Combining physical & cognitive training with iPSC-derived dopaminergic neuron transplantation promotes graft integration & better functional outcome in parkinsonian marmosets.

Parkinson's disease (PD) is a relentlessly progressive and currently incurable neurodegenerative disease with significant unmet medical needs. Since PD stems from the degeneration of midbrain dopaminergic (DA) neurons in a defined brain location, PD patients are considered optimal candidates for cell replacement therapy. Clinical trials for cell transplantation in PD are beginning to re-emerge worldwide with a new focus on induced pluripotent stem cells (iPSCs) as a source of DA neurons since they can be derived from adult somatic cells and produced in large quantities under current good manufacturing practices. However, for this therapeutic strategy to be realized as a viable clinical option, fundamental translational challenges need to be addressed including the manufacturing process, purity and efficacy of the cells, the method of delivery, the extent of host reinnervation and the impact of patient-centered adjunctive interventions. In this study we report on the impact of physical and cognitive training (PCT) on functional recovery in the nonhuman primate (NHP) model of PD after cell transplantation. We observed that at 6 months post-transplant, the PCT group returned to normal baseline in their daily activity measured by actigraphy, significantly improved in their sensorimotor and cognitive tasks, and showed enhanced synapse formation between grafted cells and host cells. We also describe a robust, simple, efficient, scalable, and cost-effective manufacturing process of engraftable DA neurons derived from iPSCs. This study suggests that integrating PCT with cell transplantation therapy could promote optimal graft functional integration and better outcome for patients with PD.

LRRK2 Attenuates Antioxidant Response in Familial Parkinson's Disease Derived Neural Stem Cells.

Parkinson's disease (PD) is the second most prevalent neurodegenerative disease, characterized by the loss of midbrain dopaminergic neurons which leads to impaired motor and cognitive functions. PD is predominantly an idiopathic disease; however, about 5% of cases are linked to hereditary mutations. The most common mutation in both familial and sporadic PD is the G2019S mutation of leucine-rich repeat kinase 2 (LRRK2). Currently, it is not fully understood how this mutation leads to PD pathology. In this study, we isolated self-renewable, multipotent neural stem cells (NSCs) from induced pluripotent stem cells (iPSCs) harboring the G2019S LRRK2 mutation and compared them with their isogenic gene corrected counterparts using single-cell RNA-sequencing. Unbiased single-cell transcriptomic analysis revealed perturbations in many canonical pathways, specifically NRF2-mediated oxidative stress response, and glutathione redox reactions. Through various functional assays, we observed that G2019S iPSCs and NSCs exhibit increased basal levels of reactive oxygen species (ROS). We demonstrated that mutant cells show significant increase in the expression for KEAP1 and decrease in NRF2 associated with a reduced antioxidant response. The decreased viability of mutant NSCs in the H2O2-induced oxidative stress assay was rescued by two potent antioxidant drugs, PrC-210 at concentrations of 500 µM and 1 mM and Edaravone at concentrations 50 µM and 100 µM. Our data suggest that the hyperactive LRRK2 G2019S kinase activity leads to increase in KEAP1, which binds NRF2 and leads to its degradation, reduction in the antioxidant response, increased ROS, mitochondria dysfunction and cell death observed in the PD phenotype.

Human Induced Pluripotent Stem Cell Phenotyping and Preclinical Modeling of Familial Parkinson's Disease.

Parkinson's disease (PD) is primarily idiopathic and a highly heterogenous neurodegenerative disease with patients experiencing a wide array of motor and non-motor symptoms. A major challenge for understanding susceptibility to PD is to determine the genetic and environmental factors that influence the mechanisms underlying the variations in disease-associated traits. The pathological hallmark of PD is the degeneration of dopaminergic neurons in the substantia nigra pars compacta region of the brain and post-mortem Lewy pathology, which leads to the loss of projecting axons innervating the striatum and to impaired motor and cognitive functions. While the cause of PD is still largely unknown, genome-wide association studies provide evidence that numerous polymorphic variants in various genes contribute to sporadic PD, and 10 to 15% of all cases are linked to some form of hereditary mutations, either autosomal dominant or recessive. Among the most common mutations observed in PD patients are in the genes LRRK2, SNCA, GBA1, PINK1, PRKN, and PARK7/DJ-1. In this review, we cover these PD-related mutations, the use of induced pluripotent stem cells as a disease in a dish model, and genetic animal models to better understand the diversity in the pathogenesis and long-term outcomes seen in PD patients.

