How differing modes of non-genetic inheritance affect population viability in fluctuating environments.
Different modes of non-genetic inheritance are expected to affect population persistence in fluctuating environments. We here analyse Caenorhabditis elegans density-independent per capita growth rate time series on 36 populations experiencing six controlled sequences of challenging oxygen level fluctuations across 60 generations, and parameterise competing models of non-genetic inheritance in order to explain observed dynamics. Our analysis shows that phenotypic plasticity and anticipatory maternal effects are sufficient to explain growth rate dynamics, but that a carryover model where 'epigenetic' memory is imperfectly transmitted and might be reset at each generation is a better fit to the data. We further find that this epigenetic memory is asymmetric since it is kept for longer when populations are exposed to the more challenging environment. Our analysis suggests that population persistence in fluctuating environments depends on the non-genetic inheritance of phenotypes whose expression is regulated across multiple generations.


Should general practitioners purchase health care for their patients? The total purchasing experiment in Britain.
Until relatively recently, general practitioners (GPs) have been allowed to work independently, with no requirement to consider the resource implications of their referral and prescribing decisions. In order to align the interests of GPs with the overall objectives of health systems a number of countries have introduced primary care based capitation, funds pooling and budget holding either as experiments or as an overall policy. Are these experiments and policies likely to work? This paper presents evidence from the UK total purchasing experiment, which was the first major quasi-market development in the NHS to be independently evaluated from the outset. Total purchasing gave volunteer groups of practices freedom to purchase all hospital and community health services for their patients. The evidence suggests that whilst GPs have great potential as purchasers, they also have considerable limitations. The expectation that they will be able to improve the quality of patient experience of care, or to alter the use of resources, may not be generally realised. GP-based purchasing may be more appropriate where the task is to alter the balance or location of care between hospital and extramural settings. However, budgetary incentives are not 'magic potions' which have similar effects on behaviour wherever they are introduced. Holding budgets and having independent contracts, while important pre-requisites for being taken seriously in a quasi-market, were not sufficient for effective total purchasing. The paper concludes that health systems should not only value innovation and experimentation and encourage learning from evaluative research; they should also recognise the importance of supportive circumstances for any innovation to effect real and sustained change.


Power-controlled phase-matching and instability of CW propagation in multicore optical fibers with a central core.
We present modulation instability analysis including azimuthal perturbations of steady-state continuous wave (CW) propagation in multicore-fiber configurations with a central core. In systems with a central core, a steady CW evolution regime requires power-controlled phase matching, which offers interesting spatial-division applications. Our results have general applicability and are relevant to a range of physical and engineering systems, including high-power fiber lasers, optical transmission in multicore fiber, and systems of coupled nonlinear waveguides.


Serology of Pasteurella multocida in laboratory rabbits: a review.
Current concepts of the structure of the capsule and cell wall of gram negative bacteria and the role of these substances on the serologic classification of bacteria were reviewed. Emphasis was placed on the methods used to serotype Pasteurella multocida as developed from studies on isolates from various animal species and the application of these methods in serotyping isolates of Pasteurella multocida from laboratory rabbits. Evidence was presented that the indirect hemagglutination test used to identify "capsular" types A, B, D, and E is based on the interaction of antibody with type specific lipopolysaccharide and is therefore a test for somatic rather than capsular materials. It also was observed that several rabbit isolates were not serologically typable by currently available reagents. Commonly used techniques to obtain relatively homogeneous bacterial extracts were discussed, and the need to characterize the extracts of Pasteurella multocida from rabbits both chemically and immunologically was emphasized.


Mixed integer programming improves comprehensibility and plan quality in inverse optimization of prostate HDR brachytherapy.
Current inverse treatment planning methods that optimize both catheter positions and dwell times in prostate HDR brachytherapy use surrogate linear or quadratic objective functions that have no direct interpretation in terms of dose-volume histogram (DVH) criteria, do not result in an optimum or have long solution times. We decrease the solution time of the existing linear and quadratic dose-based programming models (LP and QP, respectively) to allow optimizing over potential catheter positions using mixed integer programming. An additional average speed-up of 75% can be obtained by stopping the solver at an early stage, without deterioration of the plan quality. For a fixed catheter configuration, the dwell time optimization model LP solves to optimality in less than 15 s, which confirms earlier results. We propose an iterative procedure for QP that allows us to prescribe the target dose as an interval, while retaining independence between the solution time and the number of dose calculation points. This iterative procedure is comparable in speed to the LP model and produces better plans than the non-iterative QP. We formulate a new dose-volume-based model that maximizes V(100%) while satisfying pre-set DVH criteria. This model optimizes both catheter positions and dwell times within a few minutes depending on prostate volume and number of catheters, optimizes dwell times within 35 s and gives better DVH statistics than dose-based models. The solutions suggest that the correlation between the objective value and the clinical plan quality is weak in the existing dose-based models.


Pulmonary nodules and primary Sjögren syndrome: a case report.
Primary Sjögren syndrome (pSS) is a systemic autoimmune disorder that principally affects the exocrine glands but can also affect systemic or extra-glandular sites. Approximately 65-80% of patients with Sjogren's demonstrate pulmonary involvement at the CT scan and pulmonary nodules (PNs) can be encountered as a common finding. We present the case of a 49-year-old woman admitted to the emergency department for chest pain and fever. The patient was diagnosed with pSS fourteen years prior and had never taken therapy or followed regular check-ups. At the HRTC were found PNs that were studied trough a CT-PET and a needle biopsy via CT guidance, which showed diffuse large B cell lymphoma. This case report underlies the importance of check-ups and the need for a multidisciplinary approach in the care of Sjögren's syndrome patients.


Parent-adolescent communication and support for diabetes management as reported by adolescents with type 1 diabetes.
This study examined parental involvement in terms of communication and support and these variables in relationship to diabetes management responsibility and metabolic control from the perspective of adolescents. The sample consisted of 27 adolescents who were 12 to 19 years of age (M=15.0 years, SD=1.9) and had type 1 diabetes. Participants completed Independent Functioning, Independent Decision Making, Parent-Adolescent Communication, and Parental Support Checklists. Adolescents reported relatively high level of communication with parents and relatively low level of parental support. These adolescents reported more agreement than amount of communication with parents and reported more parental support received than sought. Although not significantly different, the means for amount of communication and agreement decreased from early to middle to late adolescence and the means for seeking and receiving support increased from early to middle and then decreased from middle to late adolescence. When working with parents and adolescents with type 1 diabetes, health care professionals need to be cognizant of adolescents' view of specific ways that parents are involved and the developmental influences on parent-adolescent relationships.


The impact of culture and product on the subjective importance of user experience aspects.
Many software products are created by considering targeted users from different countries. For such products, it is significant to investigate users' expectations related to cultural aspects to achieve user acceptance as broad as possible in all relevant countries. The researchers of the current study examined whether the cultural background of an individual has an influence on the subjective importance of user experience (UX) aspects for several common product categories. The researchers compared findings from a previous study conducted in Germany and a replication study carried out in Indonesia. Results show significant differences concerning the rated importance of UX aspects for many product categories. However, a detailed analysis of the results also shows that the impact of culture is considerably lower than the impact of interindividual differences between persons of the same culture. In addition, both samples show quite similar rankings of the importance of UX aspects. Thus, the product type has a much bigger impact than cultural differences.


Prevalence and correlates of knowledge of male partner HIV testing and serostatus among African-American women living in high poverty, high HIV prevalence communities (HPTN 064).
Knowledge of sexual partners' HIV infection can reduce risky sexual behaviors. Yet, there are no published studies to-date examining prevalence and characteristics associated with knowledge among African-American women living in high poverty communities disproportionately affected by HIV. Using the HIV Prevention Trial Network's (HPTN) 064 Study data, multivariable logistic regression was used to examine individual, partner, and partnership-level determinants of women's knowledge (n = 1,768 women). Results showed that women's demographic characteristics alone did not account for the variation in serostatus awareness. Rather, lower knowledge of partner serostatus was associated with having two or more sex partners (OR = 0.49, 95 % CI 0.37-0.65), food insecurity (OR = 0.68, 95 % CI 0.49-0.94), partner age >35 years (OR = 0.68, 95 % CI 0.49-0.94), and partner concurrency (OR = 0.63, 95 % CI 0.49-0.83). Access to financial support (OR = 1.42, 95 % CI 1.05-1.92) and coresidence (OR = 1.43, 95 % CI 1.05-1.95) were associated with higher knowledge of partner serostatus. HIV prevention efforts addressing African-American women's vulnerabilities should employ integrated behavioral, economic, and empowerment approaches.


Fifty Years of Biomedical Engineering Undergraduate Education in Mexico and Latin America: Results, Reflections and Perspectives.
This manuscript provides reflections and perspectives on BME education in IEEE Region 9 (Mexico and Latin America) on the 50Th anniversary of the founding of these undergraduate programs. It includes a bit of history, as well as analysis of around 150 existing programs in the region. Results of the different approaches are also included. A discussion of results as well as an analysis of new perspectives and opportunities for the future can be found in the section on conclusions.


Mechanism of pigeon liver malic enzyme: modification of essential carboxyl groups.
The maximum velocity of the reaction catalyzed by the pigeon liver malic enzyme depends on the ionization of a functional group of pKa 6.7. This pKa value is independent of temperature within the range 30 degrees-49 degrees C, suggesting the ionization of a carboxyl group. The enzyme activity is inactivated by N-ethyl-5-phenylisoxazolium-3'-sulfonate (Woodward reagent K) at pH 6.0 and 25 degrees C. N-Methylhydroxamine regenerates the enzymatic activity whereas glycine ethyl ester does not. The addition of Mn2+, NADP+, and L-malate to the incubation mixture decreases the inactivation rate, suggesting that the reaction takes place in the active center. The binding capacities of the modified enzyme with NADP+, L-malate, pyruvate, and Mn2+ are not impaired. The kinetic and chemical evidence indicates that the inactivation is due to the modification of a carboxyl group which may be from glutamyl or aspartyl residues of the enzyme. This carboxyl group might function as a general acid-base catalyst. A detailed mechanism in terms of the exact amino acid residues involved is proposed.


