English language proficiency and the accommodations for language non-concordance amongst patients utilizing chiropractic college teaching clinics.
The number of households in the United States that are not proficient in the English language is growing and presenting a challenge to the health care system. Over nineteen percent of the US population speak a language other than English in the home. This increase in language discordance generates a greater need to find and implement accommodations in the clinical setting to insure accurate and efficient diagnosis and treatment as well as provide for patient safety. The purpose of this study is to determine the percentage of patients accessing the chiropractic college teaching clinics who are not proficient in the English language and to what extent the colleges provide accommodations for that language disparity. The clinic directors and deans of the Association of Chiropractic Colleges were surveyed via an on-line survey engine. The survey queried the percentage of the patient population that is not English language proficient, the accommodations the college currently has in place, if the college has a language specific consent to treat document and if the college has a written policy concerning patients without English proficiency. Fifty percent of the contacted chiropractic colleges responded to the survey. In the respondent college clinics 16.5% of the patient population is not proficient in English, with over 75% speaking Spanish. All but one of the respondents provide some level of accommodation for the language non-concordance. Forty five percent of the responding colleges employ a language specific consent to treat form. The implementation of accommodations and the use of a language specific consent to treat form is more prevalent at colleges with a higher percentage of non-English speaking patients. The percentage of patients with limited English proficiency accessing services at the teaching clinics of the chiropractic colleges mirrors the numbers in the general population. There is a wide disparity in the accommodations that the individual colleges make to address this language discordance. There is a need to further develop accurate and meaningful accommodations to address language disparity in the chiropractic teaching clinics.


Preceptoring a student in the final clinical placement: reflections from nurses in a Canadian Hospital.
To capture personal reflections on being a preceptor and to identify the supports and challenges to enacting the role. Prior to graduation from a nursing programme, students begin the transition in roles from student to practicing health-care professional. To ease this transition, preceptorship programmes have been implemented to foster professional socialization and help students achieve confidence in their practice during their final clinical placement (consolidation experience). Preparation for the preceptor role is dependent upon the information offered by the agency as well as by the educational institution. Nursing staff are requested for much of the calendar year to work with increasing numbers of undergraduate students at various levels, function as preceptors in the final clinical experience (consolidation) as well as be involved in the orientation of newly hired nurses. This qualitative study used one-on-one tape recorded interviews with nurses who had previous experience as a preceptor. Thematic analysis of the transcribed data resulted in the emergence of an overall theme and categories. Eight nurses were interviewed from a variety of units including medical surgical as well as critical care. The overriding theme from the analysis was 'safe passage'. This safe passage was for the patient and the student and was accomplished through the process of teaching and a clear view of the preceptor role. Challenges to the role were lack of recognition by other nursing staff as well as limited support from some faculty advisors. Supports for the role were the visible presence and ongoing support by faculty advisors as well as the hospital workshop. This study highlighted the importance of support from nursing faculty as well as recognition by fellow nurses of the workload involved when being a preceptor. Preceptors play an important role with students prior to graduation. Both the hospital and educational institutions need to ensure that nurses are given the necessary support, recognition and resources.


Assessing the reliability of patient, nurse, and family caregiver symptom ratings in hospitalized advanced cancer patients.
The purpose of this study was to examine the reliability of symptom assessments in advanced cancer patients under various conditions, including multiple raters (patients, nurses, and family caregivers), occasions, and symptoms. The study sample consisted of 32 advanced cancer patients admitted to a tertiary palliative care unit. Symptom assessments were completed for each patient on two separate occasions, approximately 24 hours apart. On each occasion, the patient, the primary care nurse, and a primary family caregiver independently completed an assessment using the Edmonton Symptom Assessment System (ESAS). The ESAS is a nine-item visual analogue scale for assessing symptoms in palliative patients. The reliability of the assessments (r) was examined using generalizability theory. Three important findings emerged from this analysis. First, the analysis of individual symptom ratings provided a more meaningful representation of the symptom experience than total symptom distress ratings. Secondly, patients, nurses, and caregivers varied in their ratings across different patients, as well as in their ratings of shortness of breath, which may have been a result of individual rater variability. Finally, reliability estimates (r), based on a single rater and one occasion, were less than.70 for all symptoms, except appetite. These estimates improved substantially (r >/=.70) for all symptoms except anxiety and shortness of breath, using three raters on a single occasion or two raters across two occasions. The findings from this study reinforce the need for the development of an integrated symptom assessment approach that combines patient and proxy assessments. Further research is needed to explore individual differences among raters.


[Morphological characteristics and status of rRNA synthesis in mouse embryos with chromosome 19 trisomy].
The embryos with trisomy for chromosome 19 were obtained in the crosses of mice heterozygous by two different Robertsonian translocations. The development of these embryos was markedly delayed, in some of them abnormalities of the cranial region of nervous tube and the eyes were observed. The rate of 3H-uridine incorporation into 28S and 18S rRNA in the trisomic embryos both in the in vivo and in vitro experiments was decreased in 1.3-1.4 times, on the average, as compared with th control embryos. The concentration of cytoplasmic RNA in the tissue of trisomic embryos suffered no significant changes. The absence of active nucleolus-forming regions in chromosome 19 upon translocation Rb(5; 19)1Wh and the preservation of nucleolus-forming function of chromosome 19 involved in the centric fusion RB(9;19)163H were demonstrated by means of specific staining with silver nitrate. Possible causes of developmental delay of the trisomic embryos and of absence of the dose effect of ribosomal genes in them are discussed.


Urinary metabolite signatures reflect the altered host metabolism in severe obstructive sleep apnea.
Obstructive sleep apnea (OSA) is a common sleep-related breathing disorder. The onset and progression of OSA are often linked with severe cardiovascular and metabolic comorbidities. At the same time, given the increasing prevalence of OSA, novel methods to screen OSA and its follow-up are needed. Untargeted metabolic profiling of OSA patients and healthy controls was planned to capture a snapshot of urinary metabolites and potential biomarkers using the gas chromatography-mass spectrometry (GC-MS) method.Polysomnography (PSG) confirmed severe OSA patients with AHI index ≥ 30 were considered for urine sample collection. The sample size was constituted of OSA (n = 36) and healthy controls (n = 36). Metabolite extraction and derivatization were performed and metabolomic analysis was performed by using GC-MS.The obtained data set was statistically analyzed using univariate and multivariate analysis. The Orthogonal partial least-squares discriminant analysis (OPLS-DA) was performed to screen differential metabolites between OSA patients and healthy controls.The metabolomic analysis revealed a total of 142 significantly altered metabolites of interest.Biomarker analysis allows for the creation of a list of putative urinary biomarkers including GABA, malic acid, glutamic acid, epichoric acid etc., with an accuracy of 99.8 % to 100 % for OSA screening. Subsequently, pathway analysis revealed that related biochemical pathways like the tricarboxylic acid cycle (TCA), glutamate/glutamine, amino acid and fatty acid metabolism, that are significantly interlinked with these metabolic biomarkers can play a crucial role in the pathogenesis of OSA. This study paves the way to undertake mass screening in a larger population to identify specific and reliable biomarkers.


[Blood replacement in severely injured patients].
Haemorrhage remains a leading cause of early death in injured and application of concentrated RBC transfusion in the treatment of multiple injuries is the basis and potential component of saving lives. The aim of this study was to analyze the received amount reimbursed blood in patients with severe trauma, depending on the outcome, severity and mechanism of injury. Collected data on gender, age and age as the mechanism of injury, amount of blood recovered intraoperatively and during the first six days of hospitalization, which were analyzed according to outcome of treatment, ISS, AIS, and APACHE II score. Results showed that patients with lethal outcome received a larger amount of blood, there is a statistically significant correlation with ISS and AIS score for extremity injuries, and that larger amount of blood received patients injured in the traffic accidents, as pedestrians and motorcycle riders/bike, and there is no correlation with APACHE II score. Based on the importance of this topic for further research are necessary in this area in order to more accurately define indications and dosage and method of reimbursement of blood in patient with severe trauma.


Emerging issues with diagnosis and management of fungal infections in solid organ transplant recipients.
Invasive fungal infections (IFIs) are being increasingly recognized in solid organ transplant (SOT) recipients, and delayed diagnosis can lead to graft loss and death. Therefore, there is a low threshold for prophylaxis and early initiation of empiric antifungal treatment, in this patient population. Meanwhile, the increasing consumption of antifungals is associated with high cost, medication toxicities and the emergence of resistance in Candida species, all of which call for rational use of antifungal agents. The implementation of fungal biomarkers, molecular diagnostic methods and direct detection of volatile fungal metabolites in breath samples could lead to faster diagnosis, early appropriate treatment and improved clinical outcomes, but also aid in the de-escalation of antifungal treatment. Those novel diagnostic modalities need to be validated specifically in SOT recipients. Infectious diseases consultation can contribute to optimization of care through prompt initiation and appropriate modification of antifungal treatment, management of medication toxicities and drug-drug interactions, as well as source control. In this review, we conceptually summarize recent advances in the diagnosis and management of IFI in SOT recipients, and highlight the importance of early diagnostic tools and good stewardship of antifungal drugs.


STAT2-dependent restriction of Zika virus by human macrophages but not dendritic cells.
Zika virus (ZIKV) is an emerging mosquito-borne flavivirus that poses significant threats to global public health. Macrophages and dendritic cells are both key sentinel cells in the host immune response and play critical roles in the pathogenesis of flavivirus infections. Recent studies showed that ZIKV could productively infect monocyte-derived dendritic cells (moDCs), but the role of macrophages in ZIKV infection remains incompletely understood. In this study, we first compared ZIKV infection in monocyte-derived macrophages (MDMs) and moDCs derived from the same donors. We demonstrated that while both MDMs and moDCs were susceptible to epidemic (Puerto Rico) and pre-epidemic (Uganda) strains of ZIKV, virus replication was largely restricted in MDMs but not in moDCs. ZIKV induced significant apoptosis in moDCs but not MDMs. The restricted virus replication in MDMs was not due to inefficient virus entry but was related to post-entry events in the viral replication cycle. In stark contrast with moDCs, ZIKV failed to inhibit STAT1 and STAT2 phosphorylation in MDMs. This resulted in the lack of efficient antagonism of the host type I interferon-mediated antiviral responses. Importantly, depletion of STAT2 but not STAT1 in MDMs significantly rescued the replication of ZIKV and the prototype flavivirus yellow fever virus. Overall, our findings revealed a differential interplay between macrophages and dendritic cells with ZIKV. While dendritic cells may be exploited by ZIKV to facilitate virus replication, macrophages restricted ZIKV infection.