Molecular and cellular evolution of the primate dorsolateral prefrontal cortex.

The granular dorsolateral prefrontal cortex (dlPFC) is an evolutionary specialization of primates that is centrally involved in cognition. We assessed more than 600,000 single-nucleus transcriptomes from adult human, chimpanzee, macaque, and marmoset dlPFC. Although most cell subtypes defined transcriptomically are conserved, we detected several that exist only in a subset of species as well as substantial species-specific molecular differences across homologous neuronal, glial, and non-neural subtypes. The latter are exemplified by human-specific switching between expression of the neuropeptide somatostatin and tyrosine hydroxylase, the rate-limiting enzyme in dopamine production in certain interneurons. The above molecular differences are also illustrated by expression of the neuropsychiatric risk gene FOXP2, which is human-specific in microglia and primate-specific in layer 4 granular neurons. We generated a comprehensive survey of the dlPFC cellular repertoire and its shared and divergent features in anthropoid primates.

Dopamine D3 receptor ligand suppresses the expression of levodopa-induced dyskinesia in nonhuman primate model of parkinson's disease.

Parkinson's disease (PD) is a complex multisystem, chronic and so far incurable disease with significant unmet medical needs. The incidence of PD increases with aging and the expected burden will continue to escalate with our aging population. Since its discovery in the 1961 levodopa has remained the gold standard pharmacotherapy for PD. However, the progressive nature of the neurodegenerative process in and beyond the nigrostriatal system causes a multitude of side effects, including levodopa-induced dyskinesia within 5 years of therapy. Attenuating dyskinesia has been a significant challenge in the clinical management of PD. We report on a small molecule that eliminates the expression of levodopa-induced dyskinesia and significantly improves PD-like symptoms. The lead compound PD13R we discovered is a dopamine D3 receptor partial agonist with high affinity and selectivity, orally active and with desirable drug-like properties. Future studies are aimed at developing this lead compound for treating PD patients with dyskinesia.

Age-related cognitive decline in baboons: modeling the prodromal phase of Alzheimer's disease and related dementias.

The aging of brain cells and synaptic loss are the major underlying pathophysiological processes contributing to the progressive decline in cognitive functions and Alzheimer's disease. The difference in cognitive performances observed between adult and aged subjects across species highlights the decline of brain systems with age. The inflection point in age-related cognitive decline is important for our understanding of the pathophysiology of neurodegenerative diseases and for timing therapeutic interventions. Humans and nonhuman primates share many similarities including age-dependent changes in gene expression and decline in neural and immune functions. Given these evolutionary conserved organ systems, complex human-like behavioral and age-dependent changes may be modeled and monitored longitudinally in nonhuman primates. We integrated three clinically relevant outcome measures to investigate the effect of age on cognition, motor function and diurnal activity in aged baboons. We provide evidence of a naturally-occurring age-dependent precipitous decline in movement planning, in learning novel tasks, in simple discrimination and in motivation. These results suggest that baboons aged ~20 years (equivalent to ~60 year old humans) may offer a relevant model for the prodromal phase of Alzheimer's disease and related dementias to investigate mechanisms involved in the precipitous decline in cognitive functions and to develop early therapeutic interventions.

