Adaptive plasticity of spino-extraocular motor coupling during locomotion in metamorphosing Xenopus laevis.
During swimming in the amphibian ITALIC! Xenopus laevis, efference copies of rhythmic locomotor commands produced by the spinal central pattern generator (CPG) can drive extraocular motor output appropriate for producing image-stabilizing eye movements to offset the disruptive effects of self-motion. During metamorphosis, ITALIC! X. laevisremodels its locomotor strategy from larval tail-based undulatory movements to bilaterally synchronous hindlimb kicking in the adult. This change in propulsive mode results in head/body motion with entirely different dynamics, necessitating a concomitant switch in compensatory ocular movements from conjugate left-right rotations to non-conjugate convergence during the linear forward acceleration produced during each kick cycle. Here, using semi-intact or isolated brainstem/spinal cord preparations at intermediate metamorphic stages, we monitored bilateral eye motion along with extraocular, spinal axial and limb motor nerve activity during episodes of spontaneous fictive swimming. Our results show a progressive transition in spinal efference copy control of extraocular motor output that remains adapted to offsetting visual disturbances during the combinatorial expression of bimodal propulsion when functional larval and adult locomotor systems co-exist within the same animal. In stages at metamorphic climax, spino-extraocular motor coupling, which previously derived from axial locomotor circuitry alone, can originate from both axial and ITALIC! de novohindlimb CPGs, although the latter's influence becomes progressively more dominant and eventually exclusive as metamorphosis terminates with tail resorption. Thus, adaptive interactions between locomotor and extraocular motor circuitry allows CPG-driven efference copy signaling to continuously match the changing spatio-temporal requirements for visual image stabilization throughout the transitional period when one propulsive mechanism emerges and replaces another.


Heteropatric speciation in a duck, Anas crecca.
Heteropatric differentiation is a mode of speciation with gene flow in which divergence occurs between lineages that are in sympatry and allopatry at different times during cyclic spatial movements. Empirical evidence suggests that heteropatric differentiation may prove to be common among seasonally migratory organisms. We examined genetic differentiation between the sedentary Aleutian Islands population of green-winged teal (Anas crecca-nimia) and its close migratory relative, the Eurasian, or Old World (OW), Anas c. crecca population, a portion of which passes through the range of nimia during its seasonal migrations. We also examined its relationship with the parapatric North American, New World (NW), A. c. carolinensis population. Sequence data from eight nuclear introns and the mtDNA control region showed that the nimia-crecca divergence occurred much more recently than the deeper crecca-carolinensis split (~83 000 years vs. ~1.1 Myr). Despite considerable spatial overlap between crecca and nimia during seasonal migration, three key predictions of heteropatric differentiation are supported: significant genetic divergence (overall mean Φst = 0.07), low gene flow (2Ne m ~ 1.8), and an effective population size in nimia that is not especially low (Ne ~ 80 000 individuals). Similar levels of gene flow have come into nimia from carolinensis, but no detectable nuclear gene flow has gone out of nimia into either OW (crecca) or NW (carolinensis) populations. We infer that adaptations of these populations to local optima in different places (e.g. each matching their reproductive effort to different resource blooms) promote genetic isolation and divergence despite periods of sympatry between them, as the heteropatric model predicts.


Platelet-Therapeutics to Improve Tissue Regeneration and Wound Healing-Physiological Background and Methods of Preparation.
Besides their function in primary hemostasis, platelets are critically involved in the physiological steps leading to wound healing and tissue repair. For this purpose, platelets have a complex set of receptors allowing the recognition, binding, and manipulation of extracellular structures and the detection of pathogens and tissue damage. Intracellular vesicles contain a huge set of mediators that can be released to the extracellular space to coordinate the action of platelets as other cell types for tissue repair. Therapeutically, the most frequent use of platelets is the intravenous application of platelet concentrates in case of thrombocytopenia or thrombocytopathy. However, there is increasing evidence that the local application of platelet-rich concentrates and platelet-rich fibrin can improve wound healing and tissue repair in various settings in medicine and dentistry. For the therapeutic use of platelets in wound healing, several preparations are available in clinical practice. In the present study we discuss the physiology and the cellular mechanisms of platelets in hemostasis and wound repair, the methods used for the preparation of platelet-rich concentrates and platelet-rich fibrin, and highlight some examples of the therapeutic use in medicine and dentistry.


Combined chemotherapy and photodynamic therapy using a nanohybrid based on layered double hydroxides to conquer cisplatin resistance.
A nanohybrid is assembled by ratiometrically co-loading Pt(IV) prodrugs and photosensitizers into layered double hydroxide nanoparticles. The nanohybrid shows synergistic cell-killing effects and is significantly active against the proliferation of cisplatin-resistant human cancer cells with nanomolar IC50 values. Profound mechanistic investigations confirm its action mode of combined chemo- and photodynamic therapy.


Anaerobic and aerobic bacterial flora of acute conjunctivitis in children.
Aerobic and anaerobic cultures and clinical data were obtained from 126 pediatric patients with acute conjunctivitis. Similar cultures were obtained from 66 persons who did not have a conjunctival inflammation. Anaerobes were isolated from 47 patients (37.3%). In 26 cases (20.6%), they were in mixed cultures with aerobes, and in 21 cases (16.7%), they were the only isolates. Aerobes alone were recovered in 72 patients (57.1%). No bacterial growth was noted in seven patients (5.6%). The organisms recovered from eyes with conjunctivitis in statistically significant numbers were Staphylococcus aureus, Streptococcus pneumoniae, Haemophilus influenzae, and anaerobic Gram-postive cocci.


Patient satisfaction after total knee and hip arthroplasty.
Patient satisfaction is an important outcome measurement in TKA/THA surgery. Patient satisfaction can be evaluated from 2 perspectives, determinants of satisfaction and components of satisfaction.(5) In total joint arthroplasty, improvements in satisfaction can be achieved by examining these perspectives. Patient satisfaction is one of the many PROMs used in orthopedic surgery and is an integral part of the growing sentiment to evaluate surgery from the patient's perspective as well as from the surgeon's. The importance of measuring outcomes from the patient perspective is integral to today's patient-centered models of care.


Association Between Discrimination and Objective and Subjective Sleep Measures in the Midlife in the United States Study Adult Sample.
Evidence suggests that sleep quality is worse in nonwhite minorities compared with whites. Poor sleep is associated with higher levels of perceived interpersonal discrimination, which is consistently reported among minorities. However, the literature is limited in exploring discrimination with both objective and subjective sleep outcomes in the same sample. We examined the relationship between discrimination and markers of subjective and objective sleep in a racially diverse sample. The analytic sample included 441 participants of the Midlife in the United States II (MIDUS) study (M [SD] age, 46.6 [1.03]; female, 57.9%; male, 42.1%; nonwhite, 31.7%). Complete data were available for 361 participants. Sleep measures included the Pittsburgh Sleep Quality Index, sleep latency, wake after sleep onset, and sleep efficiency derived from 7-day actigraphy. Discrimination was measured with the Williams Everyday Discrimination Scale. Ordinary least squares and logistic regression models were used to assess the relationship between discrimination and the subjective and objective measures of sleep. After adjusting for covariates, respondents with higher discrimination scores were significantly more likely to experience poor sleep efficiency (odds ratio, 1.12; p = .005) and report poorer sleep quality (odds ratio, 1.09; p = .029) on the basis of the Pittsburgh Sleep Quality Index. Higher discrimination scores were also associated with longer wake after sleep onset (b = 0.032, p < .01) and more sleep difficulties (b = 0.049, p = .01). Discrimination attenuated all differences in the sleep measures between whites and nonwhites except for sleep efficiency. The findings support the model that discrimination acts as a stressor that can disrupt subjective and objective sleep. These results suggest that interpersonal discrimination explains some variance in worse sleep among nonwhites compared with whites.


DNA fragmentation in human spermatozoa: significance in the diagnosis and treatment of infertility.
The integrity of the paternal genome is of paramount importance in the initiation and maintenance of a pregnancy in vivo and in vitro. The presence in the embryonic genome of chemical modifications at the level of DNA nucleotides and/or DNA strand breaks coming from the paternal genome (that have not been repaired by the oocyte after fertilization), is not compatible with normal embryo and fetal development. DNA fragmentation in human spermatozoa has been recently shown to be an important contributing factor to the etiology of unexplained infertility. In this review, the mechanisms responsible for DNA fragmentation in sperm, including defects in chromatin remodeling during the process of spermiogenesis, apoptosis and ROS-induced damage during sperm migration from the seminiferous tubules to the epididymis, are discussed. Also, the different methodologies used to determine DNA fragmentation in human sperm (with special emphasis on the SCSA test) and the applications of the SCSA test in the diagnosis and treatment of infertility, are presented. Finally, answers to common questions asked about the SCSA test are also included.


Sulfide as an alternative electron donor to glucose for power generation in mediator-less microbial fuel cell.
The objective of this study was to investigate the power generation in a dual-chamber microbial fuel cell (MFC). As one of the effective parameters, glucose concentration was studied in the range of 100-1000 mg/L. At the optimum concentration of 500 mg/L of glucose, maximum power generation was 186 mW/m2. As an alternative, sulfide was used as an electron donor and maximum power output was 401 mW/m2 at the concentration of 100 mg/L; which was more than twice of power produced using glucose. Moreover, sulfide removal efficiencies of 70%, 66%, 60%, and 64% were obtained when initial sulfide concentrations of 10, 20, 80, and 100 mg/L were used, respectively.


N6-methyladenosine-mediated overexpression of long noncoding RNA ADAMTS9-AS2 triggers neuroblastoma differentiation via regulating LIN28B/let-7/MYCN signaling.
Neuroblastomas have shed light on the differentiation disorder that is associated with spontaneous regression or differentiation in the same tumor at the same time. Long noncoding RNAs (lncRNAs) actively participate in a broad spectrum of biological processes. However, the detailed molecular mechanisms underlying lncRNA regulation of differentiation in neuroblastomas remain largely unknown. Here, we sequenced clinical samples of ganglioneuroma, ganglioneuroblastoma, and neuroblastoma. We compared transcription profiles of neuroblastoma cells, ganglion cells, and intermediate state cells; verified the profiles in a retinoic acid-induced cell differentiation model and clinical samples; and screened out the lncRNA ADAMTS9 antisense RNA 2 (ADAMTS9-AS2), which contributed to neuroblastoma differentiation. ADAMTS9-AS2 upregulation in neuroblastoma cell lines inhibited proliferation and metastatic potential. Additional mechanistic studies illustrated that the interactions between ADAMTS9-AS2 and LIN28B inhibited the association between LIN28B and primary let-7 (pri-let-7) miRNA, then released pri-let-7 into cytoplasm to form mature let-7, resulting in the inhibition of oncogene MYCN activity that subsequently affected cancer stemness and differentiation. Furthermore, we showed that the observed differential expression of ADAMTS9-AS2 in neuroblastoma cells was due to N6-methyladenosine methylation. Finally, ADAMTS9-AS2 upregulation inhibited proliferation and cancer stem-like capabilities in vivo. Taken together, these results show that ADAMTS9-AS2 loss leads to malignant neuroblastoma by increasing metastasis and causing dysfunctional differentiation.


