Late-onset Bartter syndrome type II

Mutations in the ROMK1 potassium channel gene (KCNJ1) cause antenatal/neonatal Bartter syndrome type II (aBS II), a renal disorder that begins in utero, accounting for the polyhydramnios and premature delivery that is typical in affected infants, who develop massive renal salt wasting, hypokalaemic metabolic alkalosis, secondary hyperreninaemic hyperaldosteronism, hypercalciuria and nephrocalcinosis. This BS type is believed to represent a disorder of the infancy, but not in adulthood. We herein describe a female patient with a remarkably late-onset and mild clinical manifestation of BS II with compound heterozygous KCNJ1 missense mutations, consisting of a novel c.197T > A (p.I66N) and a previously reported c.875G > A (p.R292Q) KCNJ1 mutation. We implemented and evaluated the performance of two different bioinformatics-based approaches of targeted massively parallel sequencing [next generation sequencing (NGS)] in defining the molecular diagnosis. Our results demonstrate that aBS II may be suspected in patients with a late-onset phenotype. Our experimental approach of NGS-based mutation screening combined with Sanger sequencing proved to be a reliable molecular approach for defining the clinical diagnosis in our patient, and results in important differential diagnostic and therapeutic implications for patients with BS. Our results could have a significant impact on the diagnosis and methodological approaches of genetic testing in other patients with clinical unclassified phenotypes of nephrocalcinosis and congenital renal electrolyte abnormalities

NSAID Enteropathy: Novel Aspects of Pathophysiology, Diagnosis, and Treatment

Although non-steroidal anti-inflammatory drugs (NSAIDs) are among the most frequently used classes of medications in the world, they are well-known to induce an enteropathy that is associated with high morbidity and mortality in upwards of 70% of users. The diagnosis of NSAID enteropathy is difficult. Furthermore, the underlying mechanisms by which NSAIDs induce enteropathy remain ill-defined although microbiota-host interactions appear to play an important role. Importantly, in addition to difficulty in diagnosing this disease, there are also no effective treatment strategies. Therefore, the purpose of this research was to determine if the microbiota-derived metabolite indole, could attenuate severity of NSAID enteropathy. A second goal was to determine if the transcriptome of exfoliated intestinal epithelial cells (IECs) found in the stool could be reflective of NSAID enteropathy, thereby allowing a non-invasive approach to studying how the mucosal transcriptome is altered by NSAIDs and potentially discriminating between healthy and diseased animals. We utilized a mouse model of NSAID enteropathy, whereby mice were assigned to 1 of 4 groups: 1) NSAID; 2) indole; 3) NSAID + indole; and, 4) untreated controls. Disease severity was determined by a number of assays including: fecal calprotectin, microscopic pathology, neutrophil infiltration, and RNA-seq of the ileal mucosa. Diversity and composition of the fecal microbiota was determined by 16S rRNA sequencing. Non-invasive examination of the mucosal transcriptome was determined by isolation and sequencing of polyA+ RNA from the stool followed by novel computational approaches to assess the inter-relatedness of exfoliated and tissue-level transcriptomes. Results from these assays revealed that indole did in fact attenuate disease severity and this improvement appeared to be related to composition of the microbiota. In addition, approximately 96% of all genes that were mapped from the exfoliated cell RNA were also present in the tissue-level RNA and the pathways represented by these genes and their directional changes were similar in both the small intestinal mucosa and exfoliated IEC transcriptome. These findings demonstrate that the exfoliated cell transcriptome correlates to the tissue-level transcriptome and can be used to gain longitudinal information related to NSAID-induced alterations of the mucosal transcriptome and to discriminate between diseased and healthy animals

Association between Chronotype and Nutritional, Clinical and Sociobehavioral Characteristics of Adults Assisted by a Public Health Care System in Brazil

