FDG PET of pleural effusions in patients with non-small cell lung cancer.
We determined the ability of 18F-fluorodeoxyglucose (FDG) positron emission tomography (PET) to differentiate benign and malignant pleural effusions in patients with non-small cell lung cancer. Over a 6-year period, we reviewed all patients with primary non-small cell lung cancer and a pleural effusion on staging CT who underwent FDG PET. We examined 25 patients (18 men and seven women; age range, 37-86 years; mean age, 65 years). FDG PET revealed positive findings if pleural activity was greater than background mediastinal activity; FDG PET revealed negative findings if pleural activity was the same as or less than background mediastinal activity. Results of FDG PET were correlated with pathologic diagnosis determined with thoracentesis or pleural biopsy. All patients had effusions on the same side as the primary tumor. Twenty-two patients had a malignant pleural effusion confirmed with thoracentesis (n = 19) or biopsy (n = 3). FDG PET revealed positive findings in 21 patients and negative findings in one. Three patients had no evidence of malignancy in the pleural space determined with cytologic findings (n = 2) or biopsy results (n = 1). FDG PET uptake revealed positive findings in one of these patients and negative findings in two. Therefore, of 22 patients with positive findings on FDG PET, 21 had pleural metastases, and of three patients with negative findings on FDG PET, one had metastases. The sensitivity, specificity, positive predictive value, negative predictive value, and accuracy of FDG PET for detecting pleural metastases were 95%, 67%, 95%, 67%, and 92%, respectively. This study suggests that FDG PET may be useful in improving staging evaluation in patients with non-small cell lung cancer and a pleural effusion. Increased pleural FDG uptake usually indicates pleural metastases; however, because the number of benign effusions studied was small, the relevance of negative findings on FDG PET in this setting is uncertain.


Denatured class I human leukocyte antigen antibodies in sensitized kidney recipients: prevalence, relevance, and impact on organ allocation.
Single antigen flow beads assays may overestimate sensitization because of the detection of supposedly irrelevant antibodies recognizing denatured class I human leukocyte antigens (HLAs). Sera of 323 HLA-sensitized kidney transplant candidates positive with a class I HLA single antigen flow beads assay were retested after acid treatment of the beads. Denatured HLA antibodies were identified according to ratio between the measured fluorescence intensity for treated and nontreated beads. T-lymphocyte flow cytometry crossmatches were performed to characterize the ability of these antibodies to recognize HLA on normal cells as a surrogate of their potential clinical relevance. Their impact on organ allocation was evaluated through a calculated panel reactive antibody. The utility of single antigen flow beads largely devoid of denatured HLA (iBeads) was also evaluated. Denatured HLA antibodies were detected in 39% of the patients. They provided much less positive flow cytometry crossmatches than anti-native HLA antibodies (16% vs. 83%, P<0.0001). Removing the HLA-A and HLA-B antigens targeted by denatured HLA antibodies from unacceptable antigens lowered the calculated panel reactive antibody for 90 patients, sometimes dramatically. The iBeads assay demonstrated nearly the same ability to predict crossmatch results than the acid treatment assay. Denatured class I HLA antibodies are common, but the antigens they target should not be considered as unacceptable in most cases, because they negatively impact access to a transplant while predominantly providing negative sensitive crossmatches. The iBeads assay seems to be a valuable alternative to better define unacceptable antigens.


[Temporal analysis of cardiac frequency variability in basal condition in elderly chagasic subjects in indeterminate form in endemic área].
With the aim of evaluating the cardiac autonomic function in elderly chagasic patients living in an endemic area, we evaluated, by using computadorized heart rate variability, 28 elderly chagasic with the indeterminate form, 28 elderly non chagasic and 28 young healthy control. In all patients we performed conventional electrocardiogram, radiological investigation of thorax, and with contrast of esophagus and colons and echodopplercardiogram. Non chagasic patients did not perform only the exams with contrast. The systolic ventricular function was preserved in all subjects. There was no statistically significant difference between the groups with regard to mean duration of RR intervals. Considering the variance, standard deviation, variation coefficient and pNN50 there was statistically significant difference between the young and elderly groups but no difference was found when the analysis was performed in each one separately for these temporal indexes. We conclude that, in basal condition, the groups of elderly chagasic and no chagasic subjects did not differ as much as the cardiac autonomic modulation in time domain.


Transgene Expression in Dogs After Liver-Directed Hydrodynamic Delivery of Sleeping Beauty Transposons Using Balloon Catheters.
The Sleeping Beauty transposon system has been extensively tested for integration of reporter and therapeutic genes in vitro and in vivo in mice. Dogs were used as a large animal model for human therapy and minimally invasive infusion of DNA solutions. DNA solutions were delivered into the entire liver or the left side of the liver using balloon catheters for temporary occlusion of venous outflow. A peak intravascular pressure between 80 and 140 mmHg supported sufficient DNA delivery in dog liver for detection of secretable reporter proteins. Secretable reporters allowed monitoring of the time course of gene products detectable in the circulation postinfusion. Canine secreted alkaline phosphatase reporter protein levels were measured in plasma, with expression detectable for up to 6 weeks, while expression of canine erythropoietin was detectable for 7-10 days. All animals exhibited a transient increase in blood transaminases that normalized within 10 days; otherwise the treated animals were clinically normal. These results demonstrate the utility of a secreted reporter protein for real-time monitoring of gene expression in the liver in a large animal model but highlight the need for improved delivery in target tissues to support integration and long-term expression of Sleeping Beauty transposons.


Our future in the Anthropocene biosphere.
The COVID-19 pandemic has exposed an interconnected and tightly coupled globalized world in rapid change. This article sets the scientific stage for understanding and responding to such change for global sustainability and resilient societies. We provide a systemic overview of the current situation where people and nature are dynamically intertwined and embedded in the biosphere, placing shocks and extreme events as part of this dynamic; humanity has become the major force in shaping the future of the Earth system as a whole; and the scale and pace of the human dimension have caused climate change, rapid loss of biodiversity, growing inequalities, and loss of resilience to deal with uncertainty and surprise. Taken together, human actions are challenging the biosphere foundation for a prosperous development of civilizations. The Anthropocene reality-of rising system-wide turbulence-calls for transformative change towards sustainable futures. Emerging technologies, social innovations, broader shifts in cultural repertoires, as well as a diverse portfolio of active stewardship of human actions in support of a resilient biosphere are highlighted as essential parts of such transformations.


Behavioral effects of non-opioid fragments of beta-endorphin.
The opioid peptide beta-endorphin (beta E) is converted by brain enzymes to a variety of non-opioid peptide molecules. Several of these peptides specifically affect brain processes in a different manner as assessed in behavioral test procedures. The peptide beta E-(2-9) exhibits behavioral effects resembling psychostimulant drugs in certain aspects and potentiates apomorphine-induced stereotypy following peripheral and intrastriatal treatment. The peptide beta E-(10-16), like serotonin and antidepressant drugs antagonizes the behavioral effects of intra-accumbens injected melatonin. The peptide beta E-(6-17) induces several effects which resemble those of neuroleptic drugs, including an antipsychotic action, and may control the activity of specific dopaminergic systems present in the nucleus accumbens. Thus, non-opioid fragments of beta-endorphin may be involved in the modulation of neurotransmitter systems and consequently in brain homeostasis and possibly in psychopathological syndromes.


Multiscale analyses reveal native-like lamellar bone repair and near perfect bone-contact with porous strontium-loaded bioactive glass.
The efficient healing of critical-sized bone defects using synthetic biomaterial-based strategies is promising but remains challenging as it requires the development of biomaterials that combine a 3D porous architecture and a robust biological activity. Bioactive glasses (BGs) are attractive candidates as they stimulate a biological response that favors osteogenesis and vascularization, but amorphous 3D porous BGs are difficult to produce because conventional compositions crystallize during processing. Here, we rationally designed a porous, strontium-releasing, bioactive glass-based scaffold (pSrBG) whose composition was tailored to deliver strontium and whose properties were optimized to retain an amorphous phase, induce tissue infiltration and encourage bone formation. The hypothesis was that it would allow the repair of a critical-sized defect in an ovine model with newly-formed bone exhibiting physiological matrix composition and structural architecture. Histological and histomorphometric analyses combined with indentation testing showed pSrBG encouraged near perfect bone-to-material contact and the formation of well-organized lamellar bone. Analysis of bone quality by a combination of Raman spectral imaging, small-angle X-ray scattering, X-ray fluorescence and focused ion beam-scanning electron microscopy demonstrated that the repaired tissue was akin to that of normal, healthy bone, and incorporated small amounts of strontium in the newly formed bone mineral. These data show the potential of pSrBG to induce an efficient repair of critical-sized bone defects and establish the importance of thorough multi-scale characterization in assessing biomaterial outcomes in large animal models.


Role of ovarian hormones in hoarding pattern.
Hoarding pattern studied in 28 adult female albino rats indicated cyclic changes in hoarding corresponding to alterations in estrus cycle. It was observed that the hoarding score was maximum at proestrus and the least at diestrus. Animals ovariectomised at proestrus maintained higher hoarding score and those ovariectomised at diestrus stablised on lower hoarding score. Progesterone administration reduced the score in high-score group and Oestrogen administration improved the score in low score group. Alterations in ovarian hormone levels were thus observed to influence hoarding pattern in rats.


