Conspecific reproductive success affects age of recruitment in a great cormorant, Phalacrocorax carbo sinensis, colony.
Few studies have addressed the proximate factors affecting the age at which individuals of long-lived bird species are recruited into the breeding population. We use capture-recapture analysis of resightings of 16 birth cohorts of colour-ringed great cormorants, Phalacrocorax carbo sinensis, in a Danish colony to assess the evidence for two hypotheses: conspecific attraction (earlier recruitment when the colony is large) and conspecific reproductive success (earlier recruitment following years of high breeding success). For both males and females, conspecific reproductive success was the most important covariate explaining the interannual variation in age of recruitment; colony size was also important for females. These covariates explained nearly 60% of the year-to-year variation for both sexes. The age of recruitment increased for cohorts born after 1990, and this increase was correlated with a decline in breeding success in the colony; we interpret this as an indirect and delayed density-dependent effect. Females were recruited earlier than males (mean age of recruitment for cohorts born before 1990: 2.98 years versus 3.53 years); the most plausible reason for this is a skewed sex ratio in favour of males in the adult population. Recruitment of males may thus, to some extent, be constrained by the availability of females. This study provides the first evidence that conspecific reproductive success can affect the age at which individual birds start to breed.


A mouse model of severe von Willebrand disease: defects in hemostasis and thrombosis.
von Willebrand factor (vWf) deficiency causes severe von Willebrand disease in humans. We generated a mouse model for this disease by using gene targeting. vWf-deficient mice appeared normal at birth; they were viable and fertile. Neither vWf nor vWf propolypeptide (von Willebrand antigen II) were detectable in plasma, platelets, or endothelial cells of the homozygous mutant mice. The mutant mice exhibited defects in hemostasis with a highly prolonged bleeding time and spontaneous bleeding events in approximately 10% of neonates. As in the human disease, the factor VIII level in these mice was reduced strongly as a result of the lack of protection provided by vWf. Defective thrombosis in mutant mice was also evident in an in vivo model of vascular injury. In this model, the exteriorized mesentery was superfused with ferric chloride and the accumulation of fluorescently labeled platelets was observed by intravital microscopy. We conclude that these mice very closely mimic severe human von Willebrand disease and will be very useful for investigating the role of vWf in normal physiology and in disease models.


Attraction of Pollinators to Atemoya (Annona squamosa × Annona cherimola) in Puerto Rico Using Commercial Lures and Food Attractants.
Atemoya is a hybrid between Annona squamosa L. and Annona cherimola Miller (Annonaceae) and has potential to be an important fruit crop in tropical and subtropical areas. A major impediment to fruit production is low fruit set due to inadequate pollinator visits, typically, by beetles in the family Nitidulidae. We used Universal moth traps to monitor the attractiveness of two commercially available Nitidulidae lures in combination with various food attractants, including raw bread dough, apple juice, and malta beverage, a soft drink by-product of the brewing process. The most commonly trapped beetles were, in order of decreasing frequency, Carpophilus dimidiatus (F.), Brachypeplus mutilatus Erichson, Urophorus humeralis (F.) (Coleoptera: Nitidulidae), and Europs fervidus Blatchley (Coleoptera: Monotomidae). All traps, except the unbaited control traps, caught beetles. In a previous study, we found that combining two commercial lures had a synergistic effect on the attraction of these beetle species. In this study, the addition of food attractants increased the number of beetles trapped compared with traps baited with only the commercial lures. Also, food attractants appear to be key in attracting U. humeralis; only one U. humeralis individual of the 206 caught during the experiment was trapped without a food attractant. The variation between the number of beetles caught in traps containing the same treatments was high and may explain the erratic results reported in other studies of pollination in Annona spp. The results are discussed with respect to the use of nitidulid lures and food attractants to increase fruit set in atemoya and other Annonaceae.


Early planarian brain regeneration is independent of blastema polarity mediated by the Wnt/β-catenin pathway.
Analysis of anteroposterior (AP) axis specification in regenerating planarian flatworms has shown that Wnt/β-catenin signaling is required for posterior specification and that the FGF-like receptor molecule nou-darake (ndk) may be involved in restricting brain regeneration to anterior regions. The relationship between re-establishment of AP identity and correct morphogenesis of the brain is, however, still poorly understood. Here we report the characterization of two axin paralogs in the planarian Schmidtea mediterranea. Although Axins are well known negative regulators of Wnt/β-catenin signaling, no role in AP specification has previously been reported for axin genes in planarians. We show that silencing of Smed-axin genes by RNA interference (RNAi) results in two-tailed planarians, a phenotype previously reported after silencing of Smed-APC-1, another β-catenin inhibitor. More strikingly, we show for the first time that while early brain formation at anterior wounds remains unaffected, subsequent development of the brain is blocked in the two-tailed planarians generated after silencing of Smed-axin genes and Smed-APC-1. These findings suggest that the mechanisms underlying early brain formation can be uncoupled from the specification of AP identity by the Wnt/β-catenin pathway. Finally, the posterior expansion of the brain observed following Smed-ndk RNAi is enhanced by silencing Smed-APC-1, revealing an indirect relationship between the FGFR/Ndk and Wnt/β-catenin signaling systems in establishing the posterior limits of brain differentiation.


The Effect of Side of Implantation on the Cortical Processing of Frequency Changes in Adult Cochlear Implant Users.
Cochlear implants (CI) are widely used in children and adults to restore hearing function. However, CI outcomes are vary widely. The affected factors have not been well understood. It is well known that the right and left hemispheres play different roles in auditory perception in adult normal hearing listeners. It is unknown how the implantation side may affect the outcomes of CIs. In this study, the effect of the implantation side on how the brain processes frequency changes within a sound was examined in 12 right-handed adult CI users. The outcomes of CIs were assessed with behaviorally measured frequency change detection threshold (FCDT), which has been reported to significantly affect CI speech performance. The brain activation and regions were also examined using acoustic change complex (ACC, a type of cortical potential evoked by acoustic changes within a stimulus), on which the waveform analysis and the standardized low-resolution brain electromagnetic tomography (sLORETA) were performed. CI users showed activation in the temporal lobe and non-temporal areas, such as the frontal lobe. Right-ear CIs could more efficiently activate the contralateral hemisphere compared to left-ear CIs. For right-ear CIs, the increased activation in the contralateral temporal lobe together with the decreased activation in the contralateral frontal lobe was correlated with good performance of frequency change detection (lower FCDTs). Such a trend was not found in left-ear CIs. These results suggest that the implantation side may significantly affect neuroplasticity patterns in adults.


GLI2 but not GLI1/GLI3 plays a central role in the induction of malignant phenotype of gallbladder cancer.
We previously reported that Hedgehog (Hh) signal was enhanced in gallbladder cancer (GBC) and was involved in the induction of malignant phenotype of GBC. In recent years, therapeutics that target Hh signaling have focused on molecules downstream of smoothened (SMO). The three transcription factors in the Hh signal pathway, glioma‑associated oncogene homolog 1 (GLI1), GLI2, and GLI3, function downstream of SMO, but their biological role in GBC remains unclear. In the present study, the biological significance of GLI1, GLI2, and GLI3 were analyzed with the aim of developing novel treatments for GBC. It was revealed that GLI2, but not GLI1 or GLI3, was involved in the cell cycle‑mediated proliferative capacity in GBC and that GLI2, but not GLI1 or GLI3, was involved in the enhanced invasive capacity through epithelial‑mesenchymal transition. Further analyses revealed that GLI2 may function in mediating gemcitabine sensitivity and that GLI2 was involved in the promotion of fibrosis in a mouse xenograft model. Immunohistochemical staining of 66 surgically resected GBC tissues revealed that GLI2‑high expression patients had fewer numbers of CD3+ and CD8+ tumor‑infiltrating lymphocytes (TILs) and increased programmed cell death ligand 1 (PD‑L1) expression in cancer cells. These results suggest that GLI2, but not GLI1 or GLI3, is involved in proliferation, invasion, fibrosis, PD‑L1 expression, and TILs in GBC and could be a novel therapeutic target. The results of this study provide a significant contribution to the development of a new treatment for refractory GBC, which has few therapeutic options.


In vivo glucoregulation and tissue-specific glucose uptake in female Akt substrate 160 kDa knockout rats.
The Rab GTPase activating protein known as Akt substrate of 160 kDa (AS160 or TBC1D4) regulates insulin-stimulated glucose uptake in skeletal muscle, the heart, and white adipose tissue (WAT). A novel rat AS160-knockout (AS160-KO) was created with CRISPR/Cas9 technology. Because female AS160-KO versus wild type (WT) rats had not been previously evaluated, the primary objective of this study was to compare female AS160-KO rats with WT controls for multiple, important metabolism-related endpoints. Body mass and composition, physical activity, and energy expenditure were not different between genotypes. AS160-KO versus WT rats were glucose intolerant based on an oral glucose tolerance test (P<0.001) and insulin resistant based on a hyperinsulinemic-euglycemic clamp (HEC; P<0.001). Tissue glucose uptake during the HEC of female AS160-KO versus WT rats was: 1) significantly lower in epitrochlearis (P<0.05) and extensor digitorum longus (EDL; P<0.01) muscles of AS160-KO compared to WT rats; 2) not different in soleus, gastrocnemius or WAT; and 3) ~3-fold greater in the heart (P<0.05). GLUT4 protein content was reduced in AS160-KO versus WT rats in the epitrochlearis (P<0.05), EDL (P<0.05), gastrocnemius (P<0.05), soleus (P<0.05), WAT (P<0.05), and the heart (P<0.005). Insulin-stimulated glucose uptake by isolated epitrochlearis and soleus muscles was lower (P<0.001) in AS160-KO versus WT rats. Akt phosphorylation of insulin-stimulated tissues was not different between the genotypes. A secondary objective was to probe processes that might account for the genotype-related increase in myocardial glucose uptake, including glucose transporter protein abundance (GLUT1, GLUT4, GLUT8, SGLT1), hexokinase II protein abundance, and stimulation of the AMP-activated protein kinase (AMPK) pathway. None of these parameters differed between genotypes. Metabolic phenotyping in the current study revealed AS160 deficiency produced a profound glucoregulatory phenotype in female AS160-KO rats that was strikingly similar to the results previously reported in male AS160-KO rats.


Germ-line gene modification and disease prevention: some medical and ethical perspectives.
There has been considerable debate about the ethics of human germ-line gene modification. As a result of recent advances in the micromanipulation of embryos and the laboratory development of transgenic mice, a lively discussion has begun concerning both the technical feasibility and the ethical acceptability of human germ-line modification for the prevention of serious disease. This article summarizes some of the recent research on germ-line gene modification in animal models. Certain monogenic deficiency diseases that ultimately might be candidates for correction by germ-line intervention are identified. Several of the most frequently considered ethical issues relative to human germ-line gene modification are considered in the context of professional ethics, parental responsibility, and public policy. Finally, it is suggested that there is merit in continuing the discussion about human germ-line intervention, so that this technique can be carefully compared with alternative strategies for preventing genetic disease.


