Adsorption of gamma-globulin, a model protein for antibody, on colloidal particles.
The effect of surface properties on the adsorption of bovine gamma-globulin, a model protein for antibody, was studied. Polystyrene latex (PS), hydrophilic copolymer lattices of styrene/2-hydroxyethyl methacrylate [P(S/HEMA)], styrene/ methacrylic acid [P(S/MAA)] and methyl methacrylate/ 2-hydroxyethyl methacrylate [P(MMA/HEMA)], and colloidal silica were used. The adsorption isotherms of gamma-globulin on these colloidal particles were measured as a function of pH and ionic strength. The hydrophilic particles showed low affinities for gamma-globulin at alkaline pH, while PS showed high affinities for gamma-globulin over the whole range of pH and ionic strength. The gamma-globulin adsorption on hydrophilic particles was highly reversible with respect to the pH and ionic strength compared with that on PS. These differences indicate that the dominant driving forces of adsorption are related to the hydrophilicity of particles. The adsorption isotherms of all colloidal particles showed the plateau values, and the order of maximum values of plateau adsorption was P(S/MAA) > PS or P(S/HEMA), silica > P(MMA/HEMA). Thus, they were also affected by the charged groups and the hydrophilicity of the surfaces. On the other hand, the plateau values of all colloidal particles were more or less symmetrical with a maximum at around the isoelectric point of gamma-globulin at an ionic strength of 0.01. This behavior is attributed to the important role of the lateral interaction between the adsorbed molecules at low ionic strength.


Clinical and histologic variations among thirty patients with Lucio's phenomenon and pure and primitive diffuse lepromatosis (Latapi's lepromatosis).
The clinical and histologic experience with 30 patients who had Lucio's phenomenon, and pure and primitive diffuse lepromatosis (Latapi's lepromatosis) has been reviewed. The unanticipated clinical findings were a male to female ratio of nearly 1:1, a 21 month median time of onset of erythema nodosum leprosum (Type 2 reaction) after starting antibacterial treatment, and an absence of a stocking-glove pattern of anesthesia in 7 patients. The only unanticipated histologic finding was a lepromatous-granulomatous vasculitis, occurring in comparatively large vessels, or in vessels made large by pathologic changes, located near the dermal-subcutaneous interface. This finding was present in 6 of the 22 patients with histologic material available for review. In 2 of these 6 this vasculitis was identified before the onset of Lucio's phenomenon. With one conspicuous exception, the onset of treatment with a microbicidal agent was associated with a cessation of new lesions of Lucio's phenomenon within one week. Long-term morbidity, other than Type 2 reaction, was found in 22 of the 25 patients followed for more than 1.3 years. Usually this was the consequence of Latapi's lepromatosis, specifically venous insufficiency and/or loss of protective sensation, and only rarely from Lucio's phenomenon, specifically scar formation. Briefly summarized are the seven patients who had had a skin biopsy before the onset of Lucio's phenomenon, as well as the two patients who were considered to be atypical. Criteria for the diagnosis of Latapi's lepromatosis, in the absence of Lucio's phenomenon, are also considered.


Mechanisms responsible for increased circulating levels of galectin-3 in cardiomyopathy and heart failure.
Galectin-3 is a biomarker of heart disease. However, it remains unknown whether increase in galectin-3 levels is dependent on aetiology or disease-associated conditions and whether diseased heart releases galectin-3 into the circulation. We explored these questions in mouse models of heart disease and in patients with cardiomyopathy. All mouse models (dilated cardiomyopathy, DCM; fibrotic cardiomyopathy, ischemia-reperfusion, I/R; treatment with β-adrenergic agonist isoproterenol) showed multi-fold increases in cardiac galectin-3 expression and preserved renal function. In mice with fibrotic cardiomyopathy, I/R or isoproterenol treatment, plasma galectin-3 levels and density of cardiac inflammatory cells were elevated. These models also exhibited parallel changes in cardiac and plasma galectin-3 levels and presence of trans-cardiac galectin-3 gradient, indicating cardiac release of galectin-3. DCM mice showed no change in circulating galectin-3 levels nor trans-cardiac galectin-3 gradient or myocardial inflammatory infiltration despite a 50-fold increase in cardiac galectin-3 content. In patients with hypertrophic cardiomyopathy or DCM, plasma galectin-3 increased only in those with renal dysfunction and a trans-cardiac galectin-3 gradient was not present. Collectively, this study documents the aetiology-dependency and diverse mechanisms of increment in circulating galectin-3 levels. Our findings highlight cardiac inflammation and enhanced β-adrenoceptor activation in mediating elevated galectin-3 levels via cardiac release in the mechanism.


Ciona as a Simple Chordate Model for Heart Development and Regeneration.
Cardiac cell specification and the genetic determinants that govern this process are highly conserved among Chordates. Recent studies have established the importance of evolutionarily-conserved mechanisms in the study of congenital heart defects and disease, as well as cardiac regeneration. As a basal Chordate, the Ciona model system presents a simple scaffold that recapitulates the basic blueprint of cardiac development in Chordates. Here we will focus on the development and cellular structure of the heart of the ascidian Ciona as compared to other Chordates, principally vertebrates. Comparison of the Ciona model system to heart development in other Chordates presents great potential for dissecting the genetic mechanisms that underlie congenital heart defects and disease at the cellular level and might provide additional insight into potential pathways for therapeutic cardiac regeneration.


Post-COVID-19 assessment in a specialist clinical service: a 12-month, single-centre, prospective study in 1325 individuals.
Post-COVID-19 complications require simultaneous characterisation and management to plan policy and health system responses. We describe the 12-month experience of the first UK dedicated post-COVID-19 clinical service to include hospitalised and non-hospitalised patients. In a single-centre, observational analysis, we report the demographics, symptoms, comorbidities, investigations, treatments, functional recovery, specialist referral and rehabilitation of 1325 individuals assessed at the University College London Hospitals post-COVID-19 service between April 2020 and April 2021, comparing by referral route: posthospitalised (PH), non-hospitalised (NH) and post emergency department (PED). Symptoms associated with poor recovery or inability to return to work full time were assessed using multivariable logistic regression. 1325 individuals were assessed (PH: 547, 41.3%; PED: 212, 16%; NH: 566, 42.7%). Compared with the PH and PED groups, the NH group were younger (median 44.6 (35.6-52.8) years vs 58.3 (47.0-67.7) years and 48.5 (39.4-55.7) years), more likely to be female (68.2%, 43.0% and 59.9%), less likely to be of ethnic minority (30.9%, 52.7% and 41.0%) or seen later after symptom onset (median (IQR): 194 (118-298) days, 69 (51-111) days and 76 (55-128) days; all p<0.0001). All groups had similar rates of onward specialist referral (NH 18.7%, PH 16.1% and PED 18.9%, p=0.452) and were more likely to require support for breathlessness (23.7%, 5.5% and 15.1%, p<0.001) and fatigue (17.8%, 4.8% and 8.0%, p<0.001). Hospitalised patients had higher rates of pulmonary emboli, persistent lung interstitial abnormalities and other organ impairment. 716 (54.0%) individuals reported <75% optimal health (median 70%, IQR 55%-85%). Less than half of employed individuals could return to work full time at first assessment. Post-COVID-19 symptoms were significant in PH and NH patients, with significant ongoing healthcare needs and utilisation. Trials of interventions and patient-centred pathways for diagnostic and treatment approaches are urgently required.


Prefrontal cortical contributions to working memory: evidence from event-related fMRI studies.
Working memory refers to the short-term retention of information that is no longer accessible in the environment, and the manipulation of this information, for subsequent use in guiding behavior. In this review, we will present data from a series of event-related functional magnetic-resonance-imaging (fMRI) studies of delayed-response tasks that were designed to investigate the role of different regions of the prefrontal cortex (PFC) during different working-memory component processes. From these data, we conclude that: (1) lateral PFC is anatomically organized according to the types of cognitive operations that one performs when attempting to temporarily maintain and manipulate information; and (2) consistent with the picture that has emerged from the monkey electrophysiological literature, human lateral PFC is involved in several encoding- and response-related processes as well as mnemonic and nonmnemonic processes that are engaged during the temporary maintenance of information. Thus, lateral PFC activity cannot be ascribed to the function of a single, unitary cognitive operation.


[Systematic analysis of the geometry of a defined contrast medium bolus--implications for contrast enhanced 3D MR-angiography of thoracic vessels].
Little is known about the dispersion of a defined contrast bolus during its passage through the heart and pulmonary vasculature. The purpose of this study was to analyze factors influencing a defined contrast bolus for ce-MRA of thoracic vessels. For analysis of bolus geometry, an ECG-gated saturation-recovery Turbo-Flash sequence with a TI of 20 msec was used. It was acquired axially at the level of the pulmonary trunc, so that with one data acquisition a curve analysis was possible in the ascending and descending aorta, and in the pulmonary trunc. Twenty-nine patients received 3 ml of Gd-DTPA diluted with saline to a total of 20 ml. Contrast injection was done using a MR compatible power injector with injection rates varying between 1, 2 and 4 ml/sec. Each injection was followed by a saline flush of 20 ml with the same injection rate and mode. Cardiac function was assessed by cine imaging, and phase contrast measurements. After normalization to baseline signal intensity (SI), bolus curves were fitted using a gamma-variate fit and peak signal intensity (peak SI), time-to-peak (TP), upslope, mean transit time (MTT) and dispersion of the contrast bolus were calculated. Furthermore, T (1) and [Gd] in the experimental setting were calculated as follows: T (1) = T (1 o)/ ln [SI/SI (0)], and [Gd] (exp) = [1/T (1) - 1/T (1 o)]/ R (1.) They were then extrapolated [Gd] to clinical conditions by [Gd] (clin) = [Gd] (exp) . 10/1.5, and minimal blood T (1) by T (1)(clin) = 1 / [1/T (1 o) + R (1) [Gd] (clin)]. With increasing injection rate, there was a significant decrease (p < 0.001) of MTT in all target vessels. However, this decrease was not linear: a 4-fold increase in injection rate lead to a 2-fold decrease in MTT e. g. in the ascending aorta. MTT was significantly shorter in the pulmonary trunc compared with that in the ascending and descending aorta (p < 0.001), regardless of injection rate (p < 0.001). Vice versa, dispersion of the contrast bolus was significantly lower in the pulmonary trunc, and increased with higher injection rates. There was no clinically relevant difference in minimal blood T (1) between the different target vessels, for clinical conditions extrapolated values ranged between 20 und 79 msec. Heart function parameters only had a minor influence of bolus curve parameters. Analysis of bolus geometry enables determination of transit times of a defined contrast bolus through a defined target vessel in the thoracic cavity. Bolus geometry is mainly determined by injection parameters, cardiac function is of minor importance. Dispersion of contrast bolus and MTT increase from the pulmonary trunc to the ascending aorta. The knowledge of these facts may help optimizing of injection parameters and the total amount of contrast agent for contrast-enhanced MRA of thoracic vessels.