Therapeutic isolation and expansion of human skeletal muscle-derived stem cells for the use of muscle-nerve-blood vessel reconstitution.
Skeletal muscle makes up 40-50% of body mass, and is thus considered to be a good adult stem cell source for autologous therapy. Although, several stem/progenitor cells have been fractionated from mouse skeletal muscle showing a high potential for therapeutic use, it is unclear whether this is the case in human. Differentiation and therapeutic potential of human skeletal muscle-derived cells (Sk-Cs) was examined. Samples (5-10 g) were obtained from the abdominal and leg muscles of 36 patients (age, 17-79 years) undergoing prostate cancer treatment or leg amputation surgery. All patients gave informed consent. Sk-Cs were isolated using conditioned collagenase solution, and were then sorted as CD34(-)/CD45(-)/CD29(+) (Sk-DN/29(+)) and CD34(+)/CD45(-) (Sk-34) cells, in a similar manner as for the previous mouse Sk-Cs. Both cell fractions were appropriately expanded using conditioned culture medium for about 2 weeks. Differentiation potentials were then examined during cell culture and in vivo transplantation into the severely damaged muscles of athymic nude mice and rats. Interestingly, these two cell fractions could be divided into highly myogenic (Sk-DN/29(+)) and multipotent stem cell (Sk-34) fractions, in contrast to mouse Sk-Cs, which showed comparable capacities in both cells. At 6 weeks after the separate transplantation of both cell fractions, the former showed an active contribution to muscle fiber regeneration, but the latter showed vigorous engraftment to the interstitium associated with differentiation into Schwann cells, perineurial/endoneurial cells, and vascular endothelial cells and pericytes, which corresponded to previous observations with mouse SK-Cs. Importantly, mixed cultures of both cells resulted the reduction of tissue reconstitution capacities in vivo, whereas co-transplantation after separate expansion showed favorable results. Therefore, human Sk-Cs are potentially applicable to therapeutic autografts and show multiple differentiation potential in vivo.


Individual medication management system (IMMS) implementation in pharmacists' opinion.
Many countries of the world including Poland, are taking actions for improving the role of the pharmacist as a health care professional. One of those is implementation of pharmaceutical care (PC), as a documented specialist medical service, which also includes pharmacist interventions, such as preparing Individual Medication Management System (IMMS), to enhance patient's adherence. Because of the chance to monitor the dosage and to detect and prevent drug problems occurrence, IMMS is thought to be an opportunity for individualized, effective and safe patient's pharmacotherapy. The aim of the study was to define pharmacists' attitudes toward IMMS. The study included also the evaluation of pharmacist-physician cooperation to determine whether IMMS can improve partnership among health care professionals for proper patient's care. The survey was conducted in Poznań, between June 2011 and March 2012. An anonymous questionnaire was delivered personally to pharmacists. Each questionnaire was provided with a short information brochure attached and presentation of demos how to use IMMS. The survey covered 129 pharmacists (76.7% women and 23.3% men) where 48.8% had up to 5 years length of service as a pharmacist, 24.8% - 6-10 years, 14.9% - 11-20 years and 11.5% - 21 and more years. Most of the participants did not have specialization (80.6%) and only 5.4% had Ph.D. degree. Survey confirmed that 64.8% of pharmacists (p < 0.0001), mainly with the shortest length of service (p = 0.02268) and without specialty (p = 0.00244) didn't cooperate with physicians, but 68.8% of respondents emphasized that the range of cooperation could increase by IMMS application (p < 0.00001). About 50.0% of respondents' considered that patients would be interested in IMMS usage (p = 0.00079) and in 71.9% opinions, it would attach the patient to specific community pharmacy (p < 0.00001). This statement was confirmed by respondents with the shortest length of services (p = 0.00659). Proposed dosing system also improved patient's care serving by family or carers in pharmacists' opinion (p < 0.00001). A majority of pharmacists (85.3%) indicated also that IMMS would have a positive influence on PC implementation in Poland (p < 0.00001) and 69.0% of them confirmed that this service should be refunded by the National Health Fund (p < 0.00001). According to the scale of non-compliance, implementation of IMMS as a part of PC can be a chance both for patients and their physicians to increase the safety and effectiveness of therapy and for pharmacists, who are intended to highlight their role as a part of health care system.


Influence of AT1 blockers on obesity and stress induced eating of cafeteria diet.
Based on findings that treatment with AT1 receptor blocker (ARB) prevents diet-induced obesity and that the activity of the hypothalamic-pituitary-adrenal (HPA) axis is stimulated by AngII and blocked by ARBs, we aimed to investigate whether ARB treatment can reduce stress-induced eating of cafeteria diet (CD) , thus contributing to alterations in eating behavior. Sprague Dawley rats were fed with chow or CD and treated with telmisartan (TEL, 8mg/kg/d) or vehicle. At weeks 2 and 12, rats were stressed over 5 consecutive days by restraint stress (RS, 4h) and by additional shaking at d5. Tail blood was sampled during RS to determine hormone levels. During the first period of RS, ACTH and corticosterone responses were diminished at d5 in CD- compared to chow-fed rats. Independently of feeding, TEL did not reduce stress hormones. Compared to food behavior before RS, the stress-induced CD eating increased in controls but remained unchanged in TEL-treated rats. After 12 weeks, TEL reduced weight gain and energy intake, particularly in CD-fed rats. Similar to the first RS period, corticosterone response was reduced in CD-fed rats at d5 during the second RS period. TEL did not further reduce stress hormones and did not lessen the CD eating upon RS. We conclude that CD feeding compensates for stress reactions. However, stress-induced CD eating was only reduced by TEL after short-term, but not after long-term drug treatment. Thus, the potency of ARBs to lower HPA activity only plays a minor role in reducing energy intake to prevent obesity.


Photodynamic therapy-induced cell surface expression and release of heat shock proteins: relevance for tumor response.
Almost instantaneously after the treatment of mouse SCCVII tumor cells with Photofrin-based photodynamic therapy (PDT), a fraction (15-25%) of total cellular heat shock protein 70 (HSP70) became exposed at the cell surface. The level of this surface-expressed HSP70 then remained unchanged for the next 6 hours and persisted at lower levels even at 18 hours after PDT. A similar induction of surface HSP70 expression was found with PDT-treated human umbilical vein endothelial cells. The same analysis for several other HSPs revealed the induced surface expression of HSP60 and GRP94, but not GRP78, on PDT-treated SCCVII cells. A fraction of total HSP70 existing in SCCVII cells at the time of PDT treatment was promptly (within 1 hour) released from cells after high treatment doses, whereas even lower PDT doses induced a substantial HSP70 release at later time intervals. Macrophages coincubated with PDT-treated SCCVII cells displayed elevated levels of both HSP70 and GRP94 on their surface and were stimulated to produce tumor necrosis factor alpha, whose production was inhibited by the presence of antibodies against either HSP70, Toll-like receptors 2 and 4, or specific NF-kappaB inhibitor in the coincubation medium. The induction of cell surface expression and release of HSPs by PDT may represent an important event in the response of tumors to this treatment modality with a critical role in the induced inflammatory and immune responses that contribute to the therapeutic outcome.


Structural insights into the conformational diversity of ClpP from Bacillus subtilis.
ClpP is a cylindrical protease that is tightly regulated by Clp-ATPases. The activation mechanism of ClpP using acyldepsipeptide antibiotics as mimics of natural activators showed enlargement of the axial entrance pore for easier processing of incoming substrates. However, the elimination of degradation products from inside the ClpP chamber remains unclear since there is no exit pore for releasing these products in all determined ClpP structures. Here we report a new crystal structure of ClpP from Bacillus subtilis, which shows a significantly compressed shape along the axial direction. A portion of the handle regions comprising the heptameric ring-ring contacts shows structural transition from an ordered to a disordered state, which triggers the large conformational change from an extended to an overall compressed structure. Along with this structural change, 14 side pores are generated for product release and the catalytic triad adopts an inactive orientation. We have also determined B. subtilis ClpP inhibited by diisopropylfluoro-phosphate and analyzed the active site in detail. Structural information pertaining to several different conformational steps such as those related to extended, ADEP-activated, DFP-inhibited and compressed forms of ClpP from B. subtilis is available. Structural comparisons suggest that functionally important regions in the ClpP-family such as N-terminal segments for the axial pore, catalytic triads, and handle domains for the product releasing pore exhibit intrinsically dynamic and unique structural features. This study provides valuable insights for understanding the enigmatic cylindrical degradation machinery of ClpP as well as other related proteases such as HslV and the 20S proteasome.


The effects of root-knot nematode infection and mi-mediated nematode resistance in tomato on plant fitness.
The Mi-1.2 resistance gene in tomato (Solanum lycopersicum) confers resistance against several species of root-knot nematodes (Meloidogyne spp.). This study examined the impact of M. javanica on the reproductive fitness of near-isogenic tomato cultivars with and without Mi-1.2 under field and greenhouse conditions. Surprisingly, neither nematode inoculation or host plant resistance impacted the yield of mature fruits in field microplots (inoculum=8,000 eggs/plant), or fruit or seed production in a follow-up greenhouse bioassay conducted with a higher inoculum level (20,000 eggs/plant). However, under heavy nematode pressure (200,000 eggs/plant), greenhouse-grown plants carrying Mi-1.2 had more than ten-fold greater fruit production than susceptible plants and nearly forty-fold greater estimated lifetime seed production, confirming prior reports of the benefits of Mi-1.2. In all cases Mi-mediated resistance significantly reduced nematode reproduction. These results indicated that tomato can utilize tolerance mechanisms to compensate for moderate levels of nematode infection, but that the Mi-1.2 resistance gene confers a dramatic fitness benefit under heavy nematode pressure. No significant cost of resistance was detected in the absence of nematode infection.


A framework for community ownership of a text messaging programme to improve adherence to antiretroviral therapy and client-provider communication: a mixed methods study.
Mobile phone text messaging has been shown to improve adherence to antiretroviral therapy and to improve communication between patients and health care workers. It is unclear which strategies are most appropriate for scaling up text messaging programmes. We sought to investigate acceptability and readiness for ownership (community members designing, sending and receiving text messages) of a text message programme among a community of clients living with human immunodeficiency virus (HIV) in Yaoundé, Cameroon and to develop a framework for implementation. We used the mixed-methods sequential exploratory design. In the qualitative strand we conducted 7 focus group discussions (57 participants) to elicit themes related to acceptability and readiness. In the quantitative strand we explored the generalizability of these themes in a survey of 420 clients. Qualitative and quantitative data were merged to generate meta-inferences. Both qualitative and quantitative strands showed high levels of acceptability and readiness despite low rates of participation in other community-led projects. In the qualitative strand, compared to the quantitative strand, more potential service users were willing to pay for a text messaging service, preferred participation of health personnel in managing the project and preferred that the project be based in the hospital rather than in the community. Some of the limitations identified to implementing a community-owned project were lack of management skills in the community, financial, technical and literacy challenges. Participants who were willing to pay were more likely to find the project acceptable and expressed positive feelings about community readiness to own a text messaging project. Community ownership of a text messaging programme is acceptable to the community of clients at the Yaoundé Central Hospital. Our framework for implementation includes components for community members who take on roles as services users (demonstrating clear benefits, allowing a trial period and ensuring high levels of confidentiality) or service providers (training in project management and securing sustainable funding). Such a project can be evaluated using participation rate, clinical outcomes, satisfaction with the service, cost and feedback from users.