The association between physical activity and the development of acute coronary syndromes in treated and untreated hypertensive subjects.
The objective of this study was to evaluate the effect of physical activity on the risk of coronary events in different groups of hypertensive patients. During 2000-2001, 848 patients hospitalized for a first event of coronary heart disease and 1078 hospitalized controls without any suspicion of coronary heart disease, paired by sex and age, were randomly selected from all Greek regions. A total of 418 (49%) of the patients and 303 (28%) of the controls were classified as hypertensives, while 88 (21%) of the hypertensive patients and 88 (29%) of the hypertensive controls, reported regular leisure-time physical activity. Compared to physical inactivity, the analysis showed that light to moderate physical activity was associated with a reduction by 12% of the coronary risk in controlled hypertensive subjects (p=0.03), by 9% (p=0.04) in hypertensives who were untreated or unaware of their condition, and by 5% (p=0.087) in uncontrolled hypertensives. The practice of regular physical activity seems to be associated with lower coronary risk in various groups of hypertensives. However, these data cannot prove causality, and prospective studies will be necessary to confirm or refute the authors findings.


Association of pre-eclampsia with the R563Q mutation of the beta-subunit of the epithelial sodium channel.
The R563Q mutation of the beta-subunit of the epithelial sodium channel (ENaC) is associated with hypertension in black and mixed ancestry (MA) men and women in South Africa. The frequency of the R563Q mutation in black and MA women with pre-eclampsia (n= 230) and in controls (n= 198) was studied. The R563Q mutation was found in 7.8% of the women with pre-eclampsia and in 2.6% of controls (P= 0.014). This remained significant if the black women were analysed separately (P= 0.031). We have demonstrated that a genetic variant of the ENaC is associated with pre-eclampsia. This has implications for understanding the pathogenesis and treatment of pre-eclampsia.


Effect of the full implementation of the European Working Time Directive on operative training in adult cardiac surgery.
Surgical specialties rely on practice and apprenticeship to acquire technical skills. In 2009, the final reduction in working hours to 48 per week, in accordance with the European Working Time Directive (EWTD), has also led to an expansion in the number of trainees. We examined the effect of these changes on operative training in a single high-volume [>1500 procedures/year] adult cardiac surgical center. Setting: A single high-volume [>1500 procedures/year] adult cardiac surgical center. Design: Consecutive data were prospectively collected into a database and retrospectively analyzed. Procedures and Main Outcome Measures: Between January 2006 and August 2010, 6688 consecutive adult cardiac surgical procedures were analyzed. The proportion of cases offered for surgical training were compared for 2 non-overlapping consecutive time periods: 4504 procedures were performed before the final implementation of the EWTD (Phase 1: January 2006-December 2008) and 2184 procedures after the final implementation of the EWTD (Phase 2: January 2009-August 2010). Other predictors of training considered in the analysis were grade of trainee, logistic European system for cardiac operative risk evaluation (EuroSCORE), type of surgical procedure, weekend or late procedure, and consultant. Logistic regression analysis was used to determine the predictors of training cases (procedure performed by trainee) and to evaluate the effect of the EWTD on operative surgical training after correcting for confounding factors. Proportion of training cases rose from 34.6% (1558/4504) during Phase 1 to 43.6% (953/2184) in Phase 2 (p < 0.0001), despite higher mean logistic EuroSCORE [4.29 (6.8) during Phase 1 vs 4.95 (7.2) during Phase 2, p < 0.0001] and higher proportion of cases performed out of hours [153 (3.4) during Phase 1 vs 116 (5.3) during Phase 2, p < 0.0001]. During Phase 1, senior trainees (last 2 years of training) performed 803 (17.8%) procedures, whereas other trainees (first 4 years of training) performed 755(16.8%) cases. During Phase 2, senior trainees performed 763 (34.9%) procedures, whereas other trainees performed 190 (8.7%) cases (p < 0.0001). Independent positive predictors of training cases emerging from the multivariable logistic regression model included consultant in charge, final EWTD, and senior trainees. Independent negative predictors of training cases included logistic EuroSCORE, out-of-hours' procedures, and surgery other than coronary artery bypass grafts. Implementation of the final phase of EWTD has not decreased training in a high-volume center. The positive adjustment of trainers' attitudes and efforts to match trainees' needs allow maintenance of adequate training, despite reduction in working hours and increasing patients' risk profile.


Shear bond strength of composite resin and amalgam adhesive systems to dentin.
To determine the effects of several multi-purpose dental adhesive systems on the shear bond strength of both composite resin (Herculite XRV) and amalgam (Tytin) to dentin. 160 extracted human molar teeth were randomly assigned to 16 treatment groups (n = 10/group), embedded in resin, and ground flat on both the occlusal and apical surfaces to expose a 3.0 mm thickness of dentin. In each specimen, a 3.18 mm diameter channel was drilled through the dentin perpendicular to the ground surface. The cylindrical preparations were treated with one of seven adhesive systems or one of two controls (37% H3PO4 or Copalite varnish) according to manufacturers' recommendation, then restored with either composite resin or amalgam. Specimens were thermocycled and subjected to a punch-out shear force using a materials testing machine. All examined multi-purpose adhesive systems provided increased shear bond strength in comparison to the controls. Although the individual performance of each adhesive system varied with specific restorative materials, OptiBond FL demonstrated the highest mean shear bond strength to both composite resin and amalgam. Mean amalgam shear bond strength was significantly greater than mean composite resin strengths.


Direct comparison of spontaneous functional connectivity and effective connectivity measured by intracortical microstimulation: an fMRI study in macaque monkeys.
Correlated spontaneous activity in the resting brain is increasingly recognized as a useful index for inferring underlying functional-anatomic architecture. However, despite efforts for comparison with anatomical connectivity, neuronal origin of intrinsic functional connectivity (inFC) remains unclear. Conceptually, the source of inFC could be decomposed into causal components that reflect the efficacy of synaptic interactions and other components mediated by collective network dynamics (e.g., synchronization). To dissociate these components, it is useful to introduce another connectivity measure such as effective connectivity, which is a quantitative measure of causal interactions. Here, we present a direct comparison of inFC against emEC (effective connectivity probed with electrical microstimulation [EM]) in the somatosensory system of macaque monkeys. Simultaneous EM and functional magnetic resonance imaging revealed strong emEC in several brain regions in a manner consistent with the anatomy of somatosensory system. Direct comparison of inFC and emEC revealed colocalization and overall positive correlation within the stimulated hemisphere. Interestingly, we found characteristic differences between inFC and emEC in their interhemispheric patterns. Our results suggest that intrahemispheric inFC reflects the efficacy of causal interactions, whereas interhemispheric inFC may arise from interactions akin to network-level synchronization that is not captured by emEC.


[Combined effect of Pb2+ and divalent mental complexes on superprecipation and ATPase activity of myometrial actomyosin].
The inhibiting effect of Pb2+ (0.1-1.0 mM) on superprecipitation and ATPase activity of myometrium actomyosin has been shown. It is found out that of 11 studied chelators of bivalent cations only monosodium salt of 4-guanidino-1-hydroxybutyliden-1.1-bisphosphonic acid can efficiently renews the value of superprecipitation and ATPase activity of actomyosin in presence of lead ions. It is supposed that this renewal is underlied by binding of guanidin group of Pb ions.


New Insights Towards 1,4-Benzodiazepines from Curcumin. Design, Synthesis and Antimicrobial Activities.
Curcumin is a safe, versatile natural product with unlimited number of biological activities and a precursor for various heterocyclic compounds. The present study was aimed to the development of a curcumin based antimicrobial reagent with high potency against gram-positive and gram-negative bacteria. Herein we report a simple and convenient one step method for synthesizing a series of 1,4-benzodiazepines via condensation cyclization reaction between curcumin and various 1,2- phenylenediamine in refluxed ethanol. A series of new 1,4-benzodiazepins were synthesized and their structures were supported by FT-IR, 1H NMR, 13C NMR, and mass spectral analysis. Synthesized 1,4-benzodiazepins were evaluated for their in vitro antimicrobial activity against gram positive (S. aureus and S. epidermidis) and gram negative (E. coli and P. aeruginosa) bacteria. They exhibited low to high potency against the tested organisms. In particular, dichlorinated 1,4-benzodiazepine 9 exhibited a remarkable potency against the gram-positive bacteria S. aureus (MIC: 3.125 μg mL-1, MBC: 12 μg mL-1). It showed a higher potency than most of the tested reference drugs. Compound 9 showed the medium activity against E. coli. Genotoxic study revealed that, benzodiazepines 9 attacked the DNA of E. coli strains and damaged it. The potency of compound 9, could be attributed to the multiple chlorine atoms present on the aromatic ring. Some of the synthesized curcumin based benzodiazepines showed excellent potency against gram positive bacteria. These benzodiazepines could be a great candidate as a future antimicrobial agent.


Vimentin induces changes in cell shape, motility, and adhesion during the epithelial to mesenchymal transition.
Vimentin is used widely as a marker of the epithelial to mesenchymal transitions (EMTs) that take place during embryogenesis and metastasis, yet the functional implications of the expression of this type III intermediate filament (IF) protein are poorly understood. Using form factor analysis and quantitative Western blotting of normal, metastatic, and vimentin-null cell lines, we show that the level of expression of vimentin IFs (VIFs) correlates with mesenchymal cell shape and motile behavior. The reorganization of VIFs caused by expressing a dominant-negative mutant or by silencing vimentin with shRNA (neither of which alter microtubule or microfilament assembly) causes mesenchymal cells to adopt epithelial shapes. Following the microinjection of vimentin or transfection with vimentin cDNA, epithelial cells rapidly adopt mesenchymal shapes coincident with VIF assembly. These shape transitions are accompanied by a loss of desmosomal contacts, an increase in cell motility, and a significant increase in focal adhesion dynamics. Our results demonstrate that VIFs play a predominant role in the changes in shape, adhesion, and motility that occur during the EMT.


UDP-glucuronyltransferase activity exhibits two developmental groups in liver from foetal rhesus monkeys.
UDP-glucuronyltransferase was assayed in liver from adult rhesus monkeys and foetuses during late gestation. Activities toward 2-aminophenol, 5-hydroxytryptamine, 1-naphthol and 4-nitrophenol in the foetal liver ranged from 46 to 114% of adult values, whereas activities toward bilirubin, oestradiol and testosterone were less than 5% of adult values. This suggests that in primates UDP-glucuronyltransferase develops differentially in two clusters analogous to that in the rat.