Nonconformities in the pre-analytical phase identified in a public health laboratory / Não conformidades na fase pré-analítica identificadas em um laboratório de saúde pública

ABSTRACT Introduction: The nonconformities detected in the pre-analytical phase of laboratory tests sent to the Central Public Health Laboratories (Lacen) culminate in the loss of epidemiological data of great importance for public health and are detrimental to health surveillance. This study aimed to identify the most frequent pre-analytical nonconformities recorded by Lacen/PR and the major difficulties encountered by the primary and regional health units in the registration of exams in the Laboratory Environment Manager (GAL) system. Results: The analysis of data from the Paraná GAL system in 2017 identified 9,723 discards for disagreeing samples in a total of 132,567 tests performed in the same period. The most frequent nonconformities were: request canceled by the GAL management due to expiration of the screening period (28%), and sample unsuitable for the requested analysis (28%). Discussion: After identifying the vulnerabilities of this stage of the process, the greatest detected difficulty was requesting the correct test. Conclusion: Data indicate the need to strengthen training and improve the pre-analytical process in order to ensure patient safety and epidemiological data.

RESUMEN Introducción: Las no conformidades detectadas en la fase preanalítica de las pruebas enviadas a los laboratorios centrales (Lacen) del estado culminan en pérdida de datos epidemiológicos de gran importancia para la salud pública, además de perjudicar la vigilancia en salud. Objetivos: Este estudio intentó identificar las no conformidades preanalíticas más frecuentes registradas por el Lacen/PR y las mayores dificultades encontradas por unidades primarias y regionales de salud en el registro de pruebas en el sistema administrador del ambiente de laboratorio (GAL). Resultados: Del total de 132.765 pruebas realizadas en 2017, el análisis de datos del sistema GAL-Paraná identificó 9.723 descartes de muestras en desacuerdo. Las no conformidades más frecuentes fueron: solicitud rechazada por la gerencia de GAL pues la muestra está fuera de la fecha de caducidad (28%) y muestra inadecuada para el análisis solicitado (28%). Discusión: Al identificar los puntos débiles de esa etapa del proceso, la mayor dificultad detectada fue la solicitud de la prueba correcta. Conclusión: Los datos indican la necesidad de fortalecer las capacidades y la mejora del proceso preanalítico, para garantizar la seguridad del paciente y de los datos epidemiológicos.

RESUMO Introdução: As não conformidades detectadas na fase pré-analítica dos exames enviados aos laboratórios centrais (Lacen) do estado culminam em perda de dados epidemiológicos de grande importância para a saúde pública, além de prejudicar a vigilância em saúde. Objetivos: Este trabalho teve como objetivo identificar as não conformidades pré-analíticas mais frequentes registradas pelo Lacen/PR e as maiores dificuldades encontradas pelas unidades primárias e regionais de saúde no cadastro dos exames no sistema Gerenciador de Ambiente Laboratorial (GAL). Resultados: Do total de 132.567 exames realizados no ano de 2017, a análise dos dados do sistema GAL-Paraná identificou 9.723 descartes de amostras em desacordo. As não conformidades mais frequentes foram: requisição cancelada pela gerência do GAL devido à expiração do prazo de triagem (28%) e amostra imprópria para a análise solicitada (28%). Discussão: Ao identificar os pontos vulneráveis dessa etapa do processo, a maior dificuldade detectada foi solicitação do exame correto. Conclusão: Os dados indicam a necessidade de reforçar as capacitações e a melhoria do processo pré-analítico, a fim de garantir a segurança do paciente e dos dados epidemiológicos.

Rectocele plication: description of a novel surgical technique and review of clinical results.

INTRODUCTION AND HYPOTHESIS: A rectocele is the bulging of the anterior rectal wall into the posterior vaginal compartment. The route of surgical repair can be transvaginal, transrectal or abdominal. The aim of this retrospective study is to describe a novel transvaginal surgical procedure and investigate the associated subjective and objective clinical outcomes. METHODS: Database records were retrieved for all women who underwent a rectocele plication for the period from January 2010 until December 2015 in a referral urogynecology unit with a minimum follow-up period of 12 months. This transvaginal technique entails a plication of the anterior rectal wall by suturing of the rectal muscularis layer. Clinical findings and quality of life (QOL) metrics were evaluated and reported on. RESULTS: One hundred thirty-nine women met the initial inclusion criteria with full data available for 123. The presenting symptoms included a vaginal bulge in 73 (52.5%), overactive bladder (OAB) in 73 (52.5%), obstructed defecation (OD) in 49 (35.3%) and anal incontinence (AI) in 35 (25.2%). The majority of women (n = 72, 51.8%) had stage 3-4 posterior prolapse. The mean follow-up period was 27 ± 15 months. The postoperative symptoms were significantly improved for all, except AI (p = 0.43). There was a significant improvement in posterior prolapse (p < 0.001) with the majority of women noted to have a stage 0 or 1 (n = 109; 88.6%) posterior prolapse at follow-up. CONCLUSIONS: The rectocele plication is a novel surgical technique with good subjective and objective clinical outcomes in the medium term.

