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BACKGROUND & AIMS: Cell stress signaling pathways result in phosphorylation of the eukaryotic translation initiation factor 2 subunit alpha (EIF2S1 or EIF2A), which affects regulation of protein translation. Translation reprogramming mitigates stress by activating pathways that result in autophagy and cell death, to eliminate damaged cells. Actin is modified during stress and EIF2A is dephosphorylated to restore homeostasis. It is not clear how actin affects EIF2A signaling. We studied the actin-binding proteins villin 1 (VIL1) and gelsolin (GSN) in intestinal epithelial cells (IECs) to determine whether they respond to cell stress response and affect signaling pathways. METHODS: We performed studies with mice with disruptions in Vil1 and Gsn (double-knockout mice). Wild-type (WT) mice either were or were not (controls) exposed to cell stressors such as tumor necrosis factor and adherent-invasive Escherichia coli. Distal ileum tissues were collected from mice; IECs and enteroids were cultured and analyzed by histology, immunoblots, phalloidin staining, immunohistochemistry, electron microscopy, and flow cytometry. HT-29 cells were incubated with cell stressors such as DTT, IFN, and adherent-invasive E coli or control agents; cells were analyzed by immunoblots and quantitative polymerase chain reaction. Green fluorescent protein and green fluorescent protein tagged mutant EIF2A were expressed from a lentiviral vector. The mouse immunity-related GTPase (IRGM1) was overexpressed in embryonic fibroblasts from dynamin1 like (DNM1L) protein-knockout mice or their WT littermates. IRGM1 was overexpressed in embryonic fibroblasts from receptor interacting serine/threonine kinase 1-knockout mice or their WT littermates. Human IRGM was overexpressed in human epithelial cell lines incubated with the DNM1L-specific inhibitor Mdivi-1. Mitochondria were analyzed by semi-quantitative confocal imaging. We performed immunohistochemical analyses of distal ileum tissues from 6-8 patients with Crohn's disease (CD) and 6-8 individuals without CD (controls). RESULTS: In IECs exposed to cell stressors, EIF2A signaling reduced expression of VIL1 and GSN. However, VIL1 and GSN were required for dephosphorylation of EIF2A and recovery from cell stress. In mouse and human IECs, prolonged, unresolved stress was accompanied by continued down-regulation of VIL1 and GSN, resulting in constitutive phosphorylation of EIF2A and overexpression of IRGM1 (or IRGM), which regulates autophagy. Overexpression of IRGM1 (or IRGM) induced cell death by necroptosis, accompanied by release of damage-associated molecular patterns (DAMPs). In double-knockout mice, constitutive phosphorylation of EIF2A and over-expression of IRGM1 resulted in spontaneous ileitis that resembled human CD in symptoms and histology. Distal ileum tissues from patients with CD had lower levels of VIL1 and GSN, increased phosphorylation of EIF2A, increased levels of IRGM and necroptosis, and increased release of nuclear DAMPs compared with controls. CONCLUSIONS: In studies of intestinal epithelial tissues from patients with CD and embryonic fibroblasts from mice, along with enteroids and human IEC lines, we found that induction of cell stress alters the cytoskeleton in IECs via changes in the actin-binding proteins VIL1 and GSN. Acute changes in actin dynamics increase IEC survival, whereas long-term changes in actin dynamics lead to IEC death and intestinal inflammation. IRGM regulates necroptosis and release of DAMPs to induce gastrointestinal inflammation, linking IRGM activity with CD.
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Citoesqueleto de Actina/metabolismo , Doença de Crohn/metabolismo , Células Epiteliais/metabolismo , Gelsolina/metabolismo , Íleo/metabolismo , Mucosa Intestinal/metabolismo , Proteínas dos Microfilamentos/metabolismo , Transdução de Sinais , Estresse Fisiológico , Citoesqueleto de Actina/patologia , Alarminas/metabolismo , Animais , Morte Celular , Sobrevivência Celular , Doença de Crohn/genética , Doença de Crohn/patologia , Modelos Animais de Doenças , Células Epiteliais/patologia , Fator de Iniciação 2 em Eucariotos/metabolismo , Proteínas de Ligação ao GTP/genética , Proteínas de Ligação ao GTP/metabolismo , Gelsolina/deficiência , Gelsolina/genética , Células HT29 , Células HeLa , Humanos , Íleo/patologia , Mucosa Intestinal/patologia , Camundongos Knockout , Proteínas dos Microfilamentos/genética , Mitocôndrias/metabolismo , Mitocôndrias/patologia , Fosforilação , Interferência de RNA , Fatores de Tempo , TransfecçãoRESUMO
BACKGROUND: India faces a high burden of child undernutrition. We evaluated the effects of two community strategies to reduce undernutrition among children under 3 years in rural Jharkhand and Odisha, eastern India: (1) monthly Participatory Learning and Action (PLA) meetings with women's groups followed by home visits; (2) crèches for children aged 6 months to 3 years combined with monthly PLA meetings and home visits. METHODS: We tested these strategies in a non-randomised, controlled study with baseline and endline cross-sectional surveys. We purposively selected five blocks of Jharkhand and Odisha, and divided each block into three areas. Area 1 served as control. In Area 2, trained local female workers facilitated PLA meetings and offered counselling to mothers of children under three at home. In Area 3, workers facilitated PLA meetings, did home visits, and crèches with food and growth monitoring were opened for children aged 6 months to 3 years. We did a census across all study areas and randomly sampled 4668 children under three and their mothers for interview and anthropometry at baseline and endline. The evaluation's primary outcome was wasting among children under three in areas 2 and 3 compared with area 1, adjusted for baseline differences between areas. Other outcomes included underweight, stunting, preventive and care-seeking practices for children. RESULTS: We interviewed 83% (3868/4668) of mothers of children under three sampled at baseline, and 76% (3563/4668) at endline. In area 2 (PLA and home visits), wasting among children under three was reduced by 34% (adjusted Odds Ratio [aOR]: 0.66, 95%: 0.51-0.88) and underweight by 25% (aOR: 0.75, 95% CI: 0.59-0.95), with no change in stunting (aOR: 1.23, 95% CI: 0.96-1.57). In area 3, (PLA, home visits, crèches), wasting was reduced by 27% (aOR: 0.73, 95% CI: 0.55-0.97), underweight by 40% (aOR: 0.60, 95% CI: 0.47-0.75), and stunting by 27% (aOR: 0.73, 95% CI: 0.57-0.93). CONCLUSIONS: Crèches, PLA meetings and home visits reduced undernutrition among children under three in rural eastern India. These interventions could be scaled up through government plans to strengthen home visits and community mobilisation with Accredited Social Health Activists, and through efforts to promote crèches. TRIAL REGISTRATION: The evaluation was registered retrospectively with Current Controlled Trials as ISCRTN89911047 on 30/01/2019.
