Migration in far west Nepal: intergenerational linkages between internal and international migration of rural-to-urban migrants.
In Nepal, international labor migration to India and overseas, as well as internal migration to the rural Nepalese lowlands, is of high socioeconomic significance. Scholarly debates about migration in Nepal have gradually shifted from an economic to a more holistic perspective, also incorporating social dimensions. However, little evidence has been generated about internal migration to urban destinations and the potential linkages between international and internal migration. This article draws on Bourdieu's "Theory of Practice" and sees migration as a social practice. Accordingly, migration practice is regarded as a strategy social agents apply to increase or transfer capitals and ultimately secure or improve their social position. Evidence for this argument is based on a qualitative case study of rural to urban migrants in Far West Nepal conducted in July and August 2009. The study at hand addresses linkages between internal and international migration practices and provides insight about a social stratum that is often neglected in migration research: the middle class and, more precisely, government employees. The authors show that social relations are crucial for channeling internal migration to a specific destination. Furthermore, they unveil how internal migration is connected to the international labor migration of former generations. Finally, the authors examine how migration strategies adopted over generations create multi-local social networks rooted in the family's place of origin.


Occurrence and susceptibility to antibiotics of Shigella species in stools of hospitalized children with bloody diarrhea in Pakistan.
The aim of the present investigation was to study the frequency of Shigella spp. in patients with bloody diarrhea in Pakistan and the susceptibility of isolated Shigella to three antibiotics: ampicillin, cotrimoxazole and nalidixic acid. In addition, the frequency of Campylobacter and Salmonella was also determined. Stool samples (n = 152) were collected from 152 diarrheic children less than six years of age passing blood and mucus in their stools who were admitted to Paediatric Department of Mayo Hospital in Lahore, Pakistan from June to September 1990. The samples were cultivated on standard media for Shigella, Campylobacter, and Salmonella. Susceptibility of Shigella isolates was tested by disk diffusion method. The frequency of isolation was 19.1% for Shigella spp., 7.9% for Campylobacter, and 4.6% for Salmonella. Shigella flexneri (7.9%) was the most frequently isolated species, followed by S. dysenteriae (6.6%), S. boydii, (3.3%) and S. sonnei (1.3%). All Shigella isolates were susceptible to nalidixic acid (100%), while only a few were susceptible to cotrimoxazole (7.0%) and ampicillin (3.5%). In Pakistan, self-medication and purchases of drugs without a prescription are commonly practiced. Thus, there is a greater possibility of development of resistant strains due to over use of antibiotics.


From classroom environment to mathematics achievement: The mediating role of self-perceived ability and subject interest.
Drawing on Bandura's triadic reciprocal causation model, perceived classroom environment and three intrapersonal factors (mathematics self-efficacy, maths interest and academic self-concept) were considered as predictors of test performance in two correlated mathematics assessments: a public examination (GCSE) and an on-line test, both taken by UK pupils at age 16 (n = 6689). Intrapersonal factors were significantly associated with both test scores, even when the alternative score was taken into account. Classroom environment did not correlate with mathematics achievement once intrapersonal factors and alternative test performance were included in the model, but was associated with subject interest and academic self-concept. Perceptions of classroom environment may exercise an indirect influence on achievement by boosting interest and self-concept. In turn, these intrapersonal factors have direct relationships with achievement and were found to mediate the relationship between perceived classroom environment and maths performance. Findings and their implications for mathematics education are discussed.


Itraconazole as 'bridge therapy' to anti-IgE in a patient with severe asthma with fungal sensitisation.
Sensitisation to fungi has been reported to play an important role in a particular phenotype of severe asthma, the so-called severe asthma with fungal sensitisation, characterised by high levels of total IgE, which may be an obstacle to anti-IgE therapy. We describe here the case of a polysensitised woman with refractory asthma, sensitised to Aspergillus fumigatus with high total IgE values (1793 kUA/l), but without the diagnostic criteria for allergic bronchopulmonary aspergillosis. Additional therapy with itraconazole leads to the decrease of total IgE to the limits recommended for proper omalizumab dosing (30-1500 kUA/l). Itraconazole, used as bridge therapy, provided us the opportunity to start anti-IgE treatment in a patient with high levels of total IgE, beyond the upper limits recommended for proper prescription of omalizumab.


NextGen sequencing reveals short double crossovers contribute disproportionately to genetic diversity in Toxoplasma gondii.
Toxoplasma gondii is a widespread protozoan parasite of animals that causes zoonotic disease in humans. Three clonal variants predominate in North America and Europe, while South American strains are genetically diverse, and undergo more frequent recombination. All three northern clonal variants share a monomorphic version of chromosome Ia (ChrIa), which is also found in unrelated, but successful southern lineages. Although this pattern could reflect a selective advantage, it might also arise from non-Mendelian segregation during meiosis. To understand the inheritance of ChrIa, we performed a genetic cross between the northern clonal type 2 ME49 strain and a divergent southern type 10 strain called VAND, which harbors a divergent ChrIa. NextGen sequencing of haploid F1 progeny was used to generate a genetic map revealing a low level of conventional recombination, with an unexpectedly high frequency of short, double crossovers. Notably, both the monomorphic and divergent versions of ChrIa were isolated with equal frequency. As well, ChrIa showed no evidence of being a sex chromosome, of harboring an inversion, or distorting patterns of segregation. Although VAND was unable to self fertilize in the cat, it underwent successful out-crossing with ME49 and hybrid survival was strongly associated with inheritance of ChrIII from ME49 and ChrIb from VAND. Our findings suggest that the successful spread of the monomorphic ChrIa in the wild has not been driven by meiotic drive or related processes, but rather is due to a fitness advantage. As well, the high frequency of short double crossovers is expected to greatly increase genetic diversity among progeny from genetic crosses, thereby providing an unexpected and likely important source of diversity.


Tonotopic organization of the auditory cortex: pitch versus frequency representation.
According to the place principles of the classical hearing theory, the physical entity frequency is encoded in the auditory periphery as place information (tonotopic representation), which is decoded in more central parts of the auditory system to form the subjective entity pitch. However, this relation is true only for pure-tone signals (spectral pitch); it can be quite different in the case of complex auditory stimuli (virtual pitch), thus requiring a multistage process for pitch formation. Neuromagnetic measurements showed that the tonotopic organization of the primary auditory cortex reflects the pitch rather than the frequency of the stimulus; that is, the pitch formation process must take place in subcortical regions.


Temporal stability and moderating effects of age and sex on CNTRaCS task performance.
Research in schizophrenia has increasingly focused on incorporating measures from cognitive neuroscience, but little is known about their psychometric characteristics. Here, we extend prior research by reporting on temporal stability, as well as age and sex effects, for cognitive neuroscience paradigms optimized as part of the Cognitive Neuroscience Test Reliability and Clinical applications for Schizophrenia consortium. Ninety-nine outpatients with schizophrenia and 131 healthy controls performed 5 tasks assessing 4 constructs at 3 sessions. The constructs were (1) Goal maintenance (Dot Probe Expectancy [DPX] and AX continuous performance tasks [AX-CPT]); (2) Episodic memory (Relational and Item-Specific Encoding and Retrieval task [RiSE]); (3) Visual integration (Jittered Orientation Visual Integration task [JOVI]); and (4) Perceptual gain control (Contrast-Contrast Effect Task [CCE]). Patients performed worse than controls on all but the CCE, and the magnitude of these group differences was stable across sessions, with no sex differences observed. Improvements over sessions were seen for the AX-CPT, the DPX, and the JOVI though practice effects for the AX-CPT and the DPX were primarily present in older participants. For the AX-CPT and the JOVI, practice effects were larger for T1 to T2 than for T2 to T3. Age was associated with poor associative recognition on the RiSE and accuracy on the JOVI. Test-rest reliability ranged from poor for the JOVI threshold score to adequate to good for the DPX, AX-CPT, and JOVI accuracy measures, with RiSE and CCE measures in the moderate range. These results suggest that group differences in DPX, AX-CPT, RiSE, and JOVI are robust and consistent across repeated testing.


Efficient CdSe quantum dot-sensitized solar cells prepared by an improved successive ionic layer adsorption and reaction process.
In pursuit of efficient quantum dot (QD)-sensitized solar cells based on mesoporous TiO(2) photoanodes, a new procedure for preparing selenide (Se(2-)) was developed and used for depositing CdSe QDs in situ over TiO(2) mesopores by the successive ionic layer adsorption and reaction (SILAR) process in ethanol. The sizes and density of CdSe QDs over TiO(2) were controlled by the number of SILAR cycles applied. After some optimization of these QD-sensitized TiO(2) films in regenerative photoelectrochemical cells using a cobalt redox couple [Co(o-phen)(3)(2+/3+)], including addition of a final layer of CdTe, over 4% overall efficiencies were achieved at 100 W/m(2) with about 50% IPCE at its maximum. Light-harvesting properties and transient voltage decay/impedance measurements confirmed that CdTe-terminated CdSe QD cells gave better charge-collection efficiencies and kinetic parameters than corresponding CdSe QD cells. In a preliminary study, a CdSe(Te) QD-sensitized TiO(2) film was combined with an organic hole conductor, spiro-OMeTAD, and shown to exhibit a promising efficiency of 1.6% at 100 W/m(2) in inorganic/organic hybrid all-solid-state cells.


Isolation of Streptococcus thoraltensis from rabbit faeces.
Bacteria were isolated from rabbit faeces using equine caecal fluid as a growth medium. Two new isolates of the genus Streptococcus are described in terms of their biochemical properties. One of these has a 16S rRNA gene with 97.7%, and the other 98.5%, identity to Streptococcus thoraltensis. While S. thoraltensis has been described in the intestinal tract of pigs, it is generally considered to inhabit the porcine genital tract. The biochemical properties of these bacteria indicate that both new isolates showed an ability to digest xylose, an adaptation beneficial for survival in a niche where much of the nutrient supply is of plant origin. Moreover, having bacteria able to digest xylose in the digestive tract should be beneficial to the rabbit, allowing more effective utilisation and digestion of food. This work provides one of the few examples of an analysis of the physiological properties of a bacterium found in the hindgut of the rabbit. By building up a number of such studies, the mechanisms of bacterial digestion in the rabbit will become better understood.


