New mutations in acetylcholine receptor subunit genes reveal heterogeneity in the slow-channel congenital myasthenic syndrome.
Mutations in genes encoding the epsilon, delta, beta and alpha subunits of the end plate acetylcholine (ACh) receptor (AChR) are described and functionally characterized in three slow-channel congenital myasthenic syndrome patients. All three had prolonged end plate currents and AChR channel opening episodes and an end plate myopathy with loss of AChR from degenerating junctional folds. Genetic analysis revealed heterozygous mutations: epsilon L269F and delta Q267E in Patient 1, beta V266M in Patient 2, and alpha N217K in Patient 3 that were not detected in 100 normal controls. Patients 1 and 2 have no similarly affected relatives; in Patient 3, the mutation cosegregates with the disease in three generations. epsilon L269F, delta Q267E and beta V266M occur in the second and alpha N217K in the first transmembrane domain of AChR subunits; all have been postulated to contribute to the lining of the upper half of the channel lumen and all but delta Q267E are positioned toward the channel lumen, and introduce an enlarged side chain. Expression studies in HEK cells indicate that all of the mutations express normal amounts of AChR. epsilon L269F, beta V266M, and alpha N217K slow the rate of channel closure in the presence of ACh and increase apparent affinity for ACh; epsilon L269F and alpha N217K enhance desensitization, and epsilon L269F and beta V266M cause pathologic channel openings in the absence of ACh, rendering the channel leaky, delta Q267E has none of these effects and is therefore a rare polymorphism or a benign mutation. The end plate myopathy stems from cationic overloading of the postsynaptic region. The safety margin of neuromuscular transmission is compromised by AChR loss from the junctional folds and by a depolarization block owing to temporal summation of prolonged end plate potentials at physiologic rates of stimulation.


[Gunshot wounds of rectum].
The experience of treatment of 73 wounded with gunshot injuries of the rectum is reviewed. Classification of gunshot injuries of the rectum is proposed which permits to choose rational surgical policy depending on the location of the rectal injury is proposed. Terms of closing colostomas in remote periods after operation were determined. The authors believe that because of the complicated anatomo-topographic characteristics of the rectum and frequency of the combined injuries it is advisable to perform operations bor gunshot wounds of the rectum as an urgent specialized aid.


Single-isomer R-salbutamol is not superior to racemate regarding protection for bronchial hyperresponsiveness.
Bronchial hyper-reactivity (BHR) has been suggested to follow cessation of regular medication with racemic salbutamol. This study aimed at investigating the effects from medication with R,S- and R-salbutamol on bronchial response to provocation with isocapnic hyperventilation of cold air (IHCA). Twenty-six patients with mild to moderate asthma were enrolled in a double-blind, randomised, cross-over study. Bronchial response to provocation was measured before and after 1 week's medication. Doses of 0.63 mg R-salbutamol or 1.25 mg R/S-salbutamol were inhaled three times daily during medication-weeks and a wash-out week intervened. Tests were performed 6 h after the last dose of test drug. Impulse oscillometry and forced expiratory volume during one second were methods used to identify bronchial response to provocation. Two patients withdrew from the investigation due to side-effects, one from R- the other from R,S-salbutamol. Comparable resting bronchial conditions were indicated by differences in baseline lung function values of <2% between study days. No statistically significant medication-dependent differences in BHR could be demonstrated between treatment groups. However, 15 patients exhibited higher (P = 0.03) post-treatment BHR after pure R-salbutamol than after R,S-salbutamol. Furthermore, plasma concentrations of R-salbutamol tended to be lower (P = 0.08) after medication with R- than after R,S-salbutamol despite equal doses of R-salbutamol given during the two separate treatment periods. We also found that considerable amounts of S-salbutamol were retrieved in plasma after medication with pure R-salbutamol. We conclude that we were unable to demonstrate favourable effects of R-salbutamol over R,S-salbutamol regarding response to provocation with IHCA after regular medication of 1 week's duration.


Synthetic molecules that modulate transcription and differentiation: hints for future drug discovery.
Regulation of gene transcription and cell differentiation often induces drastic phenotypes in living organisms. External, precise control over these processes through small organic molecules represents a challenge in chemistry and biology. Our laboratory has been discovering small organic molecules that modulate transcription or differentiation and using them as a tool to understand biological phenomena. This personal perspective summarizes our contributions to chemical biology and chemical genetics in the fields of gene transcription and cell differentiation. Our case studies may foreshadow the promise and the challenge of future drug discovery.


Young Women's Stated Preferences for Biomedical HIV Prevention: Results of a Discrete Choice Experiment in Kenya and South Africa.
Integrating end-user perspectives into the design of new biomedical HIV prevention products is recognized as vital to informing the product development pipeline. Kisumu, Kenya; and Soshanguve, South Africa. We conducted a discrete choice experiment survey with 536 women aged 18-30 years to assess preferences for hypothetical HIV prevention products characterized by the attributes of efficacy, pregnancy prevention, delivery form, dosing frequency, and side effects. Participants included product-experienced women from Tablet, Ring, Injection as Options TRIO, a cross-over clinical study evaluating 3 placebo delivery forms (oral tablets, vaginal rings, and injections), and a product-naive sample recruited from the same communities. Analyses used random parameters logit and latent class models. HIV prevention efficacy was a strong determinant of stated choice overall; however, in South Africa, delivery form was just as important, with an injection every 2-3 months most preferred and a daily oral tablet least preferred. In Kenya, product-experienced women preferred monthly injections and least preferred a monthly ring. Respondents indicated a preference for multipurpose prevention technologies that combine HIV and pregnancy protection. Latent class analyses confirmed these findings and delineated heterogeneity in preferences across subgroups defined by age, past experience with the delivery forms, and education. Despite an overall preference for products with high efficacy, we identified attributes salient to future uptake and use of HIV prevention products. Preferences for injectable products underscored interest in this pre-exposure prophylaxis delivery form. Likewise, the multipurpose prevention technology feature was valued in both Kenya and South Africa and most influenced interest in vaginal rings.


Mean value of pulse pressure: The key feature in ambulatory arterial stiffness index estimation using regression models.
Ambulatory arterial stiffness index (AASI) is an index which indicates arterial stiffness. This work aims to explore the mathematical relationship between AASI and mean value of PP (PP‾), and reveal the importance of PP‾ during AASI estimating. Meanwhile, a well-performing AASI estimation model is presented. To evaluate AASI, electrocardiograph (ECG) signal, photoplethysmogram (PPG) signal and arterial blood pressure (ABP) are used as the source of AASI estimation. Features are extracted from the above three signals. Meanwhile, fitting curve analysis and regression models are implemented to describe the relationship between AASI and PP‾. Among three fitting curves on AASI and PP‾, cubic polynomial curve performs best. The introduction of feature PP‾ in AASI estimation reduced LR's MAE from 0.0556 to 0.0372, SVMR's MAE from 0.0413 to 0.0343 and RFR's MAE from 0.0386 to 0.0256. All three estimation models obtain considerable improvement, especially on the previous worst-performing linear regression. This work presents the mathematical association between AASI and PP‾. AASI estimation using regression models can be significantly improved by involving PP‾ as its key feature, which is not only meaningful for exploring the connection between vascular elasticity function and pulse pressure, but also hold importance for the diagnosis of cardiovascular arteriosclerosis and atherosclerosis at the early stage.


Is It Possible to Prevent the Progression of Mild Cognitive Impairment Through Non-Pharmacological Treatments?
Mild cognitive impairment produces slight cognitive and motor disturbances without affecting daily life during aging, however, if this symptomatology is not controlled, the speed of deterioration can increase, and even some cases of dementia can appear in the elderly population. To describe non-pharmacological therapies that seek to prevent, control and reduce the symptoms of mild cognitive impairment. An initial search was carried out in the databases of PubMed, Lilacs, EBSCO, ScienceDirect, Taylor & Francis and ProQuest. The results found were filtered through the PRISMA system and biases evaluated using the Cochrane Handbook for Systematic Reviews of Interventions. Four categories of non-pharmacological therapies were created, using 50 articles found in the search, which contribute to controlling and improving cognitive and motor areas, in order to reduce the symptoms presented by mild cognitive impairment. The treatments have different methods, instruments and objectives, so that no meta-analysis of the studies could be performed. In addition, limitations related to the sample, the effectiveness of the results and the methodological quality were found. It was found that non-pharmacological therapies prevent, improve and control the symptoms caused by mild cognitive impairment, however, it is necessary to carry out more studies with better methodologies to corroborate these results.


The kappaB sites in the human immunodeficiency virus type 1 long terminal repeat enhance virus replication yet are not absolutely required for viral growth.
The dependence of human immunodeficiency virus type 1 (HIV-1) on its NF-kappaB binding sites (kappaB sites) for replication in transformed and primary T-cell targets was examined by infecting cells with HIV-1 reporter viruses containing kappaB site enhancer mutations. Viral transcription was measured either with luciferase-expressing HIV-1 that infects for a single round or by flow cytometric analyses with HIV-1 expressing placental alkaline phosphatase (PLAP) or green-fluorescent protein (GFP). Both PLAP- and GFP-expressing viruses spread from cell to cell and allowed analysis of viral gene expression patterns in single cells. Infection of a panel of T-cell lines with different basal levels of NF-kappaB demonstrated a direct correlation between the amount of constitutive nuclear NF-kappaB and the degree to which a wild-type virus outperformed kappaB site mutants. One T-cell line with a constitutively high level of nuclear NF-kappaB, PM1, showed a 20-fold decrease in transcription when its kappaB sites were mutated. In contrast, in a T-cell line with a low basal level of NF-kappaB, SupT1, mutation of the kappaB site in the enhancer had no effect on viral transcription or growth rate. Phytohemagglutinin-activated peripheral blood mononuclear cells showed a large dependence on the kappaB sites for optimal virus growth. Viruses without marker genes corroborated the finding that mutations to the kappaB sites impair virus production in cells with a high basal level of NF-kappaB. These data show that in T cells, HIV-1 can use NF-kappaB to enhance its growth but the virus is clearly able to grow in its absence.


