Dynamics and control of percutaneous drug absorption in the presence of epidermal turnover.
The integration of epidermal turnover into the study of transdermal drug-delivery kinetics is addressed in light of classical control theory. A mathematical representation of the process, which includes Fickian diffusion and advection, was formulated in the frequency domain. This transformation facilitated a detailed analysis of the system dynamics and revealed the intricate relationships among a medicament transient absorption through the skin, the epidermal turnover rate, its physicochemical properties and the amount of drugs in a reservoir. The process, represented by transcendental transfer functions, was reduced to a second-order system with dead-time by minimizing the squared magnitude of the complex error between the original and simplified models. Clinically relevant parameters, such as the time to reach steady-state flux or drug concentration in the skin layers, are readily available from the low-order models. The time it takes to deliver a specified dose of drug to a particular depth in the skin is a function of the penetration depth and the diffusion coefficients of the drug molecules in the stratum corneum and the viable epidermis. An optimum administration protocol was developed for the transdermal delivery of chemicals when epidermal turnover is likely to affect their absorption into the systemic circulation.


Evidence for a PGF2α auto-amplification system in the endometrium in mares.
In mares, prostaglandin F2α (PGF2α) secreted from the endometrium is a major luteolysin. Some domestic animals have an auto-amplification system in which PGF2α can stimulate its own production. Here, we investigated whether this is also the case in mares. In an in vivo study, mares at the mid-luteal phase (days 6-8 of estrous cycle) were injected i.m. with cloprostenol (250 µg) and blood samples were collected at fixed intervals until 72 h after treatment. Progesterone (P4) concentrations started decreasing 45 min after the injection and continued to decrease up to 24 h (P < 0.05). In turn, 13,14-dihydro-15-keto-PGF2α (PGFM) metabolite started to increase 4h after an injection and continued to increase up to 72 h (P < 0.05). PGF receptor (PTGFR) mRNA expression in the endometrium was significantly higher in the late luteal phase than in the early and regressed luteal phases (P < 0.05). In vitro, PGF2α significantly stimulated (P < 0.05) PGF2α production by endometrial tissues and endometrial epithelial and stromal cells and significantly increased (P < 0.05) the mRNA expression of prostaglandin-endoperoxide synthase-2 (PTGS2), an enzyme involved in PGF2α synthesis in endometrial cell. These findings strongly suggest the existence of an endometrial PGF2α auto-amplification system in mares.


Genomes and geography: genomic insights into the evolution and phylogeography of the genus Schistosoma.
Blood flukes within the genus Schistosoma still remain a major cause of disease in the tropics and subtropics and the study of their evolution has been an area of major debate and research. With the advent of modern molecular and genomic approaches deeper insights have been attained not only into the divergence and speciation of these worms, but also into the historic movement of these parasites from Asia into Africa, via migration and dispersal of definitive and snail intermediate hosts. This movement was subsequently followed by a radiation of Schistosoma species giving rise to the S. mansoni and S. haematobium groups, as well as the S. indicum group that reinvaded Asia. Each of these major evolutionary events has been marked by distinct changes in genomic structure evident in differences in mitochondrial gene order and nuclear chromosomal architecture between the species associated with Asia and Africa. Data from DNA sequencing, comparative molecular genomics and karyotyping are indicative of major constitutional genomic events which would have become fixed in the ancestral populations of these worms. Here we examine how modern genomic techniques may give a more in depth understanding of the evolution of schistosomes and highlight the complexity of speciation and divergence in this group.


Combining degradations: The effect of background noise on intelligibility of disordered speech.
The effect of background noise on intelligibility of disordered speech was assessed. Speech-shaped noise was mixed with neurologically healthy (control) and disordered (dysarthric) speech at a series of signal-to-noise ratios. In addition, bandpass filtered control and dysarthric speech conditions were assessed to determine the effect of noise on both naturally and artificially degraded speech. While significant effects of both the amount of noise and the type of speech were revealed, no interaction between the two factors was observed, in either the broadband or filtered testing conditions. Thus, it appears that there is no multiplicative effect of the presence of background noise on intelligibility of disordered speech relative to control speech. That is, the decrease in intelligibility due to increasing levels of noise is similar for both types of speech, and both types of testing conditions, and the function for dysarthric speech is simply shifted downward due to the inherent source degradations of the speech itself. Last, large-scale online crowdsourcing via Amazon Mechanical Turk was utilized to collect data for the current study. Findings and implications for this data and data collection approach are discussed.


A general reaction-diffusion model of acidity in cancer invasion.
We model the metabolism and behaviour of a developing cancer tumour in the context of its microenvironment, with the aim of elucidating the consequences of altered energy metabolism. Of particular interest is the Warburg Effect, a widespread preference in tumours for cytosolic glycolysis rather than oxidative phosphorylation for glucose breakdown, as yet incompletely understood. We examine a candidate explanation for the prevalence of the Warburg Effect in tumours, the acid-mediated invasion hypothesis, by generalising a canonical non-linear reaction-diffusion model of acid-mediated tumour invasion to consider additional biological features of potential importance. We apply both numerical methods and a non-standard asymptotic analysis in a travelling wave framework to obtain an explicit understanding of the range of tumour behaviours produced by the model and how fundamental parameters govern the speed and shape of invading tumour waves. Comparison with conclusions drawn under the original system--a special case of our generalised system--allows us to comment on the structural stability and predictive power of the modelling framework.


Assessing overall risk in reproductive experiments.
Toxicologists are often interested in assessing the joint effect of an exposure on multiple reproductive endpoints, including early loss, fetal death, and malformation. Exposures that occur prior to mating or extremely early in development can adversely affect the number of implantation sites or fetuses that form within each dam and may even prevent pregnancy. A simple approach for assessing overall adverse effects in such studies is to consider fetuses or implants that fail to develop due to exposure as missing data. The missing data can be imputed, and standard methods for the analysis of quantal response data can then be used for quantitative risk assessment or testing. In this article, a new bias-corrected imputation procedure is proposed and evaluated. The procedure is straightforward to implement in standard statistical packages and has excellent operating characteristics when used in combination with a marginal model fit with generalized estimating equations. The methods are applied to data from a reproductive toxicity study of Nitrofurazone conducted by the National Toxicology Program.


Match running performance and fitness in youth soccer.
The activity profiles of highly trained young soccer players were examined in relation to age, playing position and physical capacity. Time-motion analyses (global positioning system) were performed on 77 (U13-U18; fullbacks [FB], centre-backs [CB], midfielders [MD], wide midfielders [W], second strikers [2 (nd)S] and strikers [S]) during 42 international club games. Total distance covered (TD) and very high-intensity activities (VHIA; >16.1 km·h (-1)) were computed during 186 entire player-matches. Physical capacity was assessed via field test measures (e. g., peak running speed during an incremental field test, VVam-eval). Match running performance showed an increasing trend with age ( P<0.001, partial eta-squared (η (2)): 0.20-0.45). When adjusted for age and individual playing time, match running performance was position-dependent ( P<0.001, η (2): 0.13-0.40). MD covered the greater TD; CB the lowest ( P<0.05). Distance for VHIA was lower for CB compared with all other positions ( P<0.05); W and S displayed the highest VHIA ( P<0.05). Relationships between match running performance and physical capacities were position-dependent, with poor or non-significant correlations within FB, CB, MD and W (e. g., VHIA vs. VVam-eval: R=0.06 in FB) but large associations within 2 (nd)S and S positions (e. g., VHIA vs. VVam-eval: R=0.70 in 2 (nd)S). In highly trained young soccer players, the importance of fitness level as a determinant of match running performance should be regarded as a function of playing position.


Prognostic value of glomerular C4d staining in patients with IgA nephritis.
Mesangial IgA deposition is the initiative factor in the pathogenesis of IgA nephropathy (IgAN). Glomerular IgA depositon leads to activation local complement system. C4d positivity shows that complement activation occurs via alternative pathway. C4d positivity at the time of renal biopsy can be associated with poor prognosis in IgA nephropathy. We aimed to evaluate C4d deposition and renal outcome in patients with IgA nephritis. Between January 2005 and December 2009, 40 patients with IgA nephritis were enrolled. Renal biopsy specimens of 33 patients have been evaluated. C4d immunohistochemical staining was performed 3-μm deparaffinized and rehydrated sections of formaldehyde-fixed renal tissues, using rabbit polyclonal anti-human C4d as the antibody. Baseline demographical, clinical and laboratory data were recorded retrospectively. Mean age of the patients was 35.9 ± 12.9 years and female/male ratio was 19/21. Mean duration of follow-up was 32.8 (12-60) months. Baseline glomerular filtration ratio (GFR) and proteinuria were 55.8 ml/min and 2.44 gr/day respectively at the time of renal biopsy. Eleven patients were C4d positive. Presence of hypertension (p=0.133), proteinuria (p=0.007), serum creatinine levels (p=0.056) and glomerulosclerosis (p=0.004), mesengial hypersellularity (p=0.0001) and interstitial fibrosis (p=0.006) at the time of renal biopsy were higher in C4d positive group rather than negative group. Evolution to renal failure were 63.6% in C4d positive group and 13.6% in negative group (p=0.006). Renal survival at 3 years was 39% in C4d-positive patients versus 66.7% in the C4d-negative patients (log rank- p=0.0072).