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Transtornos da Nutrição Infantil/terapia , Aconselhamento/métodos , Desnutrição/terapia , Educação de Pacientes como Assunto/métodos , Mulheres/psicologia , Adulto , Transtornos da Nutrição Infantil/epidemiologia , Transtornos da Nutrição Infantil/psicologia , Pré-Escolar , Estudos Transversais , Feminino , Visita Domiciliar , Humanos , Índia/epidemiologia , Lactente , Masculino , Desnutrição/epidemiologia , Desnutrição/psicologia , Mães/psicologia , Ensaios Clínicos Controlados não Aleatórios como Assunto , Aceitação pelo Paciente de Cuidados de Saúde , População RuralRESUMO
BACKGROUND: In Bangladesh, India and Nepal, neonatal outcomes of poor infants are considerably worse than those of better-off infants. Understanding how these inequalities vary by country and place of delivery (home or facility) will allow targeting of interventions to those who need them most. We describe socio-economic inequalities in newborn care in rural areas of Bangladesh, Nepal and India for all deliveries and by place of delivery. METHODS: We used data from surveillance sites in Bangladesh, India and from Makwanpur and Dhanusha districts in Nepal, covering periods from 2001 to 2011. We used literacy (ability to read a short text) as indicator of socioeconomic status. We developed a composite score of nine newborn care practices (score range 0-9 indicating infants received no newborn care to all nine newborn care practices). We modeled the effect of literacy and place of delivery on the newborn care score and on individual practices. RESULTS: In all study sites (60,078 deliveries in total), use of facility delivery was higher among literate mothers. In all sites, inequalities in newborn care were observed: the difference in new born care between literate and illiterate ranged 0.35-0.80. The effect of literacy on the newborn care score reduced after adjusting for place of delivery (range score difference literate-illiterate: 0.21-0.43). CONCLUSION: Socioeconomic inequalities in facility care greatly contribute to inequalities in newborn care. Improving newborn care during home deliveries and improving access to facility care are a priority for addressing inequalities in newborn care and newborn mortality.
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Entorno do Parto/estatística & dados numéricos , Parto Obstétrico/estatística & dados numéricos , Disparidades em Assistência à Saúde/estatística & dados numéricos , Cuidado do Lactente/estatística & dados numéricos , Fatores Socioeconômicos , Adulto , Bangladesh , Estudos Transversais , Demografia , Feminino , Parto Domiciliar/estatística & dados numéricos , Humanos , Índia/epidemiologia , Recém-Nascido , Masculino , Nepal , Gravidez , População RuralRESUMO
The ER-mitochondrial junction provides a local calcium signaling domain that is critical for both matching energy production with demand and the control of apoptosis. Here, we visualize ER-mitochondrial contact sites and monitor the localized [Ca(2+)] changes ([Ca(2+)](ER-mt)) using drug-inducible fluorescent interorganelle linkers. We show that all mitochondria have contacts with the ER, but plasma membrane (PM)-mitochondrial contacts are less frequent because of interleaving ER stacks in both RBL-2H3 and H9c2 cells. Single mitochondria display discrete patches of ER contacts and show heterogeneity in the ER-mitochondrial Ca(2+) transfer. Pericam-tagged linkers revealed IP(3)-induced [Ca(2+)](ER-mt) signals that exceeded 9 microM and endured buffering bulk cytoplasmic [Ca(2+)] increases. Altering linker length to modify the space available for the Ca(2+) transfer machinery had a biphasic effect on [Ca(2+)](ER-mt) signals. These studies provide direct evidence for the existence of high-Ca(2+) microdomains between the ER and mitochondria and suggest an optimal gap width for efficient Ca(2+) transfer.
