI >35 kg·m2) have increased dramatically in recent years. Current clinical guidelines suggest diet and exercise as first line treatment for adults throughout the spectrum of overweight and obesity. However, to date there is no systematic review that examines the effects of diet and exercise on this high risk population. This systematic review will examine the combined effects of diet versus diet and exercise on body composition in severe obesity. Medline and Cinahl were searched for randomised controlled trials comparing diet and exercise to diet alone. Studies published until July 2013 were included if they used reliable methods for analysing body composition in adults with BMI ≥ 35 kg·m2. Five of 459 studies met the inclusion criteria. Two studies, both in older adults, reported that exercise reduced lean mass loss during weight loss. Two studies showed that exercise facilitated (greater) fat mass loss. The remaining study reported no differences in body composition when exercise is added to energy restriction. Exercise training during energy restriction for individuals with BMI ≥35 kg.m2 may influence body composition outcomes but the evidence is limited. Further studies should focus on the efficacy of different exercise protocols during energy restriction for this population in order to better inform decision making for the treatment of severe obesity in respect to favourable body composition outcomes.

Identification of natural killer cell receptor genes in the genome of the marsupial Tasmanian devil (Sarcophilus harrisii)

Within the mammalian immune system, natural killer (NK) cells contribute to the first line of defence against infectious agents and tumours. Their activity is regulated, in part, by cell surface NK cell receptors. NK receptors can be divided into two unrelated, but functionally analogous superfamilies based on the structure of their extracellular ligand-binding domains. Receptors belonging to the C-type lectin superfamily are predominantly encoded in the natural killer complex (NKC), while receptors belonging to the immunoglobulin superfamily are predominantly encoded in the leukocyte receptor complex (LRC). Natural killer cell receptors are emerging as a rapidly evolving gene family which can display significant intra- and interspecific variation. To date, most studies have focused on eutherian mammals, with significantly less known about the evolution of these receptors in marsupials. Here, we describe the identification of 43 immunoglobulin domain-containing LRC genes in the genome of the Tasmanian devil (Sarcophilus harrisii), the largest remaining marsupial carnivore and only the second marsupial species to be studied. We also identify orthologs of NKC genesKLRK1, CD69, CLEC4E, CLEC1B, CLEC1A and an ortholog of an opossum NKC receptor. Characterisation of these regions in a second, distantly related marsupial provides new insights into the dynamic evolutionary histories of these receptors in mammals. Understanding the functional role of these genes is also important for the development of therapeutic agents against Devil Facial Tumour Disease, a contagious cancer that threatens the Tasmanian devil with extinction.

Persistence on therapy and propensity matched outcome comparison of two subcutaneous interferon beta 1a dosages for multiple sclerosis

To compare treatment persistence between two dosages of interferon β-1a in a large observational multiple sclerosis registry and assess disease outcomes of first line MS treatment at these dosages using propensity scoring to adjust for baseline imbalance in disease characteristics. Treatment discontinuations were evaluated in all patients within the MSBase registry who commenced interferon β-1a SC thrice weekly (n = 4678). Furthermore, we assessed 2-year clinical outcomes in 1220 patients treated with interferon β-1a in either dosage (22 µg or 44 µg) as their first disease modifying agent, matched on propensity score calculated from pre-treatment demographic and clinical variables. A subgroup analysis was performed on 456 matched patients who also had baseline MRI variables recorded. Overall, 4054 treatment discontinuations were recorded in 3059 patients. The patients receiving the lower interferon dosage were more likely to discontinue treatment than those with the higher dosage (25% vs. 20% annual probability of discontinuation, respectively). This was seen in discontinuations with reasons recorded as “lack of efficacy” (3.3% vs. 1.7%), “scheduled stop” (2.2% vs. 1.3%) or without the reason recorded (16.7% vs. 13.3% annual discontinuation rate, 22 µg vs. 44 µg dosage, respectively). Propensity score was determined by treating centre and disability (score without MRI parameters) or centre, sex and number of contrast-enhancing lesions (score including MRI parameters). No differences in clinical outcomes at two years (relapse rate, time relapse-free and disability) were observed between the matched patients treated with either of the interferon dosages. Treatment discontinuations were more common in interferon β-1a 22 µg SC thrice weekly. However, 2-year clinical outcomes did not differ between patients receiving the different dosages, thus replicating in a registry dataset derived from “real-world” database the results of the pivotal randomised trial. Propensity score matching effectively minimised baseline covariate imbalance between two directly compared sub-populations from a large observational registry.