The ward round--patient experiences and barriers to participation.
Patients' participation is essential to their well-being and sense of coherence, as well as to their understanding of and adherence to prescribed treatments. Ward rounds serve as a forum for sharing information between patient and caregiver. The purpose of the ward round is to obtain information and plan medical and nursing care through staff-patient communication. The aim and objective of this study was to investigate patients' experiences during the ward round and their ability to participate in their care. The study was qualitative and descriptive in design. Fourteen inpatients at a cardiovascular ward were interviewed. Qualitative content analysis was used for the analysis. The ethics of scientific work were adhered to. Each study participant gave his/her informed consent based on verbal and written information. The study was approved by the Research Ethics Committee at Uppsala University. The analysis revealed one theme and three subthemes related to patients' experiences of ward rounds. The main theme was handling of information from the daily ward round while waiting for private consultation. The subthemes were making the best of the short time spent on ward rounds; encountering traditional roles and taking comfort in staff competency; and being able to choose the degree to which one participates in the decision-making process. Several aspects of traditional ward round routines could be improved in regard to the two-way information exchange process between caregivers and patient. Patients' and caregivers' ability to communicate their goals and the environment in which the communication occurs are of great importance. The information provided by nurses is easier to understand than that provided by physicians. The atmosphere must be open; the patient should be treated with empathy by staff; and patients' right to participate must be acknowledged by all healthcare professionals involved.


The crashing patient: hemodynamic collapse.
Rapid restoration of tissue perfusion and oxygenation are the main goals in the resuscitation of a patient with circulatory collapse. This review will focus on providing an evidence based framework of the technological and conceptual advances in the evaluation and management of the patient with cardiovascular collapse. The initial approach to the patient in cardiovascular collapse continues to be based on the Ventilate-Infuse-Pump rule. Point of care ultrasound is the preferred modality for the initial evaluation of undifferentiated shock, providing information to narrow the differential diagnosis, to assess fluid responsiveness and to evaluate the response to therapy. After the initial phase of resuscitative fluid administration, which focuses on re-establishing a mean arterial pressure to 65 mmHg, the use of dynamic parameters to assess preload responsiveness such as the passive leg raise test, stroke volume variation, pulse pressure variation and collapsibility of the inferior vena cava in mechanically ventilated patients is recommended. The crashing patient remains a clinical challenge. Using an integrated approach with bedside ultrasound, dynamic parameters for the evaluation of fluid responsiveness and surrogates of evaluation of tissue perfusion have made the assessment of the patient in shock faster, safer and more physiologic.


The acyltransferase gene bus-1 exhibits conserved and specific expression in nematode rectal cells and reveals pathogen-induced cell swelling.
Susceptibility to the rectal pathogen Microbacterium nematophilum provides a means of examining hindgut differentiation in C. elegans. Mutants of bus-1 are resistant to infection with this pathogen. We show here that bus-1 encodes a predicted acyltransferase expressed in rectal epithelial cells (K, F, and U), suggesting its involvement in regional surface modification. bus-1 reporter genes were used to show spatial regulation by hindgut developmental control genes: egl-38, mab-9, and mab-23. A bus-1::GFP reporter reveals the conspicuous rectal epithelial swelling induced by M. nematophilum. The C. briggsae ortholog of bus-1 exhibits conserved function and rectal expression, but it is expressed in vulval as well as rectal cells, correlated with pathogen adhesion to both vulval and rectal cells in this species. Another acyltransferase affecting bacterial adhesion, bus-18/acl-10, was also identified, which also shows strong rectal expression, but it is expressed in additional epithelial tissues and is required for general surface integrity.


Early cost-utility estimation of the surgical correction of pectus excavatum with the Nuss bar.
The surgical correction of pectus excavatum (PE) with a Nuss bar provides satisfactory outcomes, but its cost-effectiveness is yet unproven. We prospectively analysed early outcomes and costs for Nuss bar placement. Fifty-four patients aged 16 years or older (6 females and 48 males; mean age, 17.9 years; range 16.0-29.4 years) with a PE filled out a Short Form-36 Health Survey (SF-6D) preoperatively and 1 year after a Nuss procedure. Costs included professional fees and fees for the operating room, materials and hospital care. Changes in the responses to the SF-36 or its domains were compared using the Wilcoxon signed rank test and the utility test results were calculated preoperatively and postoperatively from the SF-6D. The quality-adjusted life years (QALYs) were calculated from the results of these tests. Significant improvements in physical functioning, social functioning, mental health and health transition (all P < 0.05) were noted. The other SF-36 subgroups showed improvement; however, the improvement was not significant. The SF-6D utility showed improvement from 0.76 preoperatively to 0.79 at the 1-year follow-up (P = 0.096). The mean direct costs were €8805. The 1-year discounted QALY gain was 0.03. The estimated cost-utility ratio was €293 500 per QALY gained. Despite a significant improvement in many domains of the SF-36, the results of the SF-6D cost-utility analysis showed only a small improvement in cost-effectiveness (> €80 000/QALY) for patients with PE 1 year after Nuss bar placement. Based on this discrepancy, general health outcome measurements as the basis for cost-utility analysis in patients with PE may not be the best way forward.


Simultaneous Bilateral Anterior and Posterior Lenticonus in Alport Syndrome.
Alport syndrome is an inherited disease characterized by progressive renal failure, hearing loss, and ocular abnormalities like anterior lenticonus, corneal opacities, cataract, central perimacular and peripheral coalescing fleck retinopathies, and temporal retinal thinning. Although anterior lenticonus is common in Alport syndrome, simultaneous anterior and posterior lenticonus is a rare presentation. We report a case of a 22-year-old female with simultaneous anterior and posterior lenticonus presentation in which ocular examination lead to the detection of Alport syndrome. The patient had sensorineural deafness as well as microscopic haematuria. Clear lens extraction was performed in both eyes to eliminate lenticular irregular astigmatism for visual rehabilitation.


Surface antigens of Toxoplasma gondii: variations on a theme.
Toxoplasma gondii is an obligate intracellular protozoan parasite with an exceptionally broad host range. Recently, it has become apparent that the number of surface antigens (SAGs) it expresses may rival the number of genera it can infect. Most of these antigens belong to the developmentally regulated and distantly related SAG1 or SAG2 families. The genes encoding the surface antigens are distributed throughout the T. gondii genome, with remarkably little polymorphism observed at each locus. Results from a number of studies have suggested that the surface antigens play an important role in the biology of the parasite. For example, SAG3 null mutants generated by targeted disruption provide convincing evidence that this surface antigen, at least, functions during parasite attachment. Analyses of a SAG1 knockout in rodents, however, indicate that this surface antigen may play a crucial role in immune modulation or virulence attenuation. The current understanding of the SAG1 and SAG2 families will be discussed here.


Inhibitory effect of glycyrrhizin on the in vitro infectivity and cytopathic activity of the human immunodeficiency virus [HIV (HTLV-III/LAV)].
Glycyrrhizin (GL), one of the plant extracts, was investigated for its antiviral action on the human immunodeficiency virus [HIV (HTLV-III/LAV)] in vitro, using cytopathic effect and plaque forming assay system in MT-4 cells (a HTLV-I-carrying cell line). Cloned Molt-4 cells (clone No. 8), which are sensitive to HIV and fuse to giant cells after infection, were also used as a parameter for cytopathic effect of HIV. GL completely inhibited HIV-induced plaque formation in MT-4 cells at a concentration of 0.6 mM, the 50% inhibitory dose being 0.15 mM. GL completely inhibited the cytopathic effect of HIV and the HIV-specific antigen expression in MT-4 cells at a concentration of 0.3 and 0.6 mM, respectively. Furthermore, GL inhibited giant cell formation of HIV-infected Molt-4 clone No. 8 cells. GL had no direct effect on the reverse transcriptase of HIV. Its mechanism of anti-HIV action remains to be elucidated.


Virtual Touch™ Quantification to Diagnose and Monitor Liver Fibrosis in Hepatitis B and Hepatitis C: A NICE Medical Technology Guidance.
Virtual Touch™ Quantification (VTq) is a software application used with Siemens Acuson ultrasound scanners to assess the stiffness of liver tissue. The National Institute for Health and Care Excellence (NICE) Medical Technologies Advisory Committee (MTAC) selected VTq for evaluation and invited the company to submit clinical and economic evidence. King's Technology Evaluation Centre, an External Assessment Centre (EAC) commissioned by NICE, independently assessed the evidence submitted. The EAC conducted its own systematic review, meta-analysis and economic analysis to supplement the company's submitted evidence. The meta-analyses comparing VTq and transient elastography (TE) with liver biopsy (LB) provided pooled estimates of liver stiffness and stage of fibrosis for the study populations (hepatitis B, hepatitis C or combined populations). When comparing significant fibrosis (Metavir score F ≥ 2) for both hepatitis B and C, VTq had slightly higher values for both sensitivity and specificity (77 and 81 %) than TE (76 and 71 %). The overall prevalence of cirrhosis (F4, combined populations) was similar with VTq and TE (23 vs. 23 %), and significant fibrosis (F ≥ 2) was lower for VTq than for TE (55 vs. 62 %). The EAC revised the company's de novo cost model, which resulted in a cost saving of £53 (against TE) and £434 (against LB). Following public consultation, taking into account submitted comments, NICE Medical Technology Guidance MTG27 was published in September 2015. This recommended the adoption of the VTq software to diagnose and monitor liver fibrosis in patients with hepatitis B or hepatitis C.


Episodes of opposing survival and reproductive selection cause strong fluctuating selection on seasonal migration versus residence.
Quantifying temporal variation in sex-specific selection on key ecologically relevant traits, and quantifying how such variation arises through synergistic or opposing components of survival and reproductive selection, is central to understanding eco-evolutionary dynamics, but rarely achieved. Seasonal migration versus residence is one key trait that directly shapes spatio-seasonal population dynamics in spatially and temporally varying environments, but temporal dynamics of sex-specific selection have not been fully quantified. We fitted multi-event capture-recapture models to year-round ring resightings and breeding success data from partially migratory European shags (Phalacrocorax aristotelis) to quantify temporal variation in annual sex-specific selection on seasonal migration versus residence arising through adult survival, reproduction and the combination of both (i.e. annual fitness). We demonstrate episodes of strong and strongly fluctuating selection through annual fitness that were broadly synchronized across females and males. These overall fluctuations arose because strong reproductive selection against migration in several years contrasted with strong survival selection against residence in years with extreme climatic events. These results indicate how substantial phenotypic and genetic variation in migration versus residence could be maintained, and highlight that biologically important fluctuations in selection may not be detected unless both survival selection and reproductive selection are appropriately quantified and combined.