Chronotype (CT) has been associated with predisposition to chronic noncommunicable diseases (CNCDs), such as diabetes mellitus and obesity. However, the effects of CT on individuals assisted by public health systems (PHSs) in middle-up economies are still poorly explored. The objective of this study was to evaluate the relationship between CT and clinical, sociobehavioral and nutritional aspects in adults assisted by a PHS in Brazil. This is a population-based cross-sectional study. The sample consisted of 380 individuals, selected through probabilistic sampling by clusters, in all health units in a city of approximately 100 thousand inhabitants. Data collection was performed during home visits, by means of general and nutritional interviews, anthropometric measurements and the Morningness–Eveningness Questionnaire (MEQ). Statistical analysis comprised chi-square test and principal component analysis (CPA) followed by Fisher’s discriminant analysis to determine aspects associated with each CT (morning, evening or intermediate). With the aim of explaining the variation in the CT scores, the consumption of micronutrients (corrected to the total energy intake) and other individual and sociodemographic variables were used as explanatory factors in the adjustment of a linear regression model. The morning group was characterized by older men, with less than eight years of schooling, with low body mass index (BMI) and with low intake of omega-6, omega-3, sodium, zinc, thiamine, pyridoxine and niacin. The evening group, on the other hand, was composed of younger individuals, with a high consumption of these same nutrients, with high BMI and a higher frequency of heart diseases (p < 0.05). It was concluded that most morning CT individuals were elderly thin males with lower consumption of omega-6 and -3, sodium, zinc, thiamine, pyridoxine and niacin, whereas evening individuals were younger, had higher BMI and had higher consumption of the studied micronutrients. The identification of circadian and behavioral risk groups can help to provide preventive and multidisciplinary health promotion measures

Effects of financial incentives for treatment supporters on tuberculosis treatment outcomes in Swaziland: a pragmatic interventional study

Background: Swaziland has the highest national incidence of tuberculosis (TB) in the world, with treatment success rates well below the 85 % international target. Treatment support as part of comprehensive TB services is a core component of the Stop TB Strategy. This study investigated the effects of financial incentives for treatment supporters on TB treatment outcomes in Swaziland. Methods: This was a controlled study that compared treatment outcomes for patients with a treatment supporter who received or did not receive a financial incentive. Results: The intervention group had a higher chance of treatment success as compared with the control group: 73 % (95 % confidence intervals [CIs] 66–80 %) versus 60 % (95 % CIs 57–64 %), respectively, p = 0.003. This improvement remained significant when treatment success rates were adjusted for differences in baseline characteristics, with the effect of incentivised treatment supporters on treatment outcomes having an odds ratio (OR) of 1.8. There was also a significant improvement in the death rate in the intervention group, as compared with the control group (10.6 versus 23.5 %, p = <0.001). Conclusion: Incentives provided to TB treatment supporters appear to significantly improve TB treatment outcomes. Incentivising treatment support may be appropriate as an effective addition to support and supervision measures (199 words)

Interprofessional Education: An evaluation of a joint learning workshop for podiatry and pharmacy students

"Interprofessional Education occurs when two or more professionals learn with, from and about each other to improve collaboration and the quality of care" (CAIPE 2002). Interprofessional education forms part of the Standards for the Initial Education and Training of Pharmacists. Working with and understanding the role of another profession has been shown to positively impact on the quality of care of the patient. Following positive pharmacy student feedback from visits to podiatry clinics an interprofessional learning workshop with case - based scenarios was developed. These were based on patients with high risk medical conditions that would impact on the work of both professions. Data from the feedback forms was evaluated and analysed to determine whether the workshop increased knowledge of the British National Formulary (BNF), the prescribing process and gave an insight in to the role of other healthcare professionals. We discuss how the student’s learning has been enhanced by the contribution of another professional group. The workshop was positively received. Students were observed working together discussing the patients’ conditions and issues relating to their care. This initially revolved around the students’ area of knowledge; however, as the session progressed it became apparent that the students were learning with, from and about each other for the benefit of patient care