Mechanistic Insights into the Roles of the IL-17/IL-17R Families in Pancreatic Cancer.
The members of the cytokine interleukin 17 (IL-17) family, along with their receptors (IL-17R), are vital players in a range of inflammatory diseases and cancer. Although generally regarded as proinflammatory, the effects they exhibit on cancer progression are a double-edged sword, with both antitumor and protumor activities being discovered. There is growing evidence that the IL-17 signaling pathways have significant impacts on the tumor microenvironment (TME), immune response, and inflammation in various types of cancer, including pancreatic cancer. However, the detailed mechanistic functions of the IL-17/IL-17R families in pancreatic cancer were rarely systematically elucidated. This review considers the role of the IL-17/IL-17R families in inflammation and tumor immunity and elaborates on the mechanistic functions and correlations of these members with pathogenesis, progression, and chemoresistance in pancreatic cancer. By summarizing the advanced findings on the role of IL-17/IL17R family members and IL-17 signaling pathways at the molecular level, cellular level, and disease level in pancreatic cancer, this review provides an in-depth discussion on the potential of IL-17/IL-17R as prognostic markers and therapeutic targets in pancreatic cancer.


Catatonia as a putative nosological entity: A historical sketch.
Kahlbaum was the first to propose catatonia as a separate disease following the example of general paresis of the insane, which served as a model for establishing a nosological entity. However, Kahlbaum was uncertain about the nosological position of catatonia and considered it a syndrome, or "a temporary stage or a part of a complex picture of various disease forms". Until recently, the issue of catatonia as a separate diagnostic category was not entertained, mainly due to a misinterpretation of Kraepelin's influential views on catatonia as a subtype of schizophrenia. Kraepelin concluded that patients presenting with persistent catatonic symptoms, which he called "genuine catatonic morbid symptoms", particularly including negativism, bizarre mannerisms, and stereotypes, had a poor prognosis similar to those of paranoid and hebephrenic presentations. Accordingly, catatonia was classified as a subtype of dementia praecox/schizophrenia. Despite Kraepelin's influence on psychiatric nosology throughout the 20th century, there have only been isolated attempts to describe and classify catatonia outside of the Kraepelinian system. For example, the Wernicke-Kleist-Leonhard school attempted to comprehensively elucidate the complexities of psychomotor disturbances associated with major psychoses. However, the Leonhardian categories have never been subjected to the scrutiny of modern investigations. The first three editions of the DSM included the narrow and simplified version of Kraepelin's catatonia concept. Recent developments in catatonia research are reflected in DSM-5, which includes three diagnostic categories: Catatonic Disorder due to Another Medical Condition, Catatonia Associated with another Mental Disorder (Catatonia Specifier), and Unspecified Catatonia. Additionally, the traditional category of catatonic schizophrenia has been deleted. The Unspecified Catatonia category could encourage research exploring catatonia as an independent diagnostic entity.


Synapse proteomics: current status and quantitative applications.
Chemical synapses are key organelles for neurotransmission. The coordinated actions of protein networks in diverse synaptic subdomains drive the sequential molecular events of transmitter release from the presynaptic bouton, activation of transmitter receptors located in the postsynaptic density and the changes of postsynaptic potential. Plastic change of synaptic efficacy is thought to be caused by the alteration of protein constituents and their interaction in the synapse. As a first step toward the understanding of the organization of synapse, several proteomics studies have been carried out to profile the protein constituents and the post-translational modifications in various rodent excitatory chemical synaptic subdomains, including postsynaptic density, synaptic vesicle and the synaptic phosphoproteome. Quantitative proteomics have been applied to examine the changes of synaptic proteins during brain development, in knockout mice model developed for studies of synapse physiology and in rodent models of brain disorders. These analyses generate testable hypotheses of synapse function and regulation both in health and disease.


The Future Impact of Healthcare Services Digitalization on Health Workforce: The Increasing Role of Medical Informatics.
The digital revolution is gradually transforming our society. What about the effects of digitalization and Internet of Things in healthcare? Among researchers two ideas are dominating, opposing each other. These arguments will be explored and analyzed. A mix-method approach combining literature review with the results from a focus group on eHealth impact on employment is used. Several experts from the WHO and from Health Professional Associations contributed for this analysis. Depending on the type of service it will entail reductions or more need of healthcare workers, yet whatever the scenario medical informatics will play an increasing role.


Computed tomography in penetrating wounds of the orbit with retained foreign bodies.
Penetrating wounds of the orbit can have serious immediate and delayed effects on the eye and the CNS. Infection, vessel erosion, or interference with ocular function necessitates removal of the foreign object. Precise localization of the retained material and its relationship to the globe, extraocular muscles, optic nerve, and brain is essential, when surgery is contemplated. We describe two children with retained foreign bodies that required removal. Computed tomography (CT) was essential in one instance in planning the surgical approach. In the other patient, the retained foreign body and an associated brain abscess were recognized only by CT. The contribution of CT to the assessment of retained foreign bodies is discussed and its present limits are defined. Computed tomography is highly recommended as the single most informative diagnostic modality for this type of injury.


Separation of tubulin subunits under nondenaturing conditions.
The dissociation and separation of the tubulin alpha- and beta-subunits have been achieved by binding alpha-subunits to an immunoadsorbent gel and selectively inducing release of free beta-subunits. The immunoadsorbent gel was prepared by coupling the monoclonal antibody YL1/2 to Sepharose 4B which specifically recognizes the C-terminal end of tyrosinated alpha-subunits. Extensive tubulin subunit dissociation and separation occurred in Tris buffer at neutral pH but was greatly enhanced at basic pHs (8. 0-8.5). The binding of colchicine to heterodimeric tubulin resulted in a marked protection against dissociation. The dissociation of tubulin subunits was accompanied by loss of colchicine binding capacity, and ability to polymerize into microtubules. As shown by circular dichroism, loss of functional properties was not due to extensive denaturation of tubulin, as tubulin retained most of its secondary structure. Neither of the separated alpha- or beta-subunits was able to bind colchicine, but functional tubulin that was able to bind colchicine could be reconstituted from the dissociated subunits by changing the buffer to a neutral mixture of Tris and Pipes. The yield of reconstitution, as estimated from kinetic measurements of colchicine binding capacity, amounted to about 25%. Such a yield can probably be improved with minor changes in experimental conditions. The quantitative dissociation of tubulin into separated "native" alpha- and beta-subunits should provide a powerful tool for further studies on the properties of the individual tubulin subunits and the structure-function relationships of the tubulins.


Epigenetic Heterogeneity in Human Colorectal Tumors Reveals Preferential Conservation And Evidence of Immune Surveillance.
Genomic intratumoral heterogeneity (ITH) is common in cancers, but the extent of phenotypic ITH is uncertain because most subclonal mutations are passengers. Since tumor phenotypes are largely driven by epigenetics, methylomic analyses can provide insights into phenotypic ITH. Following this principle, we determined the extent of epigenetic ITH in 16 human colorectal tumors by comparing the methylomes from spatially separated regions in each tumor. Methylomes from opposite tumor sides were similar (Pearson correlation >0.95) with little evidence of ITH or stepwise selection during growth, suggesting that the epigenome of a sampled tumor largely reflects that of its founder cell. Epigenetic conservation was functional, with higher conservation at promoters and expressed genes compared to non-coding regions. Despite epigenomic conservation, RNA expression varied between individual tumor glands, indicating continued adaption during growth. Because many promoters and enhancers were unmethylated, continued adaptation may be due to phenotypic plasticity. Gene enrichment analyses identified that interferon signaling and antigen-processing and presenting pathways were strongly conserved during tumor growth, suggesting a mechanism for immune evasion. In summary, our findings suggest that epigenomes are preferentially conserved during tumor growth and that early tumor cells are poised for rapid growth, phenotypic adaptation, and immune evasion.


Improving the Design of Undergraduate Biology Courses toward the Goal of Retention: The Case of Real-World Inquiry and Active Learning through Metagenomics.
Retention in science is low in undergraduate populations, especially for under-represented minority (URM) and first generation (FG) college students. Thus, educators have been called upon to design curricula to counteract this trend. This study examined variables most likely to lead to retention, such as increased achievement, improved attitudes, and self-efficacy beliefs, through participation in active learning and real-world research experiences in an introductory biology course. The research experience was embedded in metagenomics content and processes that have increasingly gained focus in microbiology. This study also investigated differences in learning outcomes when the curriculum was infused with more active learning. The active learning components included integrating interactive technology into the pre-lab lectures, providing students with authentic protocols to conduct lab work, and allowing students to rerun problematic samples. Results showed increased achievement for URM/FG students, although this was not strongly tied to the active learning elements incorporated into the three-week metagenomics research experience. However, students participating in research with more active learning did report higher frequencies of engaging in mastery experiences (an important source of self-efficacy) when compared with students engaged in research with less active learning. This analysis can aid in identifying specific curricular design features associated with promoting retention in undergraduate biology and science programs in general.


Impact of Risk and Volume on Procedural Traning of Pulmonary and Critical Care Fellows.
Background: Invasive procedures are a core aspect of pulmonary and critical care practice. Procedures performed in the intensive care unit can be divided into high-risk, low-volume (HRLV) procedures and low-risk, high-volume (LRHV) procedures. HRLV procedures include cricothyroidotomy, pericardiocentesis, Blakemore tube placement, and bronchial blocker placement. LRHV procedures include arterial line placement, central venous catheter placement, thoracentesis, and flexible bronchoscopy. Despite the frequency and importance of procedures in critical care medicine, little is known about the similarities and differences in procedural training between different Pulmonary and Critical Care Medicine (PCCM) and Critical Care Medicine (CCM) training programs. Furthermore, differences in procedural training practices for HRLV and LRHV procedures have not previously been described. Objective: To assess procedural training practices in PCCM and CCM fellowship programs in the United States, and compare differences in training between HRLV and LRHV procedures. Methods: A novel survey instrument was developed and disseminated to PCCM and CCM program directors and associate program directors at PCCM and CCM fellowship programs in the United States to assess procedural teaching practices for HRLV and LRHV procedures. Results: The survey was sent to 221 fellowship programs, 168 PCCM and 34 CCM, with 70 unique respondents (31.7% response rate). Of the procedural educational strategies assessed, each strategy was used significantly more frequently for LRHV versus HRLV procedures. The majority of respondents (51.1%) report having no dedicated training for HRLV procedures versus 6.9% reporting no dedicated training for any LRHV procedure (P < 0.001). For HRLV procedures, 76.9% of respondents indicated that there was no set number of procedures required to determine competency, versus 25.3% for LRHV procedures (P < 0.001). For LRHV procedures, fellows were allowed to perform procedures independently without supervision 21.7% of the time versus 3.9% for HRLV procedures (P = 0.004). Program directors' confidence in their ability to determine fellows' competence in performing procedures was significantly lower for HRLV versus LRHV versus HRLV procedures (P < 0.001). Conclusion: Significant differences exist in procedural training education for PCCM and CCM fellows for LRHV versus HRLV procedures, and awareness of this discrepancy presents an opportunity to address this educational gap in PCCM and CCM fellowship training.