Validation of the PFDI-20 and PFIQ-7 quality of life questionnaires in two African languages.

INTRODUCTION AND HYPOTHESIS: Self-administered quality of life (QOL) questionnaires provide objective evaluation of an individual's symptoms. The Pelvic Floor Distress Inventory-20 (PFDI-20) and the Pelvic Floor Impact Questionnaire-7 (PFIQ-7) are condition-specific short form questionnaires. There are very few validated QOL questionnaires for women in Africa. The aim of this study was to validate these questionnaires in African women for the Afrikaans and Sesotho languages. METHODS: Patients with pelvic floor disorders completed the questionnaires at baseline, 1 week later and after 6 months. A control group of women not known to have pelvic floor disorders completed the questionnaires at baseline and 1 week later. Psychometric properties tested were internal consistency, reliability, construct validity and responsiveness. RESULTS: In each language group, 100 control and 100 study participants completed the scheduled rounds. Internal consistency, as measured by the Cronbach's alpha value, was good for the PFDI-20 (0.71-0.89) and the PFIQ-7 (0.81-0.89) for both the Afrikaans-speaking and the Sesotho-speaking patients. The test-retest reliability showed very good intraclass correlation coefficients of 0.89-0.99 across all scales of both questionnaires and in both language groups. The construct validity was confirmed as was the responsiveness to treatment for both questionnaires. CONCLUSIONS: The Afrikaans and Sesotho versions of the PFDI-20 and PFIQ-7 are reliable and valid instruments that can be used in women with pelvic floor disorders speaking these languages.

How do low-birthweight neonates fare 2 years after discharge from a low-technology neonatal care unit in a rural district hospital in Burundi?

OBJECTIVES: As neonatal care is being scaled up in economically poor settings, there is a need to know more on post-hospital discharge and longer-term outcomes. Of particular interest are mortality, prevalence of developmental impairments and malnutrition, all known to be worse in low-birthweight neonates (LBW, <2500 g). Getting a better handle on these parameters might justify and guide support interventions. Two years after hospital discharge, we thus assessed: mortality, developmental impairments and nutritional status of LBW children. METHODS: Household survey of LBW neonates discharged from a neonatal special care unit in Rural Burundi between January and December 2012. RESULTS: Of 146 LBW neonates, 23% could not be traced and 4% had died. Of the remaining 107 children (median age = 27 months), at least one developmental impairment was found in 27%, with 8% having at least five impairments. Main impairments included delays in motor development (17%) and in learning and speech (12%). Compared to LBW children (n = 100), very-low-birthweight (VLBW, <1500 g, n = 7) children had a significantly higher risk of impairments (intellectual - P = 0.001), needing constant supervision and creating a household burden (P = 0.009). Of all children (n-107), 18% were acutely malnourished, with a 3½ times higher risk in VLBWs (P = 0.02). CONCLUSIONS: Reassuringly, most children were thriving 2 years after discharge. However, malnutrition was prevalent and one in three manifested developmental impairments (particularly VLBWs) echoing the need for support programmes. A considerable proportion of children could not be traced, and this emphasises the need for follow-up systems post-discharge.

Emergency obstetric care in a rural district of Burundi: What are the surgical needs?

