Miracle-dz/UniFAR-FTUs huggingface dataset:
Reducing maternal and neonatal deaths in ruralMalawi: evaluating the impact of a community-basedwomen’s group intervention

Background: Maternal and neonatal mortality are high in Malawi, and cost-effective and sustainable interventions are needed in order to reduce mortality rates and make progress to achieve Millennium Development Goals 4 and 5 for mother and child health. Where health systems are weak and many women deliver at home, community-based interventions have the potential to make an important contribution to health improvements. Methods: A cluster-randomised study with a factorial design was used to evaluate the impact of two community-based interventions on maternal and child health outcomes. A prospective pregnancy and birth monitoring system was developed to collect information on pre-specified pregnancy, birth and infant outcomes. The research presented here focuses on the women’s group intervention, which uses participatory methods to mobilise communities to take actions for maternal and child health problems they identify. Results: 18,562 pregnancies were followed up, resulting in 18,340 live births, 362 stillbirths, 434 neonatal deaths and 73 maternal deaths. 11,450 live births were identified retrospectively, resulting in 484 infant deaths. Statistically significant reductions in maternal and neonatal mortality as a result of the women’s group intervention were not seen (adjusted odds ratio 0.94 (95% CI 0.56-1.61) and 0.95 (95% CI 0.71-1.28) respectively). There were significant improvements in antenatal care and immunisation, and reductions in births attended by traditional birth attendants, and there were non-significant reductions in mortality and increases in health-care seeking. Discussion: Although women’s groups showed promising signs of community-level action for mother and child health, methodological factors, such as low power and baseline imbalance after randomisation, may have limited the ability of this study to detect an impact of the intervention on mother and child health outcomes. Design and implementation factors may also have caused delays and limited the measurable impact of the intervention at this time. Follow-up over a longer period may show greater impact.
PANORAMA 2: A phase II study of panobinostat (LBH589) in combination with bortezomib (BTZ) and dexamethasone (DEX) in patients with relapsed and BTZ-refractory multiple myeloma (MM).

TPS308 Background: BTZ, a backbone of novel therapy for patients (pts) with MM, is an effective agent but pts will relapse and ultimately become refractory to BTZ-based therapy as well as other novel agents, thereby constituting a high unmet medical need. Panobinostat (PAN; LBH589) is a potent pan-deacetylase inhibitor (pan-DACi) that targets HDAC6, disrupts aggresome and HSP90 activity, and promotes MM cell death. Combination with BTZ has shown synergistic cytotoxicity in preclinical studies. In a phase Ib MM study, combination of oral PAN with iv BTZ displayed a predictable and manageable safety profile with limited neurotoxicity and clinical efficacy seen with CR + PR + MR in 68% of pts, including 8 of 13 (62%) BTZ-refractory pts. Hence this combination is to be further evaluated in the PANORAMA program (PANobinostat ORAl in Multiple myelomA) Phase III (PANORAMA 1) and Phase II (PANORAMA 2) studies. PANORAMA 2is a U.S.-based, multicenter, single-arm study to evaluate the efficacy of PAN + BTZ + DEX in .
Karotis artere stent yerleştirme: Tek merkez deneyimi ve klinik sonuçları

Amac: Bu calismada klinigimize basvuran, karotis arter hastaligi tanisi almis ve karotis arter stentleme (KAS) ile revaskularize edilen hastalarin ozelliklerini ve orta vadeli klinik sonuclarini sunmayi amacladik. Yontemler: Tek merkezli, geriye donuk Mayis 2012- Mayis 2014 tarihleri arasinda karotis artere mudahale gerekliligi olan ve KAS islemini kabul eden hastalar calismaya dahil edildi. Hastanin klinik ozellikleri ve islem ile ilgili verileri hasta dosyalari taranarak elde edildi. Daha sonra taburculuk sonrasi hastanin yasayip yasamadigi ve islem sonrasi yeni inme gecirip gecirmedigi hastane kayitlarindan ve/veya telefon ile ogrenildi. Bulgular: Dahil edilme kriterlerini saglayan 26 hasta calismaya alindi. Hastalarin %69\'u bayan olup, yas ortalamasi 66±9 yil saptandi. Hastalarin %73\'u semptomatik olup, %73\'unde hipertansiyon, %27\'sinde diabetes mellitus, %39\'unda hiperlipidemi, % 69\'unda koroner arter hastaligi ve %31\'inde aktif sigara iciciligi mevcuttu. Butun hastalarda self ekspandable stent ve distal emboli koruyucu cihaz kullanildi. Islem ile iliskili olarak 18 hastaya sol, 6 hastaya sag ve 2 hastaya ayri seanslarda iki tarafli olmak uzere 26 hastaya toplamda 28 basarili KAS islemi yapildi. Sadece 1 hastaya rezidu darlik nedeniyle ikinci stent yerlestirme ihtiyaci oldu. Islemle iliskili sadece 1 hastada 24 saate tamamen duzelen hava embolisine bagli guc kaybi oldu. Hastalar tekrarlayan inme ve olum acisindan 11,5±8 (en az 2-en cok 27, median 10) ay takip edildi. Takip suresince hicbir hastada tekrarlayan inme ve trans iskemik atak saptanmadi. Sadece 1 hastada 8 ay sonra olum gozlendi. Sonuc: Deneyimli merkezlerde KAS basarili bir sekilde uygulanmakta olup komplikasyon riski oldukca dusuktur. KAS\'in orta vadeli klinik sonuclari oldukca yuz guldurucudur.
Interleukin-6 (IL-6) Regulates Claudin-2 Expression and Tight Junction Permeability in Intestinal Epithelium*