Is lithium in a class of its own? A brief profile of its clinical use

Lithium is a unique and effective psychotropic agent with a long-standing history of clinical use yet it is increasingly overlooked in lieu of newer agents. The purpose of the present paper was to succinctly review the therapeutic profile of lithium particularly with respect to the treatment of mood disorders and consider its unique properties and clinical utility. A comprehensive literature review pertaining to lithium was undertaken using electronic database search engines to identify relevant clinical trials, meta-analyses and Cochrane reviews. In addition articles and book chapters known to the authors were carefully reviewed, and the authors appraised published guidelines. The evidence from these sources was rated using National Health and Medical Research Council evidence levels and synthesized according to phenotype and mood states. In addition, the authors have drawn upon published guidelines and their own clinical experience. Lithium has specificity for mood disorders with proven efficacy in the treatment of both unipolar depression and bipolar disorder. The recommendations are based predominantly on Level I evidence, but its clinical use has to be tempered against potential side-effects and the need for ongoing monitoring. In practice, lithium should be considered a first-line option in bipolar disorder, especially in prophylaxis and when onset of action is not an imperative. Lithium has been in use in modern medicine for 60 years and as such has been tried and tested across the full range of mood disorders. Arguably, lithium is the only true mood stabilizer and because of its unique properties is in a class of its own.

Medicating mood with maintenance in mind : bipolar depression pharmacotherapy

Objectives:  Bipolar depression is a core feature of bipolar disorder, a phase in which many patients spend the majority of time and one that confers a significant degree of burden and risk. The purpose of this paper is to briefly review the evidence base for the pharmacotherapy of bipolar depression and to discuss the recommendations for its optimal management.Methods:  A detailed literature review was undertaken with a particular emphasis on pharmacological treatment strategies for bipolar depression across the acute and maintenance phases of the illness. Electronic library and Web-based searches were performed using recognised tools (MEDLINE, PubMED, EMBASE and PsychINFO) to identify the pertinent literature. A summary of the evidence base is outlined and then distilled into broad clinical recommendations to guide the pharmacological management of bipolar depression.Results:  Partitioning treatment into acute and maintenance therapy is difficult based on the paucity of current evidence. The evidence from treatment trials favours the use of lithium and lamotrigine as first-line treatment in preference to valproate, and indicates that, for acute episodes, quetiapine and olanzapine have perhaps achieved equivalence at least in terms of efficacy. However, the effectiveness of the atypical antipsychotics in maintenance therapy is constrained by the potential for significant side effects of individual agents and the lack of both long-term research data and clinical experience in treating bipolar disorder as compared to other agents. Conversely, lithium and the anticonvulsants are generally slower to effect symptomatic change, and this limits their usefulness.Conclusions:  There has been a tendency for research trials of bipolar depression to differentiate the illness cross-sectionally into the acute and maintenance phases of bipolar depression; however, in clinical terms, bipolar depression invariably follows a longitudinal course in which the phases of illness are inextricably linked, and useful acute treatments are typically continued in maintenance. Therefore, when medicating mood in acute bipolar depression it is imperative to keep maintenance in mind as it is this aspect of treatment that determines long-term success.

The integrative management of treatment-resistant depression: a comprehensive review and perspectives.

Major depressive disorder is a prevalent and disabling illness. Notwithstanding numerous advances in the pharmacological treatment of depression, approximately 70% of patients do not remit after first-line antidepressant treatment.

The addition of fluoxetine to cognitive behavioural therapy for youth depression (YoDA-C): study protocol for a randomised control trial.

The aim of the Youth Depression Alleviation-Combined Treatment (YoDA-C) study is to determine whether antidepressant medication should be started as a first-line treatment for youth depression delivered concurrently with psychotherapy. Doubts about the use of medication have been raised by meta-analyses in which the efficacy and safety of antidepressants in young people have been questioned, and subsequent treatment guidelines for youth depression have provided only qualified support.

The role of lamotrigine in the management of bipolar disorder.

