Reduction of Skeletal Muscle Power in Adolescent Males Carrying H63D Mutation in the HFE Gene.
Iron overload resulting from the mutation of genes involved in iron metabolism or excess dietary intake has been reported to negatively influence human physical performance. The aim of this study was to test the hypothesis that adolescents bearing a hemochromatosis gene (HFE) mutation in contrast to adults with the same mutation will not experience iron accumulation and their aerobic capacity will be similar to that of age-matched controls. Thirteen boys participated in the study. Seven of them are carriers of H63D mutation in the HFE gene and six were wild type. Fitness levels were assessed using the cardiopulmonary exercise test. In addition, iron status and inflammatory markers were determined. We observed that cardiovascular fitness was significantly lower in the group bearing the HFE mutation compared to the control group. Moreover, the HFE mutation group achieved lower maximal power output compared to the control group. There were no differences in blood ferritin concentrations between the two groups which indicates similar amounts of stored iron. Obtained data do not confirm our hypothesis. On the contrary, it was demonstrated that HFE mutation is associated with a lower level of aerobic capacity, even in the absence of iron accumulation.


Oxidative stress in 5/6 nephrectomized rat model: effect of alpha-lipoic acid.
Alpha-lipoic acid (ALA) is a powerful antioxidant, and its effect in ameliorating complications of diabetes mellitus has been widely documented. The aim of this study was to investigate the role of ALA in the disease progression of remnant kidneys (RK). Systolic blood pressure (SBp), hemoglobin, renal function, kidney malondialdehyde (MDA), glutathione (GSH), vitamin E (Vit E) concentrations, p65 nuclear factor (NF)-κB activity, and macrophage infiltration were analyzed in sham and RK rats supplemented with ALA (100 mg/kg body weight, i.p., every other day) or vehicle for 12 weeks. RK rats exhibited increases in SBp, kidney MDA concentration, p65 NF-κB activity, and macrophage infiltration, which were prominent in weeks 4 and 8 and decreased at week 12. RK rats also showed anemia, microalbuminuria, and decreased renal function and kidney GSH and Vit E concentrations. These changes were all attenuated by 8 weeks of ALA treatment compared to RK vehicle group. But the continued ALA treatment after week 8 reversed the beneficial effect on SBp, kidney MDA concentration, p65 NF-κB activity, macrophage infiltration, anemia, microalbuminuria, and renal function, while the beneficial effect was maintained if the treatment was discontinued after week 8. Furthermore, ALA increased albuminuria and kidney MDA concentration in sham animals. In conclusion, ALA administration attenuates oxidative stress, inflammation, and hypertension and delayed the deterioration of kidney function in RK rats with enhanced oxidative stress, while in healthy animals or RK rats with a well-balanced redox state, ALA may act as a pro-oxidant, contributing to renal dysfunction.


Membrane interaction and self-assembly within phospholipid membranes of synthetic segments corresponding to the H-5 region of the shaker K+ channel.
The voltage-activated K+ channels are assumed to be formed by the coassembly of four polypeptide monomers. Each of these monomers is postulated to consist of six transmembrane segments (S1 to S6), and long N- and C-terminal domains. The highly conserved linker, H-5, between the fifth and the sixth transmembrane segments, is hypothesized to line the lumen of the K+ channel formed by the bundle of the transmembrane segments of the monomers. Herein we utilize the spectrofluorometric approach and investigate the interaction with phospholipid membranes of fluorescently-labeled synthetic peptides, whose sequences are derived from the H-5 region. Binding experiments reveal that the peptides can strongly bind to phospholipid membranes with partition coefficients on the order of 10(4) M-1. However, a truncated peptide without four amino acids within the most conserved region (amino acids 432-435) did not bind to the membranes at all. Moreover, the single substitution of a conserved tryptophan at position 435 to serine reduced the partition coefficient of the peptide approximately 5-fold, which may account for a mutated K+ channel with this substitution not producing functional channels (Yool & Schwarz, 1991). Structural characterization using circular dichroism spectroscopy (CD) reveals that H-5 can partially adopt an alpha-helix structure in hydrophobic environments. Resonance energy transfer (RET) experiments reveal that the H-5-derived segments can self-assemble within the membrane but cannot coassemble with other unrelated membrane-bound peptides. The results herein support the hypothesis that H-5 segments are packed in close proximity and might participate in mediating the appropriate assembly of the core region of K+ channel monomers.


Validation of a Questionnaire for Family Physicians: Knowledge, Attitude, Practice on Dementia Care.
Our study objective was to develop and validate a questionnaire assessing the knowledge, attitude, and practice (KAP) of family physicians regarding dementia care and dementia strategies in Canada. Using a multistage process with a panel of experts, we developed and distributed an 83-item questionnaire to 542 eligible family physicians in 42 interdisciplinary primary care teams participating in the Quebec Alzheimer Plan implementation. Altogether, 369 physicians (68%) returned questionnaires. Median item-specific non-response rate was 0.8 per cent (0.3%-8.1%). Exploratory factor analyses and scale correlation supported the questionnaire validity. The final questionnaire contained five factors and 31 items. The KAP questionnaire has proved to be a reliable instrument for assessing the KAP of family physicians regarding dementia care and dementia strategies. This questionnaire provides researchers, clinicians, managers, and decision-makers with a tool to assess an intervention, a program, or a policy change implemented in primary health care for patients with dementia.


Hepatic beta-adrenoceptor adaptation during propranolol administration is impaired in aging rats.
Aging has been associated with changes in beta-adrenoceptor responses and adaptation to prolonged removal of catecholamine stimulation. We have examined the effect of chronic propranolol administration on rat hepatic membrane beta-adrenoceptor density, agonist affinity and response in young (6-7 months) and old (26-7 months) male Wistar rats. Propranolol administration via miniosmotic pumps for 7 days resulted in similar and sustained plasma propranolol levels (approximately 100 ng/ml) in old and young rats. Pretreatment beta-adrenoceptor responses to isoprenaline were significantly higher in old rats. Propranolol administration was associated with significant increases in beta-adrenoceptor response and density (Bmax) in young rats only. Cyclic adenosine 3',5'-monophosphate (cyclic AMP) responses to prostaglandin E1 (PGE1), guanosine triphosphate (GTP), 5'-guanyl-imidodiphosphate (Gpp(NH)p), forskolin and Mn2+ were not significantly different between young and old rats and were not affected by propranolol administration. Neither aging or propranolol administration was associated with a change in beta-adrenoceptor agonist affinity. These findings demonstrate elevated hepatic beta-adrenoceptor response and impaired hepatic beta-adrenoceptor adaptation to beta-adrenoceptor blockade in aging rats.


Cardiopulmonary exercise testing in lung transplantation: a review.
There has been an increase in lung transplantation in the USA. Lung allocation is guided by the lung allocation score (LAS), which takes into account one measure of exercise capacity, the 6-minute walk test (6MWT). There is a paucity of data regarding the role and value of cardiopulmonary stress test (CPET) in the evaluation of lung transplant recipients while on the transplant waiting list and after lung transplantation. While clearly there is a need for further prospective investigation, the available literature strongly suggests a potential role for CPET in the setting of lung transplant.


Not so Splendid for the Gut Microbiota.
A critically important new study by leading inflammatory bowel disease (IBD) researcher Fabio Cominelli and colleagues reveals that, in mice, the artificial sweetener SPLENDA deleteriously impacts the intestinal microbiota in a manner that promotes Crohn's-type disease in genetically susceptible hosts. These results suggest that consumption of this product may be a risk factor for IBD.


Clinician perspectives on cross-education in stroke rehabilitation.
Cross-education is a neural phenomenon where strength of an untrained muscle improves after unilateral training of the opposite homologous muscle. It has been extensively studied in healthy populations and shows promise for post-stroke rehabilitation. The purpose of this study is to understand current post-stroke upper extremity rehabilitation practice; clinician's perspectives on cross-education and; facilitators and barriers to implementation of a cross-education intervention. This qualitative study used an interpretive description framework. Twenty-three occupational therapists and two physiotherapists who worked with individuals with stroke were interviewed. Digital audio files were transcribed and then line-by-line coding for units of information was conducted by two investigators. A third investigator, who was not present during the interviews, participated in category development. Cross-education is paradoxical yet promising was the primary theme. This theme was elucidated by three descriptive categories: (1) therapists worked in a forced-use paradigm; (2) there was gap in current practice for those with more severe impairments in arm function; and (3) cross-education used as an adjunct could be useful within current practice for specific patients. Therapists suggested that educational materials for clinicians, patients, and patient families would be essential to the success of cross-education to explain training the less affected limb. This study provides important foundational information about clinician perspectives that will facilitate future translational research in this area. Implications for rehabilitation Cross education, or training the stronger arm to increase strength in the weaker arm, is an intervention particularly appropriate for people with stroke who have severe impairments in arm strength. This intervention should not replace the forced use paradigm, but may be a useful adjunct in rehabilitation. Therapists perceived that education of patients, families, therapists, and doctors would be critical for cross education to be implemented successfully - as it is opposite the forced use paradigm that characterizes most of stroke rehabilitation.


Cross-transmission of Eimeria spp. (Protozoa, Apicomplexa) of rodents--a review.
A total of 169 cross-transmission attempts has been made with 44 (11.8%) of the 372 named species of Eimeria of rodents. Of these, 161 were rodent-to-rodent, 6 rodent-to-lagomorph, and 1 each rodent-to-carnivore and rodent-to-bird. None of the last three categories was successful. In the rodent-to-rodent combinations, 39 (80%) of the 49 attempts to transmit a coccidian species from one rodent species to another of the same genus were successful, and only 14 (12.5%) of the 112 attempts to transmit a coccidium to a rodent of a different genus were successful. Eight of the successful attempts were with E. chinchillae, which was the only truly euryxenous species of Eimeria in the group. Two successful attempts were between between the closely related rodent genera Spermophilus and Cynomys, and two were both of E. separata from Rattus norvegicus to some genetic strains but not to others of Mus musculus. One attempt with E. vermiformis from Mus musculus to Rattus norvegicus required treatment of the rat with the immunosuppressant dexamethasone to succeed. More cross-transmission studies are needed to determine the host spectra of the species of Eimeria and other coccidian genera, and to determine the roles of genetics and immunosuppression in their transmission.