Where have all the children gone? Women's reports of more childlessness at older ages than when they were younger in a large-scale continuous household survey in Britain.
Levels of childlessness reported by the same cohorts of women and surveyed by the British General Household Survey increase with age by over 50 per cent between their early 40s and their late 50s for women born in the early 1940s. Yet the reported mean fertility of parous women remains constant with increasing age. Similar results hold within sub-groups such as different educational and marital status groups. Possible reasons for these findings include declining comparability of the base population over time due to differential migration, mortality, or institutionalization, changes in survey design and content, and differential non-response by childless and parous women. The evidence shows that these are not adequate explanations. The most likely reason is deliberate under-reporting of childbearing among older cohorts of women. The findings have implications for the interpretation of retrospective data in surveys and for the availability of informal care for older people.


Source apportionment of size resolved particulate matter at a European air pollution hot spot.
Positive Matrix Factorization-PMF was applied to hourly resolved elemental composition of fine (PM0.15-1.15) and coarse (PM1.15-10) aerosol particles to apportion their sources in the airshed of residential district, Ostrava-Radvanice and Bartovice in winter 2012. Multiple-site measurement by PM2.5 monitors complements the source apportionment. As there were no statistical significant differences amongst the monitors, the source apportionment derived for the central site data is expected to apply to whole residential district. The apportioned sources of the fine aerosol particles were coal combustion (58.6%), sinter production-hot phase (22.9%), traffic (15%), raw iron production (3.5%), and desulfurization slag processing (<0.5%) whilst road dust (47.3%), sinter production-cold phase (27.7%), coal combustion (16.8%), and raw iron production (8.2%) were resolved being sources of the coarse aerosol particles. The shape and elemental composition of size-segregated aerosol airborne-sampled by an airship aloft presumed air pollution sources helped to interpret the PMF solution.


Familial automaticity-conduction disorder with associated cardiomyopathy.
An unusually large family of European descent was afflicted over four generations by an automaticity and conduction disorder with an associated dilated cardiomyopathy of variable expression. Ten living members affected with the disorder and three presumed affected but dead members were identified. Typically, the disorder presented as a sinoatrial bradyarrhythmia/tachyarrhythmia syndrome, followed by atrial enlargement and, variably, ventricular enlargement and dysfunction. Three family members required pacemaker implantation. Longevity did not seem to be greatly affected, but the demonstrated potential for embolic cerebrovascular events stresses an associated morbidity. The familial incidence was best explained by autosomal dominant inheritance with incomplete penetrance (greater in males and usually occurring first in adolescence) and variable expressivity. The large size of the family, frequency and profile of disease manifestations and disease tracking through at least four generations are unusual features of the familial disease described.


Barriers and facilitators perceived by women while homeless and pregnant in accessing antenatal and or postnatal healthcare: A qualitative evidence synthesis.
Evidence indicates that homelessness is increasing within Europe and the United States (US), particularly for women. Pregnancy rates among homeless women are exceptionally high compared to their housed counterparts and homeless women engage poorly with antenatal care. The aim of this review is to explore the barriers and facilitators perceived by homeless women, while pregnant, or within six weeks postpartum in accessing antenatal and/or postnatal healthcare. A qualitative systematic review and synthesis was conducted. Key words and search terms were derived using the SPIDER (Sample, Phenomenon of Interest, Design, Evaluation, Research type) framework. Titles and abstracts were screened in accordance with inclusion and exclusion criteria. The methodological quality of included papers was assessed using criteria described by the Critical Appraisal Skills Programme (CASP) with data analysis using thematic synthesis. Two primary linked themes were generated: (a) lack of person-centred care; (b) complexity of survival. At an organisational level, a fragmented health service and accessibility to the health system were barriers, and resulted in poor person-centred care. At a clinical level, attitude & treatment from healthcare providers together with health knowledge all combined to illustrate poor person-centred care as barriers to homeless women accessing antenatal/postnatal healthcare. Sub-themes associated with complexity of survival included: disillusion with life, distrust of services, competing lifestyle demands and support and relationships. The findings of this review highlight that poor engagement may be partly explained by the complex interplay between both the healthcare system (person-centred care) and the individual (complexity of survival). Future services should be delivered in a way that recognises homeless people's complex and diverse needs, and should be reconfigured in order to try to meet them, through decreasing fragmentation of health services and staff training.


Development of a novel in vitro insulin resistance model in primary human tenocytes for diabetic tendinopathy research.
Type 2 diabetes mellitus (T2DM) had been reported to be associated with tendinopathy. However, the underlying mechanisms of diabetic tendinopathy still remain largely to be discovered. The purpose of this study was to develop insulin resistance (IR) model on primary human tenocytes (hTeno) culture with tumour necrosis factor-alpha (TNF-α) treatment to study tenocytes homeostasis as an implication for diabetic tendinopathy. hTenowere isolated from human hamstring tendon. Presence of insulin receptor beta (INSR-β) on normal tendon tissues and the hTeno monolayer culture were analyzed by immunofluorescence staining. The presence of Glucose Transporter Type 1 (GLUT1) and Glucose Transporter Type 4 (GLUT4) on the hTeno monolayer culture were also analyzed by immunofluorescence staining. Primary hTeno were treated with 0.008, 0.08, 0.8 and 8.0 µM of TNF-α, with and without insulin supplement. Outcome measures include 2-[N-(7-nitrobenz-2-oxa-1,3-diazol-4-yl) amino]-2-deoxy-d-glucose (2-NBDG) assay to determine the glucose uptake activity; colourimetric total collagen assay to quantify the total collagen expression levels; COL-I ELISA assay to measure the COL-I expression levels and real-time qPCR to analyze the mRNA gene expressions levels of Scleraxis (SCX), Mohawk (MKX), type I collagen (COL1A1), type III collagen (COL3A1), matrix metalloproteinases (MMP)-9 and MMP-13 in hTeno when treated with TNF-α. Apoptosis assay for hTeno induced with TNF-α was conducted using Annexin-V FITC flow cytometry analysis. Immunofluorescence imaging showed the presence of INSR-β on the hTeno in the human Achilles tendon tissues and in the hTeno in monolayer culture. GLUT1 and GLUT4 were both positively expressed in the hTeno. TNF-α significantly reduced the insulin-mediated 2-NBDG uptake in all the tested concentrations, especially at 0.008 µM. Total collagen expression levels and COL-I expression levels in hTeno were also significantly reduced in hTeno treated with 0.008 µM of TNF-α. The SCX, MKX and COL1A1 mRNA expression levels were significantly downregulated in all TNF-α treated hTeno, whereas the COL3A1, MMP-9 and MMP-13 were significantly upregulated in the TNF-α treated cells. TNF-α progressively increased the apoptotic cells at 48 and 72 h. At 0.008 µM of TNF-α, an IR condition was induced in hTeno, supported with the significant reduction in glucose uptake, as well as significantly reduced total collagen, specifically COL-I expression levels, downregulation of candidate tenogenic markers genes (SCX and MKX), and upregulation of ECM catabolic genes (MMP-9 and MMP-13). Development of novel IR model in hTeno provides an insight on how tendon homeostasis could be affected and can be used as a tool for further discovering the effects on downstream molecular pathways, as the implication for diabetic tendinopathy.


Impaired SMAD1/5 Mechanotransduction and Cx37 (Connexin37) Expression Enable Pathological Vessel Enlargement and Shunting.
Impaired ALK1 (activin receptor-like kinase-1)/Endoglin/BMP9 (bone morphogenetic protein 9) signaling predisposes to arteriovenous malformations (AVMs). Activation of SMAD1/5 signaling can be enhanced by shear stress. In the genetic disease hereditary hemorrhagic telangiectasia, which is characterized by arteriovenous malformations, the affected receptors are those involved in the activation of mechanosensitive SMAD1/5 signaling. To elucidate how genetic and mechanical signals interact in AVM development, we sought to identify targets differentially regulated by BMP9 and shear stress. Approach and Results: We identify Cx37 (Connexin37) as a differentially regulated target of ligand-induced and mechanotransduced SMAD1/5 signaling. We show that stimulation of endothelial cells with BMP9 upregulated Cx37, whereas shear stress inhibited this expression. This signaling was SMAD1/5-dependent, and in the absence of SMAD1/5, there was an inversion of the expression pattern. Ablated SMAD1/5 signaling alone caused AVM-like vascular malformations directly connecting the dorsal aorta to the inlet of the heart. In yolk sacs of mouse embryos with an endothelial-specific compound heterozygosity for SMAD1/5, addition of TNFα (tumor necrosis factor-α), which downregulates Cx37, induced development of these direct connections bypassing the yolk sac capillary bed. In wild-type embryos undergoing vascular remodeling, Cx37 was globally expressed by endothelial cells but was absent in regions of enlarging vessels. TNFα and endothelial-specific compound heterozygosity for SMAD1/5 caused ectopic regions lacking Cx37 expression, which correlated to areas of vascular malformations. Mechanistically, loss of Cx37 impairs correct directional migration under flow conditions. Our data demonstrate that Cx37 expression is differentially regulated by shear stress and SMAD1/5 signaling, and that reduced Cx37 expression is permissive for capillary enlargement into shunts.