In inflammatory bowel diseases (IBD), intestinal barrier function is impaired as a result of deteriorations in epithelial tight junction (TJ) structure. IL-6, a pleiotropic cytokine, is elevated in IBD patients, although the role of IL-6 in barrier function remains unknown. We present evidence that IL-6 increases TJ permeability by stimulating the expression of channel-forming claudin-2, which is required for increased caudal-related homeobox (Cdx) 2 through the MEK/ERK and PI3K pathways in intestinal epithelial cells. IL-6 increases the cation-selective TJ permeability without any changes to uncharged dextran flux or cell viability in Caco-2 cells. IL-6 markedly induces claudin-2 expression, which is associated with increased TJ permeability. The colonic mucosa of mice injected with IL-6 also exhibits an increase in claudin-2 expression. The claudin-2 expression and TJ permeability induced by IL-6 are sensitive to the inhibition of gp130, MEK, and PI3K. Furthermore, expression of WT-MEK1 induces claudin-2 expression in Caco-2 cells. Claudin-2 promoter activity is increased by IL-6 in a MEK/ERK and PI3K-dependent manner, and deletion of Cdx binding sites in the promoter sequence results in a loss of IL-6-induced promoter activity. IL-6 increases Cdx2 protein expression, which is suppressed by the inhibition of MEK and PI3K. These observations may reveal an important mechanism by which IL-6 can undermine the integrity of the intestinal barrier.
Improving Access to Care among Underserved Populations: The Role of Health Workforce Data in Health Workforce Policy, Planning and Practice

Universal health coverage (UHC) is central to the post-2015 development agenda. In Namibia, optimal organization of HIV and high-priority health services requires robust, policy-relevant health workforce evidence. This paper examines Namibia’s use of the Workload Indicators of Staffing Need (WISN) tool, which estimates staffing requirements based on health facility workload. Namibia’s public health sector applied WISN regionally and nationally. We analyzed four health workforce decisionmaking scenarios (staff redeployment, scarce skill allocation, staffing norms and task sharing) and used spatial analytic techniques to consider facility under/overstaffing in association with regional HIV prevalence, finding significant staff shortages in densely populated regions with high HIV burdens. Innovative use of WISN results by health systems managers and policymakers can help rationalize staff deployment, provide concrete information on staffing needs and model the impact of potential policy changes. These examples illustrate WISN’s value for policy and practice decisions that can further global commitments to achieve UHC. Background Globally, efforts are underway to define the post-2015 development agenda. For the health-related goals, the cornerstone is country movement toward universal health coverage (UHC), which aims to ensure that all people obtain the health services they need without suffering financial hardship. The global community has also reached a “defining moment” in its response to HIV, as ending the epidemic becomes an attainable goal (WHO 2014a). The relationship between UHC and HIV is closely interconnected, according to the WHO (2014a), which notes that the global response to HIV has been a trailblazer for UHC (WHO 2014a). In settings where UHC or conditions approximating universal coverage are lacking, the uneven distribution of health services and resources will typically result in inequities and underserved populations. The UHC agenda requires attention to country-level human resources for health (HRH) needs (WHO 2014b). Nearly a decade ago, the WHO (2006a) suggested that 2.28 health workers (physicians, nurses and midwives) per 1,000 of the population represents the HRH threshold necessary to achieve 80% population coverage to provide attended childbirths and immunizations, which are core Millennium Development Goal health indicators. According to some, however, this “minimalist” threshold vastly underestimates meeting population health needs and required HRH stock, masks regional/national disparities and ignores shortages of other cadres (O’Brien and Gostin 2011). Health worker shortages and imbalances represent a particular challenge in Africa, where three-fifths (63%) of the WHO-designated HRH crisis countries are located (Mdege et al. 2012; Moosa et al. 2014;
Extra-long Gαs Variant XLαs Protein Escapes Activation-induced Subcellular Redistribution and Is Able to Provide Sustained Signaling*