OBJECTIVES: In a rural district hospital in Burundi offering Emergency Obstetric care-(EmOC), we assessed the a) characteristics of women at risk of, or with an obstetric complication and their types b) the number and type of obstetric surgical procedures and anaesthesia performed c) human resource cadres who performed surgery and anaesthesia and d) hospital exit outcomes. METHODS: A retrospective analysis of EmOC data (2011 and 2012). RESULTS: A total of 6084 women were referred for EmOC of whom 2534(42%) underwent a major surgical procedure while 1345(22%) required a minor procedure (36% women did not require any surgical procedure). All cases with uterine rupture(73) and extra-uterine pregnancy(10) and the majority with pre-uterine rupture and foetal distress required major surgery. The two most prevalent conditions requiring a minor surgical procedure were abortions (61%) and normal delivery (34%). A total of 2544 major procedures were performed on 2534 admitted individuals. Of these, 1650(65%) required spinal and 578(23%) required general anaesthesia; 2341(92%) procedures were performed by 'general practitioners with surgical skills' and in 2451(96%) cases, anaesthesia was provided by nurses. Of 2534 hospital admissions related to major procedures, 2467(97%) were discharged, 21(0.8%) were referred to tertiary care and 2(0.1%) died. CONCLUSION: Overall, the obstetric surgical volume in rural Burundi is high with nearly six out of ten referrals requiring surgical intervention. Nonetheless, good quality care could be achieved by trained, non-specialist staff. The post-2015 development agenda needs to take this into consideration if it is to make progress towards reducing maternal mortality in Africa.

Caesarean sections in rural Burundi: how well are mothers doing two years on?

SETTING: A caesarean section (C-section) is a life-saving emergency intervention. Avoiding pregnancies for at least 24 months after a C-section is important to prevent uterine rupture and maternal death. OBJECTIVES: Two years following an emergency C-section, in rural Burundi, we assessed complications and maternal death during the post-natal period, uptake and compliance with family planning, subsequent pregnancies and their maternal and neonatal outcomes. METHODS: A household survey among women who underwent C-sections. RESULTS: Of 156 women who underwent a C-section, 116 (74%) were traced; 1 had died of cholera, 8 had migrated and 31 were untraceable. Of the 116 traced, there were no post-operative complications and no deaths. At hospital discharge, 83 (72%) women accepted family planning. At 24 months after hospital discharge (n = 116), 23 (20%) had delivered and 17 (15%) were pregnant. Of the remaining 76 women, 48 (63%) were not on family planning. The main reasons for this were religion or husband's non-agreement. Of the 23 women who delivered, there was one uterine rupture, no maternal deaths and three stillbirths. CONCLUSIONS: Despite encouraging maternal outcomes, this study raises concerns around the effectiveness of current approaches to promote and sustain family planning for a minimum of 24 months following a C-section. Innovative ways of promoting family planning in this vulnerable group are urgently needed.

Contexte : Une césarienne est une intervention d'urgence destinée à sauver une vie. Eviter une nouvelle grossesse pendant au moins 24 mois après une césarienne est important afin de prévenir une rupture utérine et un décès maternel.Objectifs : Deux ans après une césarienne en urgence, dans le Burundi rural, nous avons évalué : les complications et les décès maternels pendant la période post-natale ; la couverture de la planification familiale et son adhérence ; les grossesses suivantes et leur devenir pour la mère et le nouveau-né.Méthodes : Enquête à domicile auprès de femmes qui ont bénéficié d'une césarienne.Résultat : Sur 156 femmes qui ont bénéficié d'une césarienne, 116 (74%) ont pu être retrouvées ; 1 était décédée du choléra, 8 avaient déménagé et 31 n'ont pas pu être localisées. Sur les 116 femmes retrouvées, il n'y a eu aucune complication post-opératoire et aucun décès. Lors de leur sortie de l'hôpital, 83 (72%) femmes ont accepté une contraception. A 24 mois après leur sortie (n = 116), 23 (20%) avaient accouché et 17 (15%) étaient enceintes. Sur les 76 femmes restantes, 48 (63%) n'avaient pas de contraception. Les motifs principaux étaient la religion ou le désaccord du mari. Parmi les 23 qui avaient accouché, il y a eu une rupture utérine, aucun décès maternel, mais il y a eu trois mort-nés.Conclusion : En dépit de résultats encourageants pour les mères, cette étude pose la question de l'efficacité des approches actuelles de la promotion et de la pérennité de la planification familiale pendant un minimum de 24 mois. Il est urgent de trouver des manières innovantes de promouvoir la planification familiale dans ce groupe vulnérable.