Angiogenic activity of swine granulosa cells: effects of hypoxia and vascular endothelial growth factor Trap R1R2, a VEGF blocker.
The possible role played by hypoxia and vascular endothelial growth factor (VEGF) in the regulation of follicular angiogenesis was studied in a three-dimensional fibrin gel model. Granulosa cells from follicles >5mm were subjected to normoxia (19% O2), partial (5% O2) or total (1% O2) hypoxia and their culture media were collected and used to stimulate porcine Aortic Endothelial Cells (AOC) included in the fibrin matrix. A suspension of AOC on microcarrier beads was pipetted in a fibrinogen solution (1 mg/ml PBS) before the addition of 1250 IU thrombine (250 microl) to catalize the gel formation. Granulosa cell conditioned media were tested in the presence or absence of VEGF Trap R1R2 (150 ng/ml), a potent VEGF inhibitor, that had its efficacy tested by adding VEGF (100 ng/ml) to AOC culture. Endothelial cell proliferation was measured at 48, 96, 144, 192 h by means of Scion Image Beta. A significant (p < 0.01) increase of AOC proliferation at each time of measurement was induced by culture media from granulosa cells subjected to partial (except at the end of the first 48 h) and total hypoxia compared to control and normoxia conditions, and by VEGF. VEGF Trap significantly (p < 0.01) inhibited the stimulatory effect of media conditioned by granulosa cells cultured in hypoxic conditions. These data suggest that hypoxia stimulates angiogenic activity of granulosa cells possibly by means of VEGF which could represent the main effector in promoting endothelial cell proliferation.


Designing small universal k-mer hitting sets for improved analysis of high-throughput sequencing.
With the rapidly increasing volume of deep sequencing data, more efficient algorithms and data structures are needed. Minimizers are a central recent paradigm that has improved various sequence analysis tasks, including hashing for faster read overlap detection, sparse suffix arrays for creating smaller indexes, and Bloom filters for speeding up sequence search. Here, we propose an alternative paradigm that can lead to substantial further improvement in these and other tasks. For integers k and L > k, we say that a set of k-mers is a universal hitting set (UHS) if every possible L-long sequence must contain a k-mer from the set. We develop a heuristic called DOCKS to find a compact UHS, which works in two phases: The first phase is solved optimally, and for the second we propose several efficient heuristics, trading set size for speed and memory. The use of heuristics is motivated by showing the NP-hardness of a closely related problem. We show that DOCKS works well in practice and produces UHSs that are very close to a theoretical lower bound. We present results for various values of k and L and by applying them to real genomes show that UHSs indeed improve over minimizers. In particular, DOCKS uses less than 30% of the 10-mers needed to span the human genome compared to minimizers. The software and computed UHSs are freely available at github.com/Shamir-Lab/DOCKS/ and acgt.cs.tau.ac.il/docks/, respectively.


Association Between Survival and Time of Day for Rapid Response Team Calls in a National Registry.
Decreased staffing at nighttime is associated with worse outcomes in hospitalized patients. Rapid response teams were developed to decrease preventable harm by providing additional critical care resources to patients with clinical deterioration. We sought to determine whether rapid response team call frequency suffers from decreased utilization at night and how this is associated with patient outcomes. Retrospective analysis of a prospectively collected registry database. National registry database of inpatient rapid response team calls. Index rapid response team calls occurring on the general wards in the American Heart Association Get With The Guidelines-Medical Emergency Team database between 2005 and 2015 were analyzed. None. The primary outcome was inhospital mortality. Patient and event characteristics between the hours with the highest and lowest mortality were compared, and multivariable models adjusting for patient characteristics were fit. A total of 282,710 rapid response team calls from 274 hospitals were included. The lowest frequency of calls occurred in the consecutive 1 AM to 6:59 AM period, with 266 of 274 (97%) hospitals having lower than expected call volumes during those hours. Mortality was highest during the 7 AM hour and lowest during the noon hour (18.8% vs 13.8%; adjusted odds ratio, 1.41 [1.31-1.52]; p < 0.001). Compared with calls at the noon hour, those during the 7 AM hour had more deranged vital signs, were more likely to have a respiratory trigger, and were more likely to have greater than two simultaneous triggers. Rapid response team activation is less frequent during the early morning and is followed by a spike in mortality in the 7 AM hour. These findings suggest that failure to rescue deteriorating patients is more common overnight. Strategies aimed at improving rapid response team utilization during these vulnerable hours may improve patient outcomes.


Behavioral characterization of DAT-KO rats and evidence of asocial-like phenotypes in DAT-HET rats: The potential involvement of norepinephrine system.
Dopamine (DA) is a key neurotransmitter of the central nervous system, whose availability is regulated by the dopamine transporter (DAT). Deletion of DAT gene leading to hyperdopaminergia was previously performed on mouse models. This enabled recapitulation of the core symptoms of Attention-Deficit / Hyper-activity Disorder (ADHD), which include hyperactivity, inattention and cognitive impairment. We used recently developed DAT knockout (DAT-KO) rats to carry out further behavioral profiling on this novel model of hyperdopaminergia. DAT-KO rats display elevated locomotor activity and restless environmental exploration, associated with a transient anxiety profile. Furthermore, these rats show pronounced stereotypy and compulsive-like behavior at the Marble-Burying test. Homozygous DAT-KO rats mantain intact social interaction when tested in a social-preference task, while heterozygous (HET) rats show high inactivity associated with close proximity to the social stimulus. Ex-vivo evaluation of brain catecholamines highlighted increased levels of norepinephrine in the hippocampus and hypothalamus exclusively of heterozygous rats. Taken together, our data present evidence of unexpected asocial tendencies in heterozygous (DAT-HET) rats associated with neurochemical alterations in norepinephrine neurotransmission. We shed light on the behavioral and neurochemical consequences of altered DAT function in a higher, more complex model of hyperdopaminergia. Unraveling the role of DA neurotransmission in DAT-KO rats has very important implications in the understanding of many psychiatric illnesses, including ADHD, where alterations in DA system have been demonstrated.


A clinical evaluation of absorbable polydioxanone ligating clips in abdominal and pelvic operations.
An absorbable vascular ligating clip made of polydioxanone polymer was evaluated in 44 patients who underwent abdominal and pelvic operations. These clips were used in place of conventional metallic clips primarily in performing pelvic and para-aortic lymphadenectomy. The polydioxanone clips were found to be superior to the metallic clips in ease of clip loading to the applier, security of clips in the transfer to the surgeon and security of the clip in the applier when positioning to ligate vessels. The use of polydioxanone clips, which absorb within 210 days, may also lead to improved CAT or NMR imaging by precluding energy scatter which is known to occur with some metallic clips. Clip applier function, security on tissues ligated and clip visibility were equivalent to previous experience using metallic clips. Selection of proper clip size is important so that excessive amounts of tissue are not contained within the clip jaws which might prevent clip closure. No postoperative complications were noted in the use of these clips.


Synthesis of nickel and palladium complexes with diarylamido-based unsymmetrical pincer ligands and application for norbornene polymerization.
A set of diarylamido-based unsymmetrical [PNNox] pincer ligands containing a chiral oxazoline ring have been synthesized and their nickel and palladium complexes [(2-PPh2(R1)ArN(R1)Ar-2-(R)oxazoline)MCl] (R1 = 4-H, R = (S)-4-iPr, M = Pd (Pd1); R1 = 4-H, R = (S)-4-Bn, M = Pd (Pd2); R1 = 4-H, R = (S)-4-Ph, M = Pd (Pd3); R1 = 4-Me, R = (S)-4-Bn, M = Pd (Pd4); R1 = 4-Me, R = (S)-4-Ph, M = Pd (Pd5); R1 = 4-H, R = 4-Me2, M = Pd (Pd6); R1 = 4-H, R = Benzo[d]-, M = Pd (Pd7); R1 = 4-H, R = (S)-4-Bn, M = Ni (Ni1); R1 = 4-H, R = (S)-4-Ph, M = Ni (Ni2); R1 = 4-Me, R = (S)-4-Bn, M = Ni (Ni3); R1 = 4-Me, R = (S)-4-Ph, M = Pd (Ni4)) were tested to show high catalytic activities for polymerization of norbornene. After activation of methylaluminoxane (MAO), all the nickel and palladium complexes could catalyze the polymerization of norbornene to yield vinyl-type polymers with activities up to 40.3 × 105 g of PNB (mol of Pd)-1 h-1. The copolymerization of norbornene with functional norbornene comonomers was also investigated by catalyst Pd2, accompanied by decreased catalytic activity and low incorporation of functional comonomers.


The paradox of canine conspecific coprophagy.
Canine conspecific coprophagy, the tendency or predisposition of some dogs to eat their own faeces or those of other dogs, seems paradoxical because dogs typically show an aversion to conspecific faeces. In an attempt to resolve this paradox, we set out to determine the factors associated with the occurrence of this behaviour and to evaluate the efficacy of 11 products marketed for treating coprophagy as well as behaviour modification procedures. Because a large sample of dogs was needed to address these issues, two web-based surveys were utilized. One, intended to compare coprophagic dogs and non-coprophagic dogs, yielded 1552 returns. The other, yielding 1475 usable returns, specifically recruited owners of coprophagic dogs to gather information about the characteristics of coprophagy and treatment success. The findings revealed that 16% of dogs sampled engaged in frequent conspecific coprophagy, defined as having been seen eating stools at least six times. No evidence was found relating the coprophagy to diet or the dog's age. Coprophagic dogs were as easily house trained as non-coprophagic dogs, suggesting a normal aversion to faeces. Coprophagic dogs were more likely to be reported as greedy eaters than non-coprophagic dogs. The reported success rate of the commercial products and behaviour modification approaches was close to zero, indicating that the behaviour is not readily changed. The coprophagy was overwhelmingly directed at fresh stools, defined as being no more than 2 days old. A hypothesis is offered that coprophagy reflects a tendency inherited from the ancestral wolf to keep the den area free of faecal-borne intestinal parasites that might be deposited in the den resting area and would typically have parasite ova that are not initially infective, but could develop infective larvae after 2 days. An evolved parasite defence strategy to consume fresh faeces in the rest area would be adaptive.