Graphene nanofillers as a player to improve the dynamic compressive response and failure behavior of carbon/epoxy composite.
Vast research has been going on to improve the mechanical performance of carbon fiber reinforced polymers composite (CFRP) when subjected to quasi-static loading but investigation and modification of their dynamic behavior are still underdeveloped. This paper presents an experimental investigation on the effect of randomly dispersed graphene nanoplatelets (GNPs) on the mechanical properties of CFRP composites under dynamic loading. Four different mass fractions of GNPs, 0%, 0.5%, 1%, and 2%, were considered in the experiments. Specimens were tested experimentally using the split Hopkinson pressure bar device (SHPB) to examine their dynamic response and damage behavior at high strain rates. During the dynamic compression tests, a high-speed camera was used to monitor and record the damage kinetics. The experimental characterization showed that the integration of GNPs has greatly influenced the dynamic response and damage mechanism of the CFRP. Composite doped with 1% GNPs demonstrates the optimum enhancement of the mechanical properties of the composite specimens and shows an increase of the dynamic characteristics and fracture resistance.


Changes in platelet function, hemostasis, and prostaglandin expression after treatment with nonsteroidal anti-inflammatory drugs with various cyclooxygenase selectivities in dogs.
To determine the effects of nonsteroidal anti-inflammatory drugs of various cyclooxygenase selectivities on hemostasis and prostaglandin expression in dogs. 8 client-owned dogs with clinical signs of osteoarthritis. Dogs received aspirin (5 mg/kg, PO, q 12 h), carprofen (4 mg/kg, PO, q 24 h), deracoxib (2 mg/kg, PO, q 24 h), and meloxicam (0.1 mg/kg, PO, q 24 h) for 10 days each, with an interval of at least 14 days between treatments. On days 0 and 10, blood was collected for platelet aggregation assays, thrombelastography, and measurement of lipopolysaccharide-stimulated prostaglandin E(2), platelet thromboxane B(2) (TXB(2)), and free serum TXB(2) and 6-keto-prostaglandin F (PGF)-1alpha concentrations. Platelet aggregation decreased after treatment with aspirin and carprofen, whereas significant changes from baseline were not detected for the other drugs tested. Thrombelastograms obtained after treatment with carprofen revealed decreased maximum amplitude and alpha-angle, suggesting hypocoagulability. Maximum amplitude and coagulation index increased after treatment with deracoxib. Plasma concentrations of prostaglandin E(2) decreased after treatment with carprofen or deracoxib, and platelet TXB(2) production increased after treatment with aspirin. Serum concentrations of the prostacyclin metabolite 6-keto-PGF-1alpha did not change significantly after treatment with any of the drugs, although the ratio of free TXB(2) to 6-keto-PGF-1alpha decreased slightly after treatment with carprofen and increased slightly after treatment with deracoxib. At the dosages tested, treatment with meloxicam affected platelet function minimally in dogs with osteoarthritis. Treatment with carprofen decreased clot strength and platelet aggregation. Clot strength was increased after treatment with deracoxib.


Point source exposure of cattle to Neospora caninum consistent with periods of common housing and feeding and related to the introduction of a dog.
Eight dairy herds with evidence of post-natal transmission of Neospora caninum were used to test the hypothesis of a point source exposure by a retrospective analysis of the housing and feeding of infected age-groups. The first N. caninum-associated abortion or birth of N. caninum-seropositive offspring from the post-natally infected age-group was considered as the first indication of the infection. In seven of the eight dairy herds, a point source exposure to N. caninum of the infected age-groups was found during a limited period of common housing and feeding. In all herds studied, the analysis indicated that the cattle had been infected shortly before the first abortions occurred. In all, except one herd, the post-natal infection was more directly related to housing than to feeding. Therefore, it appeared that the feed was contaminated in the feeding alley. In one herd, the total mixed ration was found to be the probable path of infection. In all farms studied, a new dog (young, adult dog or litter) had been introduced within a period of 1.5 years prior to the first indication of N. caninum infection in the cattle. As there was evidence in all herds of vertical transmission of neosporosis for years, it is hypothesized that the newly introduced dog was infected with N. caninum by materials from already infected cattle and subsequently transmitted the infection to other cattle by shedding of oocysts.


Malaria increased the risk of stunting and wasting among young children in Ethiopia: Results of a cohort study.
Given the high prevalence of malnutrition in a malaria-endemic setting, improving nutritional status could serve as a tool to prevent malaria. However, the relationship between the two conditions remains unclear. Therefore, this study assessed the association between under-nutrition and malaria among a cohort of children aged 6 to 59 months old. Two cohorts of children were followed for 89 weeks in a rural Rift Valley area of Ethiopia. In the first approach (malaria-malnutrition), a cohort of 2,330 non-stunted and 4,204 non-wasted children were included to assess under-nutrition (outcome) based on their previous malaria status (exposure). In the second approach (malnutrition-malaria), a cohort of 4,468 children were followed-up to measure malaria (outcome), taking under-nutrition as an exposure. A weekly home visit was carried out to identify malaria cases. Four anthropometry surveys were conducted, and generalized estimating equation (GEE) method was used to measure the association between undernutrition and malaria. The prevalence of stunting was 44.9% in December 2014, 51.5% in August 2015, 50.7% in December 2015 and 48.1% in August 2016. We observed 103 cases with 118 episodes of malaria, 684 new stunting and 239 new wasting cases. The incidence rate per 10,000 weeks of observation was 3.8 for malaria, 50.4 for stunting and 8.2 for wasting. Children with malaria infection, [Adjusted Odds Ratio (AOR) = 1.9; 95% Confidence Interval (CI), 1.2-2.9)] and younger age (AOR = 1.3; 95% CI, 1.1-1.5) were more likely to be stunted. Furthermore, children with malaria infection (AOR = 8.5; 95% CI, 5.0-14.5) and young age group (AOR = 1.6; 95% CI, 1.2-2.1) were more likely to be wasted. However, stunting and wasting were not risk factors of subsequent malaria illness. Malaria infection was a risk factor for stunting and wasting, but stunting or wasting was not associated with subsequent malaria illness. As our study shows that malaria is a risk factor for stunting and wasting, a close follow-up of the nutritional status of such children may be needed. PACT R2014 11000 882128 (8 September 2014).


Functional connectivity map of retinal ganglion cells for retinal prosthesis.
Retinal prostheses are being developed to restore vision for the blind with retinal diseases such as retinitis pigmentosa (RP) or age-related macular degeneration (AMD). Among the many issues for prosthesis development, stimulation encoding strategy is one of the most essential electrophysiological issues. The more we understand the retinal circuitry how it encodes and processes visual information, the greater it could help decide stimulation encoding strategy for retinal prosthesis. Therefore, we examined how retinal ganglion cells (RGCs) in in-vitro retinal preparation act together to encode a visual scene with multielectrode array (MEA). Simultaneous recording of many RGCs with MEA showed that nearby neurons often fired synchronously, with spike delays mostly within 1 ms range. This synchronized firing - narrow correlation - was blocked by gap junction blocker, heptanol, but not by glutamatergic synapse blocker, kynurenic acid. By tracking down all the RGC pairs which showed narrow correlation, we could harvest 40 functional connectivity maps of RGCs which showed the cell cluster firing together. We suggest that finding functional connectivity map would be useful in stimulation encoding strategy for the retinal prosthesis since stimulating the cluster of RGCs would be more efficient than separately stimulating each individual RGC.


Chronic Voluntary Alcohol Drinking Causes Anxiety-like Behavior, Thiamine Deficiency, and Brain Damage of Female Crossed High Alcohol Preferring Mice.
The central nervous system is vulnerable to chronic alcohol abuse, and alcohol dependence is a chronically relapsing disorder which causes a variety of physical and mental disorders. Appropriate animal models are important for investigating the underlying cellular and molecular mechanisms. The crossed High Alcohol Preferring mice prefer alcohol to water when given free access. In the present study, we used female cHAP mice as a model of chronic voluntary drinking to evaluate the effects of alcohol on neurobehavioral and neuropathological changes. The female cHAP mice had free-choice access to 10% ethanol and water, while control mice had access to water alone at the age of 60-day-old. The mice were exposed to alcohol for 7 months then subjected to neurobehavioral tests including open field (OF), elevated plus maze (EPM), and Morris water maze (MWM). Results from OF and EPM tests suggested that chronic voluntary drinking caused anxiety-like behaviors. After behavior tests, mice were sacrificed, and brain tissues were processed for biochemical analyses. Alcohol altered the levels of several neurotransmitters and neurotrophic factors in the brain including gamma-Aminobutyric acid (GABA), corticotropin-releasing factor, cAMP response element-binding protein (CREB) and brain-derived neurotrophic factor. Alcohol increased the expression of neuroinflammation markers including interleukin-6 (IL-6), tumor necrosis factor alpha (TNF-α), monocyte chemoattractant protein-1 (MCP-1) and C-C chemokine receptor 2 (CCR2). Alcohol also induced cleaved caspase-3 and glial fibrillary acidic protein, indicative of neurodegeneration and gliosis. In addition, alcohol inhibited the expression of thiamine transporters in the brain and reduced thiamine levels in the blood. Alcohol also caused oxidative stress and endoplasmic reticulum (ER) stress, and stimulated neurogenesis.


Mutations affecting the development of the embryonic zebrafish brain.
In a large scale mutagenesis screen for embryonic mutants in zebrafish, we have identified 63 mutations in 24 loci affecting the morphogenesis of the zebrafish brain. The expression of marker genes and the integrity of the axonal scaffold have been studied to investigate abnormalities in regionalization, neurogenesis and axonogenesis in the brain. Mutants can be broadly classified into two groups, one affecting regionalization along the anterior-posterior or dorsal-ventral axis, and the other affecting general features of brain morphology. The first group includes one locus that is required to generate the anlage of the midbrain-hindbrain boundary region at the beginning of somitogenesis. Four loci were identified that affect dorsal-ventral patterning of the brain, including the previously described cyclops locus. Mutant embryos of this class show a reduction of ventral neuroectodermal structures and variable fusion of the eyes. The second group includes a large class of mutations affecting the formation of brain ventricles. Analysis of this class reveals the requirement of a functional cardiovascular system for ventricle enlargement during embryogenesis. Mutations in one locus lead to the formation of supernumerary primary neurons, a phenotype reminiscent of neurogenic mutants in Drosophila. Other mutant phenotypes described here range from abnormalities in the fasciculation and outgrowth of axons to defects in the diameter of the neural tube. The identified loci establish the genetic foundation for a further analysis of the development of the zebrafish embryonic brain.