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Cálcio/metabolismo , Retículo Endoplasmático/metabolismo , Imageamento Tridimensional/métodos , Mitocôndrias/metabolismo , Animais , Sinalização do Cálcio , Linhagem Celular , Membrana Celular/metabolismo , Membrana Celular/ultraestrutura , Permeabilidade da Membrana Celular , Sobrevivência Celular , Retículo Endoplasmático/ultraestrutura , Receptores de Inositol 1,4,5-Trifosfato/metabolismo , Mitocôndrias/ultraestrutura , Membranas Mitocondriais/metabolismo , Membranas Mitocondriais/ultraestrutura , Ratos , Fatores de TempoRESUMO
BACKGROUND: In 2005, the Indian Government introduced the Janani Suraksha Yojana (JSY) scheme - a conditional cash transfer program that incentivizes women to deliver in a health facility - in order to reduce maternal and neonatal mortality. Our study aimed to measure and explain socioeconomic inequality in the receipt of JSY benefits. METHODS: We used prospectively collected data on 3,682 births (in 2009-2010) from a demographic surveillance system in five districts in Jharkhand and Odisha state, India. Linear probability models were used to identify the determinants of receipt of JSY benefits. Poor-rich inequality in the receipt of JSY benefits was measured by a corrected concentration index (CI), and the most important drivers of this inequality were identified using decomposition techniques. RESULTS: While the majority of women had heard of the scheme (94% in Odisha, 85% in Jharkhand), receipt of JSY benefits was comparatively low (62% in Odisha, 20% in Jharkhand). Receipt of the benefits was highly variable by district, especially in Jharkhand, where 5% of women in Godda district received the benefits, compared with 40% of women in Ranchi district. There were substantial pro-rich inequalities in JSY receipt (CI 0.10, standard deviation (SD) 0.03 in Odisha; CI 0.18, SD 0.02 in Jharkhand) and in the institutional delivery rate (CI 0.16, SD 0.03 in Odisha; CI 0.30, SD 0.02 in Jharkhand). Delivery in a public facility was an important determinant of receipt of JSY benefits and explained a substantial part of the observed poor-rich inequalities in receipt of the benefits. Yet, even among public facility births in Jharkhand, pro-rich inequality in JSY receipt was substantial (CI 0.14, SD 0.05). This was largely explained by district-level differences in wealth and JSY receipt. Conversely, in Odisha, poorer women delivering in a government institution were at least as likely to receive JSY benefits as richer women (CI -0.05, SD 0.03). CONCLUSION: JSY benefits were not equally distributed, favouring wealthier groups. These inequalities in turn reflected pro-rich inequalities in the institutional delivery. The JSY scheme is currently not sufficient to close the poor-rich gap in institutional delivery rate. Important barriers to institutional delivery remain to be addressed and more support is needed for low performing districts and states.
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Parto Obstétrico , Instalações de Saúde/estatística & dados numéricos , Acessibilidade aos Serviços de Saúde/economia , Disparidades em Assistência à Saúde/economia , Serviços de Saúde Materna/economia , Motivação , Classe Social , Feminino , Financiamento Governamental , Programas Governamentais , Humanos , Índia , Lactente , Mortalidade Infantil , Mortalidade Materna , Gravidez , Fatores SocioeconômicosRESUMO
BACKGROUND: Child stunting (low height-for-age) is a marker of chronic undernutrition and predicts children's subsequent physical and cognitive development. Around one third of the world's stunted children live in India. Our study aims to assess the impact, cost-effectiveness, and scalability of a community intervention with a government-proposed community-based worker to improve growth in children under two in rural India. METHODS: The study is a cluster randomised controlled trial in two rural districts of Jharkhand and Odisha (eastern India). The intervention tested involves a community-based worker carrying out two activities: (a) one home visit to all pregnant women in the third trimester, followed by subsequent monthly home visits to all infants aged 0-24 months to support appropriate feeding, infection control, and care-giving; (b) a monthly women's group meeting using participatory learning and action to catalyse individual and community action for maternal and child health and nutrition. Both intervention and control clusters also receive an intervention to strengthen Village Health Sanitation and Nutrition Committees. The unit of randomisation is a purposively selected cluster of approximately 1000 population. A total of 120 geographical clusters covering an estimated population of 121,531 were randomised to two trial arms: 60 clusters in the intervention arm receive home visits, group meetings, and support to Village Health Sanitation and Nutrition Committees; 60 clusters in the control arm receive support to Committees only. The study participants are pregnant women identified in the third trimester of pregnancy and their children (n = 2520). Mothers and their children are followed up at seven time points: during pregnancy, within 72 hours of delivery, and at 3, 6, 9, 12 and 18 months after birth. The trial's primary outcome is children's mean length-for-age Z scores at 18 months. Secondary outcomes include wasting and underweight at all time points, birth weight, growth velocity, feeding, infection control, and care-giving practices. Additional qualitative and quantitative data are collected for process and economic evaluations. DISCUSSION: This trial will contribute to evidence on effective strategies to improve children's growth in India. TRIAL REGISTRATION: ISRCTN register 51505201 ; Clinical Trials Registry of India number 2014/06/004664.