Inattention/hyperactivity and aggression from early childhood to adolescence: heterogeneity of trajectories and differential influence of family environment characteristics.
Inattention/hyperactivity and aggressive behavior problems were measured in 335 children from school entry throughout adolescence, at 3-year intervals. Children were participants in a high-risk prospective study of substance use disorders and comorbid problems. A parallel process latent growth model found aggressive behavior decreasing throughout childhood and adolescence, whereas inattentive/hyperactive behavior levels were constant. Growth mixture modeling, in which developmental trajectories are statistically classified, found two classes for inattention/hyperactivity and two for aggressive behavior, resulting in a total of four trajectory classes. Different influences of the family environment predicted development of the two types of behavior problems when the other behavior problem was held constant. Lower emotional support and lower intellectual stimulation by the parents in early childhood predicted membership in the high problem class of inattention/hyperactivity when the trajectory of aggression was held constant. Conversely, conflict and lack of cohesiveness in the family environment predicted membership in a worse developmental trajectory of aggressive behavior when the inattention/hyperactivity trajectories were held constant. The implications of these findings for the development of inattention/hyperactivity and for the development of risk for the emergence of substance use disorders are discussed.


Application of potassium chloride to a Chernobyl-contaminated lake: modelling the dynamics of radiocaesium in an aquatic ecosystem and decontamination of fish.
This study tests a whole-lake experiment to reduce the bioaccumulation of radiocaesium (137Cs) in fish in lakes contaminated by the Chernobyl accident. In many lakes in the Chernobyl contaminated areas, radiocaesium activity concentrations in fish are still significantly higher (up to 100 times in some species) than acceptable limits for human consumption. Estimates of the long-term rate of decline of 137Cs in fish in these regions, in the absence of countermeasures, show that radioactivity in fish in some lakes may remain above acceptable consumption limits for a further 50-100 years from the present date. In February 1998 we applied 15 t of potassium chloride to Lake Svyatoe, Kostiukovichy. The addition of potassium chloride fertilizer to the lake resulted in a decrease in activity concentration of 137Cs to approximately 40% of pre-countermeasure values in a number of different fish species. In contrast to Lake Svyatoe, 137Cs activity concentrations in fish from four control lakes showed no systematic decrease over the study period. Simplified models for transfers of 137Cs in lakes successfully 'blind' predicted the changes in 137Cs in water and fish resulting from this major alteration of the potassium concentration of the lake. The experiment represents the first test of a predictive model for the dynamics of radiocaesium in response to a major perturbation in potassium (its major competitor ion) in a whole lake ecosystem.


Arachidonic acid containing phosphatidylcholine increases due to microglial activation in ipsilateral spinal dorsal horn following spared sciatic nerve injury.
Peripheral nerve injury induces substantial molecular changes in the somatosensory system that leads to maladaptive plasticity and cause neuropathic pain. Understanding the molecular pathways responsible for the development of neuropathic pain is essential to the development of novel rationally designed therapeutics. Although lipids make up to half of the dry weight of the spinal cord, their relation with the development of neuropathic pain is poorly understood. We aimed to elucidate the regulation of spinal lipids in response to neuropathic peripheral nerve injury in mice by utilizing matrix-assisted laser desorption/ionization imaging mass spectrometry, which allows visualization of lipid distribution within the cord. We found that arachidonic acid (AA) containing [PC(diacyl-16:0/20:4)+K]+ was increased temporarily at superficial ipsilateral dorsal horn seven days after spared nerve injury (SNI). The spatiotemporal changes in lipid concentration resembled microglia activation as defined by ionized calcium binding adaptor molecule 1 (Iba1) immunohistochemistry. Suppression of microglial function through minocycline administration resulted in attenuation of hypersensitivity and reduces [PC(diacyl-16:0/20:4)+K]+ elevation in the spinal dorsal horn. These data suggested that AA containing [PC(diacyl-16:0/20:4)+K]+ is related to hypersensitivity evoked by SNI and implicate microglial cell activation in this lipid production.


Effects of antimicrobials on Shiga toxin production in high-virulent Shiga toxin-producing Escherichia coli.
Antimicrobial treatment of Shiga toxin-producing Escherichia coli (STEC) infections is controversial because antimicrobials may stimulate Shiga toxin (Stx) production, and thereby increase the risk of developing haemolytic uremic syndrome (HUS). Previous in vitro studies have shown this mainly in infections caused by STEC serotype O157:H7. The aim of this study was to investigate induction of Stx transcription and production in different serotypes of STEC isolated from severely ill patients, following their exposure in vitro to six different classes of antimicrobials. We investigated Stx transcription and production in 12 high-virulent STEC strains, all carrying the stx2a gene, of six different serotypes following their exposure to six classes of antimicrobials. Liquid cultures of the STEC strains were incubated with sub-inhibitory concentrations of the antimicrobials. We used reverse-transcription quantitative PCR to measure the relative expression of Stx2a mRNA and an enzyme-linked immunosorbent assay to quantify Stx production. In general the antibiotics tested showed only minor effects on transcriptional levels of Stx2a. Ciprofloxacin caused an increase of Stx production in all but two strains, while gentamicin, meropenem and azithromycin did not induce Stx production in any of the STEC strains examined. STEC O104:H4 was the serotype that in greatest extent responded to antimicrobial exposure with an increase of stx2a transcription and Stx production. Gentamicin, meropenem and azithromycin exposure did not result in elevated Stx production. We recommend that this finding is investigated further in the search for candidates for future antimicrobial treatment of STEC.


Non-linear model for the kinetics of 10B in blood after BPA-fructose complex infusion.
A numerical model with a memory effect was created to describe the kinetics of 10B in blood after a single 4-dihydroxyborylphenylalanine-fructose complex (BPA-F) infusion in boron neutron capture therapy (BNCT). The model formulation was based on the averaged data from 10 glioma patients from the Brookhaven National Laboratory (BNL) BNCT-trials. These patients received a 2 h i.v. infusion of a BPA-fructose complex that delivered 290 mg BPA/kg body weight. The model was validated by fitting the original BNL patient data and new patient data from the Finnish BNCT-trials. The new 3-parameter non-linear model provided mean absolute differences between the measured and estimated 10B concentrations in blood that were less than 3.9% when used to simulate actual patient irradiations that comprised two irradiation fields separated by a break to reposition the patient. The flexibility of the model was successfully tested with two different infusion protocols. The patient data were modelled with a two-compartment model and a bi-exponential fit for comparison. The 3-parameter model is better than previously described models in predicting the time course of blood 10B concentration after cessation of intravenous infusion of BPA-fructose.


Plastidial NAD-Dependent Malate Dehydrogenase: A Moonlighting Protein Involved in Early Chloroplast Development through Its Interaction with an FtsH12-FtsHi Protease Complex.
Malate dehydrogenases (MDHs) convert malate to oxaloacetate using NAD(H) or NADP(H) as a cofactor. Arabidopsis thaliana mutants lacking plastidial NAD-dependent MDH (pdnad-mdh) are embryo-lethal, and constitutive silencing (miR-mdh-1) causes a pale, dwarfed phenotype. The reason for these severe phenotypes is unknown. Here, we rescued the embryo lethality of pdnad-mdh via embryo-specific expression of pdNAD-MDH. Rescued seedlings developed white leaves with aberrant chloroplasts and failed to reproduce. Inducible silencing of pdNAD-MDH at the rosette stage also resulted in white newly emerging leaves. These data suggest that pdNAD-MDH is important for early plastid development, which is consistent with the reductions in major plastidial galactolipid, carotenoid, and protochlorophyllide levels in miR-mdh-1 seedlings. Surprisingly, the targeting of other NAD-dependent MDH isoforms to the plastid did not complement the embryo lethality of pdnad-mdh, while expression of enzymatically inactive pdNAD-MDH did. These complemented plants grew indistinguishably from the wild type. Both active and inactive forms of pdNAD-MDH interact with a heteromeric AAA-ATPase complex at the inner membrane of the chloroplast envelope. Silencing the expression of FtsH12, a key member of this complex, resulted in a phenotype that strongly resembles miR-mdh-1. We propose that pdNAD-MDH is essential for chloroplast development due to its moonlighting role in stabilizing FtsH12, distinct from its enzymatic function.


Potential initiators of HIV-related stigmatization: ethical and programmatic challenges for PMTCT programs.
HIV/AIDS continues to constitute a serious threat to the social and physical wellbeing of African mothers and their babies. In the hardest hit countries of sub-Saharan Africa, more than 60% of all new HIV infections are occurring in women, infants and young children.Mother-to-child transmission (MTCT) constitutes 90% of new HIV infections among infants and young children. Most of these infection scan be prevented. However, the social stigma of HIV/AIDS insidiously continues to undermine the success of prevention programs.Ironically, some attributes or characteristics of prevention of mother-to-child transmission (PMTCT) programs may in fact serve as catalysts to the stigmatization process. This paper identifies and discusses six potential initiators: (1) Routine HIV testing, (2) Six months exclusive breastfeeding, (3) Incentives, (4) Home visits, (5) Location of PMTCT program, and (6) PMTCT terminology. In all these areas, there are practical strategies that may be applied to reduce the chances of being stigmatized. These strategies are introduced and discussed.


Correlating 3D Surface Atomic Structure and Catalytic Activities of Pt Nanocrystals.
Active sites and catalytic activity of heterogeneous catalysts is determined by their surface atomic structures. However, probing the surface structure at an atomic resolution is difficult, especially for solution ensembles of catalytic nanocrystals, which consist of heterogeneous particles with irregular shapes and surfaces. Here, we constructed 3D maps of the coordination number (CN) and generalized CN (CN_) for individual surface atoms of sub-3 nm Pt nanocrystals. Our results reveal that the synthesized Pt nanocrystals are enclosed by islands of atoms with nonuniform shapes that lead to complex surface structures, including a high ratio of low-coordination surface atoms, reduced domain size of low-index facets, and various types of exposed high-index facets. 3D maps of CN_ are directly correlated to catalytic activities assigned to individual surface atoms with distinct local coordination structures, which explains the origin of high catalytic performance of small Pt nanocrystals in important reactions such as oxygen reduction reactions and CO electro-oxidation.