The signaling pathway of Campylobacter jejuni-induced Cdc42 activation: Role of fibronectin, integrin beta1, tyrosine kinases and guanine exchange factor Vav2.
Host cell invasion by the foodborne pathogen Campylobacter jejuni is considered as one of the primary reasons of gut tissue damage, however, mechanisms and key factors involved in this process are widely unclear. It was reported that small Rho GTPases, including Cdc42, are activated and play a role during invasion, but the involved signaling cascades remained unknown. Here we utilised knockout cell lines derived from fibronectin-/-, integrin-beta1-/-, focal adhesion kinase (FAK)-/- and Src/Yes/Fyn-/- deficient mice, and wild-type control cells, to investigate C. jejuni-induced mechanisms leading to Cdc42 activation and bacterial uptake. Using high-resolution scanning electron microscopy, GTPase pulldowns, G-Lisa and gentamicin protection assays we found that each studied host factor is necessary for induction of Cdc42-GTP and efficient invasion. Interestingly, filopodia formation and associated membrane dynamics linked to invasion were only seen during infection of wild-type but not in knockout cells. Infection of cells stably expressing integrin-beta1 variants with well-known defects in fibronectin fibril formation or FAK signaling also exhibited severe deficiencies in Cdc42 activation and bacterial invasion. We further demonstrated that infection of wild-type cells induces increasing amounts of phosphorylated FAK and growth factor receptors (EGFR and PDGFR) during the course of infection, correlating with accumulating Cdc42-GTP levels and C. jejuni invasion over time. In studies using pharmacological inhibitors, silencing RNA (siRNA) and dominant-negative expression constructs, EGFR, PDGFR and PI3-kinase appeared to represent other crucial components upstream of Cdc42 and invasion. siRNA and the use of Vav1/2-/- knockout cells further showed that the guanine exchange factor Vav2 is required for Cdc42 activation and maximal bacterial invasion. Overexpression of certain mutant constructs indicated that Vav2 is a linker molecule between Cdc42 and activated EGFR/PDGFR/PI3-kinase. Using C. jejuni mutant strains we further demonstrated that the fibronectin-binding protein CadF and intact flagella are involved in Cdc42-GTP induction, indicating that the bacteria may directly target the fibronectin/integrin complex for inducing signaling leading to its host cell entry. Collectively, our findings led us propose that C. jejuni infection triggers a novel fibronectin→integrin-beta1→FAK/Src→EGFR/PDGFR→PI3-kinase→Vav2 signaling cascade, which plays a crucial role for Cdc42 GTPase activity associated with filopodia formation and enhances bacterial invasion.


The implications of maternal grandmother coresidence and involvement for adolescent adjustment in South Africa.
Maternal grandmothers residing in 3-generation households often provide care and support to their grandchildren. However, the implications of grandmother coresidence and involvement for adolescent adjustment have been neglected in the South African literature. This study examined whether the involvement of maternal grandmothers who coreside with grandchildren and their parents differed from that of non-coresident grandmothers. In addition, we assessed the associations between maternal grandmother coresidence and involvement, and adolescents' internalising problems, externalising problems and prosocial behaviour. Self-report survey data were obtained from a sample of 384 "coloured" (mixed-race) and black African Grade 8 and Grade 9 students in Cape Town. The mean age of the participants was 13.96 years, 58% were females and 27% lived in 3-generation households. Results indicated that there was no significant difference in the involvement of coresident and non-coresident grandmothers, and that adolescents in 3-generation and 2-generation households displayed similar levels of adjustment. Hierarchical multiple regression analyses revealed that greater maternal grandmother involvement was associated with more adolescent prosocial behaviour (p < .001) regardless of household structure, and with fewer adolescent internalising problems in 3-generation households (p = .03). Findings underscore the need to move beyond the immediate family to consider how grandparents may influence adolescent development.


Concurrent and prospective associations between HPA axis activity and depression symptoms in newlywed women.
We investigated the extent to which individual differences in activity of the hypothalamic pituitary adrenal axis (HPA) are associated with depressive symptoms among newlywed couples. Participants were 218 couples (M age 28.4 years; 94% White) who provided 5 saliva samples (later assayed for cortisol and DHEA-S) before and after participation in a discussion of a major area of disagreement in their relationship. Depressive symptoms were assessed initially, and approximately 19- and 37-months later. Results revealed an interactive effect suggesting that concordant levels of cortisol and DHEA-S (either both high or both low) were concurrently and prospectively associated with higher depression scores. Interestingly, this interactive effect was observed for wives only - not for husbands. These observations underscore contemporary theoretical assumptions that the expression of the association between HPA activity and depression is dependent on factors related to the interaction between characteristics of the person and features of the social environment, and moderated by co-occurring variation in endocrine milieu.


A sequence in subdomain 2 of DBL1α of Plasmodium falciparum erythrocyte membrane protein 1 induces strain transcending antibodies.
Immunity to severe malaria is the first level of immunity acquired to Plasmodium falciparum. Antibodies to the variant antigen PfEMP1 (P. falciparum erythrocyte membrane protein 1) present at the surface of the parasitized red blood cell (pRBC) confer protection by blocking microvascular sequestration. Here we have generated antibodies to peptide sequences of subdomain 2 of PfEMP1-DBL1α previously identified to be associated with severe or mild malaria. A set of sera generated to the amino acid sequence KLQTLTLHQVREYWWALNRKEVWKA, containing the motif ALNRKE, stained the live pRBC. 50% of parasites tested (7/14) were positive both in flow cytometry and immunofluorescence assays with live pRBCs including both laboratory strains and in vitro adapted clinical isolates. Antibodies that reacted selectively with the sequence REYWWALNRKEVWKA in a 15-mer peptide array of DBL1α-domains were also found to react with the pRBC surface. By utilizing a peptide array to map the binding properties of the elicited anti-DBL1α antibodies, the amino acids WxxNRx were found essential for antibody binding. Complementary experiments using 135 degenerate RDSM peptide sequences obtained from 93 Ugandan patient-isolates showed that antibody binding occurred when the amino acids WxLNRKE/D were present in the peptide. The data suggests that the ALNRKE sequence motif, associated with severe malaria, induces strain-transcending antibodies that react with the pRBC surface.


Headache in stroke.
The etiology of headache in stroke is not known, and its relation to migraine and tension-type headache is unclear. The aim of our study was to investigate and classify headache appearing in stroke patients prospectively, using the new headache classification as determined by the Headache Classification Committee of the International Headache Society (1988). Two hundred eighty consecutively admitted patients aged younger than 81 years with acute stroke were examined and questioned about headache and prior headache complaints; 238 (85%) were able to communicate. Sixty-five (27%) of the 238 patients experienced headache from 3 days before to 3 days after stroke. Headache occurred in 50% of patients with intracerebral hemorrhage, in 26% with infarction, and in 15% of patients with lacunar infarction. Headache was more common when stroke occurred in posterior circulation than anterior circulation (P < .02). Fifty-six patients were able to give further information about headache characteristics. The headache in thromboembolic stroke was classified as tension-type headache (25 patients), migraine-like headache (14 patients), and other headache (12 patients). Migraine was more frequent in vertebrobasilar stroke. Headache was lateralized in 33% of cases. In patients with unilateral headache and unilateral stroke lesion, the headache was ipsilateral in 14 of 17 cases. In infarction, severity of headache showed no relation to lesion size or lesion localization. Patients with previous tension-type headache and migraine experienced reactivation of known headache equally often. (1) Headache occurs in one fourth of patients with acute stroke. (2) Unilateral headache is usually ipsilateral to stroke lesion. (3) Headache severity is not related to size of ischemic stroke lesion.


Simulation of chemical metabolism for fate and hazard assessment. I: approach for simulating metabolism.
Information regarding the metabolism of xenobiotic chemicals plays a central role in regulatory risk assessments. In regulatory programmes where metabolism studies are required, the studies of metabolic pathways are often incomplete and the identification of activated metabolites and important degradation products are limited by analytical methods. Because so many more new chemicals are being produced than can be assessed for potential hazards, setting assessment priorities among the thousands of untested chemicals requires methods for predictive hazard identification which can be derived directly from chemical structure and their likely metabolites. In a series of papers we are sharing our experience in the computerized management of metabolic data and the development of simulators of metabolism for predicting the environmental fate and (eco)toxicity of chemicals. The first paper of the series presents a knowledge-based formalism for the computer simulation of non-intermediary metabolism for untested chemicals, with an emphasis on qualitative and quantitative aspects of modelling metabolism.


Racial-ethnic variations in paid and unpaid caregiving: Findings among persons with traumatic spinal cord injury.
The effects of race-ethnicity on the use of paid and unpaid caregivers for those with spinal cord injury (SCI) have received little attention in the literature. Compare the amount of paid and unpaid caregiver hours received and sources of caregiving between non-Hispanic White and non-Hispanic Black participants with SCI, controlling for demographic, injury-related, and economic variables. Participants were identified from a large specialty hospital. Self-report data were collected by mail. Five aspects of caregiving were assessed: (a) paid assistance hours, (b) satisfaction with care, (c) unpaid assistance hours, (d) sources of informal care, and (e) evaluation of whether needs were met. Whites were more satisfied with paid care. Approximately 43.4% of Whites received informal care from their spouse every day, 14.7% higher than Blacks. Blacks were more likely to receive informal care from other family members, friends, church, and others. When controlling for gender, injury severity, chronological age, and years post injury, Blacks reported 1.50 more paid assistance hours (95% CI, 0.31-2.68 hours) and 1.83 less unpaid assistance hours than Whites (95% CI, 0.25-3.41 hours). Differences diminished and were not statistically significant after adding marital status and income into regression models. The results did not provide strong evidence of racial disparities regarding caregiver assistance for those with SCI. Level of income appears to be directly related to satisfaction of quality caregiving and the use of paid versus unpaid care for those living with SCI.