[Evaluation of the effectiveness of a school-based alcohol and cannabis prevention programme among adolescents.]
Alcohol and cannabis consumption in young people aged 14 to 18 years show high and stable prevalence and incidence. The Instituto de Adicciones de Madrid Salud (IAMS) within its prevention strategy aimed at adolescents and young people in Madrid, implements an universal 3-sessions school-based prevention program. To evaluate the effectiveness of a program aimed at alcohol and cannabis from the Theory of Planned Behavior (TPB, Ajzen, 1991), we analysed the changes in consumption and intention of consumption, attitudes and subjective norm as well as in the risk perception. Quasi-experimental design. Participants: Over 1,529 students belonging to 12 high schools in Madrid (M=15.36 years, DT=1.13, range: 13-18, 51.8% boys) Experimental group: N=790, intervention period October-December 2018. Control group: N=469. The Student's t test was used for the repeated means test. When the difference between the means was significant, the effect size was calculated using Cohen's d index. Alcohol: consumption (t=2.08, p<0.05, d=0.07), intention (t=3.01, p<0.01, d=0.12), risk perception (t=-502, p<0.001, d=0.20), attitudes (t=5.77, p<0.001, d=0.21), subjective norm (t=2.17, p<0.05, d=0.08). Cannabis: intention (t=2.98, p<0.01, d=0.11), risk perception (t=-3.99, p<0.001, d=0.14), attitudes (t=6.19, p<0.001, d=0.23). Students who received the intervention reduced the favourable attitudes and intention of alcohol and cannabis consumption and alcohol consumption, and increased the risk perception on both substances, with significant differences, but low effect sizes. Related to control group and regarding cannabis there were no significant differences. The program has been shown to be potentially effective, but would benefit from a review for fit to its theoretical framework.


Potential role of amino acids in pathogenesis of schizophrenia.
Schizophrenia is a syndrome of inconclusive etiopathogenesis with a prevalence of about 1% in general population. Underlying factors include genetic predisposition and defected neurodevelopment in early stages of life. The role of amino acids has been indicated in some reports. However, very few workers have detailed the effect of each amino acid in the pathophysiology of schizophrenia. Thus, in the present review, we aimed to provide an insight into the potential role of amino acids levels during schizophrenia. Any single amino acid defect cannot lead to the development of the disease. Higher concentration of glycine, serine, glutamate, homocysteine, and arginine are reported by many scientists in blood samples of patients of schizophrenia. Levels of rest of the amino acids show inconsistent results. Involvement of glutamate in pathophysiology of schizophrenia was hypothesized as early as the 1980s. It was demonstrated that dissociative anesthetics which are N-methyl-D-aspartate (NMDA) receptor antagonists can produce all negative, psychotic, cognitive, and physiological features of schizophrenia in healthy controls. This led to the development of hypothesis of NMDA receptor hypofunctioning in the pathophysiology of schizophrenia. Later on, it was also found that agents enhancing functioning of NMDA receptor at glycine modulatory site, improved symptoms in patients of schizophrenia receiving antipsychotic medications. Thus, the relationship of perturb amino acid levels with the biological basis and pathophysiology of schizophrenia is an important area to be further explored for effective management of schizophrenic patients.


Beneficial Effects of Dietary Nitrate on Endothelial Function and Blood Pressure Levels.
Poor eating habits may represent cardiovascular risk factors since high intake of fat and saturated fatty acids contributes to dyslipidemia, obesity, diabetes mellitus, and hypertension. Thus, nutritional interventions are recognized as important strategies for primary prevention of hypertension and as adjuvants to pharmacological therapies to reduce cardiovascular risk. The DASH (Dietary Approach to Stop Hypertension) plan is one of the most effective strategies for the prevention and nonpharmacological management of hypertension. The beneficial effects of DASH diet on blood pressure might be related to the high inorganic nitrate content of some food products included in this meal plan. The beetroot and other food plants considered as nitrate sources account for approximately 60-80% of the daily nitrate exposure in the western population. The increased levels of nitrite by nitrate intake seem to have beneficial effects in many of the physiological and clinical settings. Several clinical trials are being conducted to determine the broad therapeutic potential of increasing the bioavailability of nitrite in human health and disease, including studies related to vascular aging. In conclusion, the dietary inorganic nitrate seems to represent a promising complementary therapy to support hypertension treatment with benefits for cardiovascular health.


[Unilateral congenital anophthalmos with Trabecular agenesia and hydrophthalmos of the other eye (author's transl)].
In a one-year-old female patient, unilateral anophthalmos was ascertained by clinical, echographic and X-ray examination. In addition, the cranial computer tomogram showed trabecular agenesia. The globe of the other eye was existent and was enlarged by hydrophthalmos. Pediatrically this case represents a syndrome with multiple anomalies of etiologically unknown origin; apart from the ocular malformation there are a severe cerebral developmental disturbance, an apallic syndrome, hypsarrhythmia, peculiar disproportional bodily structure with skeletal anomalies as well as an abnormal susceptibility to infections of the respiratory system and a marked, isolated IgA-deficiency. Neither chromosomal anomaly nor familiarity was discovered.


Distinct ATOH1 and Neurog3 requirements define tuft cells as a new secretory cell type in the intestinal epithelium.
The unique morphology of tuft cells was first revealed by electron microscopy analyses in several endoderm-derived epithelia. Here, we explore the relationship of these cells with the other cell types of the intestinal epithelium and describe the first marker signature allowing their unambiguous identification. We demonstrate that although mature tuft cells express DCLK1, a putative marker of quiescent stem cells, they are post-mitotic, short lived, derive from Lgr5-expressing epithelial stem cells, and are found in mouse and human tumors. We show that whereas the ATOH1/MATH1 transcription factor is essential for their differentiation, Neurog3, SOX9, GFI1, and SPDEF are dispensable, which distinguishes these cells from enteroendocrine, Paneth, and goblet cells, and raises from three to four the number of secretory cell types in the intestinal epithelium. Moreover, we show that tuft cells are the main source of endogenous intestinal opioids and are the only epithelial cells that express cyclooxygenase enzymes, suggesting important roles for these cells in the intestinal epithelium physiopathology.


Fine-structure resolved rovibrational transitions for SO + H2 collisions.
Cross sections and rate coefficients for sulfur monoxide (SO) + H2 collisions are calculated using a full six-dimensional (6D) potential energy surface (PES). The coupled states (CS) approximation is used to compute fine-structure resolved cross sections for rovibrational transitions between states with v = 0-2, where v is the vibrational quantum number of the SO molecule. The CS calculations for Δv = 1 are benchmarked against close-coupling (CC) results for spin-free interactions. For Δv = 0, the present fine-structure resolved CS results are benchmarked against existing CC results obtained with a rigid rotor approximation. In both cases, the agreement is found to be satisfactory, which suggests that the present results may provide reliable estimates for fine-structure resolved rovibrational transitions. These estimates are the first of their kind based on a full 6D PES. Rate coefficients are reported for temperatures between 10 K and 3000 K for both para- and ortho-H2 colliders. A comparison of the para-H2 rates with mass-scaled results for He shows substantial differences that may be important in astrophysical models.


PillCamColon Capsule for the study of colonic pathology in clinical practice. Study of agreement with colonoscopy.
several studies have pointed out the effectiveness of the PillCam colon capsule endoscopy (CCE) compared with the colonoscopy in the study of the colonic pathology. the objective of our study was to assess the agreement in the diagnosis of CCE with conventional colonoscopy as well as its sensitivity and specificity, and to describe the findings of the CCE in our clinical practice. Consecutive patients with abdominal symptoms were included in the study. The CCE was performed as previously reported (with PEG and sodium phosphate as laxative agents). The nature and location of the findings, colonic transit time, complications, cleanliness degree and consistency with diagnostic colonoscopy, when performed, were analyzed. a total of 144 subjects (67 women and 77 men); (52.17 ± 16.71 years) with the following indications were included: screening of Colorectal cancer (88 patients), control after polipectomy (24), incomplete colonoscopy (7), rectal bleeding (10), anemia (8), diarrhea (7). The CCE exploration was complete in 134/144 cases (93%), with no case of retention. The preparation was good-very good in 88/134 (65,6%), fair in 26/134 (19,4%) and poor in 20/134 (15%) of the cases. The average colonic transit was of 140.76 min (9-603). Any adverse effect was notified.In 44 cases a colonoscopy was carried out after CCE (results were hidden from another endoscopist). Compared to colonoscopy, the rate of agreement was 75,6%, the sensitivity was 84% and the specificity 62,5%, PPV was 77,7% and NPV was 71,4%.The colonic findings in 134 CCE were: in 34 cases CCE it did not show lesions, diverticulosis in 63 explorations, polyps in 43, angiodysplasias in 15, Crohn's Disease in 9 and ulcerative colitis in other 8 cases. the CCE is an effective and reliable technique for the detection of lesions in colon, and because of its high agreement with the colonoscopy, it could be useful in clinical practice. Further studies with large seria and cost-effectiveness analysis are needed to confirm these data.


Ab initio prediction of the critical thickness of a precipitate.
Segregation and precipitation of second phases in metals and metallic alloys is an important phenomenon that has a strong influence on the mechanical properties of the material. Models exist that describe the growth of coherent, semi-coherent and incoherent precipitates. One important parameter of these models is the energy of the interface between matrix and precipitate. In this work we apply ab initio density functional theory calculations to obtain this parameter and to understand how it depends on chemical composition and mechanical strain at the interface.Our example is a metastable Mo-C phase, the body-centred tetragonal structure, which exists as a semi-coherent precipitate in body-centred cubic molybdenum. The interface of this precipitate is supposed to change from coherent to semi-coherent during the growth of the precipitate. We predict the critical thickness of the precipitate by calculating the different contributions to a semi-coherent interface energy by means of ab initio density functional theory calculations. The parameters in our model include the elastic strain energy stored in the precipitate, as well as a misfit dislocation energy that depends on the dislocation core width and the dislocation spacing. Our predicted critical thickness agrees well with experimental observations.