Lamotrigine has emerged with a distinct place in the pharmacological treatment of bipolar disorder, with the potential to treat and prevent bipolar depression, which is the dominant and arguably most disabling and under-treated phase of the illness. This review examines the published clinical trials of lamotrigine in bipolar treatment. While the data supports its tolerability and safety, the strongest evidence for its efficacy lies in the prevention of bipolar depression, with weaker evidence for the treatment of acute bipolar depression, refractory unipolar and bipolar depression, and rapid cycling bipolar disorder. The total number of published well designed trials is small, even the maintenance evidence is derived from two studies. However, this relative inadequacy compares favorably with the alternative treatment options for bipolar depression, which are marked by poor efficacy or risk of polarity switch. The designation of lamotrigine as first-line treatment for bipolar depression prophylaxis should be done in cognizance of this context, and it would seem prudent to await greater evidence of efficacy before designating lamotrigine as first-line treatment for other bipolar indications. Further randomized controlled trials are required to consolidate the available findings and to explore the boundaries of lamotrigine's efficacy, which may encompass the soft spectral disorders.

An adjunctive antidepressant nutraceutical combination in treating major depression: study protocol and clinical considerations

Current treatment for major depressive disorder (MDD), a prevalent and disabling mental illness, is inadequate, with two-thirds of people treated with first-line antidepressants not achieving remission. MDD is for many a chronic condition, often requiring multiple treatment attempts, thus development of additional interventions is urgently required. An emerging approach to improve non-response to antidepressants is the use of adjunctive nutraceuticals. The pathophysiology of MDD is considered to involve a range of abnormalities (monoamine impairment, neuro-endocrinological changes, reduced brain-derived neurotrophic factor, and cytokine alterations). By targeting an array of these key neurobiological pathways via specific nutraceuticals (S-adenosyl methionine; [SAMe], 5-HTP [active tryptophan], folinic acid [active folic acid], omega-3 fatty acids, and zinc), there is the potential to provide a more comprehensive therapeutic biological approach to treat depression. We are currently conducting a National Health and Medical Research Council funded study in Australia (APP1048222). The clinical trial is phase II/III, multi-site, 3-arm, 8-week, randomised, double-blind, placebo-controlled study using SAMe + folinic acid versus a combination nutraceutical (SAMe, 5-HTP, folinic acid, omega-3, and zinc) or matching placebo in 300 currently depressed participants with diagnosed MDD who are non-responsive to current antidepressants (ANZCTR, protocol number: 12613001300763). The results may provide evidence for a novel adjunctive neurobiological approach for treating depression.

Effects of depression and serotonergic antidepressants on bone: mechanisms and implications for the treatment of depression

Osteoporosis is a chronic skeletal disease marked by microarchitectural deterioration of the bone matrix and depletion of bone mineral density (BMD), with a consequent increased risk for fragility fractures. It has been frequently associated with depression, which is also a chronic and debilitating disorder with high prevalence. Selective serotonin reuptake inhibitors (SSRIs), first-line agents in the pharmacological treatment of mood and anxiety disorders, have also been shown to negatively affect bone metabolism. SSRIs are the most prescribed antidepressants worldwide and a large number of persons at risk of developing osteoporosis, including older patients, will receive these antidepressants. Therefore, a proper musculoskeletal evaluation of individuals who are being targeted for or using SSRIs is a priority. The aim of this article is to review the evidence regarding the effects of depression and serotonergic antidepressants on bone and its implications for clinical care.

Nurse-led titration of angiotensin converting enzyme inhibitors, beta-adrenergic blocking agents, and angiotensin receptor blockers for people with heart failure with reduced ejection fraction

