Adaptive lag synchronization for competitive neural networks with mixed delays and uncertain hybrid perturbations.
This paper investigates the problem of adaptive lag synchronization for a kind of competitive neural network with discrete and distributed delays (mixed delays), as well as uncertain nonlinear external and stochastic perturbations (hybrid perturbations). A simple but robust adaptive controller is designed such that the response system can lag-synchronize with a drive system. Based on the Lyapunov stability theory and some suitable Lyapunov-Krasovskii functionals, several sufficient conditions ensuring the lag synchronization are developed. Our synchronization criteria are easily verified and do not need to solve any linear matrix inequality. Some existing results are improved and extended. Moreover, the designed adaptive controller has better anti-interference capacity and is more practical than the usual adaptive controller. Numerical simulations are exploited to show the effectiveness of the theoretical results.


Laser treatment of glans penis hemangioma.
We present a case of a glans penis hemangioma. These lesions are extremely rare, and as a consequence there is controversy concerning their treatment and outcome. Our patient was treated with a neodymium:YAG laser irradiation, with complete morphological recuperation. To our knowledge this is the first case of a glans penis hemangioma treated with this technique.


Exploring the configurational space of amorphous graphene with machine-learned atomic energies.
Two-dimensionally extended amorphous carbon ("amorphous graphene") is a prototype system for disorder in 2D, showing a rich and complex configurational space that is yet to be fully understood. Here we explore the nature of amorphous graphene with an atomistic machine-learning (ML) model. We create structural models by introducing defects into ordered graphene through Monte-Carlo bond switching, defining acceptance criteria using the machine-learned local, atomic energies associated with a defect, as well as the nearest-neighbor (NN) environments. We find that physically meaningful structural models arise from ML atomic energies in this way, ranging from continuous random networks to paracrystalline structures. Our results show that ML atomic energies can be used to guide Monte-Carlo structural searches in principle, and that their predictions of local stability can be linked to short- and medium-range order in amorphous graphene. We expect that the former point will be relevant more generally to the study of amorphous materials, and that the latter has wider implications for the interpretation of ML potential models.


Training responses of two age groups during treadmill walking.
The purpose of the present study was to use a previously developed treadmill walking test to determine training-induced changes within and between two groups of untrained men during a six week training period. One group consisted of seven middle-aged (mean age, 41.3 yr), and the second group consisted of seven young adult (mean age, 19.9 yr), men. Heart rates following training were significantly lower at all work intensities for the middle-aged men (p less than 0.005) whilst for the young adults only the 12.5% and 15% (p less than 0.025) work levels were significantly lower. Blood lactic acid concentrations (p less than 0.005), Respiratory Exchange Ratios (p less than 0.05), Ventilatory Equivalents (p less than 0.005) and mean Two Mile times (p less than 0.005) were all significantly lower after training for the older age group but this was not so for the younger adult group. The oxygen cost of the walking test was lower for four of the workloads of the middle-aged, but only for the final workload (p less than 0.005) for the young adults, after training. The performance test did not disadvantage the middle-aged subjects yet the results demonstrated that the test provided a common means of reflecting the training state of the two groups whether the level of activity took place on the treadmill or on the track.


An Update on the Anatomy of the Forehead Compartments.
The forehead is one of the most frequent locations for neuromodulator and soft tissue filler applications; however, the underlying anatomy is still poorly understood. Thus far, the presence of deep forehead compartments has not been confirmed. Twenty Caucasian cephalic specimens, 15 fresh frozen (six female and nine male) and five with formalin-phenol embalmment (three female and two male) were investigated using contrast-enhanced computed tomographic scans, dye injections, and anatomical dissections. Three superficial (one central and two lateral) and three deep (one central and two lateral) forehead compartments were identified. The superficial fat compartments were found within the subcutaneous fat tissue (layer 2) and measured 2.1 × 4.6 mm for the superficial central forehead compartments and the right superficial lateral forehead compartments and 2.6 × 3.2 cm for the left superficial lateral forehead compartments, with a mean volume of 2.5, 3.1, and 3.4 cc, respectively. The deep fat compartments were identified deep to the frontalis muscle but superficial to the periosteum with an extent of 6.4 × 5.9 cm for the deep central forehead compartments, 2.6 × 5.8 cm for the right deep lateral forehead compartments, and 2.7 × 5.8 cm for the left deep lateral forehead compartments, and a mean volume of 9.1, 1.6, and 1.4 cc, respectively. The results presented in this study increase the understanding of the forehead anatomy. Understanding the presence of the superficial and the deep forehead compartments allows one to change the signs of frontal aging. The deep forehead compartments are in general avascular planes and permit blunt dissection for access to the supraorbital region.


[The care needs of women infected with the human papilloma virus: a comprehensive approach].
This study is founded on the phenomenology of Martin Heidegger, with the objective to understand the care needs of women infected with the human papilloma virus. Participants were fourteen women who had been diagnosed with this infection. The guiding questions were: What is it like to have this diagnosis? Tell me your experience, from when you received your diagnosis until today. What has your health care been like? The questions revealed the theme - seeking care as solitude - which showed the importance of the support of family and friends. The presence of the infection as the cause of marital conflicts and separation was another highlighted aspect. The statements showed that there was a sense of resignation after an unsuccessful attempt to find accurate and clear information in order to make assertive decisions. Health interventions for infected women must overcome the traditional models of care, including interventions for health promotion and prevention, with trained professionals who are sensitive to the subjective dimension.


Public health delivery systems: evidence, uncertainty, and emerging research needs.
The authors review empirical studies published between 1990 and 2007 on the topics of public health organization, financing, staffing, and service delivery. A summary is provided of what is currently known about the attributes of public health delivery systems that influence their performance and outcomes. This review also identifies unanswered questions, highlighting areas where new research is needed. Existing studies suggest that economies of scale and scope exist in the delivery of public health services, and that key organizational and governance characteristics of public health agencies may explain differences in service delivery across communities. Financial resources and staffing characteristics vary widely across public health systems and have expected associations with service delivery and outcomes. Numerous gaps and uncertainties are identified regarding the mechanisms through which organizational, financial, and workforce characteristics influence the effectiveness and efficiency of public health service delivery. This review suggests that new research is needed to evaluate the effects of ongoing changes in delivery system structure, financing, and staffing.


Probiotics for prevention of necrotizing enterocolitis in preterm infants.
Necrotizing enterocolitis (NEC) and nosocomial sepsis are associated with increased morbidity and mortality in preterm infants. Through prevention of bacterial migration across the mucosa, competitive exclusion of pathogenic bacteria, and enhancing the immune responses of the host, prophylactic enteral probiotics (live microbial supplements) may play a role in reducing NEC and associated morbidity. To compare the efficacy and safety of prophylactic enteral probiotics administration versus placebo or no treatment in the prevention of severe NEC and/or sepsis in preterm infants. The standard search strategy for the Cochrane Neonatal Review Group was performed by two review authors. Searches were made of MEDLINE (1966 to December 2006), EMBASE (1980 to December 2006), Cochrane Library Controlled Trials Register (CENTRAL, The Cochrane Library Issue 3, 2006), and abstracts of annual meetings of the Society for Pediatric Research (1995 - 2006). The authors of published articles were contacted. Only randomized or quasi-randomized controlled trials that enrolled preterm infants < 37 weeks gestational age and/or < 2500 g birth weight were considered. Trials were included if they involved enteral administration of any live microbial supplement (probiotics) and measured at least one prespecified clinical outcome. Standard methods of the Cochrane Collaboration and its Neonatal Group were used to assess the methodologic quality of the trials. Retrieved articles were assessed for eligibility and data abstracted independently by two review authors. Where data were incomplete, the primary investigator were contacted for further information and clarification. Where appropriate, data of individual trials were combined using meta-analytic techniques to provide a pooled estimate of effect assuming a fixed effect model. Nine eligible trials randomizing 1425 infants were included. Included trials were highly variable with regard to enrollment criteria (i.e. birth weight and gestational age), baseline risk of NEC in the control groups, timing, dose, formulation of the probiotics, and feeding regimens. Data regarding extremely low birth weight infants (ELBW) could not be extrapolated. In a meta-analysis of trial data, enteral probiotics supplementation significantly reduced the incidence of severe NEC (stage II or more) [typical RR 0.32 (95% CI 0.17, 0.60)] and mortality [typical RR 0.43 (95% CI 0.25, 0.75]. There was no evidence of significant reduction of nosocomial sepsis [typical RR 0.93 (95% CI 0.73, 1.19)] or days on total parenteral nutrition (TPN) [WMD -1.9 (95% CI -4.6, 0.77)]. The included trials reported no systemic infection with the probiotics supplemental organism. The statistical test of heterogeneity for NEC, mortality and sepsis was insignificant. Enteral supplementation of probiotics reduced the risk of severe NEC and mortality in preterm infants. This analysis supports a change in practice in premature infants > 1000 g at birth. Data regarding outcome of ELBW infants could not be extracted from the available studies; therefore, a reliable estimate of the safety and efficacy of administration of probiotic supplements cannot be made in this high risk group. A large randomized controlled trial is required to investigate the potential benefits and safety profile of probiotics supplementation in ELBW infants.


Modeling Extracellular Vesicles-Mediated Interactions of Cells in the Tumor Microenvironment.
Interactions of cells via extracellular vesicles (EVs) manipulate various actions, including cancer initiation and progression, inflammation, anti-tumor signaling and cell migration, proliferation and apoptosis in the tumor microenvironment. EVs as the external stimulus can activate or inhibit some receptor pathways in a way that amplify or attenuate a kind of particle release at target cells. This can also be carried out in a biological feedback-loop where the transmitter is affected by the induced release initiated by the target cell due to the EVs received from the donor cell, to create a bilateral process. In this paper, at first we derive the frequency response of internalization function in the framework of a unilateral communication link. This solution is adapted to a closed-loop system to find the frequency response of a bilateral system. The overall releases of the cells, given by the combination of the natural release and the induced release, are reported at the end of this paper and the results are compared in terms of distance between the cells and reaction rates of EVs at the cell membranes.