Relationship of partially purified factor concentrates to immune tests and AIDS. The Hemophilia-AIDS. Collaborative Study Group.
We evaluated those members of a cohort of 203 hemophilic men providing all necessary information at their 1984 and 1985 evaluations, to determine whether non-heated or less than 80 degrees C dry heat-treated partially purified factor products were associated with 1) the development of AIDS in human immunodeficiency virus (HIV)-infected persons or 2) abnormal immune test results in participants seroconverting or remaining HIV seronegative. We found no relationship between type of factor (VIII vs. IX) (n = 162), frequency of usage (greater than or equal to once a week vs. less than once a week) (n = 141) or yearly doses of non-heated or dry heat-treated partially purified factor (n = 118) and the development of AIDS. Seroconverting participants using partially purified factor products greater than or equal to once a week in 1984 had lower T-helper cell numbers in 1985 than those receiving factor less frequently (median 515 vs. 772/mm3, n = 9), as did those using factor greater than or equal to once a week in 1985 (median 515 vs. 726/mm3, n = 10). A similar relation was seen between 1984 frequency and 1985 T-helper cell numbers of seronegative participants (median 741 vs. 1037/mm3, n = 31). The yearly dose of heat-treated products was not associated with any immune test result or changes in results between years. These findings suggested that frequency of administration of partially purified factor materials may have had an effect upon the immune system, but that total yearly dose did not. Previously used partly purified, dry heat-treated factor concentrates were not associated with the development of AIDS.


Detection of DNA abnormalities by arbitrarily primed PCR fingerprinting: amplification of the MDM2 gene in a mediastinum fibrosarcoma.
Arbitrarily primed PCR (AP-PCR) fingerprinting method is easy and useful for analysis of genetic alterations in anonymous chromosomal regions. We applied this technology to analysis of DNA from human primary cancers and found amplification of a DNA fragment in a mediastinum fibrosarcoma. PCR-based analysis of radiation hybrid panels following cloning and nucleotide sequence determination of the fragment revealed that it was derived from a region of chromosome 12q13-q15. In this region, the MDM2 and IFNG genes were noted as known genes that could be involved in human carcinogenesis. Southern blot analysis of genomic DNA of the tumor revealed the amplification of the MDM2 gene together with the fragment locus, but not the IFNG gene. Our results demonstrated that detection of DNA alterations by AP-PCR fingerprinting without any previous knowledge of the genes and subsequent analysis of radiation hybrid panels could lead to easy identification of candidates for genes involved in carcinogenesis.


"The opening of the mouth"--a new perspective for an ancient Egyptian mummification procedure.
"The opening of the mouth ritual" (OMR) is a central and well-documented component of the Ancient Egyptian mortuary ceremony. In the scientific literature, we find various references that indicate that parts of this ritual correspond to physical opening of the deceased's mouth during its mummification. We denote this physical treatment of the dead the "opening of the mouth procedure," to underline the distinction against the "opening of the mouth ritual," which is performed ceremonially later on the mummy or even the statue. The mummifying procedure itself however is known only from rare pictorial representations and the later summary descriptions of Greek authors. Nevertheless, recently some authors tried, on the basis of paleopathological findings, to demonstrate that the mouth of the deceased had to be opened physically before mummifying. Careful examination of the mummies of the Swiss Mummy Project and other cases reported in the literature showed frequent dental pathologies including fractured and totally luxated teeth, which were up to now not sufficiently taken into consideration. The detailed report of the preliminary procedures of mummifying the Apis bull-as appropriate detailed descriptions for humans are missing-gives us insight into the treatment of the oral cavity. Our results, when combined with the available historical literature, indicate that the OMR can be regarded as a ritualized counterpart of a real "opening of mouth procedure" during mummification.


Are electrostatic potentials between regions of different chemical composition measurable? The Gibbs-Guggenheim Principle reconsidered, extended and its consequences revisited.
As indicated by Gibbs and made explicit by Guggenheim, the electrical potential difference between two regions of different chemical composition cannot be measured. The Gibbs-Guggenheim Principle restricts the use of classical electrostatics in electrochemical theories as thermodynamically unsound with some few approximate exceptions, notably for dilute electrolyte solutions and concomitant low potentials where the linear limit for the exponential of the relevant Boltzmann distribution applies. The Principle invalidates the widespread use of forms of the Poisson-Boltzmann equation which do not include the non-electrostatic components of the chemical potentials of the ions. From a thermodynamic analysis of the parallel plate electrical condenser, employing only measurable electrical quantities and taking into account the chemical potentials of the components of the dielectric and their adsorption at the surfaces of the condenser plates, an experimental procedure to provide exceptions to the Principle has been proposed. This procedure is now reconsidered and rejected. No other related experimental procedures circumvent the Principle. Widely-used theoretical descriptions of electrolyte solutions, charged surfaces and colloid dispersions which neglect the Principle are briefly discussed. MD methods avoid the limitations of the Poisson-Bolzmann equation. Theoretical models which include the non-electrostatic components of the inter-ion and ion-surface interactions in solutions and colloid systems assume the additivity of dispersion and electrostatic forces. An experimental procedure to test this assumption is identified from the thermodynamics of condensers at microscopic plate separations. The available experimental data from Kelvin probe studies are preliminary, but tend against additivity. A corollary to the Gibbs-Guggenheim Principle is enunciated, and the Principle is restated that for any charged species, neither the difference in electrostatic potential nor the sum of the differences in the non-electrostatic components of the thermodynamic potential difference between regions of different chemical compositions can be measured.


Polygenicity and Epistasis Underlie Fitness-Proximal Traits in the Caenorhabditis elegans Multiparental Experimental Evolution (CeMEE) Panel.
Understanding the genetic basis of complex traits remains a major challenge in biology. Polygenicity, phenotypic plasticity, and epistasis contribute to phenotypic variance in ways that are rarely clear. This uncertainty can be problematic for estimating heritability, for predicting individual phenotypes from genomic data, and for parameterizing models of phenotypic evolution. Here, we report an advanced recombinant inbred line (RIL) quantitative trait locus mapping panel for the hermaphroditic nematode Caenorhabditis elegans, the C. elegans multiparental experimental evolution (CeMEE) panel. The CeMEE panel, comprising 507 RILs at present, was created by hybridization of 16 wild isolates, experimental evolution for 140-190 generations, and inbreeding by selfing for 13-16 generations. The panel contains 22% of single-nucleotide polymorphisms known to segregate in natural populations, and complements existing C. elegans mapping resources by providing fine resolution and high nucleotide diversity across > 95% of the genome. We apply it to study the genetic basis of two fitness components, fertility and hermaphrodite body size at time of reproduction, with high broad-sense heritability in the CeMEE. While simulations show that we should detect common alleles with additive effects as small as 5%, at gene-level resolution, the genetic architectures of these traits do not feature such alleles. We instead find that a significant fraction of trait variance, approaching 40% for fertility, can be explained by sign epistasis with main effects below the detection limit. In congruence, phenotype prediction from genomic similarity, while generally poor ([Formula: see text]), requires modeling epistasis for optimal accuracy, with most variance attributed to the rapidly evolving chromosome arms.


Coxarthrosis and physical work load.
A case-referent study was performed on the possible relationship between physical work loads and an increased risk of developing coxarthrosis. The cases were 239 male recipients of a hip prosthesis as a result of severe idiopathic coxarthrosis; the referents were 302 men randomly selected from the general population. The work load was assessed through an interview and a self-administered questionnaire on the men's specific work periods. Men highly exposed to dynamic or static work loads had an increased relative risk of 2.42 (95% confidence interval 1.45-4.04) for developing coxarthrosis when compared with men with low exposure. Men with high exposure to heavy lifting between the ages of 30 and 49 years had the highest relative risk, 3.31 (95% confidence interval 1.97-5.57). Long-time exposure to physical work loads seems to be a risk factor for severe coxarthrosis among men.


Case report of paediatric oxalate urolithiasis and a review of enteric hyperoxaluria.
The formation of renal calculi secondary to enteric hyperoxaluria is rare in the paediatric population. We present the case of an 8-year-old boy who had short bowel syndrome resulting in enteric hyperoxaluria which led to the development of urolithiasis and bilateral ureteric strictures, both of which resolved with medical management. We also review the literature on enteric hyperoxaluria.


The study of human Y chromosome variation through ancient DNA.
High throughput sequencing methods have completely transformed the study of human Y chromosome variation by offering a genome-scale view on genetic variation retrieved from ancient human remains in context of a growing number of high coverage whole Y chromosome sequence data from living populations from across the world. The ancient Y chromosome sequences are providing us the first exciting glimpses into the past variation of male-specific compartment of the genome and the opportunity to evaluate models based on previously made inferences from patterns of genetic variation in living populations. Analyses of the ancient Y chromosome sequences are challenging not only because of issues generally related to ancient DNA work, such as DNA damage-induced mutations and low content of endogenous DNA in most human remains, but also because of specific properties of the Y chromosome, such as its highly repetitive nature and high homology with the X chromosome. Shotgun sequencing of uniquely mapping regions of the Y chromosomes to sufficiently high coverage is still challenging and costly in poorly preserved samples. To increase the coverage of specific target SNPs capture-based methods have been developed and used in recent years to generate Y chromosome sequence data from hundreds of prehistoric skeletal remains. Besides the prospects of testing directly as how much genetic change in a given time period has accompanied changes in material culture the sequencing of ancient Y chromosomes allows us also to better understand the rate at which mutations accumulate and get fixed over time. This review considers genome-scale evidence on ancient Y chromosome diversity that has recently started to accumulate in geographic areas favourable to DNA preservation. More specifically the review focuses on examples of regional continuity and change of the Y chromosome haplogroups in North Eurasia and in the New World.