Immunosuppressive effects of FTY720 alone or in combination with cyclosporine and/or sirolimus.
We examined the ability of FTY720, a novel immunosuppressant that prolongs the survival of allografts in experimental animal models, to potentiate the immunosuppressive effects of cyclosporine (CsA) and/or sirolimus (SRL) in vitro and in vivo. FTY720 alone (10-5000 ng/ml) or in combination with other drugs was added to human peripheral blood lymphocytes (PBLs) undergoing stimulation in vitro with phytohemagglutinin (PHA) or OKT3 monoclonal antibody. The combination index (CI) values were calculated to evaluate the nature of the interactions between FTY720 and CsA and/or SRL: CI values <1 reflect synergistic, CI=1, additive, and CI>1, antagonistic interactions. In addition, Wistar Furth (RT1u) rat recipients of Buffalo (RT1b) heart allografts were treated with FTY720 alone or in combination with other agents. FTY720 alone was also tested to block small bowel or liver allograft rejection in rats. FTY720 alone produced only modest inhibition of the proliferation of human PBL stimulated with PHA or OKT3 monoclonal antibody. In combination with CsA or SRL, however, FTY720 produced synergistic effects, namely, CI values of 0.58 and 0.36, respectively. A 14-day course of FTY720 (0.05-8.0 mg/kg/day) by oral gavage prolonged heart allograft survival in dose-dependent fashion. Although a 14-day oral course of CsA (1.0 mg/kg/day) alone was ineffective (mean survival time=7.0+/-0.7 vs. 6.4+/-0.6 days in treated vs. untreated hosts), treatment with a combination of 1.0 mg/kg/day CsA and 0.1 mg/kg/day FTY720 extended allograft survival to 62.4+/-15.6 days (P<0.001; CI=0.15). Similarly, a 14-day oral course of 0.08 mg(kg/day SRL alone was ineffective (6.8+/-0.6 days; NS), but the combination of SRL with 0.5 mg/kg/day FTY720 extended the mean survival time to 34.4+/-8.8 days (CI=0.28). The CsA/SRL (0.5/0.08 mg/kg/day) combination acted synergistically with FTY720 (0.1 mg/kg/day) to prolong heart survivals to >60 days (CI=0.18). FTY720 potentiates the immunosuppressive effects of CsA and/or SRL both in vitro (by inhibiting of T-cell proliferative response) and in vivo (by inhibiting allograft rejection).


[Allelopathic effects of phenolic compounds of melon root exudates on Fusarium oxysporum f. sp. melonis].
In this study, the phenolic compounds of melon root exudates were identified by HPLC and seven phenolic compounds including gallic acid, phthalic acid, syringic acid, salicylic acid, ferulic acid, benzoic acid and cinnamic acid were observed. The laboratory experiment showed that ferulic acid, benzoic acid and cinnamic acid of 0.1 and 0.25 mmol x L(-1) could significantly promote the germination of Fusarium oxysporum f. sp. melonis spore while salicylic acid inhibited the spore germination to some degree. Syringic acid and ferulic acid significantly promoted the mycelium growth at the late stage of incubation. The pot experiments demonstrated that cinnamic acid, benzoic acid and ferulic acid enhanced melon infection at concentrations of 0.5, 0.1 and 0.5 mmol x L(-1).


Echogenicity of medium-to-large carotid plaques predicts future vascular events.
Although the echolucent plaque in carotid stenosis is associated with future ischemic stroke, the predictive value of echogenicity in small and medium size carotid plaques on vascular events has not been thoroughly examined. Thus, we prospectively tested the hypothesis that plaque echogenicity of carotid atheroma can predict the future total cardiovascular events in patients with vascular risk factors. Ultrasound assessment of carotid intima-media complex thickness (IMT) and plaque echogenicity using integrated backscatter (IBS) analysis was performed in 596 patients aged 40 or more, with any history of vascular events or with at least 1 risk factor, who were enrolled between 2001 and 2006 in the Osaka Follow-up Study for Carotid Atherosclerosis, part 2 (OSACA2). We followed the incidence of total cardiovascular events including cerebrovascular events, coronary heart disease (CHD), and peripheral artery disease (PAD) for 6.4 years. We divided the patients into two groups according to the IBS index above (echorich plaques) and under (echolucent plaque) the median value, and calculated the hazard ratios (HR) of the echolucent group compared with the echogenic group in the risk of cardiovascular events. Among 596 patients, carotid stenosis was found only in 87 patients. During the follow-up period, we observed 121 cardiovascular events including 63 cerebrovascular events, 45 CHD cases, and 13 PAD cases. The patients with incident cardiovascular events had larger plaque thickness and lower IBS index than those without incident vascular events. The relative risk of vascular events for echolucent versus echorich plaques was 1.45 (95% confidence interval [CI] 0.99-2.13, p = 0.058) after adjustment for risk factors and plaque thickness. In patients with plaque size above the median value (>2.1 mm), the relative risk of vascular events for echolucent plaques was 1.72 (95% CI 1.06-2.85, p = 0.029), but this association was not observed in patients with plaque size <2.0 mm. The association between echogenicity of carotid plaque and incident vascular events is dependent on the plaque size. Echolucent medium-to-large plaques, but not small plaques, are associated with the risk of future total cardiovascular events. This finding suggests that measurement of echolucency in medium-to-large carotid plaques may improve selection of patients at high risk for total vascular events.


Model-free prediction of atmospheric warp based on artificial neural network.
This paper presents the application of artificial neural network for predicting the warping of images of remote objects or scenes ahead of time. The algorithm is based on estimating the pattern of warping of previously captured short-exposure frames through a generalized regression neural network (GRNN) and then predicting the warping of the upcoming frame. A high-accuracy optical flow technique is employed to estimate the dense motion fields of the captured frames, which are considered as training data for the GRNN. The proposed approach is independent of the pixel-oscillatory model unlike the state-of-the-art Kalman filter (KF) approach. Simulation experiments on synthetic and real-world turbulence degraded videos show that the proposed GRNN-based approach performs better than the KF approach in atmospheric warp prediction.


Long-term Duration of First-Line Axitinib Treatment in Advanced Renal Cell Carcinoma.
We conducted a retrospective analysis of two clinical trials in treatment-naïve patients (n = 402) with advanced renal cell carcinoma (RCC) treated with axitinib. Our objective was to compare duration of treatment (DT) and clinical outcome in patients who achieved DT >18 months (longer DT) versus ≤18 months (shorter DT). DT, objective response rate (ORR), tumor shrinkage, and overall survival (OS) were summarized for patients with longer and shorter DT. Overall, 152 patients (37.8%) had longer DT and 250 (62.2%) had shorter DT (median, 34.7 vs. 6.5 months, respectively). ORR in all 402 patients with advanced RCC was 43.5%. ORR was 75% for longer DT versus 24.4% for shorter DT (p < 0.0001). More patients with longer DT versus shorter DT had ≥10% tumor shrinkage at first scan (74.8% vs. 55.3%; p = 0.0001) and maximum on-study tumor shrinkage was greater in longer-DT versus shorter-DT group (-51.8% vs. -22.1%; p < 0.0001). Median OS was 32.6 months in the overall population while in the patients with longer DT the median was not reached. Treatment-related adverse events (AEs) grade ≥3 were more frequent in longer-DT versus shorter-DT and included hypertension (25.7% vs. 18.8%), diarrhea (15.1% vs. 4.4%), and weight decrease (11.2% vs. 3.2%); however, these AEs decreased over time in both groups. Eastern Cooperative Oncology Group performance status 0, favorable hematology values, no bone or liver metastases, and baseline tumor burden below the overall median were associated with longer DT. Longer duration (>18 months) of axitinib treatment was associated with increased frequency of early tumor shrinkage, greater magnitude of tumor shrinkage, and a favorable OS.


Spinal Accessory Nerve: Ultrasound Findings and Correlations with Neck Lymph Node Levels.
Purpose: To evaluate the ultrasound characteristics of the spinal accessory nerve (SAN) and correlate nerve location with neck lymph node level. Materials and Methods: 50 participants with 100 SANs were enrolled in this study. The SAN was traced from the trapezius muscle to the upper neck and was identified by a hypoechoic linear structure without color Doppler flow. The ultrasound characteristics of the SAN, such as visibility, diameter, relationship with adjacent structures, and its correlation with lymph node levels, were evaluated. Results: The SAN was identified in 96 %-100 % of segments. The mean diameter of the SAN was 0.54 ± 0.09 mm. The SANs was located between the trapezius and levator scapulae muscles and 90.8 % were traced into the trapezius muscle. In the upper neck, the SAN passed deep into the sternocleidomastoid (SCM) muscle in 38 % of cases and between the two heads of the SCM muscle in 62 % of cases. The SAN was found at neck lymph node levels II, III, IV, and V, but not I or VI. Conclusion: Continuous ultrasound monitoring of the SAN and its correlation with lymph node levels is possible in most patients. Our current findings may assist in the future prevention of SAN injury during ultrasound-guided procedures.


Protecting public trust in immunization.
Public trust in the safety and efficacy of vaccines is one key to the remarkable success of immunization programs within the United States and globally. Allegations of harm from vaccination have raised parental, political, and clinical anxiety to a level that now threatens the ability of children to receive timely, full immunization. Multiple factors have contributed to current concerns, including the interdependent issues of an evolving communications environment and shortfalls in structure and resources that constrain research on immunization safety (immunization-safety science). Prompt attention by public health leadership to spreading concern about the safety of immunization is essential for protecting deserved public trust in immunization.


Drug Use and Spatial Dynamics of Household Allocation.
Household space allocation by women who consume drugs in New York and North Florida is depicted to demonstrate the complex character of household space and social relations. Some parents attempt to hide their drug consumption through the allocation space in the household for drug use. Women allocation of space for drug use within their households and the impact of this on the household are relevant issues with implications for therapy and prevention. The use of household space has not been a focus of social scientists. Middle class households have been used by decoration literature to specify space utilization. Modest literature pay attention to the utilization of household space among drug focused households. Analysis herein looks at the lived social relations of drug users to their children through controlling household space. Data presented comes from two studies, New York and Florida. The studies involved a total of 158 participants in 72 families from New York and 26 participants in 23 families in North Florida. Both researches used an ethnographic methodology focusing on a variety of behavior patterns and conduct norms occurring within drug abusing households. Repeated interviews and observations took place in households which were visited at different times and days of the week. Florida study was conducted over a 2-year period; New York study took place over a 5-year period. Data suggest parents attempted to conceal their drug use from their offspring by using various strategies. Mental, social, and physical were tied together in space allocation. Household space acquired a different meaning and arose from use practice. In urban and rural settings a pattern of household allocation space and drug consumption is emerging. Although drug consumption is still prominent, it is not all consuming or the primary focus in the lives of women who use drugs. These women may have learned to integrate their consumption into their daily household/family life through the reallocation of space in their homes.