The co-operative university: Labour, property and pedagogy

I begin this article by discussing the recent work of academics and activists to identify the advantages and issues relating to co-operative forms of higher education, and then focus on the ‘worker co-operative’ organisational form and its applicability and suitability to the governance of and practices within higher educational institutions. Finally, I align the values and principles of worker co-ops with the critical pedagogic framework of ‘Student as Producer’. Throughout I employ the work of Karl Marx to theorise the role of labour and property in a ‘co-operative university’, drawing particularly on later Marxist writers who argue that Marx’s labour theory of value should be understood as a critique of labour under capitalism, rather than one developed from the standpoint of labour

Опыт ведения пациентов с болезнью Фабри после изменения дозы или смены препарата в процессе проведения ферментозаместительной терапии

В связи с перебоями в поставках агалсидазы бета в 2009 г. многие пациенты с болезнью Фабри (БФ) были переведены на терапию меньшими дозами этого фермента или на лечение другим ферментом – агалсидазой альфа. В настоящем наблюдательном исследовании проведена оценка изменения состояния «таргетных» органов и симптомов, возникающих вследствие снижения доз или смены препарата на агалсидазу альфа. Под наблюдением находились 105 взрослых пациентов с БФ, получавшие агалсидазу бета (в дозе 1 мг / кг массы тела) в течение 1 года и более, которые были неслучайным образом разделены на тех, кто продолжил лечение по данной схеме (группа обычных доз, n = 38), тех, кому доза была снижена до 0,3–0,5 мг / кг (группа сниженных доз, n = 29), и тех, которые были переведены на лечение агалсидазой альфа в дозе 0,2 мг / кг (группа смены фермента), с последующим проспективным наблюдением в течение 1 года. Оценивались клинические события (смерть, инфаркт миокарда, тяжелая аритмия, инсульт, прогрессирование до терминальной стадии почечной недостаточности); изменения функции сердца и почек, неврологический статус и симптомы, связанные с БФ (невропатическая боль, гипогидроз, диарея и тяжесть заболевания). В группе обычных доз функциональное состояние органов и симптомы, связанные с БФ, оставались стабильными. В группе ниженных доз отмечено уменьшение рассчитанной скорости клубочковой фильтрации примерно на 3 мл / мин / 1,73 м2 (p = 0,01), а в группе смены препарата – повышение медианного соотношения альбумин / креатинин со 114 (0–606) мг / г до 216 (0–2062) мг / г (p = 0,03). Кроме того, в группах сниженных доз и смены препарата обнаруживалось существенное повышение средних оценок по индексу оценки тяжести Майнц и частоты приступов боли, хронической боли, боли в желудочно-кишечном тракте и диареи. У пациентов, получавших агалсидазу бета в обычных дозах, наблюдали стабильное течение болезни, в то время как снижение доз привело к ухудшению функции почек и усугублению симптомов. Переход на агалсидазу альфа безопасен, однако возможны прогрессирование микроальбуминурии и усиление выраженности симптомов БФ

Nurse led, primary care based antiretroviral treatment versus hospital care: a controlled prospective study in Swaziland

<p>Abstract</p> <p>Background</p> <p>Antiretroviral treatment services delivered in hospital settings in Africa increasingly lack capacity to meet demand and are difficult to access by patients. We evaluate the effectiveness of nurse led primary care based antiretroviral treatment by comparison with usual hospital care in a typical rural sub Saharan African setting.</p> <p>Methods</p> <p>We undertook a prospective, controlled evaluation of planned service change in Lubombo, Swaziland. Clinically stable adults with a CD4 count > 100 and on antiretroviral treatment for at least four weeks at the district hospital were assigned to either nurse led primary care based antiretroviral treatment care or usual hospital care. Assignment depended on the location of the nearest primary care clinic. The main outcome measures were clinic attendance and patient experience.</p> <p>Results</p> <p>Those receiving primary care based treatment were less likely to miss an appointment compared with those continuing to receive hospital care (RR 0·37, <it>p </it>< 0·0001). Average travel cost was half that of those receiving hospital care (<it>p </it>= 0·001). Those receiving primary care based, nurse led care were more likely to be satisfied in the ability of staff to manage their condition (RR 1·23, <it>p </it>= 0·003). There was no significant difference in loss to follow-up or other health related outcomes in modified intention to treat analysis. Multilevel, multivariable regression identified little inter-cluster variation.</p> <p>Conclusions</p> <p>Clinic attendance and patient experience are better with nurse led primary care based antiretroviral treatment care than with hospital care; health related outcomes appear equally good. This evidence supports efforts of the WHO to scale-up universal access to antiretroviral treatment in sub Saharan Africa.</p