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Transtornos da Nutrição Infantil/prevenção & controle , Agentes Comunitários de Saúde/organização & administração , Visita Domiciliar , Centros de Saúde Materno-Infantil/organização & administração , Educação de Pacientes como Assunto/organização & administração , Adulto , Desenvolvimento Infantil , Pré-Escolar , Agentes Comunitários de Saúde/economia , Análise Custo-Benefício , Aconselhamento , Feminino , Humanos , Índia/epidemiologia , Lactente , Recém-Nascido , Centros de Saúde Materno-Infantil/economia , Mães , Estado Nutricional , Educação de Pacientes como Assunto/economia , Cuidado Pós-Natal , Gravidez , Terceiro Trimestre da Gravidez , População RuralRESUMO
BACKGROUND: Provision of essential newborn care (ENC) can save many newborn lives in poor resource settings but coverage is far from universal and varies by country and place of delivery. Understanding gaps in current coverage and where coverage is good, in different contexts and places of delivery, could make a valuable contribution to the future design of interventions to reduce neonatal mortality. We sought to describe the coverage of essential newborn care practices for births in institutions, at home with a skilled birth attendant, and at home without a skilled birth attendant (SBA) in rural areas of Bangladesh, Nepal, and India. METHODS: We used data from the control arms of four cluster randomised controlled trials in Bangladesh, Eastern India and from Makwanpur and Dhanusha districts in Nepal, covering periods from 2001 to 2011. We used these data to identify essential newborn care practices as defined by the World Health Organization. Each birth was allocated to one of three delivery types: home birth without an SBA, home birth with an SBA, or institutional delivery. For each study, we calculated the observed proportion of births that received each care practice by delivery type with 95% confidence intervals, adjusted for clustering and, where appropriate, stratification. RESULTS: After exclusions, we analysed data for 8939 births from Eastern India, 27 553 births from Bangladesh, 6765 births from Makwanpur and 15 344 births from Dhanusha. Across all study areas, coverage of essential newborn care practices was highest in institutional deliveries, and lowest in home non-SBA deliveries. However, institutional deliveries did not provide universal coverage of the recommended practices, with relatively low coverage (20%-70%) across all study areas for immediate breastfeeding and thermal care. Institutions in Bangladesh had the highest coverage for almost all care practices except thermal care. Across all areas, fewer than 20% of home non-SBA deliveries used a clean delivery kit, the use of plastic gloves was very low and coverage of recommended thermal care was relatively poor. There were large differences between study areas in handwashing, immediate breastfeeding and delayed bathing. CONCLUSIONS: There remains substantial scope for health facilities to improve thermal care for the newborn and to encourage immediate and exclusive breastfeeding. For unattended home deliveries, increased handwashing, use of clean delivery kits and basic thermal care offer great scope for improvement.
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Parto Obstétrico/métodos , Países em Desenvolvimento , Parto Domiciliar , Cuidado Pré-Natal/organização & administração , População Rural , Bangladesh/epidemiologia , Análise por Conglomerados , Feminino , Humanos , Índia/epidemiologia , Mortalidade Infantil/tendências , Recém-Nascido , Tocologia/organização & administração , Nepal/epidemiologia , Gravidez , Estudos ProspectivosRESUMO
OBJECTIVE: To determine whether a women's group intervention involving participatory learning and action has a sustainable and replicable effect on neonatal survival in rural, eastern India. METHODS: From 2004 to 2011, births and neonatal deaths in 36 geographical clusters in Jharkhand and Odisha were monitored. Between 2005 and 2008, these clusters were part of a randomized controlled trial of how women's group meetings involving participatory learning and action influence maternal and neonatal health. Between 2008 and 2011, groups in the original intervention clusters (zone 1) continued to meet to discuss post-neonatal issues and new groups in the original control clusters (zone 2) met to discuss neonatal health. Logistic regression was used to examine neonatal mortality rates after 2008 in the two zones. FINDINGS: Data on 41,191 births were analysed. In zone 1, the intervention's effect was sustained: the cluster-mean neonatal mortality rate was 34.2 per 1000 live births (95% confidence interval, CI: 28.3-40.0) between 2008 and 2011, compared with 41.3 per 1000 live births (95% CI: 35.4-47.1) between 2005 and 2008. The effect of the intervention was replicated in zone 2: the cluster-mean neonatal mortality rate decreased from 61.8 to 40.5 per 1000 live births between two periods: 2006-2008 and 2009-2011 (odds ratio: 0.69, 95% CI: 0.57-0.83). Hygiene during delivery, thermal care of the neonate and exclusive breastfeeding were important factors. CONCLUSION: The effect of participatory women's groups on neonatal survival in rural India, where neonatal mortality is high, was sustainable and replicable.