Speak, friend, and enter: signalling systems that promote beneficial symbiotic associations in plants.
Plants associate with a wide range of microorganisms, with both detrimental and beneficial outcomes. Central to plant survival is the ability to recognize invading microorganisms and either limit their intrusion, in the case of pathogens, or promote the association, in the case of symbionts. To aid in this recognition process, elaborate communication and counter-communication systems have been established that determine the degree of ingress of the microorganism into the host plant. In this Review, I describe the common signalling processes used by plants during mutualistic interactions with microorganisms as diverse as arbuscular mycorrhizal fungi and rhizobial bacteria.


Behavioral estimates of basilar-membrane compression: additivity of forward masking in noise-masked normal-hearing listeners.
Cochlear hearing loss is often associated with a loss of basilar-membrane (BM) compression, which in turn may contribute to degraded processing of suprathreshold stimuli. Behavioral estimates of compression may therefore be useful as long as they are valid over a wide range of levels and frequencies. Additivity of forward masking (AFM) may provide such a measure, but research to date lacks normative data from normal-hearing (NH) listeners at high sound levels, which is necessary to evaluate data from hearing-impaired (HI) listeners. The present study measured AFM in six NH listeners for signal frequencies of 500, 1500, and 4000 Hz in the presence of background noise, designed to elevate signal thresholds to levels similar to those experienced by HI listeners. Results consistent with compressive BM responses were found for all six listeners at 500 Hz, five listeners at 1500 Hz, but only two listeners at 4000 Hz. Further measurements in the absence of background noise also indicated a lack of consistent compression at 4000 Hz at higher signal levels, in contrast to earlier results collected at lower levels. A better understanding of this issue will be required before AFM can be used as a general behavioral estimate of BM compression.


The transcriptional landscape of endogenous retroelements delineates esophageal adenocarcinoma subtypes.
Most cancer types exhibit aberrant transcriptional activity, including derepression of retrotransposable elements (RTEs). However, the degree, specificity and potential consequences of RTE transcriptional activation may differ substantially among cancer types and subtypes. Representing one extreme of the spectrum, we characterize the transcriptional activity of RTEs in cohorts of esophageal adenocarcinoma (EAC) and its precursor Barrett's esophagus (BE) from the OCCAMS (Oesophageal Cancer Clinical and Molecular Stratification) consortium, and from TCGA (The Cancer Genome Atlas). We found exceptionally high RTE inclusion in the EAC transcriptome, driven primarily by transcription of genes incorporating intronic or adjacent RTEs, rather than by autonomous RTE transcription. Nevertheless, numerous chimeric transcripts straddling RTEs and genes, and transcripts from stand-alone RTEs, particularly KLF5- and SOX9-controlled HERVH proviruses, were overexpressed specifically in EAC. Notably, incomplete mRNA splicing and EAC-characteristic intronic RTE inclusion was mirrored by relative loss of the respective fully-spliced, functional mRNA isoforms, consistent with compromised cellular fitness. Defective RNA splicing was linked with strong transcriptional activation of a HERVH provirus on Chr Xp22.32 and defined EAC subtypes with distinct molecular features and prognosis. Our study defines distinguishable RTE transcriptional profiles of EAC, reflecting distinct underlying processes and prognosis, thus providing a framework for targeted studies.


Physiologically based pharmacokinetic modeling of a ternary mixture of alkyl benzenes in rats and humans.
The objective of the present study was to develop a physiologically based pharmacokinetic (PBPK) model for a ternary mixture of alkyl benzenes [toluene (TOL), m-xylene (XYL), and ethylbenzene (EBZ)] in rats and humans. The approach involved the development of the mixture PBPK model in the rat and extrapolation to humans by substituting rat physiological parameters and blood:air partition coefficients in the model with those of humans, scaling maximal velocity for metabolism on the basis of body weight0.75 and keeping all other model parameters species-invariant. The development of the PBPK model for the ternary mixture in the rat was accomplished by initially validating or refining the existing PBPK models for TOL, XYL, and EBZ and linking the individual chemical models via the hepatic metabolism term. Accordingly, the Michaelis-Menten equation for each solvent was modified to test four possible mechanisms of metabolic interaction (i.e., no interaction, competitive inhibition, noncompetitive inhibition, and uncompetitive inhibition). The metabolic inhibition constant (Ki) for each binary pair of alkyl benzenes was estimated by fitting the binary chemical PBPK model simulations to previously published data on blood concentrations of TOL, XYL, and EBZ in rats exposed for 4 hr to a binary combination of 100 or 200 ppm of each of these solvents. Competitive metabolic inhibition appeared to be the most plausible mechanism of interaction at relevant exposure concentrations for all binary mixtures of alkyl benzenes in the rat (Ki,TOL-XYL = 0.17; Ki,TOL-EBZ = 0.79; Ki,XYL-TOL = 0.77; Ki,XYL-EBZ = 1.50; Ki,EBZ-TOL = 0.33; Ki,EBZ-XYL = 0.23 mg/L). Incorporating the Ki values obtained with the binary chemical mixtures, the PBPK model for the ternary mixture simulated adequately the time course of the venous blood concentrations of TOL, XYL, and EBZ in rats exposed to a mixture containing 100 ppm each of these solvents. Following the validation of the ternary mixture model in the rat, it was scaled to predict the kinetics of TOL, XYL, and EBZ in blood and alveolar air of human volunteers exposed for 7 hr to a combination of 17, 33, and 33 ppm, respectively, of these solvents. Model simulations and experimental data obtained in humans indicated that exposure to atmospheric concentrations of TOL, XYL, and EBZ that remain within the permissible concentrations for a mixture would not result in biologically significant modifications of their pharmacokinetics. Overall, this study demonstrates the utility of PBPK models in the prediction of the kinetics of components of chemical mixtures, by accounting for mechanisms of binary chemical interactions.


Enhancement of plasminogen activator activity by the culture medium of Rous sarcoma virus-transformed cells.
We have tested the effect of the culture medium of chicken embryo fibroblasts (CEF) transformed by Rous sarcoma virus (RSV) on plasminogen activator (PA) activity of normal and RSV-infected cells. The results obtained showed that fibrin digestion by cultures of normal uninfected and RSV-infected cells directly attached to a fibrin substrate was increased when the cells were exposed to the supernatant of an 18 h-culture of CEF transformed by RSV. Addition of cycloheximide to the supernatant completely abolished this effect. Similarly, exposure of both normal and RSV-infected cells to the culture medium of RSV-transformed CEF resulted in a marked increase of the soluble PA activity present in the supernatant. This effect, however, was not abolished by inhibition of protein synthesis. For both the cell-bound and soluble PA activities of normal and RSV-infected cells the stimulatory effect was transient, being maximal between 8 and 12 h of exposure to the transformed cell-conditioned medium and disappearing after 24 h. A possible correlation with transformation-enhancing factor(s), previously reported to be present in the culture medium of transformed cells, is discussed.


Experiences with fecal microbiota transplantation in Clostridium difficile infections via upper gastrointestinal tract.
Dramatic changes in the epidemiology of Clostridium difficile infections have been reported from the western world in the past decade. The proportion of severe cases is significantly elevating and clinicians now have to contend with the problem of additional and more frequent episodes of recurrences including an upward trend in the mortality rate. This situation led us to investigate the possibility of the fecal microbiota transplantation (FMT). An amount of 100 ml of fecal microbiota solution was instilled into a nasojejunal (NJ) tube in 16 cases and into a nasogastric (NG) tube in 44 cases. In all of the cases, where the solution was instilled via nasojejunal tubes, the symptoms resolved within 24 h. We did not note any recurrences in this group. When the material was flushed in through nasogastric tubes, the symptoms resolved in 39 (88.64%) cases within 24 h. In this group, we have experienced a recurrent episode of C. difficile infection in five (11.36%) cases. Three of them were cured with a second transplantation. We have found that in our practice the upper gastrointestinal tract methods had the primary cure rate of 91.67%, whereas the secondary cure rate is 96.67%. When we compared the NJ and NG methods, we have found that the differences in the outcomes are not significant statistically (p = 0.3113 using Fisher's exact probability test). In conclusion, FMT proved to be very effective, particularly in recurrent infections and in cases where conventional treatment had failed.


Maturation of phagosomes is accompanied by changes in their fusion properties and size-selective acquisition of solute materials from endosomes.
Maturation of phagosomes is characterized by changes in their polypeptides, phosphorylated proteins and phospholipid composition. Kinetic analyses have shown that a variety of proteins associate and dissociate from latex-containing phagosomes at precise intervals during phagolysosome biogenesis. In an attempt to link these temporal biochemical modifications to functional changes, we have examined the in vivo fusion properties of aging endosomes and phagosomes. Using an in vivo fusion assay at the electron microscope, we measured the rate of exchange of bovine serum albumin-gold (5 and 16 nm particles) between endosomes and latex-bead-containing phagosomes. The results obtained indicate that the maturation of phagosomes is accompanied by changes of their fusion properties. Early phagosomes were shown to fuse preferentially with early endocytic organelles and to gradually acquire the ability to fuse with late endocytic organelles. Furthermore, the transfer of bovine serum albumin-gold from endosomes to phagosomes is size-dependent, a process also modulated by the maturation of these organelles, in agreement with the concept that transient fusion events occur between endosomes and phagosomes. Biochemical analysis showed variations in the levels of rab proteins associated with phagosomes during maturation while other 'fusion' proteins, including synaptobrevin1 and synaptobrevin2, remained constant.


Importance of gradients in membrane properties and electrical coupling in sinoatrial node pacing.
The sinoatrial node (SAN) is heterogeneous in terms of cell size, ion channels, current densities, connexins and electrical coupling. For example, Nav1.5 (responsible for INa) and Cx43 (responsible for electrical coupling) are absent from the centre of the SAN (normally the leading pacemaker site), but present in the periphery (at SAN-atrial muscle junction). To test whether the heterogeneity is important for the functioning of the SAN, one- and two-dimensional models of the SAN and surrounding atrial muscle were created. Normal functioning of the SAN (in terms of cycle length, position of leading pacemaker site, conduction times, activation and repolarization sequences and space constants) was observed when, from the centre to the periphery, (i) cell characteristics (cell size and ionic current densities) were changed in a gradient fashion from a central-type (lacking INa) to a peripheral-type (possessing INa) and (ii) coupling conductance was increased in a gradient fashion. We conclude that the heterogeneous nature of the node is important for its normal functioning. The presence of Nav1.5 and Cx43 in the periphery may be essential for the node to be able to drive the atrial muscle: Nav1.5 provides the necessary depolarizing current and Cx43 delivers it to the atrial muscle.