[Familial diabetes frequency as a factor in diabetics suffering from cancer].
Although type 2 diabetes contributes to the risk of development of certain tumors; factors which modify this relationship need to be further examined. Familial diabetes frequency was followed in (a) diabetes-free cancer patients (132), aged 60.3 +/- 1.2; (b) cancer patients with apparent (62.3 +/- 0.4; n=371) or occult type 2 diabetes (61.6 +/- 1.2; n=65) and (c) cancer-free patients with type 2 diabetes (61.8 +/- 0.4; n=237); the latter group (172 females and 65 males) featured almost identical diabetes frequencies: 30.8 +/- 3.5% and 30.8 +/- 5.7%, respectively. They significantly exceeded a relevant index occurring in families free from cancer concomitant with diabetes (6.1 +/- 2.1%). Significantly lower frequencies of familial diabetes were reported in cancer patients as compared with cancer-free patients (12.9 +/- 2.1% females, p < or = 0.01; 19.4 +/- 3.8% - males, p=0.1). To sum up, it cannot be ruled out that familial diabetes is a marker of relative decrease in potential risk of cancer rather than that of increase. The causes of this phenomenon and its possible dependence on gender need to be explored.


An improved compound Poisson model for the number of motif hits in DNA sequences.
Transcription factors play a crucial role in gene regulation by binding to specific regulatory sequences. The sequence motifs recognized by a transcription factor can be described in terms of position frequency matrices. When scanning a sequence for matches to a position frequency matrix, one needs to determine a cut-off, which then in turn results in a certain number of hits. In this paper we describe how to compute the distribution of match scores and of the number of motif hits, which are the prerequisites to perform motif hit enrichment analysis. We put forward an improved compound Poisson model that supports general order-d Markov background models and which computes the number of motif-hits more accurately than earlier models. We compared the accuracy of the improved compound Poisson model with previously proposed models across a range of parameters and motifs, demonstrating the improvement. The importance of the order-d model is supported in a case study using CpG-island sequences. The method is available as a Bioconductor package named 'motifcounter' https://bioconductor.org/packages/motifcounter. firstname.lastname@example.com. Supplementary data are available at Bioinformatics online.


Pyramidal cell axons show a local specialization for GABA and 5-HT inputs in monkey and human cerebral cortex.
Various mechanisms are thought to control excitation of pyramidal cells of the cerebral cortex. With immunocytochemical methods, we found that the proximal portions of numerous pyramidal cell axons (Pyr-axons) in the human and monkey neocortex are immunoreactive for the serotonin (5-HT) receptor 5-HT-(1A). With double-labeling experiments and confocal laser microscopy, we found that most (93.4%) of the 5-HT(1A)-immunoreactive Pyr-axons present in layers II and III were innervated by parvalbumin-immunoreactive chandelier cell axon terminals. In addition, Pyr-axons were compartmentalized: 5-HT-(1A) receptors were found proximal to inputs from chandelier cells. Although we found close appositions between GABAergic chandelier cell axon terminals and Pyr-axons, suggesting synaptic connections, we did not observe 5-HT-immunoreactive fibers in close proximity to the Pyr-axons. These results suggested that Pyr-axons are under the influence of 5-HT in a paracrine manner (via 5-HT-(1A) receptors) and, more distally, are under the influence of gamma-aminobutyric acid (GABA) in a synaptic manner (through the axons of chandelier cells). The local axonal specialization might represent a powerful inhibitory mechanism by which the responses of large populations of pyramidal cells can be globally controlled by subcortical serotonin afferents, in addition to local inputs from GABAergic interneurons.


Stability of Tringo's hierarchy of preference toward disability groups: 30 years later.
The hierarchy of preference toward disability groups was measured for 171 subjects on 16 disabilities. Results indicated that the hierarchy of preference reported by Tringo (1970) exists today despite many efforts by society to remove such stereotypes. Further, the rank-order of the hierarchy appears to be quite stable in that only individuals with cancer show an appreciable change in relative position.


Risk of Fungi Associated with Aflatoxin and Fumonisin in Medicinal Herbal Products in the Kenyan Market.
Utilization of herbal products is a major concern due to the possibility of contamination by toxigenic fungi that are mycotoxin producers such as Aspergillus species during processing and packaging. Research was carried out to determine the presence of aflatoxins and fumonisins in herbal medicinal products sold in Eldoret and Mombasa towns in Kenya. The study employed both exploratory and laboratory experimental design. The herbal products were purchased from the market and transported to Kenya Medical Research Institute for processing and analysis. Fungal contaminants were determined according to Pharmacopoeia specifications. The toxins were quantified using ELISA based technique. The genus Aspergillus was the most dominant followed by Penicillium. Fungal counts ranged between 1 CFU/g and >1000 cfu/g. Analysis of variance showed that the rate of fungal contaminants for Eldoret and Mombasa samples had significant association (p ≤ 0.001). Aflatoxin levels ranged from 1 to 24 ppb, while fumonisin levels ranged from 1 to >20 ppb. Only 31% of samples met the standards for microbial limits as specified in Pharmacopoeia. There is need for product microbial quality improvement through proper harvesting, processing, storage, and marketing. It is recommended that a policy be enacted to enable regulation of herbal products in Kenya.


An enzyme-linked immunoassay for the possible detection of non-A, non-B viral antigen in patients with epidemic viral hepatitis.
An enzyme-linked immunosorbent assay has been developed by using IgM antibodies from the acute stage as a source to capture the antigen in stools of patients with epidemic non-A, non-B (NANB) viral hepatitis. 29/69 (42.3%) of the patients and 3/9 (33.3%) contacts were positive for a suspected NANB viral antigen. However, only 1/27 (3.7%) of the negative controls drawn from amongst the patients with amoebiasis, giardiasis, hepatitis due to virus A and healthy individuals was positive for NANB antigen in the stool. The suspected NANB viral antigen was more frequently detected in stools collected between the 14th and 18th day of icteric hepatitis. The study suggests that IgM antibodies from patients with acute viral NANB hepatitis react with an antigen present in the stools of a high proportion of patients with epidemic NANB viral hepatitis. This serological test may be useful to establish the etiological diagnosis of non-A, non-B (fecal-oral) viral hepatitis. ELISA-positive stools contained 27 nm viral particles.


Delta hepatitis: molecular biology and clinical and epidemiological features.
Hepatitis delta virus, discovered in 1977, requires the help of hepatitis B virus to replicate in hepatocytes and is an important cause of acute, fulminant, and chronic liver disease in many regions of the world. Because of the helper function of hepatitis delta virus, infection with it occurs either as a coinfection with hepatitis B or as a superinfection of a carrier of hepatitis B surface antigen. Although the mechanisms of transmission are similar to those of hepatitis B virus, the patterns of transmission of delta virus vary widely around the world. In regions of the world in which hepatitis delta virus infection is not endemic, the disease is confined to groups at high risk of acquiring hepatitis B infection and high-risk hepatitis B carriers. Because of the propensity of this viral infection to cause fulminant as well as chronic liver disease, continued incursion of hepatitis delta virus into areas of the world where persistent hepatitis B infection is endemic will have serious implications. Prevention depends on the widespread use of hepatitis B vaccine. This review focuses on the molecular biology and the clinical and epidemiologic features of this important viral infection.


Pectic Bee Pollen Polysaccharide from Rosa rugosa Alleviates Diet-Induced Hepatic Steatosis and Insulin Resistance via Induction of AMPK/mTOR-Mediated Autophagy.
Despite it is used as a nutraceutical against diabetes and obesity, the mechanism of action of bee pollen is still unclear. Pectic bee pollen polysaccharide (RBPP-P) was isolated from Rosa rugosa, and its structure was characterized by 13C-NMR and Fourier transform-infrared spectroscopy (FT-IR). Using high glucose and fatty acids-treated HepG2 cells and high fat diet (HFD)-induced obesity mice, we detected its effect on insulin function and lipid metabolism based on autophagy. RBPP-P contained arabinogalactan, rhamnogalacturonan I, and homogalacturonan domains. In vivo studies demonstrated that RBPP-P markedly ameliorated insulin resistance, glucose intolerance, and liver steatosis in obese mice. The suppressive effects of RBPP-P on liver steatosis and triglyceride content were mediated by increased autophagy and lipase expression in liver. In AMPK knockdown cells (prkaa 1/2-/- MEF) and HFD-fed mice tissues (liver, gonadal white adipose, and inguinal white adipose), RBPP-P enhanced autophagy in AMPK/mTOR-dependent way in liver, but not in adipose tissue. These findings demonstrated that bee pollen polysaccharide alleviated liver steatosis and insulin resistance by promoting autophagy via an AMPK/mTOR-mediated signaling pathway, suggesting that RBPP-P could be a novel therapeutic agent used for the treatment of obesity and diabetes.


Healthspan Enhancement by Olive Polyphenols in C. elegans Wild Type and Parkinson's Models.
Parkinson's disease (PD) is the second most prevalent late-age onset neurodegenerative disorder, affecting 1% of the population after the age of about 60 years old and 4% of those over 80 years old, causing motor impairments and cognitive dysfunction. Increasing evidence indicates that Mediterranean diet (MD) exerts beneficial effects in maintaining health, especially during ageing and by the prevention of neurodegenerative disorders. In this regard, olive oil and its biophenolic constituents like hydroxytyrosol (HT) have received growing attention in the past years. Thus, in the current study we test the health-promoting effects of two hydroxytyrosol preparations, pure HT and Hidrox® (HD), which is hydroxytyrosol in its "natural" environment, in the established invertebrate model organism Caenorhabditis elegans. HD exposure led to much stronger beneficial locomotion effects in wild type worms compared to HT in the same concentration. Consistent to this finding, in OW13 worms, a PD-model characterized by α-synuclein expression in muscles, HD exhibited a significant higher effect on α-synuclein accumulation and swim performance than HT, an effect partly confirmed also in swim assays with the UA44 strain, which features α-synuclein expression in DA-neurons. Interestingly, beneficial effects of HD and HT treatment with similar strength were detected in the lifespan and autofluorescence of wild-type nematodes, in the neuronal health of UA44 worms as well as in the locomotion of rotenone-induced PD-model. Thus, the hypothesis that HD features higher healthspan-promoting abilities than HT was at least partly confirmed. Our study demonstrates that HD polyphenolic extract treatment has the potential to partly prevent or even treat ageing-related neurodegenerative diseases and ageing itself. Future investigations including mammalian models and human clinical trials are needed to uncover the full potential of these olive compounds.