Gait asymmetry, ankle spasticity, and depression as independent predictors of falls in ambulatory stroke patients.
Falls are the leading cause of injury in stroke patients. However, the cause of a fall is complicated, and several types of risk factors are involved. Therefore, a comprehensive model to predict falls with high sensitivity and specificity is needed. This study was a prospective study of 112 inpatients in a rehabilitation ward with follow-up interviews in patients' homes. Evaluations were performed 1 month after stroke and included the following factors: (1) status of cognition, depression, fear of fall and limb spasticity; (2) functional assessments [walking velocity and the Functional Independence Measure (FIM)]; and (3) objective, computerized gait and balance analyses. The outcome variable was the number of accidental falls during the 6-month follow-up period after baseline measurements. The non-faller group exhibited significantly better walking velocity and FIM scale compared to the faller group (P < .001). The faller group exhibited higher levels of spasticity in the affected limbs, asymmetry of gait parameters in single support (P < .001), double support (P = .027), and step time (P = .003), and lower stability of center of gravity in the medial-lateral direction (P = .008). Psychological assessments revealed that the faller group exhibited more severe depression and lower confidence without falling. A multivariate logistic regression model identified three independent predictors of falls with high sensitivity (82.6%) and specificity (86.5%): the asymmetry ratio of single support [adjusted odds ratio, aOR = 2.2, 95% CI (1.2-3.8)], the level of spasticity in the gastrocnemius [aOR = 3.2 (1.4-7.3)], and the degree of depression [aOR = 1.4 (1.2-1.8)]. This study revealed depression, in additional to gait asymmetry and spasticity, as another independent factor for predicting falls. These results suggest that appropriate gait training, reduction of ankle spasticity, and aggressive management of depression may be critical to prevent falls in stroke patients.


Efficient mutagenesis by Cas9 protein-mediated oligonucleotide insertion and large-scale assessment of single-guide RNAs.
The CRISPR/Cas9 system has been implemented in a variety of model organisms to mediate site-directed mutagenesis. A wide range of mutation rates has been reported, but at a limited number of genomic target sites. To uncover the rules that govern effective Cas9-mediated mutagenesis in zebrafish, we targeted over a hundred genomic loci for mutagenesis using a streamlined and cloning-free method. We generated mutations in 85% of target genes with mutation rates varying across several orders of magnitude, and identified sequence composition rules that influence mutagenesis. We increased rates of mutagenesis by implementing several novel approaches. The activities of poor or unsuccessful single-guide RNAs (sgRNAs) initiating with a 5' adenine were improved by rescuing 5' end homogeneity of the sgRNA. In some cases, direct injection of Cas9 protein/sgRNA complex further increased mutagenic activity. We also observed that low diversity of mutant alleles led to repeated failure to obtain frame-shift mutations. This limitation was overcome by knock-in of a stop codon cassette that ensured coding frame truncation. Our improved methods and detailed protocols make Cas9-mediated mutagenesis an attractive approach for labs of all sizes.


Understanding hospital readiness for computerized physician order entry.
Many hospitals in the United States are in early stages of decision making and planning to implement computerized physician order entry (CPOE) to improve patient safety and quality of care. The targeted processes and the software for CPOE are complex, and implementation is a large-scale change effort for most hospitals. Hospitals can increase the likelihood of success by understanding and addressing gaps in CPOE readiness. ASSESSING CPOE READINESS: A CPOE readiness assessment tool was developed that includes several different components: external environment; organizational leadership, structure, and culture; care standardization;, order management; access to information; information technology composition; and infrastructure. The presence or absence of these indicators in a particular hospital was determined by on-site interviews, walkarounds with direct observations, and document review. Assessment results for the first 17 hospitals (bed size, 75-906 beds) indicated that the lowest average component score was in care standardization, while the highest average component score was in organizational structure and function. Organizational culture and the order management process also had low average scores. This CPOE readiness assessment revealed significant gaps in all the hospitals examined. Identifying these gaps and addressing them before CPOE implementation can reduce risks. Organizations need to develop expertise at accomplishing and sustaining change; understanding and building CPOE readiness is an important first step.


The Dangers of Electrosurgical Smoke to Operating Room Personnel: A Review.
A 2007 study in the United Kingdom showed that three of 98 surgeons surveyed admitted using dedicated smoke extractors; 72% of respondents believed inadequate precautions were in place to protect staff from the potential dangers of electrosurgical smoke. Surgical smoke contains harmful chemicals (e.g., hydrogen cyanide, acetylene, and butadiene) that can circumvent standard masks used in the operating room (OR). In addition, bacteria and viruses can be transmitted through this smoke. The topic of electrosurgical smoke is important to occupational health nurses not only because of their responsibility to protect workers, but also because they, like other health care providers, may be exposed to smoke routinely. The authors of this review recommend the regular use of smoke evacuation in ORs and avoidance of electrosurgery whenever possible to protect OR personnel from the potential long-term harmful effects of electrosurgical smoke.


The Usefulness of the Pretreatment Neutrophil/Lymphocyte Ratio as a Predictor of the 5-Year Survival in Stage 1-3 Triple Negative Breast Cancer Patients.
We have previously shown that the neutrophil/lymphocyte ratio (NLR) is a predictor of survival among breast cancer patients. The aim of this study was to determine the predictive value of NLR among different nodal and chemotherapy subgroups of triple negative breast cancer (TNBC). Patients with stage 1-3 TNBC who underwent treatment from 2007 to 2014 and had blood counts prior to treatments were included. Patients were categorized into high (≥2) and low (<2) NLR groups. Primary outcomes were overall survival (OS) and disease-free survival (DFS). The average follow-up time was 54 months. The high NLR group had worse OS (HR 2.8, CI 1.3-5.9, p < 0.001) and DFS (HR 2.3, CI 1.2-4.2, p < 0.001) than the low NLR group. After adjusting for confounding variables, high NLR was an independent prognostic factor for both OS (HR 5.5, CI 2.2-13.7, p < 0.0001) and DFS (HR 5.2, CI 2.3-11.6, p < 0.0001). Categorization of TNBC patients by NLR (high vs. low) and nodal status (positive vs. negative) resulted in four groups with significantly different OS and DFS (log rank p < 0.0001). Significant improvements in OS (p < 0.001) and DFS (p < 0.001) were observed for patients who received chemotherapy and had high NLR but not for patients with low NLR (p = 0.65 and p = 0.07, respectively). High pretreatment NLR is an independent predictor of poor OS and DFS among TNBC patients. Combining NLR and pN provides better risk stratification for TNBC patients. Chemotherapy appears to be beneficial only in patients with high NLR. Larger prospective studies are needed to validate these findings.


Integrated EPANET-MSX process models of chlorine and its by-products in drinking water distribution systems.
EPANET and its commercial derivatives are the most widely-used software packages for modeling free chlorine and its by-products in drinking water distribution systems. Yet, they are not sufficiently accurate, general, or efficient for deriving optimal chlorine dosing strategies at different seasonal temperatures. To overcome EPANET's limitations, an integrated set of rigorously validated multispecies process models are proposed for application within the EPANET-MSX environment. An executable (command-line) version of these MSX models is supplied for use either within the MSX environment or embedded in commercial versions of MSX. A new general method was devised to obtain output of any intermediate coefficient or variable involved in the simulation. This overcomes MSX's limited output options. When the debugged models were applied to a real distribution system, the optimal chlorine dose for summer required almost double the chlorine dose needed in winter. A lower initial dose combined with a downstream booster dose required less chlorine in total. Formal optimization techniques are needed to efficiently obtain similar strategies in more complex systems. PRACTITIONER POINTS: EPANET water quality models are not accurate or general enough for deriving optimal chlorine dosing strategies in distribution systems. Integrated EPNET-MSX models of chlorine reactions in bulk water and at pipe walls, and associated by-product formation, overcome EPANET's limitations. To verify model authenticity, a general technique was developed to obtain values of coefficients and variables within an EPANET-MSX simulation. EPANET-MSX command lines implementing these integrated EPANET-MSX models are presented with verified results for optimal initial and booster dosing strategies. Optimal summer dosing in a real system of rough pipes was almost double that required in winter.


First comparison of French and Australian OsHV-1 µvars by bath exposure.
Economically devastating mortality events of farmed and wild shellfish due to infectious disease have been reported globally. Currently, one of the most significant disease threats to Pacific oyster Crassostrea gigas culture is the ostreid herpesvirus 1 (OsHV-1), in particular the emerging OsHV-1 microvariant genotypes. OsHV-1 microvariants (OsHV-1 µvars) are spreading globally, and concern is high among growers in areas unaffected by OsHV-1. No study to date has compared the relative virulence among variants. We provide the first challenge study comparing survival of naïve juvenile Pacific oysters exposed to OsHV-1 µvars from Australia (AUS µvar) and France (FRA µvar). Oysters challenged with OsHV-1 µvars had low survival (2.5% exposed to AUS µvar and 10% to FRA µvar), and high viral copy number as compared to control oysters (100% survival and no virus detected). As our study was conducted in a quarantine facility located ~320 km from the ocean, we also compared the virulence of OsHV-1 µvars using artificial seawater made from either facility tap water (3782 µmol kg-1 seawater total alkalinity) or purchased distilled water (2003 µmol kg-1). Although no differences in survival or viral copy number were detected in oysters exposed to seawater made using tap or distilled water, more OsHV-1 was detected in tanks containing the lower-alkalinity seawater, indicating that water quality may be important for virus transmission, as it may influence the duration of viral viability outside of the host.


