Mycobacterium tuberculosis lineage 4 comprises globally distributed and geographically restricted sublineages

Generalist and specialist species differ in the breadth of their ecological niches. Little is known about the niche width of obligate human pathogens. Here we analyzed a global collection of Mycobacterium tuberculosis lineage 4 clinical isolates, the most geographically widespread cause of human tuberculosis. We show that lineage 4 comprises globally distributed and geographically restricted sublineages, suggesting a distinction between generalists and specialists. Population genomic analyses showed that, whereas the majority of human T cell epitopes were conserved in all sublineages, the proportion of variable epitopes was higher in generalists. Our data further support a European origin for the most common generalist sublineage. Hence, the global success of lineage 4 reflects distinct strategies adopted by different sublineages and the influence of human migration.We thank S. Lecher, S. Li and J. Zallet for technical support. Calculations were performed at the sciCORE scientific computing core facility at the University of Basel. This work was supported by the Swiss National Science Foundation (grants 310030_166687 (S.G.) and 320030_153442 (M.E.) and Swiss HIV Cohort Study grant 740 to L.F.), the European Research Council (309540-EVODRTB to S.G.), TB-PAN-NET (FP7-223681 to S.N.), PathoNgenTrace projects (FP7-278864-2 to S.N.), SystemsX.ch (S.G.), the German Center for Infection Research (DZIF; S.N.), the Novartis Foundation (S.G.), the Natural Science Foundation of China (91631301 to Q.G.), and the National Institute of Allergy and Infectious Diseases (5U01-AI069924-05) of the US National Institutes of Health (M.E.)

High-dose chemoradiotherapy followed by surgery versus surgery alone in esophageal cancer: a retrospective cohort study

<p>Abstract</p> <p>Background</p> <p>We aimed to assess whether high-dose preoperative chemoradiotherapy (CRT) improves outcome in esophageal cancer patients compared to surgery alone and to define possible prognostic factors for overall survival.</p> <p>Methods</p> <p>Hundred-and-seven patients with disease stage IIA - III were treated with either surgery alone (n = 45) or high-dose preoperative CRT (n = 62). The data were collected retrospectively. Sixty-seven patients had adenocarcinomas, 39 squamous cell carcinomas and one undifferentiated carcinoma. CRT was given as three intensive chemotherapy courses by cisplatin 100 mg/m²on day 1 and 5-fluorouracil 1000 mg/m²/day, from day 1 through day 5 as continuous infusion. One course was given every 21 days. The last two courses were given concurrent with high-dose radiotherapy, 2 Gy/fraction and a median dose of 66 Gy. Kaplan-Meier survival analysis with log rank test was used to obtain survival data and Cox Regression multivariate analysis was used to define prognostic factors for overall survival.</p> <p>Results</p> <p>Toxicity grade 3 of CRT occurred in 30 (48.4%) patients and grade 4 in 24 (38.7%) patients of 62 patients. One patient died of neutropenic infection (grade 5). Fifty percent (31 patients) in the CRT group did undergo the planned surgery. Postoperative mortality rate was 9% and 10% in the surgery alone and CRT+ surgery groups, respectively (p = 1.0). Median overall survival was 11.1 and 31.4 months in the surgery alone and CRT+ surgery groups, respectively (log rank test, p = 0.042). In the surgery alone group one, 3 and 5 year survival rates were 44%, 24% and 16%, respectively and in the CRT+ surgery group they were 68%, 44% and 29%, respectively. By multivariate analysis we found that age of patient, performance status, alcoholism and > = 4 pathological positive lymph nodes in resected specimen were significantly associated with overall survival, whereas high-dose preoperative CRT was not.</p> <p>Conclusion</p> <p>We found no significant survival advantage in esophageal cancer stage IIA-III following preoperative high-dose CRT compared to surgery alone. Patient's age, performance status, alcohol abuse and number of positive lymph nodes were prognostic factors for overall survival.</p