Mdm2 haplo-insufficiency profoundly inhibits Myc-induced lymphomagenesis.
Mdm2 harnesses the p53 tumor suppressor, yet loss of one Mdm2 allele in Mdm2(+/-) mice has heretofore not been shown to impair tumor development. Here we report that Mdm2 haplo-insufficiency profoundly suppresses lymphomagenesis in E micro -myc transgenic mice. Mdm2(+/-)E micro -myc transgenics had greatly protracted rates of B cell lymphoma development with life spans twice that of wild-type transgenic littermates. Im paired lymphoma development was associated with drastic reductions in peripheral B cell numbers in Mdm2(+/-)E micro -myc transgenics, and primary pre-B cells from Mdm2(+/-)E micro -myc transgenics and Mdm2(+/-) littermates were extremely susceptible to spontaneous apoptosis. Loss of p53 rescued all of the effects of Mdm2 haplo-insufficiency, indicating they were p53 dependent. Furthermore, half of the lymphomas that ultimately emerged in Mdm2(+/-)E micro -myc transgenics harbored inactivating mutations in p53, and the majority overcame haplo-insufficiency by overexpressing Mdm2. These results support the concept that Mdm2 functions are rate limiting in lymphomagenesis and that targeting Mdm2 will enhance p53-mediated apoptosis, compromising tumor development and/or maintenance.


Prevalence study of dermatoses referred to the phototherapy unit at the Dermatology Service of the Clinics Hospital of Porto Alegre, RS, Brazil.
Phototherapy consists of exposure to ultraviolet radiation for therapeutic reasons. Radiation is already used in dermatological practice, and many studies have already proved the beneficial effect of UV light treatment for chronic inflammatory or lymphoproliferative skin diseases. The Dermatology Service of the Clinics Hospital of Porto Alegre (Hospital de Clínicas de Porto Alegre) has been using phototherapy for a long time, and no official data have been described so far. To study the prevalence of dermatoses referred to the phototherapy unit at the Clinics Hospital of Porto Alegre and describe the total number of patients who have already been referred to this sector and their phototype. This is a descriptive cross-sectional study. Data were collected through a review of the phototherapy patients' records (secondary data), which are available on a database of the Dermatology Service of the Clinics Hospital of Porto Alegre, from August 1997 to July 2011. A total of 653 records were analyzed. Phototype 3 was the most prevalent (n=313). Distribution of the prevalence of dermatoses referred to the phototherapy unit was as follows: vitiligo (279), psoriasis (255), cutaneous T-cell lymphoma/mycosis fungoides (29), graftversus-host disease (15), scleroderma (11), atopic dermatitis (10), alopecia areata (6), parapsoriasis (5), eczema (4), granuloma annulare (4), and others (35). As vitiligo and psoriasis were the two most prevalent dermatoses, they were analyzed separately, with no statistical difference in prevalence between them (P=0,177). Our findings are in accordance with the literature, showing that although phototherapy is still mostly indicated to treat psoriasis, it has been used to treat other dermatoses, since the results are promising.


Spasticity and electrophysiologic changes after extracorporeal shock wave therapy on gastrocnemius.
To evaluate the spasticity and electrophysiologic effects of applying extracorporeal shock wave therapy (ESWT) to the gastrocnemius by studying F wave and H-reflex. Ten healthy adults and 10 hemiplegic stroke patients with ankle plantarflexor spasticity received one session of ESWT on the medial head of the gastrocnemius. The modified Ashworth scale (MAS), tibial nerve conduction, F wave, and H-reflex results were measured before and immediately after the treatment. The Visual Analogue Scale (VAS) was used during ESWT to measure the side effects, such as pain. There were no significant effects of ESWT on the conduction velocity, distal latency and amplitude of tibial nerve conduction, minimal latency of tibial nerve F wave, latency, or H-M ratio of H-reflex in either the healthy or stroke group. However, the MAS of plantarflexor was significantly reduced from 2.67±1.15 to 1.22±1.03 (p<0.05) after applying ESWT in the stroke group. After applying ESWT on the gastrocnemius in stroke patients, the spasticity of the ankle plantarflexor was significantly improved, with no changes of F wave or H-reflex parameters. Further studies are needed to evaluate the mechanisms of the antispastic effect of ESWT.


Hole dynamics in a photovoltaic donor-acceptor couple revealed by simulated time-resolved X-ray absorption spectroscopy.
Theoretical and experimental methodologies that can characterize electronic and nuclear dynamics, and the coupling between the two, are needed to understand photoinduced charge transfer in molecular building blocks used in organic photovoltaics. Ongoing developments in ultrafast pump-probe techniques such as time-resolved X-ray absorption spectroscopy, using an X-ray free electron laser in combination with an ultraviolet femtosecond laser, present desirable probes of coupled electronic and nuclear dynamics. In this work, we investigate the charge transfer dynamics of a donor-acceptor pair, which is widely used as a building block in low bandgap block copolymers for organic photovoltaics. We simulate the dynamics of the benzothiadiazole-thiophene molecule upon photoionization with a vacuum ultraviolet (VUV) pulse and study the potential of probing the subsequent charge dynamics using time-resolved X-ray absorption spectroscopy. The photoinduced dynamics are calculated using on-the-fly nonadiabatic molecular dynamics simulations based on Tully's Fewest Switches Surface Hopping approach. We calculate the X-ray absorption spectrum as a function of time after ionization at the Hartree-Fock level. The changes in the time-resolved X-ray absorption spectrum at the sulfur K-edge reveal the ultrafast charge carrier dynamics in the molecule occurring on a femtosecond time scale. These theoretical findings anticipate that ultrafast time-resolved X-ray absorption spectroscopy using an X-ray probe in combination with a VUV pump offers a new approach to investigate the detailed dynamics of organic photovoltaic materials.


Small deletions in the potato leafroll virus readthrough protein affect particle morphology, aphid transmission, virus movement and accumulation.
Potato leafroll virus (PLRV) capsid comprises 180 coat protein (CP) subunits, with some percentage containing a readthrough domain (RTD) extension located on the particle's surface. The RTD N terminus is highly conserved in luteovirids and this study sought to identify biologically active sites within this region of the PLRV RTD. Fourteen three-amino-acid-deletion mutants were generated from a cloned infectious PLRV cDNA and delivered to plants by Agrobacterium inoculations. All mutant viruses accumulated locally in infiltrated tissues and expressed the readthrough protein (RTP) containing the CP and RTD sequences in plant tissues; however, when purified, only three mutant viruses incorporated the RTP into the virion. None of the mutant viruses were aphid transmissible, but the viruses persisted in aphids for a period sufficient to allow for virus transmission. Several mutant viruses were examined further for systemic infection in four host species. All mutant viruses, regardless of RTP incorporation, moved systemically in each host, although they accumulated at different rates in systemically infected tissues. The biological properties of the RTP are sensitive to modifications in both the RTD conserved and variable regions.


Generation of all-fiber optical Manchester code using nonlinear polarization rotation.
We experimentally demonstrate all-fiber optical Manchester code generation at 10 Gbit/s using nonlinear polarization rotation in a single 1- km highly-nonlinear fiber with the nonlinearity of 20.4 W-1km-1. 33-dB extinction ratio is achieved in a -4-dBm CW dummy channel by coinjecting orthogonally aligned two 8-dBm pumps into the Kerr medium. Our encoder functions with 10 Gbit/s NRZ data stream and 10 GHz optical clock as the pumps. We present the resultant waveform as well as the optical spectrum of the Manchester-coded output.


Diet and Alzheimer's disease.
Alzheimer's disease (AD) is increasing in prevalence. There are no known preventive or curative measures. There is evidence that oxidative stress, homo-cysteine-related vitamins, fats, and alcohol have a role in the pathogenesis of AD. Some epidemiologic studies suggest that higher dietary intake of antioxidants, vitamins B(6), B(12), and folate, unsaturated fatty acids, and fish are related to a lower risk of AD, but reports are inconsistent. Modest to moderate alcohol intake, particularly wine, may be related to a lower risk of AD. The Mediterranean diet may also be related to lower AD risk. However, randomized clinical trials of supplements of vitamins E, B(12), B(6), and folate have shown no cognitive benefit, and randomized trials for other nutrients or diets in AD are not available. The existing evidence does not support the recommendation of specific supplements, foods, or diets for the prevention of AD.


External and intrinsic anchoring in nematic liquid crystals: a Monte Carlo study.
We present a Monte Carlo study of external surface anchoring in nematic cells with partially disordered solid substrates, as well as of intrinsic anchoring at free nematic interfaces. The simulations are based on the simple hexagonal lattice model with a spatially anisotropic intermolecular potential. We estimate the corresponding extrapolation length b by imposing an elastic deformation in a hybrid cell-like nematic sample. Our estimates for b increase with increasing surface disorder and are essentially temperature independent. Experimental values of b are approached only when both the coupling of nematic molecules with the substrate and the anisotropy of nematic-nematic interactions are weak.


Molecular surveillance detects high prevalence of the neglected parasite Mansonella ozzardi in the Colombian Amazon.
Mansonellosis is an undermapped insect-transmitted disease caused by filarial nematodes that are estimated to infect hundreds of millions of people globally. Despite their prevalence, there are many outstanding questions regarding the general biology and health impacts of the responsible parasites. Historical reports suggest that the Colombian Amazon is endemic for mansonellosis and may serve as an ideal location to pursue these questions in the backdrop of other endemic and emerging pathogens. We deployed molecular and classical diagnostic approaches to survey Mansonella prevalence among adults belonging to indigenous communities along the Amazon River and its tributaries near Leticia, Colombia. Deployment of a loop-mediated isothermal amplification (LAMP) assay on blood samples revealed an infection prevalence of ∼40% for Mansonella ozzardi . This assay identified significantly more infections than blood smear microscopy or LAMP assays performed using plasma, likely reflecting greater sensitivity and the ability to detect low microfilaremias or occult infections. Mansonella infection rates increased with age and were higher among males compared to females. Genomic analysis confirmed the presence of M. ozzardi that clusters closely with strains sequenced in neighboring countries. We successfully cryopreserved and revitalized M. ozzardi microfilariae, advancing the prospects of rearing infective larvae in controlled settings. These data suggest an underestimation of true mansonellosis prevalence, and we expect that these methods will help facilitate the study of mansonellosis in endemic and laboratory settings.


