Eavesdropping on Tinnitus Using MEG: Lessons Learned and Future Perspectives.
Tinnitus has been widely investigated in order to draw conclusions about the underlying causes and altered neural activity in various brain regions. Existing studies have based their work on different tinnitus frameworks, ranging from a more local perspective on the auditory cortex to the inclusion of broader networks and various approaches towards tinnitus perception and distress. Magnetoencephalography (MEG) provides a powerful tool for efficiently investigating tinnitus and aberrant neural activity both spatially and temporally. However, results are inconclusive, and studies are rarely mapped to theoretical frameworks. The purpose of this review was to firstly introduce MEG to interested researchers and secondly provide a synopsis of the current state. We divided recent tinnitus research in MEG into study designs using resting state measurements and studies implementing tone stimulation paradigms. The studies were categorized based on their theoretical foundation, and we outlined shortcomings as well as inconsistencies within the different approaches. Finally, we provided future perspectives on how to benefit more efficiently from the enormous potential of MEG. We suggested novel approaches from a theoretical, conceptual, and methodological point of view to allow future research to obtain a more comprehensive understanding of tinnitus and its underlying processes.


Role of the PB2 627 Domain in Influenza A Virus Polymerase Function.
The RNA genome of influenza A viruses is transcribed and replicated by the viral RNA-dependent RNA polymerase, composed of the subunits PA, PB1, and PB2. High-resolution structural data revealed that the polymerase assembles into a central polymerase core and several auxiliary highly flexible, protruding domains. The auxiliary PB2 cap-binding and the PA endonuclease domains are both involved in cap snatching, but the role of the auxiliary PB2 627 domain, implicated in host range restriction of influenza A viruses, is still poorly understood. In this study, we used structure-guided truncations of the PB2 subunit to show that a PB2 subunit lacking the 627 domain accumulates in the cell nucleus and assembles into a heterotrimeric polymerase with PB1 and PA. Furthermore, we showed that a recombinant viral polymerase lacking the PB2 627 domain is able to carry out cap snatching, cap-dependent transcription initiation, and cap-independent ApG dinucleotide extension in vitro, indicating that the PB2 627 domain of the influenza virus RNA polymerase is not involved in core catalytic functions of the polymerase. However, in a cellular context, the 627 domain is essential for both transcription and replication. In particular, we showed that the PB2 627 domain is essential for the accumulation of the cRNA replicative intermediate in infected cells. Together, these results further our understanding of the role of the PB2 627 domain in transcription and replication of the influenza virus RNA genome.IMPORTANCE Influenza A viruses are a major global health threat, not only causing disease in both humans and birds but also placing significant strains on economies worldwide. Avian influenza A virus polymerases typically do not function efficiently in mammalian hosts and require adaptive mutations to restore polymerase activity. These adaptations include mutations in the 627 domain of the PB2 subunit of the viral polymerase, but it still remains to be established how these mutations enable host adaptation on a molecular level. In this report, we characterize the role of the 627 domain in polymerase function and offer insights into the replication mechanism of influenza A viruses.


Audit of a system for dealing with a practice's laboratory test results.
In order to improve efficiency in a non-computerized practice of 4700 patients the system for dealing with laboratory test results and communicating them to patients was audited over a two-week period. The audit involved a questionnaire for the practice team, a postal questionnaire to 36 patients, and an analysis of doctors' and receptionists' workload when dealing with laboratory test results. A new system was introduced, with two receptionists logging investigation details into a newly designed results book, and with date/process stamping of results. The new system was re-audited using another practice questionnaire and analysis of doctors' and receptionists' workload and found to be as effective as the old system but less time consuming, largely owing to the layout of the new results book. All members of the practice team were more satisfied with the new system. The function of a results book and its role in doctor-patient communication is discussed.


Human rights responsibilities of pharmaceutical companies in relation to access to medicines.
Although access to medicines is a vital feature of the right to the highest attainable standard of health ("right to health"), almost two billion people lack access to essential medicines, leading to immense avoidable suffering. While the human rights responsibility to provide access to medicines lies mainly with States, pharmaceutical companies also have human rights responsibilities in relation to access to medicines. This article provides an introduction to these responsibilities. It briefly outlines the new UN Guiding Principles on Business and Human Rights and places the human rights responsibilities of pharmaceutical companies in this context. The authors draw from the work of the first UN Special Rapporteur on the right to the highest attainable standard of health, in particular the Human Rights Guidelines for Pharmaceutical Companies in Relation to Access to Medicines that he presented to the UN General Assembly in 2008, and his UN report on GlaxoSmithKline (GSK). While the Guiding Principles on Business and Human Rights are general human rights standards applicable to all business entities, the Human Rights Guidelines for Pharmaceutical Companies consider the specific human rights responsibilities of one sector (pharmaceutical companies) in relation to one area of activity (access to medicines). The article signals the human rights responsibilities of all pharmaceutical companies, with particular attention to patent-holding pharmaceutical companies. Adopting a right-to-health "lens," the article discusses GSK and accountability. The authors argue that human rights should shape pharmaceutical companies' policies, and provide standards in relation to which pharmaceutical companies could, and should, be held accountable. They conclude that it is now crucial to devise independent, accessible, transparent, and effective mechanisms to monitor pharmaceutical companies and hold them publicly accountable for their human rights responsibilities.


Alteration of normal gastric flora in neonates receiving ranitidine.
To determine if the administration of ranitidine to neonates leads to an increase in gastric pH to > or = 4 and if this increase in gastric pH correlates with gastric colonization. 628 pH measurements and 276 gastric cultures were obtained from 86 neonates. Twenty-three patients received ranitidine and 63 patients served as controls. Treated patients had a mean gastric pH of 5.6 compared with a control mean pH of 4.4 (p < 0.0001). Gastric pH was significantly affected by feeding and postnatal age. 54 patients were colonized with pathogenic bacteria and/or yeast (n = 20 treated, n = 34 control). Length of hospitalization (p < 0.0001), increase in gastric pH (p < 0.01), days of antibiotics before culture (p < 0.0001), and ranitidine use (p < 0.0001) were associated with an increased rate of colonization. The use of ranitidine did lead to a significant increase in gastric pH and with this increase in gastric pH gastric colonization rates increased. No increased frequency of infection was found in ranitidine-treated infants.


Stereotactic radiosurgery for convexity meningiomas.
Meningiomas of the cerebral convexity are often surgically curable because both the mass and involved dura mater can be removed. Stereotactic radiosurgery has become an important primary or adjuvant treatment for patients with intracranial meningiomas. The authors evaluated clinical and imaging outcomes in patients with convexity meningiomas after radiosurgery. The patient cohort consisted of 125 patients with convexity meningiomas managed using radiosurgery at some point during an 18-year period. The patient series included 76 women, 55 patients who had undergone prior resection, and 6 patients with neurofibromatosis Type 2. Tumors were located in frontal (80 patients), parietal (24 patients), temporal (12 patients), and occipital (9 patients) areas. The WHO tumor grades in patients with prior resections were Grade I in 34 patients, Grade II in 15 patients, and Grade III in 6 patients. Seventy patients underwent primary radiosurgery and therefore had no prior histological tumor diagnosis. The mean tumor volume was 7.6 ml. Radiosurgery was performed using the Leksell Gamma Knife with a mean tumor margin dose of 14.2 Gy. Serial imaging was evaluated in 115 patients (92%). After primary radiosurgery, the tumor control rate was 92%. After adjuvant radiosurgery, the control rate was 97% for Grade I tumors. The actuarial tumor control rates at 3 and 5 years for the entire series were 86.1+/-3.8% and 71.6+/-8.6%, respectively. For patients with benign tumors (Grade I) and those without prior surgery, the actuarial tumor control rate was 95.3+/-2.3% and 85.8+/-9.3%, respectively. Delayed resection after radiosurgery was performed in 9 patients (7%) at an average of 35 months. No patient developed a subsequent radiation-induced tumor. The overall morbidity rate was 9.6%. Symptomatic peritumoral imaging changes compatible with edema or adverse radiation effects developed in 5%, at a mean of 8 months. Stereotactic radiosurgery provides satisfactory control rates either after resection or as an alternate to resection, particularly for histologically benign meningiomas. Its role is most valuable for patients whose tumors affect critical neurological regions and who are poor candidates for resection. Both temporary and permanent morbidity are related to brain location and tumor volume.


Potassium-Containing Fluids for Diabetic Ketoacidosis.
The purpose of this process improvement project was to determine the appropriate potassium concentration of stocked IV fluids used in the treatment of diabetic ketoacidosis (DKA) at the Children's Hospital of The King's Daughters (CHKD) Emergency Department. This is a retrospective chart review from July 1, 2018, through June 30, 2019. Patients ≤21 years of age with laboratory-confirmed DKA were included. The primary outcome was to determine the most used potassium concentration (20 mEq/L or 40 mEq/L) for stocked IV fluids. Secondary efficacy and safety outcomes included the percent of appropriately ordered fluids per the DKA treatment protocol, percent of patients who maintained goal serum potassium concentration, comparison of time from physician ordering to administration of prescribed IV fluids (t-elapsed), and comparison of serum potassium concentrations between the point of care (POC) test and basic metabolic panel (BMP). Of the 113 patients included, 73 (64.6%) received 40 mEq/L, 7 of whom received half potassium acetate plus half potassium phosphate, and 40 (35.4%) received 20 mEq/L potassium IV fluids. In 101 patients (89.4%), fluids were ordered appropriately per protocol. Of these patients, 53 (52.5%) maintained goal serum potassium concentration. The t-elapsed from physician ordering to administration of the prescribed fluid concentrations was not statistically significant. The mean POC versus BMP potassium concentration was statistically significant (4.56 mmol/L versus 4.96 mmol/L, respectively; 95% CI: -0.49 to -0.30; p < 0.001). The CHKD pharmacy should stock the most used 40 mEq/L potassium IV fluids for DKA treatment.