Integrated sensory motor system in prematurely born children

Objetivo: Investigar a existência de sistema sensório motor integrado em recém-nascidos (RNs) prematuros submetidos à estimulação gustativa. Métodos: Estudo experimental analítico e duplo-cego. Participaram 90 RNs prematuros, divididos em dois grupos (água e sacarose para análise (PA) 12%), filmados durante 15 minutos (primeiro e último momentos, sem estimulação; e segundo momento com estimulação gustativa). Três juízes independentes analisaram os comportamentos mão na boca direita e esquerda e sucção da mão direita e esquerda durante os diversos estados comportamentais, inseridos no banco de dados do Statistical Package for Social Science, sendo considerados em concordância os eventos observados por pelo menos dois deles. Empregou-se teste de correlação de Spearman com nível de significância valor de p<0,05. Resultados: Tanto ao serem considerados os grupos separadamente quanto juntos, mão na boca direita e esquerda tiveram inicialmente correlação moderada, sendo que mão na boca direita manteve-se forte no final e mão na boca esquerda finalizou com correlação moderada e forte, de acordo com cada estado comportamental. Sucção de mão direita na totalidade e em sacarose apresentou-se inicialmente com correlação forte no estado sonolento, passando para moderada ao final. No estado alerta houve inicialmente correlação fraca em ambos os estímulos, finalizando com correlação moderada em sacarose e forte em água. Sucção de mão esquerda apresentou-se inicialmente correlação moderada em alerta, finalizando com correlação fraca no grupo sacarose, o que não ocorreu na água, que iniciou e finalizou forte. Conclusão: A estimulação oral influenciou na coordenação mão-boca, independente do estímulo, evidenciando integração sensório motora precoce, mas não inferindo sobre capacidade de discriminação gustativa nos prematuros. _________________________________________________________________________________________ ABSTRACT: Purpose: To investigate about an integrated sensory motor system existence in premature newborns, submitted to gustatory stimulation. Methods: Analytical and experimental study of contents, double-blind. Being participants 90 premature newborns, divided into two groups (water or sucrose analysis 12%). Recorded by 15 minutes (first and last moments, without stimulation; and second time with gustatory stimulation). Three independent judges analyzed the behaviors in the right hand and left hand in the mouth and suction in the left and right and hand during the various behavioral states, those being inserted in the database of Statistical Package for Social Science, being then considered that the events observed by at least two of them. It was made use of Spearman’s rank correlation test on a significance level by p<0.05. Results: Considering the groups both separately and together, right and left had initially moderate correlation, being right hand in the mouth remained strong at the end and left hand in the mouth finished on moderate and strong correlation, according to each behavioral state. Right hand suction in its total and sucrose showed a strong correlation initially in drowsy state, becoming moderate at the end. In alertness state there was initially a weak correlation in both stimuli ending in moderate correlation in sucrose and strong in water. Left hand suction presented initially moderate correlation on the alert state, ending in weak correlation in sucrose stimuli, which did not occur in the water that started and finished strong. Conclusion: The oral stimulation influenced the hand-mouth coordination, showing early motor sensory integration. However, there was no discrimination about the gustatory capacity on the newborns

Evaluation of high-dose daptomycin for therapy of experimental Staphylococcus aureus foreign body infection