Primaquine-induced hemolytic anemia: formation and hemotoxicity of the arylhydroxylamine metabolite 6-methoxy-8-hydroxylaminoquinoline.
Primaquine is an important antimalarial agent because of its activity against exoerythrocytic forms of Plasmodium spp. However, methemoglobinemia and hemolytic anemia are dose-limiting side effects of primaquine therapy that limit its efficacy. These hemotoxicities are thought to be mediated by metabolites; however, the identity of the toxic species has remained unclear. Since N-hydroxy metabolites are known to mediate the hemotoxicity of several arylamines, the present studies were undertaken to determine whether 6-methoxy-8-aminoquinoline (6-MAQ), a known human metabolite of primaquine, could undergo N-hydroxylation to form a hemotoxic metabolite. When 6-MAQ was incubated with rat and human liver microsomes, a single metabolite was detected by high performance liquid chromatography (HPLC) with electrochemical detection. This metabolite was identified as 6-methoxy-8-hydroxylaminoquinoline (MAQ-NOH) by HPLC and mass spectral analyses. As measured by decreased survival of (51)Cr-labeled erythrocytes in rats, MAQ-NOH was hemolytic in vivo. Furthermore, in vitro exposure of (51)Cr-labeled erythrocytes to MAQ-NOH caused a concentration-dependent decrease in erythrocyte survival (EC(50) of 350 microM) when the exposed cells were returned to the circulation of isologous rats. MAQ-NOH also induced the formation of methemoglobin when incubated with suspensions of rat erythrocytes. These data indicate that 6-MAQ can be metabolized to MAQ-NOH by both rat and human liver microsomes and that MAQ-NOH has the requisite properties to be a hemotoxic metabolite of primaquine. The contribution of MAQ-NOH to the hemotoxicity of primaquine in vivo remains to be assessed.


Exploration of lagged relationships between mastitis and milk yield in dairy cows using a Bayesian structural equation Gaussian-threshold model.
A Gaussian-threshold model is described under the general framework of structural equation models for inferring simultaneous and recursive relationships between binary and Gaussian characters, and estimating genetic parameters. Relationships between clinical mastitis (CM) and test-day milk yield (MY) in first-lactation Norwegian Red cows were examined using a recursive Gaussian-threshold model. For comparison, the data were also analyzed using a standard Gaussian-threshold, a multivariate linear model, and a recursive multivariate linear model. The first 180 days of lactation were arbitrarily divided into three periods of equal length, in order to investigate how these relationships evolve in the course of lactation. The recursive model showed negative within-period effects from (liability to) CM to test-day MY in all three lactation periods, and positive between-period effects from test-day MY to (liability to) CM in the following period. Estimates of recursive effects and of genetic parameters were time-dependent. The results suggested unfavorable effects of production on liability to mastitis, and dynamic relationships between mastitis and test-day MY in the course of lactation. Fitting recursive effects had little influence on the estimation of genetic parameters. However, some differences were found in the estimates of heritability, genetic, and residual correlations, using different types of models (Gaussian-threshold vs. multivariate linear).


Prevalence and correlates of posttraumatic stress and postpartum depression in parents of infants in the Neonatal Intensive Care Unit (NICU).
The purpose of this study was to assess the prevalence and correlates of acute stress disorder (ASD) and posttraumatic stress disorder (PTSD) in mothers and fathers, and postpartum depression (PPD) in mothers, of infants in the Neonatal Intensive Care Unit (NICU). 86 mothers and 41 fathers completed measures of ASD and of parent perception of infant medical severity 3-5 days after the infant's NICU admission (T1), and measures of PTSD and PPD 30 days later (T2). 35% of mothers and 24% of fathers met ASD diagnostic criteria at T1, and 15% of mothers and 8% of fathers met PTSD diagnostic criteria at T2. PTSD symptom severity was correlated with concurrent stressors and family history of anxiety and depression. Rates of ASD/PTSD in parents of hospitalized infants are consistent with rates in other acute illness and injury populations, suggesting relevance of traumatic stress in characterizing parent experience during and after the NICU.


Relationship of LRP-human major vault protein to in vitro and clinical resistance to anticancer drugs.
Multidrug resistance (MDR) has been related to two members of the ABC-superfamily of transporters, P-glycoprotein (Pgp) and Multidrug Resistance-associated Protein (MRP). We have described a 110 kD protein termed the Lung Resistance-related Protein (LRP) that is overexpressed in several non-Pgp MDR cells lines of different histogenetic origin. Reversal of MDR parallels a decrease in LRP expression. In a panel of 61 cancer cell lines which have not been subjected to laboratory drug selection, LRP was a superior predictor for in vitro resistance to MDR-related drugs when compared to Pgp and MRP, and LRP's predictive value extended to MDR unrelated drugs, such as platinum compounds. LRP is widely distributed in clinical cancer specimens, but the frequency of LRP expression inversely correlates with the known chemosensitivity of different tumour types. Furthermore, LRP expression at diagnosis has been shown to be a strong and independent prognostic factor for response to chemotherapy and outcome in acute myeloid leukemia and ovarian carcinoma (platinum-based treatment) patients. Recently, LRP has been identified as the human major protein. Vaults are novel cellular organelles broadly distributed and highly conserved among diverse eukaryotic cells, suggesting that they play a role in fundamental cell processes. Vaults localise to nuclear pore complexes and may be the central plug of the nuclear pore complexes. Vaults structure and localisation support a transport function for this particle which could involve a variety of substrates. Vaults may therefore play a role in drug resistance by regulating the nucleocytoplasmic transport of drugs.


Frequency and Methods of Nonsuicidal Self-Injury in Relation to Acquired Capability for Suicide Among Adolescents.
The objective of this study was to test the Interpersonal Psychological Theory of Suicide (IPTS) proposal that the association of nonsuicidal self-injury (NSSI) with suicide attempt is mediated by acquired capability. Inpatient adolescents (n = 134) reported on suicide ideation and attempts, NSSI frequency and methods, depressive symptoms, and acquired capability for suicide. Consistent with the IPTS, both measures of NSSI were positively associated with acquired capability after accounting for depressive symptoms and past history of attempts. However, both NSSI measures explained independent variance in number of suicide attempts after controlling for suicide ideation and acquired capability. These findings contradict the IPTS and suggest that the role of NSSI in suicide attempt is mediated by variables external to the IPTS.


Validation of the Identification and Intervention for Dementia in Elderly Africans (IDEA) cognitive screen in Nigeria and Tanzania.
We have previously described the development of the Identification and Intervention for Dementia in Elderly Africans (IDEA) cognitive screen for use in populations with low levels of formal education. The IDEA cognitive screen was developed and field-tested in an elderly, community-based population in rural Tanzania with a relatively high prevalence of cognitive impairment. The aim of this study was to validate the IDEA cognitive screen as an assessment of major cognitive impairment in hospital settings in Nigeria and Tanzania. In Nigeria, 121 consecutive elderly medical clinic outpatients reviewed at the University College Hospital, Ibadan were screened using the IDEA cognitive screen. In Tanzania, 97 consecutive inpatients admitted to Mawenzi Regional Hospital (MRH), Moshi, and 108 consecutive medical clinic outpatients attending the geriatric medicine clinic at MRH were screened. Inter-rater reliability was assessed in Tanzanian outpatients attending St Joseph's Hospital in Moshi using three raters. A diagnosis of dementia or delirium (DSM-IV criteria) was classified as major cognitive impairment and was provided independently by a physician blinded to the results of the screening assessment. The area under the receiver operating characteristic (AUROC) curve in Nigerian outpatients, Tanzanian outpatients and Tanzanian inpatients was 0.990, 0.919 and 0.917 respectively. Inter-rater reliability was good (intra-class correlation coefficient 0.742 to 0.791). In regression models, the cognitive screen did not appear to be educationally biased. The IDEA cognitive screen performed well in these populations and should prove useful in screening for dementia and delirium in other areas of sub-Saharan Africa.


Antiherpetic medication use and the risk of gastroschisis: findings from the National Birth Defects Prevention Study, 1997-2007.
Previous studies examining the teratogenic effects of antiherpetic medications have found no associations for birth defects overall but have not examined the risk of specific birth defects. The National Birth Defects Prevention Study ascertains population-based cases with birth defects and live-born controls without birth defects in 10 states across the United States for the purpose of identifying potential teratogenic risk factors. Mothers of cases and controls are interviewed within 2 years of their estimated date of delivery about demographic, medical and behavioural factors before and during pregnancy. This analysis examined the possible association between use of antiherpetic medications (acyclovir, valacyclovir or famciclovir) during early pregnancy and gastroschisis, a birth defect of the abdominal wall. The mothers of 1.1% (n = 10) of 941 gastroschisis cases and 0.3% (n = 27) of 8339 controls reported antiherpetic medication use during the month before conception through the third month of pregnancy. The adjusted odds ratios for such use in relation to gastroschisis were 4.7 [95% confidence interval 1.7, 13.3] and 4.7 [95% CI 1.2, 19.0] among women with and without self-reported genital herpes, respectively, when compared with women without antiherpetic use or herpes. Among women reporting no antiherpetic medication use, the odds ratio for self-reported genital herpes in relation to gastroschisis was 3.0 [95% CI 1.6, 5.7]. Our study raises the possibility of an increased risk of gastroschisis because of either antiherpetic medication use during early pregnancy or the underlying genital herpes infection for which it was indicated.


From gene networks to gene function.
We propose a novel method to identify functionally related genes based on comparisons of neighborhoods in gene networks. This method does not rely on gene sequence or protein structure homologies, and it can be applied to any organism and a wide variety of experimental data sets. The character of the predicted gene relationships depends on the underlying networks;they concern biological processes rather than the molecular function. We used the method to analyze gene networks derived from genome-wide chromatin immunoprecipitation experiments, a large-scale gene deletion study, and from the genomic positions of consensus binding sites for transcription factors of the yeast Saccharomyces cerevisiae. We identified 816 functional relationships between 159 genes and show that these relationships correspond to protein-protein interactions, co-occurrence in the same protein complexes, and/or co-occurrence in abstracts of scientific articles. Our results suggest functions for seven previously uncharacterized yeast genes: KIN3 and YMR269W may be involved in biological processes related to cell growth and/or maintenance, whereas IES6, YEL008W, YEL033W, YHL029C, YMR010W, and YMR031W-A are likely to have metabolic functions.


Derivation of human induced pluripotent stem cells for cardiovascular disease modeling.
The successful derivation of human induced pluripotent stem cells (hiPSCs) by dedifferentiation of somatic cells offers significant potential to overcome obstacles in the field of cardiovascular disease. hiPSC derivatives offer incredible potential for new disease models and regenerative medicine therapies. However, many questions remain regarding the optimal starting materials and methods to enable safe, efficient derivation of hiPSCs suitable for clinical applications. Initial reprogramming experiments were carried out using lentiviral or retroviral gene delivery methods. More recently, various nonviral methods that avoid permanent and random transgene insertion have emerged as alternatives. These include transient DNA transfection using plasmids or minicircles, protein transduction, or RNA transfection. In addition, several small molecules have been found to significantly augment hiPSC derivation efficiency, allowing the use of a fewer number of genes during pluripotency induction. We review these various methods for the derivation of hiPSCs, focusing on their ultimate clinical applicability, with an emphasis on their potential for use as cardiovascular therapies and disease-modeling platforms.