The mode of mitosis is dramatically modified by deletion of a single nuclear pore complex gene in Aspergillus nidulans.
Nuclear pore complex (NPC) proteins (Nups) play multiple roles during mitosis. In this study we expand these roles and reveal that in Aspergillus nidulans, compromising the core Nup84-120 subcomplex of the NPC modifies the mitotic behavior of the nuclear envelope (NE). In wildtype cells, the NE undergoes simultaneous double pinching events to separate daughter nuclei during mitotic exit, whereas in Nup84-120 complex mutants, only one restriction of the NE is observed. Investigating the basis for this modified behavior of the NE in Nup deleted cells uncovered previously unrealized roles for core Nups in mitotic exit. During wildtype anaphase, the NE surrounds the two separating daughter DNA masses which typically flank the central nucleolus, to form three distinct nuclear compartments. In contrast, deletion of core Nups frequently results in early nucleolar eviction from the mitotic nucleus, in turn causing an uncharacteristic dumbbell-shaped NE morphology of anaphase nuclei with a nuclear membrane bridge connecting the two forming G1 nuclei. Importantly, the absence of the nucleolus between the separating daughter nuclei during anaphase delays chromosome segregation and progression into G1 as nuclei remain connected by chromatin bridges. Proteins localizing to late segregating chromosome arms are observed between forming daughter nuclei, and the mitotic spindle fails to resolve in a timely manner. These chromatin bridges are occupied by the Aurora kinase until nuclei have fully separated, suggesting involvement of Aurora in monitoring mitotic spindle and nuclear membrane resolution during mitotic exit. Our findings thus reveal a novel requirement for core Nups in mediating nucleolar positioning during mitosis, which dictates the pattern of NE fissions during karyokinesis and facilitates normal chromosome segregation. The findings additionally demonstrate that the mode of mitosis can be dramatically modified by deletion of a single NPC gene and reveals surprising fluidity in mitotic mechanisms.


Cost of providing the expanded programme on immunization: findings from a facility-based study in Viet Nam, 2005.
To estimate and analyse the costs for providing the expanded programme on immunization (EPI) in a rural community in the north of Viet Nam in 2005. An ingredient approach was used to collect cost data from the perspective of the service providers. The total annual cost of EPI in Bavi district was US$58,460 [purchasing power parity (PPP) 282,076]. Vaccines and supplies were the largest cost category (33%), followed by personnel costs (30.2%). The largest share of the total cost was due to activities at commune level (38%). The average cost per fully vaccinated child (FVC) was US$4.81 (PPP 23.21), much lower than the figure of US$15 that is generally accepted as the cost-effective threshold for EPI in developing countries. This empirical study indicates that EPI has been implemented efficiently in rural Viet Nam, but that opportunities exist to make it even more efficient.


Distribution and Prognostic Significance of Left Ventricular Global Longitudinal Strain in Asymptomatic Significant Aortic Stenosis: An Individual Participant Data Meta-Analysis.
In this individual participant data meta-analysis on left ventricular global longitudinal strain (LVGLS), our objective was to: 1) describe its distribution; 2) identify the most predictive cutoff values; and 3) assess its impact on mortality in asymptomatic patients with significant aortic stenosis (AS) and preserved left ventricular ejection fraction (LVEF). The evidence supporting the prognostic role of LVGLS in asymptomatic patients with AS has been obtained from several relatively small studies. A literature search was performed for studies published between 2005 and 2017 without language restriction according to the following criteria: "aortic stenosis" AND "longitudinal strain." The corresponding authors of selected studies were contacted and invited to share their data that we computerized in a specific database. The primary endpoint was all-cause mortality. Among the 10 studies included, 1,067 asymptomatic patients with significant AS and LVEF >50% were analyzed. The median of LVGLS was 16.2% (from 5.6% to 30.1%). There were 91 deaths reported during follow-up with median of 1.8 (0.9 to 2.8) years, resulting in a pooled crude mortality rate of 8.5%. The LVGLS performed well in the prediction of death (area under the curve: 0.68). The best cutoff value identified was LVGLS of 14.7% (sensitivity, 60%; specificity, 70%). Using random effects model, the risk of death for patients with LVGLS <14.7% is multiplied by >2.5 (hazard ratio: 2.62; 95% confidence interval: 1.66 to 4.13; p < 0.0001), without significant heterogeneity between studies (I2 = 18.3%; p = 0.275). The relationship between LVGLS and mortality remained significant in patients with LVEF ≥60% (p = 0.001). This individual participant data meta-analysis demonstrates that in asymptomatic patients with significant AS and normal LVEF, impaired LVGLS is associated with reduced survival. These data emphasize the potential usefulness of LVGLS for risk stratification and management of these patients.


Comorbidities and perioperative complications in HIV-positive patients undergoing primary total hip and knee arthroplasty.
Highly active antiretroviral therapy has prolonged the lifespan of individuals infected with human immunodeficiency virus (HIV). We hypothesized that the number of primary total joint arthroplasties performed in this population has been increasing and that HIV infection is not an independent risk factor for postoperative complications. The Nationwide Inpatient Sample for the years 2000 through 2008 was queried to identify patients who underwent primary total joint arthroplasty. HIV, comorbidities, and complications were identified with use of ICD-9-CM (International Classification of Diseases, Ninth Revision, Clinical Modification) codes. Data were analyzed with use of multivariate logistic regression, the Pearson chi-square test, and the Mann-Kendall trend test. Of the estimated 5,681,024 admissions for primary total hip and knee arthroplasty in the United States during this period, 8229 (0.14%) were in patients who had HIV. Compared with HIV-negative patients (controls), infected patients were more likely to be younger, be male, and have a history of osteonecrosis, liver disease, drug use, and coagulopathy. The number of total hip and total knee arthroplasties in HIV-positive patients increased from 2000 to 2008 (p < 0.05). Seventy-nine percent (6499) of the total joint arthroplasties in the HIV-positive patients involved the hip. Compared with HIV-negative patients undergoing total hip arthroplasty, HIV-positive patients were more likely to develop acute renal failure (1.3% compared with 0.8%, p = 0.04), develop a wound infection (0.6% compared with 0.3%, p = 0.02), and undergo postoperative irrigation and debridement (0.2% compared with 0.1%, p = 0.01). They were less likely to have a myocardial infarction (0.4% compared with 0.9%, p = 0.04). There was no difference in total complications (8.3% compared with 7.8%, p = 0.52). Similarly, there was no difference in total complications in patients undergoing total knee arthroplasty (7.8% compared with 8.0%, p = 0.76). HIV was not an independent risk factor for complications in total hip arthroplasty (odds ratio [OR], 1.18; 95% confidence interval [CI], 0.95 to 1.47) or total knee arthroplasty (OR, 0.78; 95% CI, 0.49 to 1.25). The incidence of primary total joint arthroplasty in HIV-positive patients has been increasing. These patients were at slightly higher risk of certain immediate postoperative complications because of a higher rate of medical comorbidities. HIV infection was not an independent risk factor for the total rate of perioperative complications. Prognostic Level II. See Instructions for Authors for a complete description of levels of evidence.


Quality of life of Taiwanese adults with autism spectrum disorder.
To date, few recent studies have investigated the quality of life of adults with autism spectrum disorder (ASD). It remains unclear how individuals with ASD view their own quality of life. The primary purpose of this study was to compare the quality of life scores among adults with ASD with those of a non-ASD control group and the Taiwanese health population reference group. The study comprised 41 adults with ASD (M age = 26.9, SD = 5.0), and without intellectual disabilities (IQ>70). A comparison sample of 41 adults without ASD was selected by matching the age and sex of the participants with ASD. A validated measure, the Taiwanese version of the World Health Organization Quality of Life-BREF (WHOQOL-BREF), was used. Independent t-tests were performed to examine the differences in the quality of life between groups. The highest quality of life was scored in the environment domain, followed by the physical health and psychological health domains. The lowest quality of life score was found in the social relationship domain. Adults with ASD scored significantly lower in all domains than did the non-ASD control group. Additionally, adults with ASD scored significantly lower in the physical health, psychological health, and social relationship domains than did the Taiwanese health population reference group. Comorbid psychiatric disorders, self-rated health status, and perceived happiness were correlated with quality of life among adults with ASD. The preliminary findings suggest that adults with ASD need more supportive social contexts and interventions to promote their quality of life. Based on our findings, social relationship must be considered in designing and applying treatment programs for adults with ASD.


Adiponectin Downregulates TNF-α Expression in Degenerated Intervertebral Discs.
Given the results of previous in vitro investigations of the expression patterns of adiponectin and its receptors in healthy and degenerated intervertebral discs (IVDs), we studied the effects of adiponectin on tumor necrosis factor-alpha (TNF-α) production in degenerated nucleus pulposus (NP) cells and analyzed the association between adiponectin levels in IVD tissues and IVD Pfirrmann grades. The aim of this study was to investigate the potential role of adiponectin in the pathogenesis of IVD degeneration. Adiponectin has been reported to be involved in physiologic and pathologic processes associated with bone and cartilage diseases. However, the expression profiles of adiponectin and its receptors in human IVD tissues and the function of adiponectin in the pathogenesis of IVD degeneration remain unknown. Real-time polymerase chain reaction, immunohistochemistry, and western blotting were performed to examine the expression levels of adiponectin, adiponectin receptors, and TNF-α in IVD tissues and isolated NP cells. The effects of adiponectin on TNF-α production in degenerated NP cells were detected by enzyme linked immunosorbent assay. Adiponectin expression levels were downregulated, while adiponectin receptor 1 (adipoR1) and adipoR2 expression levels were upregulated in degenerated IVD tissues and degenerated NP cells compared with those in healthy IVD tissues and healthy NP cells. Moreover, we confirmed that TNF-α production by degenerated NP cells was downregulated by adiponectin administration in a dose- and time-dependent manner. Furthermore, our data showed that adiponectin levels in degenerated IVD tissues were inversely correlated with IVD Pfirrmann grades. These results indicated that adiponectin may play an anti-inflammatory role with respect to the maintenance of IVD homeostasis by downregulating TNF-α production. N/A.