Early Intravascular Events Are Associated with Development of Acute Respiratory Distress Syndrome. A Substudy of the LIPS-A Clinical Trial.
Acute respiratory distress syndrome (ARDS) is a devastating illness with limited therapeutic options. A better understanding of early biochemical and immunological events in ARDS could inform the development of new preventive and treatment strategies. To determine select peripheral blood lipid mediator and leukocyte responses in patients at risk for ARDS. Patients at risk for ARDS were randomized as part of a multicenter, double-blind clinical trial of aspirin versus placebo (the LIPS-A [Lung Injury Prevention Study with Aspirin] trial; NCT01504867). Plasma thromboxane B2 (TXB2), aspirin-triggered lipoxin A4 (15-epi-LXA4, ATL), and peripheral blood leukocyte number and activation were determined on enrollment and after treatment with either aspirin or placebo. Thirty-three of 367 subjects (9.0%) developed ARDS after randomization. Baseline ATL levels, total monocyte counts, intermediate monocyte counts, and monocyte-platelet aggregates were associated with the development of ARDS. Peripheral blood neutrophil count and monocyte-platelet aggregates significantly decreased over time. Of note, nine subjects developed ARDS after randomization yet before study drug initiation, including seven subjects assigned to aspirin treatment. Subjects without ARDS at the time of first dose demonstrated a lower incidence of ARDS with aspirin treatment. Compared with placebo, aspirin significantly decreased TXB2 and increased the ATL/TXB2 ratio. Biomarkers of intravascular monocyte activation in at-risk patients were associated with development of ARDS. The potential clinical benefit of early aspirin for prevention of ARDS remains uncertain. Together, results of the biochemical and immunological analyses provide a window into the early pathogenesis of human ARDS and represent potential vascular biomarkers of ARDS risk. Clinical trial registered with www.clinicaltrials.gov (NCT01504867).


Cardiopulmonary exercise testing to detect chronic thromboembolic pulmonary hypertension in patients with normal echocardiography.
Chronic thromboembolic pulmonary hypertension (CTEPH) is a serious complication of pulmonary embolism (PE). Taking into account the reported incidence of CTEPH after acute PE, the number of patients with undiagnosed CTEPH may be high. We aimed to determine if cardiopulmonary exercise testing (CPET) could serve as complementary tool in the diagnosis of CTEPH and can detect CTEPH in patients with normal echocardiography. At diagnosis, we analyzed the data of CPET parameters in 42 patients with proven CTEPH and 51 controls, and evaluated the performance of two scores. VE/VCO2 slope, EQO2, EQCO2, P(A-a)O2, end-tidal partial pressure of CO2 at anaerobic threshold (PETCO2) and capillary to end-tidal carbon dioxide gradient [P(c-ET)CO2] were significantly different between patients with CTEPH and controls (p < 0.001). P(c-ET)CO2 was the single parameter with the highest sensitivity (85.7%) and specificity (88.2%). A score combining VE/VCO2 slope, P(A-a)O2, P(c-ET)CO2, PETCO2 [4-parameter-CPET (4-P-CPET) score] reached a sensitivity of 83.3% and a specificity of 92.2% after cross-validation. In 42 patients with CTEPH, echocardiography identified PH in 29 patients (69%), but it was normal in 13 patients (31%). All patients with normal or unmeasurable right ventricular systolic pressure had a pathological CPET. Twelve of the 13 patients (92%) were detected by both CPET scores. CPET is a useful noninvasive diagnostic tool for the detection of CTEPH in patients with suspected PH but normal echocardiography. The 4-P-CPET score provides a high sensitivity with the highest specificity.


The emerging genetic and molecular basis of Fanconi anaemia.
The past few years have witnessed a considerable expansion in our understanding of the pathways that maintain chromosome stability in dividing cells through the identification of genes that are mutated in certain human chromosome instability disorders. Cells that are derived from patients with Fanconi anaemia (FA) show spontaneous chromosomal instability and mutagen hypersensitivity, but FA poses a unique challenge as the nature of the DNA-damage-response pathway thought to be affected by the disease has long been a mystery. However, the recent cloning of most of the FA-associated genes, and the characterization of their protein products, has provided tantalizing clues as to the molecular basis of this disease.


Induction of Drosophila eye development by decapentaplegic.
The Drosophila decapentaplegic (dpp) gene, encoding a secreted protein of the transforming growth factor-beta (TGF-beta) superfamily, controls proliferation and patterning in diverse tissues, including the eye imaginal disc. Pattern formation in this tissue is initiated at the posterior edge and moves anteriorly as a wave; the front of this wave is called the morphogenetic furrow (MF). Dpp is required for proliferation and initiation of pattern formation at the posterior edge of the eye disc. It has also been suggested that Dpp is the principal mediator of Hedgehog function in driving progression of the MF across the disc. In this paper, ectopic Dpp expression is shown to be sufficient to induce a duplicated eye disc with normal shape, MF progression, neuronal cluster formation and direction of axon outgrowth. Induction of ectopic eye development occurs preferentially along the anterior margin of the eye disc. Ectopic Dpp clones situated away from the margins induce neither proliferation nor patterning. The Dpp signalling pathway is shown to be under tight transcriptional and post-transcriptional control within different spatial domains in the developing eye disc. In addition, Dpp positively controls its own expression and suppresses wingless transcription. In contrast to the wing disc, Dpp does not appear to be the principal mediator of Hedgehog function in the eye.


Frequent detection of human papilloma viruses in cervical dysplasia by PCR single-strand DNA-conformational polymorphism analysis.
To clarify the pathogenicity of multiple human papilloma virus (HPV) infection, we applied SSCP (single-strand DNA conformation polymorphism) analysis for cervical neoplastic lesions. Two hundred and sixty-six cervical swab specimens from normal cervix (n=64), cervical dysplasia (n=95), carcinoma in situ (n=79) and cervical cancer (n=28), were studied by nested PCR-SSCP analysis using L1 consensus primers. In 95 samples of cervical dysplasia, HPV infection was detected in 98.9% (94 out of 95), multiple HPV infection was detected in 38.3% (36 out of 94). In 19 squamous cell carcinomas (SCC) and 9 adenocarcinomas, the detection rate of HPV infection was 84.2% (16 out of 19) and 55.6% (5 out of 9), respectively, and all HPV-positive cases showed infection of a single HPV, among which HPV 16 occupied 68.6% (11 out of 16) in SCC and HPV 18 occupied 100% (5 out of 5) in adenocarcinoma. Multiple HPV infections may be concerned with pathogenicity in cervical dysplasia; however, the single infection with only a few HPV types, such as type 16 in SCC and type 18 in adenocarcinoma, may play a role in cervical carcinogenesis.


The functional range of motion of the finger joints.
The purpose of this study was to measure the functional range of motion of the finger joints needed to perform activities of daily living. Using the Sollerman hand grip function test, 20 activities were assessed in ten volunteers. The active and passive range of motion was measured with a computerized electric goniometer. The position of each finger joint was evaluated in the pre-grasp and grasp positions. The functional range of motion was defined as the range required to perform 90% of the activities, utilizing the pre-grasp and grasp measurements. The functional range of motion was 19°-71°, 23°-87°, and 10°-64° at the metacarpophalangeal, proximal interphalangeal, and distal interphalangeal joints, respectively. This represents 48%, 59%, and 60% of the active motion of these joints, respectively. There was a significant difference in the functional range of motion between the joints of the fingers, with the ulnar digits having greater active and functional range. The functional range of motion is important for directing indications for surgery and rehabilitation, and assessing outcome of treatment.


Mother-to-child transmission of human immunodeficiency virus type 1 in relation to the season in Yaounde, Cameroon.
A public health program to prevent mother-to-child transmission (MTCT) of human immunodeficiency virus type 1 (HIV-1) by treatment with nevirapine has been ongoing in Yaounde, Cameroon since January 2000. After 24 months, plasma samples from 119 children born to HIV-1-positive mothers were tested for HIV-1 RNA between six and eight weeks after birth. Thirteen (10.9%) tested positive (95% confidence interval = 5.2-16.7%). Risk factors associated with MTCT in this study were maternal viral load (P < 0.05), low birth weight (chi2 for trend = 8.78, P = 0.01), and birth during the second half of the year. A high correlation was repeatedly observed between rainfall in a given month and the risk of MTCT of HIV-1 in children born three months later (r = 0.634, P < 0.001). Although we cannot rule out other tropical infections related to the rainy season, the role of malaria is highly suspected since the interval of three months we observed between the peaks of rainfall and the rate of transmission is consistent with the Plasmodium life cycle.


Dynamic changes of the ecological environment quality in a river basin: a case study of the main stream of Songhua river basin.
This paper reports the investigation and analysis of the status and dynamic changes of ecological environment quality in the main stream of Songhua river basin. The evaluation index system was established and the eco-environment quality in the year of 2000 and 2008 was studied in depth. Based on our research, the trend of dynamic changes of the eco-environment quality and its origins have been further discussed: In the year of 2000, the range of evaluation index covered from 0.31 to 0.47. Harbin and Yichun was relatively better than the rest of study areas. In the year of 2008, except districts of Daqing and Qitaihe, the environmental quality of Songhua river basin has entirely improved, wherein the evaluation index of the eco-environment covered from 0.31 to 0.57. Particularly, the eco-environment quality of Hegang and Shuangyashan has obtained significant improvement, whereas the improvement of Jiamusi was not obvious. According to the evaluation results, the environmental quality in the study area has an upward trend with the average growth rate 0.13% per year.


Prostate Cancer Nonascitic Peritoneal Carcinomatosis After Robot-assisted Laparoscopic Radical Prostatectomy: 3 Case Reports and Review of the Literature.
Robot-assisted laparoscopic radical prostatectomy is one of the treatment options for localized prostate cancer, with an excellent disease control rate. However, these patients can experience late disease recurrence with metastatic dissemination. Peritoneal metastases are an uncommon recurrence site. Here, we discuss 3 cases of peritoneal metastases following robot-assisted laparoscopic radical prostatectomy and the mechanisms of peritoneal invasion. Through a literature review and our case reports, we postulate the existence of 2 distinct mechanisms of peritoneal invasion: one being iatrogenic, following a laparoscopic surgery with a well differentiated prostate cancer at a nonadvanced stage of the disease, the other involving the natural course of poor-prognosis tumors, even without surgery.