Bacterial culture and immunohistochemical detection of bacteria and endotoxin in cats with suppurative cholangitis-cholangiohepatitis syndrome.
To characterize the frequency and type of bacterial infection by culture- and immunohistochemical (IHC)-based methods and determine the impact of infection on clinical features and survival time in cats with suppurative cholangitis-cholangiohepatitis syndrome (S-CCHS). 168 client-owned cats with S-CCHS (cases). Clinical features, bacterial culture results, culture-inoculate sources, and survival details were recorded. Cases were subcategorized by comorbidity (extrahepatic bile duct obstruction, cholelithiasis, cholecystitis, ductal plate malformation, biopsy-confirmed inflammatory bowel disease, and biopsy-confirmed pancreatitis) or treatment by cholecystectomy or cholecystoenterostomy. Culture results, bacterial isolates, Gram-stain characteristics, and IHC staining were compared among comorbidities. Lipoteichoic acid IHC staining detected gram-positive bacterial cell wall components, and toll-like receptor expression IHC reflected pathologic endotoxin (gram-negative bacteria) exposure. Clinical features were similar among cases except for more frequent abdominal pain and lethargy in cats with positive culture results and pyrexia, abdominal pain, and hepatomegaly for cats with polymicrobial infections. Bacteria were cultured in 93 of 135 (69%) cats, with common isolates including Enterococcus spp and Escherichia coli. IHC staining was positive in 142 of 151 (94%) cats (lipoteichoic acid, 107/142 [75%]; toll-like receptor 4, 99/142 [70%]). With in-parallel interpretation of culture and IHC-based bacterial detection, 154 of 166 (93%) cats had bacterial infections (gram-positive, 118/154 [77%]; gram-negative, 111/154 [72%]; polymicrobial, 79/154 [51%]). Greater frequency of bacterial isolation occurred with combined tissue, bile, and crushed cholelith inoculates. Infection and gram-positive bacterial isolates were associated with significantly shorter long-term survival times. S-CCHS was associated with bacterial infection, pathologic endotoxin exposure, and frequent polymicrobial infection in cats. Combined tissue inoculates improved culture detection of associated bacteria.


Consequences of introducing geometric GTV to CTV margin expansion in DAHANCA contouring guidelines for head and neck radiotherapy.
Defining margins around the Gross Tumour Volume (GTV) to create a Clinical Target Volume (CTV) for head and neck cancer radiotherapy has traditionally been based on presumed knowledge of anatomical routes of spread. However, using a concentric geometric expansion around the GTV may be more reproducible. The purpose of this study was to analyse the inter-observer consistency of geometric CTV delineation with adaptation for anatomical boundaries versus anatomically defined CTVs. Radiation oncologists at four Danish cancer centres delineated high, intermediate and elective dose CTVs (CTV1, CTV2 and CTV3, respectively) in a patient-case template (stage IV squamous cell carcinoma of the oropharynx), first using mainly anatomical margins (original standard) and then using concentric geometric expansion (new standard). Each centre made a dummy-run radiotherapy plan based on the delineated CTVs. The difference between the CTV contours and the radiotherapy plans was evaluated across the centres. Anatomy-based contours were significantly more heterogenous and showed larger volume differences between centres than geometric margins. Dice similarity coefficient increased by 0.29 and mean surface distance decreased by 4mm for CTV1. Use of consistent CTV volumes resulted in more consistent irradiated volumes between centres. Introduction of geometric margins resulted in more uniform CTV1 and CTV2 delineation. Geometric CTV expansion was easier, left less room for misinterpretation, and resulted in more uniform treatment plans with similar irradiated high and intermediate dose volumes across all centres.


Calmodulin mediates Fas-induced FADD-independent survival signaling in pancreatic cancer cells via activation of Src-extracellular signal-regulated kinase (ERK).
Pancreatic cancer remains a devastating malignancy with a poor prognosis and is largely resistant to current therapies. To understand the resistance of pancreatic tumors to Fas death receptor-induced apoptosis, we investigated the molecular mechanisms of Fas-activated survival signaling in pancreatic cancer cells. We found that knockdown of the Fas-associated protein with death domain (FADD), the adaptor that mediates downstream signaling upon Fas activation, rendered Fas-sensitive MiaPaCa-2 and BxPC-3 pancreatic cells resistant to Fas-induced apoptosis. By contrast, Fas activation promoted the survival of the FADD knockdown MiaPaCa-2 and BxPC-3 cells in a concentration-dependent manner. The pharmacological inhibitor of ERK, PD98059, abrogated Fas-promoted cell survival in FADD knockdown MiaPaCa-2 and BxPC-3 cells. Furthermore, increased phosphorylation of Src was demonstrated to mediate Fas-induced ERK activation and cell survival. Immunoprecipitation of Fas in the FADD knockdown cells identified the presence of increased calmodulin, Src, and phosphorylated Src in the Fas-associated protein complex upon Fas activation. Trifluoperazine, a calmodulin antagonist, inhibited Fas-induced recruitment of calmodulin, Src, and phosphorylated Src. Consistently, trifluoperazine blocked Fas-promoted cell survival. A direct interaction of calmodulin and Src and their binding site were identified with recombinant proteins. These results support an essential role of calmodulin in mediating Fas-induced FADD-independent activation of Src-ERK signaling pathways, which promote survival signaling in pancreatic cancer cells. Understanding the molecular mechanisms responsible for the resistance of pancreatic cells to apoptosis induced by Fas-death receptor signaling may provide molecular insights into designing novel therapies to treat pancreatic tumors.


The neuroendocrine paraventricular hypothalamus: receptors, signal transduction, mRNA and neurosecretion.
The hypothalamus is one of the most studied areas of the central nervous system. Many of its functions are understood and there is an extensive literature on its role in the control of pituitary hormone secretion, autonomic nervous system activity, regulation of salt, water and food ingestion, body temperature regulation and aspects of behaviour. Although the role of the hypothalamus in the control of pituitary secretion was postulated in the early 1900s, the chemical nature of these control mechanisms has only been documented in the last few years. The opioid peptides represent one particular family of chemical compounds which have been shown to have many effects on pituitary hormone secretion. Exogenous opioids inhibit the neurosecretion of both vasopressin and oxytocin from the posterior pituitary neurosecretory terminals of hypothalamic cell bodies. Opioids also have major actions on the secretory activity of the anterior pituitary which has no innervation from the hypothalamus, but which is regulated by blood-borne factors in the hypophyseal portal circulation which runs from the median eminence of the hypothalamus. It was therefore of considerable interest when it was discovered that endogenous opioid peptides could be detected both in the neurohypophyseal system and in cells which project into the median eminence. The simple presence of a peptide in a neurone does not necessarily imply a function. If, however, we can demonstrate that regulation of the synthesis of the peptide occurs in a manner which corresponds with the expected role of the agent, this provides powerful data in support of a genuine physiological function. The elucidation of the genomic structure of the precursors for the three endogenous opioid peptides has provided us with the ability to measure mRNA for these peptides in defined areas of the brain and to assess their response to appropriate stimuli. Not only does mRNA for the endogenous opioid dynorphin coexist in the same cells as vasopressin but we have now been able to demonstrate that stimuli to vasopressin secretion also result in a markedly increased accumulation of dynorphin mRNA. Similarly, previous studies have shown that opioid peptides derived from another precursor--pro-enkephalin A--coexist with corticotrophin releasing factor in a different group of hypothalamic cells. We have now been able to demonstrate that stresses which result in an accumulation of corticotrophin releasing factor mRNA also result in increased pro-enkephalin mRNA in the same area. This considerably strengthens the hypothesis that endogenous opioids do play a significant role in the control of hypophyseal secretion.(ABSTRACT TRUNCATED AT 400 WORDS)


ESBL-Producing Escherichia coli Carrying CTX-M Genes Circulating among Livestock, Dogs, and Wild Mammals in Small-Scale Farms of Central Chile.
Antibiotic-resistant bacteria of critical importance for global health such as extended-spectrum beta-lactamases-producing (ESBL)-Escherichia coli have been detected in livestock, dogs, and wildlife worldwide. However, the dynamics of ESBL-E. coli between these animals remains poorly understood, particularly in small-scale farms of low and middle-income countries where contact between species can be frequent. We compared the prevalence of fecal carriage of ESBL-E. coli among 332 livestock (207 cows, 15 pigs, 60 horses, 40 sheep, 6 goats, 4 chickens), 82 dogs, and wildlife including 131 European rabbits, 30 rodents, and 12 Andean foxes sharing territory in peri-urban localities of central Chile. The prevalence was lower in livestock (3.0%) and wildlife (0.5%) compared to dogs (24%). Among 47 ESBL-E. coli isolates recovered, CTX-M-group 1 was the main ESBL genotype identified, followed by CTX-M-groups 2, 9, 8, and 25. ERIC-PCR showed no cluster of E. coli clones by either host species nor locality. To our knowledge, this is the first report of ESBL-E. coli among sheep, cattle, dogs, and rodents of Chile, confirming their fecal carriage among domestic and wild animals in small-scale farms. The high prevalence of ESBL-E. coli in dogs encourages further investigation on their role as potential reservoirs of this bacteria in agricultural settings.


Altered gray matter volumes in post-stroke depressive patients after subcortical stroke.
Stroke survivors are known to suffer from post-stroke depression (PSD). However, the likelihood of structural changes in the brains of PSD patients has not been explored. This study aims to extract changes in the gray matter of these patients and test how these changes account for the PSD symptoms. High-resolution T1 weighted images were collected from 23 PSD patients diagnosed with subcortical stroke. Voxel-based morphometry and support vector machine analyses were used to analyze the data. The results were compared with those collected from 33 non-PSD patients. PSD group showed decreased gray matter volume (GMV) in the left middle frontal gyrus (MFG) when compared to the non-PSD patients. Together with the clinical and demographic variables, the MFG's GMV predictive model was able to distinguish PSD from the non-PSD patients (0•70 sensitivity and 0•88 specificity). The changes in the left inferior frontal gyrus (61%) and dorsolateral prefrontal cortex (39%) suggest that the somatic/affective symptoms in PSD is likely to be due to patients' problems with understanding and appraising negative emotional stimuli. The impact brought by the reduced prefrontal to limbic system connectivity needs further exploration. These findings indicate possible systemic involvement of the frontolimbic network resulting in PSD after brain lesions which is likely to be independent from the location of the lesion. The results inform specific clinical interventions to be provided for treating depressive symptoms in post-stroke patients.