Antinociception after nicotine administration into the mesopontine tegmentum of rats: evidence for muscarinic actions.
The ability of nicotine to induce antinociception after subcortical administration was investigated in the rat. Adult male Sprague-Dawley rats were implanted unilaterally with guide cannulas aimed at the pedunculopontine tegmental nucleus of the mesopontine tegmentum. After 1 week, nicotine was injected in 0.5 microliter of 0.2 M pH 7.4 phosphate buffer. Antinociception was assessed using the 52 degrees C hot-plate test and the tail-flick method; for the most part, the results in the hot-plate test parallelled those in the tail-flick test. Nicotine inhibited nociceptive responses at a median effective antinociceptive dose (A5O) of 1.6 nmol in the hot-plate test and 3.4 nmol in the tail-flick test. Mecamylamine, 0.8 nmol coadministered with nicotine, antagonized nicotine antinociception as evidenced by 5- to 8-fold increases in the nicotine A5O. Nicotine antinociception was also antagonized by coadministrations of either 0.8 nmol of (-)-scopolamine or 0.4 nmol of the M1 antagonist pirenzepine by over 12-fold in the hot-plate test and 5-fold in the tail-flick test. The M2 antagonist methoctramine had antinociceptive effects of its own when injected into the mesopontine tegmentum at a dose of 0.1 nmol; when coinjected with nicotine, the effects of the methoctramine-nicotine combination appeared to be additive. One hour preinjection into the mesopontine tegmentum with 13.5 nmol of (-)-vesamicol, an agent which interferes with acetylcholine storage and/or release, markedly inhibited nicotine antinociception; only a 24% antinociceptive response could be elicited by nicotine in the hot-plate test whereas the nicotine A5O was increased 3-fold in the tail-flick test. Pretreatment with the inactive isomer (+)-vesamicol had no effect. In other experiments, mesopontine tegmental injection of (+)-cis-dioxolane, a high affinity muscarinic cholinergic agonist, elicited strong antinociceptive responses which were potently antagonized by coadministration with 0.5 nmol of pirenzepine but not by 0.8 nmol of mecamylamine. The data indicate that nicotine-induced antinociception may depend upon intact neurotransmission at M1 sites in addition to nicotinic sites within the mesopontine tegmentum.


Neuroanatomy goes viral!
The nervous system is complex not simply because of the enormous number of neurons it contains but by virtue of the specificity with which they are connected. Unraveling this specificity is the task of neuroanatomy. In this endeavor, neuroanatomists have traditionally exploited an impressive array of tools ranging from the Golgi method to electron microscopy. An ideal method for studying anatomy would label neurons that are interconnected, and, in addition, allow expression of foreign genes in these neurons. Fortuitously, nature has already partially developed such a method in the form of neurotropic viruses, which have evolved to deliver their genetic material between synaptically connected neurons while largely eluding glia and the immune system. While these characteristics make some of these viruses a threat to human health, simple modifications allow them to be used in controlled experimental settings, thus enabling neuroanatomists to trace multi-synaptic connections within and across brain regions. Wild-type neurotropic viruses, such as rabies and alpha-herpes virus, have already contributed greatly to our understanding of brain connectivity, and modern molecular techniques have enabled the construction of recombinant forms of these and other viruses. These newly engineered reagents are particularly useful, as they can target genetically defined populations of neurons, spread only one synapse to either inputs or outputs, and carry instructions by which the targeted neurons can be made to express exogenous proteins, such as calcium sensors or light-sensitive ion channels, that can be used to study neuronal function. In this review, we address these uniquely powerful features of the viruses already in the neuroanatomist's toolbox, as well as the aspects of their biology that currently limit their utility. Based on the latter, we consider strategies for improving viral tracing methods by reducing toxicity, improving control of transsynaptic spread, and extending the range of species that can be studied.


Manipulating wavelength-selective emission with heterogeneous photonic crystals.
The usual near-field radiation profile of a light beam emanating from a photonic crystal waveguide (PCW) has a main lobe at the center line of the waveguide. However, a centrally symmetric profile for the emission pattern with two sidelobes can be required in some applications, e.g., Y-type power dividers, wavelength multiplexers, and semiconductor lasers. With such motivations in mind, we present the design of a compact structure that deflects the beam propagation direction in this manner. The idea utilizes the manipulation of the dispersion diagram of cascaded photonic crystals by exploiting the bandgap and self-collimation properties. The waveguide mode in the PCW can be transformed from a propagating mode into a diffusive one by altering the filling factor, which, in turn, leads to off-axis light emission. By using the finite-difference time-domain method, we show that the emission takes place into free space at the inclined output surfaces of the PCW with deviation angles of ±45°.


Caffeine supplementation in the hospital: Potential role for the treatment of caffeine withdrawal.
Caffeine use in the population is widespread. Caffeine withdrawal in the hospital setting is an underappreciated syndrome with symptoms including drowsiness, difficulty concentrating, mood disturbances, low motivation, flu-like symptoms, and headache. Withdrawal may occur upon abstinence from chronic daily exposure at doses as low as 100 mg/day and following only 3-7 days of consumption at higher doses. There are limited data investigating how caffeine withdrawal contributes to hospital morbidity. Some studies suggest caffeine withdrawal may contribute to intensive care delirium and that caffeine may promote wakefulness post-anesthesia. Caffeine supplementation has also shown promise in patients at risk of caffeine withdrawal, such as those placed on nil per os (NPO) status, in preventing caffeine withdrawal headache. These data on caffeine supplementation are not entirely consistent, and routine caffeine administration has not been implemented into clinical practice for patients at risk of withdrawal. Notably, caffeine serves a therapeutic role in the hospital for other conditions. Our review demonstrates that caffeine is largely safe in the general population and may be an appropriate therapeutic option for future studies, if administered properly. There is a need for a randomized controlled trial investigating in-hospital caffeine supplementation and the population that this would best serve.


Asymptomatic bacteriuria may be considered a complication in women with diabetes. Diabetes Mellitus Women Asymptomatic Bacteriuria Utrecht Study Group.
To study the prevalence of and risk factors for asymptomatic bacteriuria (ASB) in women with and without diabetes. A total of 636 nonpregnant women with diabetes (type 1 and type 2) who were 18-75 years of age and had no abnormalities of the urinary tract, and 153 women without diabetes who were visiting the eye and trauma outpatient clinic (control subjects) were included. We defined ASB as the presence of at least 10(5) colony-forming units/ml of 1 or 2 bacterial species in a culture of clean-voided midstream urine from an individual without symptoms of a urinary tract infection (UTI). The prevalence of ASB was 26% in the diabetic women and 6% in the control subjects (P < 0.001). The prevalence of ASB in women with type 1 diabetes was 21%. Risk factors for ASB in type 1 diabetic women included a longer duration of diabetes, peripheral neuropathy, and macroalbuminuria. The prevalence of ASB was 29% in women with type 2 diabetes. Risk factors for ASB in type 2 diabetic women included age, macroalbuminuria, a lower BMI, and a UTI during the previous year. No association was evident between current HbA1c level and the presence of ASB. The prevalence of ASB is increased in women with diabetes and might be added to the list of diabetic complications in these women.


Treat-to-target versus dose-adapted statin treatment of cholesterol to reduce cardiovascular risk.
Clinical guidelines should be based on the best available evidence and are of great importance for patient care and disease prevention. In this respect, the 2013 American College of Cardiology/American Heart Association report is highly appreciated and well-recognized. The report included critical questions concerning hypercholesterolaemia, but its translation into a clinical guideline initiated intense debate worldwide because of the recommendation to switch from a treat-to-target approach for low-density-lipoprotein-cholesterol to a statin dose-based strategy.


Addressing the primary care physician shortage in an evolving medical workforce.
Primary care physicians have been shown to play an important role in the general health of the communities in which they serve. In spite of their importance, however, there has been a decrease in the number of physicians interested in pursuing primary care fields, while the proportion of specialists continues to increase. The prediction of an overall physician shortage only augments this issue in the US, where this uneven distribution is particularly evident. As such, serious effort to increase the number of practicing primary care physicians is both necessary and beneficial for meeting this country's health care needs. There are several factors at play which contribute to the decrease in the number of practicing physicians in primary specialties. Lifestyle concerns, such as schedule and income, as well as the lack of prestige associated with this field seem to be among the most prevalent reasons cited for the diminishing interest. Multifaceted concerns such as these, however, are difficult to adequately invalidate; doing so would not only require a great deal research, but also a good deal of time - a resource which is in short supply given the current physician shortage being faced. Thus, a more immediate solution may lie in the increased recruitment and continued support of those individuals who are already associated with primary care service. This is particularly relevant given the Association of American Medical College's goal of increasing medical school enrollment by 15% over the next 10 years.Several groups have been shown to be large contributors to primary care in the US. Here, we focus on three such groups: minority students, International Medical Graduates (IMGs) and Osteopathic Physicians (DOs). Although these groups are highly diverse individually, they all share the distinction of being underutilized in regard to the current primary care shortages faced. Thus, through more fully accentuating these resources, some of the problems being faced by this nation's healthcare industry may be ameliorated. To improve our nation's heath and healthcare, it is our opinion in this commentary that we must determine a comprehensive approach to increase the number of practicing physicians in primary care which may include minority and underserved medical student recruitment, and acceptance of international medical graduates and osteopathic physicians. Although overtime some of the more underlying causes of primary care under-representation must be addressed, these previous options may offer more immediate aid, while recognizing and augmenting populations who already contribute greatly to our nation's medical system.


Cloning of murine Stat6 and human Stat6, Stat proteins that are tyrosine phosphorylated in responses to IL-4 and IL-3 but are not required for mitogenesis.
By searching a database of expressed sequences, we identified a member of the signal transducers and activators of transcription (Stat) family of proteins. Human and murine full-length cDNA clones were obtained and sequenced. The sequence of the human cDNA was identical to the recently published sequence for interleukin-4 (IL-4)-Stat (J. Hou, U. Schindler, W.J. Henzel, T.C. Ho, M. Brasseur, and S. L. McKnight, Science 265:1701-1706, 1994), while the murine Stat6 amino acid and nucleotide sequences were 83 and 84% identical to the human sequences, respectively. Using Stat6-specific antiserum, we demonstrated that Stat6 is rapidly tyrosine phosphorylated following stimulation of appropriate cell lines with IL-4 or IL-3 but is not detectably phosphorylated following stimulation with IL-2, IL-12, or erythropoietin. In contrast, IL-2, IL-3, and erythropoietin induce the tyrosine phosphorylation of Stat5 while IL-12 uniquely induces the tyrosine phosphorylation of Stat4. Inducible tyrosine phosphorylation of Stat6 requires the membrane-distal region of the IL-4 receptor alpha chain. This region of the receptor is not required for cell growth, demonstrating that Stat6 tyrosine phosphorylation does not contribute to mitogenesis.