BACKGROUND: Daptomycin is a novel cyclic lipopeptide whose bactericidal activity is not affected by current antibiotic resistance mechanisms displayed by S. aureus clinical isolates. This study reports the therapeutic activity of high-dose daptomycin compared to standard regimens of oxacillin and vancomycin in a difficult-to-treat, rat tissue cage model of experimental therapy of chronic S. aureus foreign body infection. METHODS: The methicillin-susceptible S. aureus (MSSA) strain I20 is a clinical isolate from catheter-related sepsis. MICs, MBCs, and time-kill curves of each antibiotic were evaluated as recommended by NCCLS, including supplementation with physiological levels (50 mg/L) of Ca(2+ )for daptomycin. Two weeks after local infection of subcutaneously implanted tissue cages with MSSA I20, each animal received (i.p.) twice-daily doses of daptomycin, oxacillin, or vancomycin for 7 days, or was left untreated. The reductions of CFU counts in each treatment group were analysed by ANOVA and Newman-Keuls multiple comparisons procedures. RESULTS: The MICs and MBCs of daptomycin, oxacillin, or vancomycin for MSSA strain I20 were 0.5 and 1, 0.5 and 1, or 1 and 2 mg/L, respectively. In vitro elimination of strain I20 was more rapid with 8 mg/L of daptomycin compared to oxacillin or vancomycin. Twice-daily administered daptomycin (30 mg/kg), oxacillin (200 mg/kg), or vancomycin (50 mg/kg vancomycin) yielded bactericidal antibiotic levels in infected cage fluids throughout therapy. Before therapy, mean (± SEM) viable counts of strain I20 were 6.68 ± 0.10 log(10 )CFU/mL of cage fluid (n = 74). After 7 days of therapy, the mean (± SEM) reduction in viable counts of MSSA I20 was 2.62 (± 0.30) log(10 )CFU/mL in cages (n = 18) of daptomycin-treated rats, exceeding by >2-fold (P < 0.01) the viable count reductions of 0.92 (± 0.23; n = 19) and 0.96 (± 0.24; n = 18) log(10 )CFU/mL in cages of oxacillin-treated and vancomycin-treated rats, respectively. Viable counts in cage fluids of untreated animals increased by 0.48 (± 0.24; n = 19) log(10 )CFU/mL. CONCLUSION: The improved efficacy of the twice-daily regimen of daptomycin (30 mg/kg) compared to oxacillin (200 mg/kg) or vancomycin (50 mg/kg) may result from optimisation of its pharmacokinetic and bactericidal properties in infected cage fluids

Development of cognitive enhancers based on inhibition of insulin-regulated aminopeptidase

The peptides angiotensin IV and LVV-hemorphin 7 were found to enhance memory in a number of memory tasks and reverse the performance deficits in animals with experimentally induced memory loss. These peptides bound specifically to the enzyme insulin-regulated aminopeptidase (IRAP), which is proposed to be the site in the brain that mediates the memory effects of these peptides. However, the mechanism of action is still unknown but may involve inhibition of the aminopeptidase activity of IRAP, since both angiotensin IV and LVV-hemorphin 7 are competitive inhibitors of the enzyme. IRAP also has another functional domain that is thought to regulate the trafficking of the insulin-responsive glucose transporter GLUT4, thereby influencing glucose uptake into cells. Although the exact mechanism by which the peptides enhance memory is yet to be elucidated, IRAP still represents a promising target for the development of a new class of cognitive enhancing agents

Natural history of human Calicivirus infection: A prospective cohort study

We investigated the natural history of human Calicivirus infection in the community. Clinical information was obtained from 99 subjects infected with Norwalk-like viruses (NLV) and 40 subjects infected with Sapporo-like viruses (SLV) in a prospective, community-based cohort study. NLV infection was common in all age groups, whereas SLV infection was mainly restricted to children aged 75% for NLV and >67% for SLV). Overall, NLV was detected in 26% of patients up to 3 weeks after the onset of illness. This proportion was highest (38%) for children aged <1 year. SLV shedding subsided after 14 days. These data show that the durations of disease and viral shedding of caliciviruses are longer than has been described elsewhere. Therefore, the impact of these infections may have been underestimated

Unconventional Low-Cost Fabrication and Patterning Techniques for Point of Care Diagnostics

The potential of rapid, quantitative, and sensitive diagnosis has led to many innovative ‘lab on chip’ technologies for point of care diagnostic applications. Because these chips must be designed within strict cost constraints to be widely deployable, recent research in this area has produced extremely novel non-conventional micro- and nano-fabrication innovations. These advances can be leveraged for other biological assays as well, including for custom assay development and academic prototyping. The technologies reviewed here leverage extremely low-cost substrates and easily adoptable ways to pattern both structural and biological materials at high resolution in unprecedented ways. These new approaches offer the promise of more rapid prototyping with less investment in capital equipment as well as greater flexibility in design. Though still in their infancy, these technologies hold potential to improve upon the resolution, sensitivity, flexibility, and cost-savings over more traditional approaches