Machine learning-based in-hospital mortality prediction models for patients with acute coronary syndrome.
The purpose of this study is to identify the risk factors of in-hospital mortality in patients with acute coronary syndrome (ACS) and to evaluate the performance of traditional regression and machine learning prediction models. The data of ACS patients who entered the emergency department of Fujian Provincial Hospital from January 1, 2017 to March 31, 2020 for chest pain were retrospectively collected. The study used univariate and multivariate logistic regression analysis to identify risk factors for in-hospital mortality of ACS patients. The traditional regression and machine learning algorithms were used to develop predictive models, and the sensitivity, specificity, and receiver operating characteristic curve were used to evaluate the performance of each model. A total of 6482 ACS patients were included in the study, and the in-hospital mortality rate was 1.88%. Multivariate logistic regression analysis found that age, NSTEMI, Killip III, Killip IV, and levels of D-dimer, cardiac troponin I, CK, N-terminal pro-B-type natriuretic peptide (NT-proBNP), high-density lipoprotein (HDL) cholesterol, and Stains were independent predictors of in-hospital mortality. The study found that the area under the receiver operating characteristic curve of the models developed by logistic regression, gradient boosting decision tree (GBDT), random forest, and support vector machine (SVM) for predicting the risk of in-hospital mortality were 0.884, 0.918, 0.913, and 0.896, respectively. Feature importance evaluation found that NT-proBNP, D-dimer, and Killip were top three variables that contribute the most to the prediction performance of the GBDT model and random forest model. The predictive model developed using logistic regression, GBDT, random forest, and SVM algorithms can be used to predict the risk of in-hospital death of ACS patients. Based on our findings, we recommend that clinicians focus on monitoring the changes of NT-proBNP, D-dimer, Killip, cTnI, and LDH as this may improve the clinical outcomes of ACS patients.


The role of psychiatric comorbidity in the prediction of readmission for detoxification.
In a prospective study over a 28-month period in Iceland using a representative sample (N = 351), the association among patients seeking detoxification between comorbid psychopathology and (1) number of lifetime admissions, (2) readmissions for detoxification, and (3) a "revolving-door" career (i.e., at least four admissions within 30 months) was studied. Psychiatric diagnoses were assigned using the Diagnostic Interview Schedule (DIS), and the patients were asked about prior admissions for detoxification and then evaluated for 28 months for readmissions. Patients with no comorbid diagnoses had the fewest lifetime admissions. Agoraphobia/panic disorder predicted readmission (odds ratio [OR], 5.8) for those with less than two prior admissions. For those with more than three prior admissions, readmissions were primarily related to polysubstance abuse. The development of a revolving-door career was rare (6%) among those with less than four prior admissions. Among others (27%), it was primarily predicted by polysubstance abuse. Thus, early recognition and treatment of anxiety disorders among substance abusers might prevent further readmissions.


Ethics and financing: overview of the U.S. health care system.
An overview of the financing decisions that occurred with the U.S. health system during the past five decades was presented in relation to the ethical issues which gave rise to and resulted from those financing decisions. This health system evolved from decision-making grounded in altruism through increasing the access and supply of resources to a position of caution and financial prudence. Recently the decision-making became grounded in pragmatism with the realization that attempts to provide everyone with all possible health services on demand cannot be achieved. Financing decision have resulted in a health care system based on acute care and sophisticated technology but with too many hospital beds and physicians, both geographically maldistributed. Since this acute care system has been successful in preventing premature deaths, our population now lives longer and develops chronic illnesses which require different interventions; the system has neglected to focus on prevention and adequate care for long-term diseases. It has created a growing population of uninsured who are unable to afford health care when illness occurs. Alternative strategies were discussed at three levels of the health system. At the overall system level, the following was proposed: consistent application of ethical principles most appropriate to allocation decisions and the creation of health policy which encompasses chronic care and disease prevention components. At the organizational level, health administrators and local community leaders must cooperatively address local health issues; medical education should focus on long-term care and disease prevention; and medical practice should reduce variation in treatment patterns. At the population level, healthy lifestyles must be encouraged in addition to the development of alternative reimbursement plans to maximize access to health care. Davis and Rowland (1990:298) have stated that our nation's image is strained" ... as a just and humane society when significant portions of the population endure avoidable pain, suffering and even death because of an inability to pay for health." These are turbulent times in health care but addressing the ethical issues at many levels may lead to successful alternatives and ultimately to a workable health strategy for this country.


Effects of a Paternal Participation Program during Cesarean Section on Paternal Infant Attachment.
In this study effects of a paternal participation program during cesarean section on paternal infant attachment were investigate. The experimental treatment was an integrative nursing intervention to promote father to infant attachment. Study design was a non-equivalent control group posttest design. The program consisted of emotional support to spouse and father towards infant attachment immediately following cesarean birth. Participants were 66 men, partners of women with normal full term pregnancy having a cesarean section with spinal or epidural anesthesia, (experimental group, 34; control group, 32). The experiment was carried out from August 1 to October 30, 2010. Control group data were obtained from May 1 to June 30, 2012. Posttest was performed 72 hours after cesarean birth. A self-report questionnaire including a paternal attachment instrument was used. Data were analyzed using t-test, propensity score matching, and analysis of covariance with the SPSS/WIN 18.0 program. Total score for paternal infant attachment in the experimental group was significantly higher than the control group (p<.001). After matching, significant differences were found between the two groups through all subcategories. Adjusted mean score for paternal infant attachment verified experimental effects. Results indicate that this paternal participation program during cesarean section is effective in improving paternal infant attachment.


Diencephalic locomotor region in the lamprey--afferents and efferent control.
In vertebrates, locomotion can be initiated by stimulation of the diencephalic locomotor region (DLR). Little is known of the different forebrain regions that provide input to the neurons in DLR. In the lamprey, it had been shown previously that DLR provides monosynaptic input to reticulospinal neurons, which in turn elicit rhythmic ventral root activity at the spinal level. To show that actual locomotor movements are produced from DLR, we use a semi-intact preparation in which the brain stem is exposed and the head fixed, while the body is left to generate actual swimming movements. DLR stimulation induced symmetric locomotor movements with an undulatory wave transmitted along the body. To explore if DLR is under tonic GABAergic input under resting conditions, as in mammals, GABAergic antagonists and agonists were locally administered into DLR. Injections of GABA agonists inhibited locomotion, whereas GABA antagonists facilitated the induction of locomotion. These findings suggest that GABAergic projections provide tonic inhibition that once turned off can release locomotion. Double-labeling experiments were carried out to identify GABAergic projections to the DLR. Populations of GABAergic projection neurons to DLR originated in the caudoventral portion of the medial pallium, the lateral and dorsal pallium, and the striatal area. These different GABAergic projection neurons, which also project to other brain stem motor centers, may represent the basal ganglia output to DLR. Moreover, electrical stimulation of striatum induced long-lasting plateau potentials in reticulospinal cells and associated locomotor episodes dependent on DLR being intact, suggesting that striatum may act via the basal ganglia output identified here.


Characterization of Capsicum species using anatomical and molecular data.
Capsicum species are frequently described in terms of genetic divergence, considering morphological, agronomic, and molecular databases. However, descriptions of genetic differences based on anatomical characters are rare. We examined the anatomy and the micromorphology of vegetative and reproductive organs of several Capsicum species. Four Capsicum accessions representing the species C. annuum var. annuum, C. baccatum var. pendulum, C. chinense, and C. frutescens were cultivated in a greenhouse; leaves, fruits and seeds were sampled and their organ structure analyzed by light and scanning electronic microscopy. Molecular accession characterization was made using ISSR markers. Polymorphism was observed among tector trichomes and also in fruit color and shape. High variability among accessions was detected by ISSR markers. Despite the species studied present a wide morphological and molecular variability that was not reflected by anatomical features.


Beta-lactamase activity in Shigella sonnei.
The basis of ampicillin resistance in Shigella sonnei was analyzed for a number of isolates. Most isolates that were resistant to ampicillin and cephalothin failed to transfer resistance. Isolates resistant to cephalothin and ampicillin were inhibited by mecillinam, cefamandole, and cefoxitin. Six strains were selected for study. These differed on the basis of inhibition by 10 beta-lactam antibiotics and on differences in beta-lactamase activity. There was no correlation between the inhibitory concentration of antibiotic and the amount of antibiotic hydrolyzed. Use of sodium chloride and cloxacillin inhibition and acrylamide electrophoresis demonstrated that ampicillin resistance in Shigella is mediated by a number of different beta-lactamases. Organisms can contain more than one type of beta-lactamase.


A novel stent coated with antibodies to endoglin inhibits neointimal formation of porcine coronary arteries.
Endoglin/CD105 is an accessory protein of the transforming growth factor-β receptor system that plays a critical role in proliferation of endothelial cells and neovasculature. Here, we aimed to assess the effect of novel stents coated with antibodies to endoglin (ENDs) on coronary neointima formation. Thirty ENDs, thirty sirolimus-eluting stents (SESs), and thirty bare metal stents (BMSs) were randomly assigned and placed in the coronary arteries in 30 juvenile pigs. Histomorphometric analysis and scanning electron microscopy were performed after stent implantation. Our results showed that after 7 days, there was no difference in the neointimal area and percent area stenosis in ENDs compared with SMSs or BMSs. After 14 days, the neointima area and percent area stenosis in ENDs were markedly decreased than those in BMSs or SESs (P < 0.05). Moreover, the percentage of reendothelialization was significantly higher in ENDs than that in SESs or BMSs (P < 0.01) at 7 and 14 days. The artery injury and the inflammation scores were similar in all groups at 7 and 14 days. In conclusion, our results demonstrated for the first time to our knowledge that endoglin antibody-coated stents can markedly reduce restenosis by enhancing reendothelialization in the porcine model and potentially offer a new approach to prevent restenosis.


Melanoma addiction to the long non-coding RNA SAMMSON.
Focal amplifications of chromosome 3p13-3p14 occur in about 10% of melanomas and are associated with a poor prognosis. The melanoma-specific oncogene MITF resides at the epicentre of this amplicon. However, whether other loci present in this amplicon also contribute to melanomagenesis is unknown. Here we show that the recently annotated long non-coding RNA (lncRNA) gene SAMMSON is consistently co-gained with MITF. In addition, SAMMSON is a target of the lineage-specific transcription factor SOX10 and its expression is detectable in more than 90% of human melanomas. Whereas exogenous SAMMSON increases the clonogenic potential in trans, SAMMSON knockdown drastically decreases the viability of melanoma cells irrespective of their transcriptional cell state and BRAF, NRAS or TP53 mutational status. Moreover, SAMMSON targeting sensitizes melanoma to MAPK-targeting therapeutics both in vitro and in patient-derived xenograft models. Mechanistically, SAMMSON interacts with p32, a master regulator of mitochondrial homeostasis and metabolism, to increase its mitochondrial targeting and pro-oncogenic function. Our results indicate that silencing of the lineage addiction oncogene SAMMSON disrupts vital mitochondrial functions in a cancer-cell-specific manner; this silencing is therefore expected to deliver highly effective and tissue-restricted anti-melanoma therapeutic responses.