Update on hormone therapy for the management of postmenopausal women.
Hormone therapy (HT) has been used in postmenopausal women for decades in clinical practice. With further analysis and newer studies, the benefits and risks of HT have been repeatedly verified and discussed. HT is recommended for the treatment of vasomotor symptoms (VMS), genitourinary syndrome of menopause (GSM) and the prevention of osteoporosis. However, the precise association between HT and the risks of cardiovascular diseases, venous thromboembolism, neurodegenerative diseases, breast cancer, and endometrial cancer remains controversial. Therefore, determining how to take advantage of and control the risks of HT by adjusting the initiation time, regimen, and duration is crucial. Recent studies have indicated that HT is not related to the risk of all-cause, cardiovascular, or breast cancer mortality although it might increase the incidence of some chronic diseases. For symptomatic postmenopausal women under the age of 60 without contraindications, early initiation of HT is safe and probably has a mortality benefit over the long term. Initiating HT close to menopause at the lowest effective dose is more likely to have maximal benefits and the lowest risks. Transdermal and vaginal HT may have a lower risk, but recent evidence suggests additional clinical benefits of oral HT formulations in relieving VMS and preventing osteoporosis. The pooled cohort risk equation for atherosclerotic cardiovascular disease (ASCVD) and the free app named Menopro can be used to perform individual risk assessments. In addition, Chinese herbal medicines have benefits in alleviating hot flashes, depression, and menopausal symptoms, although further data are needed to strongly support their efficacy. Acupuncture and electroacupuncture have definite efficacy in the treatment of postmenopausal symptoms with few adverse effects, so they are a reasonable option as an alternative therapy for high-risk women. This review discusses the history of, guidelines on, and strategies for HT in order to make suggestions based on the most up-to-date evidence for the management of postmenopausal women.


Tissue factor-factor VIIa complex induces epithelial ovarian cancer cell invasion and metastasis through a monocytes-dependent mechanism.
Tumor-associated macrophage infiltration and up-regulation of tissue factor-factor VII (TF-FVIIa) complex have been observed in the peritoneum and stroma of epithelial ovarian cancer (EOC). However, it is not clear how tumor-associated macrophage and TF-FVIIa complex promotes EOC invasion. In the present study, we aimed to determine the mechanism by which interaction of TF-FVIIa and monocytes (MOs) promotes EOC metastasis. Matrigel invasion assay was used to analyze the potential of EOC metastasis. Enzyme-linked immunosorbent assay and real-time polymerase chain reaction were used to detect expressions of cytokines and chemokines. Fluorescence-activated cell sorting was used to count the percentage of CD14, CD68, and CD163 of MOs. We found that the TF-FVIIa complex caused dynamic changes in MOs cytokine and chemokine expression. CD14 and CD163 were also upregulated on MOs by TF-FVIIa. Epithelial ovarian cancer cells were cocultured with TF-FVIIa-stimulated MOs, demonstrating increased invasion potential. Interleukin 8 (IL-8) was proposed as the major chemoattractant mediating EOC invasion based on MOs messenger RNA and protein expression profiles. Anti-IL-8 monoclonal neutralizing antibody attenuated EOC cell invasion in a concentration-dependent manner, and tumor necrosis factor α from TF-FVIIa-stimulated MOs was observed to amplify IL-8 production. The following transcription factors in MOs were activated by TF-FVIIa and inhibited by the tissue factor pathway inhibitor: oncogenes HIF-1α, HIF-1β, Oct I, Oct II, and Egr-1; inflammatory mediators c-Fos and c-Rel; and STAT family members STAT5A and STAT5B. Our study suggested that the interaction between the TF-FVIIa complex might play a role in mediating EOC invasion and metastasis depending on MOs mechanism.


A nanocomposite hydrogel for co-delivery of multiple anti-biofilm therapeutics to enhance the treatment of bacterial biofilm-related infections.
The characteristics of biofilms have exacerbated the issue of clinical antibiotic resistance, rendering it a pressing challenge in need of resolution. The combination of biofilm-dispersing agents and antibiotics can eliminate biofilms and promote healing synergistically in infected wounds. In this study, we developed a novel nanocomposite hydrogel (NC gel) comprised of the poly(lactic acid)-hyperbranched polyglycerol (PLA-HPG) based bioadhesive nanoparticles (BNPs) and a hydrophilic carboxymethyl chitosan (CS) network. The NC gel was designed to co-deliver two biofilm-dispersing agents (an NO-donor SNO, and an α-amylase Am) and an antibiotic, cefepime (Cef), utilizing a synergistic anti-biofilm mechanism in which Am loosens the matrix structure and NO promotes the release of biofilm bacteria via quorum sensing, and Cef kills bacteria. The drug-loaded NC gel (SNO/BNP/CS@Am-Cef) demonstrated sustained drug release, minimal cytotoxicity, and increased drug-bacterial interactions at the site of infection. When applied to mice infected with methicillin-resistant Staphylococcus aureus (MRSA) biofilms in vivo, SNO/BNP/CS@Am-Cef enhanced biofilm elimination and promoted wound healing compared to traditional antibiotic treatments. Our work demonstrates the feasibility of the co-delivery of biofilm-dispersing agents and antibiotics using the NC gel and presents a promising approach for the polytherapy of bacterial biofilm-related infections.


Response of osteoblast-like cells cultured on zirconia to bone morphogenetic protein-2.
The aim of this study was to compare osteoblast behavior on zirconia and titanium under conditions cultured with bone morphogenetic protein-2. MC3T3-E1 cells were cultured on sandblasted zirconia and sandblasted/etched titanium discs. At 24 hours after seeding MC3T3-E1, the demineralized bone matrix (DBM) gel alone and the DBM gel with bone morphogenetic protein-2 (BMP-2) were added to the culture medium. The surface topography was examined by confocal laser scanning microscopy. Cellular proliferation was measured at 1, 4, and 7 days after gel loading. Alkaline phosphatase activity was measured at 7 days after gel loading. The mRNA expression of ALPase, bone sialoprotein, type I collagen, runt-related transcription factor 2 (Runx-2), osteocalcin, and osterix were evaluated by real-time polymerase chain reaction at 4 days and 7 days. At 1, 4, and 7 days after loading the DBM gel alone and the DBM gel with BMP-2, cellular proliferation on the zirconia and titanium discs was similar and that of the groups cultured with the DBM gel alone and the DBM gel with BMP-2 was not significantly different, except for titanium with BMP-2 gel. ALPase activity was higher in the cells cultured with BMP-2 than in the other groups, but there was no difference between the zirconia and titanium. In ALPase, bone sialoprotein, osteocalcin, Runx-2 and osterix gene expression, that of cells on zirconia or titanium with BMP-2 gel was much more highly increased than titanium without gel at day 7. The gene expression level of cells cultured on zirconia with BMP-2 was higher than that on titanium with BMP-2 at day 7. The data in this study demonstrate that the osteoblastic cell attachment and proliferation of zirconia were comparable to those of titanium. With the stimulation of BMP-2, zirconia has a more pronounced effect on the proliferation and differentiation of the osteoblastic cells compared with titanium.


Cyclic formation and decay of the blood-testis barrier in the mink (Mustela vison), a seasonal breeder.
The correlations between the germ cell population and the blood-testis barrier were studied during puberty and throughout the reproductive cycle in a seasonal breeder, the mink. A classification of 12 stages, corresponding to the cellular associations appearing during the cycle of the seminiferous epithelium, was proposed and used to identify the stages of the cycle in pubertal mink. In adult mink, the reproductive cycle was divided into two spermatogenic phases--an active phase lasting 9 months, and an inactive phase lasting 3 months. The active spermatogenic phase was broken down into three distinct periods: the first spermatogenic wave, the peak of spermatogenic activity, and the last spermatogenic wave. Degenerating germ cells were found in comparable and relatively low proportions during puberty and during the first and last spermatogenic waves of the adult reproductive cycle. The permeability of the blood-testis barrier to intravascularly infused electron-opaque tracers (i.e., horseradish peroxidase and lanthanum) was tested at the time of the first spermatogenic wave at puberty and throughout the reproductive cycle of the adult. The relationship between epithelial permeability and germ cell populations prevailing during puberty and during the first and last spermatogenic waves of the adult active phase was the same. During puberty, the establishment of the blood-testis barrier did not coincide with the appearance of a particular step of meiosis but was correlated with the development of a tubular lumen. In adult mink, the barrier cyclically decayed during the last wave of the active spermatogenic phase and reformed during the first wave of the next active phase. The decay and the reformation of the barrier were not coincident with the appearance or disappearance of a particular generation of the germ cell population from the seminiferous epithelium but were correlated with cyclic cytological changes in Sertoli cells and the rhythmic development and occlusion of the lumen. During the peak months of the active spermatogenic phase, however, a blood-testis barrier secluded spermatogonia and young spermatocytes from older generations of germ cells. It is concluded that during puberty and also during the first and last spermatogenic wave of the adult mink reproductive cycle, the development of germ cells is possible in the absence of a competent, impermeable blood-testis barrier, and the transient presence of a permeable epithelial barrier does not initiate an autoimmune response of sufficient magnitude to cause destruction of the seminiferous epithelium.


The role of C-4-substituted mannose analogues in protein glycosylation. Effect of the guanosine diphosphate esters of 4-deoxy-4-fluoro-D-mannose and 4-deoxy-D-mannose on lipid-linked oligosaccharide assembly.
The effects of the guanosine diphosphate esters of 4-deoxy-4-fluoro-D-mannose (GDP-4FMan) and 4-deoxy-D-mannose (GDP-4dMan) on reactions of the dolichol pathway in chick-embryo cell microsomal membranes were investigated by studies with chick-embryo cell microsomal membranes in vitro and in baby-hamster kidney (BHK) cells in vivo. Each nucleotide sugar analogue inhibited lipid-linked oligosaccharide biosynthesis in a concentration-dependent manner. GDP-4FMan blocked in vitro the addition of mannose to Dol-PP-(GlcNAc)2Man from GDP-Man (where Dol represents dolichol), but did not interfere with the formation of Dol-P-Man, Dol-P-Glc and Dol-PP-(GlcNAc)2. Although GDP-4FMan and Dol-P-4FMan were identified as metabolites of 4FMan in BHK cells labelled with [1-14C]4FMan, GDP-4FMan was a very poor substrate for GDP-Man:Dol-P mannosyltransferase and Dol-P-4FMan could only be synthesized in vitro if the chick-embryo cell membranes were primed with Dol-P. It therefore appears that the inhibition of lipid-linked oligosaccharide formation in BHK cells treated with 4FMan [Grier & Rasmussen (1984) J. Biol. Chem. 259, 1027-1030] is due primarily to a blockage in the formation of Dol-PP-(GlcNAc)2Man2 by GDP-4FMan. In contrast, GDP-4dMan was a substrate for those mannosyltransferases that catalyse the transfer of the first five mannose residues to Dol-PP-(GlcNAc)2. In addition, GDP-4dMan was a substrate for GDP-Man:Dol-P mannosyltransferase, which catalysed the formation of Dol-P-4dMan. As a consequence of this, the formation of Dol-P-Man, Dol-P-Glc and Dol-PP-(GlcNAc)2 may be inhibited through competition for Dol-P. In BHK cells treated with 10 mM-4dMan, Dol-PP-(GlcNAc)2Man9 was the major lipid-linked oligosaccharide detected. Nearly normal extents of protein glycosylation were observed, but very little processing to complex oligosaccharides occurred, and the high-mannose structures were smaller than in untreated cells.