An amphipathic trans-acting phosphorothioate RNA element delivers an uncharged phosphorodiamidate morpholino sequence in mdx mouse myotubes.
An efficient method for the delivery of uncharged polyA-tailed phosphorodiamidate morpholino sequences (PMO) in mammalian cells consists of employing a synthetic 8-mer amphipathic trans-acting poly-2'-O-methyluridylic thiophosphate triester element (2'-OMeUtaPS) as a transfection reagent. Unlike the dTtaPS DNA-based element, this RNA element is potent at delivering polyA-tailed PMO sequences to HeLa pLuc 705 cells or to myotube muscle cells. However, much like dTtaPS, the 2'-OMeUtaPS-mediated internalization of PMO sequences occurs through an energy-dependent mechanism; macropinocytosis appears to be the predominant endocytic pathway used for cellular uptake. The transfected PMO sequences induce alternate splicing of either the pre-mRNA encoding luciferase in HeLa pLuc 705 cells or the excision of exon 23 from the pre-mRNA encoding dystrophin in myotube muscle cells of the mdx mouse model of muscular dystrophy with an efficiency comparable to that of commercial cationic lipid reagents but without detrimental cytotoxicity.


In vivo tracking and immunological properties of pulsed porcine monocyte-derived dendritic cells.
Cellular therapies using immune cells and in particular dendritic cells (DCs) are being increasingly applied in clinical trials and vaccines. Their success partially depends on accurate delivery of cells to target organs or migration to lymph nodes. Delivery and subsequent migration of cells to regional lymph nodes is essential for effective stimulation of the immune system. Thus, the design of an optimal DC therapy would be improved by optimizing technologies for monitoring DC trafficking. Magnetic resonance imaging (MRI) represents a powerful tool for non-invasive imaging of DC migration in vivo. Domestic pigs share similarities with humans and represent an excellent animal model for immunological studies. The aim of this study was to investigate the possibility using pigs as models for DC tracking in vivo. Porcine monocyte derived DC (MoDC) culture with superparamagnetic iron oxide (SPIO) particles was standardized on the basis of SPIO concentration and culture viability. Phenotype, cytokine production and mixed lymphocyte reaction assay confirmed that porcine SPIO-MoDC culture were similar to mock MoDCs and fully functional in vivo. Alike, similar patterns were obtained in human MoDCs. After subcutaneous inoculation in pigs, porcine SPIO-MoDC migration to regional lymph nodes was detected by MRI and confirmed by Perls staining of draining lymph nodes. Moreover, after one dose of virus-like particles-pulsed MoDCs specific local and systemic responses were confirmed using ELISPOT IFN-γ in pigs. In summary, the results in this work showed that after one single subcutaneous dose of pulsed MoDCs, pigs were able to elicit specific local and systemic immune responses. Additionally, the dynamic imaging of MRI-based DC tracking was shown using SPIO particles. This proof-of-principle study shows the potential of using pigs as a suitable animal model to test DC trafficking with the aim of improving cellular therapies.


Relative bioavailabilities of organic zinc sources with different chelation strengths for broilers fed a conventional corn-soybean meal diet.
An experiment was conducted to estimate relative bioavailability of Zn in 3 organic zinc sources with different chelation strength (Q(f)) compared with ZnSO(4). A total of 1,092, 1-d-old male broiler chicks were assigned randomly to 6 replicate cages (14 chicks per cage) for each of 13 treatments. Dietary treatments included the basal corn-soybean meal diet (27.82 mg of Zn/kg of DM) supplemented with 0, 30, 60, or 90 mg of added Zn as reagent ZnSO(4), or Zn sources with Q(f) of 6.5 (11.93% Zn; Zn AA C), 30.7 (13.27% Zn; Zn Pro B), or 944.0 (18.61% Zn; Zn Pro A)/kg, which are considered as weak, moderate, or strong Q(f), respectively. Bone Zn, pancreas Zn, pancreas metallothionein (MT) concentration, and pancreas MT messenger RNA (mRNA) were analyzed at 6, 10, or 14 d of age. The results showed that bone Zn, pancreas Zn, pancreas MT concentration, and pancreas MT mRNA increased linearly (P < 0.001) as dietary Zn concentration increased at all ages. At 6 d of age, pancreas MT mRNA differed (P < 0.001) among dietary Zn sources, and the same tendency was observed at 10 (P = 0.08) or 14 d (P = 0.06) of age. The R(2) for a linear model was greater on d 6 than d 10 or 14 for all the response criteria. Based on slope ratios from the multiple linear regression of pancreas MT mRNA concentration on daily intake of dietary Zn, the bioavailability of Zn AA C, Zn Pro B, and Zn Pro A relative to ZnSO(4) (100%) were 100.0, 121.1, and 72.3%, respectively, at 6 d of age. The results indicated that MT mRNA concentration in pancreas was more sensitive in reflecting differences in bioavailability among organic Zn sources than the MT concentration in pancreas or other indices. Moreover, the bioavailability of organic Zn sources was closely related to their Q(f).


Biomechanical stimulation promotes blood vessel growth despite VEGFR-2 inhibition.
Angiogenesis, or the growth of new vasculature from existing blood vessels, is widely considered a primary hallmark of cancer progression. When a tumor is small, diffusion is sufficient to receive essential nutrients; however, as the tumor grows, a vascular supply is needed to deliver oxygen and nutrients into the increasing mass. Several anti-angiogenic cancer therapies target VEGF and the receptor VEGFR-2, which are major promoters of blood vessel development. Unfortunately, many of these cancer treatments fail to completely stop angiogenesis in the tumor microenvironment (TME). Since these therapies focus on the biochemical activation of VEGFR-2 via VEGF ligand binding, we propose that mechanical cues, particularly those found in the TME, may be a source of VEGFR-2 activation that promotes growth of blood vessel networks even in the presence of VEGF and VEGFR-2 inhibitors. In this paper, we analyzed phosphorylation patterns of VEGFR-2, particularly at Y1054/Y1059 and Y1214, stimulated via either VEGF or biomechanical stimulation in the form of tensile strains. Our results show prolonged and enhanced activation at both Y1054/Y1059 and Y1214 residues when endothelial cells were stimulated with strain, VEGF, or a combination of both. We also analyzed Src expression, which is downstream of VEGFR-2 and can be activated through strain or the presence of VEGF. Finally, we used fibrin gels and microfluidic devices as 3D microtissue models to simulate the TME. We determined that regions of mechanical strain promoted increased vessel growth, even with VEGFR-2 inhibition through SU5416. Overall, understanding both the effects that biomechanical and biochemical stimuli have on VEGFR-2 activation and angiogenesis is an important factor in developing effective anti-angiogenic therapies. This paper shows that VEGFR-2 can be mechanically activated through strain, which likely contributes to increased angiogenesis in the TME. These proof-of-concept studies show that small molecular inhibitors of VEGFR-2 do not fully prevent angiogenesis in 3D TME models when mechanical strains are introduced.


Spinal Cord Atrophy and Early Motor Recovery following Transverse Myelitis in Pediatric Patients.
To compare the motor recovery following transverse myelitis in pediatric patients with and without spinal cord atrophy. From January 1995 through December 2009, twenty children (8 boys and 12 girls with an onset at 5.7±3.8 years) that were diagnosed with transverse myelitis at a Children's Hospital in Korea, and undertaken an initial and follow-up spine magnetic resonance image (MRI) were included. Medical records and spine MRI scans were reviewed retrospectively. An initial MRI was taken 5.1±8.7 days after the onset. The interval between an initial and follow-up MRIs was 33.4±23.0 days. The motor recovery differences between subjects with and without spinal cord atrophy on follow-up MRIs were determined. Motor recovery was defined as the elevation of one or more grades of manual muscle tests of the Medical Research Council. Eight patients had developed spinal cord atrophies and 12 patients had not. Of the 8 patients with spinal cord atrophy, 7 showed no motor improvement. Among the 12 patients without atrophy, 11 had motor improvement. Spinal cord atrophy on follow-up MRIs were related to the risk of no motor improvement (odds ratio=77.0, 95% confidence interval [4.114-1441.049], p-value=0.001). Children with transverse myelitis who had developed spinal cord atrophy on follow-up MRIs had poor motor recovery than those who had not. The appearance of spinal cord atrophy on follow-up MRI could be an indicator of poor prognosis in pediatric transverse myelitis.


EFEMP1 expression promotes in vivo tumor growth in human pancreatic adenocarcinoma.
The progression of pancreatic cancer is dependent on local tumor growth, angiogenesis, and metastasis. EFEMP1, a recently discovered member of the fibulin family, was characterized with regard to these key elements of pancreatic cancer progression. Differential gene expression was assessed by mRNA microarray hybridization in FG human pancreatic adenocarcinoma cells and L3.6pl cells, a highly metastatic variant of FG. In vivo orthotopic tumor growth of EFEMP1-transfected FG cells was examined in nude mice. To assess the angiogenic properties of EFEMP1, vascular endothelial growth factor (VEGF) production of tumor cells, endothelial cell proliferation and migration, and tumor microvessel density were analyzed in response to EFEMP1. Further, tumor cell apoptosis, cell cycle progression, and resistance to cytotoxic agents were quantitated by propidium iodide staining and flow cytometry. In microarray hybridization, EFEMP1 was shown to be significantly up-regulated in L3.6pl cells compared with FG cells. Concordantly, EFEMP1 transfection of FG cells stimulated orthotopic and metastatic tumor growth in vivo. EFEMP1 expression resulted in a stimulation of VEGF production by tumor cells and an increased number of CD31-positive microvessels. Endothelial cell proliferation and migration were not altered by EFEMP1, indicating an indirect angiogenic effect. Further, EFEMP1 expression decreased apoptosis and promoted cell cycle progression in response to serum starvation or exposure to gemcitabine, 5-fluorouracil, and irinotecan. EFEMP1 has protumorigenic effects on pancreatic cancer in vivo and in vitro mediated by VEGF-driven angiogenesis and antiapoptotic mechanisms. Hence, EFEMP1 is a promising candidate for assessing prognosis and individualizing therapy in a clinical tumor setting.