Gastrodermis ultrastructure of the different life stages of the polyopisthocotylean monogenean gill parasite Discocotyle sagittata.
The polyopisthocotylean Discocotyle sagittata is a blood-feeding monogenean that infects the gill lamellae of rainbow trout, Oncorhynchus mykiss, and brown trout, Salmo trutta. The ultrastructure of their alimentary tract, at different stages of the life cycle, was previously unknown. Here, we show that the gastrodermis of the oncomiracidium, subadult, and adult D. sagittata follows the same structural organization as that of other blood-feeding polyopisthocotyleans, being composed of digestive cells alternating with a connecting syncytium. Digestive cells of the oncomiracidium are found in three developmental forms: undifferentiated, developing differentiated, and differentiated (presumably functioning) cells whereas those of adult and subadult are present in a single functioning state with variable size and content. The apical cytoplasm of adult digestive cells forms conical outgrowths, a feature which is absent in the oncomiracidium. The connecting syncytium of the oncomiracidium has no evidence of metabolic activity, while that of adult and subadult is metabolically active. The lamellae of the connecting syncytium of adults and subadults are more numerous and larger, and their terminal portions are expanded, compared with those of the oncomiracidium. Parallel, tubular, membranous structures are characteristic of the apical cytoplasm of the connecting syncytium of the oncomiracidium. Luminal lamella in the oncomiracidium, subadult, and adult form balloon-like structures enclosing some luminal contents, but those of the oncomiracidium are larger, bounded by nucleated cytoplasmic layer, and enclose more luminal contents. The possible functions of these structures and mechanism of digestion in both oncomiracidium and adult are discussed.


A Comparison and Analysis of Three Methods of Aluminum Crown Forgings in Processing Optimization.
In this study, three parameter optimization methods and two designs of experiments (DOE) were used for the optimization of three major design parameters ((bill diameter (D), billet length (L), and barrier wall design (BWD)) in crown forging to improve the formability of aluminum workpiece for shock absorbers. The first optimization method is the response surface method (RSM) combined with Box-Behnken's experimental design to establish fifteen (15) sets of parameter combinations for research. The second one is the main effects plot method (MEP). The third one is the multiobjective optimization method combined with Taguchi's experimental design method, which designed nine (9) parameter combinations and conducted research and analysis through grey relational analysis (GRA). Initially, a new type of forging die and billet in the controlled deformation zone (CDZ) was established by CAD (computer-aided design) modeling and the finite element method (FEM) for model simulation. Then, this investigation showed that the optimal parameter conditions obtained by these three optimization approaches (RSM, MEP, and multiobjective optimization) are consistent, with the same results. The best optimization parameters are the dimension of the billet ((D: 40 mm, the length of the billet (L): 205 mm, and the design of the barrier wall (BWD): 22 mm)). The results indicate that the optimization methods used in this research all have a high degree of accuracy. According to the research results of grey relational analysis (GRA), the size of the barrier wall design (BWD) in the controllable deformation zone (CDZ) has the greatest influence on the improvement of the preforming die, indicating that it is an important factor to increase the filling rate of aluminum crown forgings. At the end, the optimized parameters are verified by FEM simulation analysis and actual production validation as well as grain streamline distribution, processing map, and microstructure analysis on crown forgings. The novelty of this work is that it provides a novel preforming die through the mutual verification of different optimization methods to solve a typical problem such as material underfill.


Climate change and community fisheries in the arctic: A case study from Pangnirtung, Canada.
Coastal fishery systems in the Arctic are undergoing rapid change. This paper examines the ways in which Inuit fishers experience and respond to such change, using a case study from Pangnirtung, Canada. The work is based on over two years of fieldwork, during which semi-structured interviews (n = 62), focus group discussions (n = 6, 31 participants) and key informant interviews (n = 25) were conducted. The changes that most Inuit fishers experience are: changes in sea-ice conditions, Inuit people themselves, the landscape and the seascape, fish-related changes, and changes in weather conditions, markets and fish selling prices. Inuit fishers respond to change individually as well as collectively. Fishers' responses were examined using the characteristics of a resilience-based conceptual framework focusing on place, human agency, collective action and collaboration, institutions, indigenous and local knowledge systems, and learning. Based on results, this paper identified three community-level adaptive strategies, which are diversification, technology use and fisheries governance that employs a co-management approach. Further, this work recognised four place-specific attributes that can shape community adaptations, which are Inuit worldviews, Inuit-owned institutions, a culture of sharing and collaborating, and indigenous and local knowledge systems. An examination of the ways in which Inuit fishers experience and respond to change is essential to better understand adaptations to climate change. This study delivers new insights to communities, scientists, and policymakers to work together to foster community adaptation.


Trends in birth across high-parity groups by race/ethnicity and maternal age.
The changing racial and ethnic diversity of the U.S. population along with delayed childbearing suggest that shifts in the demographic composition of gravidas are likely. It is unclear whether trends in the proportion of births to parous women in the United States have changed over the decades by race and ethnicity, reflecting parallel changes in population demographics. Singleton deliveries > or = 20 weeks of gestation in the United States from 1989 through 2000 were analyzed using data from the "Natality data files" assembled by the National Center for Health Statistics (NCHS). We classified maternal age into three categories; younger mothers (aged < 30 years), mature mothers (30-39 years) and older mothers (> or = 40 years) and maternal race/ethnicity into three groups: blacks (non-Hispanic), Hispanics and whites (non-Hispanic). We computed birth rates by period of delivery across the entire population and repeated the analysis stratified by age and maternal race. Chi-squared statistics for linear trend were utilized to assess linear trend across three four-year phases: 1989-1992, 1993-1996 and 1997-2000. In estimating the association between race/ethnicity and parity status, the direct method of standardization was employed to adjust for maternal age. Over the study period, the total number of births to blacks and whites diminished consistently (p for trend < 0.001), whereas among Hispanics a progressive increase in the total number of deliveries was evident (p for trend < 0.001). Black and white women experienced a reduction in total deliveries equivalent to 10% and 9.3%, respectively, while Hispanic women showed a substantial increment in total births (25%). Regardless of race or ethnicity, birth rate was associated with increase in maternal age in a dose-effect fashion among the high (5-9 previous live births), very high (10-14 previous live births) and extremely high (> or = 15 previous live births) parity groups (p for trend < 0.001). After maternal age standardization, black and Hispanic women were more likely to have higher parity as compared to whites. Our findings demonstrate substantial variation in parity patterns among the main racial and ethnic populations in the United States. These results may help in formulating strategies that will serve as templates for optimizing resource allocation across the different racial/ethnic subpopulations in the United States.


Pseudomonas aeruginosa exotoxin: purification by preparative polyacrylamide gel electrophoresis and the development of a highly specific antitoxin serum.
Pseudomonas aeruginosa exotoxin has been purified to a specific activity of 12,000 to 16,000 mouse median lethal doses/mg of protein. Total recovery was about 25%, and the degree of purification was approximately 3,000-fold. Preparative polyacrylamide gel electrophoresis greatly facilitated purification. As judged by analytical disc gel electrophoresis, the purified toxin contained one major band of protein and only a negligible amount of contamination. Antiserum prepared against the purified toxin neutralized the lethal activity of crude toxin preprations and reacted by double immunodiffusion with a single component of concentrated broth cultures of P. aeruginosa isolates obtained from a clinical source.


Carboxyl-terminal mutations of Gq alpha and Gs alpha that alter the fidelity of receptor activation.
The carboxyl terminus of the G protein alpha subunit is a key determinant of the fidelity of receptor activation. We have previously shown that the Gq alpha subunit (alpha q) can be made to respond to alpha i-coupled receptors by replacing its carboxyl terminus with the corresponding alpha i2, alpha o, alpha z residues. We now extend these findings in three ways: 1) carboxyl-terminal mutations of alpha q/alpha i chimeras show that the critical amino acids are in the -3 and -4 positions, 2) exchange of carboxyl termini between alpha q and alpha z allows activation by receptors appropriate to the carboxyl-terminal residues, and 3) we identify receptors that either do or do not activate the expected carboxyl-terminal chimeras (alpha q/alpha i, alpha q/alpha s, alpha s/alpha q). Replacement of the five carboxyl-terminal amino acids of alpha q with the alpha s sequence permitted an alpha s-coupled receptor (the V2 vasopressin receptor but not the beta 2-adrenergic receptor) to stimulate phospholipase C. Replacement of the five carboxyl-terminal amino acids of alpha z with residues of alpha q permitted certain alpha q-coupled receptors (bombesin and V1a vasopressin receptors but not the oxytocin receptor) to stimulate adenylyl cyclase. Thus, the relative importance of the G alpha carboxyl terminus in permitting coupling to a new receptor depends on the receptor with which it is paired. These studies refine our understanding and provide new tools with which to study the fidelity of receptor/G alpha activation.


An optimized microarray platform for assaying genomic variation in Plasmodium falciparum field populations.
We present an optimized probe design for copy number variation (CNV) and SNP genotyping in the Plasmodium falciparum genome. We demonstrate that variable length and isothermal probes are superior to static length probes. We show that sample preparation and hybridization conditions mitigate the effects of host DNA contamination in field samples. The microarray and workflow presented can be used to identify CNVs and SNPs with 95% accuracy in a single hybridization, in field samples containing up to 92% human DNA contamination.