Cognitive Functions as Predictors of Alzheimer's Disease Biomarker Status in the European Prevention of Alzheimer's Dementia Cohort.
Alterations in Alzheimer's disease (AD) biomarkers have been observed decades before the onset of dementia. Cognitive dysfunction, while central to the clinical diagnosis of AD, has long been considered as a late-stage phenomenon. This assumption is currently challenged and signals on some cognitive tests are now being observed within the preclinical stage. As part of the European Prevention of Alzheimer's Dementia (EPAD) project, a battery of cognitive tests has been proposed (the EPAD Neuropsychological Examination, ENE) which is designed to detect cognitive changes in persons without clinical signs of AD but who are at high risk. Analysis of results from the 361 participants with complete measures and without dementia recruited into the EPAD Longitudinal Cohort Study showed that the majority have elevated biomarker levels, with significant associations between an episodic verbal memory task and tau, while amyloid-β (Aβ) was associated with a central executive task. These preliminary findings suggest that profiles of cognitive performance may be specific to a given biomarker, with a primarily hippocampal task being associated with higher levels of tau and a frontal executive task being associated with higher levels of Aβ. While previous research has focused on the relationship between cognition and levels of Aβ, our findings suggest that p-tau may potentially be a more significant correlate.


[The understanding and implementation of health promotion at higher education institutions in Colombia].
Objective To characterize the implementation and understanding of health promotion at higher education institutions in Colombia. Methods A qualitative study with an ethnographic approach was carried out at eleven institutions selected in five cities. It was conducted through research tools such as an exploratory survey, interviews, direct observation and review of documents. The information was analyzed considering conceptualizations about health promotion, health settings, and health-promoting universities. Results These institutions have implemented policies and programs and have undertaken actions like education, reorientation of health services, participation and intervention on the environment, as well as research and activities with family and community outreach. Conclusion At these institutions, different scopes related to the development of health promotion were found, i.e. there was a preventive approach along with an inter-sectorial outlook with broad extent. Some of the main challenges for institutions are the training of professionals as agents of change, and fostering health promotion as a process of organizational change.


Genomic transmission clusters and circulating lineages of Mycobacterium tuberculosis among refugees residing in refugee camps in Ethiopia.
Understanding the transmission dynamics of Mycobacterium tuberculosis (Mtb) could benefit the design of tuberculosis (TB) prevention and control strategies for refugee populations. Whole Genome Sequencing (WGS) has not yet been used to document the Mtb transmission dynamics among refugees in Ethiopia. We applied WGS to accurately identify transmission clusters and Mtb lineages among TB cases in refugee camps in Ethiopia. We conducted a cross-sectional study of 610 refugees in refugee camps in Ethiopia presenting with symptoms of TB. WGS data of 67 isolates was analyzed using the Maximum Accessible Genome for Mtb Analysis (MAGMA) pipeline; iTol and FigTree were used to visualize phylogenetic trees, lineages, and the presence of transmission clusters. Mtb culture-positive refugees originated from South Sudan (52/67, 77.6%), Somalia (9/67, 13.4%). Eritrea (4/67, 6%), and Sudan (2/67, 3%). The majority (52, 77.6%) of the isolates belonged to Mtb lineage (L) 3, and one L9 was identified from a Somalian refugee. The vast majority (82%) of the isolates were pan-susceptible Mtb, and none were multi-drug-resistant (MDR)-TB. Based on the 5-single nucleotide polymorphisms cutoff, we identified eight potential transmission clusters containing 23.9% of the isolates. Contact investigation confirmed epidemiological links with either family or social interaction within the refugee camps or with neighboring refugee camps. Four lineages (L1, L3, L4, and L9) were identified, with the majority of strains being L3, reflecting the Mtb L3 dominance in South Sudan, where the majority of refugees originated from. Recent transmission among refugees was relatively low (24%), likely due to the short study period. The improved understanding of the Mtb transmission dynamics using WGS in refugee camps could assist in designing effective TB control programs for refugees.


Respiratory signal estimation for cardiac perfusion SPECT using deep learning.
Respiratory motion induces artifacts in reconstructed cardiac perfusion SPECT images. Correction for respiratory motion often relies on a respiratory signal describing the heart displacements during breathing. However, using external tracking devices to estimate respiratory signals can add cost and operational complications in a clinical setting. We aim to develop a deep learning (DL) approach that uses only SPECT projection data for respiratory signal estimation. A modified U-Net was implemented that takes temporally finely sampled SPECT sub-projection data (100 ms) as input. These sub-projections are obtained by reframing the 20-s list-mode data, resulting in 200 sub-projections, at each projection angle for each SPECT camera head. The network outputs a 200-time-point motion signal for each projection angle, which was later aggregated over all angles to give a full respiratory signal. The target signal for DL model training was from an external stereo-camera visual tracking system (VTS). In addition to comparing DL and VTS, we also included a data-driven approach based on the center-of-mass (CoM) strategy. This CoM method estimates respiratory signals by monitoring the axial changes of CoM for counts in the heart region of the sub-projections. We utilized 900 subjects with stress cardiac perfusion SPECT studies, with 302 subjects for testing and the remaining 598 subjects for training and validation. The Pearson's correlation coefficient between the DL respiratory signal and the reference VTS signal was 0.90, compared to 0.70 between the CoM signal and the reference. For respiratory motion correction on SPECT images, all VTS, DL, and CoM approaches partially de-blured the heart wall, resulting in a thinner wall thickness and increased recovered maximal image intensity within the wall, with VTS reducing blurring the most followed by the DL approach. Uptake quantification for the combined anterior and inferior segments of polar maps showed a mean absolute difference from the reference VTS of 1.7% for the DL method for patients with motion >12 mm, compared to 2.6% for the CoM method and 8.5% for no correction. We demonstrate the capability of a DL approach to estimate respiratory signal from SPECT projection data for cardiac perfusion imaging. Our results show that the DL based respiratory motion correction reduces artefacts and achieves similar regional quantification to that obtained using the stereo-camera VTS signals. This may enable fully automatic data-driven respiratory motion correction without relying on external motion tracking devices.


Inhibition of ELF3 confers synthetic lethality of PARP inhibitor in non-small cell lung cancer.
E74 Like ETS Transcription Factor 3 (ELF3) functions as a transcriptional factor to regulate non-small cell lung cancer (NSCLC) differentiation and progression. Poly(ADP-ribose) polymerase (PARP) inhibitors demonstrate anti-tumor effect in NSCLC. This study aimed to investigate whether ELF3 confers synthetic lethal with PARP inhibitor in NSCLC. The sensitivity of PARP inhibitor, Olaparib, to different NSCLC cell lines was determined by half maximal inhibitory concentration (IC50). Expression of ELF3 in NSCLC cell lines was evaluated by western blot. The effects of ELF3 on cytotoxicity of Olaparib to NSCLC were investigated by MTT (3-(4,5- di methyl thiazol -2-yl)-2,5-di phenyl tetrazolium bromide) and colony formation assays. The underlying mechanism involved in synthetic lethality with ELF3 and PARP inhibitors in NSCLC were detected by immunofluorescence and Western blot. ELF3 was up-regulated in NSCLC cell lines exhibiting resistance to PARP inhibitor, Olaparib. Knock down of ELF3 decreased the sensitivity and enhanced cytotoxicity of Olaparib to NSCLC cells. Moreover, knock down of ELF3 increased S139 phosphorylated histone H2AX (γH2AX), and inhibited homologous recombination activity via down-regulation of DNA repair protein RAD51 homolog 1 (RAD51), thus showing deficiency in DNA damage repair. Over-expression of ELF3 could up-regulate phosphorylation of AKT (Protein kinase B), while knock down of ELF3 regulated homologous recombination-mediated DNA repair via down-regulation of phosphorylation of AKT. Knock down of ELF3 revealed homologous recombination deficiency via AKT signaling pathway, and synthetic lethality with ELF3 inhibition and PARP inhibitor indicated the clinical significance of PARP inhibitor in ELF3-deficient NSCLC.


Corneal Biomechanical Parameters With Corneoscleral Contact Lenses in Post-Laser In Situ Keratomileusis Eyes.
To evaluate corneal biomechanical parameters wearing corneoscleral contact lenses (CScL) in patients with irregular corneas after laser in situ keratomileusis (LASIK). Data from patients fitted with CScL because of corneal surface irregularities after complicated LASIK surgery were selected by two eye clinics. Previously and after 1 year of CScL fitting, corneal hysteresis (CH), corneal resistance factor (CRF), corneal-compensated intraocular pressure (IOPcc), and central corneal thickness were evaluated. In addition, visual acuity, subjective comfort, and wearing time CScL were reported. The study comprised 27 eyes. Statistically significant differences were found in visual acuity between the best spectacle-corrected vision and after CScL fitting [mean±SD, 0.16±0.03 logarithm of the minimum angle of resolution (logMAR) and 0.01±0.06 logMAR, respectively; P<0.001]. In addition, the patients reported high subjective comfort ratings (22 eyes were comfortable or very comfortable) and prolonged usage times (mean±SD, 12.67±1.98 hr of continuous wear a day). Statistically significant differences were found in the CRF between before CScL fitting and after 1 year of CScL wear (mean±SD, 7.57±0.87 and 7.68±0.84 mm Hg, respectively; P=0.015). Central corneal thickness, CH, and IOPcc showed slight differences after 1 year of CScL wear (1.78 μm, 0.04 and 0.21 mm Hg, respectively). Corneal biomechanical parameters increased slightly, although significantly for CRF, apparently without adverse clinical effects in post-LASIK eyes with irregular corneas after wearing CScL for 1 year.