Idiopathic membranous occlusion of the foramen of Monro: an unusual cause of hydrocephalus and headache in adults.
Occlusion of foramen of Monro is an uncommon clinical entity that usually presents in children. Common causes are obstructing mass, infectious etiologies or vascular malformation. Rarely, it may be an idiopathic stricture or membrane. We report a case of idiopathic membranous obstruction of the foramen of Monro in a 45-year-old male with no past medical or surgical history. He presented with new intermittent dull and burning bifrontal severe headache for 2 d, which was alleviated slightly by non-steroidal anti-inflammatory medication. Imaging showed marked dilation of the lateral ventricles with normal third and fourth ventricles. The patient was discharged initially with conservative medical management and close follows up; however, the headache continued to progress and neurosurgical intervention was offered. The patient underwent endoscopic exploration, fenestration of the septum pellucidum, and right ventriculoperitoneal shunt placement. Bilateral membranous obstruction of foramina of Monro and an auto-fenestrated cavum septum pellucidum were identified intraoperatively. The patient reported resolution of headache post-operatively without recurrence on 1-month follow up. This case is unusual in that the patient presented without any known neurologic history or prior intracranial infections. It became apparent at the time of surgery that chronic obstruction of the bilateral foramina with collapse of the third ventricle had developed, and the safest durable treatment for him was septostomy and cerebrospinal fluid (CSF) shunt placement.


'All the burden on all the carers': exploring quality of life with family caregivers of Huntington's disease patients.
Existing research suggests that family caregivers of persons with Huntington's disease face a unique series of problems, linked to the complex nature of the disease. There is little research that explicitly investigates the impact of HD on the quality of life (QoL) of the family caregiver. The purpose of this study was to explore the quality of life issues for family carers of Huntington's disease patients in a focus group setting. Participants were recruited via a Huntington's Disease Association (HDA) family conference day. Six semi-directed focus groups (n = 47) explored disease-specific aspects of QoL that were deemed important to family carers of this carer group. Data were analysed using Interpretative Phenomenological Analysis (IPA). Analysis of the focus group data identified four superordinate themes: 'Levels of Support', 'Dissatisfaction with Caregiving Role', 'Practical Aspects of Caring' and 'Feelings and Emotional Well-being'. These data provide evidence that QoL is compromised in many ways for HD family carers. The carers in this study often negated their own needs as their caregiving role overwhelmed them and 'took over' their lives.


[Cryptococcus meningitis: clinical course, development and histopathologic aspects depending on the predisposing factors].
Seventeen consecutive cases of cryptococcal meningitis diagnosed at Hospital das Clínicas of Ribeirão Preto Medical School (São Paulo State Brazil) between 1969 and 1985 were reviewed. For analysis the patients were separated in 3 groups: I. three patients without immunodeficiency; II. six patients with associated disease: cancer (3), diabetes (2) and alcoholism (1); III. Eight renal transplant recipients that developed cryptococcosis after 18 to 67 months of immunosupression with steroids and azathioprine. The median interval between onset of symptoms and diagnosis of infection was greater in Group II (53 days) than in Groups I (25 days) or III (28 days). Neck stiffness, cranial nerve involvement and papilledema were more frequent in Group I than in Group II or III, but fever and focal neurological signs were observed only in patients of two last groups. Cerebrospinal fluid examination showed a mild lymphocytic pleocytosis in most patients, but transplant cases had polymorphonuclear cells more frequently. Late mortality was higher in patients with underlying disease and the prognosis was better for transplant patients that received effective antifungal therapy. Besides cryptococci, autopsy findings in 8 cases revealed granuloma formation in tissues, except in patients of Group II (2 cases). The differences between the groups suggest that clinical characteristics, evolution and postmortem findings of the cryptococcal meningitis are changed according to type of immunodeficiency presented by the patient.


Coordination of Kinesin motors pulling on fluid membranes.
Intracellular transport relies on the action of motor proteins, which work collectively to either carry small vesicles or pull membranes tubes along cytoskeletal filaments. Although the individual properties of kinesin-1 motors have been extensively studied, little is known on how several motors coordinate their action and spatially organize on the microtubule when pulling on fluid membranes. Here we address these questions by studying, both experimentally and numerically, the growth of membrane tubes pulled by molecular motors. Our in vitro setup allows us to simultaneously control the parameters monitoring tube growth and measure its characteristics. We perform numerical simulations of membrane tube growth, using the experimentally measured values of all parameters, and analyze the growth properties of the tube considering various motor cooperation schemes. The comparison of the numerical results and the experimental data shows that motors use simultaneously several protofilaments of a microtubule to pull a single tube, as motors moving along a single protofilament cannot generate the forces required for tube extraction. In our experimental conditions, we estimate the average number of motors pulling the tube to be approximately nine, distributed over three contiguous protofilaments. Our results also indicate that the motors pulling the tube do not step synchronously.


Observation of Sub-10 nm Transition Metal Dichalcogenide Nanocrystals in Rapidly Heated van der Waals Heterostructures.
Two-dimensional materials, such as transition metal dichalcogenides (TMDCs), have the potential to revolutionize the field of electronics and photonics due to their unique physical and structural properties. This research presents a novel method for synthesizing crystalline TMDCs crystals with <10 nm size using ultrafast migration of vacancies at elevated temperatures. Through in situ and ex situ processing and using atomic-level characterization techniques, we analyzed the shape, size, crystallinity, composition, and strain distribution of these nanocrystals. These nanocrystals exhibit electronic structure signatures that differ from the 2D bulk: i.e., uniform mono- and multilayers. Further, our in situ, vacuum-based synthesis technique allows observation and comparison of defect and phase evolution in these crystals formed under van der Waals heterostructure confinement versus unconfined conditions. Overall, this research demonstrates a solid-state route to synthesizing uniform nanocrystals of TMDCs and lays the foundation for materials science in confined 2D spaces under extreme conditions.


The effect of a skilled reaching task on hippocampal plasticity after intracerebral hemorrhage in adult rats.
[Purpose] The primary objective of this study was to assess the effects of a skilled reaching task on cognition, as indexed by the pattern of GAP-43 expression in the hippocampus, following intracerebral hemorrhage (ICH) in rats (when the hippocampus plays a critical role in spatial memory and learning). [Subjects and Methods] The model of ICH used in the present study involved intrastriatal injection of collagenase. Sixty male Sprague-Dawley rats (aged 12 weeks) were randomly assigned to either a control (n = 30; CON) or skilled reaching training group (n = 30; SRT). The SRT group were trained 5 days per week for 4 weeks following ICH. Animals were sacrificed 1, 2, or 4 weeks after ICH. Western blot analysis was used to evaluate GAP-43 expression. [Results] GAP-43 expression was increased in the SRT group, in accordance with greater elapsed time, but decreased in the CON group. At 1 week post injury, there were no significant differences between the CON and SRT groups. However, there were significant differences at both 2 and 4 weeks. [Conclusion] The present findings suggest that increased GAP-43 expression in the hippocampus following skilled reaching training may result in enhanced cognition and neural plasticity following ICH.


[Carcinoma of the esophagus: clinical, radiologic, endoscopic, and histologic evaluation. Experience in Torreón City, Coahuila].
Between january 1981 to may 1988, we performed 2,478 flexible esophagogastro-duodenoscopies in adult patients; in 90 patients we suspected esophageal carcinoma. Only in 79 we corroborated the diagnosis in clinical, radiological, endoscopical and histopathological basis. Male were commonest than female (3.5:1). The clinical picture included dysphagia and weight loss. Endoscopically, location was commonest in medium esophagus, with infiltrative type and histo-pathologically squamos cell carcinoma. The endoscopy showed a sensibility of 92% and specificity of 84% in esophageal cancer diagnosis.


Liver conditioning after cardiac arrest: the use of normothermic recirculation in an experimental animal model.
The aim of this study was to compare the possible role of normothermic recirculation with the role of liver transplants from non-heart-beating donor pigs after 20 min of cardiac arrest. Three groups were studied, of which two were control groups: group 1, in which the liver was harvested from a heart-beating donor; group 2, in which the liver was harvested after a period of cardiac arrest followed by total body cooling; and group 3, in which the liver was procured as in group 2, but including a period of 30 min of cardiopulmonary bypass and tissue oxygenation at 37 degrees C before total body cooling. Survival at 5 days; endothelial (hyaluronic acid) and hepatocellular damage (AST, ALT, and alpha-GST); adenine nucleotides (energy charge), and histological changes were evaluated. Normothermic recirculation during 30 min showed a significant effect on survival (p = .03), endothelial damage (p < .05), and histological changes after reperfusion (p = .04). Cardiopulmonary bypass significantly increased the energy charge during the normothermic recirculation period (p = .001). Moreover, this study shows that a significant survival (100%) can be achieved with a liver allograft after 20 min of cardiac arrest. Although the liver suffers a major insult in terms of endothelial damage and hepatocellular damage, lesions caused by the ischemic injury are reversible. Histological changes also indicate lesion reversibility, since they almost disappear after 5 days.


Alcohol's effects on emotionally motivated attention, defensive reactivity and subjective anxiety during uncertain threats.
Developing a better understanding of how and under what circumstances alcohol affects the emotions, cognitions and neural functions that precede and contribute to dangerous behaviors during intoxication may help to reduce their occurrence. Alcohol intoxication has recently been shown to reduce defensive reactivity and anxiety more during uncertain vs certain threat. However, alcohol's effects on emotionally motivated attention to these threats are unknown. Alcohol may disrupt both affective response to and attentional processing of uncertain threats making intoxicated individuals less able to avoid dangerous and costly behaviors. To test this possibility, we examined the effects of a broad range of blood alcohol concentrations on 96 participants' sub-cortically mediated defensive reactivity (startle potentiation), retrospective subjective anxiety (self-report) and cortically assessed emotionally motivated attention (probe P3 event related potential) while they experienced visually cued uncertain and certain location electric shock threat. As predicted, alcohol decreased defensive reactivity and subjective anxiety more during uncertain vs certain threat. In a novel finding, alcohol dampened emotionally motivated attention during uncertain but not certain threat. This effect appeared independent of alcohol's effects on defensive reactivity and subjective anxiety. These results suggest that alcohol intoxication dampens processing of uncertain threats while leaving processing of certain threats intact.