Primary care physicians' approach to depressive disorders. Effects of physician specialty and practice structure.
Because primary care physicians (PCPs) are the initial health care contact for most patients with depression, they are in a unique position to provide early detection and integrated care for persons with depression and coexisting medical illness. Despite this opportunity, care for depression is often suboptimal. To better understand how to design interventions to improve care, we examine PCPs' approach to recognition and management and the effects of physician specialty and degree of capitation on barriers to care for 3 common depressive disorders. A 53-item questionnaire was mailed to 3375 randomly selected subjects, divided equally among family physicians, general internists, and obstetrician-gynecologists. The questionnaire assessed reported diagnosis and treatment practices for each subject's most recent patient recognized to have major or minor depression or dysthymia and barriers to the recognition and treatment of depression. Eligible physicians were PCPs who worked at least half-time seeing outpatients for longitudinal care. Of 2316 physicians with known eligibility, 1350 (58.3%) returned the questionnaire. Respondents were family physicians (n = 621), general internists (n = 474), and obstetrician-gynecologists (n = 255). The PCPs report recognition and evaluation practices related to their most recent case as follows: recognition by routine questioning or screening for depression (9%), diagnosis based on formal criteria (33.7%), direct questioning about suicide (58%), and assessment for substance abuse (68.1%) or medical causes of depression (84.1%). Reported treatment practices were watchful waiting only (6.1%), PCP counseling for more than 5 minutes (39.7%), antidepressant medication prescription (72.5%), and mental health referral (38.4%). Diagnostic evaluation and treatment approaches varied significantly by specialty but not by the type of depression or degree of capitation. Physician barriers differed by specialty more than by degree of capitation. In contrast, organizational barriers, such as time for an adequate history and the affordability of mental health professionals, differed by degree of capitation more than by physician specialty. Patient barriers were common but did not vary by physician specialty or degree of capitation. A substantial proportion of PCPs report diagnostic and treatment approaches that are consistent with high-quality care. Differences in approach were associated more with specialty than with type of depressive disorder or degree of capitation. Quality improvement efforts need to (1) be tailored for different physician specialties, (2) emphasize the importance of differentiating major depression from other depressive disorders and tailoring the treatment approach accordingly, and (3) address organizational barriers to best practice and knowledge gaps about depression treatment.


SU-E-I-65: Magnetic Resonance Spectroscopy of the Prostate: A Phantom Study of Metabolite Concentrations.
Magnetic Resonance Spectroscopy (MRS) of the prostate is not used in radiotherapy departments on a regular basis due to a number of issues. The indication and severity of prostate cancer is related to the presence of choline in the prostate, in particular, the ratio of choline (plus creatine) to citrate. In-vivo data supports this theory only marginally but lacks strong correlation with biopsy data. The situation is further complicated by the lack of precise spatial information in biopsy, variation of magnetic susceptibility, and spatial dependence of MRS data on the distance from the endo-rectal coil. The latter also cause low signal-to-noise ratio (SNR). We intend to understand how the level of metabolite concentrations and spatial dependences determine what is observed in MRS. A spherical phantom is filled with water solutions containing various amounts of metabolites. It is placed on top of an endo-rectal coil with the balloon filled with per fluorocarbon. MRS data is acquired on a GE 1.5 T MR scanner. The metabolite values, their ratios etc as reported in GE software, FuncTool are studied as functions of metabolite concentrations in the phantom. Analysis of the phantom data indicates that the metabolite ratio reported in FuncTool is approximately linearly correlated to the metabolite concentrations used in the phantom to a certain point and then saturates whereas the largest metabolite value is well correlated with its concentration in the phantom. All metabolite values become weaker and SNR lower as we move away from the coil. This work indicates the potential of using metabolite values directly provided their spatial dependences on the distance of the voxels from the endo-rectal coil can be accommodated.


Synaptic inputs to granule cells of the dorsal cochlear nucleus.
The mammalian dorsal cochlear nucleus (DCN) integrates auditory nerve input with nonauditory signals via a cerebellar-like granule cell circuit. Although granule cells carry nonauditory information to the DCN, almost nothing is known about their physiology. Here we describe electrophysiological features of synaptic inputs to granule cells in the DCN by in vitro patch-clamp recordings from P12 to P22 rats. Granule cells ranged from 6 to 8 microm in cell body diameter and had high-input resistance. Excitatory postsynaptic currents consisted of both AMPA receptor-mediated and N-methyl-D-aspartate receptor-mediated currents. Synaptically evoked excitatory postsynaptic currents ranged from -25 to -140 pA with fast decay time constants. Synaptic stimulation evoked both short- and long-latency synaptic responses that summated to spike threshold, indicating the presence of a polysynaptic excitatory pathway in the granule cell circuit. Synaptically evoked inhibitory postsynaptic currents in Cl(-)-loaded cells ranged from -30 to -1,021 pA and were mediated by glycine and, to a lesser extent, GABA(A) receptors. Unlike cerebellar granule cells, DCN granule cells lacked tonic inhibition by GABA. The glycinergic synaptic conductance was mediated by heteromeric glycine receptors and was far stronger than the glutamatergic conductance, suggesting that glycinergic neurons may act to gate nonauditory signals in the DCN.


Cardiolipin membrane domains in prokaryotes and eukaryotes.
Cardiolipin (CL) plays a key role in dynamic organization of bacterial and mitochondrial membranes. CL forms membrane domains in bacterial cells, and these domains appear to participate in binding and functional regulation of multi-protein complexes involved in diverse cellular functions including cell division, energy metabolism, and membrane transport. Visualization of CL domains in bacterial cells by the fluorescent dye 10-N-nonyl acridine orange is critically reviewed. Possible mechanisms proposed for CL dynamic localization in bacterial cells are discussed. In the mitochondrial membrane CL is involved in organization of multi-subunit oxidative phosphorylation complexes and in their association into higher order supercomplexes. Evidence suggesting a possible role for CL in concert with ATP synthase oligomers in establishing mitochondrial cristae morphology is presented. Hypotheses on CL-dependent dynamic re-organization of the respiratory chain in response to changes in metabolic states and CL dynamic re-localization in mitochondria during the apoptotic response are briefly addressed.


Adverse events associated with individual statin treatments for cardiovascular disease: an indirect comparison meta-analysis.
Statins are the most widely prescribed drug available. Due to this reason, it is important to understand the risks involved with the drug class and individual statins. We conducted a meta-analysis and employed indirect comparisons to identify differing risk effects across statins. We included any randomized clinical trial (RCT) of atorvastatin, fluvastatin, lovastatin, pitavastatin, pravastatin, rosuvastatin and simvastatin used for cardiovascular disease event prevention. The main outcome was adverse events [all-cause mortality, cancers, rhabdomylosis, diabetes, aspartate and alanine aminotransferase (AST/ALT), and creatinine kinase (CK) increases beyond the upper limit of normal]. In order to evaluate the relative effects of each drug on adverse events, we calculated adjusted indirect comparisons of the adverse-event outcomes. Seventy-two trials involving 159,458 patients met our inclusion criteria. Overall, statin treatments significantly increased the rate of diabetes when compared to controls (OR: 1.09; 95% CI: 1.02-1.16) and elevated AST (OR: 1.31; 95% CI: 1.04-1.66) and ALT (OR: 1.28; 95% CI: 1.11-1.48) levels when compared to controls. Using indirect comparisons, we also found that atorvastatin significantly elevated AST levels compared to pravastatin (OR: 2.21; 95% CI: 1.13-4.29) and simvastatin significantly increased CK levels when compared to rosuvastatin (OR: 4.39; 95% CI: 1.01-19.07). Higher dose studies had increased risk of AST elevations. Although statins are generally well tolerated, there are risks associated with almost all drugs. With few exceptions, statins appear to exert a similar risk across individual drugs.


Gastrointestinal and nutritional issues in children with neurological disability.
Neurological disability is often associated with feeding and gastrointestinal disorders leading to malnutrition and growth failure. Assessment of nutritional status represents the first step in the clinical evaluation of children with neurological disability. The European Society of Gastroenterology, Hepatology, and Nutrition (ESPGHAN) recently issued a consensus statement on gastrointestinal and nutritional management in children with neurological disability. Here we critically review and address implications of this consensus for clinical practice, including assessment and monitoring of nutritional status, definition of nutritional requirements, diagnosis and treatment of gastro-oesophageal reflux disease, and indications for and modalities of nutritional support. There is a strong evidence base supporting the ESPGHAN guidelines; their application is expected to lead to better management of this group of children. Assessment of nutritional status in children with neurological disability should include the evaluation of body composition. Standard polymeric formula via gastrostomy tube is an effective, long-term nutritional intervention. Tube feeding should be started early, before the development of malnutrition.


Epidemiological, clinical and laboratory characteristics of the measles resurgence in the Republic of Serbia in 2014-2015.
The Republic of Serbia is a country with ongoing endemic transmission of measles. The aim of this study is to summarize the main characteristics of the measles resurgence that occurred in Serbia in 2014-2015. The national surveillance data on measles was analysed in relation to the clinical, epidemiological and laboratory data. Between November 2014 and December 2015 a measles resurgence with 420 cases was observed in Serbia. Measles virus was initially introduced by and spread among citizens of Bosnia and Herzegovina with temporary residence in Serbia, before spreading to the resident population. Of the 223 patients with available medical records, 173 (77.6%) were unvaccinated. The overall measles incidence during the outbreak was 5.8/100.000. The highest age-specific incidence rate was recorded in children aged ≤4 years (25.9/100.000), but most cases (67.9%) were ≥20 years old. Hospitalization rate was high (32.9%) and included two cases of encephalitis associated with measles. In total, 42 health-care workers and 22 related cases including hospitalized patients (n = 13) contracted measles. The overall percentage of laboratory confirmed cases was 81.7% (n = 343/420). All measles virus sequences except one (D9) belonged to genotype D8, suggesting interruption of transmission after the previous outbreak in 2010-2011 caused by genotype D4 viruses. The growing number of adult patients as compared to previous epidemics, suggests an urgent need for supplementary immunization activities targeting susceptible health care workers, unvaccinated or incompletely vaccinated adults as well as people without vaccination records. The comprehensive investigation of the 2014/2015 measles resurgence will contribute to decisions about appropriate countermeasures to stop the future measles resurgences in Serbia.