[Use of laser flow-type fluorescence aerosol particle counter to evaluate the concentration of microbes in the surface air under high dust content].
The paper deals with the use of a laser flow-type fluorescence aerosol particle counter to evaluate the concentrations of microbes in the surface air under high dust content. Various circuits of flow-type optic aerosol recorders are analyzed. Flow spectral luminescence analysis of some particles flow while exciting the fourth harmonics of a pulse laser on yttrium-aluminium garnet with neodymium by ultraviolet radiation is shown to be the most optimum method for indication of individual aerosol particles. Experiments were conducted on the authors' model of a pilot plant based on this method. The model of a laser flow-type optic analyzer was developed for experimental studies that give a clear display of biological aerosols in complex aerosols. The laser flow-type analyzer-based unit developed may provide a fluorescence signal of aerosol particles in the flow of a sample and that light diffusion signal from them at an exciting light wavelength of 266 nm. Experiments with BVC aerosols and soil dust particles were conducted in different regions of Russia. They showed it possible to detect and to rapidly calculate soil microorganisms by laser flow-type fluorescence assay of individual particles when excited by ultraviolet radiation.


[Sapheno-femoral venous confluence and the external pudendal network: anatomical data and new statistics].
In 1983, we had the opportunity to encounter a case of impotence following eveinage in a man aged 58. The complete aetiological investigation of the disorder proved to favour the ligation of an external pudendal artery during the operation, a cause already anticipated by Dr D. Reinharez in 1980, in an article published in Phlebologie, where he described 5 similar cases. In 1984, we demonstrated, thanks to the Doppler velocimeter and also common selective femoral angiography that, contrary to the classic descriptions, approximately 7% of men have a particular anatomical distribution; the external pudendal arteries play a not insignificant haemodynamic role in the vascularization of the erectile organs. Since then, we have encountered further cases of impotence following eveinage. This being so, we wanted to know more about the anatomical relationship between the saphenofemoral venous confluent and the external pudendal arteries such as number, calibre, and variations according to age and sex... In order to achieve this, we requested the collaboration of five surgeons known for their thoroughness, their experience and their competence in venous surgery. They were asked to complete a pre-drawn diagram after each eveinage carried out, and to draw onto it the different arterial and venous branches observed, their calibres, and the relation between them. 140 subjects were included in this study (79 women, 70 men) with longitudinal selection; 256 eveinages were carried out and indexed. The average age of patients was 42.9 years: 40.5 for women, 45.5 for men. The analysis of the results enables us to improve our knowledge of this "strategic" region for the surgeon and the phlebologist, by contributing new anatomical and statistical elements, in particular: the very large number of times that an external pudendal artery is at least encountered during dissection of the saphenofemoral venous confluent: round about 97%; the number of external pudendal arteries, classified usually as 2, proves in fact to be more often one: in about 75-80% of women and 65% of men. Triple pudendals are exceptional; the average calibre of the pudendal artery is 1/3 greater in the male sample than in the female: 0.8 mm v 0.6 mm.(ABSTRACT TRUNCATED AT 400 WORDS)


Capacity of dental equipment to interfere with cardiac implantable electrical devices.
Patients with cardiac implantable electrical devices should take precautions when exposed to electromagnetic fields. Possible interference as a result of proximity to electromagnets or electricity flow from electronic tools employed in clinical odontology remains controversial. The objective of this study was to examine in vitro the capacity of dental equipment to provoke electromagnetic interference in pacemakers and implantable cardioverter defibrillators. Six electronic dental instruments were tested on three implantable cardioverter defibrillators and three pacemakers from different manufacturers. A simulator model, submerged in physiological saline, with elements that reproduced life-size anatomic structures was used. The instruments were analyzed at differing distances and for different time periods of application. The dental instruments studied displayed significant differences in their capacity to trigger electromagnetic interference. Significant differences in the quantity of registered interference were observed with respect to the variables manufacturer, type of cardiac implant, and application distance but not with the variable time of application. The electronic dental equipment tested at a clinical application distance (20 cm) provoked only slight interference in the pacemakers and implantable cardioverter defibrillators employed, irrespective of manufacturer.


Pathophysiology of coronary microvascular dysfunction.
The term "coronary microvascular dysfunction" (CMD) encompasses several pathogenetic mechanisms resulting in functional and/or structural changes in the coronary microcirculation. CMD often determines angina and myocardial ischemia in a broad spectrum of cardiovascular diseases, including patients with ischemia with non-obstructive coronary arteries or ischemia with obstructive coronary artery disease, infarction with non-obstructive coronary arteries, cardiomyopathies, the Takotsubo syndrome and heart failure, especially heart failure with preserved ejection fraction. In this article, we provide updated evidence regarding the pathophysiological mechanisms underlying CMD across the different cardiovascular diseases, aiming to pave the way for further research and the development of novel strategies for a precision medicine approach.


X-ray sensitivity of HeLa S3 cells in the G2 phase comparison of two methods of synchronization.
The sensitivity of HeLa S3 cells to 220 kv X-rays was measured in terms of cell survival (colony development) during the G2 phase of the cell generation cycle, employing two procedures designed to free G2 cultures from contaminating cells from other phases of the cycle. Treatment of synchronous cultures (obtained initially by mitotic selection) with high specific activity tritiated thymidine (HSA-(3)HTdR) selectively eliminated S phase cells, while addition of vinblastine permitted removal of cells as they entered mitosis. It was found that HeLa S3 cells become increasingly sensitive as they progress through G2. The pattern of sensitivity fluctuations observed in synchronous HeLa S3 populations selected by the foregoing method was compared with that found in synchronous cultures prepared by the HSA-(3)HTdR method of Whitmore. The latter method had been used previously with mouse L cells, which were found to undergo a different pattern of sensitivity fluctuations. The two methods yield similar results for HeLa cells in the S and G2 phases of the cycle. It may be concluded, therefore, that the discrepancies between HeLa and mouse L cells do not arise from methodological factors, but represent fundamental differences between the cell types.


["On hidden madness"--"De amentia occulta" by Ernst Platner in early 19th-century tension of medicine and jurisprudence].
During the first half of the 19th century psychiatry became more and more influential in the evaluation of mentally ill offenders. "Doubtful" states of mind gained a particular importance for forensic practice. One of the mental disorders that was heavily disputed was amentia occulta (hidden madness) first described by the well-known Leipzig doctor and philosopher Ernst Platner. This publication (1797) preluded several other diagnoses to refer to non-obvious, "hidden mental derangements". Regardless of the differences in arguments as developed by the experts in question (E. T. A. Hoffmann, Merzdorff, E. Horn, J. C. A. Clarus), two case studies from the early 19 (th) century (D. Schmolling, J. C. Woyzeck) will exemplify the process of medicine, and psychiatry in particular, becoming more and more influential in everyday jurisdictional practice. The above-mentioned Ernst Platner, the author of manifold forensic studies and of "De amentia occulta", was one of the pioneers and promoters of this process. By emphasising the importance of mental states being evaluated by medical professionals he contributed a great deal to the establishment of forensic psychiatry.


Decline in US childhood cancer mortality. 1950 through 1980.
Cancer mortality among children in the United States, 1950 through 1979, as evaluated by death certificate diagnoses, revealed dramatic declines primarily in the second half of the 30-year interval. The numbers of deaths of persons younger than 15 years, 1965 through 1979, as compared with the number expected at 1950 rates, fell 50% for leukemia, 32% for non-Hodgkin's lymphoma, 80% for Hodgkin's disease, 50% for bone sarcoma, 68% for kidney cancer, and 31% for all other cancer. There were 17,411 fewer deaths from childhood cancer from 1965 through 1979 than expected at the 1950 rate. Leukemia mortality declined by 8,073 deaths and kidney tumor mortality by 2,393. In data subsequently received for 1980, the decline in rates persisted for leukemia and non-Hodgkin's lymphoma, but the rates for the other four cancer categories seem to have reached a plateau. The reduction in mortality is attributed to improved therapy.


Biological memories of past environments: epigenetic pathways to health disparities.
Human health tends to mirror gradients in social standing related to class, ethnicity and race. Past research in the social sciences suggests that environmental experiences related to social status contribute to these disparities, but the underlying biological mechanisms are only partially understood. Here, we review research related to three domains of environmental exposure that point to epigenetic contributions to health disparities: nutrition, psychosocial stress, and environmental toxicant exposure. Each exposure has effects that may persist across the life course and in some instances may be transmitted to offspring via epigenetic inheritance. Since epigenetic markings provide a "memory" of past experiences, minimizing future disparities in health will be partially contingent upon our ability to address inequality in the current environment. We suggest that future research in environmental epigenetics focus on establishing the reversibility of stress-induced epigenetic modifications, and also on identifying positive epigenetic effects of environmental enrichment.


Dysregulation of Sleep Behavioral States in Narcolepsy.
Patients with narcolepsy experience poor maintenance of wakefulness and fragmented night sleep, but the underlying mechanism of sleep boundary dysregulation remains little understood. The goal of this study was to quantify abnormal sleep-wake regulation in narcolepsy patients. Using a model-based approach (state space analysis), we analyzed overnight electroencephalography recordings in 10 patients with narcolepsy type 1 and age- and gender-matched healthy control subjects. We analyzed consolidated sleep states using cluster analysis in state space and transitional sleep periods as trajectories between stable clusters. Patients with narcolepsy showed a dislocation of rapid eye movement (REM) sleep in state space and overlap of REM and WAKE behavioral states. Narcolepsy patients had more trajectories between the REM and the WAKE clusters and also between the non-rapid eye movement (NREM) and WAKE clusters. Point density analysis showed more transitional periods between WAKE and REM in narcolepsy, less consolidated NREM sleep, and higher velocities between WAKE and NREM in patients. Conventional sleep analysis revealed increased NREM1 and decreased NREM2 sleep and reduced REM latency in narcolepsy patients. This study provides further evidence for narcolepsy as a disorder of state boundaries including but not limited to REM sleep and wakefulness. In particular, the increase in transitional periods between REM and WAKE but also between NREM and WAKE indicates abnormal state dynamics in narcolepsy. This pattern may be a consequence of disrupted sleep/wake stabilizing mechanisms due to loss of hypocretin/orexin neurons in the hypothalamus.