Teaching language components to deaf/hard-of-hearing and cochlear implant users: a literature review

ABSTRACT Cochlear implants are one of the possible ways for Deaf or Hard-of-Hearing (DHH) individuals to detect sounds and as a mean of insertion in the social, academic and work environments. Nevertheless, in many cases, the cochlear implant alone is not sufficient, demanding hearing and expressive language skills rehabilitation to optimize the device used. This study aimed at reviewing scientific articles that described empirical research with interventions and/or teaching methods of various language repertoires to deaf and hard-of-hearing cochlear implant users. The review was carried out in five scientific databases considering all periods. On the first phase, 156 articles were identified and from these, 24 publications were selected. After being read, these articles were categorized and analyzed as to the participants, teaching targets and procedures adopted. On the last stage of the research, 10 experimental studies were selected and analyzed regarding procedures and results, indicating important factors in teaching this population. The results point to the necessity of an increase of scientific production in the construction and evaluation of effective verbal repertoires teaching programs for cochlear implant users.RESUMO O indivíduo com deficiência auditiva encontra no implante coclear um dispositivo de reabilitação da capacidade de detectar sons e de inserção no meio social, acadêmico e do trabalho. No entanto, em muitos casos, apenas o implante não é suficiente, sendo necessário investimento na reabilitação de habilidades auditivas e da linguagem expressiva para otimizar o uso do dispositivo. O presente estudo teve como objetivo revisar artigos científicos que apresentem estudos empíricos da aplicação de intervenções e/ou métodos de ensino de repertórios de linguagem diversos a população com deficiência auditiva e usuária de implante coclear. O levantamento foi realizado em cinco bases de dados em qualquer período. Na primeira etapa foram levantadas 156 publicações, e destes, 24 artigos foram selecionados. A partir da leitura, os artigos foram categorizados e analisados quanto aos participantes, alvos de ensino e procedimentos empregados. Na última etapa da pesquisa, 10 estudos experimentais foram selecionados e analisados quanto aos procedimentos e resultados, indicando alguns fatores importantes no ensino com esta população. Os resultados sugerem a necessidade de uma maior e mais sistemática produção científica na construção e avaliação de programas de ensino de repertórios verbais efetivos para a população usuária de implante coclear

A diagnosis-based clinical decision rule for spinal pain part 2: review of the literature

<p>Abstract</p> <p>Background</p> <p>Spinal pain is a common and often disabling problem. The research on various treatments for spinal pain has, for the most part, suggested that while several interventions have demonstrated mild to moderate short-term benefit, no single treatment has a major impact on either pain or disability. There is great need for more accurate diagnosis in patients with spinal pain. In a previous paper, the theoretical model of a diagnosis-based clinical decision rule was presented. The approach is designed to provide the clinician with a strategy for arriving at a specific working diagnosis from which treatment decisions can be made. It is based on three questions of diagnosis. In the current paper, the literature on the reliability and validity of the assessment procedures that are included in the diagnosis-based clinical decision rule is presented.</p> <p>Methods</p> <p>The databases of Medline, Cinahl, Embase and MANTIS were searched for studies that evaluated the reliability and validity of clinic-based diagnostic procedures for patients with spinal pain that have relevance for questions 2 (which investigates characteristics of the pain source) and 3 (which investigates perpetuating factors of the pain experience). In addition, the reference list of identified papers and authors' libraries were searched.</p> <p>Results</p> <p>A total of 1769 articles were retrieved, of which 138 were deemed relevant. Fifty-one studies related to reliability and 76 related to validity. One study evaluated both reliability and validity.</p> <p>Conclusion</p> <p>Regarding some aspects of the DBCDR, there are a number of studies that allow the clinician to have a reasonable degree of confidence in his or her findings. This is particularly true for centralization signs, neurodynamic signs and psychological perpetuating factors. There are other aspects of the DBCDR in which a lesser degree of confidence is warranted, and in which further research is needed.</p