The interaction between the community food environment and cooking skills in association with diet-related outcomes in Dutch adults.
We examined whether associations between the food environment, frequency of home cooking, diet quality and BMI were modified by the level of cooking skills. Cross-sectional study using linear and modified Poisson regression models adjusted for age, sex, energy intake, education, income, household size and urbanisation. The frequency of home cooking was categorised into <6 and 6-7 d. Diet quality was based on a validated Dutch healthy diet index (0-150 points). Count of restaurants and food stores were determined by their count in a 1000m buffer around home and work. Cooking skills (score 1-5) were assessed using a validated questionnaire and added as interaction term. The Netherlands. 1461 adults aged 18-65 years. Count of restaurants and food stores were not associated with the frequency of home cooking. A 10-unit higher count of food stores was associated with a higher diet quality (β: 0·58 (95 % CI (0·04, 1·12)), and a 10-unit higher count of restaurants was associated with a lower BMI kg/m2 (β: -0·02 (95 % CI (-0·04, -0·004)). Better cooking skills were associated with a higher likelihood of cooking 6-7 d compared with <6 d (risk ratio: 1·24 (95 % CI (1·16, 1·31)) and a higher diet quality (β: 4·45 (95 % CI (3·27, 5·63)) but not with BMI. We observed no interaction between the food environment and cooking skills (P-for-interaction > 0·1). Exposure to food stores was associated with a higher diet quality and exposure to restaurants with a lower BMI. Better cooking skills were associated with a higher frequency of home cooking and better diet quality but did not modify associations with the food environment. Future studies should explore different approaches to understand how individuals interact with their food environment.


Pseudoachalasia as a result of metastatic cervical cancer.
Distinguishing achalasia from pseudoachalasia can be difficult, as the clinical, radiological, and manometric findings can be similar to those seen in achalasia. The features that may differentiate achalasia from pseudoachalasia are reviewed and the pathogenesis of pseudoachalasia is discussed. A patient presented with a clinical scenario of achalasia that was documented by radiographic, endoscopic, and manometric studies. Her past medical history was significant for cervical cancer. Although brief improvement in symptoms was achieved with botulinum toxin injections and esophageal dilation, she had continued progression of symptoms. This direct involvement of the esophagus by a tumor was not demonstrated by any of the routine preoperative studies. At the time of surgery, extensive involvement of the diaphragm, esophagus, and pericardium by a tumor was noted. Pathologic analysis of the tumor was consistent with metastatic cervical cancer Pseudoachalasia has been known to occur in response to both benign and malignant causes. Differentiating between pseudoachalasia and achalasia is often difficult because of the similarities. As in this case, the diagnosis of pseudoachalasia may be made by surgical exploration.


Association Analysis of Driver Gene-Related Genetic Variants Identified Novel Lung Cancer Susceptibility Loci with 20,871 Lung Cancer Cases and 15,971 Controls.
A substantial proportion of cancer driver genes (CDG) are also cancer predisposition genes. However, the associations between genetic variants in lung CDGs and the susceptibility to lung cancer have rarely been investigated. We selected expression-related single-nucleotide polymorphisms (eSNP) and nonsynonymous variants of lung CDGs, and tested their associations with lung cancer risk in two large-scale genome-wide association studies (20,871 cases and 15,971 controls of European descent). Conditional and joint association analysis was performed to identify independent risk variants. The associations of independent risk variants with somatic alterations in lung CDGs or recurrently altered pathways were investigated using data from The Cancer Genome Atlas (TCGA) project. We identified seven independent SNPs in five lung CDGs that were consistently associated with lung cancer risk in discovery (P < 0.001) and validation (P < 0.05) stages. Among these loci, rs78062588 in TPM3 (1q21.3) was a new lung cancer susceptibility locus (OR = 0.86, P = 1.65 × 10-6). Subgroup analysis by histologic types further identified nine lung CDGs. Analysis of somatic alterations found that in lung adenocarcinomas, rs78062588[C] allele (TPM3 in 1q21.3) was associated with elevated somatic copy number of TPM3 (OR = 1.16, P = 0.02). In lung adenocarcinomas, rs1611182 (HLA-A in 6p22.1) was associated with truncation mutations of the transcriptional misregulation in cancer pathway (OR = 0.66, P = 1.76 × 10-3). Genetic variants can regulate functions of lung CDGs and influence lung cancer susceptibility. Our findings might help unravel biological mechanisms underlying lung cancer susceptibility.


Anticoagulant and antiplatelet combined therapy in patients 75 years and over with atrial fibrillation: a prospective observational study assessing adherence to clinical guidelines.
According to current guidelines on atrial fibrillation (AF), the addition of an antiplatelet therapy to an anticoagulant for a stable vascular disease does not decrease the ischaemic hazard but increases the risk of bleeding. The aim of the study was to assess compliance of practices with existing clinical guidelines concerning the use of anticoagulant-antiplatelet combined therapy in patients 75 years and over with AF. This prospective observational study was carried out at the University Hospital of Strasbourg (France) between August 2016 and January 2017 with data collection on 1 day of every month. To be included, the patient had to be 75 years and over with AF and treated with anticoagulant-antiplatelet therapy. The population included all the patients admitted at the hospital excluding those from the Gynaecology-Obstetrics and Paediatrics departments. With regard to clinical ongoing guidelines (French, European, American and Canadian), the patients were sorted into three groups. Group 1: combined therapy in compliance with recommendations; Group 2: combined therapy debatable as to benefit-risk ratio; and Group 3: combined therapy not compliant with recommendations. Ninety-three out of 3307 patients 75 years and over received anticoagulant-antiplatelet combined therapy prior to their hospital admission. Thirty-two patients (34.4% - Group 1) had experienced an acute event and/or revascularisation within the past year. Twenty-four patients (25.8% - Group 2) had not experienced recent revascularisation and had stable coronary disease but were suffering from peripheral artery disease. Group 3 consisted of 37 patients (39.8%), none of which had experienced recent revascularisation or had unstable coronary disease. For all groups, the main dual therapy was acetylsalicylic acid + fluindione (59.1%). In our study, 37 antiplatelet (39.8%) treatments could have been stopped. These results should spur prescribers into regular reassessment of combination antithrombotic therapy since it contributes to polypharmacy and increases the risk of adverse events.


[The ultrasonic diagnosis of an ulnar nerve lesion in the sulcus area].
The diagnostic accuracy of ultrasound in ulnar nerve irritation syndrome was evaluated. 7 patients were examined and compared to a control group of 5 healthy persons. We correlated pathological changes with clinical signs and symptoms, nerve conduction velocity and with the operation report. Ultrasound yielded no false negative or false positive results and is therefore a valuable method for the evaluation of the ulnar nerve irritation syndrome especially in cases of vague localisation of the nerve lesion.


[Dependence of the effect of RNAase from Bacillus intermedius on the growth of baker's yeast on the concentration of the exogenous enzyme].
Bacillus intermedius RNase added at a low concentration (0.001 microgram/ml) stimulated yeast growth, while a high RNase concentration (1500 micrograms/ml) was inhibitory to yeast growth. The inhibitory effect of RNase was transient and correlated with the increase in the trehalose pool of yeast cells. The number of unbudded cells in the yeast population tended to decrease under the action of low concentrations of bacillar RNase and to increase under the action of high concentrations of this enzyme.


Programmable assembly of gold nanoparticle nanoclusters and lattices.
Deterministic assembly of metallic nanoparticles (e.g. gold nanoparticles) into prescribed configurations has promising applications in many fields such as biosensing and drug delivery. DNA-directed bottom-up assembly has demonstrated unparalleled capability to precisely organize metallic nanoparticles into assemblies of designer configurations. However, the fabrication of assemblies comprising delicate nanoparticle arrangements, especially across large dimensions (e.g. micron size), has remained challenging. In this report, we have designed DNA origami hexagon tiles that are capable of assembling into higher-order networks of honeycomb arrays or tubes with dimensions up to several microns. The versatile addressability of the unit tile enables precise and periodic positioning of nanoparticles onto these higher-order DNA origami frame structures. Overall, we have constructed a series of 9 gold nanoparticle architectures with programmable configurations ranging from nanometer-sized clusters to micrometer-sized lattices. We believe these architectures shall hold great application potential in numerous biomedical fields.


Evidence for two transferrin loci in the Salmo trutta genome.
To determine the organization of transferrin (TF) locus in the Salmo trutta genome, partial DNA and cDNA sequencing, fluorescent in situ hybridization (FISH) and Salmo salar BAC analysis were performed. TF expression levels and copy number prediction were assessed using real-time PCR. In addition to two previously reported DNA TF variant sequences of S. trutta and Salmo marmoratus (TF1), two novel variant sequences (TF2) were revealed in both species. Variant-specific sequence tags, characterizing two variants for each TF type (TF1 and TF2), were identified in genomic clones from each of the F1 hybrids between S. trutta and S. marmoratus. These clearly documented double heterozygote status at the TF loci. The real-time PCR data showed that each of the two TF types (TF1 and TF2) existed in one copy only and that the transcription of TF2 was considerably lower compared with TF1. Using FISH, hybridization signals were observed on two medium-sized acrocentric chromosomes of S. trutta karyotype. A TF type-specific PCR followed by a restriction analysis revealed the presence of two TF loci in the majority of analysed BAC clones. It was concluded that the TF gene is duplicated in the genome of S. trutta, and that the two TF loci are located adjacent to one another on the same chromosome. The differing transcription levels of TF1 and TF2 appear to depend on the corresponding promoter activity, which at least for TF2 seems to vary between different Salmo congeners.


T cell responses in the central nervous system.
T cells are required for immune surveillance of the central nervous system (CNS); however, they can also induce severe immunopathology in the context of both viral infections and autoimmunity. The mechanisms that are involved in the priming and recruitment of T cells to the CNS are only partially understood, but there has been renewed interest in this topic since the 'rediscovery' of lymphatic drainage from the CNS. Moreover, tissue-resident memory T cells have been detected in the CNS and are increasingly recognized as an autonomous line of host defence. In this Review, we highlight the main mechanisms that are involved in the priming and CNS recruitment of CD4+ T cells, CD8+ T cells and regulatory T cells. We also consider the plasticity of T cell responses in the CNS, with a focus on viral infection and autoimmunity.