Marco de referencia: La cesárea es una intervención de urgencia que salva vidas. Es importante evitar un embarazo por lo menos durante los 24 meses que siguen a la operación, con el fin de evitar la ruptura uterina y la mortalidad materna.Objetivos: El seguimiento durante 2 años después de una cesárea de urgencia en una zona rural de Burundi tuvo por objeto evaluar las complicaciones y la mortalidad materna durante el período posnatal, la aceptación y el cumplimiento del método de anticoncepción y examinar los siguientes embarazos con su desenlace materno y neonatal.Método: Se llevó a cabo una encuesta domiciliaria de las mujeres en quienes se había practicado una cesárea.Resultados: Se evaluaron 116 de las 156 mujeres (74%) que se sometieron a una cesárea; una paciente falleció por cólera, 8 migraron y fue imposible localizar 31 mujeres. Durante el seguimiento de las 116 mujeres no se observaron complicaciones postoperatorias ni defunciones. En el momento del alta hospitalaria, 83 mujeres aceptaron practicar un método anticonceptivo (72%). Veinticuatro meses después del alta hospitalaria, 23 mujeres habían tenido un parto (20%) y 17 estaban embarazadas (15%). De las 76 mujeres restantes, 48 no seguían ningún método de planificación familiar (63%); las principales razones aducidas fueron religiosas o el desacuerdo del cónyuge. En los 23 casos de mujeres que tuvieron un parto, ocurrió una ruptura uterina sin mortalidad materna, pero hubo tres mortinatos.Conclusión: Pese a la buena perspectiva de los desenlaces maternos favorables, el estudio pone de manifiesto inquietudes con respecto a la eficacia de las estrategias vigentes de promoción y mantenimiento de los métodos anticonceptivos durante un mínimo de 24 meses. Se precisan con urgencia estrategias innovadoras que estimulen la planificación familiar en este grupo vulnerable de mujeres.

Effect of vaginal infiltration with ornipressin or saline on intraoperative blood loss during vaginal prolapse surgery: a randomised controlled trial.

INTRODUCTION AND HYPOTHESIS: Hydrodissection incorporating different types of vasoconstrictors is commonly used in vaginal prolapse surgery. There is little evidence as to whether it adds clinical value or whether it exposes the patient to unnecessary risk. The aim of this study was to compare the effect of a vasoconstrictor compared with saline alone on operative blood loss and cardiovascular parameters in a randomised clinical trial setting. METHODS: Patients undergoing vaginal prolapse surgery were randomised to an ornipressin (Por-8, Ferring) solution or saline alone for hydrodissection. The surgeon and patient were blinded to the solution used. Operative blood loss was accurately quantified and blood pressure and pulse readings recorded Pre, intra- and postoperatively. RESULTS: Eighty women were randomised. There was a statistically significant difference in the median blood loss: 35 ml (1-209 ml) in the ornipressin group compared with 81 ml (2-328 ml) in the saline group, p = 0.03. There was no statistically significant difference in the median pre and postoperative blood pressure or pulse rate between groups. CONCLUSIONS: The use of a vasoconstrictor (ornipressin) resulted in a statistically significant decrease in operative blood loss during vaginal prolapse surgery. This occurred without any significant changes in measured cardiovascular parameters.

Does the Belgian diabetes type 2 care trajectory improve quality of care for diabetes patients?