Scoring ensembles of docked protein:ligand interactions for virtual lead optimization.
Ensembles of protein structures to simulate protein flexibility are widely used throughout several applications including virtual lead optimization where they have been shown to improve ligand ranking. Yet, there is no established convention for weighting individual scores generated from ensemble members. To investigate the best method for weighting ensemble scores for proper ligand ranking, a series of dihydrofolate reductase inhibitors was docked to ensembles of Candida albicans dihydrofolate reductase (CaDHFR) structures created from a molecular dynamics (MD) simulation. From a single MD simulation, two ensemble collections were generated, one of which was subjected to a minimization procedure to create a group of structures of equal probability. As expected, ligand ranking accuracy was significantly improved when Boltzmann weighting was applied to the energies of the ensemble without structural minimization (60%), relative to that achieved with averaging (36%). However, accuracy was further improved (72%) by averaging docking scores across a minimized ensemble. To examine whether this accuracy results from structural variation in the single trajectory versus the possibility that error is minimized by averaging, a third collection of receptor structures was created in which each member was taken from an independent molecular dynamics simulation after minimization. Comparison of the docking accuracy results from the single trajectory (72%) to this third collection (61%) showed decreased accuracy, suggesting that ligands are more accurately oriented and assessed when docked to the minimized ensemble from a single MD trajectory, an effect that is more than simply error minimization. Averaging docking scores over a minimized ensemble of another target, influenza A neuraminidase, yielded a ligand ranking accuracy of 83%, representing a 24% improvement over other methods tested.


Activity of mefloquine and mefloquine derivatives against Echinococcus multilocularis.
The cestode E. multilocularis causes the disease alveolar echinococcosis (AE) in humans. The continuously proliferating metacestode (larval stage) of the parasite infects mostly the liver and exhibits tumor-like growth. Current chemotherapeutical treatment options rely on benzimidazoles, which are rarely curative and have to be applied daily and life-long. This can result in considerable hepatotoxicity and thus treatment discontinuation. Therefore, novel drugs against AE are urgently needed. The anti-malarial mefloquine was previously shown to be active against E. multilocularis metacestodes in vitro, and in mice infected by intraperitoneal inoculation of metacestodes when administered at 100 mg/kg by oral gavage twice a week for 12 weeks. In the present study, the same dosage regime was applied in mice infected via oral uptake of eggs representing the natural route of infection. After 12 weeks of treatment, the presence of parasite lesions was assessed in a liver squeeze chamber and by PCR, and a significantly reduced parasite load was found in mefloquine-treated animals. Assessment of mefloquine plasma concentrations by HPLC and modeling using a two-compartment pharmacokinetic model with first-order absorption showed that >90% of the expected steady-state levels (Cmin 1.15 mg/L, Cmax 2.63 mg/L) were reached. These levels are close to concentrations achieved in humans during long-term weekly dosage of 250 mg (dose applied for malaria prophylaxis). In vitro structure-activity relationship analysis of mefloquine and ten derivatives revealed that none of the derivatives exhibited stronger activities than mefloquine. Activity was only observed, when the 2-piperidylmethanol group of mefloquine was replaced by an amino group-containing residue and when the trifluoromethyl residue on position 8 of the quinoline structure was present. This is in line with the anti-malarial activity of mefloquine and it implies that the mode of action in E. multilocularis might be similar to the one against malaria.


Hospital Quality of Care and Racial and Ethnic Disparities in Unexpected Newborn Complications.
To investigate racial and ethnic differences in unexpected, term newborn morbidity and the influence of hospital quality on disparities. We used 2010-2014 birth certificate and discharge abstract data from 40 New York City hospitals in a retrospective cohort study of 483 834 low-risk (term, singleton, birth weight ≥2500 g, without preexisting fetal conditions) neonates. We classified morbidity according to The Joint Commission's unexpected newborn complications metric and used multivariable logistic regression to compare morbidity risk among racial and ethnic groups. We generated risk-standardized complication rates for each hospital using mixed-effects logistic regression to evaluate quality, ranked hospitals on this measure, and assessed differences in the racial and ethnic distribution of births across facilities. The unexpected complications rate was 48.0 per 1000 births. Adjusted for patient characteristics, morbidity risk was higher among Black and Hispanic infants compared with white infants (odds ratio: 1.5 [95% confidence interval 1.3-1.9]; odds ratio: 1.2 [95% confidence interval 1.1-1.4], respectively). Among the 40 hospitals, risk-standardized complications ranged from 25.3 to 162.8 per 1000 births. One-third of Black and Hispanic women gave birth in hospitals ranking in the highest-morbidity tertile, compared with 10% of white and Asian American women (P < .001). Black and Hispanic women were more likely to deliver in hospitals with high complication rates than were white or Asian American women. Findings implicate hospital quality in contributing to preventable newborn health disparities among low-risk, term births. Quality improvement targeting routine obstetric and neonatal care is critical for equity in perinatal outcomes.


ANT-dependent MPTP underlies necrotic myofiber death in muscular dystrophy.
Mitochondrial permeability transition pore (MPTP) formation contributes to ischemia-reperfusion injury in the heart and several degenerative diseases, including muscular dystrophy (MD). MD is a family of genetic disorders characterized by progressive muscle necrosis and premature death. It has been proposed that the MPTP has two molecular components, the adenine nucleotide translocase (ANT) family of proteins and an unknown component that requires the chaperone cyclophilin D (CypD) to activate. This model was examined in vivo by deleting the gene encoding ANT1 (Slc25a4) or CypD (Ppif) in a δ-sarcoglycan (Sgcd) gene-deleted mouse model of MD, revealing that dystrophic mice lacking Slc25a4 were partially protected from cell death and MD pathology. Dystrophic mice lacking both Slc25a4 and Ppif together were almost completely protected from necrotic cell death and MD disease. This study provides direct evidence that ANT1 and CypD are required MPTP components governing in vivo cell death, suggesting a previously unrecognized therapeutic approach in MD and other necrotic diseases.


Human herpesvirus 8 DNA sequences in blistering skin from patients with pemphigus.
Human herpesvirus 8 (HHV-8) has been detected in Kaposi sarcoma (KS) and other lesions in patients both seropositive and seronegative for the human immunodeficiency virus (HIV). Kaposi sarcoma has been reported to develop in a disproportionate number of patients with pemphigus. Since HHV-8 is so strongly associated with KS, we wondered whether HHV-8 is present in pemphigus lesions from patients without KS or HIV infection. Pemphigus lesions and skin from healthy individuals were coded in a blinded fashion. Tissue-extracted DNA was tested using polymerase chain reaction, Southern blot hybridization, and automated sequencing of the polymerase chain reaction products for the presence of HHV-8 DNA. Six patients had pemphigus foliaceus, 6 had pemphigus vulgaris, and 2 had KS; 10 healthy individuals were used as controls. All 24 patients were HIV seronegative. Lesional skin from 4 of the 6 patients with pemphigus vulgaris, all 6 of the patients with pemphigus foliaceus, and both positive controls (KS) tested positive for HHV-8 DNA. Furthermore, the HHV-8 DNA sequences for KS330(233) differed between all 6 DNA specimens from pemphigus foliaceus, while 3 of the 4 DNA specimens from pemphigus vulgaris were identical. However, HHV-8 DNA was absent in all normal human skin analyzed. This report expands the spectrum of lesions found to contain HHV-8 DNA sequences and suggests that HHV-8 might have trophism for pemphigus lesions.


[Management of acute pulmonary thromboembolism].
Acute pulmonary embolism (APE) is considered a cardiovascular emergency and is one of the most important causes of morbidity and mortality in hospitalized patients. Pulmonary embolism diagnosis has to be made early in the course of the disease and its management installed immediately. Pulmonary embolism management includes hemodynamic support, anticoagulation, thrombolysis and embolectomy. We present an overview of the treatment of APE.


Evolution of phenotypic clusters through competition and local adaptation along an environmental gradient.
We have analyzed the evolution of a quantitative trait in populations that are spatially extended along an environmental gradient, with gene flow between nearby locations. In the absence of competition, there is stabilizing selection toward a locally best-adapted trait that changes gradually along the gradient. According to traditional ideas, gradual spatial variation in environmental conditions is expected to lead to gradual variation in the evolved trait. A contrasting possibility is that the trait distribution instead breaks up into discrete clusters. Doebeli and Dieckmann (2003) argued that competition acting locally in trait space and geographical space can promote such clustering. We have investigated this possibility using deterministic population dynamics for asexual populations, analyzing our model numerically and through an analytical approximation. We examined how the evolution of clusters is affected by the shape of competition kernels, by the presence of Allee effects, and by the strength of gene flow along the gradient. For certain parameter ranges clustering was a robust outcome, and for other ranges there was no clustering. Our analysis shows that the shape of competition kernels is important for clustering: the sign structure of the Fourier transform of a competition kernel determines whether the kernel promotes clustering. Also, we found that Allee effects promote clustering, whereas gene flow can have a counteracting influence. In line with earlier findings, we could demonstrate that phenotypic clustering was favored by gradients of intermediate slope.


Effects of D-amino acid substituents on degradation of LHRH analogues by proximal tubule.
Less than Glu-His-Trp-Ser-Tyr-Gly-Leu-Arg-Pro-Gly-NH2, the luteinizing hormone-releasing hormone, LHRH, is degraded in renal proximal tubules (PT) in vivo (rat) and in vitro (rabbit) to less than Glu-His (2), less than Glu-His-Trp (3), and less than Glu-His-Trp-Ser (4). LHRH may be cleaved by endopeptidases simultaneously at multiple bonds, or initially at Ser4-Tyr5 followed by carboxypeptidase hydrolysis of 4 to 3 and then 2. To distinguish between these mechanisms, [3H]LHRH analogues were incubated with rabbit renal brush-border membranes (BBM), microinfused into PT in vivo or in vitro, and products were analyzed by HPLC. [D-Ser4]LHRH was not cleaved at D Ser4-Tyr5 but yielded less than Glu-His-Trp-D-Ser-Tyr-Gly as the major metabolite plus 2 and 3. [D-Trp6]LHRH was cleaved by BBM and PT to 2 and 3, but not to 4. [D-Ser4, D-Trp6]LHRH was not cleaved by BBM, but was degraded to 2 by PT in vivo. Thus, D-amino acid substituents altered the expected cleavage pattern of these analogues. [3H]LHRH was cleaved by BBM or by endopeptidase-24.11 from porcine PT to metabolites 2, 4, small amounts of 3, and less than Glu-His-Trp-Ser-Tyr-Gly, but cleavage was strongly inhibited by the specific inhibitor phosphoramidon. Thus, normally LHRH may be cleaved in PT by endopeptidase-24.11 to 2 and 4, and by angiotensin I-converting enzyme to 3, its known cleavage site.