Visual question answering based on local-scene-aware referring expression generation.
Visual question answering requires a deep understanding of both images and natural language. However, most methods mainly focus on visual concept; such as the relationships between various objects. The limited use of object categories combined with their relationships or simple question embedding is insufficient for representing complex scenes and explaining decisions. To address this limitation, we propose the use of text expressions generated for images, because such expressions have few structural constraints and can provide richer descriptions of images. The generated expressions can be incorporated with visual features and question embedding to obtain the question-relevant answer. A joint-embedding multi-head attention network is also proposed to model three different information modalities with co-attention. We quantitatively and qualitatively evaluated the proposed method on the VQA v2 dataset and compared it with state-of-the-art methods in terms of answer prediction. The quality of the generated expressions was also evaluated on the RefCOCO, RefCOCO+, and RefCOCOg datasets. Experimental results demonstrate the effectiveness of the proposed method and reveal that it outperformed all of the competing methods in terms of both quantitative and qualitative results.


Selection of a picomolar antibody that targets CXCR2-mediated neutrophil activation and alleviates EAE symptoms.
Receptors and their ligands are important therapeutic targets for about one third of marketed drugs. Here, we describe an epitope-guided approach for selection of antibodies that modulate cellular signaling of targeted receptors. We chose CXC chemokine receptor 2 (CXCR2) in the G-protein coupled receptor superfamily as receptor and a CXCR2 N-terminal peptide for antibody selection. We obtain a highly selective, tight-binding antibody from a 1011-member antibody library using combinatorial enrichment. Structural and Hydrogen-Deuterium-Exchange mass spectrometry analyses demonstrate antibody interaction with an N-terminal region of CXCR2 that is part of the IL-8 epitope. The antibody strongly inhibits IL-8-induced and CXCR2-mediated neutrophil chemotaxis in vitro and alleviates hCXCR2-dependent experimental autoimmune encephalomyelitis symptoms in mice. As inappropriate neutrophil migration accompanies many diseases including inflammatory bowel disease, glomerulonephritis, allergic asthma, chronic obstructive pulmonary disease, and cancer, this antibody has potential for development as a therapeutic agent, akin to anti-TNF antibodies. However, an important difference here is that the antibody targets the chemokine receptor and competes with natural ligand, rather than targeting the ligand itself.


[Surgical tactics of obturative large bowel tumor obstruction].
Results of Hartmann operation performed on tumor left colon part obturation in general hospitals. Results of 117 patients' treatment were analysed. The local tumor recurrence was registered in 17 (14,5%) cases, mean time between initial and reconstructive operations was 7,2 months. Results of 61 patients for whom the two-step treatment scheme (decompressive colostomy followed by the radical tumor resection and a simultaneous stoma closure) was used, are analyzed. Lethality rate was 1,6%. Second operation was performed in 58 patients in the mean time of 18,3 days after colostomy. 7 (12,1%) patients had early postoperative complications. Authors conclude that a two-step treatment protocol has advantages of higher radicality and the quality of life improvement.


Prevalence of suicidal behaviour and associated factors in a large sample of Chinese adolescents.
Suicidal behaviour is prevalent among adolescents and is a significant predictor of future suicide attempts (SAs) and suicide death. Data on the prevalence and epidemiological characteristics of suicidal behaviour in Chinese adolescents are limited. This study was aimed to examine the prevalence, characteristics and risk factors of suicidal behaviour, including suicidal thought (ST), suicide plan (SP) and SA, in a large sample of Chinese adolescents. This report represents the first wave data of an ongoing longitudinal study, Shandong Adolescent Behavior and Health Cohort. Participants included 11 831 adolescent students from three counties of Shandong, China. The mean age of participants was 15.0 (s.d. = 1.5) and 51% were boys. In November-December 2015, participants completed a structured adolescent health questionnaire, including ST, SP and SA, characteristics of most recent SA, demographics, substance use, hopelessness, impulsivity and internalising and externalising behavioural problems. The lifetime and last-year prevalence rates were 17.6 and 10.7% for ST in males, 23.5 and 14.7% for ST in females, 8.9 and 2.9% for SP in males, 10.7 and 3.8% for SP in females, 3.4 and 1.3% for SA in males, and 4.6 and 1.8% for SA in females, respectively. The mean age of first SA was 12-13 years. Stabbing/cutting was the most common method to attempt suicide. Approximately 24% of male attempters and 16% of female attempters were medically treated. More than 70% of attempters had no preparatory action. Female gender, smoking, drinking, internalising and externalising problems, hopelessness, suicidal history of friends and acquaintances, poor family economic status and poor parental relationship were all significantly associated with increased risk of suicidal behaviour. Suicidal behaviour in Chinese adolescents is prevalent but less than that previously reported in Western peers. While females are more likely to attempt suicide, males are more likely to use lethal methods. Multiple child and family factors are associated with suicidal behaviour. These findings highlight the importance of early screening and intervention of suicidal behaviour in Chinese adolescents.


Pulmonary metabolism of resveratrol: in vitro and in vivo evidence.
The role of pulmonary metabolism in trans-resveratrol (RES) pharmacokinetics was studied in a mouse model. Plasma concentrations of RES and its major metabolites trans-resveratrol-3-sulfate (R3S) and trans-resveratrol-3-glucuronide (R3G) were compared after administration of RES by intravenous (IV) and intra-arterial (IA) routes. Total area under the curve (AUC) of RES decreased by approximately 50% when RES was administered by the IV route compared with the IA route. The AUC of R3G was also significantly higher in mice administered RES by the IV route compared with the IA route. In vitro studies performed with mouse and human lung fractions confirmed pulmonary metabolism of RES. Interestingly, mouse-lung fractions gave rise to both R3S and R3G, whereas human lung fractions yielded R3S. This indicates marked interspecies variation in RES conjugation, especially in the context of extrapolating rodent data to humans. Taken together, the results presented here underline, for the first time, the impact of pulmonary metabolism on resveratrol pharmacokinetics and interspecies differences in RES pulmonary metabolism.


The Positive Impact of Having Served as a Danwei Leader on Post-retirement Life Satisfaction: Experiences in China.
Relevance deprivation syndrome refers to feelings of incompetence among retired people caused by them leaving their high status or influential jobs. The question then arises: do people in positions of power, like Danwei leaders in China, have a lower life satisfaction post-retirement compared to other groups? This study investigated the influence of serving as a Danwei leader before retirement on retirees' life satisfaction, as well as differences in this influence and the channels through which they are affected. Based on the data of 5,873 respondents of the 2018 China Longitudinal Aging Social Survey, ordinary least-squares, ordered logistic regression, and propensity score matching models were used to investigate the influence, differences, and influential mechanisms of serving as a Danwei leader before retirement on retirees' life satisfaction. We found that Danwei leaders experience a significantly positive impact on their life satisfaction post-retirement. Second, the positive impact of having served in this role on peoples' post-retirement life satisfaction is related to the resulting higher income, social status, and better living habits. In contrast to the perspective of relevance deprivation syndrome, in China, having been a Danwei leader before retirement has a significantly positive impact on peoples' life satisfaction post-retirement, with there being a significant difference observed among different types of retired Danwei leaders.


Liver Stiffness Measured with Two-dimensional Shear-Wave Elastography Is Predictive of Liver-related Events in Patients with Chronic Liver Disease Due to Hepatis B Viral Infection.
Background Liver stiffness measurement has been proposed as a noninvasive marker for predicting liver-related complications of cirrhosis. Purpose To evaluate the predictive value of liver stiffness measurement by using two-dimensional (2D) shear-wave elastography (SWE) for liver-related events among patients with chronic hepatitis B. Materials and Methods This retrospective study recruited consecutive patients with chronic hepatitis B who were referred for liver biopsy between May 2011 and May 2015. All patients underwent 2D SWE before biopsy, and a subset of patients underwent transient elastography. Patients were followed up for 4 years through the electronic medical records or telephone interviews. Univariable and multivariable logistic regression analyses were used to determine prognostic factors. Accuracy of prognostic parameters was evaluated by using the area under the receiver operating characteristic curve (AUC). Results Among 430 patients (mean age, 38 years; range, 18-67 years) including 328 men and 102 women, 29 patients developed liver-related events. Multivariable analysis demonstrated that liver stiffness measured with 2D SWE, spleen longitudinal diameter at US, age, and albumin level were predictive factors of liver-related events. The AUC of the multivariable model was higher (0.89; 95% confidence interval [CI]: 0.86, 0.92) but not significantly different from that of 2D SWE (0.86; 95% CI: 0.82, 0.89; P = .23) and was significantly higher than that of the fibrosis stage (0.72; 95% CI: 0.68, 0.76; P < .001), the aspartate aminotransferase-to-platelet ratio index (0.80; 95% CI: 0.76, 0.84; P < .001), and the fibrosis-4 index (0.84; 95% CI: 0.80, 0.87; P = .02). In a subset of patients with available transient elastography (n = 188), the multivariable model, 2D SWE, and transient elastography showed comparable performance (AUC: 0.91 vs 0.86 vs 0.88, respectively). When inflammatory activity was considered, the multivariable model was highly accurate in patients with low-grade inflammation and normal levels of alanine aminotransferase (AUC: 0.97 and 0.94, respectively). Conclusion The multivariable model and two-dimensional shear-wave elastography are more accurate in predicting liver-related events than are the fibrosis stage and serum markers of liver fibrosis tests. © RSNA, 2020 Online supplemental material is available for this article.


Attempts to Limit Opioid Prescribing in Critically Ill Patients: Not So Easy, Not So Fast.
To discuss why opioids have been considered the long-standing first-line therapy for treating acute, severe nociceptive pain in critically ill patients and discuss considerations for limiting opioid overuse in the intensive care unit setting. Articles were identified through searches of PubMed and EMBASE from database inception until December 2018. Additional references were located through a review of the bibliographies of articles and clinical practice guidelines. Original research articles excluding case reports were included if they concerned nonopioid agents for pain management in critically ill patients. The focus was on studies not included in the most recent pain management guidelines. Ten studies were retrieved. Nonopioid therapies or opioid-sparing therapies have been touted as possible alternatives for critically ill patients, but they have particular adverse effects concerns in critically ill patients, often lack parenteral dosage forms, and frequently require dose adjustment or avoidance in patients with renal or hepatic dysfunction. Relevance to Patient Care and Clinical Practice: There is a well-recognized opioid epidemic that has been the subject of much discussion. Attempts to control the epidemic have focused on limiting opioid prescribing and using nonopioid alternatives, but there are special considerations when treating severe pain in critically ill patients that often preclude nonopioid analgesics. There continues to be an unmet need for medications that are as effective as opioids for severe nociceptive pain in critically ill patients but without the adverse effect and abuse concerns. Until such medications are available, clinicians need to optimize prescribing of opioid and nonopioid analgesics.