Ixazomib, Oral Metronomic Cyclophosphamide, and Dexamethasone for First-Line Treatment of Multiple Myeloma: A Phase II Brown University Oncology Group Study.
Newly diagnosed multiple myeloma patients have many available treatment options. While lenalidomide, bortezomib, and dexamethasone (RVD) is the preferred initial treatment for many patients, several other agents may provide similar efficacy with less toxicity and improved ease of administration. We evaluated the safety and efficacy of the all-oral regimen of ixazomib, cyclophosphamide, and dexamethasone with the use of metronomic cyclophosphamide dosing in the treatment of patients with newly diagnosed multiple myeloma. The study was stopped prior to planned enrollment due to slow recruitment, with 12 patients available for final analysis. The overall response rate was 58.3% with 2 patients achieving a very good partial response (16.7%) and 5 patients achieving a partial response (41.7%). Median progression-free survival was 16 months, and median overall survival was 43 months. There were no episodes of grade 3 or greater peripheral neuropathy. Grade 3 or greater dermatologic toxicity was experienced in 50% of patients. Although limited enrollment prevented full efficacy evaluation, our data do not support further study of metronomic cyclophosphamide in combination with ixazomib and dexamethasone in the treatment of newly diagnosed multiple myeloma. The activity of this regimen in the relapsed/refractory setting requires further study (ClinicalTrials.gov Identifier: NCT02412228).


Construction of ileal reservoir with longitudinal ileal myotomy.
An attempt was made to construct an ileal reservoir in 15 colectomized dogs by making a longitudinal myotomy of 15 cm length. The volume of the myotomized ileal segment did not increase, even when accompanied by more than 50 per cent obstruction of the distal sigmoid colon for periods of follow-up to 4 months. Peristalsis was not altered by the longitudinal muscular incision on the antimesenteric side of the ileum. Although the operative technique for longitudinal ileal myotomy has the benefit of simplicity compared with construction of an ileal reservoir, the latter techniques, which have been used clinically on an extensive basis, are more likely to produce a consistent distension that is suitable for fecal storage. Although there were no leaks from the mucosa and no complications occurred in the 15 dogs evaluated, the dilatation of an isolated ileal segment was so minor that this technique appears to have little application in the treatment of patients undergoing the endorectal ileal pullthrough procedure.


Visualization and analysis of eye movement data from children with typical and atypical development.
Looking at other children's interactions provides rich learning opportunities for a small child. How children with autism look at other children is largely unknown. Using eye tracking, we studied gaze performance in children with autism and neurotypical comparison children while they were watching videos of semi-naturalistic social interactions between young children. Using a novel, bottom-up approach we identified event-related measures that distinguished between groups with high accuracy. The observed effects remained in a subset of the total sample matched on IQ, and were replicated across several different stimuli. The described method facilitates the detection of meaningful patterns in complex eye tracking data. Also, the approach significantly improves visualization, which will help investigators understand, illustrate, and generate new hypotheses.


Uniform and Non-uniform Perturbations in Brain-Machine Interface Task Elicit Similar Neural Strategies.
The neural mechanisms that take place during learning and adaptation can be directly probed with brain-machine interfaces (BMIs). We developed a BMI controlled paradigm that enabled us to enforce learning by introducing perturbations which changed the relationship between neural activity and the BMI's output. We introduced a uniform perturbation to the system, through a visuomotor rotation (VMR), and a non-uniform perturbation, through a decorrelation task. The controller in the VMR was essentially unchanged, but produced an output rotated at 30° from the neurally specified output. The controller in the decorrelation trials decoupled the activity of neurons that were highly correlated in the BMI task by selectively forcing the preferred directions of these cell pairs to be orthogonal. We report that movement errors were larger in the decorrelation task, and subjects needed more trials to restore performance back to baseline. During learning, we measured decreasing trends in preferred direction changes and cross-correlation coefficients regardless of task type. Conversely, final adaptations in neural tunings were dependent on the type controller used (VMR or decorrelation). These results hint to the similar process the neural population might engage while adapting to new tasks, and how, through a global process, the neural system can arrive to individual solutions.


[Immune outcomes of sleep disorders: the hypothalamic-pituitary-adrenal axis as a modulatory factor].
To review the literature on the interaction between sleep and the immune system. A search on Web of Science and Pubmed database including the keywords sleep, sleep deprivation, stress, hypothalamic-pituitary-adrenal axis, immune system, and autoimmune diseases. On Web of Science, 588 publications were retrieved; 61 references, more significant and closer to our objective, were used, including original articles and review papers. Sleep deprivation and immune system exert a bidirectional influence on each other. Since sleep deprivation is considered a stressor, inasmuch as it induces elevation of cortisol or corticosterone levels in humans and rodents, respectively, and given the well-known immunosuppressive effect of glucocorticoids, we propose that increased activation of the hypothalamic-pituitary-adrenal axis is a major mediator of the immune alterations observed in patients with insomnia or in sleep deprived subjects.


A unique factor XIII inhibitor to a fibrin-binding site on factor XIIIA.
An 81-year-old woman, who presented with sudden episodes of spontaneous bleeding, was found to have a specific inhibitor of factor XIII. Her fibrin clots had approximately 70% gamma-gamma and no alpha polymer formation, under conditions where normal fibrin was fully cross-linked; the patient's clots were soluble in urea or monochloroacetic acid. Factor XIII activity in her plasma was 24%, measured by the dansylcadaverine incorporation assay. When mixed with normal plasma, the patient's plasma inhibited fibrin cross-linking; however, in mixtures of patient and normal plasma, there was no inhibition of factor XIII activity when assayed by the incorporation of dansylcadaverine into casein. Thus, this inhibitor was active against fibrin cross-linking but not against ligation of small molecules to casein. Consequently, gel electrophoresis of reduced, sodium dodecyl sulfate-solubilized fibrin clots was a simple, quantitative method that was used to measure inhibitor activity. This inhibitor is unique and has been designated inhibitor New Haven. It was neutralized by anti-IgG and anti-kappa. It did not inhibit the activation of factor XIII but did inhibit fibrin cross-linking. There was complex formation between the inhibitor and activated factor XIII (A', A*) but not between A2 or fibrinogen. Only A', A* and the 56-Kd fragment bound to affinity columns made with this IgG. The inhibitor significantly decreased the binding of A', A* to fibrin clots. These data indicate that the epitope for this inhibitor is in a fibrin binding site. It is hidden in the zymogen and expressed on A' and A*, indicating that the conformational change occurring with the cleavage of the activation peptide is sufficient to expose the fibrin binding site.


Evaluation of a Multifaceted Intervention to Reduce Health Disparities in Hepatitis C Screening: A Pre-Post Analysis.
Hepatitis C virus (HCV) testing in persons born from 1945 to 1965 has had limited adoption despite guidelines, particularly among racial/ethnic minorities and socioeconomically disadvantaged patients, who have a higher prevalence of disease burden. We examined the effectiveness of a multifaceted intervention to improve HCV screening in a large safety-net health system. We performed a multifaceted intervention that included provider and patient education, an electronic medical record-enabled best practice alert, and increased HCV treatment capacity. We characterized HCV screening completion before and after the intervention. To identify correlates of HCV screening, we performed logistic regression for the preintervention and postintervention groups and used a generalized linear mixed model for patients observed in both preintervention and postintervention time frames. Before the intervention, 10.1% of 48,755 eligible baby boomer patients were screened. After the intervention, 34.6% of the 34,093 eligible baby boomers were screened (P < 0.0001). Prior to the intervention, HCV screening was lower among older baby boomers and providers with large patient panels and higher in high-risk subgroups including those with signs of liver disease (e.g., elevated transaminases, thrombocytopenia), human immunodeficiency virus-positive patients, and homeless patients. Postintervention, we observed increased screening uptake in older baby boomers, providers with larger patient panel size, and patients with more than one prior primary care appointment. Conclusion: Our multifaceted intervention significantly increased HCV screening, particularly among older patients, those engaged in primary care, and providers with large patient panels.


[Use of rechargeable stimulators in 2 cases of cauda equina syndrome].
The first of the 2 cases of cauda equina syndrome we report occurred following phenolization of sacral roots after a series of operations for Hirsprung disease. The second occurred after trauma from a bullet that hit the spine. Fecal and urinary incontinence and neuropathic pain in the lower extremities were present in both cases. After various treatments failed, both patients were given dual spinal stimulation for integrated treatment of both incontinence and neuropathic pain. We applied a novel approach, connecting both stimulators to a single rechargeable generator, reducing medium- and long-term costs. Fewer generator replacements (every 2-3 years with the standard approach) and fewer generator implantations (2 each time with the usual system) are required when rechargeable generators are used. Patient quality of life is thus improved. The overall cost of the implants is reduced from their second year of use.


Migration Pathways of Thalamic Neurons and Development of Thalamocortical Connections in Humans Revealed by Diffusion MR Tractography.
The thalamus plays an important role in signal relays in the brain, with thalamocortical (TC) neuronal pathways linked to various sensory/cognitive functions. In this study, we aimed to see fetal and postnatal development of the thalamus including neuronal migration to the thalamus and the emergence/maturation of the TC pathways. Pathways from/to the thalami of human postmortem fetuses and in vivo subjects ranging from newborns to adults with no neurological histories were studied using high angular resolution diffusion MR imaging (HARDI) tractography. Pathways likely linked to neuronal migration from the ventricular zone and ganglionic eminence (GE) to the thalami were both successfully detected. Between the ventricular zone and thalami, more tractography pathways were found in anterior compared with posterior regions, which was well in agreement with postnatal observations that the anterior TC segment had more tract count and volume than the posterior segment. Three different pathways likely linked to neuronal migration from the GE to the thalami were detected. No hemispheric asymmetry of the TC pathways was quantitatively observed during development. These results suggest that HARDI tractography is useful to identify multiple differential neuronal migration pathways in human brains, and regional differences in brain development in fetal ages persisted in postnatal development.