A survey on bacterial contamination of lavage water in electric warm-water lavage toilet seats and of the gluteal cleft after lavage.
Electric warm-water lavage toilet seats are in wide use as an appliance beneficial for the maintenance of hygiene and the prophylaxis and improvement of conditions such as constipation and hemorrhoids. In this study, we surveyed the bacterial content in the lavage water of warm-water lavage toilet seats, and fecal bacterial contamination of the gluteal and genital regions due to droplet infection from post-defecation lavage, to examine the problems inherent to the use of such lavage units. The presence of viable bacteria in lavage water was confirmed in this survey. Viable bacterial counts in lavage water were 3-times higher in household units compared to units in public facilities, suggesting a correlation with the replenishment of lavage tank water with fresh water containing residual free chlorine.


Donor T cells lacking Fas ligand and perforin retain the capacity to induce severe GvHD in minor histocompatibility antigen mismatched bone-marrow transplantation recipients.
Graft-versus-host disease (GvHD) is a frequent impediment to therapeutically successful allogeneic bone-marrow transplantation (BMT). This investigation further examines the roles of two potential donor cytotoxic effector mechanisms previously implicated in tissue pathogenesis. Cytotoxically double deficient (B6-cdd) T cells (lacking functional fas ligand and perforin) and wild-type (B6-wt) donor T-cell transplantation in a minor antigen-mismatched BMT model (C57BL/6 --> C3H.SW) resulted in similar mortality and weight loss. Histopathologic findings revealed mononuclear infiltrates and cellular atrophy in GvHD target tissues (liver, stomach) in recipients of B6-wt and B6-cdd donor T cells. Both recipients also exhibited GvH-associated lymphohematopoietic compartment (LHC) alterations as evidenced by inverted CD4:CD8 ratios and B-cell hypoplasia. Notably, transplants using recombinant inbred mHAg disparate recipients demonstrated that B6-cdd T cells induced lethal GvHD in CXBE but not CXBG recipients: the same pattern induced by B6-wt T cells. This observation is consistent with previous findings that cytotoxic T lymphocyte (CTL) responses against CXBG and CXBE antigens did not correlate with GvH responses in these strains. In contrast with the typical pattern of donor T-cell expansion and contraction, T cells lacking perforin and FasL function exhibited extensive expansion postBMT. In summary, these findings support the notion that donor anti-host cytotoxicity by way of the two major pathways is not a prerequisite for induction of GvHD. In addition, the results suggest that this model will be useful to investigate the regulation of allogeneic donor T-cell expansion after major histocompatibility complex-matched allogeneic BMT.


Neural correlates of fear-induced sympathetic response associated with the peripheral temperature change rate.
Activation of the sympathetic nervous system is essential for coping with environmental stressors such as fearful stimuli. Recent human imaging studies demonstrated that activity in some cortical regions, such as the anterior cingulate cortex (ACC) and anterior insula cortex (aIC), is related to sympathetic activity. However, little is known about the functional brain connectivity related to sympathetic response to fearful stimuli. The participants were 32 healthy, right-handed volunteers. Functional magnetic resonance imaging (fMRI) was used to examine brain activity when watching horror and control movies. Fingertip temperature was taken during the scanning as a measure of sympathetic response. The movies were watched a second time, and the degree of fear (9-point Likert-type scale) was evaluated every three seconds. The brain activity of the ACC, bilateral aIC, and bilateral anterior prefrontal cortex (aPFC) was correlated with the change rate of fingertip temperature, with or without fearful stimuli. Functional connectivity analysis revealed significantly greater positive functional connectivity between the amygdala and the ACC and between the amygdala and the aIC when watching the horror movie than when watching the control movie. Whole-brain psycho-physiological interaction (PPI) analysis revealed that the functional connectivity between the left amygdala and the ACC was modulated according to the fear rating. Our results indicate that the increased functional connectivity between the left amygdala and the ACC represents a sympathetic response to fearful stimuli.


Xylella fastidiosa: an examination of a re-emerging plant pathogen.
Xylella fastidiosa is a Gram-negative bacterial plant pathogen with an extremely wide host range. This species has recently been resolved into subspecies that correlate with host specificity. This review focuses on the status of X. fastidiosa pathogenic associations in plant hosts in which the bacterium is either endemic or has been recently introduced. Plant diseases associated with X. fastidiosa have been documented for over a century, and much about what is known in the context of host-pathogen interactions is based on these hosts, such as grape and citrus, in which this pathogen has been well described. Recent attention has focused on newly emerging X. fastidiosa diseases, such as in olives. Bacteria; Gammaproteobacteria; family Xanthomonadaceae; genus Xylella; species fastidiosa. Gram-negative rod (0.25-0.35 × 0.9-3.5 μm), non-flagellate, motile via Type IV pili-mediated twitching, fastidious. Xylella fastidiosa has a broad host range that includes ornamental, ecological and agricultural plants belonging to over 300 different species in 63 different families. To date, X. fastidiosa has been found to be pathogenic in over 100 plant species. In addition, it can establish non-symptomatic associations with many plants as a commensal endophyte. Here, we list the four distinct subspecies of X. fastidiosa and some of the agriculturally relevant diseases caused by them: X. fastidiosa ssp. fastidiosa causes Pierce's disease (PD) of grapevine (Vitis vinifera); X. fastidiosa ssp. multiplex causes almond leaf scorch (ALS) and diseases on other nut and shade tree crops; X. fastidiosa ssp. pauca causes citrus variegated chlorosis (CVC) (Citrus spp.), coffee leaf scorch and olive quick decline syndrome (OQDS) (Olea europaea); X. fastidiosa ssp. sandyi causes oleander leaf scorch (OLS) (Nerium oleander). Significant host specificity seemingly exists for some of the subspecies, although this could be a result of technical biases based on the limited number of plants tested, whereas some subspecies are not as stringent in their host range and can infect several plant hosts. Most X. fastidiosa-related diseases appear as marginal leaf necrosis and scorching of the leaves. In the case of PD, X. fastidiosa can also cause desiccation of berries (termed 'raisining'), irregular periderm development and abnormal abscission of petioles. In olive trees affected with OQDS, leaves exhibit marginal necrosis and defoliation, and overall tree decline occurs. Plants with ALS and OLS also exhibit the characteristic leaf scorch symptoms. Not all X. fastidiosa-related diseases exhibit the typical leaf scorch symptoms. These include CVC and Phony Peach disease, amongst others. In the case of CVC, symptoms include foliar wilt and interveinal chlorosis on the upper surfaces of the leaves (similar to zinc deficiency), which correspond to necrotic, gum-like regions on the undersides of the leaves. Additional symptoms of CVC include defoliation, dieback and hardening of fruits. Plants infected with Phony Peach disease exhibit a denser, more compact canopy (as a result of shortened internodes, darker green leaves and delayed leaf senescence), premature bloom and reduced fruit size. Some occlusions occur in the xylem vessels, but there are no foliar wilting, chlorosis or necrosis symptoms . USEFUL WEBSITES: http://www.piercesdisease.org/; https://pubmlst.org/xfastidiosa/; http://www.xylella.lncc.br/; https://nature.berkeley.edu/xylella/; https://ec.europa.eu/food/plant/plant_health_biosecurity/legislation/emergency_measures/xylella-fastidiosa_en.


Uncertainty and health literacy in dementia care.
The number of dementia cases increases with age, and the prevalence of dementia at the age above 80 is approaching 20% in Taiwan. Dementia is not simply a neurological disorder, but also a long-term care issue in public health and a matter of social adaptation. Scientific discoveries about dementia diagnostics, therapeutics, and preventive strategy have become the focus of media attention, but always updated and overwhelmed, which appears to increase rather than decrease the uncertainty and complexity of health communication in dementia care. Health literacy is essential for patients to understand medical information, utilize medical resources, and make shared decisions; however, the capacity to handle health information is often compromised in older adults with cognitive decline. Both ends of the increased uncertainty in dementia science and the reduced capacity in older adults are major challenges in dementia care. Dementia literacy, defined as knowledge and beliefs regarding dementia that aid recognition, management, or prevention, plays a vital role in effective care risk assessment and communication. However, little is known about the current state of dementia literacy among older adults, people with dementia, and their caregivers, and how well the dementia care practice can be implemented at the individual level is questionable. Empowering caregivers with adequate dementia literacy and developing a risk communication model in practice will translate the power of knowledge to effective care strategies, thus ameliorating the caregiver burden and enhancing the life quality of people with dementia in the long run.


[Chronic eosinophilic leukemia with symptoms resembling Budd-Chiari syndrome due to liver infiltration].
A 68-year-old woman was admitted to our hospital with severe ascites, hepatomegaly and hypereosinophilia. We initially suspected Budd-Chiari Syndrome (BCS), but that was ruled out after confirming the presence of no obstruction in the major veins. A molecular biologic examination proved the clonality of the eosinophils and she was therefore diagnosed as having chronic eosinophilic leukemia (CEL). The pathologic findings of a liver biopsy showed dilation of the sinusoids with infiltration of eosinophils, portal eosinophilic infiltrations with fibrosis, and biliary damage. These findings thus suggested infiltration of the liver by the CEL. A relationship between myeloproliferative disorders and BCS has been commonly reported, however there have so far been very few reports which describe the pathology of CEL liver infiltrates. As a result, the present case in which CEL occurred while demonstrating symptoms and findings similar to BCS is therefore considered to be extremely rare. Further accumulation of such cases should therefore be carried out in the future.


Language comprehension and regional cerebral defects in frontotemporal degeneration and Alzheimer's disease.
We related profiles of language comprehension difficulty to patterns of reduced cerebral functioning obtained with high-resolution single photon emission computed tomography (SPECT) in patients with neurodegenerative conditions. We found different patterns of reduced relative cerebral perfusion in patients with frontotemporal degeneration (FD) and patients with Alzheimer's disease (AD). Cognitive assessments also showed different patterns of impaired comprehension in patients with FD and patients with AD. Grammatical comprehension difficulty in FD correlated with relative cerebral perfusion in left frontal and anterior temporal brain regions; impaired semantic processing in AD correlated with relative cerebral perfusion in inferior parietal and superior temporal regions of the left hemisphere. These findings are consistent with the hypothesis that a neural network distributed throughout the left hemisphere subserving different aspects of language comprehension, rather than a single brain region, is responsible for understanding language.