BACKGROUND: The Belgian care trajectory (CT) for diabetes mellitus type 2 (T2DM), implemented in September 2009, aims at providing integrated, evidence-based, multidisciplinary patient- centred care, based on the chronic care model. The research project ACHIL (Ambulatory Care Health Information Laboratory) studied the adherence of CT patients, in the early phases of CT programme implementation, with CT obligations, their uptake of incentives for self-management, whether the CT programme was targeting the appropriate group of patients, how care processes for these patients evolved over time and whether CT start led to better quality in the processes and outcomes of care. METHODS: This observational study took place in the period 2006-2011 and covered T2DM patients who started a CT between 01/09/2009 and 31/12/2011. Four data sources were used: outcome data, from electronic patient records (EPRs) on all CT patients, provided by general practitioners (GPs); reimbursement process data on all CT patients and clinically comparable patients; and data from a sample of CT patients and clinically comparable patients from an EPR-based regional GP network and a paper-based national GP network, respectively. Through multilevel analysis of cross-sectional and longitudinal data, the effect of CT inclusion on processes and outcome was estimated, controlling for potential confounders. RESULTS: By the end of 2011, data on 18,250 CT patients had been collected. Approximately 50 % of these CT patients had received reimbursement for a glucometer and nearly 60 % had had at least one encounter with a diabetes educator. The CT programme recruited T2DM patients who had been difficult to control in the past. In the years prior to CT start, there had been a gradual improvement in the follow up of these patients. Moreover, compared to non-CT patients, the proportion of CT patients adhering to the recommended frequency for monitoring of parameters, such as HbA1c, increased significantly around CT start. Some data sources, albeit not all, suggested there had been an improvement in certain outcomes, such as HbA1c, after CT inclusion. CONCLUSIONS: According to this study, CT enrolment is associated with better quality of care processes compared to non-CT patients. This improvement was found in several of the data sources used in this study. However, results on outcome parameters remain inconclusive.

Pelvic organ prolapse in the neonate: report of two cases and review of the literature.

Pelvic organ prolapse (POP) in the new-born baby is a rare though well-acknowledged clinical condition. We present two cases of complete utero-vaginal prolapse in new-born babies. Both infants were otherwise healthy and neurologically normal in their clinical presentation and evaluation. The prolapse was successfully managed with a non-surgical approach. There appears to be two distinct forms of POP in newborns based on the available literature. There are those that occur in newborns with spina bifida (77 % of cases) and those that occur in neurologically intact newborns (23 %). The management of these two types are distinctly different and are discussed in greater detail in this report.

Do non-monetary incentives for pregnant women increase antenatal attendance among Ethiopian pastoralists?

In a pastoralist setting in Ethiopia, we assessed changes in attendance between the first and subsequent antenatal care (ANC) visits following the implementation of non-monetary incentives in a primary health care centre over a 3-year period from October 2009 to September 2012. Incentives included the provision of a bar of soap, a bucket, a mosquito net, sugar, cooking oil, a jerrycan and a delivery kit. The first ANC visits increased by 48% in the first year to 60% in the second. Subsequent visits did not show a similar pattern due to ruptures in incentive stocks. Incentives appear to increase ANC attendance; however, ruptures in stock should be avoided to sustain the effect.

Dans une zone pastorale d'Ethiopie, nous avons évalué le changement de fréquentation entre la première consultation prénatale (ANC) et les suivantes après la mise en œuvre d'incitations non-financières sur une période de 3 ans (octobre 2009­septembre 2012) dans un centre de soins de santé primaire. Ces incitations étaient du savon, un seau, une moustiquaire, du sucre, de l'huile de cuisine, un jerrycan et un kit d'accouchement. Les ANC ont augmenté de 48% la première année à 60% la deuxième année. Les consultations suivantes n'ont pas connu la même augmentation en raison de ruptures de stock des incitations. Ces incitations ont donc un effet positif sur la fréquentation, mais il faut éviter les ruptures de stock pour que l'effet soit durable.

En un medio pastoril en Etiopía se evaluó la modificación de la asistencia a la primera consulta y a las siguientes citas en el programa de atención prenatal, tras la introducción de incentivos no monetarios durante un período de 3 años, entre octubre del 2009 y septiembre del 2012, en un centro de atención primaria de salud. Los incentivos consistieron en el suministro de jabón, un balde, un mosquitero, azúcar, aceite de cocción, un bidón y un estuche de preparativos para el parto. La asistencia a la primera consulta del programa de atención prenatal aumentó en un 48% durante el primer año y un 60% en el segundo. No se observó una modificación equivalente de la presencia a las siguientes citas, debido al desabastecimiento de los incentivos. El suministro de incentivos parece aumentar la asistencia al programa de atención prenatal, pero con el fin de mantener el efecto es preciso evitar el agotamiento de las existencias de los mismos.