Oxytocin hyperpolarizes cultured duodenum myenteric intrinsic primary afferent neurons by opening BK(Ca) channels through IP₃ pathway.
Oxytocin (OT) is clinically important in gut motility and constitutively reduces duodenum contractility. Intrinsic primary afferent neurons (IPANs), whose physiological classification is as AH cells, are the 1st neurons of the peristaltic reflex pathway. We set out to investigate if this inhibitory effect is mediated by IPANs and to identify the ion channel(s) and intracellular signal transduction pathway that are involved in this effect. Myenteric neurons were isolated from the longitudinal muscle myenteric plexus (LMMP) preparation of rat duodenum and cultured for 16-24 h before electrophysiological recording in whole cell mode and AH cells identified by their electrophysiological characteristics. The cytoplasmic Ca²⁺ concentration ([Ca²⁺](i) ) of isolated neurons was measured using calcium imaging. The concentration of IP(3) in the LMMP and the OT secreted from the LMMP were measured using ELISA. The oxytocin receptor (OTR) and large-conductance calcium-activated potassium (BK(Ca)) channels, as well as the expression of OT and the IPAN marker calbindin 28 K, on the myenteric plexus neurons were localized using double-immunostaining techniques. We found that administration of OT (10⁻⁷ to 10⁻⁵ M) dose dependently hyperpolarized the resting membrane potential and increased the total outward current. The OTR antagonist atosiban or the BK(Ca) channel blocker iberiotoxin (IbTX) blocked the effects of OT suggesting that the increased outward current resulted from BK(Ca) channel opening. OTR and the BK(Ca) α subunit were co-expressed on a subset of myenteric neurons at the LMMP. NS1619 (10⁻⁵ M, a BK(Ca) channel activator) increased the outward current similar to the effect of OT. OT administration also increased [Ca²⁺](i) and the OT-evoked outward current was significantly attenuated by thapsigargin (10⁻⁶ M) or CdCl₂. The effect of OT on the BK(Ca) current was also blocked by pre-treatment with the IP₃ receptor antagonist 2-APB (10⁻⁴ M) or the PLC inhibitor U73122 (10⁻⁵ M). OT (10⁻⁶ M) also increased the IP₃ concentration within the LMMP. Both of the spontaneous and KCl-induced secretion of OT was enhanced by atosiban. Most of OT-immunoreactive cells are also immunoreactive for calbindin 28 K. In summary, we concluded that OT hyperpolarized myenteric IPANs by activating BK(Ca) channels via the OTR-PLC-IP₃-Ca²⁺ signal pathway. OT might modulate IPANs mediated ENS reflex by an autocrine and negative feedback manner.


Characterization of the vaccinia virus L1R myristylprotein as a component of the intracellular virion envelope.
In many cases, virus-encoded acylproteins appear to localize to specific cellular and viral membranes and to be directly involved with the processes of virus morphogenesis and/or egress from the infected cell. It was therefore of interest to determine whether the major vaccinia virus (VV) myristylprotein, L1R, is specifically associated with one or more of the membranes enveloping various infectious forms of VV virions. To this end, single-membraned intracellular virions (INV) and extracellular enveloped virions (EEV), which are surrounded by at least two distinct membranes, were purified from VV-infected cell lysates. The location of the VV L1R protein was determined by using a monospecific anti-L1R serum to detect the L1R protein by immunoblot in INV- and EEV-containing fractions, by examining the proteinase K sensitivity of the L1R protein in intact INV and EEV particles, and by immunoelectron microscopy. The data obtained clearly indicate that although the L1R protein is a constituent of both the INV and EEV particles, it is exclusively found in the inner INV-specific membrane. These results are discussed with regard to the potential role of the VV L1R protein in the primary intracellular envelopment of infectious VV particles.


Spectral weighting strategies for sentences measured by a correlational method.
Listeners' ability to understand speech in adverse listening conditions is partially due to the redundant nature of speech. Natural redundancies are often lost or altered when speech is filtered, such as done in AI/SII experiments. It is important to study how listeners recognize speech when the speech signal is unfiltered and the entire broadband spectrum is present. A correlational method [R. A. Lutfi, J. Acoust. Soc. Am. 97, 1333-1334 (1995); V. M. Richards and S. Zhu, J. Acoust. Soc. Am. 95, 423-424 (1994)] has been used to determine how listeners use spectral cues to perceive nonsense syllables when the full speech spectrum is present [K. A. Doherty and C. W. Turner, J. Acoust. Soc. Am. 100, 3769-3773 (1996); C. W. Turner et al., J. Acoust. Soc. Am. 104, 1580-1585 (1998)]. The experiments in this study measured spectral-weighting strategies for more naturally occurring speech stimuli, specifically sentences, using a correlational method for normal-hearing listeners. Results indicate that listeners placed the greatest weight on spectral information within bands 2 and 5 (562-1113 and 2807-11,000 Hz), respectively. Spectral-weighting strategies for sentences were also compared to weighting strategies for nonsense syllables measured in a previous study (C. W. Turner et al., 1998). Spectral-weighting strategies for sentences were different from those reported for nonsense syllables.


Preoperative downstaging of pancreatic cancer is associated with improved survival after multi-agent chemotherapy, but not after radiation.
Downstaging has been associated with improved survival for many cancers. However, the implications of downstaging are unclear for pancreatic cancer in an era of effective neoadjuvant systemic chemotherapy. NCDB retrospective cohort study of resected pancreatic carcinoma treated with neoadjuvant therapy. The study included 73,985 patients: 66,589 with no neoadjuvant therapy, 2,102 neoadjuvant radiation therapy (N-RT), 3,195 neoadjuvant multiagent chemotherapy (N-MAC) and 2.099 with both neoadjuvant radiation and multiagent chemotherapy. There was increased use of N-MAC over the period of this study. Patients selected for treatment with N-MAC had longer survival from surgery on univariate (23.1 vs. 18.7 months, p = < 0.01) and multivariate analyses HR 0.81 (0.76-0.87, p < 0.001) compared to those selected with N-RT. Downstaging was similar in N-RT and N-MAC groups (25.1 vs. 24.1%, p = 0.43). Downstaging following N-MAC was associated with a survival benefit, HR 0.85 (0.74-0.98). However, downstaging following N-RT was not associated with a survival advantage, HR 1.12 (0.99-0.99). Clinicians have rapidly adopted N-MAC for treatment of pancreatic cancer. Although the rates of downstaging are similar between treatment groups, response translates into increased survival only with N-MAC and not with N-RT.


Effect of Acetyl Group on Mechanical Properties of Chitin/Chitosan Nanocrystal: A Molecular Dynamics Study.
Chitin fiber is the load-bearing component in natural chitin-based materials. In these materials, chitin is always partially deacetylated to different levels, leading to diverse material properties. In order to understand how the acetyl group enhances the fracture resistance capability of chitin fiber, we constructed atomistic models of chitin with varied acetylation degree and analyzed the hydrogen bonding pattern, fracture, and stress-strain behavior of these models. We notice that the acetyl group can contribute to the formation of hydrogen bonds that can stabilize the crystalline structure. In addition, it is found that the specimen with a higher acetylation degree presents a greater resistance against fracture. This study describes the role of the functional group, acetyl groups, in crystalline chitin. Such information could provide preliminary understanding of nanomaterials when similar functional groups are encountered.


Chronic Listeria infection in SCID mice: requirements for the carrier state and the dual role of T cells in transferring protection or suppression.
Listeriosis in mice with the SCID mutation results in a chronic infection. The chronic infection is characterized by abundant granulomas and neutrophil infiltrates. Both lesions were particularly noticeable in the liver. In the liver, about 95% are granulomas with 5% microabscesses involving intrahepatic infection. The majority of Listeria resided in membrane-bound vacuolar structures of the macrophages and not in the cytosol. Three manipulations resulted in alterations in the equilibrium between granulomas and liver microabscesses, with massive transfer of the infection to the hepatocyte and dissolution of the granulomas: depletion of neutrophils and neutralization of IFN-gamma and TNF-alpha. We did not find a role for IL-12, IL-10, or nitric oxide. Adoptive transfer studies showed a decisive role for both CD4+ and CD8+ T cells for an effective immune response, i.e., clearance of bacteria, granuloma formation with lymphocytes, and disappearance of microabscess. Clearance of Listeria was induced by transfer of CD8+ T cells from mice with targeted disruption of the IFN-gamma structural gene (IfgTM1KO), even in the presence of neutralizing mAb to IFN-gamma. In marked contrast, transfer of CD4+ T cells from IfgTM1KO mice exacerbated the infection in the chronically infected SCID mice, resulting in increased mortality with dissolution of the granulomas and severe hepatic infection with neutrophil infiltration. Thus, these data indicate that both IFN-gamma-dependent and -independent mechanisms are operative in the context of a chronic listerial infection.


Synthesis, in vitro evaluation, and antileishmanial activity of water-soluble prodrugs of buparvaquone.
Water-soluble phosphate prodrugs of buparvaquone (1), containing a hydroxynaphthoquinone structure, were synthesized and evaluated in vitro for improved topical and oral drug delivery against cutaneous and visceral leishmaniasis. The successful prodrug synthesis involved a strong base; e.g., sodium hydride. Buparvaquone-3-phosphate (4a) and 3-phosphonooxymethyl-buparvaquone (4b) prodrugs possessed significantly higher aqueous solubilities (>3.5 mg/mL) than the parent drug (</=0.03 microg/mL) over a pH range of 3.0-7.4. Moreover, 4a and 4b maintained adequate lipophilicity as indicated by distribution coefficients (log D) between 0.5 and 3.0 over this pH range. Both 4a and 4b were also shown to be substrates for alkaline phosphatase in vitro and thus are promising bioreversible prodrugs for the improved topical and oral bioavailability of 1. Buparvaquone and its prodrugs showed nanomolar or low-micromolar ED(50) activity values against species that cause cutaneous leishmaniasis, e.g., L. major, L. amazonensis, L. aethiopica, L. mexicana, and L. panamensis and also L. donovani, which is the causative agent of visceral leishmaniasis. From these results, the human skin permeation of the prodrugs 4a and 4b were studied in vitro. While no buparvaquone permeated across post mortem skin in vitro during 72 h of experiments, both prodrugs 4a and 4b permeated readily through the skin. In addition, 4b easily released the parent drug in human skin homogenate and, therefore, is a promising prodrug candidate to deliver buparvaquone through the skin for the treatment of cutaneous leishmaniasis.