Multicancer Early Detection Tests: An Overview of Early Results From Prospective Clinical Studies and Opportunities for Oncologists.
A multitude of blood-based multicancer early detection (MCED) tests assessing cancer-related alterations in circulating genomic analytes and other associated signatures are currently being developed with the potential to disrupt current single-organ screening paradigms. Pathways for clinical implementation of these novel MCED tests have not been delineated, particularly for the patients with signal positive results requiring additional confirmatory testing. In this overview, we highlight early results from prospective clinical studies testing the efficacy of genomic MCED tests in cohorts of patients without known cancer diagnoses. Additionally, we discuss a proposed professional expansion of the oncology practice relating to the diagnostic workup of individuals found to have an MCED signal positive for cancer. As MCED blood tests have the potential to dramatically upend current cancer screening paradigms and downstream cancer therapy, it is imperative for oncologists to be aware of important clinical studies and the multitude of unanswered questions. The current gaps in the clinical implication of these tests may serve as a meaningful and rewarding expansion of oncology practice.


The Influence of Social Supports on Graduate Student Persistence in Biomedical Fields.
Pathways to biomedical careers are not being pursued with equal vigilance among all students. Emerging research shows that historically underrepresented (HU) students who maintain a strong science identity are more likely to persist. However, the influence of social support on persistence is less studied, especially as it relates to science identity among doctoral students. To fill this gap, a 1-year study to assess similarities and differences among 101 HU and majority biomedical doctoral students was conducted to measure the extent to which 1) they report equivalent experiences of social support, science identity, and intentions to persist; 2) their experiences of social support predict intentions to persist 1 year later; and 3) science identity mediates the relationship between social support and intentions to persist in biomedical career pathways. Data were collected using online surveys. Results indicated that science identity significantly mediated the relationship between professional network support and persistence a year later for majority students. In contrast, for HU students, science identity mediated the relationship between instrumental, psychosocial, friend and family support, and persistence a year later. These study results provide evidence that reinforcing mentoring programs and support systems will be beneficial, especially for HU students.


Macrocycle-assisted synthesis of non-stoichiometric silver(i) halide electrocatalysts for efficient chlorine evolution reaction.
The electrocatalytic oxidation of chloride to chlorine is a fundamental and important electrochemical reaction in industry. Herein we report the synthesis of non-stoichiometric silver halide nanoparticles through a novel macrocycle-assisted bulk-to-cluster-to-nano transformation. The acquired positively charged nanoparticles expedite chloride transportation by electrostatic attraction and facilitate the formation of silver polychloride catalytic species on the surface, thus functioning as efficient and selective electrocatalysts for the chlorine evolution reaction (CER) at a very low overpotential and within a wide concentration range of chloride. The formation of uncommon non-stoichiometric nanoparticles prevents the formation of a AgCl precipitate and exposes more coordination unsaturated silver atoms to catalyze CER, finally causing a large enhancement of the atomic catalytic efficiency of silver. This study showcases a promising approach to achieve efficient catalysts from a bottom-up design.


What are the underlying transmission patterns of COVID-19 outbreak? An age-specific social contact characterization.
COVID-19 has spread to 6 continents. Now is opportune to gain a deeper understanding of what may have happened. The findings can help inform mitigation strategies in the disease-affected countries. In this work, we examine an essential factor that characterizes the disease transmission patterns: the interactions among people. We develop a computational model to reveal the interactions in terms of the social contact patterns among the population of different age-groups. We divide a city's population into seven age-groups: 0-6 years old (children); 7-14 (primary and junior high school students); 15-17 (high school students); 18-22 (university students); 23-44 (young/middle-aged people); 45-64 years old (middle-aged/elderly people); and 65 or above (elderly people). We consider four representative settings of social contacts that may cause the disease spread: (1) individual households; (2) schools, including primary/high schools as well as colleges and universities; (3) various physical workplaces; and (4) public places and communities where people can gather, such as stadiums, markets, squares, and organized tours. A contact matrix is computed to describe the contact intensity between different age-groups in each of the four settings. By integrating the four contact matrices with the next-generation matrix, we quantitatively characterize the underlying transmission patterns of COVID-19 among different populations. We focus our study on 6 representative cities in China: Wuhan, the epicenter of COVID-19 in China, together with Beijing, Tianjin, Hangzhou, Suzhou, and Shenzhen, which are five major cities from three key economic zones. The results show that the social contact-based analysis can readily explain the underlying disease transmission patterns as well as the associated risks (including both confirmed and unconfirmed cases). In Wuhan, the age-groups involving relatively intensive contacts in households and public/communities are dispersedly distributed. This can explain why the transmission of COVID-19 in the early stage mainly took place in public places and families in Wuhan. We estimate that Feb. 11, 2020 was the date with the highest transmission risk in Wuhan, which is consistent with the actual peak period of the reported case number (Feb. 4-14). Moreover, the surge in the number of new cases reported on Feb. 12 and 13 in Wuhan can readily be captured using our model, showing its ability in forecasting the potential/unconfirmed cases. We further estimate the disease transmission risks associated with different work resumption plans in these cities after the outbreak. The estimation results are consistent with the actual situations in the cities with relatively lenient policies, such as Beijing, and those with strict policies, such as Shenzhen. With an in-depth characterization of age-specific social contact-based transmission, the retrospective and prospective situations of the disease outbreak, including the past and future transmission risks, the effectiveness of different interventions, and the disease transmission risks of restoring normal social activities, are computationally analyzed and reasonably explained. The conclusions drawn from the study not only provide a comprehensive explanation of the underlying COVID-19 transmission patterns in China, but more importantly, offer the social contact-based risk analysis methods that can readily be applied to guide intervention planning and operational responses in other countries, so that the impact of COVID-19 pandemic can be strategically mitigated. General Research Fund of the Hong Kong Research Grants Council; Key Project Grants of the National Natural Science Foundation of China.


Daily Actigraphy Profiles Distinguish Depressive and Interepisode States in Bipolar Disorder.
Disruptions in activity are core features of mood states in bipolar disorder (BD). This study sought to identify activity patterns that discriminate between mood states in BD. Locomotor activity was collected using actigraphy for six weeks in participants with inter-episode BD type I (n=37) or participants with no lifetime mood disorders (n=39). The 24-hour activity pattern of each participant-day was characterized and within-person differences in activity patterns were examined across mood states. Results show that among participants with BD, depressive days are distinguished from other mood states by an overall lower activity level, and a pattern of later activity onset, a midday elevation of activity, and low evening activity. No distinct within-person activity patterns were found for hypomanic/manic days. Since activity can be monitored non-invasively for extended time periods, activity pattern identification may be leveraged to detect mood states in BD, thereby providing more immediate delivery of care.


Enantioselective analysis of primaquine and its impurity quinocide by capillary electrophoresis.
A capillary electrophoretic (CE) method for the baseline separation of the enantiomers of primaquine diphosphate (PQ) and quinocide (QC) (a major contaminant) in pharmaceutical formulations is proposed. Both components were separated under the following conditions: 50 mm tris phosphate buffer (pH 3.0) containing 15 mm hydroxypropyl-gamma-cyclodextrin (HP-gamma-CD) as background electrolyte; applied voltage, 16 kV; capillary temperature, 25 degrees C; detection wavelength, 254 nm; hydrostatic injection, 10 s. The separations were conducted using a 35 cm length and 50 microm i.d. uncoated fused silica capillary column. Under the optimized conditions, the components were successfully separated in about 5 min. Intraday precision of migration time and corrected peak areas when expressed as relative standard deviation ranged from 0.17 to 0.45 and 2.60 to 3.94%, respectively, while the interday precision ranged from 2.59 to 4.20 and 3.15 to 4.21%, respectively. After the validation exercise, the proposed method was applied for the determination of QC impurity in PQ formulations.


Differential IgA repopulation after transfer of autologous and allogeneic rabbit Peyer's patch cells.
The distribution and differentiation of rabbit Peyer's patch cells were studied in lethally x-irradiated autologou, and allogeneic recipients, 6 days after i.v. transfer. Immunoglobulin Ig-containing cells were detected in both frozen tissue sections and fixed smears of single cell suspensions of spleens using monospecific anti-alpha, -mu, and -iota antisera in direct immunofluorescence. The tissues of lethally x-irradiated rabbits which had not received any cells were almost devoid of Ig-containing cells whereas the intestinal lamina propria of both autologous and allogeneic Peyer's patch cell recipients had approximately equal numbers of predominantly IgA-containing cells. In the spleen of allogeneic recipients, many large colonies of IgA-containing cells were seen and these cells made up 4.6 to 16.9% (mean 8%) of all spleen cell suspension. The spleens of autologous recipients contained fewer and smaller colonies of IgA cells which made up only 0.5% of all cells in spleen cell suspensions. The numbers of IgM- and IgG-containing spleen cells were small in all animals, however, recipients of allogeneic Peyer's patch cells had four to five times as many as either non-reconstituted lethally irradiated rabbits or autologous recipients. These data confirm that rabbit Peyer's patches are relatively rich in precursors of IgA-producing cells and suggest that histocompatibility differences may either potentiate differentiation of IgA production or lead to trapping of allogeneic Peyer's patch cells in the spleen. Although these experiments did not elucidate the mechanisms of differentiation of IgA-producing cells, the fact that no differences were seen between numbers of IgA cells in gut lamina propria after either autologous or allogeneic cell transfer suggest that different mechanisms may be responsible for appearance of these cells in gut and spleen.


HCV elimination in Hong Kong - Non-government organisation (NGO) activities.
World Health Organization (WHO) calls for global hepatitis strategy to eliminate viral hepatitis by 2030. Yet many high-income countries were unable to achieve HCV elimination by 2030. Apart from the tremendous efforts and resources from the governments, many non-government organizations (NGOs) have been working very hard to contribute to HCV elimination. In Hong Kong, the Center for Liver Health of The Chinese University of Hong Kong (CUHK) has been working very closely with various NGOs to educate and screen subjects who previously use intravenous drugs. In this review article, we discussed in details the New Life New Liver Program, and the barriers to HCV elimination, with special highlight the role of NGOs in overcoming the barriers.