Astrocytes, Noradrenaline, α1-Adrenoreceptors, and Neuromodulation: Evidence and Unanswered Questions.
Noradrenaline is a major neuromodulator in the central nervous system (CNS). It is released from varicosities on neuronal efferents, which originate principally from the main noradrenergic nuclei of the brain - the locus coeruleus - and spread throughout the parenchyma. Noradrenaline is released in response to various stimuli and has complex physiological effects, in large part due to the wide diversity of noradrenergic receptors expressed in the brain, which trigger diverse signaling pathways. In general, however, its main effect on CNS function appears to be to increase arousal state. Although the effects of noradrenaline have been researched extensively, the majority of studies have assumed that noradrenaline exerts its effects by acting directly on neurons. However, neurons are not the only cells in the CNS expressing noradrenaline receptors. Astrocytes are responsive to a range of neuromodulators - including noradrenaline. In fact, noradrenaline evokes robust calcium transients in astrocytes across brain regions, through activation of α1-adrenoreceptors. Crucially, astrocytes ensheath neurons at synapses and are known to modulate synaptic activity. Hence, astrocytes are in a key position to relay, or amplify, the effects of noradrenaline on neurons, most notably by modulating inhibitory transmission. Based on a critical appraisal of the current literature, we use this review to argue that a better understanding of astrocyte-mediated noradrenaline signaling is therefore essential, if we are ever to fully understand CNS function. We discuss the emerging concept of astrocyte heterogeneity and speculate on how this might impact the noradrenergic modulation of neuronal circuits. Finally, we outline possible experimental strategies to clearly delineate the role(s) of astrocytes in noradrenergic signaling, and neuromodulation in general, highlighting the urgent need for more specific and flexible experimental tools.


Foot and Ankle Bone Marrow Edema Assessment in Long Distance Runners.
The clinical significance of foot and ankle bone marrow edema (BME) is poorly understood. Magnetic resonance imaging (MRI) and the visual analog scale (VAS) pain scores were collected for 17 runners who participated in the Twin Cities Marathon, immediately postmarathon and at a 6-week follow-up. Bone marrow edema lesions were classified using lesion frequency, anatomical location, and grading scale change to calculate a BME score for each affected bone. Spearman rank correlation coefficient test was used to identify a possible correlation between VAS and postmarathon BME. A paired Student t test was used to detect differences between total mileage ran 6 weeks postmarathon in participants with or without BME. After completing the marathon, 8 BME lesions were identified in 5 participants (29.4%; 5/17), 3 were men, and 2 were women, with a mean age of 33.8 years (range: 24-52), and BMI of 22.9 ± 4. All lesions were resolved on 6-week follow-up imaging. VAS pain scores did not correlate with postmarathon BME. A significant difference in total miles logged over 6 weeks postmarathon could not be found among participants with and without BME. Foot and ankle BME changes identified by MRI were not correlated to clinical symptoms and may resolve with self-directed activity in less time than other areas of the lower extremity. Level II, Prospective Cohort Study.


Human papillomavirus testing in primary cervical screening and the cut-off level for hybrid capture 2 tests: systematic review.
To determine the trade-off between the sensitivity and the specificity for high grade cervical intraepithelial neoplasia at hybrid capture 2 cut-off values above the standard ≥ 1 relative light units/cut-off level (rlu/co). Systematic review. PubMed. Randomised controlled trials in primary cervical screening using hybrid capture 2 testing in the intervention arms. Articles published until August 2010 were included if the numbers of women with positive test results and with cervical intraepithelial neoplasia were stratified by hybrid capture 2 cut-off levels. Women in the baseline screening rounds of the trials. Hybrid capture 2 screening in the baseline round including the diagnostic follow-up as practised in the randomised controlled trials and as reported by hybrid capture 2 cut-off values. Owing to heterogeneity in the trials, meta-analysis was not possible. Including cut-off values up to ≥ 10 rlu/co, 25 observation points were available for analysis. The relative sensitivity for cervical intraepithelial neoplasia grade III or higher at cut-off levels of ≥ 2, ≥ 4 or ≥ 5, and ≥ 10 rlu/co compared with a cut-off level of ≥ 1 rlu/co varied by trial, but at their lowest they were 0.97, 0.92, and 0.91, respectively. A similar pattern was observed for cervical intraepithelial neoplasia grade II or higher. The specificity would increase by at least 1%, 2%, and 3%, respectively, so that up to 24%, 39%, and 53%, of positive hybrid capture 2 test results not associated with high grade neoplasia could be avoided. Only two outliers existed to this general pattern. Although the data were derived from the baseline screening rounds only, the decrease in the sensitivity for high grade cervical intraepithelial neoplasia using a hybrid capture 2 cut-off level between ≥ 2 rlu/co and ≥ 10 rlu/co seemed acceptable given the international recommendations for testing for human papillomavirus DNA in cervical screening, which require 90% or more sensitivity for cervical intraepithelial neoplasia grade II or higher compared with hybrid capture 2 at ≥ 1 rlu/co. The data suggest that the hybrid capture 2 cut-off level could be increased in primary screening; this seems reasonably safe and is significantly less burdensome for women.


From the Cover: AstrocytesAre Protective Against Chlorpyrifos Developmental Neurotoxicity in Human Pluripotent Stem Cell-Derived Astrocyte-Neuron Cocultures.
Human neural progenitor cells are capable of independent, directed differentiation into astrocytes, oligodendrocytes and neurons and thus offer a potential cell source for developmental neurotoxicity (DNT) systems. Human neural progenitor-derived astrocyte-neuron cocultured at defined ratios mimic cellular heterogeneity and interaction in the central nervous system. Cytochrome P450 enzymes are expressed at a relatively high level in astrocytes and may play a critical role in the biotransformation of endogenous or exogenous compounds, including chlorpyrifos, an organophosphate insecticide that affects the central nervous system. P450 enzymes metabolize chlorpyrifos to chlorpyrifos-oxon, which is then metabolized primarily to 3, 5, 6-trichloropyridinol in addition to diethylphosphate and diethylthiophosphate. These end metabolites are less neurotoxic than chlorpyrifos and chlorpyrifos-oxon. Our objective was to identify the interactive role of astrocytes and neurons in chlorpyrifos-induced human DNT. In neuron-only cultures, chlorpyrifos inhibited neurite length, neurite number and branch points per neuron in a dose-dependent manner during a 48 h exposure, starting at 10 μM. However, in astrocyte-neuron cocultures, astrocytes protected neurons from the effects of chlorpyrifos at higher concentrations, up to and including 30 μM chlorpyrifos and endogenous astrocyte P450 enzymes effectively metabolized chlorpyrifos. The P450 inhibitor SKF525A partly negated the protective effect of astrocytes, allowing reduction in branch points with chlorpyrifos (10 μM). Thus, the scalable and defined astrocyte-neuron cocultures model that we established here has potentially identified a role for P450 enzymes in astrocytic neuroprotection against chlorpyrifos and provides a novel model for addressing DNT in a more accurate multicellular environment.


Sodium-hydrogen exchanger 6 (NHE6) deficiency leads to hearing loss, via reduced endosomal signalling through the BDNF/Trk pathway.
Acid-base homeostasis is critical for normal growth, development, and hearing function. The sodium-hydrogen exchanger 6 (NHE6), a protein mainly expressed in early and recycling endosomes, plays an important role in regulating organellar pH. Mutations in NHE6 cause complex, slowly progressive neurodegeneration. Little is known about NHE6 function in the mouse cochlea. Here, we found that all NHE isoforms were expressed in wild-type (WT) mouse cochlea. Nhe6 knockout (KO) mice showed significant hearing loss compared to WT littermates. Immunohistochemistry in WT mouse cochlea showed that Nhe6 was localized in the organ of Corti (OC), spiral ganglion (SG), stria vascularis (SV), and afferent nerve fibres. The middle and the inner ears of WT and Nhe6 KO mice were not different morphologically. Given the putative role of NHE6 in early endosomal function, we examined Rab GTPase expression in early and late endosomes. We found no change in Rab5, significantly lower Rab7, and higher Rab11 levels in the Nhe6 KO OC, compared to WT littermates. Because Rabs mediate TrkB endosomal signalling, we evaluated TrkB phosphorylation in the OCs of both strains. Nhe6 KO mice showed significant reductions in TrkB and Akt phosphorylation in the OC. In addition, we examined genes used as markers of SG type I (Slc17a7, Calb1, Pou4f1, Cal2) and type II neurons (Prph, Plk5, Cacna1g). We found that all marker gene expression levels were significantly elevated in the SG of Nhe6 KO mice, compared to WT littermates. Anti-neurofilament factor staining showed axon loss in the cochlear nerves of Nhe6 KO mice compared to WT mice. These findings indicated that BDNF/TrkB signalling was disrupted in the OC of Nhe6 KO mice, probably due to TrkB reduction, caused by over acidification in the absence of NHE6. Thus, our findings demonstrated that NHEs play important roles in normal hearing in the mammalian cochlea.


Active normothermia treatment for perioperative temperature management during bedside surgery in the NICU, a case report.
Infants in the NICU setting often require emergent bedside surgical procedures, during which, they are at high risk for developing hypothermia. Reasons for hypothermia in infants include poor temperature regulation, decreased fat stores to maintain temperature, increased insensible losses. Neonatal hypothermia is associated with an increased risk of sepsis, cardiorespiratory failure (pulmonary hypertension), hypoglycemia and death. In this case series, we describe the novel use of servo-controlled water blanket system as a method to actively maintain normothermia during three surgical cases. Although water blanket systems are frequently used in the neonatal ICU to provide active hypothermia treatment, to our knowledge there have been no prior reports of this system being deployed in normal and low-birthweight infants in the perioperative period.