Thymoma-associated multi-organ autoimmunity: A case of graft-versus-host disease-like erythroderma complicated by Good syndrome successfully treated by thymectomy.
Thymoma-associated multi-organ autoimmunity disease (TAMA) is a rare paraneoplastic disorder, clinicopathologically similar to graft-versus-host disease (GVHD). Many reported cases follow a difficult course; half of them die from serious infectious diseases subsequent to immunosuppression induced by chemotherapy for unresectable thymoma, or intensive therapies including systemic steroids for complicating autoimmune diseases and GVHD-like symptoms. We report a patient whose skin symptoms were improved subsequently to total thymectomy. The patient also presented with hypogammaglobulinemia, which led to the diagnosis of complicated Good syndrome. Taking account of her immunodeficient condition, antibiotics and i.v. immunoglobulin were administrated promptly on onset of bacterial pneumonia, which was successfully treated. According to a review of the published work, treatments with systemic steroids for skin symptoms have limited effects and may contribute to serious infection. Our case indicates that successful treatment of thymoma itself may lead to the amelioration of the disease. The management priority should be given to the treatment of thymoma and the control of subsequent immune abnormality other than GVHD-like erythroderma.


Calcium Deregulation and Mitochondrial Bioenergetics in GDAP1-Related CMT Disease.
The pathology of Charcot-Marie-Tooth (CMT), a disease arising from mutations in different genes, has been associated with an impairment of mitochondrial dynamics and axonal biology of mitochondria. Mutations in ganglioside-induced differentiation-associated protein 1 (GDAP1) cause several forms of CMT neuropathy, but the pathogenic mechanisms involved remain unclear. GDAP1 is an outer mitochondrial membrane protein highly expressed in neurons. It has been proposed to play a role in different aspects of mitochondrial physiology, including mitochondrial dynamics, oxidative stress processes, and mitochondrial transport along the axons. Disruption of the mitochondrial network in a neuroblastoma model of GDAP1-related CMT has been shown to decrease Ca2+ entry through the store-operated calcium entry (SOCE), which caused a failure in stimulation of mitochondrial respiration. In this review, we summarize the different functions proposed for GDAP1 and focus on the consequences for Ca2+ homeostasis and mitochondrial energy production linked to CMT disease caused by different GDAP1 mutations.


Schwannoma of the intermediate nerve.
The intermediate nerve is seldom identified as the site of tumor origin in cerebellopontine angle schwannomas. A 29-year-old man presented with a 6-month history of slowly progressive hearing loss and dizziness; facial nerve weakness was not observed clinically. Magnetic resonance imaging revealed a tumor in the left cerebellopontine angle region extending up to the geniculate ganglion and along the course of the superficial petrosal nerve. A CT scan showed enlargement of the facial nerve canal. Microsurgery was performed via an extended retrosigmoid approach. Intraoperative and electrophysiological findings identified the intermediate nerve as the site of tumor origin.


Measurement of symptom distress in women with early-stage breast cancer.
While symptom distress can alter the cancer experience, it is difficult to define and measure. This study's aims were (1) to determine whether the McCorkle Symptom Distress Scale (SDS) or the Rhodes Adapted Symptom Distress Scale (ASDS) was the more accurate measure of symptom distress in women with breast cancer; (2) correlate both scales with a visual analogue scale (VAS) measuring anxiety, a symptom frequently reported clinically; (3) determine tool preference; and (4) establish when during the first cycle of chemotherapy the highest levels of symptom distress were experienced. One hundred twenty women were recruited and measurement of symptom distress (SDS and ASDS) and anxiety (VAS) taken at the start of chemotherapy (Time 1), at the nadir (Time 2), and at the end of the cycle (Time 3). Both instruments were highly correlated and detected change over time; none was correlated with the VAS anxiety scale. Symptom distress scores were generally low, with fatigue, appearance, insomnia, and concentration causing the greatest distress. Other factors like functioning, body image, and menopausal symptoms cited as contributors to symptom distress levels were not measured and could account for low scores and perhaps suggest that symptom distress may not be accurately measured in today's women with early-stage breast cancer.


Modulation of cardiovascular response to dynamic exercise by fastigial nucleus.
Mongrel dogs (n = 34) were used to record the cardiovascular responses during submaximal exercise-tolerance tests (ETT) before and after the placement of lesions in rostral portions of the cerebellar fastigial nucleus (FN). Sterile surgical procedures were used to implant solid-state pressure transducers into the left ventricle or descending aorta (anesthesia 1% halothane in O2) and multipolar stainless steel electrodes into FN (anesthesia alpha-chloralose 115 mg/kg iv). Heart rate (HR), maximal left ventricular systolic pressure ( LVPmax ) and its first derivative ( dLVP /dt), and mean arterial blood pressure (MAP) were recorded during a motorized treadmill ETT. Electrolytic direct-current or radio-frequency lesions were made through the indwelling FN electrodes, and the ETT was repeated following 10-14 days recovery. Two-way analysis of variance (ANOVA), with repeated measures on one, and one-way ANOVA for simple effects indicated a significant reduction in HR and MAP (P less than 0.01) but not LVPmax and dLVP /dt occurred during exercise as a result of rostral FN lesions. Although the trend for reduced LVPmax and dLVP /dt was also evident, a relatively greater decrease in blood pressure occurred in the peripheral vasculature during exercise. It was concluded that FN acts as a modulator of HR and MAP during dynamic exercise because of the observed deficits, and because FN is known to both send efferent projections to medullary vasomotor areas and receive projections from motor cortex and muscle and joint afferents.


Clothing polymer fibers with well-aligned and high-aspect ratio carbon nanotubes.
It is believed that the crucial step towards preparation of electrical conductive polymer-carbon nanotube (CNT) composites is dispersing CNTs with a high length-to-diameter aspect ratio in a well-aligned manner. However, this process is extremely challenging when dealing with long and entangled CNTs. Here in this study, a new approach is demonstrated to fabricate conductive polymer-CNT composite fibers without involving any dispersion process. Well-aligned CNT films were firstly drawn from CNT arrays, and then directly coated on polycaprolactone fibers to form polymer-CNT composite fibers. The conductivity of these composite fibers can be as high as 285 S m(-1) with only 2.5 wt% CNT loading, and reach 1549 S m(-1) when CNT loading is 13.4 wt%. As-prepared composite fibers also exhibit 82% retention of conductivity at a strain of 7%, and have improved mechanical properties.


Elderly Patients With Single Brain Metastasis - Overall Survival After Surgery Plus Whole-Brain Irradiation and a Radiation Boost.
Elderly patients with a single brain metastasis likely benefit from personalized treatment protocols. To add to treatment personalization, a survival score was generated for these patients. This retrospective study included 36 elderly patients, each with a single brain metastasis, who received surgery followed by whole-brain irradiation and a radiation boost. Six pre-treatment characteristics were evaluated regarding survival, namely age, gender, Karnofsky performance score (KPS), type of primary tumor, non-cerebral metastasis and interval from diagnosis of the neoplasm until surgery. When applying the Cox regression model, KPS (p=0.005) and tumor type (p=0.018) were significant and incorporated in the score. Based on 12-month survival probabilities, three groups of 6-9 (n=5), 10-11 (n=15) and 14-19 points (n=16) were formed, with 12-month survival rates of 0%, 33% and 100%, respectively (p<0.0001). A survival score was generated specifically for elderly patients with a single brain metastasis that can improve personalization of their treatment.


Comparative Analysis of State Trauma Triage Criteria vs. Paramedic Discretion.
The Florida Adult Trauma Triage Criteria (FATTC) define specific parameters concerning injury mechanism and physiologic data that prompt paramedics to initiate a trauma alert and necessitate transport to a trauma center. In the state of Florida, paramedics are also given discretion to bring patients to the trauma center who do not meet those criteria. Our aim was to compare the injury characteristics and outcomes of adult patients who were evaluated in our trauma center after activation due to FATTC criteria vs. paramedic discretion (PD) and to identify predictors of PD. This retrospective study included all patients 18 years and older evaluated in our trauma center from January 1, 2007, to December 31, 2014. Descriptive statistics were computed for all variables. Bivariate and multivariate analyses were performed to compare demographic, injury severity, and outcome differences between groups. A total of 13,963 patients met FATTC during the study period, and 1,811 were brought in by PD. PD patients had lower injury severity and crude mortality. Regression modeling of demographic and injury variables found that only the combination of older age and higher heart rate predicted PD when both were lower than FATTC alone. While PD patients were less seriously injured and had lower mortality, they experienced similar lengths of stay and resource utilization after presentation. Paramedics may be able to identify patients at risk for poor outcomes who would otherwise not be captured by FATTC.


[Hermeneutic Phenomenological Study on Caring Experience of the Mothers of Children with Epilepsy].
The purpose of this study was to develop a deeper understanding of the experience of mothers caring for children with epilepsy. Data were collected through individual in-depth interviews and observation from 12 mothers of children with epilepsy. Data were collected from December, 2014 to February, 2015 and analyzed using van Manen's hermeneutic phenomenological methodology to identify essential themes of their experience. The essential themes that fit into the context of the 4-existential grounds of time, body, other people, and space were: Lived time-ongoing influence of the past, living in insecure present, fearful future with no answer; Lived body-bonded body, burned out state; Lived other-burden but also support, shrunken down; Lived space-narrowed range of activity, widened horizon. The findings in this study show in-depth understanding of the hardships of mothers who are caring for children with epilepsy. The beauty and greatness of these mothers are revealed through the analysis of various phenomenological materials such as literary and artistic work reflecting socio-cultural context, as well as vivid care experiences of mothers of children with epilepsy. This will be helpful in increasing understanding of the nature of caregivers' experience for medical professionals dealing with patients and caregivers. Also it helps to improve the understanding of the disease among the general public, followed by a more warming and caring attitude towards patients and family members. Finally, it will enhance psychological well-being and overall quality of life of the epileptic children and their families.


Expression, glycoform characterization, and antibody-binding of HIV-1 V3 glycopeptide domain fused with human IgG1-Fc.
The third variable (V3) domain of HIV-1 gp120 envelope glycoprotein is critical for HIV-1 entry and represents an attractive target for vaccine design. There are three conserved N-glycans within or around the V3 loop. The N295 and N332 glycans at the base of V3 are usually characterized as high-mannose type in gp120, and the N301 glycan is a complex type. We report in this paper the expression and characterization of glycosylated, full-size V3 domain derived from HIV-1(Bal) strain as an IgG1-Fc fusion protein, including its binding to two broadly HIV-neutralizing antibodies 2G12 and 447-52D. It was found that expressing the V3-Fc fusion protein in the HEK293T cells resulted in the production of a glycoform in which all the N-glycans were complex type, in contrast to the glycosylation pattern of V3 in the context of gp120, where the N295 and N332 glycans are high-mannose type. Controlling the glycosylation to restore an epitope of antibody 2G12 was achieved by using an inhibitor of glycan processing enzymes. Mutational studies indicate that the glycan at N301 slightly decreases the binding of V3-Fc to antibody 447-52D, but it can significantly enhance the binding of the V3-Fc to antibody 2G12 when it is changed to a high-mannose type N-glycan. The high-mannose type V3-Fc fusion protein that includes both the 2G12 and 447-52D epitopes represents an interesting immunogen that may be able to raise anti-HIV neutralizing antibodies.