Adenosine-mediated cardioprotection in the aging myocardium.
With aging, it appears the heart's ability to withstand injury declines markedly. Unfortunately, the incidence of ischemic disorders increases dramatically with age. Though the genesis of the ischemia-intolerant phenotype is incompletely understood (and likely multi-factorial), it may involve changes in intrinsic cardioprotective responses. In this respect we and others have interrogated the role of the adenosine receptor (AR) system in dictating ischemic tolerance and the impact of age on AR-mediated cardioprotection. It is intriguing to note ARs impact on many processes implicated in myocardial 'aging': adenosine counters Ca2+ influx and oxidant injury, modifies substrate metabolism to improve tolerance, is pro-angiogenic, inhibits myocardial fibrosis, and can limit apoptosis. Thus, dysregulation of the AR system could contribute to many features of aged hearts (including ischemic intolerance). The latter is borne out by observations that AR-mediated protective responses decline with intrinsic tolerance and that transgenic manipulation of the AR system restores intrinsic tolerance and protective responses in aged hearts. Mechanisms underlying failure in adenosinergic protection remain undefined. Here we review data on the effects of aging on cardiovascular AR transcription and expression, generation of signal (adenosine formation), and protective signaling coupled to ARs.


Possible role of gap junctions in activation of myometrium during parturition.
Gap junctions between smooth muscle cells of the myometrium of pregnant rats were found only immediately prior to, during and immediately after parturition by quantitative thin-section and freeze-fracture microscopy. Ovariectomy of 16- to 17-days-pregnant rats resulted in premature termination of pregnancy and the appearance of gap junctions. Methods that prolonged normal pregnancy in rats or maintained pregnancy in ovariectomized animals (progesterone treatment) prevented the appearance of gap junctions. Gap junctions formed in tissues incubated for 24--96 h in vitro without any hormonal influence. We propose that gap junctions are essential for normal labor and delivery for synchronous contraction of the muscle of the uterus. We present a model for control of parturition that may apply to other animals including humans. The model proposes: 1) the possible roles progesterone, prostaglandins, or estrogens may play in initiating gap-junction formation; 2) that the formation of gap junctions is a necessary step in activation of the myometrium leading to labor; and 3) that agents used to stimulate or inhibit labor may do so by affecting gap junctions.


Detecting sarcasm from paralinguistic cues: anatomic and cognitive correlates in neurodegenerative disease.
While sarcasm can be conveyed solely through contextual cues such as counterfactual or echoic statements, face-to-face sarcastic speech may be characterized by specific paralinguistic features that alert the listener to interpret the utterance as ironic or critical, even in the absence of contextual information. We investigated the neuroanatomy underlying failure to understand sarcasm from dynamic vocal and facial paralinguistic cues. Ninety subjects (20 frontotemporal dementia, 11 semantic dementia [SemD], 4 progressive non-fluent aphasia, 27 Alzheimer's disease, 6 corticobasal degeneration, 9 progressive supranuclear palsy, 13 healthy older controls) were tested using the Social Inference - Minimal subtest of The Awareness of Social Inference Test (TASIT). Subjects watched brief videos depicting sincere or sarcastic communication and answered yes-no questions about the speaker's intended meaning. All groups interpreted Sincere (SIN) items normally, and only the SemD group was impaired on the Simple Sarcasm (SSR) condition. Patients failing the SSR performed more poorly on dynamic emotion recognition tasks and had more neuropsychiatric disturbances, but had better verbal and visuospatial working memory than patients who comprehended sarcasm. Voxel-based morphometry analysis of SSR scores in SPM5 demonstrated that poorer sarcasm comprehension was predicted by smaller volume in bilateral posterior parahippocampi (PHc), temporal poles, and R medial frontal pole (pFWE<0.05). This study provides lesion data suggesting that the PHc may be involved in recognizing a paralinguistic speech profile as abnormal, leading to interpretive processing by the temporal poles and right medial frontal pole that identifies the social context as sarcastic, and recognizes the speaker's paradoxical intentions.


Examining the association between genetic liability for schizophrenia and psychotic symptoms in Alzheimer's disease.
Psychosis (delusions or hallucinations) in Alzheimer's disease (AD + P) occurs in up to 50% of individuals and is associated with significantly worse clinical outcomes. Atypical antipsychotics, first developed for schizophrenia, are commonly used in AD + P, suggesting shared mechanisms. Despite this implication, little empirical research has been conducted to examine whether there are mechanistic similarities between AD + P and schizophrenia. In this study, we tested whether polygenic risk score (PRS) for schizophrenia was associated with AD + P. Schizophrenia PRS was calculated using Psychiatric Genomics Consortium data at ten GWAS p value thresholds (PT) in 3111 AD cases from 11 cohort studies characterized for psychosis using validated, standardized tools. Association between PRS and AD + P status was tested by logistic regression in each cohort individually and the results meta-analyzed. The schizophrenia PRS was associated with AD + P at an optimum PT of 0.01. The strongest association was for delusions where a one standard deviation increase in PRS was associated with a 1.18-fold increased risk (95% CI: 1.06-1.3; p = 0.001). These new findings point towards psychosis in AD-and particularly delusions-sharing some genetic liability with schizophrenia and support a transdiagnostic view of psychotic symptoms across the lifespan.


Genomicus: a database and a browser to study gene synteny in modern and ancestral genomes.
Comparative genomics remains a pivotal strategy to study the evolution of gene organization, and this primacy is reinforced by the growing number of full genome sequences available in public repositories. Despite this growth, bioinformatic tools available to visualize and compare genomes and to infer evolutionary events remain restricted to two or three genomes at a time, thus limiting the breadth and the nature of the question that can be investigated. Here we present Genomicus, a new synteny browser that can represent and compare unlimited numbers of genomes in a broad phylogenetic view. In addition, Genomicus includes reconstructed ancestral gene organization, thus greatly facilitating the interpretation of the data. Genomicus is freely available for online use at http://www.dyogen.ens.fr/genomicus while data can be downloaded at ftp://ftp.biologie.ens.fr/pub/dyogen/genomicus.


Risk factors for readmission and revision surgery following rotator cuff repair.
Risk factors for revision surgery and hospitalization following rotator cuff repair (RCR) have not been clearly identified. We hypothesized patient factors and surgeon and hospital volume independently contribute to the risk of readmission within 90 days and revision RCR within one year. Using the SPARCS database, we included patients undergoing primary RCR in New York State between 1997 and 2002. These patients were tracked for readmission within 90 days and revision RCR within 1 year. A generalized estimating equation was developed to determine whether patient factors, surgeon volume, or hospital volume were independent risk factors for the above outcome measures. The total annual number of RCR increased from 6,656 in 1997 to 10,128 in 2002. Ambulatory cases increased from 57% to 82% during this time period. Independent risk factors for readmission within 90 days included increasing age and increased number of comorbidities. Independent risk factors for revision RCR included increasing age, increased comorbidity, and lower surgeon volume. Hospital volume had a minimal effect on either outcome measure. The shift toward out-patient surgery mirrors the shift from open to arthroscopic rotator cuff repair. The finding that surgeon volume is a predictor of revision RCR reflects the findings in other orthopaedic procedures.


Non-linear adaptive controllers for an over-actuated pneumatic MR-compatible stepper.
Pneumatics is one of the few actuation principles that can be used in an MR environment, since it can produce high forces without affecting imaging quality. However, pneumatic control is challenging, due to the air high compliance and cylinders non-linearities. Furthermore, the system's properties may change for each subject. Here, we present novel control strategies that adapt to the subject's individual anatomy and needs while performing accurate periodic gait-like movements with an MRI compatible pneumatically driven robot. In subject-passive mode, an iterative learning controller (ILC) was implemented to reduce the system's periodic disturbances. To allow the subjects to intend the task by themselves, a zero-force controller minimized the interaction forces between subject and robot. To assist patients who may be too weak, an assist-as-needed controller that adapts the assistance based on online measurement of the subject's performance was designed. The controllers were experimentally tested. The ILC successfully learned to reduce the variability and tracking errors. The zero-force controller allowed subjects to step in a transparent environment. The assist-as-needed controller adapted the assistance based on individual needs, while still challenged the subjects to perform the task. The presented controllers can provide accurate pneumatic control in MR environments to allow assessments of brain activation.


Practical implications of nanodosimetry in medicine.
The grandiose promises made decades ago of cost reduction, miracle cures for cancers and universal availability of nanomedicine are still a far cry. Even we do not have any viable model to exploit nanotechnology in medicine. The most important arena of the nanotechnology is the development of nanoscale drugs for routine clinical practice. The current chemo protocols are based on maximum tolerable dose philosophy. Such a dose, when translated into active nanoscale clusters, quantitatively outnumbers the cells in an average human body. These nanoscale drug issues are discussed in this paper. A theoretical framework for commonly used drug aspirin has been considered as an example. The possible quantum physical effects have also been theoretically evaluated. Further, the amount of drug molecules in a standardized aspirin dose of 100 milligram has been computed into nanoclusters. The calculations show that the processing of nanoscale drug is a monumental task which requires new types of manufacturing facilities. Also there is a need to develop new protocols which will help realize the practical implementation of nanodosimetry in day to day drug administrations. These protocols will need to examine the implications of dose-responses such as necrosis, apoptosis and hormesis in medicine for routine clinical practice.


Correlation between amino acid residues converted by RNA editing and functional residues in protein three-dimensional structures in plant organelles.
In plant organelles, specific messenger RNAs (mRNAs) are subjected to conversion editing, a process that often converts the first or second nucleotide of a codon and hence the encoded amino acid. No systematic patterns in converted sites were found on mRNAs, and the converted sites rarely encoded residues located at the active sites of proteins. The role and origin of RNA editing in plant organelles remain to be elucidated. Here we study the relationship between amino acid residues encoded by edited codons and the structural characteristics of these residues within proteins, e.g., in protein-protein interfaces, elements of secondary structure, or protein structural cores. We find that the residues encoded by edited codons are significantly biased toward involvement in helices and protein structural cores. RNA editing can convert codons for hydrophilic to hydrophobic amino acids. Hence, only the edited form of an mRNA can be translated into a polypeptide with helix-preferring and core-forming residues at the appropriate positions, which is often required for a protein to form a functional three-dimensional (3D) structure. We have performed a novel analysis of the location of residues affected by RNA editing in proteins in plant organelles. This study documents that RNA editing sites are often found in positions important for 3D structure formation. Without RNA editing, protein folding will not occur properly, thus affecting gene expression. We suggest that RNA editing may have conferring evolutionary advantage by acting as a mechanism to reduce susceptibility to DNA damage by allowing the increase in GC content in DNA while maintaining RNA codons essential to encode residues required for protein folding and activity.