Treatment of patients with chronic pruritus of unknown origin with dupilumab.
Chronic pruritus of unknown origin (CPUO) is a highly debilitating disease that lacks effective treatments. This study explores a new therapeutic strategy with dupilumab. To examine whether patients with CPUO demonstrate clinical response to dupilumab. This is a retrospective case series examining all patients with CPUO who were treated with dupilumab from March 2017 to December 2019 at a tertiary referral clinic at Washington University School of Medicine in St. Louis, MO. Numerical rating scale (NRS) itch score changes over time were recorded and analyzed. Fifteen patients (67% women; mean [SD] age, 68.7 [12.6] years [range, 42-88 years]) were included in the analysis. All patients had a diagnosis of CPUO for a mean [SD] 2.6 [2.8] years. The median [IQR] pruritus NRS itch score before dupilumab injection was 8 [8-10] and the final median [IQR] NRS itch score was 1 [0-2.5]. The mean [SD] reduction in the NRS itch score was 7.0 [1.9]. Dupilumab was well tolerated with one report of mild injection site reaction that was self-resolving. This study suggests that dupilumab may be an effective treatment for patients with CPUO and supports the design of future randomized placebo-controlled trials to prove its efficacy.


Seasonal variation in blood concentrations of interleukin-6, adrenocorticotrophic hormone, metabolites of catecholamine and cortisol in healthy volunteers.
We investigated seasonal changes in blood concentrations of interleukin-6 (IL-6), adrenocorticotrophic hormone (ACTH), metabolites of catecholamine (VMA, HVA, and 5-HIAA) and cortisol in humans. Eight volunteers were investigated at four times during the year (February, May, August and October) at latitude 35 degrees N. The mean ambient temperature at the collection periods was higher in the order of summer > autumn approximately spring > winter. Changes in mood were also monitored by a profile of mood states (POMS) questionnaire. The concentration of IL-6 was significantly higher in winter and summer than in spring and autumn. The concentrations of ACTH, HVA and VMA were significantly higher in summer. No seasonal variation was detected in cortisol. There were significant differences among the seasons in subscale tension and anger in the POMS questionnaire; the tension subscale showed significant differences between spring and autumn, with a higher score in spring. The results demonstrate that Il-6, ACTH, HVA and VMA exhibit statistically significant seasonal rhythms, which might have important diagnostic and therapeutic implications.


The characterization of undecaprenol of Lactobacillus plantarum.
Evidence for the presence of undecaprenol in the unsaponifiable lipid of Lactobacillus plantarum (N.C.I.B. 6376) is presented. Characterization of the compound was based mainly on mass, i.r. and n.m.r. spectrometry. The prenol was isolated at a concentration of 40mug/g wet wt. of bacteria and contained over 90% (1.0-5.4% of the dose) of the (14)C present in the unsaponifiable lipid after incubation of the bacteria with [2-(14)C]mevalonate. N.m.r. spectrometry indicated the presence of two internal trans-, one alpha-cis- and seven internal cis-isoprene residues per molecule. The (3)H/(14)C ratios of the prenol after incubation of the bacteria with [2-(14)C,(4R)-4-(3)H(1)]- and [2-(14)C,(4S)-4-(3)H(1)]-mevalonate were in agreement with this stereochemistry. There was no evidence of saturated isoprene residues in the molecule. The undecaprenol appeared to be accompanied by much smaller quantities of decaprenol and nonaprenol.


Comparative in-vitro activity of trovafloxacin and other related drugs against isolates of streptococcus oralis.
The in-vitro activity of trovafloxacin a new quinolone was compared with that of ciprofloxacin, erythromycin, various b-lactam and other appropriate antibiotics such as vancomycin, teicoplanin and clindamycin against 60 isolates of S. oralis. Minimal inhibitory concentration was performed using the agar dilution technique and micro-titer method. In addition minimal bactericidal concentration and time-kill studies were carried out to estimate the bactericidal activity of trovafloxacin against S. oralis isolates. Trovafloxacin showed a four-fold increase in activity over ciprofloxacin, with a narrow minimal inhibitory concentration range, MIC50 and mode values of 0.25 mg/l. Although the minimal inhibitory concentrations of trovafloxacin for S.oralis were relatively high compared to all the antibiotics tested. The in-vitro bactericidal activity of Trovafloxacin was greater than all other antibiotics against S. oralis. Five out of 10 isolates showed there was a 100% kill within 6 hours of contact; in all other cases, the kill time was between 6 and 24 hours. Overall, trovafloxacin showed superior minimal inhibitory concentration, bactericidal concentration and kill time when compared with different antibiotics.


Discrepancies between echocardiographic measurements of left ventricular mass in a healthy adult population.
Increased left ventricular (LV) mass is associated with increased cardiovascular morbidity and mortality. LV mass is commonly estimated from echocardiography according to the Penn or ASE (American Society of Echocardiography) conventions. No formal statistical test of agreement between these methods has been published. Therefore we compared M-mode echocardiographic LV mass estimates by the Penn and ASE methods in a normal adult population. M-mode echocardiographic tracings were obtained in 169 healthy volunteers and used to calculate LV mass using the Penn and ASE methods. Median values of the estimates were similar [Penn, 126 g (interquartile range 96-170 g); ASE, 129 g (105-164 g); P=0.08] and were highly intercorrelated (r=0.98, P<0.0001). However, the Bland-Altman analysis of agreement revealed significant inconsistencies between Penn and ASE LV mass values. The difference between Penn and ASE values was correlated significantly with heart size (P<0.0001), such that, for small hearts, the Penn LV mass was lower than the ASE LV mass; in contrast, for large hearts, Penn estimates were greater than ASE values. In the upper 5% of the LV mass distribution, the median value for the Penn LV mass index was 132.4 g/m(2), compared with 116.5 g/m(2) for ASE values (2P=0.017). Thus the two most common methods of echocardiographic estimation of LV mass differ significantly at the upper and lower ends of the heart size distribution. These results have important implications for both cardiac research and clinical evaluation.


Cerebral critical closing pressure in hydrocephalus patients undertaking infusion tests.
Links between cerebrospinal fluid (CSF) compensation and cerebral blood flow (CBF) have been studied in many clinical scenarios. In hydrocephalus, disturbed CSF circulation seems to be a primary problem, having been linked to CBF disturbances, particularly in white matter close to surface of dilated ventricles. We studied possible correlations between cerebral haemodynamic indices using transcranial Doppler (TCD) ultrasonography and CSF compensatory dynamics assessed during infusion tests. We analysed clinical data from infusion tests performed in 34 patients suspected to suffer from normal pressure hydrocephalus, with signals including intracranial pressure (ICP), arterial blood pressure (ABP) and TCD blood flow velocity (FV). Cerebrospinal fluid compensatory parameters (including elasticity) were calculated according to a hydrodynamic model of the CSF circulation. Critical closing pressure (CrCP) was calculated with the cerebrovascular impedance methodology, while wall tension (WT) was estimated as CrCP-ICP. Closing margin (CM) was expressed as the difference between ABP and CrCP. Intracranial pressure increased during infusion from 6.7 ± 4.6 to 25.0 ± 10.5 mmHg (mean ± SD; P < 0.001), resulting in CrCP rising by 22.9% (P < 0.001) and WT decreasing by 11.3% (P = 0.005). Closing margin showed a tendency to decrease, albeit not significantly (P = 0.070) due to rising ABP (9.1%; P = 0.005). Closing margin at baseline ICP was inversely correlated to brain elasticity (R = (0.358; P = 0.038), while being significantly different from zero for the whole duration of the tests (52.8 ± 22.8 mmHg; P < 0.001). Neither CrCP nor WT was correlated with CSF compensatory parameters. Critical closing pressure increases and WT decreases during infusion tests. Closing margin at baseline pressure may act as an indicator of the cerebrospinal compensatory reserve.


Effect of Metformin, Rapamycin, and Their Combination on Growth and Progression of Prostate Tumors in HiMyc Mice.
In this study, we compared the effect of oral administration of metformin (MET) and rapamycin (RAPA) alone or in combination on prostate cancer development and progression in HiMyc mice. MET (250 mg/kg body weight in the drinking water), RAPA (2.24 mg/kg body weight microencapsulated in the diet), and the combination inhibited progression of prostatic intraepithelial neoplasia lesions to adenocarcinomas in the ventral prostate (VP). RAPA and the combination were more effective than MET at the doses used. Inhibition of prostate cancer progression in HiMyc mice by RAPA was associated with a significant reduction in mTORC1 signaling that was further potentiated by the combination of MET and RAPA. In contrast, treatment with MET alone enhanced AMPK activation, but had little or no effect on mTORC1 signaling pathways in the VP of HiMyc mice. Further analyses revealed a significant effect of all treatments on prostate tissue inflammation as assessed by analysis of the expression of cytokines, the presence of inflammatory cells and NFκB signaling. MET at the dose used appeared to reduce prostate cancer progression primarily by reducing tissue inflammation whereas RAPA and the combination appeared to inhibit prostate cancer progression in this mouse model via the combined effects on both mTORC1 signaling as well as on tissue inflammation. Overall, these data support the hypothesis that blocking mTORC1 signaling and/or tissue inflammation can effectively inhibit prostate cancer progression in a relevant mouse model of human prostate cancer. Furthermore, combinatorial approaches that target both pathways may be highly effective for prevention of prostate cancer progression in men.


Evaluation of the Anti-Aging Effects of a Probiotic Combination Isolated From Centenarians in a SAMP8 Mouse Model.
Population aging is a prominent global problem in today's society. However, there are currently no good methods to treat or prevent aging, so anti-aging research has crucial implications. In this research, we screened bacteria from centenarians, and finally selected four probiotics (Lactobacillus fermentum SX-0718, L. casei SX-1107, Bifidobacterium longum SX-1326, and B. animalis SX-0582) to form a probiotic combination. By using the senescence accelerated mouse prone 8 (SAMP8) model, the anti-aging effects of the probiotic combination were evaluated by using behavioural testing, neuroinflammation, intestinal inflammation, and intestinal microbiota. The results showed that probiotic combination improved the impaired spatial memory, motor dysfunction, and decreased exploratory behavior in aging mice. The probiotic combination inhibited Toll-like receptor 4 (TLR4)/nuclear factor kappa B (NFκB)-induced neuroinflammation and up-regulated the expression of Sirt 1 to protect hippocampal neurons. At the same time, the probiotic combination regulated the intestinal microbiota, reduced the relative abundance of Alistipes and Prevotella in SAMP8 mice, inhibited TLR4/NFκB-induced intestinal inflammation, and increased the expression of intestinal permeability related proteins zonula occludens-1 (ZO-1) and Occuldin. The anti-aging effects of the probiotic combination may be through the regulating intestinal microbiota and inhibiting TLR4/NFκB-induced inflammation. This research provides the basis and technical support for the future production and application of the probiotic combination.