Use of lamivudine to prevent hepatitis B virus reactivation during chemotherapy in breast cancer patients.
In parts of Asia, about 10% of the population have chronic hepatitis B virus (HBV) infection, and cancer patients who are HBV carriers are frequently complicated by HBV reactivation while receiving cytotoxic chemotherapy. The condition may result in varying degrees of liver damage, causing disruption in chemotherapy and compromising the patients' prognosis. With the increasing use of chemotherapy paralleling the rise in breast cancer incidence, the occurrence of HBV reactivation is likely to further increase. Recent reports have suggested that the anti-viral agent, lamivudine, may reduce HBV reactivation and its associated morbidity. However, most studies are based on small series of lymphoma patients, while information on the other high risk population, namely breast cancer patients, has been lacking. In this study, we studied the role of lamivudine in preventing HBV reactivation and its associated morbidity in breast cancer patients with chronic HBV infection who were planned for chemotherapy. Two groups were studied. One group consisted of 31 patients who received 'prophylactic lamivudine' prior to and until 8 weeks after discontinuing chemotherapy. The other comprised of 61 historical controls who underwent chemotherapy without prophylactic lamivudine. The outcomes, in terms of the efficacy of lamivudine in reducing the incidence of HBV reactivation, and diminishing morbidity during chemotherapy were compared. The results revealed that in the prophylactic lamivudine group, despite a significantly higher proportion receiving anthracyclines, there was significantly fewer incidences of hepatitis (12.9 vs. 59.0%, p < 0.001), less HBV reactivation (6.5. vs. 31.1%, p=0.008), and less disruption of chemotherapy (16.1% vs. 45.9%, p=0.006). We conclude that prophylactic lamivudine significantly reduces the incidence of HBV reactivation and the overall morbidity of breast cancer patients undergoing chemotherapy.


Identification of a unique erythroleukemia-associated retroviral gp70 expressed during early stages of normal erythroid differentiation.
Late in the course of Friend virus (FV)-induced erythroleukemia, leukemic spleen cells express a cell surface retroviral gp70 envelope protein not detected during the early proliferative phase of the disease. Characterization of this gp70 revealed it was unrelated to the input Friend murine leukemia virus (F-MuLV), but antigenically similar to a unique subset of endogenous xenotropic viruses. This gp70 was expressed by murine erythroleukemia cell lines but has not been identified on cell lines of other lineages. A monoclonal antibody (18-6) specifically reactive with this polypeptide was used to examine hematopoietic organs of normal uninoculated mice. This antibody detected a gp70 expressed by a majority of erythroid cells in fetal liver and by a small but significant percentage of normal adult spleen and bone marrow cells. Increased erythropoietic activity induced by treatment of adult mice with phenylhydrazine ( PHZ ) resulted in a seven- to eightfold increase in the frequency of spleen and bone marrow cells expressing this gp70. Peptide map analysis indicated that the 18-6 reactive gp70 expressed by Friend erythroleukemia cells and by cells from normal fetal liver were structurally identical. These results suggested that this unique gp70 was an erythroid-specific differentiation antigen.


Interpretation of an Extended Autoantibody Profile in a Well-Characterized Australian Systemic Sclerosis (Scleroderma) Cohort Using Principal Components Analysis.
To determine the relationships between systemic sclerosis (SSc)-related autoantibodies, as well as their clinical associations, in a well-characterized Australian patient cohort. Serum from 505 Australian SSc patients were analyzed with a commercial line immunoassay (EuroLine; Euroimmun) for autoantibodies to centromere proteins CENP-A and CENP-B, RNA polymerase III (RNAP III; epitopes 11 and 155), the 90-kd nucleolar protein NOR-90, fibrillarin, Th/To, PM/Scl-75, PM/Scl-100, Ku, topoisomerase I (topo I), tripartite motif-containing protein 21/Ro 52, and platelet-derived growth factor receptor. Patient subgroups were identified by hierarchical clustering of the first 2 dimensions of a principal components analysis of quantitative autoantibody scores. Results were compared with detailed clinical data. A total of 449 of the 505 patients were positive for at least 1 autoantibody by immunoblotting. Heatmap visualization of autoantibody scores, along with principal components analysis clustering, demonstrated strong, mutually exclusive relationships between CENP, RNAP III, and topo I. Five patient clusters were identified: CENP, RNAP III strong, RNAP III weak, topo I, and other. Clinical features associated with CENP, RNAP III, and topo I were consistent with previously published reports concerning limited cutaneous and diffuse cutaneous SSc. A novel finding was the statistical separation of RNAP III into 2 clusters. Patients in the RNAP III strong cluster had an increased risk of gastric antral vascular ectasia, but a lower risk of esophageal dysmotility. Patients in the other cluster were more likely to be male and to have a history of smoking and a history of malignancy, but were less likely to have telangiectasia, Raynaud's phenomenon, and joint contractures. Five major autoantibody clusters with specific clinical and serologic associations were identified in Australian SSc patients. Subclassification and disease stratification using autoantibodies may have clinical utility, particularly in early disease.


Interval training in the fed or fasted state improves body composition and muscle oxidative capacity in overweight women.
To investigate the effects of low-volume high-intensity interval training (HIT) performed in the fasted (FAST) versus fed (FED) state on body composition, muscle oxidative capacity, and glycemic control in overweight/obese women. Sixteen women (27 ± 8 years, BMI: 29 ± 6 kg/m(2) , VO2peak : 28 ± 3 ml/kg/min) were assigned to either FAST or FED (n = 8 each) and performed 18 sessions of HIT (10× 60-s cycling efforts at ∼90% maximal heart rate, 60-s recovery) over 6 weeks. There was no significant difference between FAST and FED for any measured variable. Body mass was unchanged following training; however, dual energy X-ray absorptiometry revealed lower percent fat in abdominal and leg regions as well as the whole body level (main effects for time, P ≤ 0.05). Fat-free mass increased in leg and gynoid regions (P ≤ 0.05). Resting muscle biopsies revealed a training-induced increase in mitochondrial capacity as evidenced by increased maximal activities of citrate synthase and β-hydroxyacyl-CoA dehydrogenase (P ≤ 0.05). There was no change in insulin sensitivity, although change in insulin area under the curve was correlated with change in abdominal percent fat (r = 0.54, P ≤ 0.05). Short-term low-volume HIT is a time-efficient strategy to improve body composition and muscle oxidative capacity in overweight/obese women, but fed- versus fasted-state training does not alter this response.


A Simplified Quantitative Real-Time PCR Assay for Monitoring SARS-CoV-2 Growth in Cell Culture.
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has infected millions within just a few months, causing severe respiratory disease and mortality. Assays to monitor SARS-CoV-2 growth in vitro depend on time-consuming and costly RNA extraction steps, hampering progress in basic research and drug development efforts. Here, we developed a simplified quantitative real-time PCR assay that bypasses viral RNA extraction steps and can monitor SARS-CoV-2 growth from a small amount of cell culture supernatants. In addition, we show that this approach is easily adaptable to numerous other RNA and DNA viruses. Using this assay, we screened the activities of a number of compounds that were predicted to alter SARS-CoV-2 entry and replication as well as HIV-1-specific drugs in a proof-of-concept study. We found that E64D (inhibitor of endosomal proteases cathepsin B and L) and apilimod (endosomal trafficking inhibitor) potently decreased the amount of SARS-CoV-2 RNA in cell culture supernatants with minimal cytotoxicity. Surprisingly, we found that the macropinocytosis inhibitor ethylisopropylamiloride (EIPA) similarly decreased SARS-CoV-2 RNA levels in supernatants, suggesting that entry may additionally be mediated by an alternative pathway. HIV-1-specific inhibitors nevirapine (a nonnucleoside reverse transcriptase inhibitor [NNRTI]), amprenavir (a protease inhibitor), and allosteric integrase inhibitor 2 (ALLINI-2) modestly inhibited SARS-CoV-2 replication, albeit the 50% inhibitory concentration (IC50) values were much higher than that required for HIV-1. Taking the data together, this simplified assay will expedite basic SARS-CoV-2 research, be amenable to mid-throughput screening assays (i.e., drug, CRISPR, small interfering RNA [siRNA], etc.), and be applicable to a broad number of RNA and DNA viruses.IMPORTANCE Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the etiological agent of the coronavirus disease 2019 (COVID-19) pandemic, is continuing to cause immense respiratory disease and social and economic disruptions. Conventional assays that monitor SARS-CoV-2 growth in cell culture rely on costly and time-consuming RNA extraction procedures, hampering progress in basic SARS-CoV-2 research and development of effective therapeutics. Here, we developed a simple quantitative real-time PCR assay to monitor SARS-CoV-2 growth in cell culture supernatants that does not necessitate RNA extraction and that is as accurate and sensitive as existing methods. In a proof-of-concept screen, we found that E64D, apilimod, EIPA, and remdesivir can substantially impede SARS-Cov-2 replication, providing novel insight into viral entry and replication mechanisms. In addition, we show that this approach is easily adaptable to numerous other RNA and DNA viruses. This simplified assay will undoubtedly expedite basic SARS-CoV-2 and virology research and be amenable to use in drug screening platforms to identify therapeutics against SARS-CoV-2.


Type-II ZnO nanorod-SnO2 nanoparticle heterostructures: characterization of structural, optical and photocatalytic properties.
In this work we report, for the first time, on the preparation of ZnO nanorod-SnO2 nanoparticle (ZnO NR-SnO2 NP) heterostructures by a simple two-step thermal evaporation approach. Systematical characterization of the product reveals that the rutile SnO2 NPs, with a diameter of about 20 nm, are uniformly and tightly decorated on the entire ZnO NRs. Photoluminescence (PL) investigation on the ZnO NR-SnO2 NP heterostructures shows that they exhibit a significantly decreased UV emission compared with the bare ZnO NRs, revealing an efficient charge separation arising from the type-II band alignment. Enlightened by this merit, photocatalytic behavior of the synthesized heterostructures is studied, which shows a remarkably enhanced photodegradation performance of rhodamine B (RhB) in contrast to the pure ZnO NRs. We also carry out the stability test of the ZnO NR-SnO2 NP heterostructures and the result indicates an extremely high adhesion nature between the ZnO NR and the coated SnO2 NPs. This advantage endowed with the thermal evaporation approach can lead to an efficient spatial charge separation between the ZnO NR and the SnO2 NPs and thus effectively minimize the charge recombination along three-dimensional heterointerfaces, which makes such ZnO NR-SnO2 NP architectures highly promising for a wide range of photovoltaic and photocatalytic applications.


Verb Argument Structure in Narrative Speech: Mining AphasiaBank.
Previous research has found that verb argument structure characteristics (such as the number of participant roles in the situation described by the verb) can facilitate or hinder aphasic language production and comprehension in constrained laboratory tasks. This research needs to be complemented by studies of narrative or unrestricted speech, which can capture the spontaneous selection of verbs and grammatical structures by people with aphasia and may be particularly sensitive to the relative cost of access to different verb types in more natural conditions. Focusing on the number of subcategorization options, we investigated verb argument structure effects in a large sample of narratives from AphasiaBank, by speakers with aphasia, as well as control speakers without brain damage. Verb argument structure complexity did not negatively affect verb selection in any type of aphasia. However, people with aphasia, particularly with Broca's aphasia, used verbs in less complex and diverse ways, with fewer arguments and less diverse subcategorization options. In line with previous research, this suggests that deficits in verb use in aphasia are likely due to difficulties with the online application of or partial damage to verb argument structure knowledge.