Oncogenic role and therapeutic target of transient receptor potential melastatin 7 channel in malignancy.
The transient receptor potential (TRP) family is a superfamily of cation channels which regulates many features of malignant cancers, such as lack of differentiation, increased migratory and invasive phenotype and chemoresistance. The TRP cation channel, TRPM7 (subfamily M, member 7), is a ubiquitous, Ca²⁺ and Mg²⁺-permeant ion channel that is unique in that it is an ion channel and a serine/threonine kinase. TRPM7 has been associated with cell proliferation, survival and development and thus correlated with growth and progression of several types of tumor cells, including breast cancer, gastric cancer, head and neck cancer, nasopharyngeal carcinoma, pancreatic cancer, prostate cancer, retinoblastoma and leukemia. Increased TRPM7 expression in human breast and pancreatic cancer tissues also correlates with clinicopathological parameters, such as tumor grade, the Ki-67 proliferation index and patient survival. In this review, we focus on recent advancements in knowledge of aberrant TRPM7 channel function and its contribution to tumor progression and angiogenesis. This includes crosstalk between multiple signaling pathways. The role of TRPM7 in tumor development, particularly in regard to its channel function mediating both Ca²⁺ and Mg²⁺ influx as well as its kinase activity is also addressed. In addition, we will discuss its role in the stem cell and cancer stem cell, as well as its potential as tumor drug target. Better understanding of the structure, function and regulation of TRPM7 channel, as well as its complex crosstalk with other oncogenic signals in tumor cells will be essential to ensure rational use of treatment and development of new combinatory therapeutic possibilities.


Signal intensity alteration within infrapatellar fat pad predicts knee replacement within 5 years: data from the Osteoarthritis Initiative.
To investigate whether infrapatellar fat pad (IPFP) signal intensity (SI) alteration predicts the occurrence of knee replacement (KR) in knee osteoarthritis (OA) patients over 5 years. The subjects were selected from Osteoarthritis Initiative (OAI) study. Case knees (n = 127) were defined as those who received KR during 5 years follow-up visit. They were matched by gender, age and radiographic status with control knees (n = 127). We used T2-weighted MR images to measure IPFP SI alteration using a newly developed algorithm in MATLAB. The measurements were assessed at baseline (BL), T0 (the visit just before KR) and 1 year before T0 (T-1). Conditional logistic regression was used to analyse the associations between IPFP SI alterations and the risk of KR. Participants were mostly female (57%), with an average age of 63.7 years old and a mean body mass index (BMI) of 29.5 kg/m2. In multivariable analysis, the standard deviation (SD) of IPFP SI [sDev (IPFP)] and the ratio of high SI region volume to whole IPFP volume [Percentage (H)] measured at BL were significantly associated with increased risks of KR after adjustment for covariates. IPFP SI alterations measured at T-1 including sDev (IPFP), Percentage (H) and clustering effect of high SI [Clustering factor (H)] were significantly associated with higher risks of KR. All measurements were significantly associated with higher risks of KR at T0. IPFP SI is associated with the occurrence of KR suggesting it may play a role in end-stage knee OA.


Purification and characterization of the voltage-dependent anion channel from the outer mitochondrial membrane of yeast.
The outer mitochondrial membranes of all organisms so far examined contain a protein which forms voltage-dependent anion selective channels (VDAC) when incorporated into planar phospholipid membranes. Previous reports have suggested that the yeast (Saccharomyces cerevisiae) outer mitochondrial membrane component responsible for channel formation is a protein of 29,000 daltons which is also the major component of this membrane. In this report, we describe the purification of this 29,000-dalton protein to virtual homogeneity from yeast outer mitochondrial membranes. The purified protein readily incorporates into planar phospholipid membranes to produce ionic channels. Electrophysiological characterization of these channels has demonstrated they have a size, selectivity and voltage dependence similar to VDAC from other organisms. Biochemically, the purified protein has been characterized by determining its amino acid composition and isoelectric point (pI). In addition, we have shown that the purified protein, when reconstituted into liposomes, can bind hexokinase in a glucose-6-phosphate dependent manner, as has been shown for VDAC purified from other sources. Since physiological characterization suggests that the functional parameters of this protein have been conserved, antibodies specific to yeast VDAC have been used to assess antigenic conservation among mitochondrial proteins from a wide number of species. These experiments have shown that yeast VDAC antibodies will recognize single mitochondrial proteins from Drosophila, Dictyostelium and Neurospora of the appropriate molecular weight to be VDAC from these organisms. No reaction was seen to any mitochondrial protein from rat liver, rainbow trout, Paramecium, or mung bean. In addition, yeast VDAC antibodies will recognize a 50-kDa mol wt protein present in tobacco chloroplasts.(ABSTRACT TRUNCATED AT 250 WORDS)


Next generation antithrombotic therapy: focus on antisense therapy against coagulation factor XI.
Although the current therapeutic armamentarium of venous thrombosis encompasses the use of vitamin K antagonists, heparins, and direct oral anticoagulants, these drugs have several important drawbacks. Antisense oligonucleotides are relatively short single-stranded nucleic acid sequences, which hybridize with a target messenger RNA (mRNA) and suppress protein synthesis. Coagulation factor XI is a key player in blood coagulation, and thus represents a potential target for antisense therapy. The available evidence reviewed in this article suggests that factor XI antisense oligonucleotides may be more effective than conventional anticoagulants in preventing the onset and propagation of thrombosis, do not require factor measurement since the reduction of mRNA synthesis appears dose-dependently, robustly, and stably decreased for 3 to 5 weeks after the end of administration, with an incidence of major bleeding that is at least not greater than that associated with warfarin or low-molecular-weight heparin therapy. Despite conceptual simplicity, rational design, and relatively inexpensive cost, the preliminary findings in animal models and in patients undergoing knee surgery need to be validated in other prospective trials and cost-effective analyses before this attractive treatment option can be advocated as a new paradigm in prevention and treatment of venous thrombosis.


Atrioventricular block occurring several months after radiofrequency ablation for the treatment of atrioventricular nodal re-entrant tachycardia.
Atrioventricular (AV) block following radiofrequency (RF) ablation for the treatment of AV nodal re-entrant tachycardia (AVNRT) is a rare but well recognised complication of the procedure--the reported incidence ranges from 1% to 21%. Almost all cases of AV block occur during or shortly after the procedure, are transient, and recover quickly. Two patients (a 22 year man and a 72 year old woman) with symptomatic AV block occurring several months after slow pathway RF ablation, requiring permanent pacemaker implantation, are described. Both patients had had several 24 hour Holter recordings before the procedure, and in neither case was there any evidence of intermittent or persistent AV block. This is a rare complication with no definitive predictors; however, all efforts should be made to exclude AV block in patients presenting with suggestive symptoms following RF ablation. With the wide use of RF ablation for the treatment of AVNRT, more cases are likely to occur. A registry should allow documentation of the incidence of this complication.


Linkage and association studies of discoidin domain receptor 1 (DDR1) single nucleotide polymorphisms (SNPs) in juvenile oligoarthritis.
Multiple independent juvenile oligoarthritis susceptibility loci have been identified within the major histocompatibility complex (MHC), including HLA-A, HLA-DRB1 and an as yet unlocalized effect in the centromeric class I region. The discoidin domain receptor 1 (DDR1) gene resides within this region and codes for a receptor tyrosine kinase that plays an important role in regulating cell attachment to collagen, chemotaxis, proliferation and matrix metalloproteinase (MMP) production. DDR1 expression in chondrocytes has not been investigated. The objectives of this study were to investigate expression of DDR1 in healthy chondrocytes and to identify linkage and association of this candidate gene with juvenile oligoarthritis. A set of 135 simplex juvenile idiopathic arthritis families consisting of one affected child and healthy parent(s) and 199 healthy unrelated individuals were genotyped for six single nucleotide polymorphisms (SNPs) within the DDR1 gene using the primer extension SNaPshot trade mark method. Single-point and multipoint transmission disequilibrium tests were carried out with the ETDT and TDTPHASE packages. Allele frequency comparisons between cases and controls were carried out with the chi(2) test. DDR1 expression was investigated in normal articular cartilage by RT-PCR and immunofluorescence methods. No linkage and association with any of the six SNPs or their haplotypic combinations were observed in the families studied. No significant differences were observed in allele frequencies between patients and controls. DDR1 expression was found in normal articular cartilage by RT-PCR and by immunofluorescence. The DDR1 SNPs examined are not involved in susceptibility to juvenile oligoarthritis.


[Frequency and mortality by rebleeding in cirrhotic patients treated for bleeding esophagic varices in two hospitals in Lima Peru during years 2009 to 2011].
During the first 6 weeks after a variceal hemorrhage there is a 30-40% of probability of recurrence and those who rebleed 20- 30% die. Passed this period, the risk of rebleeding is of 60% and reaches a mortality of 60-70% in two years without treatment. Describe the frequency of rebleeding and mortality due to rebleeding in cirrhotic patients treated for variceal hemorrhage at Endoscopic Centers of Hospital Nacional Cayetano Heredia, Lima, Peru and Hospital Nacional Arzobispo Loayza, Lima, Peru during the years 2009-2011. The study type is a transversal, periodic and retrospective one in which were included 176 cirrhotic patients older than 14 years who have bleed for esophageal varices and that have received endoscopic therapy. The instruments used were a data sheet with all the information obtained from the clinical chart of each patient, the CHILD score to assess severity of hepatic disease, endoscopic informs and phone calls. The frequency of rebleeding before 6 weeks was 32.20% (56 patients). Also, the frequency of rebleeding after that time was 22.56% (37 patients). There was a mortality rate of 5.70% (10 patients) and a mortality rate due to rebleeding of 13.33% (6 patients). Variceal hemorrhage is an important cause of mobimortality in peruvian people. The frequency of rebleeding and mortality due to rebleeding resulted slightly lower than in other countries.


Properties of alpha-dehydrobiotin-resistant mutants of Escherichia coli K-12.
We have isolated four classes of mutants resistant to alpha-dehydrobiotin, a biotin analogue. One mutant group, referred to as bioR shows high excretion levels of biotin vitamers, derepressed levels of the biotin biosynthetic enzymes, and resistance to repression by biotin. The mutation has been mapped between argC and bfe at min 79. A second class of mutants, with lesions in the bioA operon at min 17.5, shows derepressed levels of the dethiobiotin synthetase enzyme and has been tentatively designated as bioO mutants. The other two mutant groups show alterations in permeability: biotin uptake is markedly reduced in one, whereas in the other proline uptake is also affected. The former mutation lies near metE at min 75 and has been designated as bioP. The permeability mutants in the second group also show poor growth on minimal media, suggesting a generalized permeability effect. This mutation, designated as P, has not been mapped.