The normal and abnormal genu of the corpus callosum: an evolutionary, embryologic, anatomic, and MR analysis.
To define the normal and abnormal genu of the corpus callosum by examining its evolution and embryology and by analyzing its normal and abnormal appearance on MR images. A reference line was drawn from the mamillary body through the anterior commissure and corpus callosum-the MAC line. This line was used to evaluate the genu in adult mammal brains, in human fetal brains, on MR images of 1800 patients with normal corpora callosi, and on MR images of 113 patients with callosal anomalies. In primates, increased frontal lobe size is associated with an anteriorly shifted genu. In human fetal development, the anterior body of the corpus callosum develops before the definitive genu. The normal human genu always projects in front of the MAC line. In none of the 113 patients with callosal anomalies was there only a normal genu. The human corpus callosum develops bidirectionally, not from front to back. The MAC line is a useful frame of reference to study the evolution and embryology of the genu and to distinguish the normal from the abnormal genu of the human corpus callosum.


Reinforced dynamics for enhanced sampling in large atomic and molecular systems.
A new approach for efficiently exploring the configuration space and computing the free energy of large atomic and molecular systems is proposed, motivated by an analogy with reinforcement learning. There are two major components in this new approach. Like metadynamics, it allows for an efficient exploration of the configuration space by adding an adaptively computed biasing potential to the original dynamics. Like deep reinforcement learning, this biasing potential is trained on the fly using deep neural networks, with data collected judiciously from the exploration and an uncertainty indicator from the neural network model playing the role of the reward function. Parameterization using neural networks makes it feasible to handle cases with a large set of collective variables. This has the potential advantage that selecting precisely the right set of collective variables has now become less critical for capturing the structural transformations of the system. The method is illustrated by studying the full-atom explicit solvent models of alanine dipeptide and tripeptide, as well as the system of a polyalanine-10 molecule with 20 collective variables.


[Food intake of Danes and cardiac risk factors].
We served a low-fat (28% of energy) high-fibre (3.3 g/MJ) diet according to Nordic Nutrition Recommendations (REC diet), and a high-fat diet (39% of energy) corresponding to the average Danish diet (DANE diet) to 21 healthy middle-aged individuals in a two times two weeks cross-over study. The REC diet resulted in lower serum concentrations of low density lipoprotein (LDL) cholesterol (medians: 2.77 vs 3.04 mmol/l, p < 0.001), and high-density lipoprotein (HDL) cholesterol (1.08 vs 1.24 mmol/l, p < 0.001), and higher fasting triglycerides (1.11 vs 0.86 mmol/l, p = 0.04) than the DANE diet. Furthermore, the REC diet lowered plasma factor VII coagulant activity (FVIIc) (88 vs 96%, p = 0.002) and raised plasma fibrinolytic activity. Our observations indicate that a low-fat high-fibre diet may not only reduce the atherogenic, but also the thrombogenic tendency of an individual compared with a diet corresponding to the average Danish diet.


Cognitive deficits in problematic internet use: meta-analysis of 40 studies.
Excessive use of the internet is increasingly recognised as a global public health concern. Individual studies have reported cognitive impairment in problematic internet use (PIU), but have suffered from various methodological limitations. Confirmation of cognitive deficits in PIU would support the neurobiological plausibility of this disorder. To conduct a rigorous meta-analysis of cognitive performance in PIU from case-control studies; and to assess the impact of study quality, the main type of online behaviour (for example gaming) and other parameters on the findings. A systematic literature review was conducted of peer-reviewed case-controlled studies comparing cognition in people with PIU (broadly defined) with that of healthy controls. Findings were extracted and subjected to a meta-analysis where at least four publications existed for a given cognitive domain of interest. The meta-analysis comprised 2922 participants across 40 studies. Compared with controls, PIU was associated with significant impairment in inhibitory control (Stroop task Hedge's g = 0.53 (s.e. = 0.19-0.87), stop-signal task g = 0.42 (s.e. = 0.17-0.66), go/no-go task g = 0.51 (s.e. = 0.26-0.75)), decision-making (g = 0.49 (s.e. = 0.28-0.70)) and working memory (g = 0.40 (s.e. = 0.20-0.82)). Whether or not gaming was the predominant type of online behaviour did not significantly moderate the observed cognitive effects; nor did age, gender, geographical area of reporting or the presence of comorbidities. PIU is associated with decrements across a range of neuropsychological domains, irrespective of geographical location, supporting its cross-cultural and biological validity. These findings also suggest a common neurobiological vulnerability across PIU behaviours, including gaming, rather than a dissimilar neurocognitive profile for internet gaming disorder. S.R.C. consults for Cambridge Cognition and Shire. K.I.'s research activities were supported by Health Education East of England Higher Training Special interest sessions. A.E.G.'s research has been funded by Innovational grant (VIDI-scheme) from ZonMW: (91713354). N.A.F. has received research support from Lundbeck, Glaxo-SmithKline, European College of Neuropsychopharmacology (ECNP), Servier, Cephalon, Astra Zeneca, Medical Research Council (UK), National Institute for Health Research, Wellcome Foundation, University of Hertfordshire, EU (FP7) and Shire. N.A.F. has received honoraria for lectures at scientific meetings from Abbott, Otsuka, Lundbeck, Servier, Astra Zeneca, Jazz pharmaceuticals, Bristol Myers Squibb, UK College of Mental Health Pharmacists and British Association for Psychopharmacology (BAP). N.A.F. has received financial support to attend scientific meetings from RANZCP, Shire, Janssen, Lundbeck, Servier, Novartis, Bristol Myers Squibb, Cephalon, International College of Obsessive-Compulsive Spectrum Disorders, International Society for Behavioral Addiction, CINP, IFMAD, ECNP, BAP, the World Health Organization and the Royal College of Psychiatrists. N.A.F. has received financial royalties for publications from Oxford University Press and payment for editorial duties from Taylor and Francis. J.E.G. reports grants from the National Center for Responsible Gaming, Forest Pharmaceuticals, Takeda, Brainsway, and Roche and others from Oxford Press, Norton, McGraw-Hill and American Psychiatric Publishing outside of the submitted work.


Risks, benefits, complications and harms: neglected factors in the current debate on non-therapeutic circumcision.
Much of the contemporary debate about the propriety of non-therapeutic circumcision of male infants and boys revolves around the question of risks vs. With its headline conclusion that the benefits outweigh the risks, the current circumcision policy of the American Academy of Pediatrics [AAP] (released 2012) is a typical instance of this line of thought. Since the AAP states that it cannot assess the true incidence of complications, however, critics have pointed out that this conclusion is unwarranted. In this paper it is argued that the AAP's conclusion is untenable not only for empirical reasons related to lack of data, but also for logical and conceptual reasons: the concept of risk employed-risk of surgical complications-is too narrow to be useful in the circumcision debate. Complications are not the only harms of circumcision: the AAP and other parties debating the pros and cons of circumcision should conceptualize their analysis more broadly as risk of harm vs. prospect of benefit, thereby factoring in the value of the foreskin to the individual and the physical and ethical harms of removing it from a non-consenting child.


Identification of in vitro HSC fate regulators by differential lipid raft clustering.
Most hematopoietic stem cells (HSC) in the bone marrow reside in a quiescent state and occasionally enter the cell cycle upon cytokine-induced activation. Although the mechanisms regulating HSC quiescence and activation remain poorly defined, recent studies have revealed a role of lipid raft clustering (LRC) in HSC activation. Here, we tested the hypothesis that changes in lipid raft distribution could serve as an indicator of the quiescent and activated state of HSCs in response to putative niche signals. A semi-automated image analysis tool was developed to map the presence or absence of lipid raft clusters in live HSCs cultured for just one hour in serum-free medium supplemented with stem cell factor (SCF). By screening the ability of 19 protein candidates to alter lipid raft dynamics, we identified six factors that induced either a marked decrease (Wnt5a, Wnt3a and Osteopontin) or increase (IL3, IL6 and VEGF) in LRC. Cell cycle kinetics of single HSCs exposed to these factors revealed a correlation of LRC dynamics and proliferation kinetics: factors that decreased LRC slowed down cell cycle kinetics, while factors that increased LRC led to faster and more synchronous cycling. The possibility of identifying, by LRC analysis at very early time points, whether a stem cell is activated and possibly committed upon exposure to a signaling cue of interest could open up new avenues for large-scale screening efforts.


The Swedish Depressive Personality Disorder Inventory: psychometrics and clinical correlates from a DSM-IV and proposed DSM-5 perspective.
Depressive personality is commonly seen in clinical practice, and today only one exclusive self-report instrument-the Depressive Personality Disorder Inventory (DPDI)-is available for its assessment based on the DSM-IV description of the construct. The purpose of this research was to evaluate a Swedish version of this measure (DPDI-Swe) in terms of its reliability, internal structure, and convergent validity using related variables from the DSM-IV criteria for depressive personality disorder (DPD) and the proposed DPD trait set for DSM-5. A non-clinical sample of 255 adults in southern Sweden completed a self-report package, which, in addition to DPD, included the assessment of self-esteem, optimism, hope, rumination, worry, depression, and anxiety. Quality of life was also measured. Results indicated that the DPDI-Swe was internally consistent (α = 0.96). Exploratory factor analysis with oblique rotation yielded three components, together accounting for 48.21% of the variance in DPDI-Swe scores. There were strong positive associations between the DPDI-Swe and measures of depression, anxiety, rumination, and worry, and strong negative associations between the DPDI-Swe and measures of self-esteem, optimism, hope, and quality of life. These significant relationships remained, albeit slightly diminished, after statistically controlling for current depressed mood. The DPDI-Swe appears to be a reliable and valid measure of DPD, and it is available for clinical and research use.


The Case for Medicaid Expansion in North Carolina.
North Carolina's refusal to expand its Medicaid program has left many thousands of North Carolinians without health insurance and has imposed unnecessary costs on all of the state's residents through higher premiums in the state's health insurance marketplace. Expanding Medicaid is the most efficient way to extend coverage to the state's uninsured population, and expansion would bring a substantial amount of new federal money into the state. This money can serve as a catalyst for ambitious reforms to the Medicaid program that can lower costs, improve quality of care, and increase value for patients and taxpayers alike.