A clinical trial comparing interviewer and computer-assisted assessment among clients with severe mental illness.
Demographic, behavioral, and diagnostic information should routinely be collected from clients with severe mental illness, and data gathering should employ the most efficient techniques available. Surveys are increasingly conducted via Web-based computer-assisted interviewing (CAI), but this technique is not well validated for patients with severe mental illness. A randomized clinical trial of 245 clients was carried out to compare face-to face and computer-assisted interviewing (233 clients completed two surveys). Self-report data were collected on demographic characteristics, substance abuse, risk behaviors for blood-borne diseases, trauma history, and posttraumatic stress disorder. Each client was assessed twice and randomly assigned to one of the four possible combinations of interviewer and computer (computer and computer, N=53; computer and interviewer, N=56; interviewer and computer, N=59; and interviewer and interviewer, N=65). The two formats were compared on feasibility, client preference, cost, reliability, convergent validity, and criterion validity. This study demonstrated the feasibility of CAI across a variety of inpatient and outpatient settings. All participants who began the CAI process completed the interview and responded to over 95% of the survey items. Participants liked using the computers as well as they liked face-to-face interviews, and they completed the CAI as quickly. CAI produced data as reliable and valid as face-to-face interviews produced and was less expensive, and results were available more quickly. The two formats were similar in criterion validity. CAI appears to be a viable technology for gathering clinical data from the population with severe mental illness and for transforming such information into a useful, quickly accessible form to aid in clinical decision making.


Effect of animal mixing as a stressor on biomarkers of autophagy and oxidative stress during pig muscle maturation.
The objective of this work was to study the postmortem evolution of potential biomarkers of autophagy (Beclin 1, LC3-II/LC3-I ratio) and oxidative stress (total antioxidant activity, TAA; superoxide dismutase activity, SOD and catalase activity, CAT) in the Longissimus dorsi muscle of entire male ((Large White×Landrace)×Duroc) pigs subjected to different management treatments that may promote stress, such as mixing unfamiliar animals at the farm and/or during transport and lairage before slaughter. During the rearing period at the farm, five animals were never mixed after the initial formation of the experimental groups (unmixed group at the farm, UF), whereas 10 animals were subjected to a common routine of being mixed with unfamiliar animals (mixed group at the farm, MF). Furthermore, two different treatments were used during the transport and lairage before slaughter: 10 pigs were not mixed (unmixed group during transport and lairage, UTL), whereas five pigs were mixed with unfamiliar animals on the lorry and during lairage (mixed group during transport and lairage, MTL). These mixing treatments were then combined into three pre-slaughter treatments - namely, UF-UTL, MF-UTL and MF-MTL. The results show that MF-UTL and MF-MTL increased significantly the muscle antioxidant defense (TAA, SOD and CAT) at short postmortem times (4 and 8 h; P<0.001), followed by an earlier depletion of the antioxidant activity at 24 h postmortem (P<0.05). We also found that mixing unfamiliar animals, both at the farm and during transport and lairage, triggers postmortem muscle autophagy, which showed an earlier activation (higher expression of Beclin 1 and LC3-II/LC3-I ratio at 4 h postmortem followed by a decreasing pattern of this ratio along first 24 h postmortem) in the muscle tissues of animals from the MF-UTL and MF-MTL groups, as an adaptive strategy of the muscle cells for counteracting induced stress. From these results, we propose that monitoring the evolution of the main biomarkers of autophagy (Beclin 1, LC3-II/LC3-I ratio) and muscle antioxidant defense (TAA, SOD, CAT) in the muscle tissue within the first 24 h postmortem may help the detection of animal stress and its potential effect on the postmortem muscle metabolism.


Optimization of the Antibacterial Spectrum and the Developability Profile of the Novel-Class Natural Product Corramycin.
Corramycin 1 is a novel zwitterionic antibacterial peptide isolated from a culture of the myxobacterium Corallococcus coralloides. Though Corramycin displayed a narrow spectrum and modest MICs against sensitive bacteria, its ADMET and physchem profile as well as its high tolerability in mice along with an outstanding in vivo efficacy in an Escherichia coli septicemia mouse model were promising and prompted us to embark on an optimization program aiming at enlarging the spectrum and at increasing the antibacterial activities by modulating membrane permeability. Scanning the peptidic moiety by the Ala-scan strategy followed by key stabilization and introduction of groups such as a primary amine or siderophore allowed us to enlarge the spectrum and increase the overall developability profile. The optimized Corramycin 28 showed an improved mouse IV PK and a broader spectrum with high potency against key Gram-negative bacteria that translated into excellent efficacy in several in vivo mouse infection models.


Regulation of a novel gene cluster involved in secondary metabolite production in Streptomyces coelicolor.
Antibiotic biosynthesis in the streptomycetes is a complex and highly regulated process. Here, we provide evidence for the contribution of a novel genetic locus to antibiotic production in Streptomyces coelicolor. The overexpression of a gene cluster comprising four protein-encoding genes (abeABCD) and an antisense RNA-encoding gene (α-abeA) stimulated the production of the blue-pigmented metabolite actinorhodin on solid medium. Actinorhodin production also was enhanced by the overexpression of an adjacent gene (abeR) encoding a predicted Streptomyces antibiotic regulatory protein (SARP), while the deletion of this gene impaired actinorhodin production. We found the abe genes to be differentially regulated and controlled at multiple levels. Upstream of abeA was a promoter that directed the transcription of abeABCD at a low but constitutive level. The expression of abeBCD was, however, significantly upregulated at a time that coincided with the initiation of aerial development and the onset of secondary metabolism; this expression was activated by the binding of AbeR to four heptameric repeats upstream of a promoter within abeA. Expressed divergently to the abeBCD promoter was α-abeA, whose expression mirrored that of abeBCD but did not require activation by AbeR. Instead, α-abeA transcript levels were subject to negative control by the double-strand-specific RNase, RNase III.


Effectiveness of national provider prescription of PPI gastroprotection among elderly NSAID users.
Our aim was to quantify the effect of provider adherence on the risk of NSAID-related upper gastrointestinal events (UGIE). We identified from national pharmacy records veterans > or = 65 yr prescribed an NSAID, a coxib, or salicylate (>325 mg/day) at any Veterans Affairs (VA) facility (January 1, 2000 to December 31, 2002). Prescription fill data were linked in longitudinal fashion to VA inpatient, outpatient, and death files and merged with demographic, inpatient, outpatient, and provider data from Medicare. Each person-day of follow-up was assessed for exposure to NSAID alone, NSAID+proton pump inhibitor (PPI), coxib, or coxib+PPI. UGIE was defined using our published, validated algorithm. Unadjusted incidence density ratios were calculated for the 365 days following exposure. We assessed risk of UGIE using Cox proportional hazards models, while adjusting for demographics, UGIE risk factors, comorbidity, prescription channeling (i.e., propensity score), geographic location, and multiple time-dependent pharmacological covariates, including aspirin, steroids, anticoagulants, antiplatelets, statins, and selective serotonin reuptake inhibitors. In our cohort of 481,980 (97.8% male, 85.3% white, mean age 73.9, standard deviation 5.6), a safer strategy was prescribed for 19.8%, and 2,753 UGIE occurred in 220,662 person-years of follow-up. When adjusted for prescription channeling, confounders, and effect modification-associated PPI, risk of UGIE was 1.8 (95% confidence interval [CI] 1.6-2.0) on NSAID alone, 1.8 (95% CI 1.5-2.0) on coxib alone, 1.1 (95% CI 0.7-4.6) on NSAID+PPI, and 1.1 (0.6-5.2) on coxib+PPI. When the analysis was adjusted for cumulative percent time spent on a PPI, risk of UGIE decreased from HR 3.0 (95% CI 2.6-3.7) when a PPI was prescribed 0-20% of the time to 1.1 (95% CI 1.0-1.3) when a PPI was prescribed 80-100% of the time. Provider adherence to safer NSAID prescribing strategies is associated with fewer UGIE among the elderly. An adherent strategy lowers, but does not eliminate, risk of an NSAID-related UGIE.


Frequency of network synchronization in the hippocampus marks learning.
The synchronization of neuronal networks may be instrumental in plasticity and learning. Hippocampal high-frequency oscillations (140-200 Hz, 'ripples') characteristic of consummatory behaviours are thought to promote memory formation. We recorded ripple oscillations from the CA1 area in temporal learning tasks. Rats learned to adjust their operant response to the timing of food reward delivery [fixed interval schedule (FI)]. The intrinsic frequency of ripples was elevated following the switch in reinforcement timing. Learning, as assessed from the response pattern, correlated with fluctuations of intraripple frequency and amplitude. Changes in motor activity did not account for the variability of ripple oscillations. At the same time, features of ripples were unaltered when the fixed interval of reward delivery was changed but did not depend on the lever press response. Thus, in addition to the known replay of neuronal firing patterns during ripple oscillations, the rhythm itself appears to be modulated in an experience-specific way and represents a direct correlate of learning.


An oncogenic role for the phosphorylated h-subunit of human translation initiation factor eIF3.
Dysregulation of protein synthesis has been implicated in oncogenesis through a mechanism whereby "weak" mRNAs encoding proteins involved in cell proliferation are strongly translated when the protein synthesis apparatus is activated. Previous work has determined that many cancer cells contain high levels of eIF3h, a protein subunit of translation initiation factor eIF3, and overexpression of eIF3h malignantly transforms immortal NIH-3T3 cells. This is a general feature of eIF3h, as high levels also affect translation, proliferation, and a number of malignant phenotypes of CHO-K1 and HeLa cells and, most significantly, of a primary prostate cell line. Furthermore, overexpressed eIF3h inhibits Myc-dependent induction of apoptosis of primary prostate cells. eIF3h appears to function through translation, as the initial appearance of overexpressed eIF3h in rapidly induced NIH-3T3 cells correlates tightly with the stimulation of protein synthesis and the generation of malignant phenotypes. This oncogenic potential of eIF3h is enhanced by phosphorylation at Ser(183). Finally, reduction of eIF3h levels in breast and prostate cancer cell lines by short interfering RNA methods reduces their rates of proliferation and anchorage-independent growth in soft agar. The results provide compelling evidence that high eIF3h levels directly stimulate protein synthesis, resulting in the establishment and maintenance of the malignant state in cells.


Role of anti-GQ1B antibody in differential diagnosis of acute ophthalmoparesis.
Miller Fisher syndrome (MFS) is a triad of total external ophthalmoplegia, ataxia, and areflexia, while botulism has the usual clinical presentation of involvement of cranial muscles and palsies with blurred vision, diplopia, ptosis, dilated pupils, and facial paralysis, caused by a bacterial neurotoxin which attacks proteins involved in presynaptic vesicle release. In this report, we needed to make the differential diagnosis between MFS and botulism in a patient who presented with acute ophthalmoparesis and a history of diarrhea three days before, which started two days after consuming tinned food. Routine laboratory, neurophysiologic, and imaging investigations were normal. A clinical diagnosis of Miller Fisher syndrome was reached by anti-ganglioside GQ1B and GM1 Ig G and M antibody investigations which proved positive. The patient was treated with intravenous immunoglobulin two weeks after (in the late period) the symptoms started and he has recovered completely. Systemic autoimmune diseases should be considered in patients with bilateral ophthalmoparesis. As in the present patient, the evaluation of specific antibodies helps in the diagnosis and thus early effective treatment is possible.