The antiepileptic and ictogenic effects of optogenetic neurostimulation of PV-expressing interneurons.
Parvalbumin (PV)-expressing interneurons exert powerful inhibitory effects on the normal cortical network; thus optogenetic activation of PV interneurons may also possess antiepileptic properties. To investigate this possibility we expressed channelrhodopsin 2 in PV interneurons by locally injecting the Cre-dependent viral vector AAV2/1-EF1a-DIO-ChETA-EYFP into the S1 barrel cortex of PV-Cre mice. Approximately 3-4 wk later recurrent electrographic seizures were evoked by local application of the chemoconvulsant 4-aminopyridine (4-AP); the ECoG and unit activity were monitored with extracellular silicone electrodes; and PV interneurons were activated optogenetically during the ictal and interictal phases. Five- to ten-second optogenetic activation of PV interneurons applied during electrographic seizures (ictal phase) terminated 33.7% of electrographic seizures compared with only 6% during sham stimulation, and the average electrographic seizure duration shortened by 38.7 ± 34.2% compared with sham stimulation. In contrast, interictal optogenetic activation of PV interneurons showed powerful and robust ictogenic effects. Approximately 60% of interictal optogenetic stimuli resulted in electrographic seizure initiation. Single-unit recordings revealed that presumptive PV-expressing interneurons markedly increased their firing during optogenetic stimulation, while many presumptive excitatory pyramidal neurons showed a biphasic response, with initial suppression of firing during the optogenetic pulse followed by a synchronized rebound increase in firing at the end of the laser pulse. Our findings indicated that ictal activation of PV-expressing interneurons possesses antiepileptic properties probably due to suppression of firing in pyramidal neurons during the laser pulse. However, in addition interictal activation of PV-expressing interneurons possesses powerful ictogenic properties, probably due to synchronized postinhibition rebound firing of pyramidal neurons.


Racial differences in cancer incidence: the significance of age-specific patterns.
Racial differences in cancer incidence between black and white populations are examined for leading cancer sites by age at diagnosis. The analysis was based on 116,858 incidents, invasive cancer cases occurring between 1973 and 1982 in black and white, male and female residents of the Detroit metropolitan area. Cases were drawn from the population-based Metropolitan Detroit Cancer Surveillance System. The results indicate that racial differences in age-specific incidence rates for many forms of cancer are more pronounced when cancer occurs in early adulthood and middle age (20 to 44 and 45 to 54 years) than in persons aged 65 and over. This is especially the case for male subjects. This may suggest that blacks and whites who survive to their senior years before developing cancer may be more alike in terms of behavior, exposures, or host susceptibility than blacks and whites for whom cancer occurs in early adulthood or middle age. The etiologic and public health implications of these race and age patterns must be considered in greater detail. Future case-control studies should include sufficient numbers of patients in both the youngest and oldest age groups to ensure that black and white differences can be adequately examined by age at diagnosis.


Viral load and CD4+ T lymphocyte response to highly active antiretroviral therapy in human immunodeficiency virus type 1-infected children: an observational study.
An observational study was performed involving 95 children with vertically transmitted human immunodeficiency virus type 1 infection to assess the sustainability of undetectable viral loads (VLs) and increased CD4+ T lymphocyte percentages after 48 months of highly active antiretroviral therapy (HAART). The median time to achieve a 10% increase in the CD4+ T lymphocyte percentage was 11.01 months. The median time to achieve an undetectable VL was 6.4 months. At the end of the study, 64.2% of the children had achieved an undetectable VL. Of the patients with an initial VL of >3.6 log10 copies/mL, 74.7% had a decrease in the VL of 1 log10 copies/mL. By contrast, of the patients who presented with an initial VL of >4.6 log10 copies/mL, 37.9% had a decrease of >2 log10 copies/mL. Higher VL at baseline, antiretroviral therapy regimens received before HAART, and multiple drug switches while receiving antiretroviral therapy were all inversely associated with an undetectable VL. A CD4+ T lymphocyte percentage of >25% was directly associated with undetectable VL during the follow-up period. In conclusion, first-line HAART induces beneficial virological and immunological outcome responses in children.


Does it blend? Exploring therapist fidelity in blended CBT for anxiety disorders.
Blended cognitive-behavioural therapy (bCBT) combines face-to-face CBT (FtFCBT) and Internet-based CBT (iCBT) into one integrated treatment protocol, opening up new ways to deliver therapy, increase cost-effectiveness and resolve scarcity of therapist availability. When traditional therapy is transformed into a new format, there is a need to evaluate whether principles of the new protocol are consistently applied. This study aimed to explore therapist fidelity to bCBT protocols for anxiety disorders in specialised mental health care and to assess whether fidelity is related to patient characteristics. Adult patients (N = 44) received bCBT within a randomised controlled trial. Ratio of FtF to online sessions, session frequency and therapist adherence to instructions were assessed. Overall therapist fidelity with regard to ratio of blending, session frequency and instructions was high. Correlations were found between patients' share of online sessions and both session frequency (r = 0.373, p = .013), as well as patient computer experience (r = 0.314, p = .038). Adherence to instructions in FtF sessions was based on a subset of patients (n = 23) and should therefore be interpreted with caution. The blended approach was generally delivered as intended, indicating that the format is feasible in specialised mental health.


Frequency of Acute Hepatitis Following Acute Paraphenylene Diamine Intoxication.
Paraphenylene diamine (PPD) ingestion is manifesting as one of the more common ways of committing suicide in Southern Punjab, Pakistan, especially Bahawalpur. PPD is an ingredient of a compound commonly known "Kala Pathar" which means "Black Stone" in Urdu. It is readily available in the market at low cost and is used to dye hair and fur. Its intoxication inhibits cellular oxidation and affects the muscles causing rhabdomyolysis. This leads to myoglobinuria followed by renal failure and edema of face and throat resulting in respiratory difficulty. Very little is known about the impact of PPD intoxication on liver tissue. The purpose of the study was to find out the frequency of acute hepatitis following PPD intoxication. We reviewed the medical records of 109 patients with PPD intoxication admitted to Medical Unit-2, Bahawalpur Victoria Hospital from January 1, 2015, to June 30, 2015, in a descriptive, cross-sectional study. We noted the frequency of acute hepatitis and other complications, and we recorded the demographic features, clinical features, and outcomes of these patients. Our study included 32 men (29%) and 77 women (71%). The mean age was 22 ± 3.4 years, and most patients were young women aged 15 to 24 years. Suicidal ingestion was the leading cause of admission for 101 patients (93%). The most common clinical presentation was cervicofacial edema (95%), throat pain (88%), dysphonia (95%), cola-colored urine (100%), and oliguria (95%). Rhabdomyolysis (86%), acute hepatitis (51%), and acute renal failure (63%) were the most common clinical conditions following poisoning. Overall mortality was noted in 39 patients (36%) while all other patients achieved complete clinical recovery (64%). In patients with mortality, 20 of 39 (51%) developed acute hepatitis. Most patients (95%) in our study underwent tracheostomy. The frequency of acute hepatitis in PPD intoxication is high in this population, especially in young women. Measures need to be instituted regarding the management of acute hepatitis in PPD intoxication to improve patient outcomes. Workups in patients with PPD poisoning should include regular monitoring of aspartate aminotransferase and alanine aminotransferase to observe any damages to the liver so that acute hepatitis can be managed in a timely fashion.


Risk Assessment of Human Listeriosis from Semisoft Cheeses Made from Raw Sheep's Milk in Lazio and Tuscany (Italy).
Semisoft cheese made from raw sheep's milk is traditionally and economically important in southern Europe. However, raw milk cheese is also a known vehicle of human listeriosis and contamination of sheep cheese with Listeria monocytogenes has been reported. In the present study, we have developed and applied a quantitative risk assessment model, based on available evidence and challenge testing, to estimate risk of invasive listeriosis due to consumption of an artisanal sheep cheese made with raw milk collected from a single flock in central Italy. In the model, contamination of milk may originate from the farm environment or from mastitic animals, with potential growth of the pathogen in bulk milk and during cheese ripening. Based on the 48-day challenge test of a local semisoft raw sheep's milk cheese we found limited growth only during the initial phase of ripening (24 hours) and no growth or limited decline during the following ripening period. In our simulation, in the baseline scenario, 2.2% of cheese servings are estimated to have at least 1 colony forming unit (CFU) per gram. Of these, 15.1% would be above the current E.U. limit of 100 CFU/g (5.2% would exceed 1,000 CFU/g). Risk of invasive listeriosis per random serving is estimated in the 10-12 range (mean) for healthy adults, and in the 10-10 range (mean) for vulnerable populations. When small flocks (10-36 animals) are combined with the presence of a sheep with undetected subclinical mastitis, risk of listeriosis increases and such flocks may represent a public health risk.


Hypoxia and reoxygenation: a possible mechanism for placental oxidative stress in preeclampsia.
Preeclampsia is a human pregnancy-specific disorder that is diagnosed by the new appearance of hypertension and proteinuria after 20 weeks' gestation. It is a leading cause of perinatal morbidity and mortality, and the only intervention that effectively reverses the syndrome is delivery. Oxidative stress of the placenta is considered to be a key intermediary step in the pathogenesis of preeclampsia, but the cause for the stress remains unknown. Hypoxia-reoxygenation (H/R) injury, as a result of intermittent placental perfusion secondary to deficient trophoblast invasion of the endometrial arteries, is a possible mechanism. In this review, we present evidence to show that there is a plausible basis from which to assume that blood flow in the intervillous space will be intermittent in all normal pregnancies. The intermittency will be exacerbated by impaired conversion of the spiral arteries, or by the presence of atherotic changes that reduce their caliber as seen in preeclampsia. Placental oxidative stress can be the consequences of fluctuations in oxygen concentrations after H/R through the actions of reactive oxygen species. On this basis, there will be a complete spectrum of placental changes among the normal, the late onset and the early onset preeclamptic states. Viewing the syndrome as a continuum of H/R insults provides new insight into the pathophysiology of pregnancy that will hope fully lead to improved clinical interventions.