The limited extent of the electronic modulation of chlorins and bacteriochlorins through chromene-annulation.
Optical data (UV-vis absorption and fluorescence emission spectra, including fluorescence yields and lifetimes) and electrochemical measurements are used to quantify the modulation of the electronic properties of meso-tetrakis(pentafluorophenyl)-chlorin diol and -bacteriochlorin tetraols upon intramolecular chromene-annulation, including the investigation of regio- and stereoisomers. The small modulations of the frontier orbitals of the porphyrinoids are rationalized using DFT computations and can be traced to small electronic effects due to the co-planarized meso-aryl groups in combination with conformational effects.


Dry mass allocation, water use efficiency and delta(13)C in clones of Eucalyptus grandis, E. grandis x camaldulensis and E. grandis x nitens grown under two irrigation regimes.
Clonal variation in water use efficiency (WUE), dry mass accumulation and allocation, and stable carbon isotope ratio (delta(13)C) of crude leaf fiber extracts was determined in six clones of Eucalyptus grandis W. Hill ex Maiden. grown for 16 months in field lysimeters in two soil water regimes. The relationships between delta(13)C and WUE calculated on the basis of leaf, harvestable stem, shoot and whole-plant dry mass accumulation were investigated. There was no clonal variation in dry mass accumulation but clonal allocation to roots, harvestable stems, branches and leaves varied. Water use efficiencies (mass of plant or plant part/water used over 16 months) differed significantly between clones. The clonal ranking of WUE varied depending on the units of dry mass accumulation used. Significant relationships between delta(13)C values and instantaneous water use efficiencies and ratios of internal leaf to ambient CO(2) concentrations were found only in the high soil water treatment. There were no relationships between delta(13)C values and whole-plant, shoot and harvestable stem water use efficiencies and soil water availability. Values of delta(13)C were negatively correlated with dry mass accumulation in the low soil water treatment. At the whole-plant level, WUE was positively correlated with dry mass accumulation in the high soil water treatment. We found significant differences in delta(13)C values between clones and the clonal rankings in delta(13)C and WUE were maintained in both soil water treatments.


Ig N-glycan orientation can influence interactions with the complement system.
This study was prompted by the paradoxical observation that a pair of dinitrophenyl-specific murine monoclonal IgG2a Abs had similar monosaccharide content and yet differed in their binding to lectins. The differential lectin-binding properties were lost when the Abs were denatured, suggesting that variations in lectin binding reflected the conformational accessibility of the N-glycans rather than intrinsic differences in the lectin binding capacity of the glycans themselves. This hypothesis was supported by experiments indicating that the degree to which the N-glycans on the Abs were reactive with beta-1,4-galactosyltransferase or susceptible to peptide N-glycosidase F corresponded directly to their relative accessibility to lectins. Moreover, the relative susceptibility to these enzymes and accessibility to lectins was inversely related to the capacity of the Abs to activate the classical pathway, suggesting that the orientation of the more accessible N-glycan might inhibit C1q binding. This hypothesis was supported by evidence that enzymatic cleavage of the more accessible N-glycan resulted in enhanced Clq, C4b, and C3b deposition. Conversely, removal of the less accessible N-glycan expressed by the other Ab inhibited C1q, C4b, and C3b deposition. The respective increase or decrease in C3b deposition on the two deglycosylated Abs was magnified when complement activation was performed in factor B-depleted serum, suggesting that N-glycan conformation primarily affects the classical pathway. Collectively, these data suggest that the orientation of the N-glycan expressed on Igs can profoundly influence interaction with the complement system.


[Care to share: Four lessons we can learn from data sharing in older person care research].
Sharing data offers opportunities to make research into older person care more efficient. However, this is not yet common practice in the Netherlands. To optimally utilize the potential of data sharing, insight into factors that promote the implementation of data sharing in older person care research is important. In the TOPICS-MDS project, research data from the National Program for Older Person Care (NPO) was collected, managed and reused on a large scale. The experiences of stakeholders involved in this project can teach us more about the needs researchers have when sharing their data. For this study, we interviewed 23 people involved in different ways in data sharing in TOPICS-MDS about their experiences in the data sharing process. Thematic analysis yielded four overarching themes, which we converted into the following lessons: those who want to promote data sharing must ensure 1) visibility of the added value of data sharing, 2) trust in the database, 3) transparency of the process and 4) communication. These lessons complement the results of previous research with concrete advice. Optimizing data sharing in older person research is both promising and challenging. It requires dedication and involvement from both the researcher and the research participant, and appreciation for both.


Protein-polyphenol interactions and in vivo digestibility of buckwheat groat proteins.
A rat model system, based on a diet with (Nb+) or without (Nb-) the inclusion of 0.7% of a 2:1 (w/w) mixture of Bacitracin and Neomycin sulfate (Nebacitin) was used to elucidate interactions of polyphenols with proteins in buckwheat. The treatment with the antibiotic Nebacitin suppresses the microflora in the large intestine and is used to obtain an estimate of the digestion occurring in the small intestine. Experimental buckwheat samples were obtained in order to contain different levels of polyphenol and were subjected to different hydrothermal treatments. It was found that a considerable interaction between polyphenols and proteins appeared during the hydrothermal treatment, and this interaction reduces the digestion of proteins through the small and large intestine. Microbial processes in the colon enhance the digestibility of protein, blocked by polyphenols in hydrothermally processed buckwheat.


Cross-Sectional Association of Food Source with Food Insecurity, Dietary Diversity and Body Mass Index in Western Kenya.
The triple burden of malnutrition in many low- and middle-income countries (LMICs) is partly a result of changing food environments and a shift from traditional diets to high-calorie Western-style diets. Exploring the relationship between food sources and food- and nutrition-related outcomes is important to understanding how changes in food environments may affect nutrition in LMICs. This study examined associations of household food source with household food insecurity, individual dietary diversity and individual body mass index in Western Kenya. Interview-administered questionnaire and anthropometric data from 493 adults living in 376 randomly-selected households were collected in 2019. Adjusted regression analyses were used to assess the association of food source with measures of food insecurity, dietary diversity and body mass index. Notably, participants that reported rearing domesticated animals for consumption ('own livestock') had lower odds of moderate or severe household food insecurity (odds ratio (OR) = 0.29 (95% CI: 0.09, 0.96)) and those that reported buying food from supermarkets had lower odds of moderate or severe household food insecurity (borderline significant, OR = 0.37 (95% CI: 0.14, 1.00)), increased dietary diversity scores (Poisson coefficient = 0.17 (95% CI: 0.10, 0.24)) and higher odds of achieving minimum dietary diversity (OR = 2.84 (95% CI: 1.79, 4.49)). Our findings provide insight into the relationship between food environments, dietary patterns and nutrition in Kenya, and suggest that interventions that influence household food source may impact the malnutrition burden in this context.


Production of multivalent fluorescent antisera for identification of organisms in the Mycobacterium avium-Mycobacterium intracellulare complex.
Antisera to ten strains of mycobacteria in the Mycobacterium avium-Mycobacterium intracellulare group were obtained by injecting rabbits with ultraviolet light-killed cells. The antisera were conjugated with fluorescein isothiocyanate and used in the direct fluorescent antibody test. Individual antisera reacted specifically with the mycobacterial serotype used to produce them. The antisera were then combined in two multivalent pools. Each multivalent pool reacted specifically with its corresponding antigens. The multivalent antisera were thus found to provide a rapid identification method for the mycobacteria studied.


Forensic soil DNA analysis using high-throughput sequencing: a comparison of four molecular markers.
Soil analysis, such as mineralogy, geophysics, texture and colour, are commonly used in forensic casework to link a suspect to a crime scene. However, DNA analysis can also be applied to characterise the vast diversity of organisms present in soils. DNA metabarcoding and high-throughput sequencing (HTS) now offer a means to improve discrimination between forensic soil samples by identifying individual taxa and exploring non-culturable microbial species. Here, we compare the small-scale reproducibility and resolution of four molecular markers targeting different taxa (bacterial 16S rRNA, eukaryotic18S rRNA, plant trnL intron and fungal internal transcribed spacer I (ITS1) rDNA) to distinguish two sample sites. We also assess the background DNA level associated with each marker and examine the effects of filtering Operational Taxonomic Units (OTUs) detected in extraction blank controls. From this study, we show that non-bacterial taxa in soil, particularly fungi, can provide the greatest resolution between the sites, whereas plant markers may be problematic for forensic discrimination. ITS and 18S markers exhibit reliable amplification, and both show high discriminatory power with low background DNA levels. The 16S rRNA marker showed comparable discriminatory power post filtering; however, presented the highest level of background DNA. The discriminatory power of all markers was increased by applying OTU filtering steps, with the greatest improvement observed by the removal of any sequences detected in extraction blanks. This study demonstrates the potential use of multiple DNA markers for forensic soil analysis using HTS, and identifies some of the standardisation and evaluation steps necessary before this technique can be applied in casework.


Risk factors, risk stratification and risk-specific surveillance strategies after endovascular aneurysm repair: study protocol for a Delphi study by the International RIsk Stratification in EVAR (IRIS-EVAR) working group.
Several risk factors for adverse events after endovascular aneurysm repair (EVAR) have been described, but there is no consensus on their comparative prognostic significance, use in risk stratification and application in determining postoperative surveillance. A scoping review of the literature was conducted to identify risk factors for adverse events after EVAR. Main adverse events were considered post-EVAR abdominal aortic aneurysm rupture and reintervention. Risk factors were grouped into four domains: (1) preoperative anatomy, (2) aortic device, (3) procedure performance and (4) postoperative surveillance. The Delphi methodology will be used to steer a group of experts in the field towards consensus organised into three tiers. In tier 1, participants will be asked to independently rate risk factors for adverse events after EVAR. In tier 2, the panel will be asked to independently rate a range of combinations of risk factors across the four domains derived from tier 1. A risk-stratification tool will then be built, which will include algorithms that map responses to signalling questions onto a proposed risk judgement for each domain. Domain-level judgements will in turn provide the basis for an overall risk judgement for the individual patient. In tier 3, risk factor-informed surveillance strategies will be developed. Each tier will typically include three rounds and rating will be conducted using a 4-point Likert scale, with an option for free-text responses. Research Ethics Committee and Health Research Authority approval has been waived, since this is a professional staff study and no duty of care lies with the National Health Service to any of the participants. The results will be presented at regional, national and international meetings and will be submitted for publication in peer-reviewed journals. The risk stratification tool and surveillance algorithms will be made publicly available for clinical use and validation.