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Mortalidade Infantil , População Rural , Sobrevida , Mulheres/educação , Humanos , Índia , Recém-Nascido , Estudos ProspectivosRESUMO
Poly(ADP-ribose) polymerase-1 (PARP-1) has two homologous zinc finger domains, Zn1 and Zn2, that bind to a variety of DNA structures to stimulate poly(ADP-ribose) synthesis activity and to mediate PARP-1 interaction with chromatin. The structural basis for interaction with DNA is unknown, which limits our understanding of PARP-1 regulation and involvement in DNA repair and transcription. Here, we have determined crystal structures for the individual Zn1 and Zn2 domains in complex with a DNA double strand break, providing the first views of PARP-1 zinc fingers bound to DNA. The Zn1-DNA and Zn2-DNA structures establish a novel, bipartite mode of sequence-independent DNA interaction that engages a continuous region of the phosphodiester backbone and the hydrophobic faces of exposed nucleotide bases. Biochemical and cell biological analysis indicate that the Zn1 and Zn2 domains perform distinct functions. The Zn2 domain exhibits high binding affinity to DNA compared with the Zn1 domain. However, the Zn1 domain is essential for DNA-dependent PARP-1 activity in vitro and in vivo, whereas the Zn2 domain is not strictly required. Structural differences between the Zn1-DNA and Zn2-DNA complexes, combined with mutational and structural analysis, indicate that a specialized region of the Zn1 domain is re-configured through the hydrophobic interaction with exposed nucleotide bases to initiate PARP-1 activation.
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Quebras de DNA de Cadeia Dupla , DNA/química , Poli(ADP-Ribose) Polimerases/química , Animais , Linhagem Celular , DNA/genética , DNA/metabolismo , Interações Hidrofóbicas e Hidrofílicas , Camundongos , Camundongos Knockout , Poli(ADP-Ribose) Polimerase-1 , Poli(ADP-Ribose) Polimerases/genética , Poli(ADP-Ribose) Polimerases/metabolismo , Ligação Proteica , Estrutura Terciária de Proteína , Relação Estrutura-Atividade , Dedos de ZincoRESUMO
Villin is a major actin-bundling protein that assembles the brush border of intestinal and renal epithelial cells. The villin "headpiece" domain and the actin-binding residues within it regulate its actin-bundling function. Substantial experimental and theoretical information about the three-dimensional structure of the isolated villin headpiece, including a description of the actin-binding residues within the headpiece, is available. Despite that, the actin-bundling site in the full-length (FL) villin protein remains unidentified. We used this existing villin headpiece nuclear magnetic resonance data and performed mutational analysis and functional assays to identify the actin-bundling site in FL human villin protein. By careful evaluation of these conserved actin-binding residues in human advillin protein, we demonstrate their functional significance in the over 30 proteins that contain a villin-type headpiece domain. Our study is the first that combines the available structural data on villin headpiece with functional assays to identify the actin-binding residues in FL villin that regulate its filament-bundling activity. Our findings could have wider implications for other actin-bundling proteins that contain a villin-type headpiece domain.
Assuntos
Proteínas dos Microfilamentos/genética , Proteínas dos Microfilamentos/metabolismo , Actinas/metabolismo , Sequência de Aminoácidos , Aminoácidos/genética , Animais , Sítios de Ligação/genética , Proteínas de Transporte/metabolismo , Citoesqueleto/metabolismo , Cães , Células HeLa , Humanos , Células Madin Darby de Rim Canino , Proteínas dos Microfilamentos/fisiologia , Ligação Proteica/genética , Domínios Proteicos/genética , Estrutura Terciária de ProteínaRESUMO
Unilateral pulmonary artery agenesis (UPAA) is a rare malformation that can present as an isolated anomaly or may be associated with certain congenital cardiac anomalies, such as tetralogy of Fallot, atrial septal defect, coarctation of aorta, right aortic arch, truncus arteriosus and pulmonary atresia. Clinical presentation is non-specific which makes the diagnosis elusive; chronic dyspnea, hemoptysis or recurrent infections are the most common manifestations. Patients may remain asymptomatic until adulthood. There is no definitive treatment for patients with UPAA. Acute respiratory distress syndrome (ARDS) is usually a bilateral disease, unilateral ARDS has been described after lung resection or trauma. We present a case of a 39 year-old woman who developed unilateral ARDS and was later diagnosed with isolated UPAA.
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BACKGROUND: Around 30% of the world's stunted children live in India. The Government of India has proposed a new cadre of community-based workers to improve nutrition in 200 districts. We aimed to find out the effect of such a worker carrying out home visits and participatory group meetings on children's linear growth. METHODS: We did a cluster-randomised controlled trial in two adjoining districts of Jharkhand and Odisha, India. 120 clusters (around 1000 people each) were randomly allocated to intervention or control using a lottery. Randomisation took place in July, 2013, and was stratified by district and number of hamlets per cluster (0, 1-2, or ≥3), resulting in six strata. In each intervention cluster, a worker carried out one home visit in the third trimester of pregnancy, monthly visits to children younger than 2 years to support feeding, hygiene, care, and stimulation, as well as monthly women's group meetings to promote individual and community action for nutrition. Participants were pregnant women identified and recruited in the study clusters and their children. We excluded stillbirths and neonatal deaths, infants whose mothers died, those with congenital abnormalities, multiple births, and mother and infant pairs who migrated out of the study area permanently during the trial period. Data collectors visited each woman in pregnancy, within 72 h of her baby's birth, and at 3, 6, 9, 12, and 18 months after birth. The primary outcome was children's length-for-age Z score at 18 months of age. Analyses were by intention to treat. Due to the nature of the intervention, participants and the intervention team were not masked to allocation. Data collectors and the data manager were masked to allocation. The trial is registered as ISCRTN (51505201) and with the Clinical Trials Registry of India (number 2014/06/004664). RESULTS: Between Oct 1, 2013, and Dec 31, 2015, we recruited 5781 pregnant women. 