Biogenesis of tight junctions: the C-terminal domain of occludin mediates basolateral targeting.
Tight junctions form a morphological and physical border between the apical and the basolateral cell surface domains of epithelial cells; hence assembly of tight junctions could occur from both of the two plasma membrane domains. We show here that the C-terminal cytoplasmic domain of occludin, the only known transmembrane protein of tight junctions, was sufficient to mediate basolateral expression of a chimeric protein. Since this chimera was transported directly to the basolateral membrane during biosynthesis, the C-terminal domain of occludin contains a basolateral targeting signal. Additionally, the C-terminal domain of occludin was also able to mediate endocytosis. Thus, the C-terminal cytoplasmic domain appears to govern intracellular transport of occludin. To test whether the basolateral membrane is an obligatory intermediate in transport of occludin to tight junctions, we analyzed the expression of occludin molecules rendered unable to efficiently integrate into tight junctions by the introduction of N-linked glycosylation sites into the two extracellular loops. Indeed, glycosylated occludin accumulated in the basolateral membrane, supporting a model in which the biogenesis of tight junctions occurs from this cell-surface domain.


Whether introduction of competency-based medical education should be advocated in India?
The healthcare needs of the general population are on the rise and to meet these demands, the healthcare professionals, especially doctors have to acquire a large number of skills. In the Indian settings, as of now, conventional system of education is being followed in medical colleges and this is despite the fact that it has many flaws associated with it. The objective of the article is to explore the utility and the need of Competency Based Medical Education (CBME) in Indian settings. It is a brief review of pertaining to the transition of delivery of medical education in India and is well-supported by the studies from different nations. CBME is a thoughtful approach to develop physicians in their future practice and encourages better accountability and flexibility. However, if so many things are good with CBME, then the question arises why it has not been implemented yet across all the medical colleges in India? This is because of the various challenges which have been identified in the planning and implementation phase of the program. In conclusion, CBME remains the ultimate solution for the problems persisting in the conventional system of medical education. However, a systemic plan and better involvement of the stakeholders in the preparedness phase will significantly enhance the chances of the success of the program.


Tunable TiO2-BN-Pd nanofibers by combining electrospinning and atomic layer deposition to enhance photodegradation of acetaminophen.
The demand for fresh and clean water sources is increasing globally, and there is a need to develop novel routes to eliminate micropollutants and other harmful species from water. Photocatalysis is a promising alternative green technology that has shown great performance in the degradation of persistent pollutants. Titanium dioxide is the most used catalyst owing to its attractive physico-chemical properties, but this semiconductor presents limitations in the photocatalysis process due to the high band gap and the fast recombination of the photogenerated carriers. Herein, a novel photocatalyst has been developed, based on titanium dioxide nanofibers (TiO2 NFs) synthesized by electrospinning. The TiO2 NFs were coated by atomic layer deposition (ALD) to grow boron nitride (BN) and palladium (Pd) on their surface. The UV-Vis spectroscopy measurements confirmed the increase of the band gap and the extension of the spectral response to the visible range. The obtained TiO2/BN/Pd nanofibers were then tested for photocatalysis, and showed a drastic increase of acetaminophen (ACT) degradation (>90%), compared to only 20% degradation obtained with pure TiO2 after 4 h of visible light irradiation. The high photocatalytic activity was attributed to the good dispersion of Pd NPs on TiO2-BN nanofibers, leading to a higher transfer of photoexcited hole carriers and a decrease of photogenerated electron-charge recombination. To confirm its reusability, recycling tests on the hybrid photocatalyst TiO2/BN/Pd have been performed, showing a good stability over 5 cycles under UV and visible light. In addition, toxicity tests as well as quenching tests were carried out to check the toxicity of the byproducts formed and to determine active species responsible for the degradation. The results presented in this work demonstrate the potential of TiO2/BN/Pd nanomaterials, and open new prospects for the preparation of tunable photocatalysts.


Relationship of the sinus anatomy to surface landmarks is a function of the sinus size difference between the right and left side: Anatomical study based on CT angiography.
Several cadaveric studies demonstrate reliable localization of the transverse sinus and the transverse sigmoid junction (TSJ). These studies use the line drawn from the inion to the posterior root of the zygoma (IZ) and the asterion, respectively. We investigated how the size difference between the right and left transverse sinuses (TS) and sigmoid sinuses (SS) affected the accuracy of their respective superficial landmarks, particularly with regards to where this relationship may result in unsafe and/or complicated surgical access. We utilized Vitrea software to render three-dimensional images based on computed tomographic angiography (CTA). We measured the relationship between the TS and SS to their respective superficial landmarks. We analyzed 50 patients in this study. The distal TS was found caudal to the inion-to-zygoma (IZ) line on average by 5.0 ± 4.3 mm on the right and 6.4 ± 9.3 mm on the left. The mid TS was found cranial on average 3.5 ± 5.7 mm on the right and 3.2 ± 6.0 mm cranial on the left to the superior nuchal line (SNL). The distance from the asterion to the SS was 11.5 ± 2.4 mm medial on the right and 12.1 ± 4.4 mm medial on the left. The average distance was greater on the left than the right when using the IZ landmark. This was directly proportional to the size difference of the sinuses (r2 = 0.15, P = 0.03). Statistically significant differences between the right and left TS and SS were seen in terms of size. This appeared to correlate nicely to the differences observed between the locations of the TSs' and their respective superficial landmarks.


Coptis chinensis and Berberine Ameliorate Chronic Ulcerative Colitis: An Integrated Microbiome-Metabolomics Study.
Coptis chinensis Franch (RC), has historically been used for the treatment of "Xiao Ke" and "Xia Li" symptoms in China. "Xia Li" is characterized by abdominal pain and diarrhea, which are similar to the clinical symptoms of ulcerative colitis (UC). For the first time, this study aims to compare the anti-colitis effects of berberine (BBR) and total RC alkaloids (TRCA) and investigate the underlying metabolites and gut microbiota biomarkers. Metabolomics results showed that several colitis-related biomarkers, including lysophosphatidyl ethanolamine, lysophosphatidylcholine, scopolamine-methyl-bromide, N1-methyl-2-pyridone-5-carboxamide, 4-hydroxyretinoic acid, and malic acid, were significantly improved in model mice after BBR and TRCA treatments. High-dose BBR and TRCA treatments reversed the mouse colon shortening caused by dextran sodium sulfate (DSS), alleviated bowel wall swelling, and reduced inflammatory cell infiltration. BBR and TRCA restored the damaged mucosa integrity in colitis mice by upregulating claudin 1 and occludin, preventing colon epithelium apoptosis by inhibiting the cleavage of caspase 3. Additionally, BBR and TRCA significantly decreased the richness of the pathogenic bacteria Bacteroides acidifaciens but increased the abundance of the probiotic Lactobacillus spp. Notably, TRCA exhibited superior anti-colitis effects to those of BBR. Thus, this agent warrants further study and application in the treatment of inflammatory bowel disease in the clinic.


[Hepatosplenic candidiasis in acute non-lymphocytic leukemia].
Eleven patients with acute non-lymphocytic leukemia developed hepatosplenic candidiasis following the termination of chemotherapy. Five who did not receive amphoteicin B (AMPH) died of liver failure, whereas the other six who received AMPH and/or miconazole or fluconazole were cured. The features of hepatosplenic candidiasis included prolonged high fever not responsive to antibiotics and hepatomegaly with right-sided hypochondrial pain developing after severe neutropenia. Even if the neutropenia recovered, these symptoms did not subside. In addition, elevation of the serum alkaline phosphatase and total bilirubin levels were observed at onset. CT scan revealed multiple low-density areas of varying size that showed no contrast enhancement. Ultrasonography also demonstrated hypoechoic or hyperechoic lesions, and a so-called "target sign appearance" in the liver and spleen. The clinical diagnosis for hepatosplenic candidiasis is not so difficult because of the uniform symptoms, signs and laboratory abnormalities. The importance of the early administration of antifungal agents to obtain a cure is discussed in this article.


Sociocognitive factors associated with nonadherence to medication after hospital discharge.
Poor adherence to prescribed medication is a well-known problem and continues to be a major challenge in all medical specialties. Unlike previous studies that have mainly focused on nonadherence behaviors in specific diseases, this study sought to examine socio-cognitive factors associated with nonadherence behavior in a sample of a general clinical population. A questionnaire investigating socio-demographic and cognitive factors and a telephone follow-up interview were administered to 84 patients recruited in a General Medicine Unit before their discharge. Half of the participants were informed about that follow-up procedure. One month after hospital discharge, 42% of uninformed patients reported nonadherence behaviors, as against 21% of informed patients. Middle-aged patients and short-term treatments were associated significantly more often with nonadherence. Among cognitive factors, patients' perceived risks and benefits of nonadherence, personal susceptibility to diseases, subjective health value, and reported memory failures were significantly associated with adherence. We conclude that a patient's perception may be more important than medication load, illness severity, and complexity of regimen in influencing medication adherence, and that a telephone call follow-up helps in monitoring medication adherence after hospital discharge.


Health literacy and patient empowerment: separating con-joined twins in the context of chronic low back pain.
While health literacy has been widely considered key to patient empowerment, an alternative approach separates both concepts and distinguishes between different types of patients according to their levels of health literacy and empowerment. These types are deemed to vary in their health-related actions and outcomes. In this study, we examine the relationship between health literacy and patient empowerment and compare socio-demographic characteristics, health-related activities, and health outcomes in four types of patients suffering from chronic low back pain (cLBP). In a cross-sectional study, 273 cLBP patients from four Swiss cantons (Vaud, Geneva, Fribourg, Ticino) and Lombardy (Italy) were invited by their healthcare providers to complete a self-administered paper-and-pencil questionnaire which assessed patients' health literacy, empowerment, involvement in the medical encounter, medication non-adherence, and perceived pain and functionality as a measure of health outcomes. Health literacy and patient empowerment were not significantly correlated with each other, r(271) = .09, p > .05, allowing to differentiate between four types of patients based on their levels of health literacy and patient empowerment. Subsequent chi-square tests and analyses of variances revealed significant differences among patients that could, however, only be attributed to health literacy, as in the case of age and educational attainment, or patient empowerment, as in the case of patients' involvement in the medical encounter. No significant differences were evident for gender, medication non-adherence, and health outcomes. The study provides empirical evidence for the need to consider health literacy and patient empowerment as independent concepts in the context of cLBP but calls for further studies to be able to conclude on how the two concepts interact and determine health-related activities and outcomes.