YcbX and yiiM, two novel determinants for resistance of Escherichia coli to N-hydroxylated base analogues.
We have shown previously that lack of molybdenum cofactor (MoCo) in Escherichia coli leads to hypersensitivity to the mutagenic and toxic effects of N-hydroxylated base analogues, such as 6-N-hydroxylaminopurine (HAP). However, the nature of the MoCo-dependent mechanism is unknown, as inactivation of all known and putative E. coli molybdoenzymes does not produce any sensitivity. Presently, we report on the isolation and characterization of two novel HAP-hypersensitive mutants carrying defects in the ycbX or yiiM open reading frames. Genetic analysis suggests that the two genes operate within the MoCo-dependent pathway. In the absence of the ycbX- and yiiM-dependent pathways, biotin sulfoxide reductase plays also a role in the detoxification pathway. YcbX and YiiM are hypothetical members of the MOSC protein superfamily, which contain the C-terminal domain (MOSC) of the eukaryotic MoCo sulphurases. However, deletion of ycbX or yiiM did not affect the activity of human xanthine dehydrogenase expressed in E. coli, suggesting that the role of YcbX and YiiM proteins is not related to MoCo sulphuration. Instead, YcbX and YiiM may represent novel MoCo-dependent enzymatic activities. We also demonstrate that the MoCo/YcbX/YiiM-dependent detoxification of HAP proceeds by reduction to adenine.


Enteral feeding--a practical approach.
Many patients in large hospitals require nutritional support to avoid the increased morbidity and mortality associated with malnutrition. Parenteral nutrition has been used for more than fifteen years but is expensive and can be hazardous. Most hospital patients requiring nutritional support can be fed through the gastrointestinal tract. Enteral nutrition can be delivered safely and cheaply orally or by tubes temporarily implanted. We outline a simple step approach from oral nutrition using a palatable, inexpensive, chemically defined, complete diet to jejunal nutrition using an implanted feeding tube and an 'elemental' dietary supplement: oral first, enteral next, parenteral when necessary.


"Depo-all-around": A novel FIB-based TEM specimen preparation technique for solid state battery composites and other loosely bound samples.
Interfacial phenomena between active cathode materials and solid electrolytes play an important role in the function of solid-state batteries. (S)TEM imaging can give valuable insight into the atomic structure and composition at the various interfaces, yet the preparation of TEM specimen by FIB (focused ion beam) is challenging for loosely bound samples like composites, as they easily break apart during conventional preparation routines. We propose a novel preparation method that uses a frame made of deposition layers from the FIB's gas injection system to prevent the sample from breaking apart. This technique can of course be also applied to other loosely bound samples, not only those in the field of batteries.


Nano-drug delivery system targeting FAP for the combined treatment of oral leukoplakia.
Oral leukoplakia (OLK) has received much attention due to its potential risk of malignant transformation. Studies have shown that when drug therapy is combined with photothermal therapy (PTT), not only can the cytotoxicity of the drug be enhanced, but also the heat energy can be used to kill the lesion cells, so we can combine drug therapy with PTT to enhance the therapeutic effect on OLK. However, with certain drawbacks due to its lack of targeting, fibroblast activating protein (FAP) has become an attractive target for OLK combination therapy. In this study, we used NGO-PEG loaded with FAP-targeting peptide (F-TP) and celecoxib (CXB) to construct a nano-drug delivery system CGPF for targeting OLK with high FAP expression and confirmed the biocompatibility and therapeutic efficacy of CGPF by in vitro and in vivo experiments. Overall, the novel nano-drug delivery system CGPF proposed in this study showed a very significant potential for the combination therapy of OLK.


The occipital flap for reconstruction after lateral temporal bone resection.
To investigate the use of the occipital rotational flap as an alternative reconstructive technique following lateral temporal bone resection. A retrospective medical record review of 10 patients who underwent reconstruction with an occipital rotational flap after auriculectomy or lateral temporal bone resection. Patient and operative variables included age, preoperative ASA (American Society of Anesthesiologists) classification, operative time, total length of hospital stay, and use of preoperative and postoperative radiotherapy. Patient demographic characteristics and medical comorbidities were also recorded. Clinical outcomes included medical complications, minor and major wound complications, and donor site complications. Patients' mean age was 73.9 years, and mean ASA classification was 2.8. The mean operative time was 8.1 hours, and the mean length of hospital stay was 5.3 days. Three patients received preoperative radiotherapy, and 7 received postoperative radiotherapy. Two patients developed postoperative medical complications, 2 developed minor wound breakdown, and 1 developed a donor site complication. The occipital flap method is reliable and should be considered as an option for reconstruction after lateral temporal bone resection in select patients.


Structural insights into BCL2 pro-survival protein interactions with the key autophagy regulator BECN1 following phosphorylation by STK4/MST1.
BECN1/Beclin 1 is a critical protein in the initiation of autophagosome formation. Recent studies have shown that phosphorylation of BECN1 by STK4/MST1 at threonine 108 (T108) within its BH3 domain blocks macroautophagy/autophagy by increasing BECN1 affinity for its negative regulators, the anti-apoptotic proteins BCL2/Bcl-2 and BCL2L1/Bcl-xL. It was proposed that this increased binding is due to formation of an electrostatic interaction with a conserved histidine residue on the anti-apoptotic molecules. Here, we performed biophysical studies which demonstrated that a peptide corresponding to the BECN1 BH3 domain in which T108 is phosphorylated (p-T108) does show increased affinity for anti-apoptotic proteins that is significant, though only minor (<2-fold). We also determined X-ray crystal structures of BCL2 and BCL2L1 with T108-modified BECN1 BH3 peptides, but only showed evidence of an interaction between the BH3 peptide and the conserved histidine residue when the histidine flexibility was restrained due to crystal contacts. These data, together with molecular dynamics studies, indicate that the histidine is highly flexible, even when complexed with BECN1 BH3. Binding studies also showed that detergent can increase the affinity of the interaction. Although this increase was similar for both the phosphorylated and non-phosphorylated peptides, it suggests factors such as membranes could impact on the interaction between BECN1 and BCL2 proteins, and therefore, on the regulation of autophagy. Hence, we propose that phosphorylation of BECN1 by STK4/MST1 can increase the affinity of the interaction between BECN1 and anti-apoptotic proteins and this interaction can be stabilized by local environmental factors. Abbreviations: asu: asymmetric unit; BH3: BCL2/Bcl-2 homology 3; DAPK: death associated protein kinase; MD: molecular dynamics; MST: microscale thermophoresis; NMR: nuclear magnetic resonance; PDB: protein data bank; p-T: phosphothreonine; SPR: surface plasmon resonance; STK4/MST1: serine/threonine kinase 4.


The Wisconsin epidemiologic study of diabetic retinopathy. III. Prevalence and risk of diabetic retinopathy when age at diagnosis is 30 or more years.
In a population-based study in southern Wisconsin, 1,370 patients given diagnoses of diabetes at age 30 years or older were examined using standard protocols to determine the prevalence and severity of diabetic retinopathy and associated risk variables. The prevalence of diabetic retinopathy varied from 28.8% in persons who had diabetes for less than five years to 77.8% in persons who had diabetes for 15 or more years. The rate of proliferative diabetic retinopathy varied from 2.0% in persons who had diabetes for less than five years to 15.5% in persons who had diabetes for 15 or more years. By using the Cox regression model, the severity of retinopathy was found to be related to longer duration of diabetes, younger age at diagnosis, higher glycosylated hemoglobin levels, higher systolic BP, use of insulin, presence of proteinuria, and small body mass.


The Utility of Nursing Notes Among Medicare Patients With Heart Failure to Predict 30-Day Rehospitalization: A Pilot Study.
For patients with heart failure (HF), there have been efforts to reduce the risk of 30-day rehospitalization, such as developing predictive models using electronic health records. Few previous studies used clinical notes to predict 30-day rehospitalization. The aim of this study was to assess the utility of nursing notes versus discharge summaries to predict 30-day rehospitalization among patients with HF. In this pilot study, we used free-text discharge summaries and nursing notes collected from a tertiary hospital. We randomly selected 500 Medicare patients with HF. We followed the natural language processing and machine learning pipeline for data analysis. Thirty-day rehospitalization risk prediction using discharge summaries (n = 500) produced an area under the receiver operating characteristic curve of 0.74 (Bag of Words + Neural Network). Thirty-day rehospitalization risk prediction using nursing notes (n = 2046) resulted in an area under the receiver operating characteristic curve of 0.85 (Bag of Words + Neural Network). Nursing notes provide a superior input to risk models for 30-day rehospitalization in Medicare patients with HF compared with discharge summaries.


Return to sport after shoulder arthroplasty: a systematic review and meta-analysis.
With increasing incidence and indications for shoulder arthroplasty, there is an increasing emphasis on the ability to return to sports. The main goal of this study was to determine the rate of return to sport after shoulder arthroplasty. The Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines were followed to perform this systematic review and meta-analysis. A search was performed on MEDLINE, Scopus, EMBASE, and the Cochrane Library. The quality of the included studies was evaluated according to the Methodological Index for Nonrandomized Studies checklist. The main judgement outcome was the rate of return to sports activity after shoulder arthroplasty and the level of play upon return (identical or higher/lower level). Thirteen studies were reviewed, including 944 patients (506 athletes), treated with shoulder arthroplasty at an average follow-up of 5.1 years (range, 0.5-12.6 years). The most common sports were swimming (n = 169), golf (n = 144), fitness sports (n = 71), and tennis (n = 63). The overall rate of return to sport was 85.1% (95% CI, 76.5-92.3%), including 72.3% (95% CI, 60.6-82.8%) returning to an equivalent or improved level of play, after 1-36 months. Patients undergoing anatomic total shoulder arthroplasty returned at a significantly higher rate (92.6%) compared to hemiarthroplasty (71.1%, p = 0.02) or reverse total shoulder arthroplasty (74.9%, p = 0.003). Most patients are able to return to one or more sports following shoulder arthroplasty, with anatomic total shoulder arthroplasty having the highest rate of return. IV.