Cardiorespiratory coupling in preterm infants.
In preterm infants, a better understanding and quantification of cardiorespiratory coupling may help improve caregiving by enabling the tracking of maturational changes and subclinical signatures of disease. Therefore, in a study of 20 preterm infants admitted to a neonatal intensive care unit, we analyzed the cardiac and respiratory regulatory mechanisms as well as the coupling between them. In particular, we selectively analyzed coupling from changes in heart rate to respiratory oscillations as well as coupling from respiratory oscillations to the heart rate. Furthermore, we stratified this coupling based on decelerations and accelerations of the heart rate and by inspiration and expiration during respiration while contrasting periods of kangaroo care, an intervention known to enhance autonomic regulation, with periods in the incubator. We identified that preterm infants exhibit cardiorespiratory coupling that is nonsymmetric with regard to the direction of coupling. We demonstrate coupling from decelerations and accelerations of the heart rate to exhalation and inhalation, respectively, both on a beat-to-beat basis as well as with sustained decelerations and accelerations. On the other hand, on average, we also observed coupling from both inspiration and expiration to marginal decelerations in the heart rate. These phenomena, especially coupling from the changes in the heart rate to respiratory oscillations, were sensitive to whether the infant was receiving kangaroo care. NEW & NOTEWORTHY Preterm infants exhibit cardiorespiratory coupling that is nonsymmetric with regard to the direction of coupling; coupling from fluctuations in the heart rate to respiratory oscillations and vice versa are asymmetric. On average, coupling is observable from decelerations or accelerations in the heart rate to inhalation or exhalation, respectively, whereas, on average, both peaks and troughs of respiration exhibit coupling to marginal decelerations in the heart rate.


Programmed DNA deletion as an RNA-guided system of genome defense.
Genomewide DNA rearrangements occur in many eukaryotes during development, but their functions and mechanisms are poorly understood. Previous studies have implicated a sequence-recognition mechanism based on RNA-mediated interactions between nuclei in ciliated protozoa. In this study, we found that the process recognized and deleted a foreign gene integrated in a Tetrahymena chromosome, suggesting an unusual mechanism of genome surveillance. We further found that injection of double-stranded RNA into the cell at specific developmental stages triggers efficient deletion of the targeted genomic regions. Together the results indicate an RNA-based mechanism that directs genomewide DNA rearrangements and serves to disable invading genetic agents.


Estrogen and the Ca2+-mobilizing agonist ATP evoke acute NO synthesis via distinct pathways in an individual human vascular endothelium-derived cell.
In this study, we have systematically evaluated the signaling mechanisms underlying stimulated nitric oxide (NO) synthesis by estrogen (E2) and other vasoactive agents at the level of a single endothelium-derived cell. To do so, we have characterized and contrasted rapid E2-evoked NO synthesis with that of ATP using single-cell microfluorimetry and patch-clamp recordings to monitor stimulated changes in cellular NO synthesis (via 4-amino-5-methylamino-2',7'-difluorofluorescein), Ca2+ transients (via Fluo-3), and membrane hyperpolarization in cultured human EA.hy926 cells. E2-evoked NO synthesis in single cells (EC50 approximately 0.3 nM) was blocked by the E2 receptor antagonist ICI 182,780 and the NO synthase inhibitor N(omega)-nitro-l-arginine methyl ester. Although both E2 and ATP stimulated comparable Ca2+ transients, E2-induced NO synthesis was insensitive to intracellular BAPTA-AM or removal of external Ca2+. In contrast, ATP-evoked NO production was abolished by either one of these treatments. ATP-evoked hyperpolarizations ( approximately 20 mV) and NO production were both inhibited by the respective small-conductance and intermediate-conductance calcium- activated K+ channel blockers apamin and charybdotoxin. E2 minimally affected membrane potential, and stimulated NO synthesis was insensitive to calcium-activated K+ channel blockers. Exposure to either the phosphatidylinositol 3-kinase inhibitor LY-294002 or the MAP kinase inhibitor PD-98059 abolished the NO response to E2, but not that to ATP. Finally, the NO response evoked by a combined stimulus of E2 plus ATP was similar to that of ATP alone. In conclusion, our data directly demonstrate that an individual human EA.hy926 cell contains at least two distinct mechanisms for stimulated NO synthesis that depend on either calcium or protein kinase signaling events.


Carcinoma of the pancreatic head and periampullary region. Tumor staging with laparoscopy and laparoscopic ultrasonography.
The authors performed a prospective evaluation of staging laparoscopy with laparoscopic ultrasonography in predicting surgical resectability in patients with carcinomas of the pancreatic head and periampullary region. Pancreatic resection with curative intent is possible in a select minority of patients who have carcinomas of the pancreatic head and periampullary region. Patient selection is important to plan appropriate therapy and avoid unnecessary laparotomy in patients with unresectable disease. Laparoscopic ultrasonography is a novel technique that combines the proven benefits of staging laparoscopy with high resolution intraoperative ultrasound of the liver and pancreas, but which has yet to be evaluated critically in the staging of pancreatic malignancy. A cohort of 40 consecutive patients referred to a tertiary referral center and with a diagnosis of potentially resectable pancreatic or periampullary cancer underwent staging laparoscopy with laparoscopic ultrasonography. The diagnostic accuracy of staging laparoscopy alone and in conjunction with laparoscopic ultrasonography was evaluated in predicting tumor resectability (absence of peritoneal or liver metastases; absence of malignant regional lymphadenopathy; tumor confined to pancreatic head or periampullary region). "Occult" metastatic lesions were demonstrated by staging laparoscopy in 14 patients (35%). Laparoscopic ultrasonography demonstrated factors confirming unresectable tumor in 23 patients (59%), provided staging information in addition to that of laparoscopy alone in 20 patients (53%), and changed the decision regarding tumor resectability in 10 patients (25%). Staging laparoscopy with laparoscopic ultrasonography was more specific and accurate in predicting tumor resectability than laparoscopy alone (88% and 89% versus 50% and 65%, respectively). Staging laparoscopy is indispensable in the detection of "occult" intra-abdominal metastases. Laparoscopic ultrasonography improves the accuracy of laparoscopic staging in patients with potentially resectable pancreatic and periampullary carcinomas.


Factors Influencing Uptake of Changes to Clinical Preventive Guidelines.
Despite widespread recognition that adherence to clinical preventive guidelines improves patient outcomes, clinicians struggle to implement guideline changes in a timely manner. Multiple factors influence guideline adoption and effective implementation. However, few studies evaluate their collective and inter-related effects. This qualitative study provides a comprehensive picture of the interplay between multiple factors on uptake of new or changed preventive guidelines. Semistructured interviews conducted in 2018 with a diverse sample of clinicians and practice leaders sought to understand patient, clinician, practice, health system, environment, and guideline factors of influence. An immersion-crystallization approach was used to identify emergent themes. Interviewees expressed motivation to adhere to guidelines but also valued sharing decisions with patients. Personal biases and fears affected both clinician and patient guideline adoption. Practices facilitated implementation through workflow optimization and encouraging a culture of evidence-based practice while a key health system function was to maintain electronic health record alerts. More traditional environmental factors, such as insurance coverage or transportation, were less of a barrier to guideline adoption and implementation than the influence of media and specialists. Various specific guideline characteristics also affected ease of adoption and implementation. Different settings expressed greater health system, practice, or clinician-centric approaches to guideline implementation. Guideline uptake is influenced by a complex interplay of multiple levels of factors including the patient, clinician, practice, health system, environment, and guideline levels. Comprehensively understanding all levels of influence for each specific clinical setting may help to determine the optimal intervention(s) for improving uptake of evidence-based guidelines.


In vitro chondrogenic commitment of human Wharton's jelly stem cells by co-culture with human articular chondrocytes.
Wharton's jelly stem cells (WJSCs) are a potential source of transplantable stem cells in cartilage-regenerative strategies, due to their highly proliferative and multilineage differentiation capacity. We hypothesized that a non-direct co-culture system with human articular chondrocytes (hACs) could enhance the potential chondrogenic phenotype of hWJSCs during the expansion phase compared to those expanded in monoculture conditions. Primary hWJSCs were cultured in the bottom of a multiwell plate separated by a porous transwell membrane insert seeded with hACs. No statistically significant differences in hWJSCs duplication number were observed under either of the culture conditions during the expansion phase. hWJSCs under co-culture conditions show upregulations of collagen type I and II, COMP, TGFβ1 and aggrecan, as well as of the main cartilage transcription factor, SOX9, when compared to those cultured in the absence of chondrocytes. Chondrogenic differentiation of hWJSCs, previously expanded in co-culture and monoculture conditions, was evaluated for each cellular passage using the micromass culture model. Cells expanded in co-culture showed higher accumulation of glycosaminoglycans (GAGs) compared to cells in monoculture, and immunohistochemistry for localization of collagen type I revealed a strong detection signal when hWJSCs were expanded under monoculture conditions. In contrast, type II collagen was detected when cells were expanded under co-culture conditions, where numerous round-shaped cell clusters were observed. Using a micromass differentiation model, hWJSCs, previously exposed to soluble factors secreted by hACs, were able to express higher levels of chondrogenic genes with deposition of cartilage extracellular matrix components, suggesting their use as an alternative cell source for treating degenerated cartilage. Copyright © 2015 John Wiley & Sons, Ltd.


Reproductive issues in the gynecologic cancer patient.
Clinicians, researchers, and survivorship communities are beginning to recognize the late effects of cancer treatment, such as infertility, and the negative impact this can have on cancer survivorship. Reproductive concerns that emerge within cancer experiences have been shown to be negatively associated with quality of life. Gynecologic cancer can present before childbearing has been started or completed, during pregnancy, or can even arise out of pregnancy, as is the case with gestational trophoblastic disease. Parenthood has been cited as an important aspect of cancer survivorship. As a result, interest concerning fertility preservation, reproductive concerns, and family-building options in cancer survivorship has increased, in addition to awareness of the emotional ramifications of cancer-related infertility. Education and support are clearly an essential component of cancer survivorship. Furthermore, more attention and investigation is still needed about the reproductive issues of gynecologic cancer survivors in the future.