Mapping the Ig superantigen-binding site of HIV-1 gp120.
The envelope glycoprotein, gp120, of HIV-1 has recently been identified as a member of the new family of Ig superantigens (Ig-SAg). This classification is based on the selective binding of gp120 to an unusually high proportion of endogenous, nonimmune Ig, and the selective activation of nonimmune B cells by gp120 in vitro. Many, if not all of the nonimmune Ig that bind to gp120 are members of the VH3 Ig gene family. The aim of this study was to determine the epitope on gp120 that was responsible for its Ig-SAg binding activity. To do this, we utilized a panel of 30 peptides derived from gp160 in a competition-binding assay. For five Igs that were tested, as well as for polyclonal serum IgM, two overlapping peptides (each 20 amino acids in length) were identified that were potent inhibitors of gp120 binding. Similarly, the 10 amino acid overlap region of these two peptides had inhibitory activity. Thus, this decamer sequence represented the optimal Ig-SAg epitope or mimotope. The amino acid residue at position 1 of the decamer, and to a lesser extent at position 10, was critical for peptide binding. In addition to this decamer peptide, other peptides that shared modest sequence homology were also selectively inhibitory for specific Ig samples. These findings provide the first definition of an Ig-SAg ligand at the peptide level and will facilitate further structural and biologic characterization of this new class of pathogenic Ags.


Combination of ICP-MS, capillary electrophoresis, and their hyphenation for probing Ru(III) metallodrug-DNA interactions.
Determination of the DNA-binding reactivity and affinity is an important part of a successful program for the selection of metallodrug candidates. For such assaying, a range of complementary analytical techniques was proposed and tested here using one of few anticancer metal-based drugs that are currently in clinical trials, indazolium trans-[tetrachloridobis(1H-indazole)ruthenate(III), and a DNA oligonucleotide. A high reactivity of the Ru drug was confirmed in affinity capillary electrophoresis (CE) mode, where adduct formation takes place in situ (i.e., in the capillary filled with an oligonucleotide-containing electrolyte). To further characterize the binding kinetics, a drug-oligonucleotide mixture was incubated for a different period of time, followed by ultrafiltration separation into two different in molecular weight fractions (>3 and <3 kDa). The time-dependent distribution profiles of the Ru drug were then assessed by CE-inductively coupled plasma mass spectrometry (ICP-MS), revealing that at least two DNA adducts exist at equilibrium conditions. Using standalone ICP-MS, dominant equilibrium amount of the bound ruthenium was found to occur in a fraction of 5-10 kDa, which includes the oligonucleotide (ca. 6 kDa). Importantly, in all three assays, the drug was used for the first time in in-vitro studies, not in the intact form but as its active species released from the transferrin adduct at simulated cancer cytosolic conditions. This circumstance makes the established analytical platform promising to provide a detailed view on metallodrug targeting, including other possible biomolecules and ex vivo samples.


The rising burden of chronic conditions among urban poor: a three-year follow-up survey in Bengaluru, India.
Chronic conditions are on rise globally and in India. Prevailing intra-urban inequities in access to healthcare services compounds the problems faced by urban poor. This paper reports the trends in self-reported prevalence of chronic conditions and health-seeking pattern among residents of a poor urban neighborhood in south India. A cross sectional survey of 1099 households (5340 individuals) was conducted using a structured questionnaire. The prevalence and health-seeking pattern for chronic conditions in general and for hypertension and diabetes in particular were assessed and compared with a survey conducted in the same community three years ago. The predictors of prevalence and health-seeking pattern were analyzed through a multivariable logistic regression analysis. The overall self-reported prevalence of chronic conditions was 12%, with hypertension (7%) and diabetes (5.8%) being the common conditions. The self-reported prevalence of chronic conditions increased by 3.8 percentage point over a period of three years (OR: 1.5). Older people, women and people living below the poverty line had greater odds of having chronic conditions across the two studies compared. Majority of patients (89.3%) sought care from private health facilities indicating a decrease by 8.7 percentage points in use of government health facility compared to the earlier study (OR: 0.5). Patients seeking care from super specialty hospitals and those living below the poverty line were more likely to seek care from government health facilities. There is need to strengthen health services with a preferential focus on government services to assure affordable care for chronic conditions to urban poor.


Failure-to-Rescue After Acute Myocardial Infarction.
Failure-to-rescue (FTR), originally developed to study quality of care in surgery, measures an institution's ability to prevent death after a patient becomes complicated. Develop an FTR metric modified to analyze acute myocardial infarction (AMI) outcomes. Split-sample design: a random 20% of hospitals to develop FTR definitions, a second 20% to validate test characteristics, and an out-of-sample 60% to validate results. Older Medicare beneficiaries admitted to short-term acute-care hospitals for AMI between 2009 and 2011. Thirty-day mortality and FTR rates, and in-hospital complication rates. The 60% out-of-sample validation included 234,277 patients across 1142 hospitals that admitted at least 50 patients over 2.5 years. In total, 72.1% of patients were defined as Medically Complicated (complex on admission or subsequently developed a complication or died without a recorded complication) of whom 19.3% died. Spearman r between hospital risk-adjusted 30-day mortality and FTR was 0.89 (P<0.0001); Mortality versus Complication=-0.01 (P=0.6198); FTR versus Complication=-0.10 (P=0.0011). Major teaching hospitals displayed 19% lower odds of FTR versus non-teaching hospitals (odds ratio=0.81, P<0.0001), while hospitals as a group defined by teaching hospital status, comprehensive cardiac technology, and having good nursing mix and staffing, displayed a 33% lower odds of FTR (odds ratio=0.67, P<0.0001) versus hospitals without any of these characteristics. A modified FTR metric can be created that has many of the advantageous properties of surgical FTR and can aid in studying the quality of care of AMI admissions.


Balance training improves function and postural control in those with chronic ankle instability.
The purpose of this randomized controlled trial was to determine the effect of a 4-wk balance training program on static and dynamic postural control and self-reported functional outcomes in those with chronic ankle instability (CAI). Thirty-one young adults with self-reported CAI were randomly assigned to an intervention group (six males and 10 females) or a control group (six males and nine females). The intervention consisted of a 4-wk supervised balance training program that emphasized dynamic stabilization in single-limb stance. Main outcome measures included the following: self-reported disability on the Foot and Ankle Disability Index (FADI) and the FADI Sport scales; summary center of pressure (COP) excursion measures including area of a 95% confidence ellipse, velocity, range, and SD; time-to-boundary (TTB) measures of postural control in single-limb stance including the absolute minimum TTB, mean of TTB minima, and SD of TTB minima in the anteroposterior and mediolateral directions with eyes open and closed; and reach distance in the anterior, posteromedial, and posterolateral directions of the Star Excursion Balance Test (SEBT). The balance training group had significant improvements in the FADI and the FADI Sport scores, in the magnitude and the variability of TTB measures with eyes closed, and in reach distances with the posteromedial and the posterolateral directions of the SEBT. Only one of the summary COP-based measures significantly changed after balance training. Four weeks of balance training significantly improved self-reported function, static postural control as detected by TTB measures, and dynamic postural control as assessed with the SEBT. TTB measures were more sensitive at detecting improvements in static postural control compared with summary COP-based measures.


Glycerol and fatty acid kinetics in rainbow trout: effects of endurance swimming
Continuous infusions of 2-[3H]glycerol and 1-[14C]palmitate were performed in vivo in rainbow trout to measure the effects of prolonged swimming on (1) the rate of appearance of glycerol (Ra glycerol or lipolytic rate), (2) the rate of appearance of non-esterified fatty acids (Ra NEFA) and (3) the rate of triacylglycerol:fatty acid cycling (TAG:FA cycling or re-esterification). Our goals were to test the hypothesis that sustained exercise for up to 4 days causes the progressive mobilization of triacylglycerol reserves to supply fuel to contracting muscles, and to assess whether TAG:FA cycling plays a role in the regulation of NEFA availability in teleosts. Contrary to expectation, the rates of lipolysis and fatty acid release in resting trout are not affected by endurance exercise. Unlike mammals, which increase the rate of lipolysis by two- to fourfold during submaximal exercise, these active teleosts do not mobilize triacylglycerol reserves beyond resting levels to supply more NEFAs to working muscles. Furthermore, they maintain Ra glycerol and Ra NEFA well in excess of oxidative fuel requirements even at rest. More than two-thirds of the NEFAs produced are re-esterified, but the results show that TAG:FA cycling is not involved in the regulation of NEFA availability during or after swimming. We propose that the observed high rates of re-esterification represent an important feature of ectothermic metabolism that allows the restructuring of membrane phospholipids to be synchronized with frequent changes in body temperature.


Replication of the parvovirus MVM. II. Isolation and characterization of intermediates in the replication of the viral deoxyribonucleic acid.
The time course of the appearance of intracellular viral DNA has been studied in mouse L cells infected with the single-stranded DNA virus MVM (minute virus of mice) by using a selective extraction procedure. Approximately half of this DNA elutes from hydroxyapatite as single-stranded DNA. It is sensitive to Escherichia coli exonuclease I and shows a sedimentation profile similar to DNA from the virus, suggesting that it is progeny viral DNA. The remainder of the selectively extracted DNA elutes from hydroxyapatite in the position of double-stranded DNA and is resistant to exonuclease I. Most of this DNA has a sedimentation coefficient of 14 to 16S, indicating that its molecular weight is twice that of the viral DNA. Denaturation renders the majority of the double-stranded DNA sensitive to exonuclease I, but a significant fraction renatures spontaneously in a monomolecular fashion, indicating that it has a cross-linked or hairpin structure. Chromatography of the double-stranded DNA on benzoylated diethylaminoethyl cellulose resolves two components, one with duplex structure and one which contains single-stranded regions. A short pulse label late in infection predominantly labels the latter class of DNA, suggesting that it contains replicating intermediates. The possible roles of these various forms of DNA in the replication of the viral genome are discussed.