Excitation Modes of Bright Matter-Wave Solitons.
We experimentally study the excitation modes of bright matter-wave solitons in a quasi-one-dimensional geometry. The solitons are created by quenching the interactions of a Bose-Einstein condensate of cesium atoms from repulsive to attractive in combination with a rapid reduction of the longitudinal confinement. A deliberate mismatch of quench parameters allows for the excitation of breathing modes of the emerging soliton and for the determination of its breathing frequency as a function of atom number and confinement. In addition, we observe signatures of higher-order solitons and the splitting of the wave packet after the quench. Our experimental results are compared to analytical predictions and to numerical simulations of the one-dimensional Gross-Pitaevskii equation.


Rapidly training African giant pouched rats (Cricetomys ansorgei) with multiple targets for scent detection.
Since 1997, APOPO, a non-profit organization based in Tanzania, has deployed African giant pouched rats (Cricetomys ansorgei) to detect landmines in post-conflict areas. More recent research suggests the pouched rats can also be trained to detect tuberculosis in human sputum samples. Despite proven success on both tasks, the potential impact of each rat is limited by the required training time and constraint to a single target odor. The aim of this project was to establish a technique to rapidly train pouched rats to detect multiple odor targets. Eight pouched rats were trained to detect five unrelated target odors in Experiment 1. In addition to training duration, we measured maintenance of all odor targets. In Experiment 2, we examined response persistence under conditions of extinction. Experiment 3 investigated whether refresher sessions before tests would maintain detection accuracy. The animals mastered all odor targets in significantly fewer sessions than APOPO's operational rats require to master a single target odor. Importantly, rats demonstrated strong discrimination between targets and non-targets despite the potential for interference and forgetting, suggesting pouched rats can be trained to detect at least five targets simultaneously. These results have the potential to increase the impact of each detection rat by both decreasing training time and expanding operational versatility, e.g., a single rat could be trained to detect multiple diseases.


SEVERE LEUKOCYTOCLASTIC VASCULITIS AFTER COVID-19 VACCINATION - CAUSE OR COINCIDENCE? CASE REPORT AND LITERATURE REVIEW.
Vaccination has been the most powerful tool to fight the COVID-19 pandemic while the specific treatment options in clinical practice have been under review for approval and authorization by regulatory bodies. After registration of different vaccines, it is important to ensure a post-marketing surveillance to identify potential risks not observed in controlled trials. Authors report on the case of an 80-year-old male patient who developed severe leukocytoclastic vasculitis of skin and oral mucous membrane after receiving the second dose of COVID-19 mRNA vaccine. He was treated successfully with prednisolone. We also provide a literature review on other reported cases of COVID-19 vaccine induced vasculitis. This type of an adverse reaction seems to be rare. Fortunately, most cases were temporary and well controlled by corticosteroids. The majority of vaccine-associated vasculitis cases have been observed in association with BONT162b2 mRNA vaccine although other vaccines also may cause the event. The knowledge of this possible adverse event is important for early diagnosis and intervention.


The European Human Biomonitoring Initiative (HBM4EU): Human biomonitoring guidance values for selected phthalates and a substitute plasticizer.
Ubiquitous use of plasticizers has led to a widespread internal exposure of the European population. Until today, metabolites are detected in almost every urine sample analysed. This raised the urgent need for a toxicological interpretation of the internal exposure levels. The European Human Biomonitoring Initiative (HBM4EU) contributes substantially to the knowledge on the actual exposure of European citizens to chemicals prioritised within HBM4EU, on their potential impact on health and on the interpretation of these data to improve policy making. On that account, human biomonitoring guidance values (HBM-GVs) are derived for the general population and the occupationally exposed population agreed at HBM4EU consortium level. These values can be used to assess phthalate exposure levels measured in HBM studies in a health risk assessment context. HBM-GVs were derived for five phthalates (DEHP, DnBP, DiBP, BBzP and DPHP) and for the non-phthalate substitute Hexamoll® DINCH. For the adult general population, the HBM-GVs for the specific metabolite(s) of the respective parent compounds in urine are the following: 0.5 mg/L for the sum of 5-oxo-MEHP and 5-OH-MEHP; 0.19 mg/L for MnBP, 0.23 mg/L for MiBP; 3 mg/L for MBzP; 0.5 mg/L for the sum of oxo-MPHP and OH-MPHP and 4.5 mg/L for the sum of OH-MINCH and cx-MINCH. The present paper further specifies HBM-GVs for children and for workers.


[Intravenous immunoglobulins in newborn infants at risk of infection. Comparative efficacy of preparations 7S and 5S].
Some reports have been published concerning the positive effects of using intravenous immunoglobulins as immunotherapy and immunoprophylaxis of infection in newborns. The safety and efficacy of intravenously administered gamma globulins 7S versus 5S was evaluated in 64 high-risk neonates. The infants admitted to this study conformed to the following criteria: birth weight less than 1800 g and gestational age less than 34 weeks; receiving intensive care. The infants were classified into two groups: one group received IgG 7S and the other IgG 5S. The incidence of infection and the mortality rate were assessed in each group. The data show that intravenous immunoglobulin infusions of both IgG 7S and IgG 5S are both safe and effective for the prophylaxis and therapy of infection in high-risk newborns.


Fetal and maternal lesions in pregnant ewes ingesting locoweed (Astragalus lentiginosus).
Locoweed (Astragalus lentiginosus) was fed to ewes from 70 to 100 days of pregnancy. Ewes were killed at 100, 115, 130, and 145 days, and selected tissues were collected from both the dam and the fetus for histologic examination. Neurovisceral cytoplasmic vacuolation and neuroaxonal dystrophy decreased in dam and fetus with time after the feeding of locoweed was discontinued.


Next-Generation Sequencing Analysis of the Within-Host Genetic Diversity of Influenza A(H1N1)pdm09 Viruses in the Upper and Lower Respiratory Tracts of Patients with Severe Influenza.
The influenza A(H1N1)pdm09 virus emerged in April 2009 with an unusual incidence of severe disease and mortality, and currently circulates as a seasonal influenza virus. Previous studies using consensus viral genome sequencing data have overlooked the viral genomic and phenotypic diversity. Next-generation sequencing (NGS) may instead be used to characterize viral populations in an unbiased manner and to measure within-host genetic diversity. In this study, we used NGS analysis to investigate the within-host genetic diversity of influenza A(H1N1)pdm09 virus in the upper and lower respiratory samples from nine patients who were admitted to the intensive care unit (ICU). A total of 47 amino acid substitution positions were found to differ between the upper and lower respiratory tract samples from all patients. However, the D222G/N substitution in hemagglutinin (HA) protein was the only amino acid substitution common to multiple patients. Furthermore, the substitution was detected only in the six samples from the lower respiratory tract. Therefore, it is important to investigate influenza A(H1N1)pdm09 virus populations using multiple paired samples from the upper and lower respiratory tract to avoid overlooking potentially important substitutions, especially in patients with severe disease.IMPORTANCE The D222G/N substitution in the hemagglutinin (HA) protein of influenza A(H1N1)pdm09 virus has been reported to be associated with disease severity and mortality in numerous previous studies. In the present study, 75% of lower respiratory samples contained heterogeneous influenza populations that carried different amino acids at position 222 of the HA protein, whereas all upper respiratory samples only contained the wild-type 222D. These results suggest the influenza A(H1N1)pdm09 virus has diversified inside the host owing to differences in tissue specificity. In this study, the within-host genetic diversity of influenza A(H1N1)pdm09 virus was investigated for the first time using next-generation sequencing analysis of the viral whole-genome in samples extracted from the upper and lower respiratory tracts of patients with severe disease.


Cholera in north Brazil: on the occurrence of strains of Vibrio cholerae O1 which fail to ferment sucrose during routine plating on thiosulphate-citrate-bile salt-sucrose agar (TCBS). A new problem in diagnosis and control?
The occurrence is recorded from a biochemical strain variant of Vibrio cholerae O1 originating from the municipality of Oiapoque, Amapá State, north Brazil and responsible for an epidemic outbreak of cholera in that region in August, 1994. The principal characteristic of the strain is its incapacity of break down sucrose on T.C.B.S. agar plates, and its delayed utilization of that sugar only after 48 hs. when cultivated in liquid medium. The strain spread rapidly in north Brazil, becoming responsible for most of the cases of cholera reported in Amazonian Brazil. The importance of this observation in laboratory diagnosis and the control of cholera is discussed.


Skin manifestations of Pseudomonas aeruginosa infections.
Pseudomonas aeruginosa is an opportunistic pathogen with considerable morbidity and mortality, particularly in vulnerable hosts. Skin manifestations are common, either representing local inoculation or secondary skin seeding following bloodstream infections. As patients with various predisposing conditions are expanding, we sought to review the most recent published evidence regarding epidemiology, risk factors and diagnosis of skin manifestations of P. aeruginosa. New data exist on epidemiology and diagnosis of skin infections; systemic infections are impacted by multidrug-resistance issues and host immune status. Green nail syndrome, toe web infection, hot tub folliculitis, hot hand-foot infection and external otitis are the most common infections originating from the skin per se. Local treatments are the cornerstone and prognosis is favorable in immunocompetent hosts. Ecthyma gangrenosum and P. aeruginosa subcutaneous nodules are usually associated with bloodstream infections and occur primarily in immunocompromised hosts. Necrotizing skin and soft tissue infections occur in diabetic, alcoholic and immunocompromised patients; management requires a multidisciplinary team with surgical approach. Burn wound infections may also be challenging, requiring a specialized team. In all the four latter types of P. aeruginosa skin infections portending significant morbidity and mortality, systemic antibiotics are an integral part of the treatment.