BACKGROUND: Heart failure is associated with high mortality and hospital readmissions. Beta-adrenergic blocking agents, angiotensin converting enzyme inhibitors (ACEIs), and angiotensin receptor blockers (ARBs) can improve survival and reduce hospital readmissions and are recommended as first-line therapy in the treatment of heart failure. Evidence has also shown that there is a dose-dependent relationship of these medications with patient outcomes. Despite this evidence, primary care physicians are reluctant to up-titrate these medications. New strategies aimed at facilitating this up-titration are warranted. Nurse-led titration (NLT) is one such strategy. OBJECTIVES: To assess the effects of NLT of beta-adrenergic blocking agents, ACEIs, and ARBs in patients with heart failure with reduced ejection fraction (HFrEF) in terms of safety and patient outcomes. SEARCH METHODS: We searched the Cochrane Central Register of Controlled Trials in the Cochrane Library (CENTRAL Issue 11 of 12, 19/12/2014), MEDLINE OVID (1946 to November week 3 2014), and EMBASE Classic and EMBASE OVID (1947 to 2014 week 50). We also searched reference lists of relevant primary studies, systematic reviews, clinical trial registries, and unpublished theses sources. We used no language restrictions. SELECTION CRITERIA: Randomised controlled trials (RCTs) comparing NLT of beta-adrenergic blocking agents, ACEIs, and/or ARBs comparing the optimisation of these medications by a nurse to optimisation by another health professional in patients with HFrEF. DATA COLLECTION AND ANALYSIS: Two review authors (AD & JC) independently assessed studies for eligibility and risk of bias. We contacted primary authors if we required additional information. We examined quality of evidence using the GRADE rating tool for RCTs. We analysed extracted data by risk ratio (RR) with 95% confidence interval (CI) for dichotomous data to measure effect sizes of intervention group compared with usual-care group. Meta-analyses used the fixed-effect Mantel-Haenszel method. We assessed heterogeneity between studies by Chi(2) and I(2). MAIN RESULTS: We included seven studies (1684 participants) in the review. One study enrolled participants from a residential care facility, and the other six studies from primary care and outpatient clinics. All-cause hospital admission data was available in four studies (556 participants). Participants in the NLT group experienced a lower rate of all-cause hospital admissions (RR 0.80, 95% CI 0.72 to 0.88, high-quality evidence) and fewer hospital admissions related to heart failure (RR 0.51, 95% CI 0.36 to 0.72, moderate-quality evidence) compared to the usual-care group. Six studies (902 participants) examined all-cause mortality. All-cause mortality was also lower in the NLT group (RR 0.66, 95% CI 0.48 to 0.92, moderate-quality evidence) compared to usual care. Approximately 27 deaths could be avoided for every 1000 people receiving NLT of beta-adrenergic blocking agents, ACEIs, and ARBs. Only three studies (370 participants) reported outcomes on all-cause and heart failure-related event-free survival. Participants in the NLT group were more likely to remain event free compared to participants in the usual-care group (RR 0.60, 95% CI 0.46 to 0.77, moderate-quality evidence). Five studies (966 participants) reported on the number of participants reaching target dose of beta-adrenergic blocking agents. This was also higher in the NLT group compared to usual care (RR 1.99, 95% CI 1.61 to 2.47, low-quality evidence). However, there was a substantial degree of heterogeneity in this pooled analysis. We rated the risk of bias in these studies as high mainly due to a lack of clarity regarding incomplete outcome data, lack of reporting on adverse events associated with the intervention, and the inability to blind participants and personnel. Participants in the NLT group reached maximal dose of beta-adrenergic blocking agents in half the time compared with participants in usual care. Two studies reported on adverse events; one of these studies stated there were no adverse events, and the other study found one adverse event but did not specify the type or severity of the adverse event. AUTHORS' CONCLUSIONS: Participants in the NLT group experienced fewer hospital admissions for any cause and an increase in survival and number of participants reaching target dose within a shorter time period. However, the quality of evidence regarding the proportion of participants reaching target dose was low and should be interpreted with caution. We found high-quality evidence supporting NLT as one strategy that may improve the optimisation of beta-adrenergic blocking agents resulting in a reduction in hospital admissions. Despite evidence of a dose-dependent relationship of beta-adrenergic blocking agents, ACEIs, and ARBs with improving outcomes in patients with HFrEF, the translation of this evidence into clinical practice is poor. NLT is one strategy that facilitates the implementation of this evidence into practice.