Reduced uptake of mass treatment for schistosomiasis control in absence of food: beyond a randomized trial.
Sustaining high uptake of praziquantel is key for long-term control of schistosomiasis. During mass treatment in 2013, we randomized 12 primary schools into two groups; one group received education messages for schistosomiasis prevention for two months prior to mass treatment, while the other, in addition to the education messages, received a pre-treatment snack shortly before mass treatment. The uptake of praziquantel in the snack schools was 94 % compared to 79 % in the non-snack schools. During mass treatment in 2014, no snack was provided. We compared the uptake of praziquantel in 2014 to that in 2013 and attempt to explain the reasons for the observed differences. Serial cross sectional surveys were conducted among a random sample of children from the 12 primary schools, 1 month after mass treatment in 2013 and 2014 to measure uptake of praziquantel, reported side effects attributable to praziquantel and prevalence and intensity of schistosomiasis infection. Differences in the demographic and descriptive variables between the 2013 and 2014 samples were compared using chi squared tests for categorical variables and student's t-test for geometric mean intensity of S. mansoni infection. Uptake of praziquantel reduced from 93.9 to 78.0 % (p = 0.002) in the snack schools but was unchanged in the non-schools 78.7 and 70.4 % (p = 0.176). The occurence of side-effects attributable to praziquantel increased from 34.4 to 61.2 % (p = 0.001) in the snack schools but was unchanged in the non-snack schools; 46.9 and 53.2 % (p = 0.443). Although the prevalence of S. mansoni infection increased in both the snack and non-snack schools, the differences did not reach statistical significance;1.3 and 7.5 % (p = 0.051) and 14.1 and 22.0 % (p = 0.141), respectively. Similarly, the difference in the geometric mean intensity of S. mansoni infection in both the snack and non-snack schools was not statistically significant; 38.3 eggs per gram of stool (epg) and 145.7 epg (p = 0.197) and 78.4 epg and 322.5 epg (p = 0.120), respectively. Our results show that in absence of food, uptake of praziquantel reduced and the side-effects of the drug increased. However, the reduced uptake did not affect the prevalence and intensity of schistosomiasis among school children. Rescinding of the provision of the snack is what probably caused the reduction in uptake of treatment in the subsequent mass treatment cycle.


Micromechanics and ultrastructure of actin filament networks crosslinked by human fascin: a comparison with alpha-actinin.
Fascin is an actin crosslinking protein that organizes actin filaments into tightly packed bundles believed to mediate the formation of cellular protrusions and to provide mechanical support to stress fibers. Using quantitative rheological methods, we studied the evolution of the mechanical behavior of filamentous actin (F-actin) networks assembled in the presence of human fascin. The mechanical properties of F-actin/fascin networks were directly compared with those formed by alpha-actinin, a prototypical actin filament crosslinking/bundling protein. Gelation of F-actin networks in the presence of fascin (fascin to actin molar ratio >1:50) exhibits a non-monotonic behavior characterized by a burst of elasticity followed by a slow decline over time. Moreover, the rate of gelation shows a non-monotonic dependence on fascin concentration. In contrast, alpha-actinin increased the F-actin network elasticity and the rate of gelation monotonically. Time-resolved multiple-angle light scattering and confocal and electron microscopies suggest that this unique behavior is due to competition between fascin-mediated crosslinking and side-branching of actin filaments and bundles, on the one hand, and delayed actin assembly and enhanced network micro-heterogeneity, on the other hand. The behavior of F-actin/fascin solutions under oscillatory shear of different frequencies, which mimics the cell's response to forces applied at different rates, supports a key role for fascin-mediated F-actin side-branching. F-actin side-branching promotes the formation of interconnected networks, which completely inhibits the motion of actin filaments and bundles. Our results therefore show that despite sharing seemingly similar F-actin crosslinking/bundling activity, alpha-actinin and fascin display completely different mechanical behavior. When viewed in the context of recent microrheological measurements in living cells, these results provide the basis for understanding the synergy between multiple crosslinking proteins, and in particular the complementary mechanical roles of fascin and alpha-actinin in vivo.


A reduction algorithm for computing the hybridization number of two trees.
Hybridization is an important evolutionary process for many groups of species. Thus, conflicting signals in a data set may not be the result of sampling or modeling errors, but due to the fact that hybridization has played a significant role in the evolutionary history of the species under consideration. Assuming that the initial set of gene trees is correct, a basic problem for biologists is to compute this minimum number of hybridization events to explain this set. In this paper, we describe a new reduction-based algorithm for computing the minimum number, when the initial data set consists of two trees. Although the two-tree problem is NP-hard, our algorithm always gives the exact solution and runs efficiently on many real biological problems. Previous algorithms for the two-tree problem either solve a restricted version of the problem or give an answer with no guarantee of the closeness to the exact solution. We illustrate our algorithm on a grass data set. This new algorithm is freely available for application at either http://www.bi.uni-duesseldorf.de/approximately linz or http://www.math.canterbury.ac.nz/approximately cas83.


Inconsistencies between human genetic cytolocations and those derived using genomic sequence.
One result of the publishing of the human genome sequence is the ability to define objects through their position on the consensus sequence. While this has simplified the process of creating order maps for genes on a chromosome, it has created discrepancies between the published cytolocations of human genes, as presented through genetic references, and those locations derived computationally from the genomic sequence. For the 6,830 records with HUGO gene symbols shared between the online version of Mendelian Inheritance in Man and Ensembl, 18% of the records have a discrepancy of at least one cytogenetic band between the datasets. Discordance between data sets at this frequency would have a significant impact on the utility of datasets created by the amalgamation of numerous biological databases.


Macroscopic anatomy of the vertebral endplate: quid significat?
Alterations of vertebral endplates have long been a subject of interest, but are of unclear clinical significance. The vertebral columns of a cohort-based sample of 850 individuals were therefore evaluated for vertebral endplate defects, noting adjacent vertebral size and shape variation, bone density and associated pathologies. Defects were found in the vertebral endplates of 458 individuals (Schmorl's nodes in 52.0% and linear defects in 10.6%). Vertebral centra osteophytes and diffuse idiopathic skeletal hyperostosis were more common; vertebral compression, less common in vertebrae with defects. Linear defects were more disseminated throughout the vertebral column, with individual defects more commonly affected either the interior half or the posterior quarter of the endplate or extended across all quarters form anterior to posterior. Individual Schmorl's nodes were predominantly limited to a single quarter. An inverse relationship was identified with tuberculosis. Spondyloarthropathy was more common in individuals with Schmorl's nodes, but not linear defects. Schmorl's nodes and linear endplate defects should be independently assessed, although they do share implications. Paradoxically, they are associated with phenomena which seem to mark increased ossification potential (osteophytes and diffuse idiopathic skeletal hyperostosis), but not with osteoporosis. Similarly, presence of Schmorl's nodes correlation with spondyloarthropathy, another disorder characterized by increased ossification potential. While correlation is not causality, inverse relationship to tuberculosis is intriguing, given the known relationship of spondyloarthropathy to tuberculosis and its antigens. Previously undescribed surface elevations were commonly associated with the presence of Schmorl's nodes and also correlated with disease, especially inflammatory arthritis, hypertrophic osteoarthropathy.


Split WHO in two: strengthening political decision-making and securing independent scientific advice.
The World Health Organization (WHO) has never fulfilled its original mission of simultaneously serving as the world's pre-eminent public health authority and intergovernmental platform for global health negotiations. While WHO's secretariat works hard to fulfill both functions, it is undermined by an institutional design that mixes technical and political mandates. This forces staff to walk uncomfortably along many fine lines: advising but never directing; guiding but never governing; leading but never advocating; evaluating but never judging. The result is mediocrity on both fronts. Instead, WHO should be split in two, separating its technical and political stewardship functions into separate entities, with collaboration in areas of overlap. The Executive Board and secretariat would be bifurcated, with technical units reporting to a Technical Board and political units reporting to a Political Board. Both boards would report to the World Health Assembly where all member states would continue to provide ultimate oversight. Such bold changes can be implemented either by revising WHO's constitution or through simpler mechanisms. Either way, structural governance reforms would need to be accompanied by complementary changes in culture that support strengthened political decision-making and scientific independence. States' inability to act on WHO's institutional design challenges will only lead them and non-state actors to continue bypassing the organization through the creation of new entities as they have done over the last 15 years. The key will be to mobilize those advocates and decision-makers who have the audacity to demand more from WHO and convince member states to elevate their ambitions in current WHO reform efforts. Continued progress in global health depends on it.


Factors related to physicians' willingness to vaccinate girls against HPV: the importance of subjective norms and perceived behavioral control.
This study assessed factors related to physicians' intentions to vaccinate patients against human papillomavirus. A random sample of physicians was surveyed. The survey questions focused on the constructs of the Theory of Planned Behavior. Structural equation modeling was used to estimate the relationship of theoretical constructs to intention to vaccinate. Of the 207 physicians who responded, intentions to vaccinate were very high (86.5%). On a scale of 1 to 7 (strongly disagree to strongly agree) physicians had positive attitudes toward the vaccine. Physicians reported the vaccine was a good idea (M = 6.65, SD = 0.79), beneficial (M = 6.64, SD = 0.76), and protected against cervical cancer (M = 6.63, SD = 0.77). Intention to vaccinate was driven by subjective norms (provided by guidelines or standards of practice by important professional and general referent groups) (beta = 1.00, p < 0.05) and perceived behavioral control (beta = 0.39, p < 0.05). These findings indicate that public health efforts to encourage physicians to adopt the human papillomavirus vaccine should focus on subjective norms, such as those provided by professional organizations.


Predicting faecal indicator fluxes using digital land use data in the UK's sentinel Water Framework Directive catchment: the Ribble study.
The Ribble drainage basin is the single UK sentinel study area chosen for examining the implementation of the EU Water Framework Directive (WFD 20/60/EC). The study which has generated the data for this paper was initiated to quantify 'catchment-derived' fluxes of faecal indicators originating from both point and diffuse sources to inform the competent authorities on the potential for, and prioritization of, further options for reducing the faecal indicator loadings to this crucial coastal environment. It represents the first UK drainage basin-scale 'profile' of faecal indicator sources as recommended by WHO [1999. Health Based Monitoring of Recreational Waters: The Feasibility of a New Approach; the "Annapolis Protocol". World Health Organisation Geneva, Switzerland; 2003. Guidelines for Safe Recreational-Water Environments Volume 1: Coastal and Fresh-Waters. World Health Organisation Geneva, Switzerland] and incorporated into current drafts of the revised Bathing Water Directive [Anon, 2004. Council of the European Communities Amended proposal for a Directive of the European Parliament and of the Council concerning the management of bathing water quality. Brussels 23rd June]. This paper focuses on the relationships between land use and faecal indicator organism concentrations in surface waters within this very large drainage basin (1583 km2) containing some extensive urban areas. A geographical information system comprising readily available digital elevation, remotely sensed land cover and digital map data was used to generate the land use variables for subcatchments draining to 41 locations across the study area. Presumptive concentrations of coliforms, Escherichia coli and enterococci (colony forming unit (cfu) 100 ml(-1)) were measured at each location on at least 20 occasions over a 44-day period within the 2002 bathing season. The sampling programme targeted hydrograph events. Hydrometric records were used to allocate results as either base flow or high flow. At each site, geometric mean faecal indicator organism concentrations were significantly elevated at high flow compared to base flow. Stepwise regression modelling produced statistically significant models predicting geometric mean base and high-flow faecal indicator organism concentrations from land use variables (r2: 49.5-68.1%). The dominant predictor variable in each case was the proportion of built-up land in subcatchments, suggesting that this land use type, with associated sewage-related inputs, is a critical source of faecal indicator organisms in this drainage basin.