[Involvement of Daikou Sunadabashi Clinic in home care to home death].
Daikou Sunadabashi Clinic provides continuous advanced medical treatment and visiting nursing services for patients with serious diseases till their death at home. The clinic has been involved in home care of 72 patients in total during the period from April 2002 to July 1 of 2003. Of the patients, 40 patients died to date and 71% (32 patients) of them died at home. 49 of the 72 patients (70%) had terminal cancer and mostly required advanced home care. The clinic provides services according to the following principles till the death of the patients: (1) All of our medical staff pool their information and stay in very close communication with one another. (2) The attending physician gives a complete explanation of the patient's condition to his/her family. (3) The staffs respond to emergency calls around the clock using 2 cell phones. Under this very meticulous and fast-response system, seriously ill patient can receive continuous and high-quality treatment at home and die at home even if the family is not adequately capable of providing care.


Involvement of heme oxygenase as antioxidant defense in soybean nodules.
We have previously demonstrated that the inducible form of heme oxygenase plays a critical role in protecting against oxidative stress in mammals. To gain further insight into the functions of this enzyme in plants, we have tested its activity and expression in soybean nodules subjected to cadmium (Cd) stress. Four-weeks-old soybean nodulated plants were treated with different cadmium chloride concentrations (0, 50 and during 48 h. Oxidative stress parameters such as TBARS content, GSH levels and antioxidant enzyme activities were measured as well as heme oxygenase activity and expression. Besides, the effect of biliverdin and Zn-protophorphyrin IX were analyzed. Treatment with 200 microM Cd during 48 h caused a 67% increase in TBARS content, whereas GSH decreased 44%, and total superoxide dismutase, gluthatione reductase and guaiacol peroxidase were also inhibited 54, 20 and 60%, respectively. A total of Cd produced the overexpression of heme oxygenase-1, as well as a 10-fold enhancement of its activity. Co-administration of biliverdin (10 microM) completely prevented the effects caused by Cd. Treatment with Zn protoporphyrin IX, a strong inhibitor of heme oxygenase, expectedly decreased heme oxygenase-1 activity to half. When the inhibitor was given together with Cd, completely prevented the enzyme induction and oxidative stress parameters were significantly enhanced. Taking together, these results are indicating that heme oxygenase plays a protective role against oxidative cell damage in soybean nodules.


Decorin transfection induces proteomic and phenotypic modulation in breast cancer cells 8701-BC.
Decorin is a prototype member of the small leucine-rich proteoglycan family widely distributed in the extracellular matrices of many connective tissues, where it has been shown to play multiple important roles in the matrix assembly process, as well as in some cellular activities. A major interest for decorin function concerns its role in tumorigenesis, as growth-inhibitor of different neoplastic cells, and potential antimetastatic agent. The aim of our research was to investigate wide-ranged effects of transgenic decorin on breast cancer cells. To this purpose we utilized the well-characterized 8701-BC cell line, isolated from a ductal infiltrating carcinoma of the breast, and two derived decorin-transfected clones, respectively, synthesizing full decorin proteoglycan or its protein core. The responses to the ectopic decorin production were examined by studying morphological changes, cell proliferation rates, and proteome modulation. The results revealed new important antioncogenic potentialities, likely exerted by decorin through a variety of distinct biochemical pathways. Major effects included the downregulation of several potential breast cancer biomarkers, the reduction of membrane ruffling, and the increase of cell-cell adhesiveness. These results disclose original aspects related to the reversion of malignant traits of a prototype of breast cancer cells induced by decorin. They also raise additional interest for the postulated clinical application of decorin.


Application of robotic lower limb orthosis for people with lower limb dysfunction.
Due to the aging of the population or diseases, the number of patients with lower limb disorders has increased, causing social concern. Scholars have designed and developed advanced robotic lower limb orthoses, which can guide patients to perform reasonable rehabilitation training with correct limb postures, enhance their daily life participation and quality of life, and help them recover quickly. In recent years, a large number of new and advanced orthopedic equipment have been developed, which require a systematic summary analysis and comparison. This article reviewed typical newly developed, robotic lower limb orthoses and their use effects, as well as the advanced theories and technologies for their applications, and systematically discussed the problems in the research, design, testing, use, and popularization of robotic lower limb orthoses, and predicted their development direction in the future research and design, to enhance the reliability, convenience, and protection functions of orthotic equipment, make its functions closer to life, and give full play to the initiative of patients in the process of rehabilitation training, and reduce costs. Robotic lower limb orthoses is poised for even greater success and development in the future.


Lead poisoning from complementary and alternative medicine in multiple sclerosis.
A patient with multiple sclerosis is described who was treated for neurological symptoms thought to be a progression of his disease but subsequently found to be caused by lead poisoning secondary to the use of alternative medicine. His clinical signs improved with oral chelation therapy. Neurologists should consider asking about the use of complementary and alternative medicine before simply attributing symptoms and signs to exacerbation of multiple sclerosis.


Polymerase δ-interacting protein 2 promotes postischemic neovascularization of the mouse hindlimb.
Collateral vessel formation can functionally compensate for obstructive vascular lesions in patients with atherosclerosis. Neovascularization processes are triggered by fluid shear stress, hypoxia, growth factors, chemokines, proteases, and inflammation, as well as reactive oxygen species, in response to ischemia. Polymerase δ-interacting protein 2 (Poldip2) is a multifunctional protein that regulates focal adhesion turnover and vascular smooth muscle cell migration and modifies extracellular matrix composition. We, therefore, tested the hypothesis that loss of Poldip2 impairs collateral formation. The mouse hindlimb ischemia model has been used to understand mechanisms involved in postnatal blood vessel formation. Poldip2(+/-) mice were subjected to femoral artery excision, and functional and morphological analysis of blood vessel formation was performed after injury. Heterozygous deletion of Poldip2 decreased the blood flow recovery and spontaneous running activity at 21 days after injury. H2O2 production, as well as the activity of matrix metalloproteinases-2 and -9, was reduced in these animals compared with Poldip2(+/+) mice. Infiltration of macrophages in the peri-injury muscle was also decreased; however, macrophage phenotype was similar between genotypes. In addition, the formation of capillaries and arterioles was impaired, as was angiogenesis, in agreement with a decrease in proliferation observed in endothelial cells treated with small interfering RNA against Poldip2. Finally, regression of newly formed vessels and apoptosis was more pronounced in Poldip2(+/-) mice. Together, these results suggest that Poldip2 promotes ischemia-induced collateral vessel formation via multiple mechanisms that likely involve reactive oxygen species-dependent activation of matrix metalloproteinase activity, as well as enhanced vascular cell growth and survival.


Text messaging intervention to support patients with chronic pain during prescription opioid tapering: protocol for a double-blind randomised controlled trial.
Increases in pain and interference with quality of life is a common concern among people with chronic non-cancer pain (CNCP) who are tapering opioid medications. Research indicates that access to social and psychological support for pain self-management may help people to reduce their opioid dose without increasing pain and interference. This study evaluates the efficacy of a text messaging intervention designed to provide people with CNCP with social and psychological support for pain self-management while tapering long-term opioid therapy (LTOT) under the guidance of their prescriber. A double-blind randomised controlled trial will be conducted. Patients with CNCP (n=74) who are tapering LTOT will be enrolled from across Australia. Participants will continue with their usual care while tapering LTOT under the supervision of their prescribing physician. They will randomly receive either a psychoeducational video and supportive text messaging (two Short Message Service (SMS) per day) for 12 weeks or the video only. The primary outcome is the pain intensity and interference assessed by the Pain, Enjoyment of Life and General Activity scale. Secondary outcomes include mood, self-efficacy, pain cognitions, opioid dose reduction, withdrawal symptoms, and acceptability, feasibility, and safety of the intervention. Participants will complete questionnaires at baseline and then every 4 weeks for 12 weeks and will be interviewed at week 12. This trial will provide evidence for the efficacy of a text messaging intervention to support patients with CNCP who are tapering LTOT. If proven to be efficacious and safe, this low-cost intervention can be implemented at scale. The study protocol was reviewed and approved by the Northern Sydney Local Health District (Australia). Study results will be published in peer-reviewed journals and presented at scientific and professional meetings. ACTRN12622001423707.


Rabies: the clinical features, management and prevention of the classic zoonosis.
The diagnosis of rabies encephalitis relies on awareness of the varied clinical features and eliciting a history of unusual contact with a mammal throughout the endemic area. The diagnosis is easily missed. Laboratory tests are not routine and only confirm clinical suspicion. Rabies infection carries a case fatality exceeding 99.9%. Palliation is appropriate, except for previously-vaccinated patients or those infected by American bats, for whom intensive care is probably indicated. However, as rabies vaccines are outstandingly effective, no one should die of dog-transmitted infection. Vaccines and rabies immunoglobulin are expensive and usually scarce in Asia and Africa. All travellers to dog rabies enzootic areas should be strongly encouraged to have pre-exposure immunisation before departure. There is no contraindication to vaccination but the cost can be prohibitive. Intradermal immunisation, using 0.1 ml and sharing vials of vaccine, is cheaper and is now permitted by UK regulations. Returning travellers may need post-exposure prophylaxis. Economical intradermal post-exposure vaccination is practicable and should be introduced into rural areas of Africa and Asia immediately. Eliminating rabies in dogs is now feasible and would dramatically reduce human mortality, if funds were made available. The high current economic burden of human prophylaxis would then be largely relieved.


Electromyographic analysis of oral habituation in rat pups.
Rat pups show decreases in mouthing activity in response to a series of repeated oral infusions of a diet. This decrease in mouthing activity has been termed "oral habituation" and these changes have been readily recorded with simple behavioral observations. Oral habituation appears to be a component of satiety in young rats. In the present study, to more specifically characterize changes in motor response topography during habituation in muscle groups used for mastication, mouthing activity was recorded by implanting fine wire electromyographic electrodes in the superficial masseter, anterior digastric, sternohyoideus, and genioglossus muscles of 12-day-old rat pups. During testing, pups received a series of brief oral infusions of a 10% sucrose diet delivered through an oral cannula. The results demonstrated that mouthing activity as observed and scored behaviorally was highly correlated with mouthing behavior recorded by EMG, with oral habituation distinctly emerging in both measures. In addition, the pattern of motor activity in the four masticatory muscles changed during the course of oral habituation. Within the minute following a single infusion, the cycle frequency, duration of activity, and relative onset time of activity in the four muscles changed. In addition, across the course of habituation, both cycle frequency and relative onset times of muscle activity changed. These results demonstrate the general reliability of behavioral observations of masticatory motor activity in young rats and provide further information on how the pattern of activity of muscles involved in the mouthing motor pattern is altered during the course of oral habituation.