A DNA binding activity for one of two closely defined phytochrome regulatory elements in an Lhcb promoter is more abundant in etiolated than in green plants.
The Lhcb2*1 gene of Lemna gibba is regulated positively by phytochrome, and two separate, 10-bp regions of this promoter have been shown to be necessary for phytochrome regulation. We have now analyzed the effects of one and two base pair mutations to define exactly two cis elements within these regions that are necessary for phytochrome regulation. These elements, designated REalpha and REbeta, consist in part of sequences highly conserved among promoter of genes encoding light-harvesting chlorophyll a/b proteins of photosystem II (Lhcb genes). They are located -134 to -129 bp and -114 to -109 bp from the transcription start site, respectively. REalpha has the sequence AACCAA and was found to interact specifically in vitro with a DNA binding activity in whole-cell extracts of plants. This activity was high in etiolated plants but much lower in green plants. REbeta has the sequence CGGATA. A GATA sequence created at a position six nucleotides upstream could replace the function of REbeta. We conclude that the phytochrome regulation of Lhcb2*1 is mediated by at least two cis elements. These elements are likely to function by repression of the promoter activity in darkness, although the REbeta region also may be able to play a role in the activation of transcription.


A distinct clinical, neuropsychological and radiological phenotype is associated with progranulin gene mutations in a large UK series.
Mutations in the progranulin gene (GRN) are a major cause of frontotemporal lobar degeneration with ubiquitin-positive, tau-negative inclusions (FTLD-U) but the distinguishing clinical and anatomical features of this subgroup remain unclear. In a large UK cohort we found five different frameshift and premature termination mutations likely to be causative of FTLD in 25 affected family members. A previously described 4-bp insertion mutation in GRN exon 2 comprised the majority of cases in our cohort (20/25), with four novel mutations being identified in the other five affected members. Additional novel missense changes were discovered, of uncertain pathogenicity, but deletion of the entire gene was not detected. The patient collection was investigated by a single tertiary referral centre and is enriched for familial early onset FTLD with a high proportion of patients undergoing neuropsychological testing, MRI and eventual neuropathological diagnosis. Age at onset was variable, but four mutation carriers presented in their 40s and when analysed as a group, the mean age at onset of disease in GRN mutation carriers was later than tau gene (MAPT) mutation carriers and duration of disease was shorter when compared with both MAPT and FTLD-U without mutation. The most common clinical presentation seen in GRN mutation carriers was behavioural variant FTLD with apathy as the dominant feature. However, many patients had language output impairment that was either a progressive non-fluent aphasia or decreased speech output consistent with a dynamic aphasia. Neurological and neuropsychological examination also suggests that parietal lobe dysfunction is a characteristic feature of GRN mutation and differentiates this group from other patients with FTLD. MR imaging showed evidence of strikingly asymmetrical atrophy with the frontal, temporal and parietal lobes all affected. Both right- and left-sided predominant atrophy was seen even within the same family. As a group, the GRN carriers showed more asymmetry than in other FTLD groups. All pathologically investigated cases showed extensive type 3 TDP-43-positive pathology, including frequent neuronal cytoplasmic inclusions, dystrophic neurites in both grey and white matter and also neuronal intranuclear inclusions. Finally, we confirmed a modifying effect of APOE-E4 genotype on clinical phenotype with a later onset in the GRN carriers suggesting that this gene has distinct phenotypic effects in different neurodegenerative diseases.


Effect of some antibiotics on Macrophomina phaseolina, a charcoal rot fungus of soybean.
Effect of agrimycin-100, ampicillin, griseofulvin and tetracycline on colony growth of Macrophomina phaseolina, incitant of charcoal rot of soybean has been studied in vitro. Amongst them tetracycline posed most effective inhibiting the growth by 73.9% at 1000 micrograms/ml concentration. On the basis of effectiveness antibiotics have been listed as tetracycline greater than ampicillin greater than griseofulvin greater than agrimycin-100.


Mutations in the B-domain of insulin-like growth factor-I influence the oxidative folding to yield products with modified biological properties.
The oxidative folding of human insulin-like growth factor (IGF)-I yields two major disulphide folding isomers. In the present study, B-domain analogues of IGF-I were used to investigate the effect of mutations on the folding reaction and to investigate the functional implications of misfolding. The analogues used were substitutions of the native Glu3 by Gly or Arg, or the native Glu9 by Lys. IGF-I and these analogues were also prepared attached to a hydrophobic 13-amino-acid N-terminal extension, Met-Phe-Pro-Ala-Met-Pro-Leu-Ser-Ser-Leu-Phe-Val-Asn, referred to as 'Long-IGF-I' analogues. Each IGF was fully reduced and refolded to yield native and misfolded isomers, which were subsequently purified for biological characterization. Analysis of the folding reaction at equilibrium revealed a distribution of folding isomers characteristic for each peptide. The yield of the native disulphide folding isomer was increased for the Glu3 substitutions, but not for the Glu9 substitution. The main alternative folding isomer was present in the IGF-I analogues in reduced proportions. Except for [Gly3]IGF-I the N-terminal extension increased the yield of the native isomer which was maximal for the analogue Long-[Arg3]IGF-I. A folding intermediate for the latter analogue was isolated and partially characterized. The biological assays showed that all the main alternative isomers bound poorly to IGF-binding proteins (IGFBPs) secreted by L6 myoblasts. Moreover, these isomers bound to the type 1 IGF receptor with 0.5-25% the affinity of the native isomer. In a rat L6 myoblast protein-synthesis assay, the observed biological activity of the native and main alternative isomers was explained by their modified IGFBP- and receptor-binding properties. We propose that the N-terminal extension imparts a steric constraint at a crucial point in folding, thus allowing native disulphide bonds to form efficiently.


Exploring the potential uses of value-added metrics in the context of postgraduate medical education.
Increasing pressure is being placed on external accountability and cost efficiency in medical education and training internationally. We present an illustrative data analysis of the value-added of postgraduate medical education. We analysed historical selection (entry) and licensure (exit) examination results for trainees sitting the UK Membership of the Royal College of General Practitioners (MRCGP) licensing examination (N = 2291). Selection data comprised: a clinical problem solving test (CPST); a situational judgement test (SJT); and a selection centre (SC). Exit data was an applied knowledge test (AKT) from MRCGP. Ordinary least squares (OLS) regression analyses were used to model differences in attainment in the AKT based on performance at selection (the value-added score). Results were aggregated to the regional level for comparisons. We discovered significant differences in the value-added score between regional training providers. Whilst three training providers confer significant value-added, one training provider was significantly lower than would be predicted based on the attainment of trainees at selection. Value-added analysis in postgraduate medical education potentially offers useful information, although the methodology is complex, controversial, and has significant limitations. Developing models further could offer important insights to support continuous improvement in medical education in future.


When falls become fatal-Clinical care sequence.
This study encompassed fall-related deaths, including those who died prior to medical care, that were admitted to multiple healthcare institutions, regardless of whether they died at home, in long-term care, or in hospice. The common element was that all deaths resulted directly or indirectly from injuries sustained during a fall, regardless of the temporal relationship. This comprehensive approach provides an unusual illustration of the clinical sequence of fall-related deaths. Understanding this pathway lays the groundwork for identification of gaps in healthcare needs. This is a retrospective study of 2014 fall-related deaths recorded by one medical examiner's office (n = 511) within a larger dataset of all trauma related deaths (n = 1848). Decedent demographic characteristics and fall-related variables associated with the deaths were coded and described. Of those falling, 483 (94.5%) were from heights less than 10 feet and 394 (77.1%) were aged 65+. The largest proportion of deaths (n = 267, 52.3%) occurred post-discharge from an acute care setting. Of those who had a documented prior fall, 216 (42.3%) had a history of one fall while 31 (6.1%) had ≥2 falls prior to their fatal incident. For the 267 post-acute care deaths, 440 healthcare admissions were involved in their care. Of 267 deaths occurring post-acute care, 129 (48.3%) were readmitted within 30 days. Preventability, defined as opportunities for improvement in care that may have influenced the outcome, was assessed. Of the 1848 trauma deaths, 511 (27.7%) were due to falls of which 361 (70.6%) were determined to be preventable or potentially preventable. Our data show that readmissions and repeated falls are frequent events in the clinical sequence of fall fatalities. Efforts to prevent fall-related readmissions should be a top priority for improving fall outcomes and increasing the quality of life among those at risk of falling.


Sex differences in UDP-glucuronosyltransferase 2B17 expression and activity.
UDP-glucuronosyltransferases (UGTs) are enzymes involved in the metabolism of steroid hormones, carcinogens, cancer chemotherapy agents, and addictive agents from cigarettes. Because the UGT2B family of genes has been linked to hormonal regulation in human cell lines in vitro, we hypothesized that there may be sex-related differences in the expression and activity of these genes in human tissues. To evaluate whether there are sex differences in UGT2B expression and activity, we examined 103 normal human liver specimens for UGT2B expression by real-time polymerase chain reaction and in vitro glucuronidation activities in human liver microsomes (HLM). Men exhibited an approximately 4-fold higher level of expression of UGT2B17 than women (p = 0.007). Consistent with the increased expression of UGT2B17 in men, HLM from men also had a higher level of glucuronidation activity than HLM from women against three UGT2B17 substrates: 3-fold higher for 17-dihydroexemestane (p = 0.002); 3-fold higher for 3-hydroxycotinine (p < 0.001); and 1.5-fold higher for suberoylanilide hydroxamic acid (p = 0.014). When we stratified by UGT2B17 gene deletion genotype, similar patterns were observed for all three substrates, with HLM from men with the UGT2B17 (+/+) or (+/0) genotypes exhibiting significantly higher levels of glucuronidation activity against all three substrates compared with HLM from women. These data suggest that men have a higher amount of UGT2B17 glucuronidation activity then women. This sex difference in UGT2B17 gene expression and corresponding protein activity could potentially result in different levels of carcinogen detoxification or drug elimination in men versus women.


The effect of xenobiotic exposure on spontaneous autoimmunity in (SWR x SJL)F1 hybrid mice.
F1 hybrids of SWR (H-2(q)) and SJL (H-2(s)) mice spontaneously develop a lupuslike condition in an age-dependent manner, and these two H-2 haplotypes also confer susceptibility to induction of systemic autoimmunity by heavy metals such as mercury, silver, and gold with anti-fibrillarin antibodies (AFA) as marker. The aim of this study was to determine how the mixing of two susceptible genomes might influence expression of idiopathic and induced autoimmunity over a period of 14 mo of exposure to mercury and silver. Spontaneous autoimmunity first appeared as antinuclear antibodies (ANA) in females at 10 wk of age and in males at 10 mo of age, and was followed by development of anti-chromatin antibodies. Antibodies to double-stranded DNA developed in 60% of males and 20% of females. Thirty percent of males and 10% of females developed a coarsely speckled ANA pattern associated with high titers of anti-Sm antibodies. Glomerular immune complex (IC) deposits and a proliferative glomerulonephritis were seen at 17 mo of age. The F1 hybrids treated with metals showed no exaggeration of spontaneous autoimmunity. However, the metals suppressed the spontaneous development of anti-Sm and antichromatin antibodies. The metal-induced AFA, linked to the H-2(s) and H-2(q) haplotype, reached a maximum after 3-4 mo of treatment and then declined; 33% of the silver-treated hybrids finally became AFA-negative, despite continuous treatment. The decline in ANoA during metal treatment is contrary to the situation in metal-treated SJL mice. This indicates that dominant SWR background genes suppressed induction of certain autoimmune traits in the (SWR x SJL)F1 hybrid mice.