Comparison of the infusion requirements and recovery profiles of vecuronium and cisatracurium 51W89 in intensive care unit patients.
The selection and administration of neuromuscular blocking (NMB) drugs in intensive care unit (ICU) patients remain controversial. We compared the dose-response and recovery pharmacodynamics of a new intermediate-acting NMB drug, cisatracurium besylate, to the intermediate-acting NMB drug, vecuronium (VEC), in a prospective, randomized, double-blind, multicenter study in critically ill adults. After informed consent, 58 mechanically ventilated ICU patients from five medical centers were randomized to receive either cisatracurium or VEC. Fifty-four of the 58 patients received NMB drugs before entering this study but demonstrated at least partial recovery (> or = one twitch) in the train-of-four (TOF) response before initiation of the NMB study drug. NMB drug infusion was titrated by peripheral nerve stimulation to maintain at least one twitch in the TOF response. NMB drugs were infused for 1-5 days. After discontinuation of NMB drug infusion, recovery of neuromuscular transmission was monitored with an accelerometer. NMB drug infusion for 28 cisatracurium patients averaged 2.6 +/- 0.2 (mean +/- SEM) micrograms.kg-1.min-1 with a mean duration of 80 +/- 7 h. After discontinuing cisatracurium administration, recovery to 70% TOF ratio averaged 68 +/- 13 min. The mean infusion rate for 30 VEC patients was 0.9 +/- 0.1 micrograms.kg-1.min-1 with a mean duration of 66 +/- 12 h. Neuromuscular recovery after VEC averaged 387 +/- 163 min, which was significantly longer (P = 0.02) than that after cisatracurium. Prolonged recovery of neuromuscular function after discontinuation of NMB drug infusion (identified by the primary investigator at each medical center) was reported in two cisatracurium patients and 13 VEC patients (P = 0.002), and occurred despite the routine use of neuromuscular twitch monitoring. Seven VEC and one cisatracurium patients died during the infusion of study drug or within 48 h after discontinuation of the NMB drug infusion. In summary, we found recovery of neuromuscular function after discontinuation of NMB drug infusion in ICU patients is significantly faster with cisatracurium than with VEC. In addition, routine neuromuscular monitoring was not sufficient to eliminate prolonged recovery and myopathy in ICU patients.


Rural clinics implementing collaborative care for low-income patients can achieve comparable or better depression outcomes.
The gap between depression treatment needs and the available mental health workforce is particularly large in rural areas. Collaborative care (CoCM) is an evidence-based approach that leverages limited mental health specialists for maximum population effect. This study evaluates depression treatment outcomes, clinical processes of care, and primary care provider experiences for CoCM implementation in 8 rural clinics treating low-income patients. We used CoCM registry data to analyze depression response and remission then used logistic regression to model variance in depression outcomes. Primary care providers reported their experiences with this practice change 18 months following program launch. Participating clinics enrolled 5,187 adult patients, approximately 15% of the adult patient population. Mean PHQ-9 depression score was 16.1 at baseline and 10.9 at last individual measurement, a statistically and clinically significant improvement (SD6.7; 95% CI [4.9, 5.3]). Suicidal ideation also reduced significantly. Multivariate logistic regression predicted the probability of depression response and remission after controlling for several demographic attributes and processes of care, showing a significant amount of variance in outcomes could be explained by clinic, length of time in treatment, and age. Primary care providers reported positive experiences overall. Three quarters of participating primary care clinics, adapting CoCM for limited resource settings, exceeded depression response outcomes reported in a controlled research trial and mirrored results of large-scale quality improvement implementations. Future research should examine quality improvement strategies to address clinic-level variation and sustain improvements in clinical outcomes achieved. (PsycInfo Database Record (c) 2020 APA, all rights reserved).


Expression of the Toll-like receptors 2 gene as a genetic determinant of the formation of newborns multiple organ failure syndrome.
Shkurupii DA. Expression of the Toll-like receptors 2 gene as a genetic determinant of the formation of newborns multiple organ failure syndrome. Turk J Pediatr 2019; 61: 500-504. Activation of the humoral immune response in newborns` multiple organ failure syndrome is associated with the production of interleukin-1β, which is recognized via Toll-like receptors 2 (TLR2). The aim of this study was to determine the role of expression of the Toll-like receptors 2 gene in the pathogenesis of newborns with multiple organ failure syndrome. A prospective observational cohort study of 149 newborns was conducted. The main group (n = 113) were newborns with multiple organ failure syndrome, whereas the comparison group (n = 36) was newborns without this syndrome. The study included analysis of the expression of the TLR2 gene and its comparison with the concentration of interleukin-1β, peripheral blood lymphocyte count and clinical signs of the course of the disease. It was found that the population risk of reducing TLR2 expression was 79.33% in the main group, and 27.62% in the comparison group. Increasing the expression of the gene TLR2 in newborns leads to an increase in the concentration of interleukin-1β, an increase in the level of peripheral blood lymphocytes and is associated with the formation of microbial loci. Expression reduction of the TLR2 gene may lead to the development of multiple organ failure syndrome, systemic inflammatory response syndrome, increase in the number of affected organs, increased frequency of involvement in the immune system, and the need for aggressive respiratory therapy.


From single steps to mass migration: the problem of scale in the movement ecology of the Serengeti wildebeest.
A central question in ecology is how to link processes that occur over different scales. The daily interactions of individual organisms ultimately determine community dynamics, population fluctuations and the functioning of entire ecosystems. Observations of these multiscale ecological processes are constrained by various technological, biological or logistical issues, and there are often vast discrepancies between the scale at which observation is possible and the scale of the question of interest. Animal movement is characterized by processes that act over multiple spatial and temporal scales. Second-by-second decisions accumulate to produce annual movement patterns. Individuals influence, and are influenced by, collective movement decisions, which then govern the spatial distribution of populations and the connectivity of meta-populations. While the field of movement ecology is experiencing unprecedented growth in the availability of movement data, there remain challenges in integrating observations with questions of ecological interest. In this article, we present the major challenges of addressing these issues within the context of the Serengeti wildebeest migration, a keystone ecological phenomena that crosses multiple scales of space, time and biological complexity.This article is part of the theme issue 'Collective movement ecology'.


Melatonin inhibits cell growth and migration, but promotes apoptosis in gastric cancer cell line, SGC7901.
The pineal hormone, melatonin (MLT), has been shown to have therapeutic effects in patients with gastric cancer; however, the mechanisms for the anti-cancer effects are unknown. We investigated the effects of melatonin on cell proliferation, apoptosis, colony formation and cell migration in the gastric adenocarcinoma cell line, SGC7901, using MTT assay, Hoechst 33258 staining, flow cytometry, western blot, caspase-3 activity assay, soft agar colony formation assay, and scratch-wound assay. Our results showed that melatonin could inhibit cell proliferation, colony formation and migration efficiency, and it promoted apoptosis of SGC7901 cells. Our findings suggest that the anti-cancer effects of melatonin may be due to both inhibition of tumor cell proliferation and reduction of the metastatic potential of tumor cells.


Strength and Brittleness of Interfaces in Fe-Al Superalloy Nanocomposites under Multiaxial Loading: An ab initio and Atomistic Study.
We present an ab initio and atomistic study of the stress-strain response and elastic stability of the ordered Fe 3 Al compound with the D0 3 structure and a disordered Fe-Al solid solution with 18.75 at.% Al as well as of a nanocomposite consisting of an equal molar amount of both phases under uniaxial loading along the [001] direction. The tensile tests were performed under complex conditions including the effect of the lateral stress on the tensile strength and temperature effect. By comparing the behavior of individual phases with that of the nanocomposite we find that the disordered Fe-Al phase represents the weakest point of the studied nanocomposite in terms of tensile loading. The cleavage plane of the whole nanocomposite is identical to that identified when loading is applied solely to the disordered Fe-Al phase. It also turns out that the mechanical stability is strongly affected by softening of elastic constants C ' and/or C 66 and by corresponding elastic instabilities. Interestingly, we found that uniaxial straining of the ordered Fe 3 Al with the D0 3 structure leads almost to hydrostatic loading. Furthermore, increasing lateral stress linearly increases the tensile strength. This was also confirmed by molecular dynamics simulations employing Embedded Atom Method (EAM) potential. The molecular dynamics simulations also revealed that the thermal vibrations significantly decrease the tensile strength.


Nanofiltration of plasma-derived biopharmaceutical products.
This review presents the current status on the use and benefits of viral removal filtration systems--known as nanofiltration--in the manufacture of plasma-derived coagulation factor concentrates and other biopharmaceutical products from human blood origin. Nanofiltration of plasma products has been implemented at a production scale in the early 1990s to improve margin of viral safety, as a complement to the viral reduction treatments, such as solvent-detergent and heat treatments, already applied for the inactivation of human immunodeficiency virus, hepatitis B and hepatitis C virus. The main reason for the introduction of nanofiltration was the need to improve product safety against non-enveloped viruses and to provide a possible safeguard against new infectious agents potentially entering the human plasma pool. Nanofiltration has gained quick acceptance as it is a relatively simple manufacturing step that consists in filtering protein solution through membranes of a very small pore size (typically 15-40 nm) under conditions that retain viruses by a mechanism largely based on size exclusion. Recent large-scale experience throughout the world has now established that nanofiltration is a robust and reliable viral reduction technique that can be applied to essentially all plasma products. Many of the licensed plasma products are currently nanofiltered. The technology has major advantages as it is flexible and it may combine efficient and largely predictable removal of more than 4 to 6 logs of a wide range of viruses, with an absence of denaturing effect on plasma proteins. Compared with other viral reduction means, nanofiltration may be the only method to date permitting efficient removal of enveloped and non-enveloped viruses under conditions where 90-95% of protein activity is recovered. New data indicate that nanofiltration may also remove prions, opening new perspectives in the development and interest of this technique. Nanofiltration is increasingly becoming a routine step in the manufacture of biopharmaceutical products.