Spasticity and hyperselective neurectomy in the upper limb.
Spasticity is a complex pathology, both in terms of assessment and treatment. This article focuses on the clinical examination (objective, capacity, performance and function), which is key for choosing a treatment and can be helped by botulinum toxin injections. The treatment involves physical therapy, occupational therapy, medications and surgery. Neurectomy has been used in the upper limb since 1912 and is one of the therapeutic options for spasticity. This treatment is usually reserved for nonfunctional hands. Cadaver studies have helped us better understand nerve anatomy and improve the hyperselective neurectomy (HSN) technique. This article describes the history of neurectomy, how anatomical dissections apply to surgery, the HSN technique in the musculocutaneous nerve, median nerve and ulnar nerve and results of preliminary prospective studies. Spasticity, mobility, performance and function were evaluated a few months after HSN and about 12 months later to assess the permanence of the results in children and adult spastic patients. No matter the nerve or function targeted (elbow extension, wrist extension, or supination), spasticity was reduced with improvements in the functional House score and appeared stable at the last follow-up. HSN seems to be a good, reliable therapeutic option for spasticity, including functional hands.


The Fate of Contaminants and Stable Pb Isotopes in a Changing Estuarine Environment: 20 Years On.
Estuarine sediments provide an important sink for contaminants discharged into fluvial, estuarine, and nearshore settings, and numerous authors have utilized this trapping function to assess historical contaminant loadings and contaminant breakdown/transformation processes. This Article examines the retention of elemental and isotopic sedimentary signatures in an industrialized estuarine system subject to a strongly upward sea-level trend, over a 20 year period. Two contrasting saltmarsh sites (at Hythe and Hamble, part of the wider Southampton Water estuarine system, UK) were examined, which had been previously cored and analyzed in the early 1990s. Much of the geochemical record of recent anthropogenic activity has been eroded and lost at the Hamble site. In contrast, radiometric, isotopic and elemental records of anthropogenic activity have been retained in the Hythe marsh, with 137Cs and Cu depth profiles showing retention of input maxima related to fallout and local industrial discharges, respectively. Stable Pb isotope data show a broad degree of correspondence in cores analyzed in 1994 and 2014 when plotted against sediment (radiometric) age, indicating the usefulness of isotopic data in retaining information on Pb sources and in disentangling Pb input histories. New ultrahigh precision, double-spike mass spectrometry stable Pb isotope data allow clearer discrimination of historical Pb input phases, and highlight within-estuary mixing and supply of reworked, secondary contamination from erosion of anthropogenically labeled sediments elsewhere in the estuary.


A systematic review of health communication strategies in Sub-Saharan Africa-2015-2022.
Background: Health communication strategies have become critical in managing public health issues across sub-Saharan Africa. In the literature, health communication strategies have been well documented. The studies are often narrow, focusing on individual countries or specific health issues. No research documented and consolidated the health communication strategies across sub-Saharan Africa. This review attempts to catalogue prevalent health communication strategies, how the various countries have implemented these strategies and the barriers to effective health communication practices in Africa. Methods: We systematically reviewed existing literature on health communication strategies in sub-Saharan Africa to answer formulated questions. A Google search was performed in October 2022 with the keywords 'health communication', 'strategies', 'promotion,' 'education,' and 'engagement,' The data reported in this article included evidence published between 2013 and 2023. Selected documents were content analyzed, and significant sections were mapped against specific strategies/themes. These subsets of data were used to present the results and analysis. Results:The review indicates that different health communication strategies have been deployed across Africa. In some countries, specific strategies are used to tackle specific health issues, while a combination of strategies is used in others. In some countries, the strategies are unclear, and implementation is improvised, sometimes misapplied, or truncated by bureaucratic red tape and incompetence. The prevalent strategies are mainly those prescribed from outside with little input from the beneficiaries. Conclusion: The review suggests that using a holistic or multi-pronged health communication approach that is context-specific and participatory could attract more uptakes of health messages.


LLE Score: A New Filter-Based Unsupervised Feature Selection Method Based on Nonlinear Manifold Embedding and Its Application to Image Recognition.
The task of feature selection is to find the most representative features from the original high-dimensional data. Because of the absence of the information of class labels, selecting the appropriate features in unsupervised learning scenarios is much harder than that in supervised scenarios. In this paper, we investigate the potential of locally linear embedding (LLE), which is a popular manifold learning method, in feature selection task. It is straightforward to apply the idea of LLE to the graph-preserving feature selection framework. However, we find that this straightforward application suffers from some problems. For example, it fails when the elements in the feature are all equal; it does not enjoy the property of scaling invariance and cannot capture the change of the graph efficiently. To solve these problems, we propose a new filter-based feature selection method based on LLE in this paper, which is named as LLE score. The proposed criterion measures the difference between the local structure of each feature and that of the original data. Our experiments of classification task on two face image data sets, an object image data set, and a handwriting digits data set show that LLE score outperforms state-of-the-art methods, including data variance, Laplacian score, and sparsity score.


Effect of amendment of bauxite processing sand with organic materials on its chemical, physical and microbial properties.
The effects of addition of a range of organic amendments (biosolids, spent mushroom compost, green waste compost and green waste-derived biochar), at two rates, on some key chemical, physical and microbial properties of bauxite-processing residue sand were studied in a laboratory incubation study. Levels of exchangeable cations were not greatly affected by additions of amendments but extractable P was increased significantly by mushroom and green waste composts and massively (i.e. from 11.8 to 966 mg P kg(-1)) by biosolids applications. Levels of extractable NO(3)(-)-N were also greatly elevated by biosolids additions and there was a concomitant decrease in pH. Addition of all amendments decreased bulk density and increased mesoporosity, available water holding capacity and water retention at field capacity (-10 kPa), with the higher rate having a greater effect. Addition of biosolids, mushroom compost and green waste compost all increased soluble organic C, microbial biomass C, basal respiration and the activities of beta-glucosidase, L-asparaginase and alkali phosphatase enzymes. The germination index of watercress grown in the materials was greatly reduced by biosolids application and this was attributed to the combined effects of a high EC and high concentrations of extractable P and NO(3)(-). It was concluded that the increases in water storage and retention and microbial activity induced by additions of the composts is likely to improve the properties of bauxite-processing residue sand as a growth medium but that allowing time for soluble salts, originating from the organic amendments, to leach out may be an important consideration before sowing seeds.


Familial segmental neurofibromatosis.
Segmental neurofibromatosis is considered to be the result of postzygotic NF1 gene mutations. We present a family in which the proband has generalized neurofibromatosis 1, whereas members of previous generations manifest segmental skin lesions. All, including the clinically asymptomatic grandmother, carry the same haplotype. This is the only case in the literature in which a parent with segmental skin findings has a child with full-blown neurofibromatosis 1 disease. The genetic mechanisms underlying this association are discussed. This family can be further investigated by examination of tissue samples from affected and unaffected sites for mutations.


Comparative activities of Bay n7133, ICI 153,066, and ketoconazole in murine cryptococcosis.
Two new antifungal triazoles, BAY n7133 and ICI 153,066, were compared with ketoconazole in treatment of mice challenged intraperitoneally with Cryptococcus neoformans. At high challenge doses, thymus-containing normal mice had prolonged survival after treatment with BAY n7133. Athymic mice, which have severely deficient cell-mediated immunity, were not protected. At low challenge doses, athymic mice also had prolonged survival. Although BAY n7133 was protective, it was less effective than either ketoconazole or ICI 153,066. BAY n7133 was also less effective in mice challenged intracerebrally than in those challenged intraperitoneally. Both ketoconazole and ICI 153,066 prolonged survival and lowered cryptococcal spleen counts to a greater extent than did BAY n7133.


Variations in reliability and validity do not influence judge, attorney, and mock juror decisions about psychological expert evidence.
We tested whether the reliability and validity of psychological testing underlying an expert's opinion influenced judgments made by judges, attorneys, and mock jurors. We predicted that the participants would judge the expert's evidence more positively when it had high validity and high reliability. In Experiment 1, judges (N = 111) and attorneys (N = 95) read a summary of case facts and proffer of expert testimony on the intelligence of a litigant. The psychological testing varied in scientific quality; either there was (a) blind administration (i.e., the psychologist did not have an expectation for the test result) of a highly reliable test, (b) nonblind administration (i.e., the psychologist did have an expectation for the test result) of a highly reliable test, or (c) blind administration of a test with low reliability. In a trial simulation (Experiment 2), we varied the scientific quality of the intelligence test and whether the cross-examination addressed the scientific quality of the test. The variations in scientific quality did not influence judges' admissibility decisions nor their ratings of scientific quality nor did it influence attorneys' decisions about whether to move to exclude the evidence. Attorneys' ratings of scientific quality were sensitive to variations in reliability but not the testing conditions. Scientifically informed cross-examinations did not help mock jurors (N = 192) evaluate the validity or the reliability of a psychological test. Cross-examination was an ineffective method for educating jurors about problems associated with nonblind testing and reliability, which highlights the importance of training judges to evaluate the quality of expert evidence. (PsycINFO Database Record (c) 2019 APA, all rights reserved).


Postpartum-acquired haemophilia A: a description of three cases and literature review.
Postpartum-acquired haemophilia A is a rare but potentially severe complication of pregnancy. Although the natural history of the disease is usually benign, with a high percentage of spontaneous remissions and a low mortality, its quick recognition is important to control bleeding episodes. The therapeutic strategies in these patients are the treatment of acute bleeding episodes and the long-term eradication of the autoantibody. We report three different cases of postpartum-acquired haemophilia demonstrating the broad heterogeneity of the clinical presentation and of therapeutic necessity of this condition. Finally, we present a review of the literature on the current therapeutic management of this haemorrhagic disorder.