Lymphomas driven by Epstein-Barr virus nuclear antigen-1 (EBNA1) are dependant upon Mdm2

Epstein-Barr virus (EBV)-associated Burkitt's lymphoma is characterised by the deregulation of c-Myc expression and a restricted viral gene expression pattern in which the EBV nuclear antigen-1 (EBNA1) is the only viral protein to be consistently expressed. EBNA1 is required for viral genome propagation and segregation during latency. However, it has been much debated whether the protein plays a role in viral-associated tumourigenesis. We show that the lymphomas which arise in EµEBNA1 transgenic mice are unequivocally linked to EBNA1 expression and that both C-Myc and Mdm2 deregulation are central to this process. Tumour cell survival is supported by IL-2 and there is a skew towards CD8-positive T cells in the tumour environment, while the immune check-point protein PD-L1 is upregulated in the tumours. Additionally, several isoforms of Mdm2 are upregulated in the EµEBNA1 tumours, with increased phosphorylation at ser166, an expression pattern not seen in Eµc-Myc transgenic tumours. Concomitantly, E2F1, Xiap, Mta1, C-Fos and Stat1 are upregulated in the tumours. Using four independent inhibitors of Mdm2 we demonstrate that the EµEBNA1 tumour cells are dependant upon Mdm2 for survival (as they are upon c-Myc) and that Mdm2 inhibition is not accompanied by upregulation of p53, instead cell death is linked to loss of E2F1 expression, providing new insight into the underlying tumourigenic mechanism. This opens a new path to combat EBV-associated disease

Mycobacterium tuberculosis Lipolytic Enzymes as Potential Biomarkers for the Diagnosis of Active Tuberculosis

BACKGROUND: New diagnosis tests are urgently needed to address the global tuberculosis (TB) burden and to improve control programs especially in resource-limited settings. An effective in vitro diagnostic of TB based on serological methods would be regarded as an attractive progress because immunoassays are simple, rapid, inexpensive, and may offer the possibility to detect cases missed by standard sputum smear microscopy. However, currently available serology tests for TB are highly variable in sensitivity and specificity. Lipolytic enzymes have recently emerged as key factors in lipid metabolization during dormancy and/or exit of the non-replicating growth phase, a prerequisite step of TB reactivation. The focus of this study was to analyze and compare the potential of four Mycobacterium tuberculosis lipolytic enzymes (LipY, Rv0183, Rv1984c and Rv3452) as new markers in the serodiagnosis of active TB. METHODS: Recombinant proteins were produced and used in optimized ELISA aimed to detect IgG and IgM serum antibodies against the four lipolytic enzymes. The capacity of the assays to identify infection was evaluated in patients with either active TB or latent TB and compared with two distinct control groups consisting of BCG-vaccinated blood donors and hospitalized non-TB individuals. RESULTS: A robust humoral response was detected in patients with active TB whereas antibodies against lipolytic enzymes were infrequently detected in either uninfected groups or in subjects with latent infection. High specifity levels, ranging from 93.9% to 97.5%, were obtained for all four antigens with sensitivity values ranging from 73.4% to 90.5%, with Rv3452 displaying the highest performances. Patients with active TB usually exhibited strong IgG responses but poor IgM responses. CONCLUSION: These results clearly indicate that the lipolytic enzymes tested are strongly immunogenic allowing to distinguish active from latent TB infections. They appear as potent biomarkers providing high sensitivity and specificity levels for the immunodiagnosis of active TB