Discharges in human muscle spindle afferents during a key-pressing task.
Most manual tasks demand a delicate control of the wrist. Sensory information for this control, e.g. about the position and movement velocity of the hand, is assumed to be primarily provided by muscle spindle afferents. It is known that human muscle spindles in relaxed muscles behave as stretch receptors but it is unclear how they discharge during 'natural' hand movements, since their discharges can also be affected by extrafusal contractions and fusimotor activity. We therefore let subjects perform a centre-out-centre key-pressing task on buttons laid out in a 3 x 3 pattern, a task that allowed unconstrained hand and finger movements and required precise control of the wrist. Microneurography recordings from muscle spindle afferents of the wrist extensor muscles were obtained along with wrist kinematics and electromyographic signals. The discharge rates of afferents were more phase advanced than expected on the length of the radial wrist extensor, which acted as an anti-gravity muscle in the key-pressing task. As such, both acceleration and velocity had significant impacts on the discharge rate of primary afferents, velocity on that of secondary afferents, and length had no impact on either afferent type. The response patterns were different for the two types of muscle spindle afferents from the predominantly eccentrically contracting ulnar wrist extensor: muscle length and velocity had significant impacts on the ensemble response of secondary afferents whereas the primary afferents showed highly variable responses. Accordingly, good predictions of the radial ulnar angular velocity were possible from spindle ensemble responses (R(2) = 0.85) whereas length could be predicted only for phases with lengthening of the ulnar wrist extensor. There are several possible explanations for the unexpectedly large phase advance of spindle afferents in the radial wrist extensor. Given the compliance of tendons, for instance, the phase relationship between the muscle fascicle length and the whole muscle length is conjectured to depend on the load. While additional phase advances are advantageous in motor control, it is concluded that if the central nervous system estimates length or velocity of a muscle from its muscle spindle discharges, this would require additional information about not only the concomitant extrafusal and fusimotor drive but also about the mechanical properties of the load on which the muscle acts.


Human cytomegalovirus: Drug resistance and new treatment options using natural products.
Human cytomegalovirus (HCMV), a member of the β-herpesvirus family, is a cause of high morbidity and mortality rates among immunosuppressed individuals and patients with acquired immunodeficiency syndrome (AIDS). Despite the availability of approved antiviral drugs, treatment of HCMV infections remains difficult. Antiviral therapies are in part limited by the small number of available drugs showing satisfactory clinical results. Other factors, such as low potency, poor oral bioavailability and the emergence of drug resistance, also contribute significantly to the obstacles confronting current therapies for HCMV infection. In search of new drugs for the treatment of HCMV infection, researchers have turned their attention to natural products. Unfortunately, not many natural compounds have proven to be efficacious against HCMV. Those that have shown good results in vitro are reviewed here, and their molecular targets and mechanisms of action are discussed along with those of established antiviral agents.


[Optimal breastfeeding to prevent hyperbilirubinaemia in healthy, term newborns].
In a newborn infant, frequent bowel movements diminish the enterohepatic circulation of bilirubin, thereby increasing bilirubin excretion. In breastfed newborn infants, the frequency of latching on and administration of supplementary feeds are associated with serum bilirubin concentrations. Frequent breast feeding (at least 8 times a day) and fewer supplementary feeds will result in increased breast milk intake, less weight loss, and lower bilirubin concentrations. In the case of a breastfed infant presenting with neonatal hyperbilirubinaemia, the advice should be to breastfeed more frequently and to withhold supplementary feedings. An icteric newborn infant should be seen and weighed daily. If the infant has lost more than 10% of its birth weight, drinks poorly, or fails to gain weight despite latching onto the breast frequently, it should be referred to the paediatrician for further diagnosis and treatment. To ensure optimal production of breast milk during the first days after birth, early latching on is recommended, preferably within one hour after birth.


Yeast eIF4B binds to the head of the 40S ribosomal subunit and promotes mRNA recruitment through its N-terminal and internal repeat domains.
Eukaryotic translation initiation factor (eIF)4B stimulates recruitment of mRNA to the 43S ribosomal pre-initiation complex (PIC). Yeast eIF4B (yeIF4B), shown previously to bind single-stranded (ss) RNA, consists of an N-terminal domain (NTD), predicted to be unstructured in solution; an RNA-recognition motif (RRM); an unusual domain comprised of seven imperfect repeats of 26 amino acids; and a C-terminal domain. Although the mechanism of yeIF4B action has remained obscure, most models have suggested central roles for its RRM and ssRNA-binding activity. We have dissected the functions of yeIF4B's domains and show that the RRM and its ssRNA-binding activity are dispensable in vitro and in vivo. Instead, our data indicate that the 7-repeats and NTD are the most critical domains, which mediate binding of yeIF4B to the head of the 40S ribosomal subunit via interaction with Rps20. This interaction induces structural changes in the ribosome's mRNA entry channel that could facilitate mRNA loading. We also show that yeIF4B strongly promotes productive interaction of eIF4A with the 43S•mRNA PIC in a manner required for efficient mRNA recruitment.


[Calcitonin and otosclerosis: a preliminary clinical note].
Otosclerosis is a disorder characterized by alternating periods of bone resorption and formation as a result of a disturbance in the enzymatic balance of the otic capsule and stapedial footplate. In some cases, calcitonin administration improved the metabolic abnormalities associated with the disease. This hormone inhibits bone resorption produced by osteoclasts and facilitates osteoblastic accretion. The authors describe the results obtained in a patient with aggressive otosclerosis who experienced an improvement in hearing and tinnitus after treatment with salmon calcitonin.


UV-Vis Spectra-Activated Droplet Sorting for Label-Free Chemical Identification and Collection of Droplets.
We introduce the UV-vis spectra-activated droplet sorter (UVADS) for high-throughput label-free chemical identification and enzyme screening. In contrast to previous absorbance-based droplet sorters that relied on single-wavelength absorbance in the visible range, our platform collects full UV-vis spectra from 200 to 1050 nm at up to 2100 spectra per second. Our custom-built open-source software application, "SpectraSorter," enables real-time data processing, analysis, visualization, and selection of droplets for sorting with any set of UV-vis spectral features. An optimized UV-vis detection region extended the absorbance path length for droplets and allowed for the direct protein quantification down to 10 μM of bovine serum albumin at 280 nm. UV-vis spectral data can distinguish a variety of different chemicals or spurious events (such as air bubbles) that are inaccessible at a single wavelength. The platform is used to measure ergothionase enzyme activity from monoclonal microcolonies isolated in droplets. In a label-free manner, we directly measure the ergothioneine substrate to thiourocanic acid product conversion while tracking the microcolony formation. UVADS represents an important new tool for high-throughput label-free in-droplet chemical analysis.


Assessing the extent of genome-wide intralocus sexual conflict via experimentally enforced gender-limited selection.
Intralocus sexual conflict, which occurs when a trait is selected in opposite directions in the two sexes, is a taxonomically widespread phenomenon. The strongest genetic evidence for a gender load due to intralocus sexual conflict comes from the Drosophila melanogaster laboratory model system, in which a negative genetic correlation between male and female lifetime fitness has been observed. Here, using a D. melanogaster model system, we utilize a novel modification of the 'middle class neighbourhood' design to relax selection in one sex, while maintaining selection in the other. After 26 generations of asymmetrical selection, we observed the expected drop in fitness of the non-selected sex compared to that of the selected sex, consistent with previous studies of intralocus sexual conflict in this species. However, the fitness of the selected sex also dropped compared to the base population. The overall decline in fitness of both the selected and the unselected sex indicates that most new mutations are harmful to both sexes, causing recurrent mutation to build a positive genetic correlation for fitness between the sexes. However, the steeper decay in the fitness of the unselected sex indicates that a substantial number of mutations are gender-limited in expression or sexually antagonistic. Our experiment cannot definitively resolve these two possibilities, but we use recent genomic data and results from previous studies to argue that sexually antagonistic alleles are the more likely explanation.


Assessment of heavy metal pollutants accumulation in the Tisza river sediments.
In this study we have worked on the evaluation of heavy metal contamination in the sediments taken from the Tisza River and its tributaries, and thereby used the sequential extraction method, geochemical normalization, the calculation of the enrichment factor (EF), and the methods of statistical analysis. The chemical fractionation of Ni, Cu, Zn, Cr, Pb, Fe, and Mn, carried out by using the modified Tessier method, points to different substrates and binding mechanisms of Cu, Zn and Pb in sediments of the tributaries and sediments of the Tisza River. The similarities in the distributions of Fe and Ni in all types of sediments are the result of geochemical similarity as well as of the fact that natural sources mainly affect the concentration levels of these elements. The calculated enrichment factors (EF, measured metal vs. background concentrations) indicated that metal contamination (Cu, Pb, Zn and Cr) was recorded in the sediments of the Tisza River, while no indications of pollution were detected in the tributaries of the Tisza River and the surrounding pools. The maximum values of the EF were close to 6 for Cu and Pb (moderately severe enrichment) and close to 4.5 for Zn (indicating moderate enrichment). It can be said that the Tisza River is slightly to moderately severely polluted with Cu, Zn, and Pb, and minorly polluted with Cr. It is concluded that sediments of the Tisza serve as a repository for heavy metal accumulation from adjacent urban and industrial areas.


Python-based Helix Indexer: A graphical user interface program for finding symmetry of helical assembly through Fourier-Bessel indexing of electron microscopic data.
Many macromolecules form helical assemblies to carry out their functions. Helical reconstruction from electron microscopic images is a powerful approach for solving high-resolution structures of such assemblies. Determination of the symmetry parameters of the helical assemblies is a prerequisite step in helical reconstruction. The most widely used method for deducing the symmetry is through Fourier-Bessel indexing the diffraction pattern of the helical assemblies. This method, however, often leads to incorrect solutions, due to intrinsic ambiguities in indexing helical diffraction patterns. Here, we present Python-based Helix Indexer (PyHI), which provides a graphical user interface (GUI) to guide the users through the process of symmetry determination. Diffraction patterns can be read into the program directly or calculated on the fly from two-dimensional class averages of helical assemblies. PyHI allows deducing the Bessel orders of diffraction peaks by using both the amplitudes and phases of the diffraction data. Based on the Bessel orders of two unit vectors, the Fourier space lattice is constructed with minimal user inputs. The program then uses a refinement algorithm to optimize the Fourier space lattice, and subsequently generate the helical assembly in real space. The program provides both a publication-quality graphic representation of the helical assembly and the symmetry parameters required for subsequent helical reconstruction steps.


Study on the antiinflammatory activity of essential oil from leaves of Cinnamomum osmophloeum.
The leaf essential oil from indigenous cinnamon (Cinnamomum osmophloeum Kaneh.) was investigated by gas chromatography-mass spectrometry, and 21 compounds were identified. The major constituents of leaf essential oil were the monoterpenes 1,8-cineole (17.0%) and santolina triene (14.2%) and the sesquiterpenes spathulenol (15.7%) and caryophyllene oxide (11.2%). In the antiinflammatory activity assay, we demonstrated that the essential oil has a higher capacity to inhibit proIL-1beta protein expression induced by LPS-treated J774A.1 murine macrophage. At dosages of 60 microg/mL, essential oil clearly inhibited proIL-1beta protein expression. Furthermore, a dose of 60 microg/mL of essential oil was effectively inhibitory for IL-1beta and IL-6 production but not for TNF-alpha, suggesting that essential oil was bioactive in antiinflammation in vitro. This study is the first to report antiinflammatory activity of extracts obtained from the leaf essential oil of C. osmophloeum.