Safety and efficacy of nivolumab in combination with S-1/capecitabine plus oxaliplatin in patients with previously untreated, unresectable, advanced, or recurrent gastric/gastroesophageal junction cancer: interim results of a randomized, phase II trial (ATTRACTION-4).
Nivolumab is approved as an option for third- or later-line treatment of advanced gastric/gastroesophageal junction (G/GEJ) cancer in several countries after ATTRACTION-2. To further improve the therapeutic efficacy of first-line therapy, exploration of a nivolumab-chemotherapy combination is warranted. In part 1 (phase II) of ATTRACTION-4, the safety and efficacy of nivolumab combined with S-1 plus oxaliplatin (SOX) or capecitabine plus oxaliplatin (CapeOX) as first-line therapy for unresectable advanced or recurrent human epidermal growth factor receptor 2 (HER2)-negative G/GEJ cancer were evaluated. Patients were randomized (1 : 1) to receive nivolumab (360 mg intravenously every 3 weeks) plus SOX (S-1, 40 mg/m2 orally twice daily for 14 days followed by 7 days off; oxaliplatin, 130 mg/m2 intravenously on day 1 every 3 weeks) or CapeOX (capecitabine, 1000 mg/m2 orally twice daily for 14 days followed by 7 days off; oxaliplatin, 130 mg/m2 intravenously on day 1 every 3 weeks) until disease progression, unacceptable toxicity, or consent withdrawal. Of 40 randomized patients, 39 (nivolumab plus SOX, 21; nivolumab plus CapeOX, 18) and 38 (21 and 17, respectively) comprised the safety and efficacy populations, respectively. Most frequent (>10%) grade 3/4 treatment-related adverse events were neutropenia (14.3%) in the nivolumab plus SOX group, and neutropenia (16.7%), anemia, peripheral sensory neuropathy, decreased appetite, type 1 diabetes mellitus, and nausea (11.1% each) in the nivolumab plus CapeOX group. No treatment-related death occurred. Objective response rate was 57.1% (95% confidence interval 34.0-78.2) with nivolumab plus SOX and 76.5% (50.1-93.2) with nivolumab plus CapeOX. Median overall survival was not reached (NR) in both groups. Median progression-free survival was 9.7 months (5.8-NR) and 10.6 months (5.6-12.5), respectively. Nivolumab combined with SOX/CapeOX was well tolerated and demonstrated encouraging efficacy for unresectable advanced or recurrent HER2-negative G/GEJ cancer. ATTRACTION-4 has proceeded to part 2 (phase III) to compare nivolumab plus SOX/CapeOX versus placebo plus SOX/CapeOX. NCT02746796.


Close-packed C(70)(3-) phases - synthesis, structure, and electronic properties.
The high symmetry and resulting electronic degeneracy of the C(60)(3)(-) anion is viewed as the key molecular feature in the high superconducting transition temperatures of fulleride and oxidized fullerene systems. The experimental evaluation of this hypothesis requires the synthesis of face-centered cubic (fcc) trivalent fulleride anion salts derived from higher fullerenes such as C(70), which have thus far proved elusive with only stable A(1)C(70), A(4)C(70), and A(6)C(70) phases known. In this paper, we report the synthesis of fcc A(3)C(70) phases stabilized by size-matching the tetrahedral site with the sodium cation. The structures are strongly dependent on the cooling protocol due to the existence of metastable partially or completely orientationally disordered phases. EPR data indicate that the phases are metallic but not superconducting. The densities of states at the Fermi level appear too low to give superconductivity at above 5 K, consistent with recent observations that four electrons per C(70) anion are required for superconductivity. Size-matching on both the octahedral and tetrahedral sites is required for A(3)C(70) stability - K(2)CsC(70) is only stable at elevated temperature and Na(2)C(70) is unstable, the composition corresponding to C(70) and a sodium-rich trigonal phase.


Honey and microbial infections: a review supporting the use of honey for microbial control.
Honey has been used as a medicine throughout the ages and has recently been reintroduced to modern medical practice. Much of the research to date has addressed honey's antibacterial properties and its effects on wound healing. Laboratory studies and clinical trials have shown that honey is an effective broad-spectrum antibacterial agent. Honey antimicrobial action explains the external and internal uses of honey. Honey has been used to treat adult and neonatal postoperative infection, burns, necrotizing fasciitis, infected and nonhealing wounds and ulcers, boils, pilonidal sinus, venous ulcers, and diabetic foot ulcers. These effects are ascribed to honey's antibacterial action, which is due to acidity, hydrogen peroxide content, osmotic effect, nutritional and antioxidants content, stimulation of immunity, and to unidentified compounds. When ingested, honey also promotes healing and shows antibacterial action by decreasing prostaglandin levels, elevating nitric oxide levels, and exerting prebiotic effects. These factors play a major role in controlling inflammation and promoting microbial control and healing processes. This article reviews data supporting the effectiveness of natural honey in eradicating human pathogens and discusses the mechanism of actions.


High speed tuning mechanism for CO2 lidar systems.
A method for rapidly tuning lasers is presented. The system utilizes a rotating eight-sided mirror and a fixed grating. It is demonstrated that the entire CO2 lasing spectrum can be tuned at effective rates of up to 400 Hz. It is shown that, although the pulse energy is diminished as the tuning rate is increased, the loss comes from the tail of the pulse, and the peak power is almost unchanged. In addition, the tuning method preserves the spatial beam profile while contributing a minimum of beam steering.


Measuring neuromuscular fatigue in cervical spinal musculature of military helicopter aircrew.
Neck pain and muscle function in aircrew have received considerable attention. We hypothesized normalized electromyography (EMG) frequency would provide insight into appropriate methods to assess muscle fatigue in helicopter aircrew. 40 helicopter aircrew performed isometric testing that included maximal voluntary contractions (MVC) and 70% MVC endurance protocols of extension, flexion, and left and right lateral flexion for cervical muscles. Bilateral muscle activity in the splenius capitis, sternocleidomastoid, and upper trapezius was monitored with EMG. Normalized mean EMG frequency was calculated for each muscle at the start and end of the 70% MVC trials to determine which muscles fatigued and limited force maintenance during each isometric movement. For extension, the left and right splenius capitis fatigued by approximately 21-22% (p < 0.01); for flexion, the left and right sternocleidomastoid fatigued by approximately 11-14% (p < 0.01); for right flexion, the right sternocleidomastoid fatigued by approximately 15% (p < 0.01); for left flexion, the left spenus capitis and left sternocleidomastoid fatigued by approximately 7.2% (p = 0.02) and approximately 11.2% (p = 0.03), respectively; in no trials did the trapezius muscles display fatigue as measured by EMG. The smaller agonist muscles were the most susceptible to fatigue during submaximal isometric endurance movements in the cervical muscles of helicopter aircrew.


Interference effects at a dielectric plate applied as a high-power-laser attenuator.
The interference effects caused by the Fresnel reflections of a Gaussian beam on the boundaries of a dielectric plate, which can be considered as a Fabry-Perot etalon, were theoretically and experimentally investigated. In addition to the incident angle and the polarization of the incident light, two additional parameters--the plate's parallelism and the temperature--which are often neglected, were analyzed. Based on the theoretical predictions and the measured behavior of the transmittance of the dielectric plate a new, temperature-controlled variable high-power-laser attenuator is proposed. Unwanted changes in the plate's transmittance caused by the absorption of laser pulses within the plate are also presented. These phenomena are important in many applications where dielectric plates are used for a variety of purposes.


Dual biorecognition by combining molecularly-imprinted polymer and antibody in SERS detection. Application to carcinoembryonic antigen.
This work reports the innovative combination of a molecularly-imprinted polymer (MIP) and a natural antibody for the accurate surface-enhanced Raman spectroscopy (SERS) detection of carcinoembryonic antigen (CEA). The MIP material acted as a pre-concentration scheme for the target protein, while the natural antibody was responsible to signal the presence of CEA on the MIP platform. Gold-based screen-printed electrodes were used as substrate and gallic acid (GA) was used herein for the first time in the assembly of a MIP film, by electropolymerization, in the presence of CEA. This layer was further covered by a second ultra-thin film of electropolymerized benzoic acid (BA), to avoid non-specific binding. The rebinding features of the MIP film were evaluated by electrochemical impedance spectroscopy (EIS) and a linear response was observed from 1 to 1000 ng/mL. For a sensitive SERS detection, the MIP film was first incubated in sample containing CEA and next incubated in SERS tag. For the SERS tag, gold nanostars (AuNSs) were employed as metal support, coupled to 4-aminothiophenol (4-ATP) as Raman reporter and to a natural antibody for CEA as recognition element. The overall system showed a sensitive response down to 1.0 ng/mL, which was different from the blank signal. Overall, the innovative approach presented herein combines the advantages of using two different targeting elements for CEA. The costs and time of MIP production were substantially low due to selection of electropolymerization approach and the proposal described herein may be extended to other target molecules.


Two alternatively spliced mouse urokinase receptor mRNAs with different histological localization in the gastrointestinal tract.
Two mouse urokinase-type plasminogen activator receptor (muPAR) cDNAs were isolated: muPAR1 is homologous to the human urokinase-type plasminogen activator receptor while muPAR2 codes for a 199 residue protein sharing the first 133 residues with muPAR1. Mouse genomic DNA sequencing indicates that the two different mRNAs arise by alternative splicing. In situ hybridization showed differential expression of the two mRNAs in mouse gastric mucosa. muPAR1 mRNA is located in luminal epithelial cells situated close to urokinase-type plasminogen activator-producing connective tissue cells of the lamina propria, pointing to plasmin generation controlled by the cooperation of different cells that may play a role in the release of gastric epithelial cells. muPAR2 mRNA is expressed in the basal epithelial cells, and the deduced protein sequence includes the receptor ligand binding domain, but omits the region involved in glycolipid-mediated membrane anchoring, suggesting that muPAR2 may code for a secreted uPA binding protein.