Effect of H2-receptor antagonists cimetidine and famotidine on interdigestive gastric motor activity and lower esophageal sphincter pressure in progressive systemic sclerosis.
The effect of the H2-receptor antagonists cimetidine and famotidine on interdigestive gastric motor activity and lower esophageal sphincter pressure was assessed in 41 patients with uncomplicated progressive systemic sclerosis. There was no significant change in gastric phasic motor activity after the intravenous administration of cimetidine (n = 6), famotidine (n = 13), and physiological saline (n = 15), or the intragastric infusion of 7% sodium bicarbonate (n = 7). The lower esophageal sphincter pressure was increased significantly by both cimetidine and famotidine, but only famotidine caused a significant pressure rise in patients without an increase of gastric motility. Cimetidine and physiological saline produced a similar pattern of change in the esophageal sphincter pressure, as did famotidine and sodium bicarbonate. These findings suggest that the inhibition of acetylcholinesterase activity and gastric acid secretion may be involved in the respective mechanisms of action of cimetidine and famotidine.


Sjögren's syndrome and chemokines.
Interferon (IFN)-γ-induced protein 10 (IP-10) and its receptor, chemokine (C-X-C motif) receptor (CXCR)3, appear to contribute to the pathogenesis of Sjögren's syndrome (SS). The expression of IP-10 and CXCR3 is increased, in salivary glands from SS patients, both in the ductal epithelium adjacent to lymphoid infiltrates and in lymphocytes. IFN-γ induces the production of high levels of IP-10 and monokine induced by IFN-γ (MIG) proteins from cultured SS salivary epithelial cells. Under the influence of IFN-γ, IP-10 secreted by salivary cells, recruits T helper (Th)1 lymphocytes that may be responsible for enhanced IFN-γ, which in turn stimulates a further IP-10 secretion from epithelial cells creating an amplification feedback loop and perpetuating the autoimmune process. Determination of high level of IP-10 in tears and saliva is therefore a marker of a Th1 orientated immune response. In experimental settings IP-10 antagonists can ameliorate the progression of autoimmune sialadenitis, providing a new therapeutic approach to SS. Further studies are needed to investigate whether IP-10 is a novel therapeutic target in SS in humans.


Repair of ventricular rupture following mitral valve replacement.
Left ventricular rupture is reported to occur in 0.5-2% of patients following mitral valve replacement and results in a high mortality rate. Three types of left ventricular rupture have been identified, each attributed to a different mechanism. Failure of repair has been due to repeated tearing of the ventricular muscle and resulting hemorrhage. We describe the repair of left ventricular rupture following mitral valve replacement with buttressed dacron patch. The repair is designed to eliminate the tension placed on the suture line. In addition, specific recommendations are made to avoid left ventricular rupture during mitral valve replacement.


Functional imaging techniques for evaluation of sarcomas.
Sarcomas are often characterised by significant histopathologic heterogeneity, both between and within tumours. This heterogeneity reflects physiologic, biochemical and genetic processes that are amenable to characterisation by functional imaging. Although anatomically based imaging modalities such as plain radiography, X-ray computed tomography (CT) and magnetic resonance imaging (MRI) remain the primary diagnostic modalities for staging sarcomas, nuclear medicine approaches including gamma camera scintigraphy and positron emission tomography (PET) are being used increasingly to provide complementary information in specific clinical situations. These include biopsy guidance within anatomically complex masses, staging, therapeutic response assessment and evaluation of residual mass lesions after treatment. This review aims to address the range of nuclear medicine techniques available for evaluation of bone and soft tissue sarcomas. A subsequent review discusses the clinical application of these techniques with a particular focus on PET.


A Survey on Awareness about the Role of Anesthesia and Anesthesiologists among the Patients Undergoing Surgeries in a Tertiary Care Teaching Women and Children Hospital.
Although anesthesiology has grown tremendously and although anesthesiologists play a crucial role in the perioperative management of patients and also outside operating theater (OT) such as critical care, pain clinic, and labor analgesia, they do not get due recognition. We conducted a study to assess the awareness about the role of anesthesia and anesthesiologists among patients scheduled to undergo surgery in a Government Tertiary Care Teaching Women and Children Hospital. A prospective cross-sectional survey with a sample size of 100 patients. Patients scheduled to undergo elective surgery in the age group of 18-65 years with the American Society of Anesthesiologists (ASA) Grades 1 and 2, who are willing to participate and given written informed consent. Patients whose age <18 years and more than 65 years, ASA health status Class 3 and above were excluded. Statistical analysis was done by calculating percentages using Chi-square test. Twenty percent of the participants were illiterate and of the educated, none were graduates or postgraduates. Patients with higher level of education had better knowledge of anesthesiology and role of an anesthesiologist with P < 0.05 than those with lesser education. Forty-eight percent of the participants had no idea about anesthesia despite the majority (62%) having previous surgery with no statistically significant difference (P > 0.05) between those with previous surgery and those without previous surgery regarding their knowledge of anesthesiology and anesthesiologist. Ninety percent did not know the complications, types of anesthesia and 44% did not know that anesthesiologist is a doctor. Most of the participants were not aware of the role of anesthesia and anesthesiologists inside and outside OT. Although this could be attributed to their lower level of education, the fraternity of anesthesiologists has to educate patients and surgeons about the role of anesthesia.


ELTD1 promotes invasion and metastasis by activating MMP2 in colorectal cancer.
Metastasis is a key factor that affects the prognosis of colorectal cancer (CRC), and patients with metastasis have limited treatment options and poor prognoses. EGF, latrophilin, and seven transmembrane domains containing 1 (ELTD1/ADGRL4) are members of the adhesion G protein-coupled receptor (aGPCR) superfamily. In this study, high expression of ELTD1 was correlated with lymph node metastasis and poor outcomes in CRC patients. Both in vitro and in vivo studies showed that ELTD1 markedly promoted the invasion and metastasis of CRC. Moreover, ELTD1 accelerated the transcriptional activity of MMP2, which could rescue the impaired invasiveness of CRC cells caused by the downregulation of ELTD1 expression. In conclusion, our study suggests that ELTD1 might be a potential novel target for the treatment of CRC metastasis.


Long-term follow-up of intravesical botulinum toxin-A injections in women with idiopathic overactive bladder symptoms.
Intravesical botulinum toxin (BoNT-A) is a safe and effective treatment for overactive bladder syndrome. There are many reports on the clinical experience with BoNT-A, especially in patients with neurogenic detrusor overactivity. The US Food and Drug Administration has recently approved its use for idiopathic overactive bladder (iOAB). Various studies have reported positive results for iOAB in the short-term. Yet little is known about the results after repeated BoNT-A injections. In this study, we evaluated the long-term results of botulinum toxin (BoNT-A) in women with iOAB. Patients treated with BoNT-A from 2004 until 2009 were evaluated in a non-academic teaching hospital (Zuyderland MC, Heerlen, the Netherlands). All female patients with a follow-up of >5 years with idiopathic bladder dysfunction were included. All patients received 200 U of onabotulinum toxin-A in 20 intradetrusor injections. In some patients, we applied a dose adjustment for repeated injections. Patients were instructed how to use clean intermittent self-catheterization (CISC) before the treatment. We advised patients to commence CISC if post-void residual exceeded 150 ml. A total of 128 women were included. All patients had at least 5-year follow-up after their first injection. The mean follow-up was 97 (60-125) months. The mean age was 67 (46-88) years. Of all patients, 30 % were still on BoNT-A treatment at the last follow-up visit. Of the 70 % that discontinued treatment, 27 % had insufficient effect and 43 % had tolerability issues. Most patients discontinued treatment after the first (79 %) and second (19 %) injections. Only 2 % of patients discontinued treatment after more than two injections during follow-up. Intravesical BoNT-A is an effective treatment for women with idiopathic OAB. However, in time, almost two-thirds of patients in our study discontinued therapy. Most patients discontinue treatment after one or two injections and mainly due to tolerability issues.


Feasibility of FitSurvivor: A technology-enhanced group-based fitness intervention for adolescent and young adult survivors of childhood cancer.
This study evaluated the feasibility of a technology-enhanced group-based fitness intervention for adolescent and young adult (AYA) survivors of childhood cancer. AYA survivors ages 13-25 years were randomized to the intervention (eight in-person group sessions with mobile app and FitBit followed by 4 weeks of app and FitBit only) or waitlist control. Assessments were at 0, 2, 3, 6, and 9 months. Feasibility was evaluated by enrollment, retention, attendance, app engagement, and satisfaction. Secondary outcomes included physical activity, muscular strength/endurance, cardiorespiratory fitness, health-related quality of life, and fatigue. A total of 354 survivors were mailed participation letters; 68 (19%) were screened, of which 56 were eligible and 49 enrolled (88% of those screened eligible, 14% of total potentially eligible). Forty-nine survivors (Mage = 18.5 years, 49% female) completed baseline assessments and were randomized (25 intervention, 24 waitlist). Thirty-seven (76%) completed the postintervention assessment and 32 (65%) completed the final assessment. On average, participants attended 5.7 of eight sessions (range 1-8). Overall intervention satisfaction was high (M = 4.3, SD = 0.58 on 1-5 scale). Satisfaction with the companion app was moderately high (M = 3.4, SD = 0.97). The intervention group demonstrated significantly greater improvement in lower body muscle strength compared to the waitlist postintervention, and small but not statistically significant changes in other secondary measures. A group-based intervention with a mobile app and fitness tracker was acceptable but has limited reach due to geographical barriers and competing demands experienced by AYA survivors.


Effect of primary tumor location and tumor size on the response to radiotherapy for liver metastases from colorectal cancer.
Metastatic liver tumors (MLTs) from colorectal cancer (CRC) are often treated with stereotactic body radiation therapy (SBRT). The present study aimed to examine the predictive factors for response of MLTs to SBRT. A total of 39 MLTs from 24 patients with CRC were retrospectively analyzed. Radiotherapy for MLT was typically performed with a prescribed dose equivalent to a biologically effective dose (BED)10 of 100 Gy. The median follow-up period was 16 months (range, 5-64 months). The median prescribed dose and total BED10 were 56 Gy (range, 45-72 Gy) and 97.5 Gy (range, 71.7-115.5 Gy), respectively, in a median of 8 fractions (range, 4-33 fractions). The 1- and 2-year local control rates were 67.2 and 35.9%, respectively. For patients with MLT treated with ablative SBRT (BED10 ≥100 Gy in ≤5 fractions), the 1- and 2-year local control rates were 83.3 and 62.5%, respectively. Univariate analysis showed that primary tumor location (left-sided colon), maximum tumor diameter (≤30 mm) and ablative SBRT (BED10 ≥100 Gy in ≤5 fractions) were significantly associated with improved local control (P=0.0058, P=0.0059 and P=0.0268, respectively). Multivariate analysis showed that tumor diameter was significantly associated with improved local control (P=0.0314). In addition, patients who received ablative SBRT had significantly prolonged overall survival times compared with those treated with non-ablative SBRT (P=0.0261). To conclude, tumors ≤30 mm that can be treated with ablative SBRT are associated with good local control rates. The primary tumor location may affect the radiosensitivity of MLTs.