[1998 social epidemiological analysis of caries incidence and degree of dental restoration in young men].
Basing on the hypothesis that adult dental health is co-determined by the conditions and influences prevailing in the family of origin during childhood and adolescence, we analysed the associations of socio-economic status of the family, personal dental care behaviour and other educational and structural factors, with caries prevalence (DMF-T) and the level of restoration in 642 young men between 18 and 24 years eligible for conscription. Additionally, we presented the changes in caries prevalence in conscripted persons during the 1990s comparing our results with those of a study conducted in 1989-90. The average number of DMF-T teeth was 5.7. 15% of subjects were caries-free. The mean level of restoration in those with a history of caries was 79.2%. The prevalence of caries and the level of restoration were strongly associated with the level of education, and the socio-economic status of the family of origin. Parental working time, number of siblings, structural deficiencies in the family, parental preventive education and training with regard to dental care, frequency of brushing the teeth, belief in the success of preventive health measures and prevalence of fissure sealings were significantly associated with DMF-T. Frequency of dental visits showed an association with the level of restoration. From 1989/90 to 1998 prevalence of caries in conscripts decreased by 42% (after adjusting for the different levels of education of both studies the decrease was 36%). Whereas in 1989/90 the average number of DMF-T in the 9-year elementary school graduates exceeded those of the high school graduates ("seniors") by 22%, this difference increased to 88% by 1998. More than 40% of the differences in the prevalence of caries among subjects of different educational levels were due to risk factors of social origin, preventive dental behaviour and utilisation of dental services, all of these being less favourable in elementary school or secondary school graduates compared to high-school graduates.


Functional role of leucine-103 in myohemerythrin.
Hemerythrins (Hrs) and myohemerythrins (Mhrs) are nonheme iron proteins that function as O2 carriers in four marine invertebrate phyla. Available amino acid sequences and X-ray structures indicate that a conserved leucine, residue 103 in the Themiste zostericola Mhr sequence, occupies a site distal to the Fe-O-Fe center. The side-chain methyl groups of the analogous leucine in Themiste dyscrita oxyHr are in van der Waals contact with bound O2 in the X-ray crystal structure, and this residue may therefore play a role in stabilizing bound dioxygen with respect to autoxidation. In order to test this hypothesis, the gene for T. zostericola Mhr was synthesized and expressed in Escherichia coli. Two mutant Mhrs, L103V and L103N, were also prepared. Optical spectra and kinetics data for these three proteins are presented. Importantly, neither mutant forms a stable oxy adduct; instead, rapid autoxidation results in formation of the corresponding met forms. In addition, the L103N Mhr displays unusually rapid reduction kinetics, suggesting that the amide functionality of Asn-103 destabilizes most bound ligands and additionally promotes rapid semi-metR <==> semi-metO isomerization.


Potentiometric Hydrogen Sensor with 3D-Printed BaCe0.6Zr0.3Y0.1O3-α Electrolyte for High-Temperature Applications.
Hydrogen is expected to play an important role in the near future in the transition to a net-zero economy. Therefore, the development of new in situ and real-time analytical tools able to quantify hydrogen at high temperatures is required for future applications. Potentiometric sensors based on perovskite-structured solid-state electrolytes can be a good option for H2 monitoring. Nevertheless, the geometry of the sensor should be designed according to the specific necessities of each technological field. Conventional shaping processes need several iterations of green shaping and machining to achieve a good result. In contrast, 3D printing methods stand out from conventional ones since they simplify the creation of prototypes, reducing the cost and the number of iterations needed for the obtainment of the final design. In the present work, BaCe0.6Zr0.3Y0.1O3-α (BCZY) was used as a proton-conducting electrolyte for potentiometric sensors construction. Two different shapes were tested for the sensors' electrolyte: pellets (BCZY-Pellet) and crucibles (BCZY-Crucible). Ceramics were shaped using extrusion-based 3D printing. Finally, parameters, such as sensitivity, response time, recovery time and the limit of detection and accuracy, were evaluated for both types of sensors (BCZY-Pellet and BCZY-Crucible) at 500 °C.


Multimodal ultrasound-photoacoustic imaging of tissue engineering scaffolds and blood oxygen saturation in and around the scaffolds.
Preclinical, noninvasive imaging of tissue engineering polymeric scaffold structure and/or the physiological processes such as blood oxygenation remains a challenge. In vitro or ex vivo, the widely used scaffold characterization modalities such as porosimetry, electron or optical microscopy, and X-ray microcomputed tomography have limitations or disadvantages-some are invasive or destructive, others have limited tissue penetration (few hundred micrometers) and/or show poor contrast under physiological conditions. Postmortem histological analysis, the most robust technique for the evaluation of neovascularization is obviously not appropriate for acquiring physiological or longitudinal data. In this study, we have explored the potential of ultrasound (US)-coregistered photoacoustic (PA) imaging as a noninvasive multimodal imaging modality to overcome some of the above challenges and/or provide complementary information. US-PA imaging was employed to characterize poly(lactic-co-glycolic acid) (PLGA) polymer scaffolds or single-walled carbon nanotube (SWCNT)-incorporated PLGA (SWCNT-PLGA) polymer scaffolds as well as blood oxygen saturation within and around the scaffolds. Ex vivo, PLGA and SWCNT-PLGA scaffolds were placed at 0.5, 2, and 6 mm depths in chicken breast tissues. PLGA scaffolds could be localized with US imaging, but generate no PA signal (excitation wavelengths 680 and 780 nm). SWCNT-PLGA scaffolds generated strong PA signals at both wavelengths due to the presence of the SWCNTs and could be localized with both US and PA imaging depths between 0.5-6 mm (lateral resolution = 90 μm, axial resolution = 40 μm). In vivo, PLGA and SWCNT-PLGA scaffolds were implanted in subcutaneous pockets at 2 mm depth in rats, and imaged at 7 and 14 days postsurgery. The anatomical position of both the scaffolds could be determined from the US images. Only SWCNT-PLGA scaffolds could be easily detected in the US-PA images. SWCNT-PLGA scaffolds had significant four times higher PA signal intensity compared with the surrounding tissue and PLGA scaffolds. In vivo blood oxygen saturation maps around and within the PLGA scaffolds could be obtained by PA imaging. There was no significant difference in oxygen saturation for the PLGA scaffolds at the two time points. The blood oxygen saturation maps complemented the histological analysis of neovascularization of the PLGA scaffolds.


Energy balance of rats with lateral hypothalamic lesions.
Rats with lateral hypothalamic (LH) lesions maintain body weight at a chronically reduced percentage of nonlesioned controls. An assessment of how they achieve energy balance at subnormal weight levels entailed a determination of both their energy intake and their energy expended or lost in processing ingested food, on basal heat production, on activity, and in feces or urine. It was found that the caloric intake and expenditure of LH-lesioned animals, though significantly lower than those of controls, were appropriate to the reduced metabolic body size (BW0.75) that they maintained. Likewise, energy expenditure in the LH-lesioned animals was normal in that the proportion of their ingested energy relegated to 1) basal metabolism, 2) the processing food, and 3) activity was the same as that of nonlesioned controls. Thus, unlike nonlesioned rats, which at lowered body weights both decrease their energy needs and reorder the pattern of energy expenditure, LH-lesioned animals display a normal pattern of energy utilization at reduced weight levels. These findings provide further evidence that lateral hypothalamic mechanisms play an important role in setting the level at which body weight is regulated.


Making wider use of the world's most widely used vaccine: Bacille Calmette-Guerin revaccination reconsidered.
Approximately 100 million newborn children receive Bacille Calmette-Guérin (BCG) annually, because vaccination is consistently protective against childhood tuberculous meningitis and miliary TB. By contrast, BCG efficacy against pulmonary TB in children and adults is highly variable, ranging from 0% to 80%, though it tends to be higher in individuals who have no detectable prior exposure to mycobacterial infections, as judged by the absence of delayed-type hypersensitivity response (a negative tuberculin skin test, TST). The duration of protection against pulmonary TB is also variable, but lasts about 10 years on average. These observations raise the possibility that BCG revaccination, following primary vaccination in infancy, could be efficacious among TST-negative adolescents as they move into adulthood, the period of highest risk for pulmonary disease. To inform continuing debate about revaccination, this paper assesses the effectiveness and cost-effectiveness of revaccinating adolescents in a setting with intense transmission-Cape Town, South Africa. For a cost of revaccination in the range US$1-10 per person, and vaccine efficacy between 10% and 80% with protection for 10 years, the incremental cost per year of healthy life recovered (disability-adjusted life years, DALY) in the vaccinated population lies between US$116 and US$9237. The intervention is about twice as cost-effective when allowing for the extra benefits of preventing transmission, with costs per DALY recovered in the range US$52-$4540. At 80% efficacy, revaccination averted 17% of cases. Under the scenarios investigated, BCG revaccination is cost-effective against international benchmarks, though not highly effective. Cost-effectiveness ratios would be more favourable if we also allow for TB cases averted by preventing transmission to HIV-positive people, for the protection of HIV-negative people who later acquire HIV infection, for the possible non-specific benefits of BCG, for the fact that some adolescents would receive BCG for the first time, and for cost sharing when BCG is integrated into an adolescent immunization programme. These findings suggest, subject to further evaluation, that BCG revaccination could be cost-effective in some settings.


Rubella Seroprevalence and real-time PCR detection of RUBV among Congolese pregnant women.
Rubella is an acute infectious disease caused by Rubella virus (RUBV). RUBV remains an important pathogen worldwide, causing approximately 100 000 cases of congenital rubella syndrome (CRS) every year; and the most severe consequence of rubella is teratogenicity. The aim of this study was to estimate the prevalence of RUBV IgG antibodies and determine RUBV genotypes in Congolese pregnant women in Kongo central province, Democratic Republic of Congo (DRC). This was a prospective cross-sectional study that consisted of a laboratory analysis of blood samples from 78 pregnant women to check for the presence of RUBV IgG antibodies, and also determine RUBV genotypes in seropositive samples (using primers targeting RUBV nucleoprotein), with the use of serological and molecular methods, respectively. Participants were pregnant women attending antenatal care clinics (ANC) at two health zones of Kisantu town in DRC. They were followed-up from the first to third trimester. Those who were negative for RUBV antibodies at the initial assay (first trimester) were tested in the second and, eventually, the third trimester. An overall rubella seroprevalence of 58.97% was observed, whereas RUBV nucleoprotein was detected in 60% of randomly selected 30 blood samples among the 46 RUBV seropositive pregnant women. Five (27.77%) of positive samples were positive for both RUBV genotypes (RV8633/9112 and RV8945/9577), whereas 11 (61.11%) of them were positive for RV8633/9112 and two (11.11%) were positive for RV8945/9577 only. Regarding rubella clinical signs and complications, two subjects (2.56%) presented with fever, whereas five pregnant women (6.41%) had experienced abortion. None (0%) of the participants has been vaccinated against RUBV. Findings from this study suggest that RUBV is prevalent in Congolese pregnant women. Further research is required to elucidate the molecular epidemiology of RUBV in order to design a rational rubella surveillance and control program in DRC.