3001 infants were born to pregnant women recruited between Oct 1, 2013, and Feb 10, 2015, and were therefore eligible for follow-up (1460 assigned to intervention; 1541 assigned to control). Three groups of children could not be included in the final analysis: 147 migrated out of the study area (67 in intervention clusters; 80 in control clusters), 77 died after the neonatal period and before 18 months (31 in intervention clusters; 46 in control clusters), and seven had implausible length-for-age Z scores (<-5 SD; one in intervention cluster; six in control clusters). We measured 1253 (92%) of 1362 eligible children at 18 months in intervention clusters, and 1308 (92%) of 1415 eligible children in control clusters. Mean length-for-age Z score at 18 months was -2·31 (SD 1·12) in intervention clusters and -2·40 (SD 1·10) in control clusters (adjusted difference 0·107, 95% CI -0·011 to 0·226, p=0·08). The intervention did not significantly affect exclusive breastfeeding, timely introduction of complementary foods, morbidity, appropriate home care or care-seeking during childhood illnesses. In intervention clusters, more pregnant women and children attained minimum dietary diversity (adjusted odds ratio [aOR] for women 1·39, 95% CI 1·03-1·90; for children 1·47, 1·07-2·02), more mothers washed their hands before feeding children (5·23, 2·61-10·5), fewer children were underweight at 18 months (0·81, 0·66-0·99), and fewer infants died (0·63, 0·39-1·00). INTERPRETATION: Introduction of a new worker in areas with a high burden of undernutrition in rural eastern India did not significantly increase children's length. However, certain secondary outcomes such as self-reported dietary diversity and handwashing, as well as infant survival were improved. The interventions tested in this trial can be further optimised for use at scale, but substantial improvements in growth will require investment in nutrition-sensitive interventions, including clean water, sanitation, family planning, girls' education, and social safety nets. FUNDING: UK Medical Research Council, Wellcome Trust, UK Department for International Development (DFID).
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Desenvolvimento Infantil , Aconselhamento , Visita Domiciliar , População Rural , Análise por Conglomerados , Feminino , Seguimentos , Humanos , Índia , Lactente , Fenômenos Fisiológicos da Nutrição do Lactente , Recém-Nascido , Masculino , GravidezRESUMO
Adenoid cystic carcinoma is a malignant neoplasm most commonly originating in salivary glands of head and neck region. Among intra oral adenoid cystic carcinoma, buccal mucosa is among the rarest sites. We report a case of adenoid cystic of buccal mucosa in a 40-year old female. We have discussed the clinical features, histopathology, diagnosis and treatment along with a brief review of the relevant literature. Although the buccal mucosa is an uncommon site for adenoid cystic carcinoma, the relatively indolent growth pattern of this case and its location which is rather atypical for this type of salivary gland malignancy primarily warrants the necessity behind reporting of this case. Secondly, adenoid cystic carcinoma should be considered in the differential diagnosis of mass of buccal mucosa. It is important to identify such cases rather early and surgical removal with adequate margins is the treatment of choice .
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In the small intestine, epithelial cells are derived from stem cells in the crypts, migrate up the villus as they differentiate and are ultimately shed from the villus tips. This process of proliferation and shedding is tightly regulated to maintain the intestinal architecture and tissue homeostasis. Apoptosis regulates both the number of stem cells in the crypts as well as the sloughing of cells from the villus tips. Previously, we have shown that villin, an epithelial cell-specific actin-binding protein functions as an anti-apoptotic protein in the gastrointestinal epithelium. The expression of villin is highest in the apoptosis-resistant villus cells and lowest in the apoptosis-sensitive crypts. In this study we report that villin is cleaved in the intestinal mucosa to generate a pro-apoptotic fragment that is spatially restricted to the villus tips. This cleaved villin fragment severs actin in an unregulated fashion to initiate the extrusion and subsequent apoptosis of effete cells from the villus tips. Using villin knockout mice, we validate the physiological role of villin in apoptosis and cell extrusion from the gastrointestinal epithelium. Our study also highlights the potential role of villin's pro-apoptotic function in the pathogenesis of inflammatory bowel disease, ischemia-reperfusion injury, enteroinvasive bacterial and parasitic infections.
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Apoptose , Homeostase , Intestinos/citologia , Proteínas dos Microfilamentos/metabolismo , Animais , Movimento Celular , Cães , Epitélio/metabolismo , Intestinos/ultraestrutura , Células Madin Darby de Rim Canino , Camundongos Knockout , Modelos BiológicosRESUMO
Villin is a tissue-specific, actin-binding protein involved in the assembly and maintenance of microvilli in polarized epithelial cells. Conversely, villin is also linked with the loss of epithelial polarity and gain of the mesenchymal phenotype in migrating, invasive cells. In this study, we describe for the first time how villin can switch between these disparate functions to change tissue architecture by moonlighting in the nucleus. Our study reveals that the moonlighting function of villin in the nucleus may play an important role in tissue homeostasis and disease. Villin accumulates in the nucleus during wound repair, and altering the cellular microenvironment by inducing hypoxia increases the nuclear accumulation of villin. Nuclear villin is also associated with mouse models of tumorigenesis, and a systematic analysis of a large cohort of colorectal cancer specimens confirmed the nuclear distribution of villin in a subset of tumors. Our study demonstrates that nuclear villin regulates epithelial-mesenchymal transition (EMT). Altering the nuclear localization of villin affects the expression and activity of Slug, a key transcriptional regulator of EMT. In addition, we find that villin directly interacts with a transcriptional corepressor and ligand of the Slug promoter, ZBRK1. The outcome of this study underscores the role of nuclear villin and its binding partner ZBRK1 in the regulation of EMT and as potential new therapeutic targets to inhibit tumorigenesis.