Pho85 kinase, a cyclin-dependent kinase, regulates nuclear accumulation of the Rim101 transcription factor in the stress response of Saccharomyces cerevisiae.
The budding yeast Saccharomyces cerevisiae alters its gene expression profile in response to changing environmental conditions. The Pho85 kinase, one of the yeast cyclin-dependent kinases (CDK), is known to play an important role in the cellular response to alterations in parameters such as nutrient levels and salinity. Several genes whose expression is regulated, either directly or indirectly, by the Rim101 transcription factor become constitutively activated when Pho85 function is absent. Because Rim101 is responsible for adaptation to alkaline conditions, this observation suggests an interaction between Pho85 and Rim101 in the response to alkaline stress. We have found that Pho85 affects neither RIM101 transcription, the proteolytic processing that is required for Rim101 activation, nor Rim101 stability. Rather, Pho85 regulates the nuclear accumulation of active Rim101, possibly via phosphorylation. Additionally, we report that Pho85 and the transcription factor Pho4 are necessary for adaptation to alkaline conditions and that PTK2 activation by Pho4 is involved in this process. These findings illustrate novel roles for the regulators of the PHO system when yeast cells cope with various environmental stresses potentially threatening their survival.


Risk factors associated with poor outcomes in patients with brain abscesses.
The purpose of this study was to describe the clinical characteristics, treatment outcomes, and prognostic factors in patients with brain abscesses treated in a single institute during a recent 10-year period. Fifty-one patients with brain abscesses who underwent navigation-assisted abscess aspiration with antibiotic treatment were included in this study. Variable parameters were collected from the patients' medical records and radiological data. A comparison was made between patients with favorable [Glasgow Outcome Scale (GOS) ≥4] and unfavorable (GOS <4) outcomes at discharge. Additionally, we investigated the factors influencing the duration of antibiotic administration. The study included 41 male and 10 female patients with a mean age of 53 years. At admission, 42 patients (82%) showed either clear or mildly disturbed consciousness (GCS ≥13) and 24 patients (47%) had predisposing factors. The offending microorganisms were identified in 25 patients (49%), and Streptococcus species were the most commonly isolated bacteria (27%). The mean duration of antibiotic administration was 42 days. At discharge, 41 patients had a favorable outcome and 10 had an unfavorable outcome including 8 deaths. The decreased level of consciousness (GCS <13) on admission was likely associated with an unfavorable outcome (p=0.052), and initial hyperglycemia (≥140 mg/dL) was an independent risk factor for prolonged antibiotic therapy (p=0.032). We found that the level of consciousness at admission was associated with treatment outcomes in patients with brain abscesses. Furthermore, initial hyperglycemia was closely related to the long-term use of antibiotic agents.


Experimental Studies on the Hydrotreatment of Kraft Lignin to Aromatics and Alkylphenolics Using Economically Viable Fe-Based Catalysts.
Limonite, a low-cost iron ore, was investigated as a potential hydrotreatment catalyst for kraft lignin without the use of an external solvent (batch reactor, initial H2 pressure of 100 bar, 4 h). The best results were obtained at 450 °C resulting in 34 wt % of liquefied kraft lignin (lignin oil) on lignin intake. The composition of the lignin oil was determined in detail (elemental composition, GC-MS, GC×GC-FID, and GPC). The total GC-detectable monomeric species amounts up to 31 wt % on lignin intake, indicating that 92 wt % of the products in the lignin oil are volatile and thus of low molecular weight. The lignin oil was rich in low-molecular-weight alkylphenolics (17 wt % on lignin) and aromatics (8 wt % on lignin). Performance of the limonite catalyst was compared to other Fe-based catalysts (goethite and iron disulfide) and limonite was shown to give the highest yields of alkylphenolics and aromatics. The limonite catalyst before and after reaction was characterized using XRD, TEM, and nitrogen physisorption to determine changes in structure during reaction. Catalyst recycling tests were performed and show that the catalyst is active after reuse, despite the fact that the morphology changed and that the surface area of the catalyst particles was decreased. Our results clearly reveal that cheap limonite catalysts have the potential to be used for the depolymerization/hydrodeoxygenation of kraft lignin for the production of valuable biobased phenolics and aromatics.


Experimental Carbonation Study for a Durability Assessment of Novel Cementitious Materials.
Durability predictions of concrete structures are derived from experience-based requirements and descriptive exposure classes. To support durability predictions, a numerical model related to the carbonation resistance of concrete was developed. The model couples the rate of carbonation with the drying rate. This paper presents the accelerated carbonation and moisture transport experiments performed to calibrate and verify the numerical model. They were conducted on mortars with a water-cement ratio of either 0.6 or 0.5, incorporating either a novel cement CEM II/C (S-LL) (EnM group) or commercially available CEM II/A-S cement (RefM group). The carbonation rate was determined by visual assessment and thermogravimetric analysis (TGA). Moisture transport experiments, consisting of drying and resaturation, utilized the gravimetric method. Higher carbonation rates expressed in mm/day-0.5 were found in the EnM group than in the RefM group. However, the TGA showed that the initial portlandite (CH) content was lower in the EnM than in the RefM, which could explain the difference in carbonation rates. The resaturation experiments indicate an increase in the suction porosity in the carbonated specimens compared to the non-carbonated specimens. The study concludes that low clinker content causes lower resistance to carbonation, since less CH is available in the surface layers; thus, the carbonation front progresses more rapidly towards the core.


Parents' evaluation of aural/oral performance of children (PEACH) scale in the Malay language: data for normal-hearing children.
The parents' evaluation of aural/oral performance of children (PEACH) scale was developed to assess the effectiveness of amplification for children, based on a systematic use of parents' observations of children's performance in real-world environments. The purpose of the present study was to adapt the PEACH scale into the Malay language, and to collect normative data on a group of children with normal hearing. The participants were parents of 74 children aged between 3 months and 13 years of age. Parents were requested to observe their children's auditory/oral behavior in everyday life and to record their observations in the PEACH booklet. High internal consistency (Cronbach's alpha = 0.93) and item-total correlation were found (0.52-0.85). Similar to the published norms for English-speaking children, near-perfect scores were achieved by Malaysian children around 40 months of age. The adapted version can be used to evaluate amplification for children in the Malay speaking environment. The normative curve relating age to scores for the Malay PEACH can be used as a reference against which functional aural/oral performance of hearing-impaired Malaysian children can be evaluated.


Sampling and processing for compressive holography [Invited].
Compressive holography applies sparsity priors to data acquired by digital holography to infer a small number of object features or basis vectors from a slightly larger number of discrete measurements. Compressive holography may be applied to reconstruct three-dimensional (3D) images from two-dimensional (2D) measurements or to reconstruct 2D images from sparse apertures. This paper is a tutorial covering practical compressive holography procedures, including field propagation, reference filtering, and inverse problems in compressive holography. We present as examples 3D tomography from a 2D hologram, 2D image reconstruction from a sparse aperture, and diffuse object estimation from diverse speckle realizations.


Enhanced Plasticity of Human Evoked Potentials by Visual Noise During the Intervention of Steady-State Stimulation Based Brain-Computer Interface.
Neuroplasticity, also known as brain plasticity, is an inclusive term that covers the permanent changes in the brain during the course of an individual's life, and neuroplasticity can be broadly defined as the changes in function or structure of the brain in response to the external and/or internal influences. Long-term potentiation (LTP), a well-characterized form of functional synaptic plasticity, could be influenced by rapid-frequency stimulation (or "tetanus") within in vivo human sensory pathways. Also, stochastic resonance (SR) has brought new insight into the field of visual processing for the study of neuroplasticity. In the present study, a brain-computer interface (BCI) intervention based on rapid and repetitive motion-reversal visual stimulation (i.e., a "tetanizing" stimulation) associated with spatiotemporal visual noise was implemented. The goal was to explore the possibility that the induction of LTP-like plasticity in the visual cortex may be enhanced by the SR formalism via changes in the amplitude of visual evoked potentials (VEPs) measured non-invasively from the scalp of healthy subjects. Changes in the absolute amplitude of P1 and N1 components of the transient VEPs during the initial presentation of the steady-state stimulation were used to evaluate the LTP-like plasticity between the non-noise and noise-tagged BCI interventions. We have shown that after adding a moderate visual noise to the rapid-frequency visual stimulation, the degree of the N1 negativity was potentiated following an ~40-min noise-tagged visual tetani. This finding demonstrated that the SR mechanism could enhance the plasticity-like changes in the human visual cortex.


Development safety update reports and proposals for effective and efficient risk communication.
The periodic safety reporting to regulatory authorities is globally harmonized for postmarketing medicinal products by the International Conference on Harmonisation (ICH) guidelines, and is being extended for investigational drugs. To facilitate effective safety risk communication regarding investigational drugs, and to reduce duplicate periodic reporting to the US and EU by sponsors during development programmes, standardized Development Safety Update Reports (DSURs) are to be implemented in the near future. In this current opinion article, after extensively reviewing the relevant report from the CIOMS VII Working Group and the ICH draft guideline regarding DSURs, we discuss an effective and efficient approach to its application. To ensure effective risk communication, we recommend that DSURs be made available to all the ethics committees and participating investigators around the world for the purpose of continuing review during ongoing clinical trials. Furthermore, in order to maintain the consistency and integrity of safety information throughout the life-cycle of a drug, we believe it would be substantially more prudent and efficient to start a single, integrated, life-cycle periodic safety report covering both development and postmarketing, as proposed by the CIOMS VII Working Group, rather than maintain separate DSURs and Periodic Safety Update Reports, which can overlap considerably in content. To this end, we believe that the international regulatory community should undertake the new initiative for integrated periodic reporting immediately.