αB-crystallin is elevated in highly infiltrative apoptosis-resistant glioblastoma cells.
We have previously established two distinct glioma phenotypes by serial xenotransplantation of human glioblastoma (GBM) biopsies in nude rats. These tumors undergo a gradual transition from a highly invasive nonangiogenic to a less-invasive angiogenic phenotype. In a protein screen to identify molecular markers associated with the infiltrative phenotype, we identified α-basic-crystallin (αBc), a small heat-shock protein with cytoprotective properties. Its increased expression in the infiltrative phenotype was validated by immunohistochemistry and Western blots, confirming its identity to be tumor-derived and not from the host. Stereotactic human GBM biopsies taken from MRI-defined areas verified stronger αBc expression in the infiltrative edge compared to the tumor core. Cell migration assays and immunofluorescence staining showed αBc to be expressed by migrating cells in vitro. To determine αBc function, we altered its expression levels. αBc siRNA depletion caused a loss of migrating tumor cells from biopsy spheroids and delayed monolayer wound closure. In contrast, glioma cell migration in a Boyden chamber assay was unaffected by either αBc knockdown or overexpression, indicating that αBc is not functionally linked to the cell migration machinery. However, after siRNA αBc depletion, a significant sensitization of cells to various apoptotic inducers was observed (actinomycin, tumor necrosis factor α, and TNF-related apoptosis-inducing ligand [TRAIL]). In conclusion, αBc is overexpressed by highly migratory glioma cells where it plays a functional role in apoptosis resistance.


Evaluation of the role of the clinical Nurse Specialist in cancer care: an integrative literature review.
Although there is growing evidence the Clinical Nurse Specialist role makes a difference to patient care, the full value of this service may not be always appreciated with current models not meeting the needs of those with cancer. The primary aim of this integrative literature review was to evaluate outcomes associated with the role of the Clinical Nurse Specialist in cancer care. The secondary aim was to identify the components of the Clinical Nurse Specialist role in cancer care from the included papers in the literature review. An integrative literature review using a systematic approach was adopted. Literature searches were undertaken in four databases and supplemented with a search in the grey literature and reference lists of included papers. Searches were limited to January 2009-July 2019 and those written in the English language. Three reviewers independently completed the searches and reviewed the papers before reaching a consensus. Fourteen eligible research papers were identified. Evaluations were predominately positive with the role contributing to improving patient outcomes with regards psychological support, information provision, symptom management, service coordination and patient satisfaction. The findings of this literature review firmly establish the Clinical Nurse Specialist as a valuable member of the multidisciplinary team in enhancing cancer care services.


Population genetic structure of Arctic charr, Salvelinus alpinus from northwest Europe on large and small spatial scales.
To examine the population genetic structure of lake-resident Arctic charr, Salvelinus alpinus from northwest Europe on multiple spatial scales, 2367 individuals from 43 lakes located in three geographical regions (Iceland, the British Isles and Scandinavia) were genotyped at six microsatellite loci. On a large scale, data provided little evidence to support clustering of populations according to geographical region. Hierarchical analysis of molecular variance indicated that, although statistically significant, only 2.17% of the variance in allelic frequencies was partitioned at the among-region level. Within regions, high levels of genetic differentiation were typically found between lakes regardless of the geographical distance separating them. These results are consistent with the hypothesis of rapid postglacial recolonization of all of northwest Europe from a single charr lineage, with subsequent restriction of gene flow. On a smaller scale, there was evidence for close genetic relationships among lakes from within common drainage basins in Scotland. Thus, interlake genetic structure reflects localized patterns of recent (or contemporary) gene flow superimposed onto a larger scale structure that is largely a result of historical processes. There was also evidence for widespread genetic structuring at the within-lake level, with sympatric populations detected in 10 lakes, and multilocus heterozygote deficits found in 23 lakes. This evidence of the Wahlund effect was found in all lakes known to contain discrete phenotypic morphs, as well as many others, suggesting that morphs may often represent separate breeding populations, and also that the phenomenon of polymorphism in this species may be more widespread than is currently realized.


Transcatheter Aortic Valve Replacement in Bicuspid Versus Tricuspid Aortic Valves From the STS/ACC TVT Registry.
This study sought to compare outcomes in patients with bicuspid versus tricuspid anatomy undergoing transcatheter aortic valve replacement (TAVR). TAVR has shown excellent safety and efficacy in patients with tricuspid aortic valve stenosis, but limited data are available on the use of self-expanding valves in patients with bicuspid valves. The Society of Thoracic Surgeons/American College of Cardiology TVT Registry was used to analyze patients who underwent TAVR with the Evolut R or Evolut PRO valves. Clinical and echocardiographic outcomes were analyzed through 1-year follow-up. Between July 2015 and September 2018 a total of 932 patients with bicuspid aortic valve stenosis underwent elective TAVR with the self-expanding Evolut R or Evolut PRO valve. These patients were compared with a group of 26,154 patients with tricuspid aortic stenosis who underwent TAVR during that same time period. At baseline, patients with bicuspid valves were younger, had fewer cardiac comorbidities, and had lower Society of Thoracic Surgeons Predicted Risk of Mortality scores (5.3 ± 4.2% vs. 6.9 ± 4.8%; p < 0.001). To account for these differences, propensity matching was performed, which resulted in 929 matched pairs. Within these match groups, the rates of all-cause mortality at 30 days (2.6% vs. 1.7%; p = 0.18) and 1 year (10.4% vs. 12.1%; p = 0.63), as well the rate of stroke at 30 days (3.4% vs. 2.7%; p = 0.41) and 1 year (3.9% vs. 4.4%; p = 0.93), were comparable. All-cause mortality, stroke, and valve hemodynamics did not differ at 30 days or 1 year between patient groups. In patients at increased surgical risk, TAVR for bicuspid aortic valve stenosis indicates acceptable safety outcomes with low complications rates.


Reduced voltage sensitivity of activation of P/Q-type Ca2+ channels is associated with the ataxic mouse mutation rolling Nagoya (tg(rol)).
Recent genetic analyses have revealed an important association of the gene encoding the P/Q-type voltage-dependent Ca(2+) channel alpha(1A) subunit with hereditary neurological disorders. We have identified the ataxic mouse mutation, rolling Nagoya (tg(rol)), in the alpha(1A) gene that leads to a charge-neutralizing arginine-to-glycine substitution at position 1262 in the voltage sensor-forming segment S4 in repeat III. Ca(2+) channel currents in acutely dissociated Purkinje cells, where P-type is the dominant type, showed a marked decrease in slope and a depolarizing shift by 8 mV of the conductance-voltage curve and reduction in current density in tg(rol) mouse cerebella, compared with those in wild-type. Compatible functional change was induced by the tg(rol) mutation in the recombinant alpha(1A) channel, indicating that a defect in voltage sensor of P/Q-type Ca(2+) channels is the direct consequence of the tg(rol) mutation. Furthermore, somatic whole-cell recording of mutant Purkinje cells displayed only abortive Na(+) burst activity and hardly exhibited Ca(2+) spike activity in cerebellar slices. Thus, in tg(rol) mice, reduced voltage sensitivity, which may derive from a gating charge defect, and diminished activity of the P-type alpha(1A) Ca(2+) channel significantly impair integrative properties of Purkinje neurons, presumably resulting in locomotor deficits.


Palladium-Catalyzed Cyclization: Regioselectivity and Structure of Arene-Fused C60 Derivatives.
The palladium-catalyzed cyclization on the fullerene C60 cage has been achieved using several aryl halides and C60. This reaction was found to be accelerated by the addition of pivalic acid, which can be rationally explained by the computational study based on the concerted metalation-deprotonation mechanism. We also demonstrated the regioselective π-functionalization using prefunctionalized designed molecules possessing the same substructure on the C60 cage. The single crystal X-ray analysis and electrostatic potential map revealed that the orientation of entrapped H2O inside the naphthalene-fused open-cage C60 derivative is electrostatically demanded due to the naphthalene-fusion and construction of the opening.


Widespread PREMA in the upper mantle indicated by low-degree basaltic melts.
Studies of ocean island basalts have identified a Prevalent Mantle (PREMA) component as a fundamental feature of mantle geochemical arrays; however, its origin and distribution are highly controversial, including its potential link to plumes sourced in low-shear-wave velocity provinces (LLSVPs) above the core-mantle boundary. In this study, we interrogate the compositional systematics of ~ 3500 Cenozoic oceanic and continental sodic basalts to provide insights into the origin and distribution of PREMA. We find that low-degree basaltic melts with high Nb concentrations located away from deep-mantle plumes have PREMA-like Sr-Nd-Hf isotopic signatures, implying that PREMA is highly fusible and not exclusively associated with LLSVPs. Geochemical modelling and mantle convection simulations indicate that PREMA could have been generated soon after Earth accretion, experiencing only minimal melting or enrichment, and then scattered throughout the upper mantle, rather than being the result of mixing between depleted and enriched mantle components.


A GH3-like domain in reaper is required for mitochondrial localization and induction of IAP degradation.
Reaper is a potent pro-apoptotic protein originally identified in a screen for Drosophila mutants defective in apoptotic induction. Multiple functions have been ascribed to this protein, including inhibition of IAPs (inhibitors of apoptosis); induction of IAP degradation; inhibition of protein translation; and when expressed in vertebrate cells, induction of mitochondrial cytochrome c release. Structure/function analysis of Reaper has identified an extreme N-terminal motif that appears to be sufficient for inhibition of IAP function. We report here that this domain, although required for IAP destabilization, is not sufficient. Moreover, we have identified a small region of Reaper, similar to the GH3 domain of Grim, that is required for localization of Reaper to mitochondria, induction of IAP degradation, and potent cell killing. Although a mutant Reaper protein lacking the GH3 domain was deficient in these properties, these defects could be fully rectified by appending either the C-terminal mitochondrial targeting sequence from Bcl-xL or a homologous region from the pro-apoptotic protein HID. Together, these data strongly suggest that IAP destabilization by Reaper in intact cells requires Reaper localization to mitochondria and that induction of IAP instability by Reaper is important for the potent induction of apoptosis in Drosophila cells.