Carnosine to Combat Novel Coronavirus (nCoV): Molecular Docking and Modeling to Cocrystallized Host Angiotensin-Converting Enzyme 2 (ACE2) and Viral Spike Protein.
Angiotensin-converting enzyme 2 (ACE2) plays an important role in the entry of coronaviruses into host cells. The current paper described how carnosine, a naturally occurring supplement, can be an effective drug candidate for coronavirus disease (COVID-19) on the basis of molecular docking and modeling to host ACE2 cocrystallized with nCoV spike protein. First, the starting point was ACE2 inhibitors and their structure-activity relationship (SAR). Next, chemical similarity (or diversity) and PubMed searches made it possible to repurpose and assess approved or experimental drugs for COVID-19. Parallel, at all stages, the authors performed bioactivity scoring to assess potential repurposed inhibitors at ACE2. Finally, investigators performed molecular docking and modeling of the identified drug candidate to host ACE2 with nCoV spike protein. Carnosine emerged as the best-known drug candidate to match ACE2 inhibitor structure. Preliminary docking was more optimal to ACE2 than the known typical angiotensin-converting enzyme 1 (ACE1) inhibitor (enalapril) and quite comparable to known or presumed ACE2 inhibitors. Viral spike protein elements binding to ACE2 were retained in the best carnosine pose in SwissDock at 1.75 Angstroms. Out of the three main areas of attachment expected to the protein-protein structure, carnosine bound with higher affinity to two compared to the known ACE2 active site. LibDock score was 92.40 for site 3, 90.88 for site 1, and inside the active site 85.49. Carnosine has promising inhibitory interactions with host ACE2 and nCoV spike protein and hence could offer a potential mitigating effect against the current COVID-19 pandemic.


Cellular mechanisms of impaired adrenergic responsiveness in neonatal dogs.
The myocardial responsiveness of conscious, instrumental dogs to exogenously administered isoproterenol and norepinephrine was investigated in neonatal, 6-wk-old, and adult animals. Comparable base-line values for peak left ventricular derivative of pressure with respect to time were observed in all age categories. However, when compared with adult responses, the sympathomimetic amine-induced increases in neonatal left ventricular dP/dt were significantly blunted at each concentration of adrenergic agonist examined, whereas the 6-wk-old puppies displayed an intermediate inotropic response. To investigate the cellular mechanisms of this blunted neonatal response, we correlated physiologic and biochemical measurements of the myocardial responses to catecholamines in each age category. When compared with adult myocardial membrane preparations, neonatal cardiac membranes were characterized in vitro by an increased density of beta-adrenergic binding sites, comparable affinity for adrenergic agonists and antagonists, and an enhanced coupling of adenylate cyclase activation to receptor occupancy. Simultaneous changes in either the serum catecholamine concentration or the membrane content of other intrinsic proteins failed to account for the observed neonatal increase in beta-adrenergic receptor density. These findings are most consistent with a compensatory mechanism of the cardiac cell membrane, whereby an inherent depression in the adrenergic responsiveness of the immature myocardium appears to induce the increase in receptor density and activation of adenylate cyclase.


The D-hormone analog alfacalcidol: the pioneer beyond the horizon of osteoporosis treatment.
Over the last 30 years, several clinical trials have reported the efficacy of D-hormone analogs to treat primary and secondary osteoporosis, and their genomic and nongenomic mode of action have been demonstrated with the progress of biochemical research technologies. Recent metaanalyses reviewed the preventive effect on falls and fractures of "vitamin D3" in the elderly population, mainly based on studies with alfacalcidol and calcitriol. In future a clear differentiation must be made between calcium and plain vitamin D supplementation in very old, vitamin D-deficient women and men (> 75 years) and the pharmacological treatment of patients with established osteoporosis using D-hormone analogs, independent of a patient's vitamin D status. The dual action of D-hormone analogs on bone and muscle is unique, and differentiates them from all other, bone-specific antiosteoporotic drugs. Based on its efficacy in preventing falls, alfacalcidol is an excellent partner for combination therapy to improve the antifracture efficacy, especially in elderly patients. Further research is required to elucidate the mechanism of new actions of D-hormone analogs on muscle, nerves, brain, and on the immune system, to determine their application in different diseases.


The prevalence of Lynch syndrome in women with endometrial cancer: a systematic review protocol.
Lynch syndrome is the most common inherited cancer syndrome, which predisposes individuals to a number of different cancers, principally colorectal and endometrial cancer. The early diagnosis of Lynch syndrome enables colorectal surveillance, which has been shown to save lives through the detection and removal of premalignant polyps and earlier detection of invasive disease. Endometrial cancer, which is often the sentinel cancer in women, provides an opportunity to diagnose Lynch syndrome and thus enable colorectal surveillance as well as the cascade testing for Lynch syndrome in other family members. These potential benefits have led to a call for the universal screening of women with endometrial cancer for Lynch syndrome, a practice that is now commonplace in colorectal cancer. Healthcare providers and clinicians are however restricted by insufficient knowledge about the prevalence of Lynch syndrome in women with endometrial cancer, with estimates varying as widely as 1-10%. The aim of this study is to perform a systematic review with a meta-analysis of the current literature base in order to estimate the prevalence of Lynch syndrome among women with endometrial cancer to inform this discussion. Medline, Embase, Cochrane Central Register of Controlled Trials (CENTRAL), Cochrane Methodology Register, NHS Health and Technology Assessment Database and the Web of Science will be systematically searched for relevant studies via the Ovid platform. Two authors will review the titles and abstracts independently, with discrepancy settled by a third author. Data extraction will be completed to record demographic, pathological and clinical data, as well as the diagnostic methods used for estimating the prevalence of Lynch syndrome in women with endometrial cancer. Bias will be assessed and recorded using the Newcastle-Ottawa Scale and that of the International Cochrane Collaboration. Dependent on the heterogeneity of the data, we aim to produce a cumulative incidence in addition to subgroup analyses as to investigate secondary outcomes. The aim of this systematic review is to provide a robust estimate of the prevalence of Lynch syndrome in women with endometrial cancer. This will enable resource allocation and decision-making regarding the appropriateness of screening all women, or certain women, with endometrial cancer for Lynch syndrome. Such a policy could enable the earlier diagnosis of Lynch syndrome in women and, through the application of colorectal cancer surveillance, improve their survival outcomes. This systematic review has been registered on PROSPERO (ref CRD42017081707 ).


Individual inorganic nanoparticles: preparation, functionalization and in vitro biomedical diagnostic applications.
Inorganic nanoparticles have become the focus of modern materials science due to their potential technological importance, particularly in bionanotechnology, which stems from their unique physical properties including size-dependent optical, magnetic, electronic, and catalytic properties. The present article provides an overview on the currently used individual inorganic nanoparticles for in vitro biomedical domains. These inorganic nanoparticles include iron oxides, gold, silver, silica, quantum dots (QDs) and second harmonic generation (SHG) particles. For each of these interesting nanoparticles, the main issues starting from preparation up to bio-related applications are presented.


Pulmonary toxicity in hamsters of smoke particles from Kuwaiti oil fires.
The Kuwaiti oil wells set on fire by retreating Iraqi troops at the end of the Persian Gulf War released complex particles, inorganic and organic gases, and hydrocarbons into the atmosphere, damaging the environment where many people live and work. In this study, we assessed the health effects of particles from the Kuwaiti oil fires by instilling hamsters intratracheally with particles (<3.5 microM in size) collected in Ahmadi, a residential area in Kuwait located downwind of hundreds of oil fires. Twenty-four hours after instillation, we performed bronchoalveolar lavage (BAL) to assess various indicators of pulmonary inflammation, including neutrophil and macrophage numbers; albumin, an index of air-blood barrier permeability; and activities of three enzymes: lactate dehydrogenase (LDH; an indicator of cell injury), myeloperoxidase (MPO; which indicates activation of neutrophils), and ss-N-acetylglucosaminidase (GLN; which is indicative of damage to macrophages or neutrophils). We compared the response of hamsters instilled with particles from Ahmadi to animals instilled with urban particles collected in St. Louis, Missouri. We also compared the Ahmadi particles against a highly fibrogenic positive control ([alpha]-quartz) and a relatively nontoxic negative control (iron oxide). When compared to hamsters instilled with particles from St. Louis, the animals treated with the Ahmadi particles had between 1.4- and 2.2-fold more neutrophils in their BAL fluids. The Ahmadi hamsters had more macrophages and lower MPO and LDH activities, but comparable albumin levels and GLN activities. Thus, the acute toxicity of the Ahmadi particles was roughly similar to that of urban particles collected in the United States, when identical masses were compared. However, the relatively higher concentrations of particles measured in Kuwait and Saudi Arabia during the oil fires (at times more than 16 times higher than the EPA standard) is of particular concern. In addition, since the long-term effects of exposure to these particles remains unknown, further studies are needed to fully assess the health effects of the Kuwaiti oil fires.


The prognostic role of inflammation-scores on overall survival in lung cancer patients.
Inflammation has been validated as a host-related prognostic marker in cancer. The Glasgow Prognostic score (GPS) and neutrophil-to-lymphocyte ratio (NLR) are suggested measures of inflammation. However, the allocation of patients has been questioned. Hence, optimized inflammation-scores has been developed, such as the combined NLR and GPS (CNG) system, and the Aarhus composite biomarker score (ACBS). So far, these optimized inflammation-scores have not been validated in lung cancer patients. We evaluated if the optimized inflammation-scores were prognostic markers of inferior survival in lung cancer patients. Furthermore, we tested which of the optimized inflammation-scores led to better patient-allocation. The cohort of this prospective study composed of 275 non-small cell lung cancer patients. We evaluated pre-diagnostic serum biomarkers for GPR, NLR, platelet-to-lymphocyte ratio as well as the optimized inflammation-scores CNG and ABCS as predictors of overall survival (OS), and we examined the patient-allocation derived from each inflammation-score. Each of the evaluated inflammation-scores could predict the overall survival even when adjustments were made for comorbidity and clinicopathological characteristics. When comparing the scores, the optimized inflammation-scores CNG and ACBS led to a better and more balanced patient-allocation. In the early clinical stages I & II, the optimized scores could reveal a subgroup of patients with poorer survival that is similar to stage III. In this cohort of lung cancer patients, we demonstrate that inflammation-scores are prognostic markers of inferior survival. Furthermore, we demonstrate that the optimized inflammation-scores CNG and ACBS lead to better patient-allocation independently of the clinicopathological characteristics and comorbidity.


