The Gut Microbiome in Adult and Pediatric Functional Gastrointestinal Disorders

The importance of gut microbiota in gastrointestinal (GI) physiology was well described, but our ability to study gut microbial ecosystems in their entirety was limited by culture-based methods prior to the sequencing revolution. The advent of high-throughput sequencing opened new avenues, allowing us to study gut microbial communities as an aggregate, independent of our ability to culture individual microbes. Early studies focused on association of changes in gut microbiota with different disease states, which was necessary to identify a potential role for microbes and generate novel hypotheses. Over the past few years the field has moved beyond associations to better understand the mechanistic implications of the microbiome in the pathophysiology of complex diseases. This movement also has resulted in a shift in our focus toward therapeutic strategies, which rely on better understanding the mediators of gut microbiota–host cross-talk. It is not surprising the gut microbiome has been implicated in the pathogenesis of functional gastrointestinal disorders given its role in modulating physiological processes such as immune development, GI motility and secretion, epithelial barrier integrity, and brain–gut communication. In this review, we focus on the current state of knowledge and future directions in microbiome research as it pertains to functional gastrointestinal disorders. We summarize the factors that help shape the gut microbiome in human beings. We discuss data from animal models and human studies to highlight existing paradigms regarding the mechanisms underlying microbiota-mediated alterations in physiological processes and their relevance in human interventions. While translation of microbiome science is still in its infancy, the outlook is optimistic and we are advancing in the right direction toward precise mechanism-based microbiota therapies

Radijo dažnio abliacija ankstyvuoju poprocedūriniu laikotarpiu skatina inkstų audinio apoptozę

ObjectiveHyperthermia induced apoptosis may lead to tumor cell death thus expanding the volume of non-viable tissue and warrant a “safety margin” of at least 10mm to exclude the possibility of tumor recurrence. We carried out an experimental study to investigate the cellular injury produced by radiofrequency ablation in the area surrounding the ablated tissue and to describe early apoptotic processes in the transition zone following radiofrequency ablation procedure in a porcine kidney model.Materials and methodsEight anesthetized pigs underwent laparotomy and local thermal ablation of the kidney parenchyma. The ablated tissue and the surrounding parenchyma were investigated for apoptosis applying Western blot analysis and immunohistochemistry.ResultsThe active (cleaved) caspase-3 17-kDa subunit was detected in the transition zone one hour after ablative procedure at a distance of 7-9 mm from the rim of the necrosis zone. In contrast analysis of tissues in necrosis zone and in surrounding normal kidney parenchyma revealed no markers of apoptotic activity.ConclusionsWe determined that apoptosis, leading to further cell death, is activated in the majority of cells in the transition zone, thus supporting the hypothesis that the “safety margin” of 8 mm is encompassed by the indirect thermal effect.ĮvadasHipertermijos indukuojama apoptozė gali lemti vėžinių ląstelių žūtį ir taip praplėsti radijo dažnio abliacijos saugią gydymoribą net iki 10 milimetrų, taip užkertant kelią ligai atsinaujinti. Hipotezei patvirtinti atlikome eksperimentinį tyrimą, kuriuosiekėme įvertinti radijo dažnio abliacijos poveikį inkstų ląstelėms audinyje aplink susidariusią nekrozės zoną bei apibūdintiankstyvus apoptozinius procesus šioje zonoje.MetodaiSukėlus bendrąją endotrachėjinę nejautrą, operuotos aštuonios eksperimentinės kiaulės. Joms atliktos vidurinės laparotomijosir inkstų parenchimos radijo dažnio abliacija. Abliacijos zona ir ją supantys audiniai buvo tiriami Western bloto bei imunohistochemijosmetodais siekiant nustatyti apoptozę.RezultataiValandą po procedūros aktyvuota trečiosios kaspazės 17-kDa dalis nustatyta tranzitorinėje abliacijos zonoje 7–9 mm atstumunuo nekrozės ribos. Tiriant nekrozės zoną bei aplink nepažeistą inksto parenchimą, apoptozės žymenų aktyvumas nebuvonustatytas.IšvadosMes nustatėme, kad po radijo dažnio abliacijos aštuonių milimetrų atstumu nuo nekrozės zonos daugumoje inksto ląsteliųyra aktyvuojama ląstelių žūtį lemianti apoptozė. Tai patvirtina hipotezę, kad po šios procedūros dėl netiesiogiai plintančioterminio poveikio aplink nekrozės zoną gali susidaryti papildomai saugi 8 mm zona

Multicenter study of hypoxemia prevalence and quality of oxygen treatment for hospitalized Malawian children

Although hypoxemic children have high mortality, little is known about hypoxemia prevalence and oxygen administration in African hospitals. We aimed to determine the hypoxemia prevalence and quality of oxygen treatment by local clinicians for hospitalized Malawian children

Low Rates of Mother-to-Child HIV Transmission in a Routine Programmatic Setting in Lilongwe, Malawi