Expressão gênica dos receptores toll-símele e sua relação com citocinas potencialmente envolvidas em lesão de reperfusão durante a fase inicial do transplante pulmonar em humanos

Introdução: Imunidade inata é a primeira linha de defesa do hospedeiro contra microorganismos invasores, a qual é mediada por moléculas específicas que reconhecem patógenos, chamadas receptores toll-símile (TLRs). Os TLRs são também capazes de reconhecer ligantes endógenos, tais como conteúdos de células necróticas e proteínas de choque térmico (HSP), resultando na produção de citocinas e ativação do sistema imune adquirido. A função exata dos TLRs ainda é pouco entendida em transplante de órgãos. No entanto, tem sido sugerido que eles podem estar envolvidos na rejeição aguda ou crônica e atuar na resposta do enxerto a lesão por isquemia e reperfusão. Objetivo: Examinar as alterações na expressão gênica dos TLRs durante a fase inicial do transplante pulmonar em humanos e sua relação com citocinas potencialmente envolvidas na lesão por isquemia e reperfusão em transplante de órgãos. Métodos: Foram analisadas biópsias pulmonares de 14 pacientes submetidos a transplante pulmonar (LTx). Estas amostras foram coletadas no final do período de isquemia fria (TIF, n=14), no final do período de isquemia quente (TIQ, n=13),1 hora (n=12) e 2 horas (n=8) após a reperfusão do enxerto. RNA total foi isolado a partir de tecido pulmonar e os níveis de RNA mensageiro (mRNA) dos TLRs (1-10) bem como citocinas (IL-8, IL-6, IL-10, IFN-γ, IL-1β) e proteína de choque térmico 70 (HSP70) foram medidos por reação em cadeia pela polimerase em tempo real. Resultados: Foi detectada a expressão de mRNA de todos TLRs em tecido pulmonar. Nas amostras no TIF, os níveis de mRNA dos TLRs apresentaram-se com diferentes expressões gênicas. Os níveis de expressão dos TLRs, com exceção para o TLR3, estavam altamente correlacionados entre si no TIF e com os níveis de mRNA de IFN-γ, IL-10 e IL-1β e menos significativamente com os níveis de IL-6 e IL-8. Houve diminuição dos níveis de mRNA na grande maioria dos TLRs após reperfusão, o que foi diferente para a maioria das citocinas e HSP70, que apresentaram tendência a aumentar após transplante. A expressão gênica de TLR4 apresentou-se correlacionada com os níveis de IL-8 e IL-1β antes e após transplante (P<0.05). Pulmões de doadores que foram intubados por períodos acima de 72 horas (n=5) apresentaram níveis mais elevados de TLR2 e TLR10 (P<0.05). Conclusão: Pela primeira vez, foi demonstrado que a expressão dos TLRs altera-se durante o período de isquemia e reperfusão em transplante pulmonar em humanos. O tempo de intubação dos doadores pulmonares pode influenciar a expressão de receptores Toll-símile específicos. A correlação entre TLR4 e IL-8/IL-1β sugere que os TLRs pulmonares podem ter alguma função na resposta precoce do enxerto.

Construção de modelos de interação in silico e in vitro do inibidor do tipo Kunitz de Adenanthera pavonina L. para as enzimas cisteínicas e serínicas

Serines proteinases inhibitors (PIs) are widely distributed in nature and are able to inhibit both in vitro and in vivo enzymatic activites. Seed PIs in than leguminous are classified in seven families, Bowman-Birk and Kunitz type families that most studied representing an important role in the first line of defense toward insects pests. Some Kunitz type inhibitors possess activities serine and cysteine for proteinases named bifunctional inhibitor, as ApTKI the inhibitor isolate from seed of Adenanthera pavonina. The A. pavonina inhibitor presenting the uncommon property and was used for interaction studies between proteinases serine (trypsin) and cysteine (papain). In order to determinate the in vitro interaction of ApTKI against enzymes inhibitor purification was carried cut by using chromatographic techniques and inhibition assays. The 3D model of the bifunctional inhibitor ApTKI was constructed SWISS-MODEL program by homology modeling using soybean trypsin inhibitor (STI, pdb:1ba7), as template which presented 40% of identity to A. pavonina inhibitor. Model quality was evaluated by PROCHECK program. Moreover in silico analyzes of formed complex between the enzymes and ApTKI was evaluated by HEX 4.5 program. In vitro results confirmed the inhibitory assays, where the inhibitor presented the ability to simultaneously inhibit trypsin and papain. The residues encountered in the inhibitor model of folder structural three-dimensional that make contact to enzymes target coud explain the specificity pattern against serine and cysteine proteinases