Lysate of engineered Escherichia coli supports high-level conversion of glucose to 2,3-butanediol.
Cell-free metabolic engineering (CFME) is emerging as a powerful approach for the production of target molecules and pathway debugging. Unfortunately, high cofactor costs, limited cofactor and energy regeneration, and low volumetric productivities hamper the widespread use and practical implementation of CFME technology. To address these challenges, we have developed a cell-free system that harnesses ensembles of catalytic proteins prepared from crude lysates, or extracts, of cells to fuel highly active heterologous metabolic conversions. As a model pathway, we selected conversion of glucose to 2,3-butanediol (2,3-BD), a medium level commodity chemical with many industrial applications. Specifically, we engineered a single strain of Escherichia coli to express three pathway enzymes necessary to make meso-2,3-BD (m2,3-BD). We then demonstrated that lysates from this strain, with addition of glucose and catalytic amounts of cofactors NAD+ and ATP, can produce m2,3-BD. Endogenous glycolytic enzymes convert glucose to pyruvate, the starting intermediate for m2,3-BD synthesis. Strikingly, with no strain optimization, we observed a maximal synthesis rate of m2,3-BD of 11.3 ± 0.1 g/L/h with a theoretical yield of 71% (0.36 g m2,3-BD/g glucose) in batch reactions. Titers reached 82 ± 8 g/L m2,3-BD in a 30 h fed-batch reaction. Our results highlight the ability for high-level co-factor regeneration in cell-free lysates. Further, they suggest exciting opportunities to use lysate-based systems to rapidly prototype metabolic pathways and carry out molecular transformations when bioconversion yields (g product/L), productivities (g product/L/h), or cellular toxicity limit commercial feasibility of whole-cell fermentation.


INDIVIDUAL VARIATION IN SPERM COMPETITION SUCCESS OF YELLOW DUNG FLIES, SCATOPHAGA STERCORARIA.
Intraspecific variation in the proportion of offspring sired by the second male to mate with a female (P2 ) is an aspect of sperm competition that has received little attention. We examined variation in the sperm competition success of individual male dung flies, Scatophaga stercoraria. In unmanipulated matings, copula duration was dependent on male size with smaller males copulating for longer. A principal component analysis was used to generate uncorrelated scores based on a male's size and copula duration. Using these scores demonstrated that P2 values were dependent both on the relative size and copula durations of competing males. When copula duration was held constant, the success of an individual male increased as his body size, relative to the first male, increased. We interrupted copulations of "large" and "small" second males and fitted the resultant P2 values to a linear model of sperm competition with unequal ejaculates. The data fit well to a model of sperm displacement in which sperm mix quickly on introduction to the sperm stores. Furthermore, they show that "large" males have a greater rate of sperm displacement than "small" males. The levels of prey availability during testis maturation may influence a male's success in sperm competition although his immediate mating history does not. We show why an understanding of variation in sperm competition success is important for understanding the mechanisms and evolutionary significance of sperm competition.


Effectiveness of Linkage to Care and Prevention Interventions Following HIV Self-Testing: A Global Systematic Review and Meta-analysis.
Over 38.4 million people were living with HIV globally in 2021. The HIV continuum includes HIV testing, diagnosis, linkage to combined antiretroviral therapy (cART), and retention in care. An important innovation in the HIV care continuum is HIV self-testing. There is a paucity of evidence regarding the effectiveness of interventions aimed at linking self-testers to care and prevention, including pre-exposure prophylaxis (PrEP). To bridge this gap, we carried out a global systematic review and meta-analysis to ascertain the effectiveness of interventions post-HIV self-testing regarding: (1) linkage to care or ART, (2) linkage to PrEP, and (3) the impact of HIV self-test (HIVST) interventions on sexual behaviors. We searched PubMed, Web of Science, SCOPUS, Cochrane Library, CINAHL Plus (EBSCO), MEDLINE (Ovid), Google Scholar, and ResearchGate. We included only published randomized controlled trials (RCTs) and quasi-experiment that compared HIVST to the standard of care (SoC). Studies with sufficient data were aggregated using meta-analysis on RevMan 5.4 at a 95% confidence interval. Cochrane's Q test was used to assess heterogeneity between the studies, while Higgins and Thompson's I2 was used to quantify heterogeneity. Subgroup analyses were conducted to identify the source of heterogeneity. Of the 2669 articles obtained from the databases, only 15 studies were eligible for this review, and eight were included in the final meta-analysis. Overall, linkage to care was similar between the HIVST arm and SoC (effect size: 0.92 [0.45-1.86]; I2: 51%; p: 0.04). In the population subgroup analysis, female sex workers (FSWs) in the HIVST arm were significantly linked to care compared to the SoC arm (effect size: 0.53 [0.30-0.94]; I2: 0%; p: 0.41). HIVST interventions did not significantly improve ART initiation in the HIVST arm compared to the SoC arm (effect size: 0.90 [0.45-1.79]; I2: 74%; p: < 0.001). We found that more male partners of women living with HIV in the SoC arm initiated PrEP compared to partners in the HIVST arm. The meta-analysis showed no difference between the HIVST and SoC arm regarding the number of clients (effect size: - 0.66 [1.35-0.02]; I2: 64%; p: 0.09) and non-clients FSWs see per night (effect size: - 1.45 [- 1.45 to 1.38]; I2: 93%; p: < 0.001). HIVST did not reduce the use of condoms during insertive or receptive condomless anal intercourse among MSM. HIVST does not improve linkage to care in the general population but does among FSWs. HIVST intervention does not improve linkage to ART nor significantly stimulate healthy sexual behaviors among priority groups. The only RCT that linked HIVST to PrEP found that PrEP uptake was higher among partners of women living with HIV in the SoC arm than in the HIVST arm. More RCTs among priority groups are needed, and the influence of HIVST on PrEP uptake should be further investigated.


The effect of Vancomycin degradation products in the topical treatment of osteomyelitis.
The topical application of Vancomycin is increasingly being used in orthopedics because of the development of methicillin resistant bacteria. Consequently, resistance to Vancomycin has recently been on the rise. One possible explanation for this phenomenon could be the thermal degradation of Vancomycin to antibacterially inactive crystalline degradation products (CDP-1s). The aim of our in vitro experiment was to compare the creation and elution characteristics of CDP-1s and the active form of Vancomycin (factor B) released from bone grafts. CDP-1s and the factor B released from bone grafts into the buffer solution were measured using the high-performance liquid chromatography method at progressive intervals. The factor B was released from bone grafts at the highest levels, typically on the first day (618.8 mg/L). CDP-1 levels kept increasing until the end of measurement on day 15, when the concentration of CDP-1s (1280.7 mg/L) was much higher compared to that of factor B (217.5 mg/L). We confirmed the tendency of Vancomycin to convert to antimicrobially ineffective CDP-1s. Although Vancomycin is decomposed into crystalline degradation products, its active forms are released from bone grafts in sufficient concentration for more than two keks (Tab. 3, Fig. 1, Ref. 15).


DNA dynamics in RecA-DNA filaments: ATP hydrolysis-related flexibility in DNA.
RecA-catalyzed DNA recombination is initiated by a mandatory, high-energy form of DNA in RecA-nucleoprotein filaments, where bases are highly unstacked and the backbone is highly unwound. Interestingly, only the energetics consequent to adenosine triphosphate (ATP) binding, rather than its hydrolysis, seems sufficient to mediate such a high-energy structural hallmark of a recombination filament. The structural consequence of ATP hydrolysis on the DNA part of the filament thus remains largely unknown. We report time-resolved fluorescence dynamics of bases in RecA-DNA complexes and demonstrate that DNA bases in the same exhibit novel, motional dynamics with a rotational correlation time of 7-10 ns, specifically in the presence of ATP hydrolysis. When the ongoing ATP hydrolysis of RecA-DNA filament is "poisoned" by a nonhydrolyzable form of ATP (ATPgammaS), the motional dynamics cease and reveal a global motion with a rotational correlation time of >20 ns. Such ATP hydrolysis-induced flexibility ensues in single-stranded as well as double-stranded bases of RecA-DNA filaments. These results suggest that the role of ATP hydrolysis is to induce a high level of backbone flexibility in RecA-DNA filament, a dynamic property that is likely to be important for efficient strand exchanges in ATP hydrolysis specific RecA reactions. It is the absence of these motions that may cause high rigidity in RecA-DNA filaments in ATPgammaS. Dynamic light scattering measurement comparisons of RecA-ss-DNA filaments formed in ATPgammaS vs that of ATP confirmed such an interpretation, where the former showed a complex of larger (30 nm) hydrodynamic radius than that of latter (12-15 nm). Taken together, these results reveal a more dynamic state of DNA in RecA-DNA filament that is hydrolyzing ATP, which encourage us to model the role of ATP hydrolysis in RecA-mediated DNA transactions.


Ionic dialysance allows an adequate estimate of urea distribution volume in hemodialysis patients.
An adequate estimation of urea distribution volume (V) in hemodialysis patients is useful to monitor protein nutrition. Direct dialysis quantification (DDQ) is the gold standard for determining V, but it is impractical for routine use because it requires equilibrated postdialysis plasma water urea concentration. The single pool variable volume urea kinetic model (SPVV-UKM), recommended as a standard by Kidney Disease Outcomes Quality Initiative (K/DOQI), does not need a delayed postdialysis blood sample but it requires a correct estimate of dialyser urea clearance. Ionic dialysance (ID) may accurately estimate dialyzer urea clearance corrected for total recirculation. Using ID as input to SPVV-UKM, correct V values are expected when end-dialysis plasma water urea concentrations are determined in the end-of-session blood sample taken with the blood pump speed reduced to 50 mL/min for two minutes (U(pwt2')). The aim of this study was to determine whether the V values determined by means of SPVV-UKM, ID, and U(pwt2') (V(ID)) are similar to those determined by the "gold standard" DDQ method (V(DDQ)). Eighty-two anuric hemodialysis patients were studied. V(DDQ) was 26.3 +/- 5.2 L; V(ID) was 26.5 +/- 4.8 L. The (V(ID)-V(DDQ)) difference was 0.2 +/- 1.6 L, which is not statistically significant (P= 0.242). Anthropometric volume (V(A)) calculated using Watson equations was 33.6 +/- 6.0 L. The (V(A)-V(DDQ)) difference was 7.3 +/- 3.3 L, which is statistically significant (P < 0.001). Anthropometric-based V values overestimate urea distribution volume calculated by DDQ and SPVV-UKM. ID allows adequate V values to be determined, and circumvents the problem of delayed postdialysis blood samples.