Argon laser application to the angle structures in the glaucomas.
The argon laser beams' effect on angle structures was studied in 20 uncontrolled glaucomatous eyes. Nineteen eyes became hypotensive quickly, but in 15, the elevated tension returned during the 20 to 40 day follow-up period. Four eyes sustained low pressures throughout the ten-month follow-up period. Two were of babies with congenital glaucoma, one had simple glaucoma following an unsuccessful filtering operation, and one was aphakic following congenital cataract extraction. Ten eyes were medically controlled postoperatively, and six were failures that had to undergo further surgery. Outflow facility measurements revealed an increase in C values during the hypotensive period. The C values were reduced later, with the decrease corresponding to the increase in intraocular pressures. The hypotensive effect together with the increase in outflow facility was probably related to laser-induced openings in the angle structures. The varying results at the later stages depended on whether or not these openings remained opened, or became partially or completely closed during healing.


The association between the peroxisome proliferator-activated receptor-gamma2 (PPARG2) Pro12Ala gene variant and type 2 diabetes mellitus: a HuGE review and meta-analysis.
The peroxisome proliferator-activated receptor-gamma gene (PPARG) has been implicated in the etiology of type 2 diabetes mellitus and has been investigated in numerous epidemiologic studies. In this Human Genome Epidemiology review, the authors assessed this relation in an updated meta-analysis of 60 association studies. Electronic literature searches were conducted on September 14, 2009. Population-based cohort, case-control, cross-sectional, or genome-wide association studies reporting associations between the PPARG Pro12Ala gene variant (rs1801282) and type 2 diabetes were included. An updated literature-based meta-analysis involving 32,849 type 2 diabetes cases and 47,456 controls in relation to the PPARG Pro12Ala variant was conducted. The combined overall odds ratio, calculated by per-allele genetic model random-effects meta-analysis for type 2 diabetes and the Pro12Ala polymorphism, was 0.86 (95% confidence interval: 0.81, 0.90). The analysis indicated a moderate level of heterogeneity attributable to genuine variation in gene effect size (I(2) = 37%). This may reflect the variation observed between ethnic populations and/or differences in body mass index. Work on PPARG Pro12Ala should now focus on the observed heterogeneity in the magnitude of the association between populations. Further investigations into gene-gene and gene-environment interactions may prove enlightening.


Hand sensory-motor cortical network assessed by functional source separation.
The functional source separation procedure (FSS) was applied to identify the activities of the primary sensorimotor areas (SM1) devoted to hand control. FSS adds a functional constraint to the cost function of the basic independent component analysis, and obtains source activity all along different processing states. Magnetoencephalographic signals from the left SM1 were recorded in 14 healthy subjects during a simple sensorimotor paradigm--galvanic right median nerve stimuli intermingled with submaximal isometric thumb opposition. Two functional sources related to the sensory flow in the primary cortex were extracted requiring maximal responsiveness to the nerve stimulation at around 20 and 30 ms (S1a, S1b). Maximal cortico-muscular coherence was required for the extraction of the motor source (M1). Sources were multiplied by the Euclidean norm of their corresponding weight vectors, allowing amplitude comparisons among sources in a fixed position. In all subjects, S1a, S1b, M1 were successfully obtained, positioned consistently with the SM1 organization, and behaved as physiologically expected during the movement and processing of the sensory stimuli. The M1 source reacted to the nerve stimulation with higher intensity at latencies around 30 ms than around 20 ms. The FSS method was demonstrated to be able to obtain the dynamics of different primary cortical network activities, two devoted mainly to sensory inflow, and the other to the motor control of the contralateral hand. It was possible to observe each source both during pure sensory processing and during motor tasks. In all conditions, a direct comparison of source intensities can be achieved.


Quinone methide dimers lacking labile hydrogen atoms are surprisingly excellent radical-trapping antioxidants.
Hydrogen atom transfer (HAT) is the mechanism by which the vast majority of radical-trapping antioxidants (RTAs), such as hindered phenols, inhibit autoxidation. As such, at least one weak O-H bond is the key structural feature which underlies the reactivity of phenolic RTAs. We recently observed that quinone methide dimers (QMDs) synthesized from hindered phenols are significantly more reactive RTAs than the phenols themselves despite lacking O-H bonds. Herein we describe our efforts to elucidate the mechanism by which they inhibit autoxidation. Four possible reaction paths were considered: (1) HAT from the C-H bonds on the carbon atoms which link the quinone methide moieties; (2) tautomerization or hydration of the quinone methide(s) in situ followed by HAT from the resultant phenolic O-H; (3) direct addition of peroxyl radicals to the quinone methide(s), and (4) homolysis of the weak central C-C bond in the QMD followed by combination of the resultant persistent phenoxyl radicals with peroxyl radicals. The insensitivity of the reactivity of the QMDs to substituent effects, solvent effects and a lack of kinetic isotope effects rule out the HAT reactions (mechanisms 1 and 2). Simple (monomeric) quinone methides, to which peroxyl radicals add, were found to be ca. 100-fold less reactive than the QMDs, ruling out mechanism 3. These facts, combined with the poor RTA activity we observe for a QMD with a stronger central C-C bond, support mechanism 4. The lack of solvent effects on the RTA activity of QMDs suggests that they may find application as additives to materials which contain H-bonding accepting moieties that can dramatically suppress the reactivity of conventional RTAs, such as phenols. This reactivity does not extend to biological membranes owing to the increased microviscosity of the phospholipid bilayer, which suppresses QMD dissociation in favour of recombination. Interestingly, the simple QMs were found to be very good RTAs in phospholipid bilayers - besting even the most potent form of vitamin E.


The Level of Knowledge of Parkinson's Disease among Nonprofessional Caregivers in a Movement Disorders Center in Turkey.
Introduction. Only a few studies have been conducted to determine the level of knowledge among caregivers about Parkinson's disease (PD). The aim of the current study was to determine the knowledge of PD among caregivers at a movement disorder clinic in Turkey. Methods. We conducted a questionnaire based interview with the subjects in a tertiary care neurology facility in Turkey. The questions were divided into two parts covering the symptomatology and treatment of PD. A questionnaire consisting of 10 questions was applied to the subjects who had to mark the correct option in a stipulated time. Results. Eighty caregivers were included in the study. The caregivers' mean age was 47.94 years (SD = 12.40). There were 47 female caregivers (58.8%). The most well-known question was that the number of drugs given to the patient may vary with time (76.3%), whereas "the benefit noted in the patient's treatment decreases over time" was the least known question (11.3%). Discussion. This study is the first in our country and shows the necessity to increase the knowledge of PD among caregivers and the public. Education programs may have a positive role in imparting knowledge to the caregivers of PD patients.


Attitudes and opinions of US neurosurgical residents toward research and scholarship: a national survey.
The analysis of resident research productivity in neurosurgery has gained significant recent interest. Resident scholarly output affects departmental productivity, recruitment of future residents, and likelihood of future research careers. To maintain and improve opportunities for resident research, the authors evaluated factors that affect resident attitudes toward neurosurgical research on a national level. An online survey was distributed to all US neurosurgical residents. Questions assessed interest in research, perceived departmental support of research, and resident-perceived limitations in pursuing research. Residents were stratified based on number of publications above the median (AM; ≥ 14) or below the median (BM; < 14) for evaluation of factors influencing productivity. A total of 278 resident responses from 82 US residency programs in 30 states were included (a 20% overall response rate). Residents predominantly desired future academic positions (53.2%), followed by private practice with some research (40.3%). Residents reported a mean ± SD of 11 ± 14 publications, which increased with postgraduate year level. The most common type of research involved retrospective cohort studies (24%) followed by laboratory/benchtop (19%) and case reports (18%). Residents as a group spent on average 14.1 ± 18.5 hours (median 7.0 hours) a week on research. Most residents (53.6%) had ≥ 12 months of protected research time. Mentorship (92.4%), research exposure (89.9%), and early interest in science (78.4%) had the greatest impact on interest in research while the most limiting factors were time (91.0%), call scheduling (47.1%), and funding/grants (37.1%). AM residents cited research exposure (p = 0.003), neurosurgery conference exposure (p = 0.02), formal research training prior to residency (p = 0.03), internal funding sources (p = 0.05), and software support (p = 0.02) as most important for their productivity. Moreover, more productive residents applied and received a higher number of < $10,000 and ≥ $10,000 grants (p < 0.05). A majority of residents (82.4%) agreed or strongly agreed with pursuing research throughout their professional careers. Overall, about half of residents (49.6%) were encouraged toward continued neurosurgical research, while the rest were neutral (36.7%) or discouraged (13.7%). Free-text responses helped to identify solutions on a departmental, regional, and national level that could increase interest in neurosurgical research. This survey evaluates various factors affecting resident views toward research, which may also be seen in other specialties. Residents remain enthusiastic about neurosurgical research and offer several solutions to the ever-scarce commodities of time and funding within academic medicine.