Background The Tingathe program utilizes community health workers to improve prevention of mother-to-child transmission (PMTCT) service delivery. We evaluated the impact of antiretroviral (ARV) regimen and maternal CD4+ count on HIV transmission within the Tingathe program in Lilongwe, Malawi. Methods We reviewed clinical records of 1088 mother-infant pairs enrolled from March 2009 to March 2011 who completed follow-up to first DNA PCR. Eligibility for antiretroviral treatment (ART) was determined by CD4+ cell count (CD4+) for women not yet on ART. ART-eligible women initiated stavudine-lamivudine-nevirapine. Early ART was defined as ART for ≥14 weeks prior to delivery. For women ineligible for ART, optimal ARV prophylaxis was maternal AZT ≥6 weeks+sdNVP, and infant sdNVP+AZT for 1 week. HIV transmission rates were determined for ARV regimens, and factors associated with vertical transmission were identified using bivariate logistic regression. Results Transmission rate at first PCR was 4.1%. Pairs receiving suboptimal ARV prophylaxis were more likely to transmit HIV (10.3%, 95% CI, 5.5–18.1%). ART was associated with reduced transmission (1.4%, 95% CI, 0.6–3.0%), with early ART associated with decreased transmission (no transmission), compared to all other treatment groups (p = 0.001). No association was detected between transmission and CD4+ categories (p = 0.337), trimester of pregnancy at enrollment (p = 0.100), or maternal age (p = 0.164). Conclusion Low rates of MTCT of HIV are possible in resource-constrained settings under routine programmatic conditions. No transmissions were observed among women on ART for more than 14 weeks prior to delivery

Determining the quality of IMCI pneumonia care in Malawian children

Although pneumonia is the leading cause of child mortality worldwide, little is known about the quality of routine pneumonia care in high burden settings like Malawi that utilize World Health Organization’s Integrated Management of Childhood Illnesses (IMCI) guidelines. Due to severe human resource constraints, the majority of clinical care in Malawi is delivered by non-physician clinicians called Clinical Officers (COs)

Development of a severity of illness scoring system (inpatient triage, assessment and treatment) for resource-constrained hospitals in developing countries

To develop a new pediatric illness severity score, called Inpatient Triage, Assessment, and Treatment (ITAT), for resource-limited settings to identify hospitalized patients at highest risk of death and facilitate urgent clinical re-evaluation

Lay-screeners and Use of WHO Growth Standards Increase Case Finding of Hospitalized Malawian Children with Severe Acute Malnutrition

Objectives: Strategies to effectively identify and refer children with severe acute malnutrition (SAM) to Nutritional Rehabilitation units (NRU) can reduce morbidity and mortality

Task shifting an inpatient triage, assessment and treatment programme improves the quality of care for hospitalised Malawian children

We aimed to improve pediatric inpatient surveillance at a busy referral hospital in Malawi with 2 new programs: (1) the provision of vital sign equipment and implementation of an inpatient triage program (ITAT) that includes a simplified pediatric severity-of-illness score; (2) task-shifting ITAT to a new cadre of health care workers called “Vital Sign Assistants” (VSAs)

Cryptosporidium Priming Is More Effective than Vaccine for Protection against Cryptosporidiosis in a Murine Protein Malnutrition Model

Cryptosporidium is a major cause of severe diarrhea, especially in malnourished children. Using a murine model of C. parvum oocyst challenge that recapitulates clinical features of severe cryptosporidiosis during malnutrition, we interrogated the effect of protein malnutrition (PM) on primary and secondary responses to C. parvum challenge, and tested the differential ability of mucosal priming strategies to overcome the PM-induced susceptibility. We determined that while PM fundamentally alters systemic and mucosal primary immune responses to Cryptosporidium, priming with C. parvum (106 oocysts) provides robust protective immunity against re-challenge despite ongoing PM. C. parvum priming restores mucosal Th1-type effectors (CD3+CD8+CD103+ T-cells) and cytokines (IFNγ, and IL12p40) that otherwise decrease with ongoing PM. Vaccination strategies with Cryptosporidium antigens expressed in the S. Typhi vector 908htr, however, do not enhance Th1-type responses to C. parvum challenge during PM, even though vaccination strongly boosts immunity in challenged fully nourished hosts. Remote non-specific exposures to the attenuated S. Typhi vector alone or the TLR9 agonist CpG ODN-1668 can partially attenuate C. parvum severity during PM, but neither as effectively as viable C. parvum priming. We conclude that although PM interferes with basal and vaccine-boosted immune responses to C. parvum, sustained reductions in disease severity are possible through mucosal activators of host defenses, and specifically C. parvum priming can elicit impressively robust Th1-type protective immunity despite ongoing protein malnutrition. These findings add insight into potential correlates of Cryptosporidium immunity and future vaccine strategies in malnourished children

Use Of Xpert For The Diagnosis Of Pulmonary Tuberculosis In Severely Malnourished Hospitalized Malawian Children

Pulmonary tuberculosis contributes to increased morbidity and mortality in severely malnourished children in endemic settings. Despite high clinical suspicion, few tuberculosis prevalence estimates exist in malnourished African children. Diagnostics such as Xpert MTB/RIF may help to determine pulmonary tuberculosis prevalence, however its performance in severely malnourished children is largely unknown