Analysis of magnetic probe signals including effect of cylindrical conducting wall for field-reversed configuration experiment.
A confinement field is disturbed by magnetohydrodynamic (MHD) motions of a field-reversed configuration (FRC) plasma in a cylindrical conductor. The effect of the conductor should be included to obtain a spatial structure of the disturbed field with a good precision. For this purpose, a toroidal current in the plasma and an eddy current on a conducting wall are replaced by magnetic dipole and image magnetic dipole moments, respectively. Typical spatial structures of the disturbed field are calculated by using the dipole moments for such MHD motions as radial shift, internal tilt, external tilt, and n=2 mode deformation. Then, analytic formulas for estimating the shift distance, tilt angle, and deformation rate of the MHD motions from magnetic probe signals are derived. It is estimated from the calculations by using the dipole moments that the analytic formulas include an approximately 40% error. Two kinds of experiment are carried out to investigate the reliability of the calculations. First, a magnetic field produced by a circular current is measured in an aluminum pipe to confirm the replacement of the eddy current with the image magnetic dipole moments. The measured fields coincide well with the calculated values including the image magnetic dipole moments. Second, magnetic probe signals measured from the FRC plasma are substituted into the analytic formulas to obtain shift distance and deformation rate. The experimental results are compared to the MHD motions measured by using a radiation from the plasma. If the error included in the analytic formulas and the difference between the magnetic and optical structures in the plasma are considered, the results of the radiation measurement support well those of the magnetic analysis.


Shared protein complex subunits contribute to explaining disrupted co-occurrence.
The gene composition of present-day genomes has been shaped by a complicated evolutionary history, resulting in diverse distributions of genes across genomes. The pattern of presence and absence of a gene in different genomes is called its phylogenetic profile. It has been shown that proteins whose encoding genes have highly similar profiles tend to be functionally related: As these genes were gained and lost together, their encoded proteins can probably only perform their full function if both are present. However, a large proportion of genes encoding interacting proteins do not have matching profiles. In this study, we analysed one possible reason for this, namely that phylogenetic profiles can be affected by multi-functional proteins such as shared subunits of two or more protein complexes. We found that by considering triplets of proteins, of which one protein is multi-functional, a large fraction of disturbed co-occurrence patterns can be explained.


Mentoring and personal development planning in postgraduate dental education: a review.
Mentoring and Personal Development Plans (PDPs) are educational tools that have been piloted in postgraduate medical education in recent years. Along with another educational tool, performance appraisal, they have been introduced nationally as part of the recent General Medical Practitioner contract of April 2003. In the light of the compulsory Continuing Professional Development and Lifelong Learning Schemes introduced recently by the General Dental Council for all dentists, mentoring and PDPs will surely have important roles to play in postgraduate dental education in the future. This article reviews the roles that mentoring and PDPs have played in postgraduate education recently.


Production of monoclonal antibodies recognizing cancer-associated antigens expressed on mucin-type sugar chains.
To obtain monoclonal antibodies directed to mucin-type sugar chains, mice were immunized with bovine submaxillary mucin (BSM) that had been conjugated with ovalbumin. Conjugation of BSM with ovalbumin enhanced the antigenicity of BSM to about five to ten times that of intact BSM and resulted in the establishment of ten hybridomas, all of which secreted monoclonal antibodies toward BSM. Most of the antibodies secreted by these hybridomas did not react with glycolipids but did react with glycoproteins. Several antibodies lost their reactivity when sialic acid residues were removed from BSM, indicating that these antibodies recognize carbohydrate moieties of mucins. Immunohistochemical studies revealed that three of the antibodies recognized human ovarian cancer-associated carbohydrate antigens. In addition, one of these three antibodies reacted with a human cultured colonic cancer cell line. The protocol described in this paper was effective in producing monoclonal antibodies that recognize mucin-carbohydrates and some of the generated antibodies can be applied to the detection of cancers.


Sequence variation analysis of HPV-18 isolates in southwest China.
Intratypic variations of HPV-18 are known to differ in the persistence of the infection, frequency of carcinogenesis and the progression of precursor lesions to advanced cervical cancer. This study was designed to analyze sequence variations of HPV-18 isolates in order to discover novel HPV-18 variants and to evaluate the variations among infected women in southwest China. Cervical biopsies from 56 HPV-18-positive women with cervical neoplasia were assayed by PCR amplification and sequencing of all eight genes (E1, E2, E4, E5, E6, E7, L1, L2) of the HPV-18 genome. The most frequently observed variation was a C to G transversion at nucleotide 287 of E6, which was found in 48.2% of samples. Analysis of E7 revealed only one specimen as having sequence variations. In addition, we have identified several novel variations: A551C in E6, G6906A in L1, and C4915T and C5147A in L2. The mutations in E6 and L2 are silent, while the E7 mutation results in a single amino acid change. This study complements and expands on previous descriptions of HPV-18 variants. The sequence variation data presented here provides a foundation for future research on HPV-induced oncogenesis and may prove valuable for developing diagnostic probes and in the design of HPV vaccines for targeted populations.


A role for the insulin-interleukin (IL)-4 receptor motif of the IL-4 receptor alpha-chain in regulating activation of the insulin receptor substrate 2 and signal transducer and activator of transcription 6 pathways. Analysis by mutagenesis.
The interleukin (IL)-4 receptor alpha-chain (IL-4Ralpha) contains a sequence motif (488PLVIAGNPAYRSFSD) termed the insulin IL-4 receptor motif (I4R motif). Mutation of the central Tyr497 to Phe blocks the tyrosine phosphorylation of the insulin receptor substrate 1 (IRS1) and diminishes proliferation in response to IL-4. Recent data suggest that the I4R motif encodes binding sites for several protein tyrosine binding (PTB) domain-containing proteins such as IRS1 and Shc and potentially for the Src homology 2 domain of signal transducer and activator of transcription 6 (STAT6). To analyze the function of the I4R motif in regulating IL-4 signaling, we changed conserved residues upstream and downstream of the central Tyr to Ala in the human IL-4Ralpha. We analyzed the ability of these constructs to signal the tyrosine phosphorylation of IRS2 and STAT6, the induction of DNA binding activity, and CD23 induction in response to human IL-4 (huIL-4) in transfected M12.4.1 cells. Mutagenesis of residues downstream of Tyr497, such as Arg498 or Phe500, to Ala had no effect on any of these responses, suggesting that the I4R motif may not be important for functional Src homology 2 domain interactions. However, mutagenesis of Pro488 to Ala (P488A) greatly diminished the tyrosine phosphorylation of IRS2 and abolished tyrosine phosphorylation of STAT6, induction of DNA binding activity, and CD23 induction in response to huIL-4. By contrast, a P488G mutant signaled these responses to huIL-4. Mutagenesis of hydrophobic amino acids previously shown to contact the PTB domain of IRS1, Leu489 or Ile491, to Ala had only minimal effects on responses to huIL-4. However, changing both Leu498 and Ile491 to Ala greatly diminished the tyrosine phosphorylation of IRS2 and abolished STAT6 activation. Taken together, these results indicate the important role of the I4R motif in regulating IRS docking and suggest that I4R docking to a PTB domain-containing protein regulates activation of the STAT6 pathway.


The impact of childbirth on the pelvic floor.
Vaginal delivery is known to be associated with trauma to the pelvic floor (PF) and its muscles and ligaments. In some cases, this can lead to issues with urinary incontinence and pelvic organ descent postpartum, either immediately or in the woman's later years. Some factors during a vaginal delivery can be modified in attempts to preserve as much functional integrity to the PF as possible. A trend has evolved in recent years regarding maternal requests for primary cesarean section (CS), with one goal being the reduction in PF trauma. However, evidence to date refutes this as a foolproof practice in decreasing PF dysfunctions, including urinary incontinence.


Anxiety Disorder Associated with the COVID-19 Pandemic Causes Deterioration of Blood Pressure Control in Primary Hypertensive Patients.
The new coronavirus disease (COVID-19) has spread rapidly all over the world and caused anxiety disorders. Recent studies have also shown that the prevalence of depression and anxiety increased during the COVID-19 outbreak. We aimed to evaluate the anxiety and depression levels during the pandemic and identify the effect of pandemic-related stress on blood pressure (BP) control in primary hypertensive patients. A total of 142 patients with primary hypertension (HT) who continued to use the same antihypertensive drugs before and during the pandemic were included in the study. Twenty-four -hour Ambulatory Blood Pressure Monitoring (ABPM) and the Hospital Anxiety and Depression Scale (HADS) questionnaire were applied to patients. We retrospectively reviewed 24-h ABPM records of the same patients for the year before the pandemic. Daytime, nighttime and 24 -hour-systolic blood pressure (SBP) levels as well as daytime, nighttime, and 24- hour-diastolic blood pressure (DBP) levels , were significantly elevated during the COVID-19 outbreak compared to the pre-pandemic period (p<0.001). Higher HADS-A scores (HADS-A ≥7) were significantly associated with much greater increase in BP compared to the patients with lower HADS-A scores. Psychological stress due to the COVID-19 outbreak led to worsening of the regulation of BP in controlled hypertensive patients whose antihypertensive treatments did not change.


A novel stabilisation model for ruthenium nanoparticles in imidazolium ionic liquids: in situ spectroscopic and labelling evidence.
In situ labelling and spectroscopic experiments are used to explain the key points in the stabilisation of ruthenium nanoparticles (RuNPs) generated in imidazolium-based ionic liquids (ILs) by decomposition of (eta(4)-1,5-cyclooctadiene)(eta(6)-1,3,5-cyclooctatriene)ruthenium(0), Ru(COD)(COT), under dihydrogen. These are found to be: (1) the presence of hydrides at the RuNP surface and, (2) the confinement of RuNPs in the non-polar domains of the structured IL, induced by the rigid 3-D organisation. These results lead to a novel stabilisation model for NPs in ionic liquids.