A Comparison of Breast Milk and Sucrose in Reducing Neonatal Pain During Eye Exam for Retinopathy of Prematurity.
This double-blind randomized controlled experimental study aimed to determine the effects of breast milk and sucrose in reducing pain in preterm infants during retinopathy of prematurity (ROP) examination. This study was conducted with 60 preterm infants (breast milk group = 20, sucrose group = 20, and control/distilled water group = 20) meeting the inclusion criteria. The data were collected with the use of an Infant Evaluation Form, Procedure Monitoring Form, and Premature Infant Pain Profile (PIPP). The preterm infants were provided with 1 mL of breast milk, sucrose, and distilled water before the ROP examination. The pain level in preterm infants was measured by the PIPP 5 minutes before, during, and 5 minutes after the ROP examination. The ROP examinations were video recorded, and videos were evaluated by three observers blinded to the study. No significant difference was determined between the three groups in terms of their postconceptional and postnatal ages, their body weights at birth and during the ROP examination. The PIPP scores of the preterm infants in the three groups were higher during the ROP examination and were not significantly different. The PIPP scores of the control group were significantly higher than those in the breast milk and sucrose groups after the ROP examination (p < 0.001). The preterm infants in the breast milk group recovered and returned to their initial values more quickly after the ROP examination than the infants in the sucrose group. To reduce pain in preterm infants during ROP examination, breast milk is recommended.


Chronology and determinants of tissue repair in diabetic lower-extremity ulcers.
The natural history of tissue repair and the critical determinants of faulty healing of diabetic ulcers remain obscure despite recent advances in our knowledge of the cellular physiology of normal cutaneous healing. To characterize the chronology and identify important factors affecting healing, we applied an objective method to quantify the rate of wound healing of full-thickness lower-extremity ulcers in 46 diabetic outpatients who received local wound care under a standardized clinical protocol. The initial ulcer healing rate, eventual status of tissue repair, and definitive clinical outcome were not significantly associated with age; diabetes type, duration, or treatment; level or change in glycosylated hemoglobin; current smoking; presence of sensory neuropathy; ulcer location or class; initial infection; or frequency of recurrent infections. However, direct measures of local cutaneous perfusion, estimated by periwound measurements of transcutaneous O2 tension (TcPo2) and transcutaneous CO2 tension (TcPco2), were significantly associated with the initial rate of tissue repair (P = 0.003 and 0.005, respectively). The strong prediction of early healing by these parameters of local skin perfusion was independent from the effects of segmental Doppler arterial blood pressure at the dorsalis pedis, although eventual ulcer reepithelialization was significantly related to foot blood pressure and periwound TcPo2 and TcPco2. We conclude that periwound cutaneous perfusion is the critical physiological determinant of diabetic ulcer healing, indicating a 39-fold increased risk of early healing failure when the average periwound TcPo2 is less than 20 mmHg.


Bedside assessment of quadriceps muscle by ultrasound after admission for acute exacerbations of chronic respiratory disease.
Hospitalization represents a major event for the patient with chronic respiratory disease. There is a high risk of readmission, which over the longer term may be related more closely to the underlying condition of the patient, such as skeletal muscle dysfunction. We assessed the risk of hospital readmission at 1 year, including measures of lower limb muscle as part of a larger clinical trial. Patients hospitalized with an exacerbation of chronic respiratory disease underwent measures of muscle function including quadriceps ultrasound. Independent factors influencing time to hospital readmission or death were identified. Patients were classified into four quartiles based on quadriceps size and compared. One hundred and ninety-one patients (mean age, 71.6 [SD, 9.1] yr) were recruited. One hundred and thirty (68%) were either readmitted or died. Factors associated with readmission or death were age (odds ratio [OR], 1.05; 95% confidence interval [CI], 1.01-1.08; P = 0.015), Medical Research Council (MRC) dyspnea grade (OR, 4.57; 95% CI, 2.62-7.95; P < 0.001), home oxygen use (OR, 12.4; 95% CI, 4.53-33.77; P < 0.001), quadriceps (rectus femoris) cross-sectional area (Qcsa) (OR, 0.34; 95% CI, 0.17-0.65; P = 0.001), and hospitalization in the previous year (OR, 4.82; 95% CI, 2.42-9.58; P < 0.001). In the multivariate analyses, home oxygen use (OR, 4.80; 95% CI, 1.68-13.69; P = 0.003), MRC dyspnea grade (OR, 2.57; 95% CI, 1.44-4.59; P = 0.001), Qcsa (OR, 0.46; 95% CI, 0.22-0.95; P = 0.035), and previous hospitalization (OR, 3.04; 95% CI, 1.47-6.29; P = 0.003) were independently associated with readmission or death. Patients with the smallest muscle spent more days in hospital than those with largest muscle (28.1 [SD, 33.9] vs. 12.2 [SD, 23.5] d; P = 0.007). Smaller quadriceps muscle size, as measured by ultrasound in the acute care setting, is an independent risk factor for unscheduled readmission or death, which may have value both in clinical practice and for risk stratification.


Using ANOVA for gene selection from microarray studies of the nervous system.
Methods are presented for detecting differential expression using statistical hypothesis testing methods including analysis of variance (ANOVA). Practicalities of experimental design, power, and sample size are discussed. Methods for multiple testing correction and their application are described. Instructions for running typical analyses are given in the R programming environment. R code and the sample data set used to generate the examples are available at http://microarray.cpmc.columbia.edu/pavlidis/pub/aovmethods/.


Diffusion lung capacity of carbon monoxide: A novel marker of airways remodeling in asthmatic children?
Asthma is universally considered a chronic inflammatory disorder of the airways. Several noninvasive markers, such as exhaled nitric oxide (FeNO) and exhaled breath temperature (PletM), have been proposed to evaluate the degree of airway inflammation and remodeling in asthmatic children. The aim of this study was to evaluate the relationship between diffusion lung capacity of carbon monoxide (DLCO) and these inflammatory markers in asthmatic children. We compared data of FeNO, PletM, and DLCO collected in 35 asthmatic children at admission (T0) and discharge (T1) after a period spent in a dust-mite-free environment (Misurina, Italian Dolomites, 1756 m). PletM showed a reduction from 29.48°C at T0 to 29.13°C at T1 (p = 0.17); DLCO passed from 93 to 102 (p = 0.085). FeNO mean value was 29.7 ppb at admission and 18.9 ppb at discharge (p = 0.014). Eosinophil mean count in induced sputum was 4 at T0 and 2 at T1 (p = 0.004). Spearman standardization coefficient beta was 0.414 between eosinophils and FeNO and -0.278 between eosinophils and DLCO. Pearson's correlation index between DLCO and PletM was -0.456 (p = 0.019). A negative correlation between DLCO and PletM was found. However, DLCO did not show a significant correlation with FeNO and eosinophils in the airways. Additional studies are needed to clarify the role of DLCO as a potential tool in monitoring childhood asthma.


Compliance with routine use of gowns by healthcare workers (HCWs) and non-HCW visitors on entry into the rooms of patients under contact precautions.
Modified contact precautions (MCP), defined as routine donning of isolation gowns (along with routine gloving) on entry into the rooms of patients under contact precautions, regardless of the likelihood of direct exposure to the patient or their immediate environment, were instituted at our medical center to reduce nosocomial transmission of common hospital pathogens. To study compliance with MCP policy regarding routine gowning in intensive care units (ICUs) and general wards and to determine the relationship between gown and glove use in the care of patients under MCP in ICUs. Prospective observational study from February 20, 2004, through January 8, 2005, involving 2,110 persons (1,504 healthcare workers [HCWs] and 606 non-HCW visitors). A 900-bed tertiary care teaching community hospital. Overall compliance with routine gown use was observed for 1,542 persons (73%), including 1,150 HCWs (76%) and 392 visitors (65%) (odds ratio [OR], 1.8 [95% confidence interval {CI}, 1.4-2.2]; P<.001). Visitors in the ICUs (186 [91%] of 204) were more likely than visitors in the general wards (202 [51%] of 398) to comply with gown use (OR, 10 [95% CI, 6.0-17.0]; P<.001). In logistic regression analysis, independent predictors of gown compliance among HCWs were female sex (OR, 2.3 [95% CI, 1.8-3.0]; P<.001) and ICU setting (OR, 2.2 [95% CI, 1.7-2.9]; P<.001). In the ICUs, gown use was highly predictive of glove use among HCWs (positive predictive value, 95%). Improvement in compliance with gown use at our medical center will require more-intensive educational efforts targeted at male HCWs and at HCWs and visitors on general wards. In the care of ICU patients under MCP, HCW compliance with gown use may be used as a proxy for their compliance with glove use.


Regenerative rehabilitation: exploring the synergistic effects of rehabilitation and implantation of a bio-functional scaffold in enhancing nerve regeneration.
Clinically, rehabilitation is one of the most common treatment options for traumatic injuries. Despite that, recovery remains suboptimal and recent breakthroughs in regenerative approaches may potentially improve clinical outcomes. To date, there have been numerous studies on the utilization of either rehabilitative or regenerative strategies for traumatic injury treatment. However, studies that document the combined effects of rehabilitation and regenerative tissue engineering options remain scarce. Here, in the context of traumatic nerve injury treatment, we use a rat spinal cord injury (SCI) model as a proof of concept to evaluate the synergistic effects of regenerative tissue engineering and rehabilitation. Specifically, we implanted a pro-regenerative hybrid fiber-hydrogel scaffold and subjected SCI rats to intensive rehabilitation. Of note, the rehabilitation session was augmented by a novel customized training device that imparts normal hindlimb gait movements to rats. Morphologically, more regenerated axons were observed when rats received rehabilitation (∼2.5 times and ∼2 times enhancement after 4 and 12 weeks of recovery, respectively, p < 0.05). Besides that, we also observed a higher percentage of anti-inflammatory cells (36.1 ± 12.9% in rehab rats vs. 3.31 ± 1.48% in non-rehab rats, p < 0.05) and perineuronal net formation in rehab rats at Week 4. Physically, rehab animals were also able to exert higher ankle flexion force (∼0.779 N vs. ∼0.495 N at Week 4 and ∼1.36 N vs. ∼0.647 N at Week 12 for rehab vs. non-rehab rats, p < 0.001) and performed better than non-rehab rats in the open field test. Taken together, we conclude that coupling rehabilitation with regenerative scaffold implantation strategies can further promote functional recovery after traumatic nerve injuries.