The relationship of cultural values with clean and healthy life behaviour (CHLB) among Islamic boarding school students in Indonesia.
Poor clean and healthy life behaviours (CHLB) are often found in students (santri) in Islamic boarding schools (pesantren) in Indonesia. Pesantren is a subculture that has derived different cultural values from society, while santri have a habit of borrowing and lending clothes and see scabies as a blessing. This study aimed to identify and describe the correlation between cultural values and CHLB practices among santri. It used descriptive analytics with a cross-sectional approach. The participants were 100 santri who lived in pesantren and were selected by using stratified random sampling. The cultural values and CHLB practices were assessed using the instruments developed by the writers in the previous study. The statistical analysis using the Spearman correlation test was applied to evaluate the association between cultural values and CHLB practices. The result shows a significant correlation between cultural values and CHLB practices among santri (p=0.004; r=0.284). Most of the santri had positive cultural values (52%) and poor CHLB practices (54%). The findings of this study showed that most of the santri adhered to positive cultural values, and most of them had poor CHLB practices. These findings also showed significant correlation between cultural values and CHLB practices among santri. This study is expected to be the basis for school nurses to provide nursing care with a cultural approach to improve CHLB practices among santri.


Clinical studies of Henoch-Schönlein purpura in Chinese children.
Over a 9-year period from 1983 to 1992, 50 patients with Henoch-Schönlein purpura were admitted to the Department of Pediatrics, Taichung Veterans General Hospital. There were 33 boys and 17 girls, with a male to female ratio of 2:1. Their ages ranged from 2 to 14 years with a mean of 6.3 years. Seventy percent of the patients were over the age of five. The months of peak incidence were October to December (48%). Fifty-four percent of the patients had evidence of preceding infections. The main clinical features were skin rashes (100%) followed by gastrointestinal symptoms (66%), joint symptoms (58%), soft tissue edema (30%) and renal involvement (30%). Hemograms showed leukocytosis, thrombocytosis, and elevated erythrocyte sedimentation rate in about half of these patients. Serological examinations were nonspecific; anti-streptolysin O titers were elevated in 40% of the patients. Forty-two percent of our patients had elevated serum IgA levels which bore no relationship to the symptomatology and duration of the illness. One patient had a complication of intussusception requiring surgical reduction. Another patient who had renal involvement progressed to end-stage renal disease. Eighty-two percent of our patients received prednisolone therapy at a dose of 1-2 mg/kg/day, with good response. Seventy-two percent of the patients recovered completely within one month after the onset of the malady. The overall prognosis remains good.


Sheltered housing compared to independent housing in the community.
With elderly people desiring to live independently as long as possible, traditional homes for the elderly are increasingly being transformed into sheltered accommodations. In order to assess the importance of housing for frail elderly people, elderly people at risk for institutionalization were studied in two living conditions: sheltered accommodation and living independently in the community. A total of 317 elderly people at risk for institutionalization [91 men and 240 women, mean age = 83.3 (SD = 6.0)] were interviewed using a structured questionnaire with questions regarding home care and social service use, quality of life, subjective well-being, life satisfaction, autonomy, functional status, feelings of insecurity and loneliness. Exactly 56.5% of the respondents were living in sheltered accommodation (n = 179) and 43.5% (n = 138) were living in regular houses. Although both groups were similar in demographic details and functional status, those in sheltered accommodation had a higher perceived autonomy, sense of security and quality of life. No differences were found with regard to subjective well-being or feelings of loneliness. Elderly people in regular houses needed more hours of housekeeping assistance. Those in sheltered accommodation participated more frequently in services like social activities and social restaurants, but made less use of day care facilities. Affordable, decent and suitable noninstitutional housing with service provision play a vital role in the lives of elderly people. Compared with independent living in the community, sheltered accommodations provide added value. Sheltered housing should therefore be an integral part of long-term care policy.


3'UTR shortening and EGF signaling: implications for breast cancer.
Alternative polyadenylation (APA) plays a role in gene expression regulation generally by shortening of 3'UTRs (untranslated regions) upon proliferative signals and relieving microRNA-mediated repression. Owing to high proliferative indices of triple negative breast cancers (TNBCs), we hypothesized APA to cause 3'UTR length changes in this aggressive subgroup of breast cancers. Our probe-based meta-analysis approach identified 3'UTR length alterations where the significant majority was shortening events (∼70%, 113 of 165) of mostly proliferation-related transcripts in 520 TNBC patients compared with controls. Representative shortening events were further investigated for their microRNA binding potentials by computational predictions and dual-luciferase assay. In silico-predicted 3'UTR shortening events were experimentally confirmed in patient and cell line samples. To begin addressing the underlying mechanisms, we found CSTF2 (cleavage stimulation factor 2), a major regulator of 3'UTR shortening to be up-regulated in response to epidermal growth factor (EGF). EGF treatment also resulted with further shortening of the 3'UTRs. To investigate the contribution of CSTF2 and 3'UTR length alterations to the proliferative phenotype, we showed pharmacological inhibition of the EGF pathway to lead to a reduction in CSTF2 levels. Accordingly, RNAi-induced silencing of CSTF2 decreased the proliferative rate of cancer cells. Therefore, our computational and experimental approach revealed a pattern of 3'UTR length changes in TNBC patients and a potential link between APA and EGF signaling. Overall, detection of 3'UTR length alterations of various genes may help the discovery of new cancer-related genes, which may have been overlooked in conventional microarray gene expression analyses.


Validity of three risk prediction models for dementia or cognitive impairment in Australia.
no studies have compared the predictive validity of different dementia risk prediction models in Australia. (i) to investigate the predictive validity of the Australian National University-Alzheimer's Disease Risk Index (ANU-ADRI), LIfestyle for BRAin Health (LIBRA) Index and cardiovascular risk factors, ageing and dementia study (CAIDE) models for predicting probable dementia/cognitive impairment in an Australian cohort. (ii) To develop and assess the predictive validity of a new hybrid model combining variables from the three models. the Hunter Community Study (HCS) included 3,306 adults aged 55-85 years with a median follow-up of 7.1 years. Probable dementia/cognitive impairment was defined using Admitted Patient Data Collection, dispensing of cholinesterase inhibitors or memantine, or a cognitive test. Model validity was assessed by calibration and discrimination. A hybrid model was developed using deep neural network analysis, a machine learning method. 120 (3.6%) participants developed probable dementia/cognitive impairment. Mean calibration by ANU-ADRI, LIBRA, CAIDE and the hybrid model was 19, 0.5, 4.7 and 3.4%, respectively. The discrimination of the models was 0.65 (95% CI 0.60-0.70), 0.65 (95% CI 0.60-0.71), 0.54 (95% CI 0.49-0.58) and 0.80 (95% CI 0.78-0.83), respectively. ANU-ADRI and LIBRA were better dementia prediction tools than CAIDE for identification of high-risk individuals in this cohort. ANU-ADRI overestimated and LIBRA underestimated the risk. The new hybrid model had a higher predictive performance than the other models but it needs to be validated independently in longitudinal studies.


The VH gene repertoire of splenic B cells and somatic hypermutation in systemic lupus erythematosus.
In systemic lupus erythematosus (SLE) it has been hypothesized that self-reactive B cells arise from virgin B cells that express low-affinity, nonpathogenic germline V genes that are cross-reactive for self and microbial antigens, which convert to high-affinity autoantibodies via somatic hypermutation. The aim of the present study was to determine whether the VH family repertoire and pattern of somatic hypermutation in germinal centre (GC) B cells deviates from normal in SLE. Rearranged immunoglobulin VH genes were cloned and sequenced from GCs of a SLE patient's spleen. From these data the GC V gene repertoire and the pattern of somatic mutation during the proliferation of B-cell clones were determined. The results highlighted a bias in VH5 gene family usage, previously unreported in SLE, and under-representation of the VH1 family, which is expressed in 20-30% of IgM+ B cells of healthy adults and confirmed a defect in negative selection. This is the first study of the splenic GC response in human SLE.


Evaluation of surgical glove integrity and factors associated with glove defect.
Surgical glove perforation may expose both patients and staff members to severe complications. This study aimed to determine surgical glove perforation rate and the factors associated with glove defect. This descriptive cross-sectional study was conducted between January and March 2017 at a Tunisian university hospital center in 3 different surgical departments: urology, maxillofacial, and general and digestive. The gloves were collected and tested to detect perforations using the water-leak test as described in European Norm NF EN 455-1. For percentage comparisons, the χ2 test was used with a significance threshold of 5%. A total of 284 gloves were collected. Of these, 47 were found to be perforated, a rate of 16.5%. All perforations were unnoticed by the surgical team members. The majority of perforated gloves (61.7%) were collected after urology procedures (P = .00005), 77% of perforated gloves were detected when the duration of the procedure exceeded 90 minutes (P = .001), and 96% were from brand A, which were the thicker gloves (P = .015). This study highlighted an important problem neglected by surgical teams. The findings reaffirm the importance of double-gloving and changing gloves in surgeries of more than 90 minutes' duration.


A placebo-controlled comparison of diltiazem and amlodipine monotherapy in essential hypertension using 24-h ambulatory monitoring.
Thirty patients (17 females, median age 55 years) with mild/moderate hypertension (sitting diastolic blood pressure 95-110 mmHg over 2 consecutive weeks) participated in a study of the efficacy and tolerability of once-daily diltiazem "controlled delivery" 180 mg-360 mg and amlodipine 5-10 mg compared with placebo (using clinic and 24-h ambulatory blood pressure measurement (Accutraker II). The study was conducted in a general practice setting using a randomized double-blind crossover design with Latin square allocation of treatment order within subjects. During each phase, doses were titrated to achieve a predose clinic sitting diastolic blood pressure of 90 mmHg. Three patients withdrew while taking amlodipine and 3 while taking placebo. The numbers of patients receiving the higher dose in each phase were as follows: placebo 22, diltiazem 12 and amlodipine 19. End-of-phase mean clinic sitting blood pressures were as follows: placebo 152/100, diltiazem 146/95 and amlodipine 140/93. End-of-phase mean 24-h ambulatory blood pressures were as follows: placebo 151/93, diltiazem 143/86 and amlodipine 137/84. Both clinic and ambulatory blood pressures were therefore significantly reduced (p < 0.01) in both active phases compared with placebo, and systolic blood pressure was also significantly lower with amlodipine compared with diltiazem. Heart rate was increased with amlodipine. Both drugs were well tolerated, and adverse events were predictable for each agent, with amlodipine causing more vasodilator side effects. Thus both amlodipine and diltiazem once-daily are effective in reducing blood pressure. While amlodipine is more potent than diltiazem in reducing systolic blood pressure, it causes more vasodilator side effects.