Interactive Guidance Intervention to Address Sustained Social Withdrawal in Preterm Infants in Chile: Protocol for a Randomized Controlled Trial.
Preterm newborns can be exposed early to significant perinatal stress, and this stress can increase the risk of altered socioemotional development. Sustained social withdrawal in infants is an early indicator of emotional distress which is expressed by low reactivity to the environment, and if persistent, is frequently associated with altered psychological development. Infants born prematurely have a higher probability of developing sustained social withdrawal (adjusted odds ratio 1.84, 95% CI 1.04-3.26) than infants born full term, and there is a correlation between weight at birth and sustained social withdrawal at 12 months of age. The aims of this study are to compare the effect of the interactive guidance intervention to that of routine pediatric care on sustained social withdrawal in infants born moderately or late preterm and to explore the relationship between sustained social withdrawal in these infants and factors such as neonatal intensive care unit hospitalization variables, parental depression, and posttraumatic stress symptoms. This study is designed as a multicenter randomized controlled trial. Moderate and late preterm newborns and their parents were recruited and randomized (1:1 allocation ratio) to control and experimental groups. During neonatal intensive care unit hospitalization, daily duration of skin-to-skin contact, breastfeeding, and parental visits were recorded. Also, a daily score for neonatal pain and painful invasive procedures were recorded. After discharge from neonatal intensive care, for the duration of the study, both groups will attend follow-up consultations with neonatologists at 2, 6, and 12 months of age (corrected for gestational age) and will receive routine pediatric care. Every consultation will be recorded and assessed with the Alarm Distress Baby Scale to detect sustained social withdrawal (indicated by a score of 5 or higher). The neonatologists will perform an interactive guidance intervention if an infant in the intervention group exhibits sustained social withdrawal. In each follow-up consultation, parents will fill out the Edinburgh Postnatal Depression Scale, the modified Perinatal Posttraumatic Stress Disorder Questionnaire, and the Impact of Event Scale-revised. Recruitment for this trial started in September 2017. As of May 2020, we have completed enrollment (N=110 infants born moderately or late preterm). We aim to publish the results by mid-2021. This is the first randomized controlled trial with a sample of infants born moderately or late preterm infants who will attend pediatric follow-up consultations during their first year (corrected for gestational age at birth) with neonatologists trained in the Alarm Distress Baby Scale and who will receive this interactive guidance intervention. If successful, this early intervention will show significant potential to be implemented in both public and private health care, given its low cost of training staff and that the intervention takes place during routine pediatric follow-up. ClinicalTrials.gov NCT03212547; https://clinicaltrials.gov/ct2/show/NCT03212547. DERR1-10.2196/17943.


Case report of modified Box and Blocks test with motion capture to measure prosthetic function.
This case study report demonstrates the use of motion analysis with a modification of the Box and Blocks test. The goal was to quantify observed improvements in compensatory movements and simultaneous control in a subject using different prostheses before and after targeted muscle reinnervation (TMR) surgery. This is a single case study with data collection using a body-powered prosthesis pre-TMR surgery and 6 mo postfitting with a TMR myoelectric prosthesis. The Box and Blocks test was modified for cyclical motion within a motion capture laboratory. With the TMR myoelectric prosthesis, the subject was able to simultaneously activate the hand and elbow. Task performance was slower, but there was improved elbow flexion and less trunk compensatory motion than with the body-powered prosthesis. There are several limitations to the case study because there is no direct comparison of myoelectric performance before and after TMR surgery; however, the current report presents a potential method to quantify quality of motion and compensatory movements of prosthetic users. With further study, this test procedure has the potential to be a useful outcome measure for future standardized assessments of upper-limb prosthetic function.


Standardization of in-house polymerase chain reaction for the identification of Mycobacterium tuberculosis at the reference Tropical Disease Hospital in the State of Goiás, Brazil.
This study compares smear, growth in Lowenstein-Jensen medium, and in-house polymerase chain reaction (PCR) techniques for the detection of Mycobacterium tuberculosis. A total of 72 specimens from 72 patients with clinical symptoms of tuberculosis, including 70 sputum and two bronchial aspirate samples, were tested in parallel by smear, culture, and in-house PCR techniques. From these, 48 (66.6%) were negative by the 3 methods, 2 (2.8%) were smear positive and negative by culture and in-house PCR, 11 (15.3%) were both smear and culture negative, and in-house PCR positive, 7 (9.7%) were positive by the 3 methods, 2 (2.8%) were positive by smear and culture, and negative by PCR, 2 (2.8%) were positive by culture and PCR, but smear negative. After the resolution of discrepancies in PCR results, the sensitivity and specificity for in-house PCR technique to M. tuberculosis relative to the culture, were 81.8% and 81.9%, respectively. These results confirm that this method, in-house PCR, may be a sensitive and specific technique for M. tuberculosis detection, occurring in both positive and negative smear and negative cultures.


Comparison of oral microbiota in tumor and non-tumor tissues of patients with oral squamous cell carcinoma.
Bacterial infections have been linked to malignancies due to their ability to induce chronic inflammation. We investigated the association of oral bacteria in oral squamous cell carcinoma (OSCC/tumor) tissues and compared with adjacent non-tumor mucosa sampled 5 cm distant from the same patient (n = 10). By using culture-independent 16S rRNA approaches, denaturing gradient gel electrophoresis (DGGE) and cloning and sequencing, we assessed the total bacterial diversity in these clinical samples. DGGE fingerprints showed variations in the band intensity profiles within non-tumor and tumor tissues of the same patient and among the two groups. The clonal analysis indicated that from a total of 1200 sequences characterized, 80 bacterial species/phylotypes were detected representing six phyla, Firmicutes, Bacteroidetes, Proteobacteria, Fusobacteria, Actinobacteria and uncultivated TM7 in non-tumor and tumor libraries. In combined library, 12 classes, 16 order, 26 families and 40 genera were observed. Bacterial species, Streptococcus sp. oral taxon 058, Peptostreptococcus stomatis, Streptococcus salivarius, Streptococcus gordonii, Gemella haemolysans, Gemella morbillorum, Johnsonella ignava and Streptococcus parasanguinis I were highly associated with tumor site where as Granulicatella adiacens was prevalent at non-tumor site. Streptococcus intermedius was present in 70% of both non-tumor and tumor sites. The underlying changes in the bacterial diversity in the oral mucosal tissues from non-tumor and tumor sites of OSCC subjects indicated a shift in bacterial colonization. These most prevalent or unique bacterial species/phylotypes present in tumor tissues may be associated with OSCC and needs to be further investigated with a larger sample size.


Genetic rearrangements of a Rhizobium phaseoli symbiotic plasmid.
Different structural changes of the Sym plasmid were found in a Rhizobium phaseoli strain that loses its symbiotic phenotype at a high frequency. These rearrangements affected both nif genes and Tn5 mob insertions in the plasmid, and in some cases they modified the expression of the bacterium's nodulation ability. One of the rearrangements was more frequent in heat-treated cells, but was also found under standard culture conditions; other structural changes appeared to be related to the conjugal transfer of the plasmid.


The relationship between glucose excursion and cognitive function in aged type 2 diabetes patients.
Evidence suggests that type 2 diabetes (T2DM) is associated with an increased risk of dementia and that glucose variability is an independent risk factor for diabetic complications. This study investigated the relationship between glucose excursion and cognitive function in aged T2DM patients. A total of 248 aged T2DM patients wore a continuous glucose monitoring system (CGMS) for 3 days in order to evaluate glucose excursion, including mean amplitude of glycemic excursions (MAGE) and mean of daily difference (MODD). All subjects were evaluated with a number of accepted cognitive function tests, including the mini-mental status examination (MMSE). The relationship between MAGE and MODD and performance on these cognitive tests was assessed. The MAGE and MMSE score were negatively correlated, likewise with the correlation between MODD and MMSE. Liner multivariate regression analysis showed that MAGE and MODD were also negatively related to MMSE independent of age, sex, glycemic control, hypertension, smoking, or coronary heart disease history. Glucose excursion is related to cognitive function in aged T2DM patients. Elevated glucose excursion decreased the MMSE score, which reflects general cognitive function. Thus, therapy aimed at controlling glucose excursion may be beneficial for maintaining cognitive function in aged T2DM patients.


Efficacy of Combination Therapies on Neck Pain and Muscle Tenderness in Male Patients with Upper Trapezius Active Myofascial Trigger Points.
Myofascial pain syndrome, thought to be the main cause of neck pain and shoulder muscle tenderness in the working population, is characterized by myofascial trigger points (MTrPs). This study aimed to examine the immediate and short-term effect of the combination of two therapeutic techniques for improving neck pain and muscle tenderness in male patients with upper trapezius active MTrPs. This study was a pretest-posttest single-blinded randomized controlled trial. Sixty male subjects with mechanical neck pain due to upper trapezius active MTrPs were recruited and randomly allocated into group A, which received muscle energy technique (MET) and ischemic compression technique (ICT) along with conventional intervention; group B, which received all the interventions of group A except ICT; and group C, which received conventional treatment only. Baseline (Pr), immediate postintervention (Po), and 2-week follow-up (Fo) measurements were made for all variables. Pain intensity and pressure pain threshold (PPT) were assessed by a visual analog scale (VAS) and pressure threshold meter, respectively. All the three groups received their defined intervention plans only. Repeated-measures analysis of variance was used to perform intra- and intergroup analyses. Cohen's d test was used to assess the effect size of the applied interventions within the groups. The intergroup analysis revealed significant differences among groups A, B, and C in VAS and PPT at Po (VAS-Po: F = 13.88, p=0.0001; PPT-Po: F = 17.17, p=0.0001) and even after 2 weeks of follow-up (VAS-Fo: F = 222.35, p=0.0001; PPT-Fo: F = 147.70, p=0.0001). Cohen's d revealed a significant treatment effect size within all groups except group C (only significant for VAS-Po-VAS-Pr: mean difference = 1.33, p < 0.05, d = 1.09); however, it showed a maximum effect size in group A for its variables (VAS-Fo-VAS-Pr: mean difference = 5.27, p=0.01, d = 4.04; PPT-Fo-PPT-Pr: mean difference = 2.14, p < 0.01, d = 3.89). Combination therapies (MET plus ICT) showed immediate and short-term (2-week follow-up) improvements in neck pain and muscle tenderness in male patients with upper trapezius active MTrPs.