Background: Murine models suggest differences between cellular actions of Gαs and XLαs, but these are unknown. Results: XLαs, unlike Gαs, remains in the plasma membrane and can generate sustained cAMP signaling. Conclusion: The unique actions of XLαs likely stem from its strong affinity for plasma membrane. Significance: Cellular actions of XLαs have implications in cAMP signaling and diseases caused by mutations in this protein. Murine models indicate that Gαs and its extra-long variant XLαs, both of which are derived from GNAS, markedly differ regarding their cellular actions, but these differences are unknown. Here we investigated activation-induced trafficking of Gαs and XLαs, using immunofluorescence microscopy, cell fractionation, and total internal reflection fluorescence microscopy. In transfected cells, XLαs remained localized to the plasma membrane, whereas Gαs redistributed to the cytosol after activation by GTPase-inhibiting mutations, cholera toxin treatment, or G protein-coupled receptor agonists (isoproterenol or parathyroid hormone (PTH)(1–34)). Cholera toxin treatment or agonist (isoproterenol or pituitary adenylate cyclase activating peptide-27) stimulation of PC12 cells expressing Gαs and XLαs endogenously led to an increased abundance of Gαs, but not XLαs, in the soluble fraction. Mutational analyses revealed two conserved cysteines and the highly charged domain as being critically involved in the plasma membrane anchoring of XLαs. The cAMP response induced by M-PTH(1–14), a parathyroid hormone analog, terminated quickly in HEK293 cells stably expressing the type 1 PTH/PTH-related peptide receptor, whereas the response remained maximal for at least 6 min in cells that co-expressed the PTH receptor and XLαs. Although isoproterenol-induced cAMP response was not prolonged by XLαs expression, a GTPase-deficient XLαs mutant found in certain tumors and patients with fibrous dysplasia of bone and McCune-Albright syndrome generated more basal cAMP accumulation in HEK293 cells and caused more severe impairment of osteoblastic differentiation of MC3T3-E1 cells than the cognate Gαs mutant (gsp oncogene). Thus, activated XLαs and Gαs traffic differently, and this may form the basis for the differences in their cellular actions.
Kinetic Analysis of β-Galactosidase and β-Glucuronidase Tetramerization Coupled with Protein Translation*

Both β-galactosidase (GAL) and β-glucuronidase (GUS) are tetrameric enzymes used widely as reporter proteins. However, little is known about the folding and assembly of these enzymes. Although the refolding kinetics of GAL from a denatured enzyme have been reported, it is not known how the kinetics differ when coupled with a protein translation reaction. Elucidating the assembly kinetics of GAL and GUS when coupled with protein translation will illustrate the differences between these two reporter proteins and also the assembly process under conditions more relevant to those in vivo. In this study, we used an in vitro translation/transcription system to synthesize GAL and GUS, measured the time development of the activity and oligomerization state of these enzymes, and determined the rate constants of the monomer to tetramer assembly process. We found that at similar concentrations, GAL assembles into tetramers faster than GUS. The rate constant of monomer to dimer assembly of GAL was 50-fold faster when coupled with protein translation than that of refolding from the denatured state. Furthermore, GAL synthesis was found to lack the rate-limiting step in the assembly process, whereas GUS has two rate-limiting steps: monomer to dimer assembly and dimer to tetramer assembly. The consequence of these differences when used as reporter proteins is discussed.
The Vinculin C-terminal Hairpin Mediates F-actin Bundle Formation, Focal Adhesion, and Cell Mechanical Properties*