Short Term Evaluation of an Anatomically Shaped Polycarbonate Urethane Total Meniscus Replacement in a Goat Model.
Since the treatment options for symptomatic total meniscectomy patients are still limited, an anatomically shaped, polycarbonate urethane (PCU), total meniscus replacement was developed. This study evaluates the in vivo performance of the implant in a goat model, with a specific focus on the implant location in the joint, geometrical integrity of the implant and the effect of the implant on synovial membrane and articular cartilage histopathological condition. The right medial meniscus of seven Saanen goats was replaced by the implant. Sham surgery (transection of the MCL, arthrotomy and MCL suturing) was performed in six animals. The contralateral knee joints of both groups served as control groups. After three months follow-up the following aspects of implant performance were evaluated: implant position, implant deformation and the histopathological condition of the synovium and cartilage. Implant geometry was well maintained during the three month implantation period. No signs of PCU wear were found and the implant did not induce an inflammatory response in the knee joint. In all animals, implant fixation was compromised due to suture breakage, wear or elongation, likely causing the increase in extrusion observed in the implant group. Both the femoral cartilage and tibial cartilage in direct contact with the implant showed increased damage compared to the sham and sham-control groups. This study demonstrates that the novel, anatomically shaped PCU total meniscal replacement is biocompatible and resistant to three months of physiological loading. Failure of the fixation sutures may have increased implant mobility, which probably induced implant extrusion and potentially stimulated cartilage degeneration. Evidently, redesigning the fixation method is necessary. Future animal studies should evaluate the improved fixation method and compare implant performance to current treatment standards, such as allografts.


Antimicrobial efficacy of copper surfaces against spores and vegetative cells of Clostridium difficile: the germination theory.
Persistent contamination of surfaces by spores of Clostridium difficile is a major factor influencing the spread of C. difficile-associated diarrhoea (CDAD) in the clinical setting. In recent years, the antimicrobial efficacy of metal surfaces has been investigated against microorganisms including methicillin-resistant Staphylococcus aureus. This study compared the survival of C. difficile on stainless steel, a metal contact surface widely used in hospitals, and copper surfaces. Antimicrobial efficacy was assessed using a carrier test method against dormant spores, germinating spores and vegetative cells of C. difficile (NCTC 11204 and ribotype 027) over a 3 h period in the presence and absence of organic matter. Copper metal eliminated all vegetative cells of C. difficile within 30 min, compared with stainless steel which demonstrated no antimicrobial activity (P < 0.05). Copper significantly reduced the viability of spores of C. difficile exposed to the germinant (sodium taurocholate) in aerobic conditions within 60 min (P < 0.05) while achieving a >or=2.5 log reduction (99.8% reduction) at 3 h. Organic material did not reduce the antimicrobial efficacy of the copper surface (P > 0.05). The use of copper surfaces within the clinical environment and application of a germination solution in infection control procedures may offer a novel way forward in eliminating C. difficile from contaminated surfaces and reducing CDAD.


Ice can penetrate invertebrate tissues via paracellular pathways.
Ice-cell interactions especially the question whether and how ice crystals invade tissues and organs during freezing were examined in small transparent organs (salivary glands) in which many structural details remained visible despite of freeze-induced cell darkening. In most glands no invasion of ice into the lumen was observed since ice dendrites stopped growing after touching the gland. Here I report that in rare cases a so far unknown type of ice crystals developed which aggressively pushed against cell membranes before invading the gland via paracellular pathways (septate junctions). Aggressive ice crystals were also observed within a salivary gland cell which deformed and finally invaded the nucleus. In cell strands it was observed that intracellular freezing is indeed a two-step event in which ice developed in cytoplasm several seconds before invading the nucleus.


Central memory CD4+ T cells dominate the normal cerebrospinal fluid.
To use cerebrospinal fluid (CSF) immune phenotyping as a diagnostic and research tool, we have set out to establish reference values of white blood cell (WBC) subsets in CSF. We assessed the absolute numbers and percentages of WBC subsets by 6-color flow cytometry in paired CSF and blood samples of 84 individuals without neurological disease who underwent spinal anaesthesia for surgery. Leukocyte (i.e., lymphocytes, granulocytes, and monocytes), lymphocyte (i.e., T [CD4(+) and CD8(+) ], NK, NKT and B cells), T cell (i.e., naïve, central memory, effector memory, and regulatory) and dendritic cell subsets (i.e., myeloid and plasmacytoid) were studied. CSF showed a predominance of T cells, while granulocytes, B and NK cells were relatively rare compared to blood. The majority of T cells in CSF consisted of CD4(+) T cells (∼70%), most of them (∼90%) with a central memory phenotype, while B cells were almost absent (<1%). Among the small population of dendritic cells in CSF, those of the myeloid subtype were more frequent than plasmacytoid dendritic cells (medians: 1.7% and 0.4% of leukocytes, respectively), whilst both subsets made up 0.2% of leukocytes in blood. This study reports reference values of absolute numbers and percentages of WBC subsets in CSF, which are essential for further investigation of the immunopathogenesis of neuro-inflammatory diseases. Furthermore, the relative abundance of CD4(+) T cells, mainly with a central memory phenotype, and the presence of dendritic cells in CSF suggests an active adaptive immune response under normal conditions in the central nervous system (CNS).


Validation and further development of the WHO 10-year fracture risk assessment tool in Italian postmenopausal women: project rationale and description.
The threshold for pharmacological intervention for osteoporosis remains controversial. Tools predicting the future risk of new fractures are increasingly used to establish a convenient individual risk/benefit ratio for a long term treatment. FRAX® is likely to become the most widely used tool for assessing fracture risk also for the WHO endorsement. The inevitable limitations will not hamper its value. As for any tool like this a continuous process of validation and further development is highly warranted. The predictive and clinical value of FRAX® has to be tested in individual countries by exploring also the inclusion of additional specific relatively uncommon risk factors. The DeFRA project is intended to validate in a large cohort of postmenopausal women a new algorithm derived from FRAX®. Both, the coefficients of continuous variable and the gradients for clinical risk factors should not be considered as conclusive for the routine clinical use. The new tool will be offered for the routine clinical use only at the completion of the DeFRA project, requiring the prospective collection of at least 60.000 patient-years. Here we report the rational and the design of the project.


Synthesis of gold structures by gold-binding peptide governed by concentration of gold ion and peptide.
Although biological synthesis methods for the production of gold structures by microorganisms, plant extracts, proteins, and peptide have recently been introduced, there have been few reports pertaining to controlling their size and morphology. The gold ion and peptide concentrations affected on the size and uniformity of gold plates by a gold-binding peptide Midas-11. The higher concentration of gold ions produced a larger size of gold structures reached 125.5 μm, but an increased amount of Midas-11 produced a smaller size of gold platelets and increased the yield percentage of polygonal gold particles rather than platelets. The mechanisms governing factors controlling the production of gold structures were primarily related to nucleation and growth. These results indicate that the synthesis of gold architectures can be controlled by newly isolated and substituted peptides under different reaction conditions.


[Effectiveness and tolerance of tramadol in cancer pain. A comparative study with respect to buprenorphine].
Opioid analgesics represent one of the most important tools in a sequential pharmacological approach to oncological pain relief. They are recommended by the WHO when nonsteroidal anti-inflammatory drugs (NSAIDs) no longer provide adequate analgesia. However, the use of opioids is limited because of their numerous and often severe adverse effects. This aspect of opioids has motivated continuous research projects aimed at discovering drugs that can provide maximum pain relief but with improved tolerability. Tramadol is a new, centrally acting analgesic with a dual mechanism of action. It shows a selective interaction with mu receptors, which are responsible for nociception, and has weak pharmacodynamic activity on other opioid receptors. At the same time, it acts synergistically on neuroamine transmission by inhibiting synaptic noradrenaline (norepinephrine) reuptake and inducing intrasynaptic serotonin (5-hydroxytryptamine; 5-HT) release. From a pharmacokinetic standpoint, tramadol offers high bioavailability, with similar patterns after oral or parenteral administration (half-life 5 to 7 hours, time to peak plasma concentration 3.1 hours, and approximately 20% plasma protein binding). Although the efficacy of tramadol is comparable to that of other drugs with similar modes of action, the incidence of side effects such as constipation and respiratory depression is lower. The frequency of euphoria and dysphoria is negligible, resulting in little risk of abuse or dependence. It therefore seemed appropriate to further investigate the efficacy and tolerability of tramadol, defined as having only weak potency, in comparison with a widely used opioid, in oncological pain. Buprenorphine was selected as an opioid with a potency equivalent to half that of morphine, but with tolerability that is partially limited by the fact that it frequently gives rise to adverse reactions considered typical of stronger opioids. To compare the analgesic effect and tolerability of tramadol and buprenorphine, 60 patients (44 men, 16 women; average age 61.4 years), all presenting with advanced tumours, were treated orally in a controlled crossover trial with randomised sequences. Patients took both drugs, each for a week, with a 24-hour washout period between treatments. Tramadol was prescribed at the daily dose of 300mg, orally, and buprenorphine at 0.6 mg/day, as a sublingual preparation. Assessments were made of Karnofsky performance status and severity of pain before and during the 4 hours after taking the 2 drugs. Each patient also completed a daily diary recording the severity of pain 1 hour after the dose, the evolution of pain during the day and its severity compared with that on the previous day. They also assessed the duration and quality of sleep. The Karnofsky index changed little with either treatment, but all other variables showed worthwhile improvement, indicating the significant analgesic effect of both drugs. Buprenorphine and tramadol had a similar analgesic effect, although the improvement with the test drug was significant within 1 hour of administration (p < 0.05 compared with baseline) and more marked (p < 0.05 on day 2 compared with buprenorpine). At the end of tramadol treatment, sleep had also improved, both quantitatively and qualitatively (both p < 0.05). The final assessment was significantly in favour of tramadol as regards efficacy (p < 0.05) and patient acceptability (p < 0.01). Thus, tramadol was better tolerated than buprenorphine, and caused fewer and milder adverse reactions. Only 1 patient discontinued tramadol, compared with 18 using reference therapy. Tramadol, although theoretically less potent, nevertheless brought about as much pain relief as the comparator opioid. In conclusion, for this class of drug, tramadol provides an excellent balance between efficacy and tolerability, confirming preliminary studies.