Common Presence of Phototrophic Gemmatimonadota in Temperate Freshwater Lakes.
Members of the bacterial phylum Gemmatimonadota are ubiquitous in most natural environments and represent one of the top 10 most abundant bacterial phyla in soil. Sequences affiliated with Gemmatimonadota were also reported from diverse aquatic habitats; however, it remains unknown whether they are native organisms or represent bacteria passively transported from sediment or soil. To address this question, we analyzed metagenomes constructed from five freshwater lakes in central Europe. Based on the 16S rRNA gene frequency, Gemmatimonadota represented from 0.02 to 0.6% of all bacteria in the epilimnion and between 0.1 and 1% in the hypolimnion. These proportions were independently confirmed using catalyzed reporter deposition-fluorescence in situ hybridization (CARD-FISH). Some cells in the epilimnion were attached to diatoms (Fragilaria sp.) or cyanobacteria (Microcystis sp.), which suggests a close association with phytoplankton. In addition, we reconstructed 45 metagenome-assembled genomes (MAGs) related to Gemmatimonadota They represent several novel lineages, which persist in the studied lakes during the seasons. Three lineages contained photosynthesis gene clusters. One of these lineages was related to Gemmatimonas phototrophica and represented the majority of Gemmatimonadota retrieved from the lakes' epilimnion. The other two lineages came from hypolimnion and probably represented novel photoheterotrophic genera. None of these phototrophic MAGs contained genes for carbon fixation. Since most of the identified MAGs were present during the whole year and cells associated with phytoplankton were observed, we conclude that they represent truly limnic Gemmatimonadota distinct from the previously described species isolated from soils or sediments.IMPORTANCE Photoheterotrophic bacterial phyla such as Gemmatimonadota are key components of many natural environments. Its first photoheterotrophic cultured member, Gemmatimonas phototrophica, was isolated in 2014 from a shallow lake in the Gobi Desert. It contains a unique type of photosynthetic complex encoded by a set of genes which were likely received via horizontal transfer from Proteobacteria We were intrigued to discover how widespread this group is in the natural environment. In the presented study, we analyzed 45 metagenome-assembled genomes (MAGs) that were obtained from five freshwater lakes in Switzerland and Czechia. Interestingly, it was found that phototrophic Gemmatimonadota are relatively common in euphotic zones of the studied lakes, whereas heterotrophic Gemmatimonadota prevail in deeper waters. Moreover, our analysis of the MAGs documented that these freshwater species contain almost the same set of photosynthesis genes identified before in Gemmatimonas phototrophica originating from the Gobi Desert.


Extrabranchial chemoreceptors involved in respiratory reflexes in the neotropical fish Colossoma macropomum (the tambaqui).
In a previous study, complete denervation of the gills in the tambaqui Colossoma macropomum did not eliminate the increase in breathing amplitude seen during exposure of this species to hypoxia. The present study was designed to examine other sites of putative O(2)-sensitive receptors that could be involved in this reflex action. Superfusion of the exposed brain of decerebrate, spinalectomized fish did not reveal the presence of central chemoreceptors responsive to hyperoxic, hypoxic, hypercarbic, acidic or alkaline solutions. Subsequent central transection of cranial nerve IX and X, removing not only all innervation of the gills but also sensory input from the lateral-line, cardiac and visceral branches of the vagus nerve, did not eliminate the increase in breathing amplitude that remained following peripheral gill denervation alone. Administration of exogenous catecholamines (10 and 100 nmol kg(-1) adrenaline) to fish with intact brains and minimal surgical preparation reduced both respiratory frequency and amplitude, suggesting that humoral release of adrenaline also could not be responsible for the increase in breathing amplitude that remained following gill denervation. Denervation of the mandibular branches of cranial nerve V and the opercular and palatine branches of cranial nerve VII in gill-denervated fish (either peripheral gill denervation or central section of cranial nerves IX and X), however, did eliminate the response. Thus, our data suggest that hypoxic and hyperoxic ventilatory responses as well as ventilatory responses to internal and external injections of NaCN in the tambaqui arise from O(2)-sensitive receptors in the orobranchial cavity innervated by cranial nerves V and VII and O(2)-sensitive receptors on the gills innervated by cranial nerves IX and X. Our results also revealed the presence of receptors in the gills that account for all of the increase in ventilation amplitude and part of the increase in ventilation frequency during hyperoxic hypercarbia, a group or groups of receptors, which may be external to the orobranchial cavity (but not in the central nervous system), that contribute to the increase in ventilation frequency seen in response to hyperoxic hypercarbia and the possible presence of CO(2)-sensitive receptors that inhibit ventilation frequency, possibly in the olfactory epithelium.


Inhibitory Activities of Blasticidin S Derivatives on Aflatoxin Production by Aspergillus Flavus.
Blasticidin S (BcS) is a protein synthesis inhibitor which shows strong growth inhibitory activity against a number of microorganisms. However, BcS inhibited aflatoxin production by Aspergillus flavus without affecting its growth. In order to obtain information about the structure-activity relationship of BcS as an aflatoxin production inhibitor, BcS derivatives were prepared and their aflatoxin production inhibitory activities were evaluated. Among five derivatives, blasticidin S carboxymethyl ester, deaminohydroxyblasticidin S, and pyrimidinoblasticidin S showed inhibitory activity, while the others did not. The IC50 value for aflatoxin production of the carboxymethyl ester derivative was one-fifth of that of BcS although their antimicrobial activities were almost the same. These results indicate that the inhibitory activity of BcS against aflatoxin production was enhanced by esterification of its carboxyl group and that the carboxymethyl ester derivative might be more suitable for practical use than BcS because of the specificity of the carboxymethyl ester derivative, which inhibited aflatoxin production more than BcS.


Causes of Death and Influencing Factors in Patients with Atrial Fibrillation.
Atrial fibrillation is associated with a higher mortality, but causes of death of atrial fibrillation patients and their specific predictors have been less well defined. We aimed to identify the causes of death among atrial fibrillation patients and secondly, clinical predictors for the different modes of deaths. Patients diagnosed with atrial fibrillation in a four-hospital institution between 2000 and 2010 were identified. During a follow-up of 929 ± 1082 days (median 456, interquartile 10-1584), 1253 deaths were recorded (yearly rate 5.5%). Cardiovascular deaths accounted for 54% and noncardiovascular for 43%. The three main causes of death were heart failure (29%), infection (18%), and cancer (12%). Fatal stroke or fatal bleeding each accounted for 7% of all deaths. On multivariate analysis, the strongest predictors of death were permanent atrial fibrillation, heart failure (whether with decreased or with preserved ejection fraction), previous bleeding, and renal failure, which were independently associated with an increase in the risk of all-cause mortality (35%, 78%, 42%, and 79%, respectively), cardiovascular mortality (43%, 129%, 46%, and 93%, respectively), and noncardiovascular mortality (21%, 45%, 40%, and 50%, respectively). Oral anticoagulant use was independently associated with a lower risk of all-cause mortality (hazard ratio [HR] 0.62; 95% confidence interval [CI], 0.54-0.71; P <.0001), cardiovascular mortality (HR 0.60; 95% CI, 0.49-0.72; P <.0001), and noncardiovascular mortality (HR 0.60; 95% CI, 0.49-0.74; P <.0001). The majority of deaths were related to a cardiovascular origin, and heart failure was the most common cause of death in atrial fibrillation patients. Despite the high risk of stroke associated with atrial fibrillation, only 7% died from stroke. Optimization of management of any underlying heart disease and associated comorbidities should be a relevant therapeutic target to reduce total mortality in atrial fibrillation patients.


Discovery of two P-superfamily conotoxins, lt9a and lt9b, with different modifications on voltage-sensitive sodium channels.
In this work, two P-superfamily conotoxins, lt9a and lt9b, were purified and characterized from the crude venom of Conus litteratus. The amino acid sequences of lt9a and lt9b were determined by the Edman degradation method. It has been suggested that both lt9a and lt9b are produced from the precursor encoded by the gene Lt9.1. During the conotoxin maturation process, different post-translational modifications occurred between lt9a and lt9b. Conotoxin lt9b was predicted to have two prolines that underwent hydroxylation and one glutamate that underwent carboxylation, while lt9a had no hydroxyproline and carboxyglutamate residue. The calculated mass weights of two P-superfamily conotoxins with three proposed disulfide bonds were confirmed by matrix-assisted laser desorption/ionization-time-of-flight (MALDI-TOF) mass spectrometry after considering corresponding post-translational modifications. These two conotoxins showed different effects on tetrodotoxin-sensitive sodium currents. Conotoxin lt9a (300 nM) resulted in marked slowing of the tetrodotoxin-sensitive sodium current decay, a notable increase in the peak current, and an alteration in reversal potential. However, lt9b inhibits tetrodotoxin-sensitive sodium currents, and the inhibition showed a concentration-dependent with the half maximal inhibitory concentration (IC50) value of 504.04 nM, but there were no change in the activation and inactivation kinetics of currents. To the best of our knowledge, this is the first investigation of two P-superfamily conotoxins identified to act on voltage-sensitive sodium channels with different modifications.


An alternative picture of alkali-metal-mediated metallation: cleave and capture chemistry.
This perspective article takes an alternative look at alkali-metal-mediated chemistry (exchange of a relatively inert C-H bond for a more reactive C-metal bond by a multicomponent reagent usually containing an alkali metal and a less electropositive metal such as magnesium or zinc). It pictures that the cleavage of selected C-H bonds can be accompanied by the capturing of the generated anion by the multi (Lewis acid)-(Lewis base) character of the residue of the bimetallic base. In this way small atoms or molecules (hydrides, oxygen-based anions) as well as sensitive organic anions (of substituted aromatic compounds, ethers or alkenes) can be captured. Cleave and capture reactions which occur in special positions on the organic substrate are also included.


Expression of Pla2g2a prevents carcinogenesis in Muc2-deficient mice.
Goblet cell depletion and down-regulation of MUC2 expression are observed in a significant percentage of human non-mucinous colorectal adenocarcinomas. Direct evidence for the role of MUC2 in gastrointestinal tumor formation was demonstrated by a knockout of Muc2 in mice that resulted in the development of adenocarcinomas in the small and large intestine. The secretory phospholipase Pla2g2a is a protein that confers resistance to Apc(Min/+)-induced intestinal tumorigenesis. Like Muc2, in the large intestine Pla2g2a is exclusively expressed by the goblet cells and Pla2g2a's tumor resistance is also strongest in the large intestine. Possible genetic interactions between Muc2 and Pla2g2a were examined by creating C57BL/6-Muc2(-/-)Pla2g2a transgenic mice. Expression of a Pla2g2a transgene reduced tumorigenesis in the large intestine by 90% in male Muc2(-/-) mice and by nearly 100% in female Muc2(-/-) mice. Expression of Pla2g2a also inhibited tumor progression. Microarray gene expression studies revealed Pla2g2a target genes that modulate intestinal energy metabolism, differentiation, inflammation, immune responses and proliferation. Overall, results of the present study demonstrate an Apc-independent role for Pla2g2a in tumor resistance and indicate that Pla2g2a plays an important role, along with Muc2, in protection of the intestinal mucosa.