Cellular and molecular responses to topoisomerase I poisons. Exploiting synergy for improved radiotherapy.
The efficacy of topoisomerase (Topo) I-active drugs may be improved by better understanding the molecular and cellular responses of tumor compared to normal cells after genotoxic insults. Ionizing radiation (IR) + Topo I-active drugs (e.g., Topotecan) caused synergistic cell killing in various human cancer cells, even in cells from highly radioresistant tumors. Topo I poisons had to be added either during or immediately after IR. Synergy was caused by DNA lesion modification mechanisms as well as by concomitant stimulation of two pathways of cell death: necrosis (IR) + apoptosis (Topo I poisons). Cumulative data favor a mechanism of synergistic cell killing caused by altered DNA lesion modification and enhanced apoptosis. However, alterations in cell cycle regulation may also play a role in the synergy between these two agents in certain human cancers. We recently showed that NF-kappa B, a known anti-apoptotic factor, was activated in various cancer cells after poisoning Topo I using clinically active drugs. NF-kappa B activation was dependent on initial nuclear DNA damage followed by cytoplasmic signaling events. Cytoplasmic signaling leading to NF-kappa B activation after Topo I poisons was diminished in cytoplasts (lacking nuclei) and in CEM/C2 cells that expressed a mutant Topo I protein that did not interact with Topo I-active drugs. NF-kappa B activation was intensified in S-phase and blocked by aphidicolin, suggesting that activation was a result of double-strand break formation due to Topo I poisoning and DNA replication. Dominant-negative I kappa B expression augmented Topo I poison-mediated apoptosis. Elucidation of molecular signal transduction pathways after Topo I drug-IR combinations may lead to improved radiotherapy by blocking anti-apoptotic NF-kappa B responses. Recent data also indicate that synergy caused by IR + Topo I poisons is different from radiosensitization by beta-lapachone (beta-lap), a "reported" Topo I and II-alpha poison in vitro. In fact, beta-lap does not kill cells by poisoning either Topo I or II-alpha in vivo. Instead, the compound is "activated" by an IR (damage)-inducible enzyme, NAD(P)H:quinone oxidoreductase (NQO1), a gene cloned as x-ray-inducible transcript #3, xip3. Unlike the lesion modification pathway induced by IR + Topo I drugs, beta-lap kills cells via NQO1 futile cycle metabolism. Downstream apoptosis caused by beta-lap appears to be noncaspase-mediated, involving calpain or a calpain-like protease. Thus, although Topo I poisons or beta-lap in combination with IR both synergistically kill cancer cells, the mechanisms are very different.


The dendritic cell system and anti-tumour immunity.
Dendritic cells (DC) are essential for the initiation of T- and T-dependent immune responses by virtue of their capacities to acquire, process and present antigens and to deliver activation signals to mature resting T cells. In contrast, antigen presentation by other types of antigen-presenting cells (APC) may lead to peripheral T cell tolerance. This paper reviews the immunobiology of DC, and considers the possibility that immune unresponsiveness of tumour-bearing hosts may be due to clonal anergy of T cells. An important issue is whether it is possible to use DC to vaccinate tumour-free individuals, to overcome the immunological unresponsiveness of tumour-bearing hosts, and ultimately to cause rejection of primary and metastatic cancers.


Awareness of health care personnel about preventive aspects of HIV infection/AIDS and their practices and attitudes concerning such patients.
The study was carried out at a tertiary care hospital in Lahore to assess the level of awareness of health care personnel regarding various preventive aspects of HIV/AIDS and determine their practices and attitudes while dealing with such patients. Study population consisted of 147 (55.68%) physicians, 82 (31.06%) nurses and 35 (13.26%) paramedics. Most of the participants had awareness regarding prevention of sexual transmission, however there were gaps in their knowledge as to how spread could be checked through the use of screened blood and sterilized syringes and instruments and perinatal transmission. One hundred and twenty three (46.5%) respondents were unaware of precautionary measures to be observed by health care providers while looking after these patients and 140 (53.03%) made improper responses when inquired about their responsibility and practices concerning HIV seropositive individuals and AIDS patients. As a result of misconceptions and ignorance, 108 (40.90%) participants' responses regarding their attitudes towards HIV/AIDS cases were incorrect and improper.


A double-blind placebo-controlled study of the efficacy and safety of paroxetine in the treatment of pathological gambling.
This randomized, double-blind, placebo-controlled study investigated the efficacy and tolerability of paroxetine in the treatment of pathological gambling. Patients fulfilling DSM-IV criteria for pathological gambling and scoring > or = 5 on the South Oaks Gambling Screen were enrolled if no other Axis I disorder was present. A 1-week placebo run-in phase was followed by 8 weeks' treatment with paroxetine or placebo. The initial paroxetine dose of 20 mg/day could be increased after week 2 by 10 mg/week to a maximum of 60 mg/day. Changes in clinical status were assessed using the Gambling Symptom Assessment Scale (G-SAS) and the Clinical Global Impressions scale (CGI). Treatment-emergent symptoms were assessed weekly. Forty-five patients were included in an intent-to-treat analysis (N = 23 paroxetine, N = 22 placebo). Statistically significantly greater reductions in the total score of the G-SAS were observed in the paroxetine group compared with the placebo group at weeks 6 through 8 (p = .003, .003, and .042, respectively). Improvement on the CGI was also significantly greater in the paroxetine than in the placebo group at the same timepoints (p = .033, .014, and .025, respectively). A significantly greater proportion of patients in the paroxetine group were responders at weeks 7 and 8 (p = .011 and .010, respectively). The results of this trial indicate that paroxetine may be effective in the treatment of pathological gambling. There were no unexpected side effects from this treatment. However, additional studies with larger patient samples and a longer treatment phase are required to establish conclusively the efficacy and safety of paroxetine for this indication.


Should meta-analysts search Embase in addition to Medline?
It is widely accepted that meta-analysts should search multiple databases. The selection of databases is ideally based on the potential contribution of each database to the project or on the potential for bias if a database is excluded, as supported by research evidence. We explore whether searching Embase yields additional trials that influence a meta-analysis. We identified meta-analyses that searched Medline and Embase. A random-effects weighted mean method was used to estimate the intervention effect in articles indexed only in Embase compared with those indexed elsewhere. On average, Embase-unique trials yielded significantly smaller estimates by 29% (ratio of odds ratio [ROR] 0.71, 95% confidence interval [CI] 0.56-0.90) but influenced the pooled estimate by an average of only 6% (ROR 0.94, 95% CI 0.88-0.99). Searching Medline but not Embase risks biasing a meta-analysis by finding studies that show larger estimates, but their prevalence seems low enough that the risk may be slight, provided the rest of the search is comprehensive.


A Review of Global Health Competencies for Postgraduate Public Health Education.
During the last decade, the literature about global health has grown exponentially. Academic institutions are also exploring the scope of their public health educational programs to meet the demand for a global health professional. This has become more relevant in the context of the sustainable development goals. There have been attempts to describe global health competencies for specific professional groups. The focus of these competencies has been variable with a variety of different themes being described ranging from globalization and health care, analysis and program management, as well as equity and capacity strengthening. This review aims to describe global health competencies and attempts to distill common competency domains to assist in curriculum development and integration in postgraduate public health education programs. A literature search was conducted using relevant keywords with a focus on public health education. This resulted in identification of 13 articles that described global health competencies. All these articles were published between 2005 and 2015 with six from the USA, two each from Canada and Australia, and one each from UK, Europe, and Americas. A range of methods used to describe competency domains included literature review, interviews with experts and employers, surveys of staff and students, and description or review of an academic program. Eleven competency domains were distilled from the selected articles. These competency domains primarily referred to three main aspects, one that focuses on burden of disease and the determinants of health. A second set focuses on core public health skills including policy development, analysis, and program management. Another set of competency domains could be classified as "soft skills" and includes collaboration, partnering, communication, professionalism, capacity building, and political awareness. This review presents the landscape of defined global health competencies for postgraduate public health education. The discussion about use of "global health," "international health," and "global public health" will continue, and academic institutions need to explore ways to integrate these competencies in postgraduate public health programs. This is critical in the post-MDG era that we prepare global public health workforce for the challenges of improving health of the "global" population in the context of sustainable development goals.


Raising environmental awareness through applied biochemistry laboratory experiments.
Our environment is under constant pressure and threat from various sources of pollution. Science students, in particular chemistry students, must not only be made aware of these issues, but also be taught that chemistry (and science) can provide solutions to such real-life issues. To this end, a newly developed biochemistry laboratory experiment is described that guides students to learn about the applicability of peroxidase enzymes to degrade organic dyes (as model pollutants) in simulated waste water. In addition to showing how enzymes can potentially be used for waste water remediation, various factors than can affect enzyme-based reactions such as pH, temperature, concentration of substrates/enzymes, and denaturants can also be tested. This "applied biotechnology" experiment was successfully implemented in an undergraduate biochemistry laboratory course to enhance students' learning of environmental issues as well important biochemistry concepts. Student survey confirmed that this laboratory experiment was successful in achieving the objectives of raising environmental awareness in students and illustrating the usefulness of chemistry in solving real-life problems. This experiment can be easily adopted in an introductory biochemistry laboratory course and taught as an inquiry-guided exercise.


Long-term chemogenetic suppression of spontaneous seizures in a mouse model for temporal lobe epilepsy.
More than one-third of patients with temporal lobe epilepsy (TLE) continue to have seizures despite treatment with antiepileptic drugs, and many experience severe drug-related side effects, illustrating the need for novel therapies. Selective expression of inhibitory Designer Receptors Exclusively Activated by Designer Drugs (DREADDs) allows cell-type-specific reduction of neuronal excitability. In this study, we evaluated the effect of chemogenetic suppression of excitatory pyramidal and granule cell neurons of the sclerotic hippocampus in the intrahippocampal mouse model (IHKA) for temporal lobe epilepsy. Intrahippocampal IHKA mice were injected with an adeno-associated viral vector carrying the genes for an inhibitory DREADD hM4Di in the sclerotic hippocampus or control vector. Next, animals were treated systemically with different single doses of clozapine-N-oxide (CNO) (1, 3, and 10 mg/kg) and clozapine (0.03 and 0.1 mg/kg) and the effect on spontaneous hippocampal seizures, hippocampal electroencephalography (EEG) power, fast ripples (FRs) and behavior in the open field test was evaluated. Finally, animals received prolonged treatment with clozapine for 3 days and the effect on seizures was monitored. Treatment with both CNO and clozapine resulted in a robust suppression of hippocampal seizures for at least 15 hours only in DREADD-expressing animals. Moreover, total EEG power and the number of FRs were significantly reduced. CNO and/or clozapine had no effects on interictal hippocampal EEG, seizures, or locomotion/anxiety in the open field test in non-DREADD epileptic IHKA mice. Repeated clozapine treatment every 8 hours for 3 days resulted in almost complete seizure suppression in DREADD animals. This study shows the potency of chemogenetics to robustly and sustainably suppress spontaneous epileptic seizures and pave the way for an epilepsy therapy in which a systemically administered exogenous drug selectively modulates specific cell types in a seizure network, leading to a potent seizure suppression devoid of the typical drug-related side effects.