Hijacking transferrin bound iron: protein-receptor interactions involved in iron transport in N. gonorrhoeae.
Neisseria gonorrhoeae has the capacity to acquire iron from its human host by removing this essential nutrient from serum transferrin. The transferrin binding proteins, TbpA and TbpB constitute the outer membrane receptor complex responsible for binding transferrin, extracting the tightly bound iron from the host-derived molecule, and transporting iron into the periplasmic space of this Gram-negative bacterium. Once iron is transported across the outer membrane, ferric binding protein A (FbpA) moves the iron across the periplasmic space and initiates the process of transport into the bacterial cytosol. The results of the studies reported here define the multiple steps in the iron transport process in which TbpA and TbpB participate. Using the SUPREX technique for assessing the thermodynamic stability of protein-ligand complexes, we report herein the first direct measurement of periplasmic FbpA binding to the outer membrane protein TbpA. We also show that TbpA discriminates between apo- and holo-FbpA; i.e. the TbpA interaction with apo-FbpA is higher affinity than the TbpA interaction with holo-FbpA. Further, we demonstrate that both TbpA and TbpB individually can deferrate transferrin and ferrate FbpA without energy supplied from TonB resulting in sequestration by apo-FbpA.


Afferent and efferent innervation of the cat cochlea: quantitative analysis with light and electron microscopy.
The purpose of the present study was to describe the longitudinal and radial gradients of cochlear innervation in the cat. To this end, afferent and efferent terminals of both the inner (IHC) and outer hair cell (OHC) regions were reconstructed from serial ultrathin sections at six and eight cochlear locations, respectively, corresponding to roughly octave intervals of characteristic frequency (CF). Analysis of the afferent innervation of the IHCs showed 1) the number of radial fibers per IHC rises from 10 per IHC at the 0.25 kHz region to a maximum of 30 per IHC at the 10 kHz locus; 2) branching of radial fibers is essentially restricted to regions apical to the 1.0 kHz point; and 3) there are significant differences in synaptic-body morphology for synapses on different sides of the IHC, corresponding to known differences in afferent threshold and rate of spontaneous activity. With respect to efferent innervation in the IHC area, we found 1) that there were numerous vesicle-filled terminals contacting every IHC examined; however, those with obvious synaptic specialization were confined to the most apical regions; and 2) there were roughly the same numbers of efferent synapses per radial fiber at all cochlear locations; however, at each location, radial fibers contacting the modiolar side of the hair cell (corresponding to high-threshold afferents) showed significantly more efferent synapses than radial fibers contacting the pillar side. Analysis of the OHC afferent innervation showed 1) a clear rise in numbers of terminals per OHC from roughly 3 per cell in the base to 15 per cell in the apex, 2) no systematic differences in the numbers of terminals as a function of OHC row, and 3) that synaptic bodies at the OHC afferent synapse are common only apical to the 1.0 kHz locus. Counts of efferent terminals on OHCs revealed 1) maximal numbers (9 per OHC) between the 6 and 24 kHz regions and 2) striking decrease in terminal counts from first- to third-row OHCs. Ultrastructural data on efferent innervation were compared quantitatively with light-microscopic analysis of cochleas immunostained (with antibody to synaptophysin) to reveal all vesiculated terminals.


The value of maternity care in Queensland, 2012-18, based on an analysis of administrative data: a retrospective observational study.
To quantify the value of maternity health care - the relationship of outcomes to costs - in Queensland during 2012-18. Retrospective observational study; analysis of Queensland Perinatal Data Collection data linked with the Queensland Health Admitted Patient, Non-Admitted Patient, and Emergency Data Collections, and with the Medicare Benefits Schedule (MBS) and Pharmaceutical Benefits Scheme (PBS) databases. All births in Queensland during 1 July 2012 - 30 June 2018. Maternity care costs per birth (reported in 2021-22 Australian dollars), both overall and by funder type (public hospital funders, MBS, PBS, private health insurers, out-of-pocket costs); value of care, defined as total cost per positive birth outcome (composite measure). The mean cost per birth (all funders) increased from $20 471 (standard deviation [SD], $17 513) during the second half of 2012 to $30 000 (SD, $22 323) during the first half of 2018; the annual total costs for all births increased from $1.31 billion to $1.84 billion, despite a slight decline in the total number of births. In a mixed effects linear analysis adjusted for demographic, clinical, and birth characteristics, the mean total cost per birth in the second half of 2018 was $9493 higher (99.9% confidence interval, $8930-10 056) than during the first half of 2012. The proportion of births that did not satisfy our criteria for a positive birth outcome increased from 27.1% (8404 births) during the second half of 2012 to 30.5% (9041 births) during the first half of 2018. The costs of maternity care have increased in Queensland, and many adverse birth outcomes have become more frequent. Broad clinical collaboration, effective prevention and treatment strategies, as well as maternal health services focused on all dimensions of value, are needed to ensure the quality and viability of maternity care in Australia.


Reinnervation of denervated parasympathetic neurones in cardiac ganglia from Rana pipiens.
1. The sequence of events during reinnervation of the cardiac ganglion in the frog following interruption of the vagosympathetic nerve supply was studied with both electrophysiological and morphological techniques. 2. When cardiac ganglia were denervated by crushing the vagosympathetic nerve supply to the heart all synaptic endings on parasympathetic ganglion cells degenerated. Vacated post-synaptic densities were detected on denervated neurones for periods of at least 7 weeks. 3. The earliest signs of reinnervation were subthreshold responses evoked by stimulating the regenerating vagosympathetic trunks 2 1/2-3 weeks after crushing the cardiac branches of the vagus nerves. Analysis of the reversal potentials of these responses indicated that these synapses were distant from the cell body. 4. At slightly longer times (4-5 weeks), regenerating synapses could be recognized on post-ganglionic axons; no synapses were detected on the neuronal perikarya at these times. 5. By 6-7 weeks following denervation, vagal synapses reinnervated neuronal perikarya as well as post-ganglionic axons. At the same time, vacated post-synaptic densities declined in number. Furthermore, vagal stimulation at this stage evoked large, suprathreshold post-synaptic potentials. 6. These studies indicate that post-ganglionic axons are the initial sites for reinnervation of parasympathetic neurones in the heart. Only some time later are neuronal perikarya reinnervated and ganglionic transmission completely restored.


Field Trial of Primary and Booster Dose of Inactivated Vaccine Against Bovine Respiratory Bacteria in Young Holstein Calves.
The objective of this research was to evaluate the antibody response to multiple doses of an inactivated mixed vaccine against Histophilus somni, Pasteurella multocida, and Mannheimia haemolytica, and to investigate the influence of age at time of vaccination in the field. Healthy female Holstein calves received the vaccine at the age of 5-12 days and 2, 3, or 4 weeks later in the first experiment or at 1, 2, or 3 weeks of age and 4 weeks later in the second. Blood samples were collected at each vaccination and 3 weeks after the booster dose. Based on the antibody titres after the vaccinations, calves were divided into positive and negative groups for each of the bacteria. Calves in the control group were vaccinated only once at the age of 19-26 days. Antibody titres against H. somni and P. multocida were significantly increased by the booster. After the second vaccinations, the titres against each bacterium were higher than those of the control group, and the M. haemolytica-positive percentage in calves with high maternal antibody levels (MAL) exceeded that in calves with low MAL. In the first experiment, a majority of the M. haemolytica-positive calves tended to have received the primary dose at seven days of age or older. A booster dose of the inactivated bacterial vaccine in young Holstein calves increased antibody production and overcame the maternal antibodies. Calves should be vaccinated first at seven days of age or older.


Biomechanical Analysis of Zone 2 Flexor Tendon Repair With a Coupler Device Versus Locking Cruciate Core Suture.
To compare flexor tendon repair strength and speed between a tendon coupler and a standard-core suture in a cadaver model. In 5 matched-pair fresh cadaver hands, we cut the flexor digitorum profundus tendon of each finger in zone 2 and assigned 20 tendons to both the coupler and the suture groups. Coupler repair was with low-profile stainless steel staple plates in each tendon stump, bridged by polyethylene thread. Suture repair was performed using an 8-strand locking-cruciate technique with 4-0 looped, multifilament, polyamide suture. One surgeon with the Subspecialty Certificate in Surgery of the Hand performed all repairs. Via a load generator, each flexor digitorum profundus was loaded at 5 to 10 N and cycled through flexion just short of tip-to-palm and full extension at 0.2 Hz for 2,000 cycles to simulate 6 weeks of rehabilitation. We recorded repair gapping at predetermined cycle intervals. Our primary outcome was repair gapping at 2,000 cycles. Tendons that had not catastrophically failed by 2,000 cycles were loaded to failure on a servohydraulic frame at 1 mm/s. Tendon repair gapping was similar between coupled and sutured tendons at 2,000 cycles. Tendons repaired with the coupler had higher residual load to failure than sutured tendons. Mean coupler repair time was 4 times faster than suture repair. Zone 2 flexor repair with a coupler withstood simulated early active motion in fresh cadavers. Residual load to failure and repair speed were better with the coupler. This tendon coupler may eventually be an option for strong, reproducible, rapid flexor tendon repair.


A generalized canine transfer function accurately reconstructs central aortic pressure waveforms to enable enhanced pulse wave analysis.
Routine preclinical blood pressure evaluation is an important risk assessment tool. Although proximal aortic pressure is most relevant for key target organs, abdominal aortic pressures are more commonly recorded. Pulse pressure amplification and waveform distortion in abdominal waveforms make it inappropriate for central hemodynamic analytical methods without the use of a mathematical transfer function. Clinical transfer functions have been developed to estimate ascending aortic waveforms from brachial or radial artery waveforms in humans, but no preclinical analogues exist. The aim of this study was to develop a canine-specific transfer function to reconstruct thoracic aortic pressure waveforms from abdominal aortic data to enable the application of central hemodynamic analytical methods. Simultaneous abdominal and thoracic blood pressures were recorded from seven conscious, male beagle dogs administered 3 well-characterized pharmacologic standards and animals were appointed to a training (n = 3) or validation (n = 4) group at baseline and during dosing. A generalized transfer function was developed from the training group data and evaluated for its ability to synthesize thoracic pressure waves in the training and validation groups. Select hemodynamic parameters were evaluated in measured and synthesized thoracic data. There was a high degree of correlation between measured and synthesized thoracic parameters (r2 = 0.74-0.99). There was no difference between indices computed from synthesized or actual thoracic waveforms at baseline or after administration of pharmacologic standards. This work demonstrates that a generalized preclinical transfer function can reproduce thoracic pressure waves across a range of hemodynamic responses thus enabling the application of central hemodynamic analytical methods.