NMDA systems in the amygdala and piriform cortex and nicotinic effects on memory function.
Both nicotinic cholinergic and NMDA glutaminergic systems are important for memory function. Nicotine has been found repeatedly to significantly improve working memory performance in the radial-arm maze. The NMDA antagonist dizocilpine has been found to impair working memory performance. There is neuropharmacological evidence that these two systems are functionally related. Nicotine is potent at releasing many transmitters including glutamate. The current study was conducted to examine the interaction of nicotinic and NMDA systems within the amygdala with regard to working and reference memory. Rats were trained on a working/reference procedure on a 16-arm radial maze. After acquisition, local infusion cannulae were implanted bilaterally into the amygdala and piriform cortex using stereotaxic techniques. Then 20 min prior to running the rats on the radial-arm maze, they were injected subcutaneously with (-) nicotine ditartrate at doses of 0 and 0.4 mg/kg. Following this, the rats received local infusions of (+) dizocilpine maleate (MK-801) at doses of 0, 2, 6 and 18 microg per side into the lateral amygdala or piriform cortex 10 min prior to running on the radial-arm maze. Each of the eight nicotine and dizocilpine combinations was administered to each rat in a counterbalanced order. After completion of the drug sessions the rats were sacrificed, and using histological methods the cannulae placements were verified. Acute amygdalar infusions of the NMDA glutamate receptor antagonist dizocilpine induced dose-related working and reference memory deficits in the radial-arm maze. Systemic nicotine was not seen to reverse these effects. Dizocilpine infusions into the adjacent piriform cortex did not impair memory function, supporting the specificity of dizocilpine effects in the amygdala. Latency effects were seen with both drugs in both areas. Latencies were decreased with both systemic nicotine and dizocilpine in both the lateral amygdala and the piriform cortex. This study demonstrated the importance of NMDA glutamate systems in the amygdala for appetitively-motivated spatial memory performance.


Genome-Wide Identification of Dickeya solani Transcriptional Units Up-Regulated in Response to Plant Tissues From a Crop-Host Solanum tuberosum and a Weed-Host Solanum dulcamara.
Dickeya solani is a Gram-negative bacterium able to cause disease symptoms on a variety of crop and ornamental plants worldwide. Weeds including Solanum dulcamara (bittersweet nightshade) growing near agricultural fields have been reported to support populations of soft rot bacteria in natural settings. However, little is known about the specific interaction of D. solani with such weed plants that may contribute to its success as an agricultural pathogen. The aim of this work was to assess the interaction of D. solani with its crop plant (Solanum tuberosum) and an alternative (S. dulcamara) host plant. From a collection of 10,000 Tn5 transposon mutants of D. solani IPO2222 carrying an inducible, promotorless gusA reporter gene, 210 were identified that exhibited plant tissue-dependent expression of the gene/operon into which the Tn5 insertion had occurred. Thirteen Tn5 mutants exhibiting the greatest plant tissue induction of such transcriptional units in S. tuberosum or S. dulcamara as measured by qRT-PCR were assessed for plant host colonization, virulence, and ability to macerate plant tissue, as well as phenotypes likely to contribute to the ecological fitness of D. solani, including growth rate, carbon and nitrogen source utilization, motility, chemotaxis toward plant extracts, biofilm formation, growth under anaerobic conditions and quorum sensing. These 13 transcriptional units encode proteins involved in bacterial interactions with plants, with functions linked to cell envelope structure, chemotaxis and carbon metabolism. The selected 13 genes/operons were differentially expressed in, and thus contributed preferentially to D. solani fitness in potato and/or S. dulcamara stem, leaf, and root tissues.


A Quantitative Method for the Study of HIV-1 and Mycobacterium tuberculosis Coinfection.
Mycobacterium tuberculosis and human immunodeficiency virus-1 (HIV-1) syndemic interactions are a major global health concern. Despite the clinical significance of coinfection, our understanding of the cellular pathophysiology and the therapeutic pharmacodynamic impact of coinfection is limited. Here, we use single-round infectious HIV-1 pseudotyped viral particles expressing green fluorescent protein alongside M. tuberculosis expressing mCherry to study pathogenesis and treatment. We report that HIV-1 infection inhibited intracellular replication of M. tuberculosis and demonstrate the therapeutic activity of antiviral treatment (efavirenz) and antimicrobial treatment (rifampicin). The described method could be applied for detailed mechanistic studies to inform the development of novel treatment strategies.


Characterization of Bifidobacterium species in feaces of the Egyptian fruit bat: Description of B. vespertilionis sp. nov. and B. rousetti sp. nov.
Fifteen bifidobacterial strains were obtained from faeces of Rousettus aegyptiacus; after grouping them by RAPD PCR only eight were selected and characterized. Analysis of 16S rRNA and of five housekeeping (hsp60, rpoB, clpC, dnaJ, dna G) genes revealed that these eight strains were classified into five clusters: Cluster I (RST 8 and RST 16T), Cluster II (RST 9T and RST 27), Cluster III (RST 7 and RST 11), Cluster IV (RST 19), Cluster V (RST 17) were closest to Bifidobacterium avesanii DSM 100685T (96.3%), Bifidobacterium callitrichos DSM 23973T (99.2% and 99.7%), Bifidobacterium tissieri DSM 100201T (99.7 and 99.2%), Bifidobacterium reuteri DSM 23975 T (98.9%) and Bifidobacterium myosotis DSM 100196T (99.3%), respectively. Strains in Cluster I and strain RST 9 in Cluster II could not be placed within any recognized species while the other ones were identified as known species. The average nucleotide identity values between two novel strains, RST 16T and RST 9T and their closest relatives were lower than 79% and 89%, respectively. In silico DNA-DNA hybridization values for those closest relatives were 32.5 and 42.1%, respectively. Phenotypic and genotypic tests demonstrated that strains in Cluster I and RST 9T in Cluster II represent two novel species for which the names Bifidobacterium vespertilionis sp. nov. (RST 16T=BCRC 81138T=NBRC 113380T=DSM 106025T ; RST 8=BCRC 81135=NBRC 113377) and Bifidobacterium rousetti sp. nov. (RST 9T=BCRC 81136T=NBRC 113378T=DSM 106027T) are proposed.


Meta-analysis: formulating, evaluating, combining, and reporting.
Meta-analysis involves combining summary information from related but independent studies. The objectives of a meta-analysis include increasing power to detect an overall treatment effect, estimation of the degree of benefit associated with a particular study treatment, assessment of the amount of variability between studies, or identification of study characteristics associated with particularly effective treatments. This article presents a tutorial on meta-analysis intended for anyone with a mathematical statistics background. Search strategies and review methods of the literature are discussed. Emphasis is focused on analytic methods for estimation of the parameters of interest. Three modes of inference are discussed: maximum likelihood; restricted maximum likelihood, and Bayesian. Finally, software for performing inference using restricted maximum likelihood and fully Bayesian methods are demonstrated. Methods are illustrated using two examples: an evaluation of mortality from prophylactic use of lidocaine after a heart attack, and a comparison of length of hospital stay for stroke patients under two different management protocols.


Engagement and Effectiveness of a Healthy-Coping Intervention via Chatbot for University Students During the COVID-19 Pandemic: Mixed Methods Proof-of-Concept Study.
University students are increasingly reporting common mental health problems, such as stress, anxiety, and depression, and they frequently face barriers to seeking psychological support because of stigma, cost, and availability of mental health services. This issue is even more critical in the challenging time of the COVID-19 pandemic. Digital mental health interventions, such as those delivered via chatbots on mobile devices, offer the potential to achieve scalability of healthy-coping interventions by lowering cost and supporting prevention. The goal of this study was to conduct a proof-of-concept evaluation measuring the engagement and effectiveness of Atena, a psychoeducational chatbot supporting healthy coping with stress and anxiety, among a population of university students. In a proof-of-concept study, 71 university students were recruited during the COVID-19 pandemic; 68% (48/71) were female, they were all in their first year of university, and their mean age was 20.6 years (SD 2.4). Enrolled students were asked to use the Atena psychoeducational chatbot for 4 weeks (eight sessions; two per week), which provided healthy-coping strategies based on cognitive behavioral therapy, positive psychology, and mindfulness techniques. The intervention program consisted of conversations combined with audiovisual clips delivered via the Atena chatbot. Participants were asked to complete web-based versions of the 7-item Generalized Anxiety Disorder scale (GAD-7), the 10-item Perceived Stress Scale (PSS-10), and the Five-Facet Mindfulness Questionnaire (FFMQ) at baseline and postintervention to assess effectiveness. They were also asked to complete the User Engagement Scale-Short Form at week 2 to assess engagement with the chatbot and to provide qualitative comments on their overall experience with Atena postintervention. Participants engaged with the Atena chatbot an average of 78 (SD 24.8) times over the study period. A total of 61 out of 71 (86%) participants completed the first 2 weeks of the intervention and provided data on engagement (10/71, 14% attrition). A total of 41 participants out of 71 (58%) completed the full intervention and the postintervention questionnaires (30/71, 42% attrition). Results from the completer analysis showed a significant decrease in anxiety symptoms for participants in more extreme GAD-7 score ranges (t39=0.94; P=.009) and a decrease in stress symptoms as measured by the PSS-10 (t39=2.00; P=.05) for all participants postintervention. Participants also improved significantly in the describing and nonjudging facets, based on their FFMQ subscale scores, and asked for some improvements in the user experience with the chatbot. This study shows the benefit of deploying a digital healthy-coping intervention via a chatbot to support university students experiencing higher levels of distress. While findings collected during the COVID-19 pandemic show promise, further research is required to confirm conclusions.


Pulsed Radiofrequency Ablation for Orchialgia-A Literature Review.
Pulsed radiofrequency, short bursts of radiofrequency energy, has been used by pain practitioners as a non- or minimally neurodestructive technique, an alternative to radiofrequency heat lesions. The clinical advantages and mechanisms of this treatment remain unclear. To review the current clinical implication of the pulsed radiofrequency technique for male patients with chronic scrotal pain. We systematically searched the English literature available at the EMBASE, MEDLINE/PubMed, Google Scholar, and Cochrane Library from inception to 22 November 2022. Only reports on a pulsed radiofrequency application on male patients with chronic scrotal pain were included. The final analysis yielded six reports on the clinical use of pulsed radiofrequency applications in male patients with chronic scrotal pain: six full publications, three case reports, one case series, one prospective uncontrolled pilot study, and one prospective randomized, controlled clinical trial. The accumulation of these data shows that using pulsed radiofrequency generates an increasing interest in pain physicians, radiologists, and urologists for managing chronic scrotal pain. No side effects related to the pulsed radiofrequency technique were reported to date. Further research on the clinical and biological effects is justified. Large sample sizes and randomized clinical trials are warranted.