[Politics of human health resources: a proposal for their formation].
This article is an account of almost two years of experience in manpower policy. The authors worked together in the Central American area, one in an international cooperation agency and the other as a local official who also worked at the international level. The circumstances that have generated interest in work of this kind are examined, considerations are advanced on the framing of a definition of "policy" in relation to this particular problem, and a policy structure is proposed on the basis of elements grouped as homogeneously as possible. On the basis of the experience of three countries, the elements are determined that can be involved in the process of working out a manpower policy. A detailed description is then given of the model generated in the Community Health Training Program for Central America and Panama (PASCCAP) for the formulation and promulgation of a policy, and of the first results obtained in the Central American Area.


Arginine 127 stabilizes the transition state in carboxypeptidase.
Crystallographic studies suggest that Arg-127 is a key amino acid in the hydrolysis of peptides and esters by carboxypeptidase A. The guanidinium group of Arg-127 is hypothesized to stabilize the oxyanion of the tetrahedral intermediate formed by the attack of water on the scissile carbonyl bond. We have replaced this amino acid in rat carboxypeptidase A1 with lysine (R127K), methionine (R127M), and alanine (R127A), in order to define the role of Arg-127 in carboxypeptidase catalyzed hydrolysis. The wild-type and mutant enzymes were expressed in yeast and purified. Kinetic studies show that Arg-127 substitution decreases kcat for both ester and amide substrates, whereas Km is relatively unchanged; for R127M and R127A this corresponds to a 6 kcal/mol decrease in transition state stabilization of the rate-limiting step. The binding affinity for the phosphonate transition state analog, Cbz-Phe-Ala(P)-OAla, was decreased by 5.4 kcal/mol, whereas binding affinity for the ground state inhibitor, DL-benzylsuccinic acid, was decreased by only 1.7 kcal/mol for R127M. Electrostatic calculations employing a finite difference solution to the Poisson-Boltzmann equation predict that the positive charge of Arg-127 should stabilize the transition state by 6-8 kcal/mol. Therefore, the experimental and theoretical data suggest that the primary role of Arg-127 is stabilization of the transition state through electrostatic interaction with the oxyanion.


Molecular genetic analysis of oligodendroglial tumors shows preferential allelic deletions on 19q and 1p.
The molecular genetic alterations of oligodendroglial tumors and mixed gliomas of the central nervous system were studied in a series of 37 cases (8 oligodendrogliomas, 13 anaplastic oligodendrogliomas, 8 oligoastrocytomas, and 8 anaplastic oligoastrocytomas). A total of 180 polymorphic loci and 5 nonpolymorphic gene loci, distributed over all chromosomes, were examined by restriction fragment length polymorphism analysis. Loss of heterozygosity was most frequently observed for loci on 19q with a commonly deleted region at 19q13.2-q13.4 distal to the CYP2a gene and proximal to the D19S22 locus. The incidence of allelic loss on 19q was particularly high (81%) in oligodendroglial tumors and equal to 31% in mixed gliomas. More than 75% of the tumors with allelic deletions on 19q also showed loss of heterozygosity for loci on 1p with one tumor showing only loss of alleles distal to the NGFB gene (1p13-pter). Seven (19%) tumors had lost alleles from 17p with the deleted region including the TP53 tumor suppressor gene in all cases. Sequencing of the TP53 transcripts from exons 2 to 10, however, did not reveal mutations of the remaining allele in any of these tumors. Anaplastic oligodendrogliomas and anaplastic oligoastrocytomas demonstrated an increased incidence of additional allelic losses involving most frequently chromosomes 9p and 10. Gene amplification was detected in two anaplastic tumors, affecting the epidermal growth factor receptor gene in both cases, with additional amplification of the renin gene at 1q32 in one of these cases. In total our results indicate both differences and similarities between the molecular genetic alterations in tumors with oligodendroglial and astrocytic differentiation. The loss of genetic information from 19q and 1p as well as the rarity of TP53 mutations in oligodendroglial tumors suggests that the early events in their oncogenesis are distinct from those associated with astrocytic tumors. However, similarities are indicated by the allelic losses on 9p and 10 in the anaplastic tumors, suggesting the utilization of common pathways of progression.


Mutations in EKLF/KLF1 form the molecular basis of the rare blood group In(Lu) phenotype.
Comparison of normal erythroblasts and erythroblasts from persons with the rare In(Lu) type of Lu(a-b-) blood group phenotype showed increased transcription levels for 314 genes and reduced levels for 354 genes in In(Lu) cells. Many erythroid-specific genes (including ALAS2, SLC4A1) had reduced transcript levels, suggesting the phenotype resulted from a transcription factor abnormality. A search for mutations in erythroid transcription factors showed mutations in the promoter or coding sequence of EKLF in 21 of 24 persons with the In(Lu) phenotype. In all cases the mutant EKLF allele occurred in the presence of a normal EKLF allele. Nine different loss-of-function mutations were identified. One mutation abolished a GATA1 binding site in the EKLF promoter (-124T>C). Two mutations (Leu127X; Lys292X) resulted in premature termination codons, 2 (Pro190LeufsX47; Arg319GlufsX34) in frameshifts, and 4 in amino acid substitution of conserved residues in zinc finger domain 1 (His299Tyr) or domain 2 (Arg328Leu; Arg328His; Arg331Gly). Persons with the In(Lu) phenotype have no reported pathology, indicating that one functional EKLF allele is sufficient to sustain human erythropoiesis. These data provide the first description of inactivating mutations in human EKLF and the first demonstration of a blood group phenotype resulting from mutations in a transcription factor.


A structured observation of behavioral self-regulation and its contribution to kindergarten outcomes.
The authors examined a new assessment of behavioral regulation and contributions to achievement and teacher-rated classroom functioning in a sample (N = 343) of kindergarteners from 2 geographical sites in the United States. Behavioral regulation was measured with the Head-Toes-Knees-Shoulders (HTKS) task, a structured observation requiring children to perform the opposite of a dominant response to 4 different oral commands. Results revealed considerable variability in HTKS scores. Evidence for construct validity was found in positive correlations with parent ratings of attentional focusing and inhibitory control and teacher ratings of classroom behavioral regulation. Hierarchical linear modeling indicated that higher levels of behavioral regulation in the fall predicted stronger levels of achievement in the spring and better teacher-rated classroom self-regulation (all ps < .01) but not interpersonal skills. Evidence for domain specificity emerged, in which gains in behavioral regulation predicted gains in mathematics but not in language and literacy over the kindergarten year (p < .01) after site, child gender, and other background variables were controlled. Discussion focuses on the importance of behavioral regulation for successful adjustment to the demands of kindergarten.


Surgical management of two- versus three-column injuries of the cervicothoracic junction: biomechanical comparison of translaminar screw and pedicle screw fixation using a cadaveric model.
An in vitro cadaveric biomechanical study. To determine the stability of translaminar screws compared to pedicle screws at T1-T2 for constructs bridging the cervicothoracic junction. Instrumented fixation of the cervicothoracic junction is challenging both biomechanically, due to the transition from the mobile cervical to the rigid thoracic spine, and technically, due to the anatomic constraints of the T1-T2 pedicles. For these reasons, an alternate fixation technique at T1-T2 that combines ease of screw insertion and a favorable safety profile with biomechanical stability would be clinically beneficial. A 6-degree of freedom spine simulator was used to test multidirectional flexibility in 8 human cadaveric specimens. Flexion, extension, lateral bending, and axial rotation were tested in the intact condition, followed by destabilization via a simulated 2-column injury at C7-T1. Specimens were reconstructed using C5-C6 lateral mass screws and either translaminar or pedicle screws placed at T1, followed by caudal extension to T2. A 3-column injury at C7-T1 was then performed and specimens were tested using a posterior only approach with either translaminar or pedicle screws placed at T1 and T1-T2. Finally, anterior fixation at C7-T1 was added and multidirectional flexibility testing performed as previously described. Following a 2-column injury at C7-T1, there were no significant differences in segmental flexibility at C7-T1 between translaminar and pedicle screw fixation when placed at T1-T2 (P>0.05). For a 3-column injury treated posteriorly, translaminar screws at T1-T2 provided increased flexibility compared to pedicle screws in flexion/extension (P<0.05). There were no differences in segmental flexibility at C7-T1 between the 2 techniques following the addition of anterior fixation (P>0.05). Translaminar screws in the upper thoracic spine offer similar stability to pedicle screw fixation for constructs bridging the cervicothoracic junction. Small differences in range of motion must be weighed clinically against the potential benefits of translaminar screw insertion at T1-T2.


Examining U.S. Newspapers' Effects on COVID-19 Infection Rates Among Racial/Ethnic Minorities.
Background: The coronavirus disease 2019 (COVID-19) pandemic reveals health disparities in the United States. News media are expected to play a major role in reducing racial/ethnic disparities. Methods: Guided by agenda-setting theory in the context of health promotion and the structural approach of media effects, this study assessed the impacts of COVID-19 newspaper articles about racial/ethnic minorities on minorities' infection rates in the early stages of the pandemic, while controlling for social determinants of health (SDOHs). Results: Racial/ethnic minorities are underrepresented in COVID-19 newspaper articles, although newspapers' attention to racial/ethnic minorities' health increased over time. Public exposure to newspaper articles about racial/ethnic minorities was the only significant factor that predicted infection rates among general racial/ethnic minorities. The more the general public in the United States was exposed to related newspaper articles, the lower the infection rates among general racial/ethnic minorities would be. The impacts of SDOHs varied across different racial/ethnic minority groups. Blue states were more likely to be exposed to COVID-19 newspaper articles about racial/ethnic minorities than red states. Discussion: Findings suggest that news exposure to any racial/ethnic group can benefit all minorities. Findings also demonstrate the influence of media agenda on public agenda and policy agenda regarding minority health.


Indicators of a major depressive episode in primary care patients with a chief complaint of headache.
To identify the indicators of major depressive episode (MDE) in primary care patients with a chief complaint of headache. MDE is very frequent among headache patients in primary care. However, primary care physicians often fail to recognize the coexistence of MDE. A total of 177 consecutive new adult patients who visited 19 primary care clinics from January 2002 to December 2002 with a chief complaint of headache were enrolled in the study. All subjects completed a self-report questionnaire that included questions regarding the duration and severity of their headaches, changes in headache severity, and other symptoms. The questionnaire also identified distressed high utilizers (patients who consulted different doctors for the same episode of an illness, without being referred). MDE was diagnosed using a module of the mini international neuropsychiatric interview (MINI). To identify potential indicators of depression, both univariate analysis and multiple logistic regression analysis were performed. Forty-five of 177 patients (25.4%) fulfilled the diagnostic criteria for MDE. Univariate analysis revealed that severe headache, longer duration of headaches, multiple somatic symptoms, and being a distressed high utilizer were associated with MDE. Multiple logistic regression analysis revealed that patients with headaches lasting 6 months or longer and those with multiple somatic symptoms were more likely to be suffering from MDE (adjusted odds ratios: 3.1, 95% CI: 1.7-10.6; and 3.9, 95% CI: 1.2-8.1, respectively). MDE is highly prevalent in headache patients visiting a primary care setting. Multiple somatic symptoms and longer duration (> or =6 months) of headaches are particularly useful indicators of MDE.