Motor-unit activity responsible for 8- to 12-Hz component of human physiological finger tremor.
Tremor of the extended third digit and bipolar surface and needle electromyograms of the extensor digitorum were recorded from six healthy volunteers for the purpose of elucidating the motor-unit activity responsible for the 8- to 12-Hz component of physiological finger tremor. Tremor was measured with a force transducer during steady voluntary contractions of approximately 200-250 g. The surface EMGs were full-wave rectified and low-pass filtered (-3 dB at 21 Hz), producing the envelope of the surface EMG (the demodulated EMG). Spectral analyses of simultaneous tremor and demodulated EMG records were performed. In four of six subjects, a pronounced 8- to 12-Hz amplitude modulation in the surface EMG was present, and coherency analysis demonstrated that this modulation was strongly correlated with the well-known 8- to 12-Hz tremor. In two subjects this amplitude modulation and tremor were barely detectable, despite the sensitive recording and analysis techniques used in this study. Spectral analysis was performed on 43 motor-unit spike trains. Twenty-two spike trains, having mean firing frequencies in the range of 10-22 spikes/s, produced statistically significant spectral peaks at 8-12 Hz, in addition to the expected spectral peaks at the mean firing frequencies. Of the 22 8- to 12-Hz-producing motor units, 12 had mean firing frequencies in the range of 17-22 spikes/s and exhibited the greatest 8- to 12-Hz activities of all motor units recorded. These motor units displayed transient sequences of double discharges in which interspike intervals (ISIS) of approximately 8-30 ms alternated with ISIS of 60-90 ms, thus producing an 8- to 12-Hz spectral peak. Adjacent ISIS of these motor units were correlated in the range of -0.5 to -0.9. Coherency analyses demonstrated that the 8- to 12-Hz activities of these motor units were correlated with the 8- to 12-Hz finger tremor and surface EMG modulation. The remaining 10 8- to 12-Hz-producing motor units had mean firing frequencies in the range of 10-17 spike/s. Although these motor units did not display the intense double-discharge firing pattern of the more rapidly firing motor units, a tendency toward action potential grouping was present and resulted in 8- to 12-Hz spectral activities which were correlated with the tremor and surface EMG modulation. .. ..


Formononetin: A Review of Its Anticancer Potentials and Mechanisms.
Cancer, a complex yet common disease, is caused by uncontrolled cell division and abnormal cell growth due to a variety of gene mutations. Seeking effective treatments for cancer is a major research focus, as the incidence of cancer is on the rise and drug resistance to existing anti-cancer drugs is major concern. Natural products have the potential to yield unique molecules and combinations of substances that may be effective against cancer with relatively low toxicity/better side effect profile compared to standard anticancer therapy. Drug discovery work with natural products has demonstrated that natural compounds display a wide range of biological activities correlating to anticancer effects. In this review, we discuss formononetin (C16H12O4), which originates mainly from red clovers and the Chinese herb Astragalus membranaceus. The compound comes from a class of 7-hydroisoflavones with a substitution of methoxy group at position 4. Formononetin elicits antitumorigenic properties in vitro and in vivo by modulating numerous signaling pathways to induce cell apoptosis (by intrinsic pathway involving Bax, Bcl-2, and caspase-3 proteins) and cell cycle arrest (by regulating mediators like cyclin A, cyclin B1, and cyclin D1), suppress cell proliferation [by signal transducer and activator of transcription (STAT) activation, phosphatidylinositol 3-kinase/protein kinase-B (PI3K/AKT), and mitogen-activated protein kinase (MAPK) signaling pathway], and inhibit cell invasion [by regulating growth factors vascular endothelial growth factor (VEGF) and Fibroblast growth factor 2 (FGF2), and matrix metalloproteinase (MMP)-2 and MMP-9 proteins]. Co-treatment with other chemotherapy drugs such as bortezomib, LY2940002, U0126, sunitinib, epirubicin, doxorubicin, temozolomide, and metformin enhances the anticancer potential of both formononetin and the respective drugs through synergistic effect. Compiling the evidence thus far highlights the potential of formononetin to be a promising candidate for chemoprevention and chemotherapy.


A role for guanylate cyclase C in acid-stimulated duodenal mucosal bicarbonate secretion.
Luminal acidification provides the strongest physiological stimulus for duodenal HCO3- secretion. Various neurohumoral mechanisms are believed to play a role in acid-stimulated HCO3- secretion. Previous studies in the rat and human duodenum have shown that guanylin and Escherichia coli heat-stable toxin, both ligands of the transmembrane guanylyl cyclase receptor [guanylate cyclase C (GC-C)], are potent stimulators for duodenal HCO3- secretion. We postulated that the GC-C receptor plays an important role in acid-stimulated HCO3- secretion. In vivo perfusion studies performed in wild-type (WT) and GC-C knockout (KO) mice indicated that acid-stimulated duodenal HCO3- secretion was significantly decreased in the GC-C KO animals compared with the WT counterparts. Pretreatment with PD-98059, an MEK inhibitor, resulted in attenuation of duodenal HCO3- secretion in response to acid stimulation in the WT mice with no further effect in the KO mice. In vitro cGMP generation studies demonstrated a significant and comparable increase in cGMP levels on acid exposure in the duodenum of both WT and KO mice. In addition, a rapid, time-dependent phosphorylation of ERK was observed with acid exposure in the duodenum of WT mice, whereas a marked attenuation in ERK phosphorylation was observed in the KO animals despite equivalent levels of ERK in both groups of animals. On the basis of these studies, we conclude that transmembrane GC-C is a key mediator of acid-stimulated duodenal HCO3- secretion. Furthermore, ERK phosphorylation may be an important intracellular mediator of duodenal HCO3- secretion.


Vascularized medial sural cutaneous nerve based on the superficial sural artery: a reliable nerve graft.
The sural nerve is nourished by the single superficial sural artery proximally, but distally receives multiple contributions from musculocutaneous and fasciocutaneous perforators of the posterior tibial and peroneal (fibular) arteries. The prevalence of this proximal arterial supply is largely unknown. The authors report a large anatomic study (n = 56), together with two clinical cases, to assess the incidence and potential suitability of the sural nerve as a vascularized nerve graft. Dissections were performed on 6 fresh cadavers injected with Microfil dye and on 22 preserved cadavers. The superficial sural artery was present in 91 percent of the dissections. The mean diameter of this extrinsic artery was 1.5 mm. The mean percentage of neural tissue within the sural nerve in the region where it is supplied by the superficial sural artery was 62 percent compared to 34 percent distally, where it was supplied by the posterior tibial and fibular (peroneal) arteries. This anatomic difference provides a solid rationale for preferential utilization of the proximal portion of the nerve, as opposed to its distal segment. When a vascularized nerve graft is indicated, the proximally-based sural nerve appears to offer clear advantages, compared to other vascularized nerve grafts.


Workplace empowerment and nurses' job satisfaction: a systematic literature review.
This systematic review aimed to synthesize and analyse the studies that examined the relationship between nurse empowerment and job satisfaction in the nursing work environment. Job dissatisfaction in the nursing work environment is the primary cause of nursing turnover. Job satisfaction has been linked to a high level of empowerment in nurses. We reviewed 596 articles, written in English, that examined the relationship between structural empowerment, psychological empowerment and nurses' job satisfaction. Twelve articles were included in the final analysis. A significant positive relation was found between empowerment and nurses' job satisfaction. Structural empowerment and psychological empowerment affect job satisfaction differently. A satisfying work environment for nurses is related to structural and psychological empowerment in the workplace. Structural empowerment is an antecedent of psychological empowerment and this relationship culminates in positive retention outcomes such as job satisfaction. This review could be useful for guiding leaders' strategies to develop and maintain an empowering work environment that enhances job satisfaction. This could lead to nurse retention and positive organisational and patient outcomes.


Fc Gamma Receptor Polymorphisms Modulated the Vaccine Effect on HIV-1 Risk in the HVTN 505 HIV Vaccine Trial.
HIV Vaccine Trials Network (HVTN) 505 was a phase 2b efficacy trial of a DNA/recombinant adenovirus 5 (rAd5) HIV vaccine regimen. Although the trial was stopped early for lack of overall efficacy, later correlates of risk and sieve analyses generated the hypothesis that the DNA/rAd5 vaccine regimen protected some vaccinees from HIV infection yet enhanced HIV infection risk for others. Here, we assessed whether and how host Fc gamma receptor (FcγR) genetic variations influenced the DNA/rAd5 vaccine regimen's effect on HIV infection risk. We found that vaccine receipt significantly increased HIV acquisition compared with placebo receipt among participants carrying the FCGR2C-TATA haplotype (comprising minor alleles of four FCGR2C single-nucleotide polymorphism [SNP] sites) (hazard ratio [HR] = 9.79, P = 0.035) but not among participants without the haplotype (HR = 0.86, P = 0.67); the interaction of vaccine and haplotype effect was significant (P = 0.034). Similarly, vaccine receipt increased HIV acquisition compared with placebo receipt among participants carrying the FCGR3B-AGA haplotype (comprising minor alleles of the 3 FCGR3B SNPs) (HR = 2.78, P = 0.058) but not among participants without the haplotype (HR = 0.73, P = 0.44); again, the interaction of vaccine and haplotype was significant (P = 0.047). The FCGR3B-AGA haplotype also influenced whether a combined Env-specific CD8+ T-cell polyfunctionality score and IgG response correlated significantly with HIV risk; an FCGR2A SNP and two FCGR2B SNPs influenced whether anti-gp140 antibody-dependent cellular phagocytosis correlated significantly with HIV risk. These results provide further evidence that Fc gamma receptor genetic variations may modulate HIV vaccine effects and immune function after HIV vaccination.IMPORTANCE By analyzing data from the HVTN 505 efficacy trial of a DNA/recombinant adenovirus 5 (rAd5) vaccine regimen, we found that host genetics, specifically Fc gamma receptor genetic variations, influenced whether receiving the DNA/rAd5 regimen was beneficial, neutral, or detrimental to an individual with respect to HIV-1 acquisition risk. Moreover, Fc gamma receptor genetic variations influenced immune responses to the DNA/rAd5 vaccine regimen. Thus, Fc gamma receptor genetic variations should be considered in the analysis of future HIV vaccine trials and the development of HIV vaccines.