Vinculin is an essential and highly conserved cell adhesion protein, found at both focal adhesions and adherens junctions, where it couples integrins or cadherins to the actin cytoskeleton. Vinculin is involved in controlling cell shape, motility, and cell survival, and has more recently been shown to play a role in force transduction. The tail domain of vinculin (Vt) contains determinants necessary for binding and bundling of actin filaments. Actin binding to Vt has been proposed to induce formation of a Vt dimer that is necessary for cross-linking actin filaments. Results from this study provide additional support for actin-induced Vt self-association. Moreover, the actin-induced Vt dimer appears distinct from the dimer formed in the absence of actin. To better characterize the role of the Vt strap and carboxyl terminus (CT) in actin binding, Vt self-association, and actin bundling, we employed smaller amino-terminal (NT) and CT deletions that do not perturb the structural integrity of Vt. Although both NT and CT deletions retain actin binding, removal of the CT hairpin (1061–1066) selectively impairs actin bundling in vitro. Moreover, expression of vinculin lacking the CT hairpin in vinculin knock-out murine embryonic fibroblasts affects the number of focal adhesions formed, cell spreading as well as cellular stiffening in response to mechanical force.
Microarray based analysis of 3p25‐p26 deletions (3p‐ syndrome)

Distal deletion of chromosome 3p25‐pter (3p‐ syndrome) produces a distinct clinical syndrome characterized by low birth weight, mental retardation, telecanthus, ptosis, and micrognathia. Congenital heart disease (CHD), typically atrioventricular septal defect (AVSD) occurs in about a third of patients. Previously we reported on an association between the presence of CHD and the proximal extent of the deletion such that a CHD susceptibility gene was mapped between D3S1263 and D3S3594. In addition, we and others have suggested several candidate genes for the psychomotor retardation usually seen with constitutional 3p25 deletions. In order to further investigate genotype–phenotype correlations in 3p‐ syndrome we analyzed 14 patients with cytogenetically detectable deletions of 3p25 (including one patient with a normal phenotype) using Affymetrix 250K SNP microarrays. Deletion size varied from ∼6 to 12 Mb. Assuming complete penetrance, a candidate critical region for a CHD susceptibility gene was refined to ∼200 kb and a candidate critical region for mental retardation was mapped to an ∼1 Mb interval containing SRGAP3 but other 3p neurodevelopmental genes including CHL1, CNTN4, LRRN1, and ITPR1 mapped outside the candidate critical interval. We suggest that current evidence suggests that SRGAP3 is the major determinant of mental retardation in distal 3p deletions. © 2009 Wiley‐Liss, Inc.
Zinc Inactivates Melastatin Transient Receptor Potential 2 Channels via the Outer Pore*

Zinc ion (Zn2+) is an endogenous allosteric modulator that regulates the activity of a wide variety of ion channels in a reversible and concentration-dependent fashion. Here we used patch clamp recording to study the effects of Zn2+ on the melastatin transient receptor potential 2 (TRPM2) channel. Zn2+ inhibited the human (h) TRPM2 channel currents, and the steady-state inhibition was largely not reversed upon washout and concentration-independent in the range of 30–1000 μm, suggesting that Zn2+ induces channel inactivation. Zn2+ inactivated the channels fully when they conducted inward currents, but only by half when they passed outward currents, indicating profound influence of the permeant ion on Zn2+ inactivation. Alanine substitution scanning mutagenesis of 20 Zn2+-interacting candidate residues in the outer pore region of the hTRPM2 channel showed that mutation of Lys952 in the extracellular end of the fifth transmembrane segment and Asp1002 in the large turret strongly attenuated or abolished Zn2+ inactivation, and mutation of several other residues dramatically changed the inactivation kinetics. The mouse (m) TRPM2 channels were also inactivated by Zn2+, but the kinetics were remarkably slower. Reciprocal mutation of His995 in the hTRPM2 channel and the equivalent Gln992 in the mTRPM2 channel completely swapped the kinetics, but no such opposing effects resulted from exchanging another pair of species-specific residues, Arg961/Ser958. We conclude from these results that Zn2+ inactivates the TRPM2 channels and that residues in the outer pore are critical determinants of the inactivation.
Physiology of Consumption of Human Milk Oligosaccharides by Infant Gut-associated Bifidobacteria*