Assuntos
Transição Epitelial-Mesenquimal , Proteínas dos Microfilamentos/fisiologia , Proteínas Repressoras/metabolismo , Transporte Ativo do Núcleo Celular , Animais , Neoplasias Colorretais/metabolismo , Neoplasias Colorretais/patologia , Cães , Regulação Neoplásica da Expressão Gênica , Células HeLa , Humanos , Células Madin Darby de Rim Canino , Camundongos SCID , Transplante de Neoplasias , Sinais de Localização Nuclear , Fatores de Transcrição da Família Snail , Fatores de Transcrição/genética , Fatores de Transcrição/metabolismoRESUMO
The poly(ADP-ribose) polymerase enzyme Tankyrase-1 (TNKS) regulates multiple cellular processes and interacts with diverse proteins using five ankyrin repeat clusters (ARCs). There are limited structural insights into functional roles of the multiple ARCs of TNKS. Here we present the ARC1-3 crystal structure and employ small-angle X-ray scattering (SAXS) to investigate solution conformations of the complete ankyrin repeat domain. Mutagenesis and binding studies using the bivalent TNKS binding domain of Axin1 demonstrate that only certain ARC combinations function together. The physical basis for these restrictions is explained by both rigid and flexible ankyrin repeat elements determined in our structural analysis. SAXS analysis is consistent with a dynamic ensemble of TNKS ankyrin repeat conformations modulated by Axin1 interaction. TNKS ankyrin repeat domain is thus an adaptable binding platform with structural features that can explain selectivity toward diverse proteins, and has implications for TNKS positioning of bound targets for poly(ADP-ribose) modification.
Assuntos
Repetição de Anquirina , Proteína Axina/química , Tanquirases/química , Tanquirases/metabolismo , Adenosina Difosfato Ribose , Proteína Axina/genética , Proteína Axina/metabolismo , Cristalografia por Raios X , Humanos , Modelos Moleculares , Mutagênese , Ligação Proteica , Conformação Proteica , Estrutura Secundária de Proteína , Espalhamento a Baixo Ângulo , Especificidade por Substrato , Tanquirases/genéticaRESUMO
BACKGROUND: A quarter of the world's neonatal deaths and 15% of maternal deaths happen in India. Few community-based strategies to improve maternal and newborn health have been tested through the country's government-approved Accredited Social Health Activists (ASHAs). We aimed to test the effect of participatory women's groups facilitated by ASHAs on birth outcomes, including neonatal mortality. METHODS: In this cluster-randomised controlled trial of a community intervention to improve maternal and newborn health, we randomly assigned (1:1) geographical clusters in rural Jharkhand and Odisha, eastern India to intervention (participatory women's groups) or control (no women's groups). Study participants were women of reproductive age (15-49 years) who gave birth between Sept 1, 2009, and Dec 31, 2012. In the intervention group, ASHAs supported women's groups through a participatory learning and action meeting cycle. Groups discussed and prioritised maternal and newborn health problems, identified strategies to address them, implemented the strategies, and assessed their progress. We identified births, stillbirths, and neonatal deaths, and interviewed mothers 6 weeks after delivery. The primary outcome was neonatal mortality over a 2 year follow up. Analyses were by intention to treat. This trial is registered with ISRCTN, number ISRCTN31567106. FINDINGS: Between September, 2009, and December, 2012, we randomly assigned 30 clusters (estimated population 156â519) to intervention (15 clusters, estimated population n=82â702) or control (15 clusters, n=73â817). During the follow-up period (Jan 1, 2011, to Dec 31, 2012), we identified 3700 births in the intervention group and 3519 in the control group. One intervention cluster was lost to follow up. The neonatal mortality rate during this period was 30 per 1000 livebirths in the intervention group and 44 per 1000 livebirths in the control group (odds ratio [OR] 0.69, 95% CI 0·53-0·89). INTERPRETATION: ASHAs can successfully reduce neonatal mortality through participatory meetings with women's groups. This is a scalable community-based approach to improving neonatal survival in rural, underserved areas of India. FUNDING: Big Lottery Fund (UK).