Vestibuloocular reflex adaptation investigated with chronic motion-modulated electrical stimulation of semicircular canal afferents.
To investigate vestibuloocular reflex (VOR) adaptation produced by changes in peripheral vestibular afference, we developed and tested a vestibular "prosthesis" that senses yaw-axis angular head velocity and uses this information to modulate the rate of electrical pulses applied to the lateral canal ampullary nerve. The ability of the brain to adapt the different components of the VOR (gain, phase, axis, and symmetry) during chronic prosthetic electrical stimulation was studied in two squirrel monkeys. After characterizing the normal yaw-axis VOR, electrodes were implanted in both lateral canals and the canals were plugged. The VOR in the canal-plugged/instrumented state was measured and then unilateral stimulation was applied by the prosthesis. The VOR was repeatedly measured over several months while the prosthetic stimulation was cycled between off, low-sensitivity, and high-sensitivity stimulation states. The VOR response initially demonstrated a low gain, abnormal rotational axis, and substantial asymmetry. During chronic stimulation the gain increased, the rotational axis improved, and the VOR became more symmetric. Gain changes were augmented by cycling the stimulation between the off and both low- and high-sensitivity states every few weeks. The VOR time constant remained low throughout the period of chronic stimulation. These results demonstrate that the brain can adaptively modify the gain, axis, and symmetry of the VOR when provided with chronic motion-modulated electrical stimulation by a canal prosthesis.


Time-reversal symmetry for systems in a constant external magnetic field.
The time-reversal properties of charged systems in a constant external magnetic field are reconsidered in this paper. We show that the evolution equations of the system are invariant under a new symmetry operation that implies a new signature property for time-correlation functions under time reversal. We then show how these findings can be combined with a previously identified symmetry to determine, for example, null components of the correlation functions of velocities and currents and of the associated transport coefficients. These theoretical predictions are illustrated by molecular dynamics simulations of superionic AgI.


Male partner antenatal attendance and HIV testing in eastern Uganda: a randomized facility-based intervention trial.
The objective of the study was to evaluate the effect of a written invitation letter to the spouses of new antenatal clinic attendees on attendance by couples and on male partner acceptance of HIV testing at subsequent antenatal clinic visits. The trial was conducted with 1060 new attendees from October 2009 to February 2010 in an antenatal clinic at Mbale Regional Referral Hospital, Mbale District, eastern Uganda. The intervention comprised an invitation letter delivered to the spouses of new antenatal attendees, while the control group received an information letter, a leaflet, concerning antenatal care. The primary outcome measure was the proportion of pregnant women who attended antenatal care with their male partners during a follow-up period of four weeks. Eligible pregnant women were randomly assigned to the intervention or non-intervention groups using a randomization sequence, which was computer generated utilizing a random sequence generator (RANDOM ORG) that employed a simple randomization procedure. Respondents, health workers and research assistants were masked to group assignments. The trial was completed with 530 women enrolled in each group. Participants were analyzed as originally assigned (intention to treat). For the primary outcome, the percentage of trial participants who attended the antenatal clinic with their partners were 16.2% (86/530) and 14.2% (75/530) in the intervention and non-intervention groups, respectively (OR = 1.2; 95% CI: 0.8, 1.6). For the secondary outcome, most of the 161 male partners attended the antenatal clinic; 82 of 86 (95%) in the intervention group and 68 of 75 (91%) in the non-intervention group were tested for HIV (OR = 2.1; 95% CI: 0.6 to 7.5). The effect of the intervention and the control on couple antenatal attendance was similar. In addition, the trial demonstrated that a simple intervention, such as a letter to the spouse, could increase couple antenatal clinic attendance by 10%. Significantly, the majority of male partners who attended the antenatal clinic accepted HIV testing. Therefore, to further evaluate this simple and cost-effective intervention method, adequately powered studies are required to assess its effectiveness in increasing partner participation in antenatal clinics and the programme for prevention of mother to child transmission of HIV. ClinicalTrials.gov Identifier: NCT01144234.


Extreme antimicrobial Peptide and polymyxin B resistance in the genus burkholderia.
Cationic antimicrobial peptides and polymyxins are a group of naturally occurring antibiotics that can also possess immunomodulatory activities. They are considered a new source of antibiotics for treating infections by bacteria that are resistant to conventional antibiotics. Members of the genus Burkholderia, which includes various human pathogens, are inherently resistant to antimicrobial peptides. The resistance is several orders of magnitude higher than that of other Gram-negative bacteria such as Escherichia coli, Salmonella enterica, or Pseudomonas aeruginosa. This review summarizes our current understanding of antimicrobial peptide and polymyxin B resistance in the genus Burkholderia. These bacteria possess major and minor resistance mechanisms that will be described in detail. Recent studies have revealed that many other emerging Gram-negative opportunistic pathogens may also be inherently resistant to antimicrobial peptides and polymyxins and we propose that Burkholderia sp. are a model system to investigate the molecular basis of the resistance in extremely resistant bacteria. Understanding resistance in these types of bacteria will be important if antimicrobial peptides come to be used regularly for the treatment of infections by susceptible bacteria because this may lead to increased resistance in the species that are currently susceptible and may also open up new niches for opportunistic pathogens with high inherent resistance.


Perceptions and correlates of peer-victimization and bullying.
The experiences of peer-victimization and bullying are often treated empirically as though they are conceptually indistinct. Both involve repeated aggression, but definitions of bullying additionally emphasize the importance of aggressor intent and imbalance of power between the aggressor and the victim (Olweus, 1978; Whitney & Smith, 1993). The present study aimed to examine the extent to which peer-victimization and bullying are empirically similar. The sample comprised 1,429 pupils (50.2% male) aged between 8 and 13 years attending mainstream Scottish schools. Self-report questionnaire assessing peer-victimization and bullying, coping strategy use (WCCL: Hunter, 2000), situational appraisal and depressive symptomatology (Birleson, 1981). Almost one-third (30.7%) of pupils reported experiencing peer-victimization, and of these 38.1% (11.7% of whole sample) were categorized as victims of bullying. Victims of bullying perceived higher levels of threat and lower levels of perceived control. They also reported using more Wishful Thinking and Social Support coping strategies, but did not differ on Problem Focused coping. Bullied pupils also reported higher levels of depressive symptomatology. Peer-victimization and bullying appear to be qualitatively different experiences for children and adolescents, with bullying being the more serious phenomenon.


Lifestyle Modification for Enhancing Autonomic Cardiac Regulation in Children: The Role of Exercise.
Decreased physical activity (PA) is a global concern contributing to the rise in cardiometabolic diseases. One potential mechanism linking insufficient PA and poor health is dysregulated autonomic nervous system (ANS) activity. This relationship is established in adults and PA recommendations, with specific exercise prescription guidelines, have been proposed to overcome this societal health burden. However, research on the benefits and underlying mechanisms of exercise on ANS activity in children <18 years old is limited. This review aimed to describe the optimal exercise "dose" and potential mechanisms of action that exercise may pose on enhancing child ANS activity, represented by heart rate variability (HRV). PubMed, Web of Science and Google Scholar were searched for articles examining the influence of exercise on child HRV. Various exercise duration and frequency combinations appear to improve HRV indices, primarily those representing parasympathetic influence. Furthermore, both aerobic and resistance training benefit HRV through potentially different mechanisms with intensity proposed to be important for exercise prescription. Findings indicate that exercise is a crucial lifestyle modification with protective and therapeutic effects on cardiometabolic health associated with improvements in child ANS activity. Exercise programming must consider the various components including mode, intensity and population characteristics to optimize ANS health.


Alteration of the function of the UDP-glucuronosyltransferase 1A subfamily by cytochrome P450 3A4: different susceptibility for UGT isoforms and UGT1A1/7 variants.
Functional protein-protein interactions between UDP-glucuronosyltransferase (UGT)1A isoforms and cytochrome P450 (CYP)3A4 were studied. To this end, UGT1A-catalyzed glucuronidation was assayed in Sf-9 cells that simultaneously expressed UGT and CYP3A4. In the kinetics of UGT1A6-catalyzed glucuronidation of serotonin, both Michaelis constant (Km) and maximal velocity (Vmax) were increased by CYP3A4. When CYP3A4 was coexpressed with either UGT1A1 or 1A7, the Vmax for the glucuronidation of the irinotecan metabolite (SN-38) was significantly increased. S50 and Km both which are the substrate concentration giving 0.5 Vmax were little affected by simultaneous expression of CYP3A4. This study also examined the catalytic properties of the allelic variants of UGT1A1 and 1A7 and their effects on the interaction with CYP3A4. Although the UGT1A1-catalyzing activity of 4-methylumbelliferone glucuronidation was reduced in its variant, UGT1A1*6, the coexpression of CYP3A4 restored the impaired function to a level comparable with the wild type. Similarly, simultaneous expression of CYP3A4 increased the Vmax of UGT1A7*1 (wild type) and *2 (N129K and R131K), whereas the same was not observed in UGT1A7*3 (N129K, R131K, and W208R). In the kinetics involving different concentrations of UDP-glucuronic acid (UDP-GlcUA), the Km for UDP-GlcUA was significantly higher for UGT1A7*2 and *3 than *1. The Km of UGT1A7*1 and *3 was increased by CYP3A4, whereas *2 did not exhibit any such change. These results suggest that (1) CYP3A4 changes the catalytic function of the UGT1A subfamily in a UGT isoform-specific manner and (2) nonsynonymous mutations in UGT1A7*3 reduce not only the ability of UGT to use UDP-GlcUA but also CYP3A4-mediated enhancement of catalytic activity, whereas CYP3A4 is able to restore the UGT1A1*6 function.