Somatic Mosaicism in Amyotrophic Lateral Sclerosis and Frontotemporal Dementia Reveals Widespread Degeneration from Focal Mutations.
Although mutations in dozens of genes have been implicated in familial forms of amyotrophic lateral sclerosis (fALS) and frontotemporal degeneration (fFTD), most cases of these conditions are sporadic (sALS and sFTD), with no family history, and their etiology remains obscure. We tested the hypothesis that somatic mosaic mutations, present in some but not all cells, might contribute in these cases, by performing ultra-deep, targeted sequencing of 88 genes associated with neurodegenerative diseases in postmortem brain and spinal cord samples from 404 individuals with sALS or sFTD and 144 controls. Known pathogenic germline mutations were found in 20.6% of ALS, and 26.5% of FTD cases. Predicted pathogenic somatic mutations in ALS/FTD genes were observed in 2.7% of sALS and sFTD cases that did not carry known pathogenic or novel germline mutations. Somatic mutations showed low variant allele fraction (typically <2%) and were often restricted to the region of initial discovery, preventing detection through genetic screening in peripheral tissues. Damaging somatic mutations were preferentially enriched in primary motor cortex of sALS and prefrontal cortex of sFTD, mirroring regions most severely affected in each disease. Somatic mutation analysis of bulk RNA-seq data from brain and spinal cord from an additional 143 sALS cases and 23 controls confirmed an overall enrichment of somatic mutations in sALS. Two adult sALS cases were identified bearing pathogenic somatic mutations in DYNC1H1 and LMNA, two genes associated with pediatric motor neuron degeneration. Our study suggests that somatic mutations in fALS/fFTD genes, and in genes associated with more severe diseases in the germline state, contribute to sALS and sFTD, and that mosaic mutations in a small fraction of cells in focal regions of the nervous system can ultimately result in widespread degeneration.


Kinetic study on the inhibition of xanthine oxidase by extracts from two selected Algerian plants traditionally used for the treatment of inflammatory diseases.
In order to further understand and assess the validity of herbal medicine, we investigated the potential inhibitory effect of various extracts from Fraxinus angustifolia and Pistacia lentiscus, two plants used traditionally in Algeria against several inflammatory diseases such as rheumatism, arthritis, and gout, on purified bovine milk xanthine oxidase (XO) activity. The total phenolic contents of the leaves and bark of F. angustifolia and the leaves and seeds of P. lentiscus were estimated. P. lentiscus aqueous fractions from hexane and chloroform extractions and F. angustifolia aqueous fraction from ethyl acetate extraction inhibited XO activity by 72.74 +/- 2.63% (50% inhibitory concentration [IC(50)] = 27.52 microg/mL), 68.97 +/- 3.89% (IC(50) = 42.46 microg/mL) and 53.92 +/- 3.17% (IC(50) = 58.84 mmicroug/mL), respectively, at 100 microg/mL, compared to that of reference drug, allopurinol (98.18% [IC(50) = 6.34 microg/mL]). Moreover, at a concentration of 50 microg/mL, both P. lentiscus extracts showed inhibition rates higher than 50%. F. angustifolia leaf extracts showed only mild inhibition. Lineweaver-Burk analysis showed that the inhibitory activity exerted by F. angustifolia bark aqueous extract and P. lentiscus aqueous extracts is of mixed type, whereas the leaf extracts from F. angustifolia inhibited XO noncompetitively. Positive correlations were established between XO inhibition and total phenols (r = 0.89) and flavonoids (r = 0.93) for P. lentiscus and with total phenols (r = 0.72) and tannins (r = 0.54) for F. angustifolia. Our findings suggest that the therapeutic use of these plants may be due to the observed XO inhibition, thereby supporting their use in traditional folk medicine against inflammatory-related diseases, in particular, gout.


Drawings as tools to (re)imagine space in interdisciplinary global health research.
Understanding the role of space in infectious diseases' dynamics in urban contexts is key to developing effective mitigation strategies. Urbanism, a discipline that both studies and acts upon the city, commonly uses drawings to analyze spatial patterns and their variables. This paper revisits drawings as analytical and integrative tools for interdisciplinary research. We introduce the use of drawings in two interdisciplinary projects conducted in the field of global public health: first, a study about the heterogeneous burden of tuberculosis and COVID-19 in Lima, Peru, and second, a study about urban malaria in Jimma, Ethiopia. In both cases, drawings such as maps, plans, and sections were used to analyze spatial factors present in the urban context at different scales: from the scale of the territory, the city, and the district, to the neighborhood and the household. We discuss the methodological approaches taken in both cases, considering the nature of the diseases being investigated as well as the natural and social context in which the studies took place. We contend that the use of drawings helps to reimagine space in public health research by adding a multidimensional perspective to spatial variables and contexts. The processes and products of drawing can help to (a) identify systemic relations within the spatial context, (b) facilitate integration of quantitative and qualitative data, and (c) guide the formulation of policy recommendations, informing public and urban health planning.


Azithromycin for the cure of Helicobacter pylori infection.
Azithromycin, a new antibiotic chemically related to erythromycin, has been proposed for the cure of Helicobacter pylori, achieving high gastric tissue levels (above the MIC for H. pylori) after oral administration. The aim of the study was to establish whether azithromycin plus metronidazole in association with either omeprazole or bismuth subcitrate is useful in curing H. pylori infection of the stomach. The study involved 132 dispeptic patients who proved to be H. pylori infected by antral and corpus histology (Giemsa, modified) and rapid urease test (CLOtest); the Sydney system was used to classify the gastritis. Sixty-three patients received bismuth subcitrate 120 mg q.i.d. for 14 days plus azithromycin 500 mg o.d. for the first 3 days plus metronidazole 250 mg q.i.d. for the first 7 days; 69 patients received omeprazole 40 mg for 14 days plus azithromycin 500 mg o.d. for the first 3 days plus metronidazole 250 mg q.i.d. for the first 7 days. Patients were well matched for common clinical variables. Cure of H. pylori infection was assessed by the same methods 2 months after completion of treatment. Eleven patients dropped out of the study, only one reporting side effects (nausea, vomiting, and epigastric pain). Cumulative "per protocol" cure rate was 66.1% (CI 95%, 58.5-75.3%). There was no statistically significant difference between the two treatment groups: 58.9% (CI 95% 48.4-74.6%) versus 72.3% (CI 95%, 60.7-82.5%). Intention to treat does not substantially modify results. Few side effects were recorded. Cured patients showed a significant reduction in the activity of gastritis. Azithromycin, combined with omeprazole and metronidazole, the cure rate of H. pylori was about 70%. The cure of H. pylori infection improves the activity of gastritis.


The effect of an endothelin-receptor antagonist, bosentan, on blood pressure in patients with essential hypertension. Bosentan Hypertension Investigators.
Endothelin is a powerful vasoconstrictor peptide derived from the endothelium. We evaluated the contribution of endothelin to blood-pressure regulation in patients with essential hypertension by studying the effect of an endothelin-receptor antagonist, bosentan. We studied 293 patients with mild-to-moderate essential hypertension. After a placebo run-in period of four to six weeks, patients were randomly assigned to receive one of four oral doses of bosentan (100, 500, or 1000 mg once daily or 1000 mg twice daily), placebo, or the angiotensin-converting-enzyme inhibitor enalapril (20 mg once daily) for four weeks. Blood pressure was measured before and after treatment. As compared with placebo, bosentan resulted in a significant reduction in diastolic pressure with a daily dose of 500 or 2000 mg (an absolute reduction of 5.7 mm Hg at each dose), which was similar to the reduction with enalapril (5.8 mm Hg). There were no significant changes in heart rate. Bosentan did not result in activation of the sympathetic nervous system (as determined by measurement of the plasma norepinephrine level) or the renin-angiotensin system (as determined by measurements of plasma renin activity and angiotensin II levels). An endothelin-receptor antagonist, bosentan, significantly lowered blood pressure in patients with essential hypertension, suggesting that endothelin may contribute to elevated blood pressure in such patients. The favorable effect of treatment with bosentan on blood pressure occurred without reflexive neurohormonal activation.


Characterization of Microbiota that Influence Immunomodulatory Effects of Fermented Brassica rapa L.
Lactic acid bacteria (LAB) exert beneficial health effects by regulating immune responses. Brassica rapa L., known as Nozawana, is commonly consumed as a lactic acid-fermented food called nozawana-zuke. Few studies have investigated changes in the bacterial community and cytokine production activities during the fermentation of B. rapa L. In order to obtain more detail information, we herein conducted a study on fresh B. rapa L. fermented for 28 d. An amplicon analysis of the 16S rRNA gene revealed that Lactobacillales predominated during fermentation, and the microbiota became less diverse on day 7 or later. Fermented B. rapa L. promoted the production of interferon (IFN)-γ and interleukin (IL)-10 by mouse spleen cells more than non-fermented vegetables. Lactobacillus curvatus was the predominant species during fermentation, followed by L. plantarum and L. brevis. L. sakei was occasionally detected. A correlation analysis showed that IFN-γ concentrations positively correlated with the numbers of L. curvatus and L. plantarum, while those of IL-10 correlated with the numbers of L. sakei in addition to these 2 species. Significantly higher levels of IFN-γ and IL-10 were induced by fermented B. rapa L. when isolated Lactobacillus strains were added as starter cultures. These results suggest that the Lactobacillus species present in fermented B. rapa L. are beneficial for manufacturing vegetables with immunomodulatory effects.


[The alteration of attractiveness of intact males mice to females chemosignals, subjected of ionizing radiation in sublethal dose].
After irradiation in a dose 4 Gy female mice of CBA and C57Bl/6 (female CBA during 18-23 days, female C57Bl/6 - 4-10 days) secretes with urine volatile components (chemosignals) which possess higher, than secretes intact females, attractiveness for intact males the same strains irrespective of a genotype. When estimation relative attractiveness postradiation secretes female mice CBA and C57Bl/6 intact males prefer chemosignals singenic (genetically identical) females during 1-23 day after irradiation. Observed olfactorial reaction male mice more differ from norm. In which males prefer chemosignals of allogenic (with a strange genotype) females. This disturbances identifed as postradiation reversion attractiving males of chemosignals, dependent on the genotype of females. Typical for norm chemosignalisation at females restored for 43 days after the irradiation. The mechanism and biological advisability of this phenomenon are discussed.


Thinking outside the box in clinical practice.
During difficult times we forget that as healthcare practitioners we are immensely privileged. We have a job, with regular work and generally don't have to worry about putting food on our families' table. But from a humanities perspective, we also have front row seats on the drama of life and no two days can be the same. Yet as we struggle to master our profession, the day to day realities of the job itself struggles to master us. If we become 'too hard' we may be fully competent yet fail to discharge our duties properly; however, should we become 'too soft', we may find ourselves not being able to discharge those duties at all. Striking that 'happy' balance is a decision we each make for ourselves every day during our decades of practice. For me, it has been necessary from the outset to include medical humanities within the clinico-medical perspective of daily practice. My definition of Medical Humanities will not only include medical history but also, stories, films and plays. This article relates some practices which I have found useful.