The bifidogenic effect of human milk oligosaccharides (HMOs) has long been known, yet the precise mechanism underlying it remains unresolved. Recent studies show that some species/subspecies of Bifidobacterium are equipped with genetic and enzymatic sets dedicated to the utilization of HMOs, and consequently they can grow on HMOs; however, the ability to metabolize HMOs has not been directly linked to the actual metabolic behavior of the bacteria. In this report, we clarify the fate of each HMO during cultivation of infant gut-associated bifidobacteria. Bifidobacterium bifidum JCM1254, Bifidobacterium longum subsp. infantis JCM1222, Bifidobacterium longum subsp. longum JCM1217, and Bifidobacterium breve JCM1192 were selected for this purpose and were grown on HMO media containing a main neutral oligosaccharide fraction. The mono- and oligosaccharides in the spent media were labeled with 2-anthranilic acid, and their concentrations were determined at various incubation times using normal phase high performance liquid chromatography. The results reflect the metabolic abilities of the respective bifidobacteria. B. bifidum used secretory glycosidases to degrade HMOs, whereas B. longum subsp. infantis assimilated all HMOs by incorporating them in their intact forms. B. longum subsp. longum and B. breve consumed lacto-N-tetraose only. Interestingly, B. bifidum left degraded HMO metabolites outside of the cell even when the cells initiate vegetative growth, which indicates that the different species/subspecies can share the produced sugars. The predominance of type 1 chains in HMOs and the preferential use of type 1 HMO by infant gut-associated bifidobacteria suggest the coevolution of the bacteria with humans.
An Atg13 Protein-mediated Self-association of the Atg1 Protein Kinase Is Important for the Induction of Autophagy*

Autophagy pathways in eukaryotic cells mediate the turnover of a diverse set of cytoplasmic components, including damaged organelles and abnormal protein aggregates. Autophagy-mediated degradation is highly regulated, and defects in these pathways have been linked to a number of human disorders. The Atg1 protein kinase appears to be a key site of this control and is targeted by multiple signaling pathways to ensure the appropriate autophagic response to changing environmental conditions. Despite the importance of this kinase, relatively little is known about the molecular details of Atg1 activation. In this study we show that Atg13, an evolutionarily conserved regulator of Atg1, promotes the formation of a specific Atg1 self-interaction in the budding yeast, Saccharomyces cerevisiae. The appearance of this Atg1-Atg1 complex is correlated with the induction of autophagy, and conditions that disrupt this complex result in diminished levels of both autophagy and Atg1 kinase activity. Moreover, the addition of a heterologous dimerization domain to Atg1 resulted in elevated kinase activity both in vivo and in vitro. The formation of this complex appears to be an important prerequisite for the subsequent autophosphorylation of Thr-226 in the Atg1 activation loop. Previous work indicates that this modification is necessary and perhaps sufficient for Atg1 kinase activity. Interestingly, this Atg1 self-association does not require Atg17, suggesting that this second conserved regulator might activate Atg1 in a manner mechanistically distinct from that of Atg13. In all, this work suggests a model whereby this self-association stimulates the autophosphorylation of Atg1 within its activation loop.
Maternal Vitamin D Eksikliği Yenidoğanın Geçici Takipnesi İçin Bir Risk Faktörü Olabilir

ÖZET Amaç: Maternal vitamin D eksikliğinin yenidoğan geçici takipnesi (YGT) için bir risk faktörü olup olmadığını değerlendirmektir. Gereç ve Yöntemler: Bu çalışmada, doğumdan sonraki ilk 24 saat içinde YGT izlenen 34 yenidoğan ile bu bebeklerin annelerine ait 25-hidroksivitamin D3 (25(OH)D3) düzeyleri, 68 sağlıklı kontrolle karşılaştırılmıştır. Maternal vitamin D eksikliğine etki edebilecek faktörler bir anket ile sorgulandı. 25(OH)D3 düzeyleri izotop dilüsyon likit kromatografi-tandem kitle spektrometre (LC-MS/MS) ile ölçülmüştür. Maternal ve yenidoğan 25(OH)D3 düzeyleri arasındaki korelasyon hesaplanmıştır. Bulgular: Serum 25(OH)D3 düzeyleri, kontrol ve YGT grubunda sırasıyla annelerin 22 (%,32,5)’sinde ve 4 (%11,7)’ünde; yenidoğanların 10 (%14,7)’unda ve 2 (%5,8)’sinde normal (≥20 ng/mL) düzeyde idi. Ortalama maternal 25(OH)D3 düzeyi kontrol grubunda 15,06±6,9; YGT grubunda 11,6±5,4 (p=0,05) ve kord kanı 25(OH)D3 düzeyi kontrol grubunda 12,3±4,8; YGT grubunda 7,4±3,8 (p<0,01) olarak hesaplandı. Maternal ve umbilikal kord 25(OH)D3 düzeyleri arasında güçlü ve anlamlı bir korelasyon izlendi (r=0,8, p<0,001). Beden kitle indeksi, deniz kıyısı tatil süresi ve mevsim maternal vitamin D düzeyi üzerinde etkili faktörler olarak bulundu. Sonuç: Hem maternal hem de neonatal vitamin D eksikliği, YGT için bir risk faktörü olabilir.