Use of adult day care centers: do they offset utilization of health care services?
Based on the medical offset effect, the goal of the study was to examine the extent to which users and nonusers of adult day care centers (ADCC) differ in frequency of use of out-patient health services (visits to specialists) and in-patient health services (number of hospital admissions, length of hospitalizations, and visits to emergency departments). A case-control study was used with a sample of 800 respondents, of whom 400 were users of 13 day care centers in the southern region of Israel and 400 were nonusers, matched by age, gender, and active family physician. Data collection included face-to-face interviews using a structured questionnaire. Data on health care service utilization were drawn from the central computerized data of one of the health care organizations in Israel. Although users of ADCC significantly differed from nonusers in socioeconomic characteristics, they did not significantly differ from nonusers in the magnitude of health care services' utilization. Utilization of health care services was rather connected with morbidity rather than with use of ADCC. Therefore, no offset effect was found. The current form of ADCC in Israel focuses mainly on meeting social needs of the participants and therefore do not meet the their actual health needs. Therefore, inclusion of health services within ADCC may have an offset effect, but this necessitates further examination.


[Cost-effectiveness analysis of different imaging for the diagnosis of acute pulmonary embolism].
The optimal diagnostic test for detecting acute pulmonary embolism (APE) is still under discussion. The ventilation /perfusion scanning has been the preferred examination for several decades, but with the development of new tests the diagnostic possibilities have increased. It is necessary to evaluate them from the cost-effectiveness perspective. The goal of this study was to evaluate several methods of imaging diagnosis so as to determine the most cost-effective for detecting APE. Cost-effectiveness (CE) analysis using a decision tree to model various diagnostic test (V/Q lung scan, spiral CT, angiography by MDCT, MRI and conventional arteriography). Sensitivity and specificity values, and positive and negative predictive values of diagnostic tests were calculated. Expected outcome: "new APE case detected." The direct costs were evaluated in eurosos (euros), including the secondary complications of diagnostic methods. To assess the robustness of the findings, a one way sensitivity analysis was performed. The most cost-effective diagnostic test was angiography by MDCT. No diagnostic test were eliminated by extended dominance. The crude rate of CE for MDCT was 486 euros per case of APE detected. The marginal cost between spiral CT and V / Q lung scan was euros 103 for 8 cases of APE detected additionally, while the marginal cost between MDCT and spiral CT was 229 euros to detect an additional case of APE. The most cost-effective diagnostic test was the MDCT; this finding showed to be robust in relationship to sensitivity, specificity and costs changes. However, the incremental C-E analysis showed that MDCT was capable to detect only one additional case of APE than spiral CT, with an incremental cost of 229 euros. When peripheral branches are affected, high negative predictive value of the MDCT justify its conduct.


Antioxidative and neuroprotective potential of Acorus calamus linn. and Cordia dichotoma G. Forst. In Alzheimer's type dementia in rodent.
The goal of this research study was to see how plant extracts of Acorus calamus Linn. and Cordia dichotoma G. Forst. overcome scopolamine-induced Alzheimer's type dementia in mice by activating the cholinergic system, anti-oxidant and protection of neuronal death in the brain (hippocampus region). Scopolamine (1 mg/kg i.p.) reduced mice's routine in behavioral parameters such as Morris Water Maze (MWM), Elevated Plus Maze (EPM), and also the locomotor activity. It also decreases antioxidant levels such as Reduced glutathione (GSH) and also Superoxide dismutase (SOD) but also increases the level of Acetylcholinesterase enzyme (AChE) in brain. Assessment of various behavioral, and biochemical parameters (AChE, SOD, GSH, and Nitrite level) were compared with each group. Acorus calamus (hydro-alcoholic 1:1) 600 mg/kg p.o. and the combination (Acorus calamus 600 mg/kg p.o. + Cordia dichotoma 750 mg/kg p.o.) group showed significant results as compared to Cordia dichotoma 750 mg/kg p.o.in behavioral as well as in biochemical parameters. Histological studies showed significant neuroprotection in the Acorus calamus-treated group and the combination-treated groups. In the future, the Acorus calamus and the combination are possibly helpful in the treatment of various cognitive disorders or it may be valuable to investigate the pharmacological potential of such plant extracts during the treatment of neurodegenerative disorders.


The outset of chronic secretory otitis media: a histopathological study of the earliest stage.
Histopathological study of the earliest stage of secretory otitis was made in a 3-month-old infant. The entire mucosa was examined by the whole-mount method, with determination of gland count and goblet-cell density, followed by assessment of serial sections. The first changes are inflammatory with lymphocytic infiltration, dilatation, and increase of blood vessels. These again induce metaplasia into pseudostratified, ciliated epithelium, increased in goblet-cell density, and formation of intraepithelial and subepithelial mucous glands. Basal cells divide and grow down into lamina propria, giving rise to a solid cylinder that gets canalized. Cells of this cylinder differentiate into ciliated and mucous cells, so that tubules acquire a lining of typical pseudostratified, ciliated, columnar epithelium. The most important processes in the early stage of secretory otitis are hyperplasia, differentiation of epithelial cells, and gland formation. When glands have completed their development, they produce mucus that accumulates in the middle ear, and the disease enters the secretory stage.


Resonance properties of Ag-ZnO nanostructures at terahertz frequencies.
Nanoantennas have been fabricated by scaling down traditional antenna designs using nanolithographic techniques and testing them at different optical wavelengths, these particular nanoantennas have shown responses in a broad range of frequencies going from visible wavelengths to the range of the terahertz. Some self-assembled nanostructures exist that exhibit similar shapes and properties to those of traditional antenna structures. In this work the emission and absorption properties of self-assembled nanostructures made of zinc oxide nanorods on silver nanowires, which resemble traditional dipole antennas, were measured and simulated in order to test their antenna performance. These structures show resonant properties in the 10-120 THz range, with the main resonance at 60 THz. The radiation pattern of these nanostructures was also obtained by numerical simulations, and it is shown that it can be tailored to increase or decrease its directivity as a function of the location of the energy source of excitation. Experimental measurements were performed by Raman spectroscopy and Fourier Transform Infrared Spectroscopy (FTIR) in order to show existing vibrational frequencies at the resonant frequencies of the nanostructures, measurements were made from ~9 to 103 THz and the results were in agreement with the simulations. These characteristics make these metal-semiconductor Ag/ZnO nanostructures useful as self-assembled nanoantennas in applications such as terahertz spectroscopy and sensing at terahertz frequencies.


Cellular studies of mammary tissue from cows hormonally induced into lactation: histology and ultrastructure.
Cytological changes were investigated in mammary parenchyma of cows hormonally induced to lactate. Four cows were induced with injections of 17 beta-estradiol plus progesterone (days 1 to 7) and dexamethasone (days 17 to 19). Tissue biopsies were obtained on days 0, 8, 16, and 26; and milking commenced on day 18 or 21 of the treatment period. Mammary tissue of cow A, the most successful animal, showed marked cellular proliferation and differentiation by day 8. By day 16, the parenchyma of cow A had undergone lactogenesis and exhibited histological and ultrastructural characteristics associated with actively secreting mammary tissue. Mammary epithelia of cow D, the least successful animal, showed minimal development by day 8 and ultrastructurally resembled nondifferentiated mammary cells. Mammary parenchyma of cow D had not undergone differentiation and was involuting by day 16. Mammary tissues of cow B and C showed intermediate responses with only slight development by day 16 and only limited areas of secretory activity by day 26. Results suggest that animals successfully induced into lactation undergo critical periods of cellular proliferation and differentiation which unsuccessful animals do not experience. Cytological differences were first evident by day 8, further magnified by day 16 of the treatment period, and subsequently expressed in terms of milk production (peak milk yield equaled 30.5, 10.0, 9.2, and 2.4 kg/day for cows A, B, C, and D).


Evaluation of the Incidence of the Esophagogastric Pre-Cancerous Mucosal Lesions after Bariatric Surgery.
Bariatric surgery is associated with significant risk reduction for obesity-related and hormone-mediated cancers; however, few studies report gastric or esophageal cancer development after bariatric surgery. This study evaluates the incidence of pre-cancerous mucosal lesions one year after bariatric surgery. Eligible patients for omega-loop gastric bypass and classic Roux-en-Y gastric bypass (RYGB) underwent upper endoscopy before bariatric surgery and one year after the procedure. Several biopsies were obtained from esophagogastric mucosa, all of which were evaluated by pathologists regarding the development of any pre-cancerous lesion. A total of 108 patients were included in the study. Seventy-one underwent omega bypass and 37 classic RYGB. Follow-up endoscopy indicated no dysplastic changes in esophagogastric mucosa one year after the surgery. The number of patients with gastric intestinal metaplasia was 22 and 25 before and after the surgery, respectively, which was not a statistically significant increase. Bariatric surgeries might not increase the risk of developing pre-cancerous lesions in the esophagogastric mucosa. Further epidemiological studies may help to establish this finding.


Association of CAT polymorphisms with catalase activity and exposure to environmental oxidative stimuli.
We tested the hypotheses that catalase activity is modified by CAT single nucleotide polymorphisms (SNPs) (-262;-844), and by their interactions with oxidant exposures (coal dusts, smoking), lymphotoxin alpha (LTA, NcoI) and tumor necrosis factor (TNF, -308) in 196 miners. Erythrocyte catalase, superoxide dismutase, and glutathione peroxidase activities were measured. The CAT -262 SNP was related to lower catalase activity (104, 87 and 72 k/g hemoglobin for CC, CT and TT, respectively, p < 0.0001). Regardless of CAT SNPs, the LTA NcoI but not the TNF-308 SNP was associated with catalase activity (p = 0.04 and p = 0.8). CAT -262 T carriers were less frequent in highly exposed miners (OR = 0.39 [0.20-0.78], p = 0.007). In CAT -262 T carriers only, catalase activity decreased with high dust exposure (p = 0.01). Haplotype analyses (combined CAT SNPs) confirm these results. Results show that CAT -262 and LTA NcoI SNPs, and interaction with coal dust exposure, influenced catalase activity.