IFN-gamma induction of p21(WAF1) is required for cell cycle inhibition and suppression of apoptosis.

Interferons (IFN) inhibit the growth of tumor cells by blocking the progression of their cell cycle. Recently, we showed that this cell cycle inhibition correlates with the ability of IFN to upregulate the cyclin-dependent kinase inhibitor p21(WAF1). This, however, is not proof of a causal relationship. Using p21(WAF1)-deficient cells derived from the HCT116 colon adenocarcinoma cell line, we now show that p21(WAF1) is indeed responsible for the antiproliferative effects of the type II IFN, IFN-gamma. IFN-gamma upregulated p21(WAF1) expression in a p53-independent manner, decreased cyclin-dependent kinase 2 activity, and inhibited entry into the S phase of the cell cycle in p21+/+ but not in p21-/- HCT116 cells. We additionally found that the lack of p21(WAF1) expression resulted in an increase in the ability of IFN-gamma to induce apoptosis, as reflected by an earlier induction of DNA fragmentation and caspase 3 activity in p21-/- cell. Our results indicate that p21(WAF1) expression is necessary for IFN-gamma-mediated cell cycle inhibition and suppression of IFN-gamma-induced apoptosis.

IFNgamma induction of p21WAF1 in prostate cancer cells: role in cell cycle, alteration of phenotype and invasive potential.

Type I and type II interferons (IFNs) are known to exert antitumor effects on a variety of tissues and cell types. We have previously shown that the type I IFN IFN alpha induces the expression of the cyclin-dependent kinase inhibitor p21WAF1 and inhibits the cell cycle of the human prostate adenocarcinoma cell line, DU145, that carries mutations in the tumor suppressor gene products p53 and pRB. We now show that the type II IFN IFN gamma similarly induces the expression of p21WAF1 and inhibits the cell cycle of DU145 cells. In addition, we show that while both IFNs exert antiproliferative activity, only IFN gamma induced phenotypic changes in these cells that accompanied the antiproliferative effect. For example, IFN gamma, but not IFN alpha, caused a significant reduction in epidermal growth factor receptor expression as well as an increase in the adhesion molecules intercellular adhesion molecule-1 and integrin alpha3. These phenotypic changes in DU145 cells are suggestive of the acquisition of a non-tumorigenic state. Consistent with these findings, IFN gamma showed a significantly lower invasive ability in in vitro assays using invasion chambers. Thus, IFN gamma inhibits both the cell cycle and the metastatic potential of DU145 cells independent of the p53 and RB status, and our data describe a mechanism for mediating the antitumor capabilities of IFN gamma that bypasses tumor suppressor genes like p53.

[The role of alkaline secretion of the duodenal mucosa in protecting the mucosa from hydrochloric acid]. / A duodenumnyálkahártya alkáliszekréciójának jelentösége a sósavval szembeni védekezésben.

In animal experiments, an in vivo comparison was made of the alkaline secretion (AS) of the duodenal mucosa and of its ability to defend against hydrochloric acid. An i.v. infusion of NaHCO3 and glucagon was applied to stimulate AS, and one of NH4Cl, vasopressin and furosemide to depress it. In the stage of AS influenced via various mechanisms and to different extents, the luminal surface of the duodenum was exposed with HCl. The extent of mucosal damage was determined by quantitative morphometry. The mucosa-damaging effect of standardized HCl-exposure was significantly lower in the stage of enhanced AS than in the control experiments. In contrast, during inhibition of AS hydrochloric acid caused more extensive and deeper mucosal damage. A linear correlation was observed between the degree of AS of the duodenum and the proportion of damaged intestinal villi. In the opinion of the authors, inhibition of the As of the duodenum is accompanied by a decreased acid tolerance of the mucosa, while its stimulation enhances the ability of the mucosa to defend against hydrochloric acid.