A single-vial analytical and quantitative gas chromatography-mass spectrometry assay for terpene synthases.
A quantitative assay for the analysis of sesquiterpene synthases, wherein each reaction mixture is formulated in glass gas chromatography vials, overlaid with organic solvent such as ethyl acetate, and subsequently vortexed to extract hydrocarbon reaction products into the organic phase after a suitable incubation period, was developed. The product-enriched organic phase is then sampled in an automated fashion and injected directly into a gas chromatograph-mass spectrometer without further workup for analysis and quantification of hydrocarbon products. Application of the vial assay to the analysis of amorpha-4,11-diene synthase (ADS), a sesquiterpene synthase, demonstrated the sensitivity of the assay for detection of major and minor reaction products and most notably for the identification of several sesquiterpene products that had escaped previous detection. A steady-state kinetic analysis of tobacco 5-epi-aristolochene synthase (TEAS), another sesquiterpene synthase, validated the quantitative nature of the assay, providing an alternative means to the established method of using radiolabeled substrate, extraction, and scintillation counting. This simplified assay provides a standardized method to facilitate analysis of terpene synthases and diverse mutant enzyme libraries by supplanting the common practice of using larger scale reactions, multiple extractions, and evaporative concentration of the organic phase prior to gas chromatography-mass spectrometry (GC-MS) analysis.


Perinatal outcome in cases of isolated single umbilical artery and its effects on neonatal cord blood gas indices.
Abstract We aimed to evaluate perinatal outcomes and blood gas indices of isolated single umbilical artery (SUA). In this retrospective study, 134 fetuses with SUA were evaluated. A total of 77 (57.4%) fetuses with isolated SUA (iSUA) were compared with maternal age-matched 95 fetuses with double umbilical arteries (DUA), with respect to pregnancy outcome and umbilical cord blood gas indices. The incidence of SUA in our cohort was 1.04%. Patients with iSUA had lower neonatal birth weight compared with the control group (2,635 ± 972 g vs 2,991 ± 669 g; p = 0.009). Small for gestational age (SGA) frequency was higher in the group of iSUA when compared with fetuses with DUA (17.4% vs 5.4%; p = 0.03). Regarding the umbilical cord blood gas, the parameters were comparable between the two groups. SUA has a favourable obstetric outcome as long as the accompanying malformations are ruled out. Furthermore, neonatal cord blood gas parameters in fetuses with iSUA do not differ from fetuses with DUA.


Structure of alpha-chymotrypsin refined at 1.68 A resolution.
Diffraction data for alpha-chymotrypsin crystals at -10 degrees C were measured at 1.68 A resolution and refined by restrained structure-factor least-squares refinement. The two independent chymotrypsin molecules in the crystallographic asymmetric unit were refined independently. The overall structure of alpha-chymotrypsin is little changed from published co-ordinates. The root-mean-square shift of C alpha co-ordinates is 0.42 A, co-ordinates for the two molecules showing a root-mean-square difference of 0.19 A. Certain regions with high disorder (residues 9 to 14, 73 to 79) remain difficult to interpret and several side-chains are disordered. Some water molecule positions have been changed. The absence of the tosyl group has made a significant difference to the refined structure at the active site. This now agrees closely with other enzymes of the trypsin family that have been refined at high resolution. There is a strong hydrogen bond between N epsilon 2 (His57) and O gamma (Ser195) in the free enzyme, in line with the published description of the charge relay system.


Impact of teaching facility status and high-volume centers on outcomes for lung cancer resection: an examination of 13,469 surgical patients.
Studies suggest that institutional case volume and teaching status significantly affect patient survival. We sought to compare outcomes of surgical resection for lung cancer at teaching facilities (TF) and at high-volume centers (HVC). Patients undergoing lung cancer resection with curative intent were examined using a linked dataset from 1998 to 2002 between the Florida Cancer Data System and the Florida Agency for Health Care Administration. A total of 13,469 patients were analyzed and outcomes adjusted for comorbidities. Median survival time (MST) was superior for patients treated at TF versus nonteaching facilities (NTF) (47.1 versus 40.5 months, P < 0.001). Mortality rates at NTF were higher at 30 days (2.6% versus 1.1%, P < 0.001), 90 days (6.8% versus 3.8%, P < 0.001), and at 5 years (63.9% versus 59.2%, P = 0.005). Similarly, MST was superior in the cohort treated at HVC versus low-volume center (LVC) (45.1 versus 39.8 months, P < 0.001). Mortality was observed to be higher in LVC than HVC at 30 days (2.7% versus 1.6%, P < 0.001), 90 days (7.5% versus 4.0%, P < 0.001), and at 5 years (63.5% versus 59.3%, P = 0.002). Significant preoperative, independent predictors of survival include age, sex, smoking status, and the existence of certain comorbidities. Treatment at a TF or HVC were independent predictors of better outcome. Race, use of chemotherapy or radiation did not affect outcomes. Surgical treatment for lung cancer at TF or HVC results in significantly better short- and long-term patient outcomes.


Repeated MDMA ("Ecstasy") exposure in adolescent male rats alters temperature regulation, spontaneous motor activity, attention, and serotonin transporter binding.
Previous research in our laboratory found that repeated exposure of adolescent rats to 3,4-methylenedioxymethamphetamine (MDMA) impaired working memory and reduced anxiety. The present experiment extended these findings by investigating the physiological, behavioral, and neurotoxic effects of a modified MDMA treatment regimen. Male Sprague-Dawley rats received 5 mg/kg of MDMA hourly for a period of 4 hr on every fifth day from postnatal day 35-60. Acute effects of the MDMA treatment included hypothermia, serotonin syndrome behavior, and ejaculation. Body weight gain was attenuated by repeated drug administration. The animals completed anxiety and working memory tests beginning 4 days after the final MDMA dose. MDMA altered habituation to the open-field, increased locomotor activity in the elevated plus-maze, decreased attention in the novel object-recognition test, and reduced serotonin transporter binding in the neocortex. These results indicate that repeated exposure to a relatively moderate MDMA dose during adolescence produces later changes in behavior and neurochemistry.


[Genetic factors in gestational trophoblastic tumors].
Gestational trophoblastic tumours group together the complete hydatidiform mole (classical) and partial mole (with fetus), invasive mole and choriocarcinoma. Genetically, trophoblastic tumours can arise in different ways: they can derive from normal zygotes with the maternal and paternal haplotype (normal pregnancy), or from a triploid zygote (partial mole) or from an XX zygote possessing only a duplicated male haplotype and no maternal contribution (complete mole). The low malignancy rate in partial mole (2.4%) compared to the complete mole (10 to 20%) remains unknown. Further analysis of the genetics of these tumours may well contribute to the understanding of the process of carcinogenesis.


[Volume of distribution of drugs: an apparent data in pharmacology].
Once the drug has been given and reaches the vascular system of the patient, some drugs are distributed only to the body fluids (plasma plus extracellular water), while others are bound extensively in body tissues. Therefore, the volume of distribution of a drug is not a real volume. Indeed, it is an apparent volume giving a mathematical measure and an approach of the extent of tissue distribution of the drug into the body. Age, pregnancy, renal insufficiency and drug interactions among others, are pathophysiological factors that may alter the fraction of circulating drug bound to albumin and hence, its body distribution that may affect therapeutic response.


Diffuse liver disease: strategies for hepatic CT and MR imaging.
The liver plays several complex but essential roles in the metabolism of amino acids, carbohydrates, and lipids, as well as synthesis of proteins. The basic pathophysiology of diffuse parenchymal hepatic diseases usually represents a failure in one of these metabolic pathways. Specific parenchymal diseases can be categorized as storage, vascular, and inflammatory diseases. Cross-sectional hepatic imaging techniques, specifically multidetector computed tomography (CT) and magnetic resonance (MR) imaging, have roles in evaluation of diffuse liver disease. The prominent role of multidetector CT is primarily defined by its excellent morphologic visualization capabilities, in particular of diffuse or focal intrahepatic lesions as well as of anatomic relationships between the liver and adjacent organs. The variety of available multidetector CT scanners covers a huge spectrum of detector configurations ranging from equally sized and equally spaced detector arrays to asymmetric detector configurations, resulting in imaging protocols with unique parameters for almost each multidetector CT system. In addition to 64-detector row imaging, hepatic multidetector CT can be performed with emerging techniques such as dual-energy CT. Hepatic MR imaging has been proved to be a comprehensive modality for assessing the morphology and functional characteristics of the liver. Concurrent technical improvements as well as implementation of advanced imaging sequence designs permit high-quality examination of the liver with T1-, T2-, and diffusion-weighted pulse sequences. Three basic demands remain if MR imaging is chosen for hepatic imaging: to improve parenchymal contrast, to suppress respiratory motion, and to ensure complete anatomic coverage. Supplemental material available at http://radiographics.rsna.org/content/29/6/1591/suppl/DC1.


Effects of age on negative subsequent memory effects associated with the encoding of item and item-context information.
It has consistently been reported that "negative" subsequent memory effects--lower study activity for later remembered than later forgotten items--are attenuated in older individuals. The present functional magnetic resonance imaging study investigated whether these findings extend to subsequent memory effects associated with successful encoding of item-context information. Older (n = 25) and young (n = 17) subjects were scanned while making 1 of 2 encoding judgments on a series of pictures. Memory was assessed for the study item and, for items judged old, the item's encoding task. Both memory judgments were made using confidence ratings, permitting item and source memory strength to be unconfounded and source confidence to be equated across age groups. Replicating prior findings, negative item effects in regions of the default mode network in young subjects were reversed in older subjects. Negative source effects, however, were invariant with respect to age and, in both age groups, the magnitude of the effects correlated with source memory performance. It is concluded that negative item effects do not reflect processes necessary for the successful encoding of item-context associations in older subjects. Negative source effects, in contrast, appear to reflect the engagement of processes that are equally important for successful episodic encoding in older and younger individuals.