Variability of functional characteristics of MDCK cells.
We measured several functional parameters of MDCK cells cultured as monolayers in order to more fully characterize their ion transport properties. Most of the present studies were completed with five groups (A-E) of MDCK cells studied from passage 62 to 78. Each group represents the same subline of MDCK cells after having been frozen, stored, and thawed at passage 62 or 64. The median transmonolayer resistances of the groups were 507, 149, 284, 72, and 126 omega X cm2. Addition of amphotericin B to the apical solution induced a oubain-sensitive transepithelial current. The apical membrane voltage and fractional resistance exhibited a wide range of values in two of the groups studied, with mean values of -32 mV and 0.68 in group B and -40 mV and 0.78 in group E. Neither apical nor basolateral membrane displayed significant Na+ conductance. K+ conductance was present in the basolateral but not in the apical membrane. Acidification or alkalinization of the apical solution was dependent on the conditions used to study the cells. The 4,4'-diisothyocyano-2,2'-disulfonic stilbene inhibited acidification (or induced alkalinization), whereas increasing ambient HCO-3 concentration induced alkalinization. The results of these studies indicate qualitatively similar behavior between five groups of MDCK cells but significant quantitative differences between the groups. Analysis of the variability of the measured parameters indicated that there were no differences as a function of passage number within a group. The factors responsible for functional differences between groups are not known but may be related to the cell storage process.


A male-specific fatty acid omega-hydroxylase, SXE1, is necessary for efficient male mating in Drosophila melanogaster.
In Drosophila, sexual differentiation, physiology, and behavior are thought to be mediated by numerous male- and female-specific effector genes whose expression is controlled by sex-specifically expressed transcriptional regulators. One such downstream effector gene, sex-specific enzyme 1 (sxe1, cyp4d21), has been identified in a screen for genes with sex-biased expression in the head. Sxe1 was also identified in another screen as a circadian regulated gene. Here, we analyzed the spatial and temporal regulation of sxe1 and identified a function for this gene in male courtship. We show that male-specific transcriptional regulator DSX(M) and the clock genes are necessary for cycling of sxe1 mRNA during the diurnal cycle. Similar to sxe1 mRNA, expression of SXE1 protein oscillates in a diurnal fashion, with highest protein levels occurring around midnight. SXE1 protein expression is restricted to nonneuronal cells associated with diverse sensory bristles of both the chemo- and mechanosensory systems. Suppression or knockout of sxe1 significantly reduces mating success throughout the diurnal cycle. Finally, the metabolomic profile of wild-type and sxe1 mutant males revealed that sxe1 likely functions as a fatty acid omega-hydroxylase, suggesting that male courtship and mating success is mediated by small compounds generated by this enzyme.


Out-of-school lives of physically disabled children and young people in the United Kingdom: a qualitative literature review.
Currently there appears to be few opportunities and little evidence of physically disabled children and young people (C&YP) participating in mainstream social activities. A qualitative review was undertaken to examine the factors affecting physically disabled C&YP (8-15 years) in the United Kingdom participating in out-of-school activities. Views and experiences were explored from the perspective of the service users and providers to assess current provision and to determine the need for future research into factors that may affect participation. Searches were conducted across eight databases, the references of the included studies were checked and the websites were searched. Studies that used a qualitative design that examined the views relating to out-of-school activities were included. Nine papers were identified, which included three peer-reviewed papers and six pieces of grey literature and pertinent government documents to include views and experiences of out-of-school activity provision. The main themes emerging from the review were the need for social inclusion, out-of-school activities run by volunteers and accessibility, with threads throughout, which require further research including parental influence, provision, training and attitudes. This review highlights the absence of the service user's voice and sheds light on the limited provision and barriers affecting participation in out-of-school activities.


A new method for correcting under-estimation of disabled life expectancy and an application to the Chinese oldest-old.
This article demonstrates that disabled life expectancies that are based on conventional multistate life-table methods are significantly underestimated because of the assumption of no changes in functional status between age x and death. We present a new method to correct the bias and apply it to data from a longitudinal survey of about 9,000 oldest-old Chinese aged 80-105 collected in 1998 and 2000. In our application, the age trajectories of disability (activities of daily living--ADL), status-specific death rates, and the probabilities of transitions between ADL states of the oldest-old were investigated for the first time in a developing country. In this article, we report estimates of bias-corrected disabled and active life expectancies of the Chinese oldest-old and demonstrate patterns of large differences associated with initial status, gender, and advances in ages. Using combined information on ADL disabilities and length of having been bedridden before dying, we analyze gender and age patterns of the extent of morbidity before dying among the oldest-old and their implications for debates on the hypothesis of compression of morbidity.


Absence of hereditary p53 mutations in 10 familial leukemia pedigrees.
Germline p53 mutations have been identified in the Li-Fraumeni syndrome but the role of such mutations in familial leukemia is not established. The p53 gene was examined by single-strand conformation polymorphism analysis of exons 4-8 in 10 families with multiple members affected with leukemia. The diagnoses included acute and chronic leukemias and Hodgkin's disease. Identified in two families were p53 mutations that were nonhereditary. These included a 2-bp deletion in exon 6 found in the lymphoblast DNA of one child whose sibling, cousin, and several adult relatives had acute leukemia. The other nonhereditary p53 mutation was a transition at codon 248 (CGG to CAG, arginine to glutamine) found in the lymphoblasts of a patient with a preleukemic syndrome and acute lymphoblastic leukemia (ALL) whose brother is a long-term survivor of ALL. Thus, p53 mutations were found to occur in two families but both were nonhereditary. Moreover, in the remaining eight families no p53 mutation was identified in the regions of p53 where most mutations have been found in other cancers. Although p53 mutations sometimes may be present, they do not appear to be a primary event responsible for hereditary susceptibility to familial leukemia. This study suggests involvement of other genes or mechanisms.


Morniga-G, a T/Tn-Specific Lectin, Induces Leukemic Cell Death via Caspase and DR5 Receptor-Dependent Pathways.
Morniga-G, the Gal-specific black mulberry (Morus nigra) lectin, displays high affinity for T (CD176) and Tn (CD175) antigens, frequently expressed at the cancer cell surface. The effects of Morniga-G were investigated on a Tn-positive leukemic Jurkat cell line. The lectin, used in a concentration range between 5⁻20 μg/mL, induced cell death in leukemic Jurkat cells. Microscopic and cytofluorometric analyses indicated that Jurkat cell death was essentially apoptotic, associated with an increase in the ceramide content and a depolarization of the mitochondrial transmembrane potential. This lectin-mediated cell death was inhibited by the pan caspase-inhibitor zVAD. In addition, cleavage of caspases 8, 9, and 3 was observed in Morniga-G-treated Jurkat cells whereas Jurkat cell lines that are deficient in caspase 8⁻10, caspase 9, or FADD, survived to the lectin-mediated toxicity. Furthermore, in the presence of TRAIL- or DR5-blocking mononoclonal antibodies, Jurkat cells became resistant to Morniga-G, suggesting that the lectin triggers cell death via the TRAIL/DR5 pathway. In silico computer simulations suggest that Morniga-G might facilitate both the DR5 dimerization and the building of TRAIL/DR5 complexes. Finally, upon treatment of Jurkat cells with benzyl-GalNAc, an O-glycosylation inhibitor, a decrease in Tn antigen expression associating with a reduced Morniga-G toxicity, was observed. Taken together, these results suggest that Morniga-G induces the cell death of Tn-positive leukemic cells via concomitant O-glycosylation-, caspase-, and TRAIL/DR5-dependent pathways.


[Neumopericardium and spontaneous post partum subcutaneus emphysema. A case report and literature review].
The barotrauma cases related to childbirth are an uncommon event, especially the neumopericardium. This entity must be suspected in a patient with subcutaneuos emphysema and confirmed by chest X-ray. The management is based on closed observation, support measures and antibiotic to prevent infection. The radiological follow up is important to evaluate the resolution of this problem. The patient must be followed with caution if the neumopericardium increases because this could lead to a cardiac tamponade with fatal consequences. The description of a case diagnosed and managed in our hospital is done herein which evolution was satisfactory towards resolution of the pneumopericardium without the need of further intervention.


Management of hepatocellular carcinoma: Report of Consensus Meeting in the 45th Annual Meeting of the Japan Society of Hepatology (2009).
Hepatocellular carcinoma (HCC) is responsible for approximately 600 000-700 000 deaths worldwide. It is highly prevalent in the Asia-Pacific region and Africa, and is increasing in Western countries. The evidence-based guideline for HCC in Japan was published in 2005 and revised in 2009. Apart from this guideline, a consensus-based practice manual proposed by the HCC expert panel of the Japan Society of Hepatology (JSH), which reflects widely accepted daily practice in Japan, was published in 2007. At the occasion of the 45th Annual meeting of the JSH in Kobe 4-5 June 2009, a consensus meeting of HCC was held. Consensus statements were createdbased on 67% agreement of 200 expert members.This article describes the up-to-date consensus statements which largely reflect the real world HCC practice in Japan. We believe readers of this article will gain the newest knowledge and deep insight on the management of HCC proposed by consensus of the HCC expert members of JSH.


Health-related quality of life of children and adolescents with mental disorders.
The aim was to assess the association of internalising and externalising pathology with the child's health-related quality of life (QoL), and to determine which child and environmental characteristics beyond pathology were related to poor QoL. Data was obtained for 120 children and adolescents (aged 6 to 18) commencing outpatient psychotherapy treatment. Parents and children (aged 11 years and older) filled out questionnaires. QoL was measured with the KIDSCREEN-27. QoL was more strongly associated with internalising than externalising pathology according to both self- and parent report. Multiple regression analyses showed that beyond internalising and externalising pathology, gender, age, family functioning, functional impairment, and prior mental health treatment were associated with individual QoL scales. The data underscored the relationship between mental pathology and impaired QoL even if potential item overlap was controlled for. This stresses the importance of extending therapy goals and outcome measures from mere pathology to measures of QoL in psychotherapy research particularly for patients with internalising pathology.


Gland Instance Segmentation Using Deep Multichannel Neural Networks.
A new image instance segmentation method is proposed to segment individual glands (instances) in colon histology images. This process is challenging since the glands not only need to be segmented from a complex background, they must also be individually identified. We leverage the idea of image-to-image prediction in recent deep learning by designing an algorithm that automatically exploits and fuses complex multichannel information-regional, location, and boundary cues-in gland histology images. Our proposed algorithm, a deep multichannel framework, alleviates heavy feature design due to the use of convolutional neural networks and is able to meet multifarious requirements by altering channels. Compared with methods reported in the 2015 MICCAI Gland Segmentation Challenge and other currently prevalent instance segmentation methods, we observe state-of-the-art results based on the evaluation metrics. The proposed deep multichannel algorithm is an effective method for gland instance segmentation. The generalization ability of our model not only enable the algorithm to solve gland instance segmentation problems, but the channel is also alternative that can be replaced for a specific task.