Investigating ethnic differences in adolescent alcohol use and peer norms using semi-continuous latent growth models.
To investigate whether ethnic differences in vulnerability to peer norms supportive of alcohol use is a viable, partial explanation for the ethnic differences in reported prevalence and amount of alcohol use during high school. Survey data from a sample of 680 adolescents from Project STAR (Students Taught Awareness and Resistance) of the Midwestern Prevention Project were used. Hypotheses were tested using sequential, semi-continuous growth curve models. Relative to Black adolescents, White adolescents reported greater peer alcohol use during middle school and were much more likely to consume alcohol during high school. General peer norms in seventh grade and middle school growth in alcohol use norms among close friends was predictive of a greater propensity to consume alcohol in ninth grade among White adolescents. Lower peer norms for alcohol use among Black adolescents might better account for differences between Black and White adolescents than the possibility that White adolescents are more vulnerable to peer norms.


Primitive boron isotope composition of the mantle.
Boron isotope ratios are homogeneous in volcanic glasses of oceanic island basalts [-9.9 +/- 1.3 per mil, relative to standard NBS 951 (defined by the National Bureau of Standards)], whereas mid-oceanic ridge basalts (MORBs) and back-arc basin basalts (BABBs) show generally higher and more variable ratios. Melts that have assimilated even small amounts of altered basaltic crust show significant variations in the boron isotope ratios. Assimilation may thus account for the higher boron ratios of MORBs and BABBs. A budget of boron between mantle and crust implies that the primitive mantle had a boron isotope ratio of -10 +/- 2 per mil and that this ratio was not fractionated significantly during the differentiation of the mantle.


What are patient navigators doing, for whom, and where? A national survey evaluating the types of services provided by patient navigators.
A nationwide cross-sectional study was conducted to assess patient navigator, patient population, and work setting characteristics associated with performance of various patient navigation (PN) tasks. Using respondent-driven sampling, 819 navigators completed a survey assessing frequency of providing 83 PN services, along with information about themselves, populations they serve, and setting in which they worked. Analyses of variance and Pearson correlations were conducted to determine differences and associations in frequency of PN services provided by various patient, navigator, and work setting characteristics. Nurse navigators and navigators with lower education provide basic navigation; social workers typically made arrangements and referrals; and individuals with higher education, social workers, and nurses provide treatment support and clinical trials/peer support. Treatment support and clinical trials/peer support are provided to individuals with private insurance. Basic navigation, arrangements and referrals, and care coordination are provided to individuals with Medicaid or no insurance. Providing basic navigation is a core competency for patient navigators. There may be two different specialties of PN, one which seeks to reduce health disparities and a second which focuses on treatment and emotional support. The selection and training of patient navigators should reflect the specialization required for a position.


Health relevance of lowering postprandial glycaemia in the paediatric population through diet': results from a multistakeholder workshop.
To summarize current knowledge and gaps regarding the role of postprandial glycaemic response in the paediatric population, a workshop was organized in June 2021 by the European branch of the International Life Science Institute (ILSI). This virtual event comprised of talks given by experts followed by in-depth discussions in breakout sessions with workshop participants. The main pre-specified topics addressed by the workshop organizing committee to the invited speakers and the workshop participants were: (1) the role of glycaemic responses for paediatric health, based on mechanistic insights from animal and human data, and long-term evidence from observational and intervention studies in paediatric populations, and (2) changes in metabolism and changes in dietary needs from infancy to adolescence. Each talk as well as the discussions were summarised, including the main identified research gaps. The workshop led to the consensus on the crucial role on health of postprandial glycaemic response in paediatric population. However, a lack of scientific data has been identified regarding detailed glucose and insulin profiles in response to foods commonly consumed by paediatric populations, as well as a lack of long-term evidence including the need for suitable predictors during childhood and adolescence to anticipate health effects during adulthood.


Limitations of nonlinear PCA as performed with generic neural networks.
Kramer's nonlinear principal components analysis (NLPCA) neural networks are feedforward autoassociative networks with five layers. The third layer has fewer nodes than the input or output layers. This paper proposes a geometric interpretation for Kramer's method by showing that NLPCA fits a lower-dimensional curve or surface through the training data. The first three layers project observations onto the curve or surface giving scores. The last three layers define the curve or surface. The first three layers are a continuous function, which we show has several implications: NLPCA "projections" are suboptimal producing larger approximation error, NLPCA is unable to model curves and surfaces that intersect themselves, and NLPCA cannot parameterize curves with parameterizations having discontinuous jumps. We establish results on the identification of score values and discuss their implications on interpreting score values. We discuss the relationship between NLPCA and principal curves and surfaces, another nonlinear feature extraction method.


Bioanalytical liquid chromatography-tandem mass spectrometry method development and validation for quantification of lurasidone in rat plasma using ion pairing agent.
A bioanalytical method was developed and validated for determining lurasidone (LUR) in rat plasma. The analyte and internal standard were extracted from rat plasma using a liquid-liquid extraction method. The mobile phase consisted of methanol, acetonitrile and water, with an ion pairing agent, 0.1% heptafluorobutyric acid, added to minimise the matrix effect. The detection was achieved using a tandem mass spectrometer (API 2000) in positive ion multiple reaction monitoring mode. All parameters were validated, including selectivity, specificity, carry-over effect, linearity, precision, accuracy, matrix effect, sensitivity and stability. The linearity range was from 5.0 to 1200.0 ng/mL with a correlation coefficient of >0.99. The accuracy ranged from 100.00% to 110.22% across the quality control range. The mean absolute recovery from matrix samples for LUR and the internal standard was found to be 68.46% and 67.25%, respectively, and the relative recovery was found to be 73.89% and 77.44%, respectively. This method can determine LUR concentrations in rat plasma samples up to 12 h after oral administration, aiding in LUR pharmacokinetic (PK) investigations in rats. The method's reproducibility on a conventional LC-MS/MS system and a shorter run time of 3.0 min make it an appealing bioanalytical method for quantifying LUR in PK studies.


The evaluation of depression, suicidal ideation and coping strategies in haemodialysis patients with renal failure.
This study aimed at evaluating depression and suicidal ideation and coping strategies with stress in patients receiving haemodialysis replacement therapy. Patients undergoing haemodialysis treatment may often experience depression and accompanying suicidal ideation. Coping strategies with depression-related suicidal ideation may require regular evaluation of the patient and the support of nurses. A cross-sectional descriptive study. The sample consisted of 92 adults with an age range of 19-65 who had chronic renal failure and consecutively admitted to the Dialysis Center of Kadiköy and Dialysis Center of Kahraman in Turkey. Four instruments were used: Socio-demographic Form, Beck Depression Inventory, Suicide Behaviors Questionnaire and Coping Strategies with Stress Inventory. The points obtained from Beck Depression Inventory were above 17 (the cut-off point) in 40·2% of the patients. There were positive correlations between depression and Suicide Behaviors Questionnaire (r = 0·469, p = 0·001), between patients' age and depression (r = 0·43, p = 0·00) and suicidal ideation (r = 0·27, p = 0·01). Depression and behavioural disengagement had a positive correlation (p = 0·001, r = 0·410). Depression and suicidal ideation increased with lower education status (F = 7·42, p = 0·001; F = 4·51, p = 0·014). Haemodialysis patients frequently experience depression. This study demonstrated that suicidal ideation increased as the severity of depression increased. Depression and suicidal ideation were increasing with age in patients with chronic renal failure. Therefore, it is considered necessary for dialysis patients to be under regular psychiatric evaluation with risk assessment. It is vitally important that nurses in dialysis centres evaluate the psychosocial conditions of patients with renal failure undergoing haemodialysis treatment so as to enhance the quality of nursing care. It is also fundamental for the success of holistic care that nurses properly assess the possibility of depression and suicide as well as coping strategies. This study sheds light on the holistic evaluations of dialysis patients.


Local and average gloss from flat-faced sodium chloride tablets.
The purpose of this study was to detect local gloss and surface structure changes of sodium chloride tablets. The changes in surface structure were reflected by gloss variation, which was measured using a diffractive optical element-based glossmeter (DOG). By scanning a surface area, we constructed a 2-dimensional gloss map that characterized the tablet's surface structure. The gloss variation results were compared with scanning electron microscopy (SEM) images and average surface roughness values that were measured by conventional diamond stylus profilometry. The profilometry data showed a decrease in tablet surface roughness as a function of compression force. In general, a smoother surface contributes to higher average gloss values. The average gloss values for this material, in contrast, showed a decrease as a function of the compression force. The sequence of particle fragmentation and deformation together with crack formation in sodium chloride particles resulted in a loss of gloss for single sodium chloride particles at the tablet surfaces, which could be detected by the DOG. These results were supported by the SEM images. The results show that detailed information regarding tablets' surface structure changes can be obtained by detection of local gloss variation and average gloss.


Allosteric activation of PP2A inhibits experimental abdominal aortic aneurysm.
Although extremely important, the molecular mechanisms that govern aortic aneurysm (AA) formation and progression are still poorly understood. This deficit represents a critical roadblock toward the development of effective pharmaceutical therapies for the treatment of AA. While dysregulation of protein phosphatase 2A (PP2A) is thought to play a role in cardiovascular disease, its role in aortic aneurysm is unknown. The objective of the present study is to test the hypothesis that PP2A regulates abdominal aortic aneurysm (AAA) progression in a murine model. In an angiotensin II-induced AAA murine model, the PP2A inhibitor, LB-100, markedly accelerated AAA progression as demonstrated by increased abdominal aortic dilation and mortality. AAA progression was associated with elevated inflammation and extracellular matrix fragmentation, concomitant with increases in both metalloproteinase activity and reactive oxygen species production. Conversely, administration of a novel class of small molecule activators of PP2A (SMAPs) resulted in an antithetical effect. SMAPs effectively reduced AAA incidence along with the corresponding pathologies that were increased with LB-100 treatment. Mechanistically, modulation of PP2A activities in vivo functioned in part via alteration of the ERK1/2 and NFκB signaling pathways, known regulators of AAA progression. These studies, for the first time, demonstrate a role of PP2A in AAA etiology and demonstrate that PP2A activation may represent a novel strategy for the treatment of abdominal aortic aneurysms.