The effect of social content on deductive reasoning: an fMRI study.
Psychological studies of deductive reasoning have shown that subjects' performance is affected significantly by the content of the presented stimuli. Specifically, subjects find it easier to reason about contexts and situations with a social content. In the present study, the effect of content on brain activation was investigated with functional magnetic resonance imaging (fMRI) while subjects were solving two versions of the Wason selection task, which previous behavioral studies have shown to elicit a significant content effect. One version described an arbitrary relation between two actions (Descriptive: "If someone does ..., then he does ..."), whereas the other described an exchange of goods between two persons (Social-Exchange: "If you give me ..., then I give you ..."). Random-effect statistical analyses showed that compared to baseline, both tasks activated frontal medial cortex and left dorsolateral frontal and parietal regions, confirming the major role of the left hemisphere in deductive reasoning. In addition, although the two reasoning conditions were identical in logical form, the social-exchange task was also associated with right frontal and parietal activations, mirroring the left-sided activations common to both reasoning tasks. These results suggest that the recruitment of the right hemisphere is dependent on the content of the stimuli presented.


Toll-like receptor 4 gene (TLR4), but not TLR2, polymorphisms modify the risk of tonsillar disease due to Streptococcus pyogenes and Haemophilus influenzae.
Tonsillar disease (recurrent tonsillitis and/or tonsillar hypertrophy) is one of the most common human disorders, with Streptococcus pyogenes (group A beta-hemolytic streptococcus [GAS]) and Haemophilus influenzae representing the most common pathogens. Until now, no study has investigated why some individuals are more susceptible to tonsillar infections caused by specific bacteria than others. The aim of this study was to uncover possible associations between common Toll-like receptor gene (TLR) polymorphisms and tonsillar disease. The TLR2-R753Q, TLR4-D299G, and TLR4-T399I polymorphisms were determined in a cohort of 327 patients subjected to tonsillectomy due to recurrent tonsillitis (n = 245) and tonsillar hypertrophy (n = 82) and 245 healthy bone marrow donors. Associations of the aforementioned polymorphisms with the isolated bacterial strains after tonsillectomy were also investigated. Interestingly, carriers of the TLR4 polymorphisms displayed an approximately 3-fold increased risk for GAS infections (for TLR4-D299G, odds ratio [OR] = 2.81, 95% confidence interval [CI] = 1.16 to 6.79, P = 0.038; for TLR4-T399I, OR = 3.01, 95% CI = 1.29 to 7.02, P = 0.023), and this association was more profound in patients with recurrent tonsillitis. On the contrary, the presence of the TLR4-T399I polymorphism was associated with a 2-fold decreased risk of Haemophilus influenzae carriage (OR = 0.38, 95% CI = 0.15 to 0.96, P = 0.038). In the end, no significant differences were observed, considering the genotype and allele frequencies of the above-mentioned polymorphisms, between patients and controls. Our findings indicate that, regarding tonsillar infections, TLR4 polymorphisms predispose individuals to GAS infection, while they are protective against Haemophilus influenzae infection. This result further elucidates the role that host immune genetic variations might play in the susceptibility to common infections and tonsillar disease.


Directed dispersal by rotational shepherding supports landscape genetic connectivity in a calcareous grassland plant.
Directed dispersal by animal vectors has been found to have large effects on the structure and dynamics of plant populations adapted to frugivory. Yet, empirical data are lacking on the potential of directed dispersal by rotational grazing of domestic animals to mediate gene flow across the landscape. Here, we investigated the potential effect of large-flock shepherding on landscape-scale genetic structure in the calcareous grassland plant Dianthus carthusianorum, whose seeds lack morphological adaptations to dispersal to animals or wind. We found a significant pattern of genetic structure differentiating population within grazed patches of three nonoverlapping shepherding systems and populations of ungrazed patches. Among ungrazed patches, we found a strong and significant effect of isolation by distance (r = 0.56). In contrast, genetic distance between grazed patches within the same herding system was unrelated to geographical distance but significantly related to distance along shepherding routes (r = 0.44). This latter effect of connectivity along shepherding routes suggests that gene flow is spatially restricted occurring mostly between adjacent populations. While this study used nuclear markers that integrate gene flow by pollen and seed, the significant difference in the genetic structure between ungrazed patches and patches connected by large-flock shepherding indicates the potential of directed seed dispersal by sheep across the landscape.


[Guidelines for the management of arterial hypertension in general practice].
Guidelines for the management of arterial hypertension are regularly updated. This article summarizes the last international guidelines in this field published last year. The decision to initiate an antihypertensive treatment will not only depend on blood pressure levels, but also on global cardiovascular risk assessment.


HIV-positive patients in the intensive care unit: A retrospective audit.
The indications for and outcomes of intensive care unit (ICU) admission of HIV-positive patients in resource-poor settings such as sub-Saharan Africa are unknown. To identify indications for ICU admission and determine factors associated with high ICU and hospital mortality in HIV-positive patients. We reviewed case records of HIV-positive patients admitted to the medical and surgical ICUs at Groote Schuur Hospital, Cape Town, South Africa, from 1 January 2012 to 31 December 2012. Seventy-seven HIV-positive patients were admitted to an ICU, of whom two were aged <18 years and were excluded from the final analysis. HIV infection was newly diagnosed in 37.3% of the patients admitted during the study period. HIV-positive patients had a median CD4 count of 232.5 (interquartile range 59 - 459) cells/µL. Respiratory illness, mainly community-acquired pneumonia, accounted for 30.7% of ICU admissions. ICU and hospital mortality rates were 25.3% and 34.7%, respectively. Predictors of ICU mortality included an Acute Physiology and Chronic Health Evaluation ΙΙ (APACHE II) score >13 (odds ratio (OR) 1.4, 95% confidence interval (CI) 1.1 - 1.7; p=0.015), receipt of renal replacement therapy (RRT) (OR 2.2, 95% CI 1.2 - 4.1; p=0.018) and receipt of inotropes (OR 2.3, 95% CI 1.6 - 3.4; p<0.001). Predictors of hospital mortality were severe sepsis on admission (OR 2.8, 95% CI 0.9 - 9.1; p=0.07), receipt of RRT (OR 1.9, 95% CI 1.0 - 3.6; p=0.056) and receipt of inotropic support (OR 2.0, 95% CI 1.4 - 3.2; p<0.001). Use of highly active antiretroviral therapy (HAART), CD4 count, detectable HIV viral load and diagnosis at ICU admission did not predict ICU or hospital mortality. Respiratory illnesses remain the main indication for ICU in HIV-positive patients. HIV infection is often diagnosed late, with patients presenting with life-threatening illnesses. Severity of illness as indicated by a high APACHE ΙΙ score, multiple organ dysfunction requiring inotropic support and RRT, rather than receipt of HAART, CD4 count and diagnosis at ICU admission, are predictors of ICU and hospital mortality.


Involuntary movements during vitamin B12 treatment.
It has been known for many years that vitamin B12 deficiency can cause neurologic problems. One of these problems is involuntary movements that can appear both before and after the initiation of vitamin B12 treatment. Here, we report 3 infants who developed movement disorder during vitamin B12 administration. The movement disorder consisted of a combination of tremor and myoclonus affecting face, tongue, and limbs. Because of the severity of the symptoms, they all needed symptomatic treatment. In 2 of them, the involuntary movements resolved with clonazepam. The involuntary movements in the other patient were successfully treated with piracetam.


The recovery of slow axonal transport after a single intraperitoneal injection of beta, beta'-iminodipropionitrile in the rat.
A single intraperitoneal injection of beta, beta'-iminodipropionitrile (IDPN) at a dose of 1.5 g/kg was given to 4-week-old rats. Immediately following, or at 1, 2, 3, 5, 10, and 15 weeks after IDPN injection, [35S]methionine was introduced into the anterior horn area of the lumbar cord. Labeled axonal proteins in the sciatic nerve were analyzed electrophoretically and fluorographically at 5, 10, and 15 weeks post-labeling. Labeled neurofilament proteins halt for a short period just after IDPN injection, then continue migrating distally, though at a slower rate, and finally the transport of affected neurofilament proteins completely recovers by 6 weeks post-labeling.


Hepatocyte-ductal transdifferentiation is mediated by reciprocal repression of SOX9 and C/EBPα.
Primary hepatocytes rapidly dedifferentiate when cultured in vitro. We have studied the mechanism of hepatocyte dedifferentiation by using two culture media: one that maintains hepatocytes in a differentiated state and another that allows dedifferentiation. We show that dedifferentiation involves partial transformation of hepatocytes into cells that resemble biliary epithelial cells. Lineage labeling and time-lapse filming confirm that the dedifferentiated cells are derived from hepatocytes and not from contaminating ductal or fibroblastic cells in the original culture. Furthermore, we establish that the conversion of hepatocytes to biliary-like cells is regulated by mutual antagonism of CCAAT/enhancer binding protein alpha (C/EBPα) and SOX9, which have opposing effects on the expression of hepatocyte and ductal genes. Thus, hepatocyte dedifferentiation induces the biliary gene expression program by alleviating C/EBPα-mediated repression of Sox9. We propose that reciprocal antagonism of C/EBPα and SOX9 also operates in the formation of hepatocytes and biliary ducts from hepatoblasts during normal embryonic development. These data demonstrate that reprogramming of differentiated cells can be used to model the acquisition and maintenance of cell fate in vivo.


Health care improvement and continuing interprofessional education: continuing interprofessional development to improve patient outcomes.
Health care improvement and continuing professional education must be better understood if we are to promote continuous service improvement through interprofessional learning in the workplace. We propose that situating interprofessional working, interprofessional learning, work-based learning, and service improvement within a framework of social learning theory creates a continuum between work-based interprofessional learning and service improvement in which each is integral to the other. This continuum provides a framework for continuing interprofessional development that enables service improvement in the workplace to serve as a vehicle through which individual professionals and teams can continually enhance patient care through working and learning together. The root of this lies in understanding that undertaking improvement and learning about improvement are co-dependent and that health care professionals must recognize their responsibility to improve as well as complete their everyday work. We believe that significant opportunities exist for health care commissioners, service providers, and educational institutions to work together to promote continuing interprofessional development in the workplace to enhance patient outcomes, and we outline some of the opportunities we believe exist.