Assuntos
Pessoal de Saúde , Promoção da Saúde/métodos , Saúde do Lactente , Saúde Materna , Serviços de Saúde Materno-Infantil , Resultado da Gravidez , População Rural , Acreditação , Adulto , Países em Desenvolvimento , Feminino , Humanos , Índia/epidemiologia , Lactente , Mortalidade Infantil , Razão de Chances , Morte Perinatal , Gravidez , Natimorto , Adulto JovemRESUMO
OBJECTIVE: This study evaluated and compared the efficacy of mandible and iliac bone as autogenous bone graft for correction of orbital floor fractures. PATIENTS AND METHODS: Twenty patients who suffered orbital floor fractures took part in the study. The subjects enrolled in the study sustained both isolated orbital floor fracture and orbital floor fracture associated with fracture of zygomatico-maxillary complex. Each inferior orbital wall was reconstructed using either a mandible bone graft or an iliac graft. Mandibular symphysis was opted as a donor site for graft harvest from mandible and anterior iliac crest for the iliac group. CT scans were taken before the operation. Inclusion criteria consisted of at least 2 months postsurgical follow-up, pre- and post-surgical photographic documentation, and complete medical records regarding inpatient and outpatient data. To describe the distribution of complications and facilitate statistical analysis, we categorized our findings into diplopia, enophthalmos, and restriction of ocular movements before and after treatment. We also considered the time required for the harvest of the grafts and the donor site complications. A comparative study was carried out using Chi square test and student t test. We considered P value <0.05 to be statistically significant. RESULTS: Ten iliac crest grafts and ten mandible bone grafts were placed. The mean age of the patients was 33.1 years. 80 % of the patients were males. The most common complication of orbital floor fracture was diplopia, followed by enophthalmos and restriction of ocular movements. The post operative results were compared after 2 months of the surgery. In iliac crest group, diplopia got corrected in six out of seven patients (85 %), enophthalmos in four out of five patients (80 %) and restricted ocular movement showed 100 % correction. While in mandible group, diplopia and ocular movement showed 100 % correction and enophthalmos got corrected in five out of six patients (83 %). No statistically significant differences were found between the two groups on comparing these variables. On the other hand the mean time required for the harvest of iliac graft and mandible graft was 30.2 ± 3.52 min and 16.8 ± 1.75 min respectively. The difference was statistically significant. CONCLUSION: There is no difference in the ability of mandible and anterior iliac crest bone grafts to correct post-traumatic diplopia, enophthalmos and restricted ocular movements. But the time and ease of harvest of the graft from mandible was comparatively less and easy especially when the treating doctor was an oral and maxillofacial surgeon. Secondly the post-operative morbidity was low and the quality and contour of the bone graft was very adaptable for the reconstruction of the orbital floor.
RESUMO
BACKGROUND: Delivery of essential newborn care is key to reducing neonatal mortality rates, yet coverage of protective birth practices remains incomplete and variable, with or without skilled attendance. Evidence of changes over time in newborn care provision, disaggregated by care practice and delivery type, can be used by policymakers to review efforts to reduce mortality. We examine such trends in four areas using control arm trial data. METHODS AND FINDINGS: We analysed data from the control arms of cluster randomised controlled trials in Bangladesh (27 553 births), eastern India (8 939), Dhanusha, Nepal (15 344) and Makwanpur, Nepal (6 765) over the period 2001-2011. For each trial, we calculated the observed proportion of attended births and the coverage of WHO essential newborn care practices by year, adjusted for clustering and stratification. To explore factors contributing to the observed trends, we then analysed expected trends due only to observed shifts in birth attendance, accounted for stratification, delivery type and statistically significant interaction terms, and examined disaggregated trends in care practice coverage by delivery type. Attended births increased over the study periods in all areas from very low rates, reaching a maximum of only 30% of deliveries. Newborn care practice trends showed marked heterogeneity within and between areas. Adjustment for stratification, birth attendance and interaction revealed that care practices could change in opposite directions over time and/or between delivery types - e.g. in Bangladesh hygienic cord-cutting and skin-to-skin contact fell in attended deliveries but not home deliveries, whereas in India birth attendant hand-washing rose for institutional deliveries but fell for home deliveries. CONCLUSIONS: Coverage of many essential newborn care practices is improving, albeit slowly and unevenly across sites and delivery type. Time trend analyses of birth patterns and essential newborn care practices can inform policy-makers about effective intervention strategies.
Assuntos
Atenção à Saúde/tendências , Parto , Bangladesh , Humanos , Índia , Recém-Nascido , Nepal , Estudos Prospectivos , Fatores de TempoRESUMO
OBJECTIVE: Keratocystic odontogenic tumor (KCOT) has an aggressive clinical course and a high tendency of recurrence, while orthokeratinized odontogenic cyst (OOC) has different characteristics and does not show aggressive behaviour. Even the treatment of these two lesions varies considerably. A large number of epithelial molecules have been studied in order to differentiate odontogenic keratocyst (OKC) from OOC, but stromal factors have not been adequately studied. Recently, tumor stroma has evolved as a particular field of interest. In the present study, we aim to evaluate and compare the expression of stromal myofibroblasts (MFs) in these entities and correlate it to its aggressive behavior. The term 'keratocystic odontogenic tumor' has been introduced by WHO in 2005 for odontogenic keratocyst keeping in mind its aggressive behavior, however still many pathologists and clinicians use the term OKC synonymously. MATERIALS AND METHODS: A total of 10 cases of KCOT and 10 cases of OOC were stained for alpha-smooth muscle actin (αSMA) for demonstration of stromal MFs. MF frequency was assessed as the number of αSMA-positive stromal cells in 10 high power fields, presented as the mean number of positive cells per field. RESULTS: Counts showed that the mean number of positive cells in KCOT (20.6 ± 2.05) was significantly higher than that seen in OOC (10.4 ± 1.06) (P < 0.05). CONCLUSION: The different behaviors of these lesions are compatible with the finding of the present study. The increased number of stromal MFs in KCOT in comparison to OOC correlates with its aggressive behavior and increased tendency towards recurrence.