Effect of the synthetic NC-1059 peptide on diffusion of riboflavin across an intact corneal epithelium.
To investigate the effect of the peptide NC-1059 on riboflavin (RF) diffusion across an intact corneal epithelium into the stroma. NC-1059 peptide was synthesized by solid-phase synthesis with 9-fluorenylmethoxycarbonyl chemistry, characterized by reversed-phase HPLC, and matrix-assisted laser desorption ionization time-of-flight mass spectroscopy. The diffusion of RF across embryonic day 18 chick corneal epithelium ex vivo was monitored using confocal microscopy. The depth distributions of RF in the corneal stroma were calculated using a group of linear equations based on the relationship between RF fluorescence intensity and concentration. Data presented in this study demonstrate that the NC-1059 peptide can transiently open the intact epithelial barrier to allow the permeation of RF into the stroma. The effect of NC-1059 peptide on RF diffusion across the corneal epithelium was concentration and time dependent. The amount of RF reaching a 50-μm depth of chick corneal stoma increased dramatically after exposure to NC-1059 for 10 minutes, reaching a plateau by 30 minutes. The concentrations of RF in the presence of NC-1059 at corneal stromal depths of 50, 100, and 150 μm were significantly higher than in the absence of the peptide, and almost as high as in corneas in which the epithelium first had been physically removed. In addition, a cell viability assay indicated that the NC-1059 peptide did not kill corneal epithelial cells. NC-1059 peptide significantly enhances the diffusion of RF across intact corneal epithelium into the stroma.


The NAT1 C1095A polymorphism, maternal multivitamin use and smoking, and the risk of spina bifida.
The risk of having a child with a neural tube defect (NTD) can be reduced by maternal, periconceptional supplementation with folic acid, but the underlying folate-dependent protective mechanism remains unclear. N-acetyltransferase 1 is involved in acetylation of aromatic and heterocyclic amines and the catabolism of folates. Hence, functional polymorphisms in NAT1, the gene encoding N-acetyltransferase 1, are plausible risk factors for NTDs. Such variants could exert an influence on the risk of NTDs via their role in acetylation or folate catabolism and could act through the maternal or the embryonic genotype. NAT1 C1095A genotypes and information on maternal, periconceptional multivitamin use and smoking were obtained as part of a family-based study of spina bifida. Associations between spina bifida and the embryonic and maternal NAT1 C1095A genotypes, and potential NAT1 C1095A genotype-exposure interactions were evaluated using log-linear modeling. The analyses provided no evidence that the embryonic or maternal NAT1 C1095 genotypes influence the risk of spina bifida independently, or through interactions with maternal use of multivitamins. There was evidence that the embryonic, and possibly the maternal, NAT1 C1095A genotype influence the risk of spina bifida via interactions with maternal smoking status. The genotype for the NAT1 C1095A polymorphism does not appear to be an independent risk factor for spina bifida. However, the results of these analyses provide preliminary evidence that this polymorphism may be associated with the risk of spina bifida in the offspring of women who smoke during early pregnancy.


The miR-310/13 cluster antagonizes β-catenin function in the regulation of germ and somatic cell differentiation in the Drosophila testis.
MicroRNAs (miRNAs) are regulators of global gene expression and function in a broad range of biological processes. Recent studies have suggested that miRNAs can function as tumor suppressors or oncogenes by modulating the activities of evolutionarily conserved signaling pathways that are commonly dysregulated in cancer. We report the identification of the miR-310 to miR-313 (miR-310/13) cluster as a novel antagonist of Wingless (Drosophila Wnt) pathway activity in a functional screen for Drosophila miRNAs. We demonstrate that miR-310/13 can modulate Armadillo (Arm; Drosophila β-catenin) expression and activity by directly targeting the 3'-UTRs of arm and pangolin (Drosophila TCF) in vivo. Notably, the miR-310/13-deficient flies exhibit abnormal germ and somatic cell differentiation in the male gonad, which can be rescued by reducing Arm protein levels or activity. Our results implicate a previously unrecognized function for miR-310/13 in dampening the activity of Arm in early somatic and germline progenitor cells, whereby inappropriate/sustained activation of Arm-mediated signaling or cell adhesion may impact normal differentiation in the Drosophila male gonad.


Detection of hepatitis B virus DNA in tissues of hepatocellular carcinomas related to hepatitis C virus which are negative for hepatitis B virus surface antigen.
Uniform conclusions have not yet been drawn as to the frequency and copy number of hepatitis B virus (HBV) DNA in hepatocellular carcinoma (HCC) tissues from patients who are negative for hepatitis B surface antigen (HBsAg). The existence of HBV DNA was investigated with Southern blot hybridization and polymerase chain reaction (PCR) in HCC tissues from 55 patients who were negative for HBsAg and positive for hepatitis C virus antibody (HCVAb). Southern blot hybridization showed that two tissues (4%) contained HBV DNA at a frequency of more than 1 HBV copy per 10 cells. Another 5 tissues were found to be positive for HBV DNA only by PCR analysis but contained less than 3 HBV DNA copies per 10(5) cells. HCC tissues from patients seronegative for HBsAg and seropositive for HCVAb contain HBV DNA less frequently than has generally been claimed.


Exogenous miRNA-146a Enhances the Therapeutic Efficacy of Human Mesenchymal Stem Cells by Increasing Vascular Endothelial Growth Factor Secretion in the Ischemia/Reperfusion-Injured Heart.
Adult stem cells have been studied as a promising therapeutic modality for the functional restoration of the damaged heart. In the present study, a strategy for enhancing the angiogenic efficacy of human mesenchymal stem cells (hMSCs) using micro-RNA was examined. We investigated whether micro-RNA-146a (miR-146a) influences the secretion of vascular endothelial growth factor (VEGF) and angiogenesis of MSCs. Our data indicated that miR-146a-transfected hMSCs (hMSCmiR-146a) decreased the expression of neurofibromin 2, an inhibitor of p21-activated kinase-1 (PAK1). miR-146a also increased the expression of Ras-related C3 botulinum toxin substrate 1 and PAK1, which are known to induce VEGF expression, and the formation of vascular branches was increased in hMSCmiR-146a compared to hMSCs treated with VEGF. VEGF and p-Akt were increased in hMSCmiR-146a. Furthermore, injection of hMSCmiR-146a after ischemia/reperfusion (I/R) injury led to a reduction of fibrosis area and increased VEGF expression, confirming the regenerative capacity such as reparative angiogenesis in the infarcted area. Cardiac functions in I/R injury were improved following injection of hMSCmiR-146a compared to the I/R group. Taken together, these data suggest that miR-146 is a novel microRNA that regulates VEGF expression, and its use may be an effective strategy for enhancing the therapeutic efficacy of hMSC transplantation into the I/R-injured heart.


Intercellular transfer of GPRC5B via exosomes drives HGF-mediated outward growth.
How cells communicate during development and regeneration is a critical question. One mechanism of intercellular communication is via exosomes, extracellular vesicles that originate by the fusion of multivesicular endosomes with the plasma membrane [1-8]. To model exosome-based intercellular communication, we used Madin-Darby canine kidney (MDCK) cell cysts grown in 3D gels of extracellular matrix, which form tubules in response to hepatocyte growth factor (HGF). We report that GPRC5B, an orphan G protein coupled receptor, is in exosomes produced by HGF-treated cysts and released into the cyst lumen. Exosomal GPRC5B is taken up by nearby cells and together with HGF promotes extracellular signal-regulated kinase 1/2 (ERK1/2) activation and tubulogenesis, even under conditions where tubulogenesis would otherwise not occur. Recovery from injury, such as acute kidney injury (AKI), often recapitulates developmental processes. Here, we show that GPRC5B is elevated in urinary exosomes from patients with AKI. Our results elucidate how GPRC5B is carried by exosomes and augments HGF-induced morphogenesis. The unexpected role of exosomes in transporting GPRC5B between cells during morphogenesis and the ability of GPRC5B to predict the disease state of AKI elucidate a novel mechanism for intercellular communication during development and repair.


Clinical and CNS effects of oral and I.V. Thyrotropin-releasing hormone in depressed patients.
Both oral and intravenous TRH produce systematic alterations in brain function of depressive patients as determined by scalp-recorded computerized cerebral biopotentials (computer EEG). The computer EEG (CEEG) profiles of both formulations are not only very similar to each other, but also resemble the CEEG profiles of psychostimulant compounds (Bio-availability). As in CEEG findings, TSH plasma levels also indicate that oral TRH is indeed an active compound. Although some "antidepressive" effects were observed after both formulations, they were not present in every patient, and it was not always the case after repetitive TRH administration, nor were the effects on depressed mood too impressive. On the other hand, in almost all patients certain behavioral effects of TRH were seen which related to "life instincts" and "life performance". The increase of interest, desire and drive for work, food and sex was one of the most striking findings, particularly after intravenous TRH. This may be responsible for the "antidepressive" effects of TRH in patients in whom depression may be the result of an inhibition of "instinctive" functions.


Role of cholecystokinin in the anorexia produced by duodenal delivery of oleic acid in rats.
To assess the importance of triglyceride digestion products in producing satiety, we determined the effects of duodenal infusions of triolein, oleic acid, and oleic acid plus monoolein on meal patterns in ad libitum-feeding rats. Oleic acid and oleic acid plus monoolein inhibited feeding similarly; triolein's effect was delayed and fourfold less potent. We then used the type A cholecystokinin (CCK-A)-receptor antagonist devazepide to assess the importance of CCK in mediating the anorexia produced by oleic acid. Oleic acid (at 320, 440, and 640 mumol/h) inhibited 3-h intake dose dependently by 32, 56, and 75%, respectively. Devazepide (1 or 2 mg/kg) blocked the responses to the 320 mumol/h dose, but had little if any effect on responses to the larger doses. Devazepide (1 mg/kg) did block anorexic responses to 3-h cholecystokinin octapeptide infusions (3 and 10 nmol.kg-1.h-1 iv) that inhibited 3-h intake by 25 and 65%, respectively. Our results suggest that the satiety response to triolein is produced by the products of triolein digestion and that CCK plays a significant, indispensable role in mediating the satiety response to duodenal delivery of small but not large loads of oleic acid.