Altered Functional Connectivity in Patients With Sloping Sensorineural Hearing Loss.
Sensory deprivation, such as hearing loss, has been demonstrated to change the intrinsic functional connectivity (FC) of the brain, as measured with resting-state functional magnetic resonance imaging (rs-fMRI). Patients with sloping sensorineural hearing loss (SNHL) are a unique population among the hearing impaired, as they have all been exposed to some auditory input throughout their lifespan and all use spoken language. Twenty patients with SNHL and 21 control subjects participated in a rs-fMRI study. Whole-brain seed-driven FC maps were obtained, with audiological scores of patients, including hearing loss severity and speech performance, used as covariates. Most profound differences in FC were found between patients with prelingual (before language development, PRE) vs. postlingual onset (after language development, POST) of SNHL. An early onset was related to enhancement in long-range network connections, including the default-mode network, the dorsal-attention network and the fronto-parietal network, as well as in local sensory networks, the visual and the sensorimotor. A number of multisensory brain regions in frontal and parietal cortices, as well as the cerebellum, were also more internally connected. We interpret these effects as top-down mechanisms serving optimization of multisensory experience in SNHL with a prelingual onset. At the same time, POST patients showed enhanced FC between the salience network and multisensory parietal areas, as well as with the hippocampus, when they were compared to those with PRE hearing loss. Signal in several cortex regions subserving visual processing was also more intra-correlated in POST vs. PRE patients. This outcome might point to more attention resources directed to multisensory as well as memory experience. Finally, audiological scores correlated with FC in several sensory and high-order brain regions in all patients. The results show that a sloping hearing loss is related to altered resting-state brain organization. Effects were shown in attention and cognitive control networks, as well as visual and sensorimotor regions. Specifically, we found that even in a partial hearing deficit (affecting only some of the hearing frequency ranges), the age at the onset affects the brain function differently, pointing to the role of sensitive periods in brain development.


Cerebellar magnetic stimulation decreases levodopa-induced dyskinesias in Parkinson disease.
The neural mechanisms and the circuitry involved in levodopa-induced dyskinesia (LID) are still partially obscure. LID can be considered the consequence of an abnormal pattern or code of activity that originates and is conveyed from the basal ganglia to the thalamus and the cortical motor areas. However, not only striatothalamocortical motor circuits but also other interconnected pathways could be implicated in its pathogenesis. In a series of experiments, we applied repetitive transcranial magnetic stimulation (rTMS) over the lateral cerebellum in a group of patients with advanced Parkinson disease, to investigate whether modulation of cerebellothalamocortical circuits by means of rTMS may result in a modification of a dyskinetic state induced by levodopa ingestion. We found that a single session of cerebellar continuous theta burst stimulation (cTBS) was capable of transiently reducing LID. In the same patients, we observed that cerebellar cTBS changed the profile of activation of intracortical circuits in the contralateral primary motor cortex. Cerebellar cTBS reduced short intracortical inhibition and increased long intracortical inhibition, inducing a cortical reorganization that is associated with a reduction of LID. Furthermore, in another experiment, we observed that a 2-week course of bilateral cerebellar cTBS induced persistent clinical beneficial effects, reducing peak-dose LID for up to 4 weeks after the end of the daily stimulation period. Our study demonstrates that cerebellar continuous theta burst stimulation has an antidyskinetic effect in Parkinson disease patients with levodopa-induced dyskinesia, possibly due to modulation of cerebellothalamocortical pathways.


Glucose-6-phosphate dehydrogenase deficiency and malaria.
Glucose-6-phosphate dehydrogenase (G6PD) is a cytoplasmic enzyme that is essential for a cell's capacity to withstand oxidant stress. G6PD deficiency is the commonest enzymopathy of humans, affecting over 400 million persons worldwide. The geographical correlation of its distribution with the historical endemicity of malaria suggests that 66PD deficiency has risen in frequency through natural selection by malaria. This is supported by data from in vitro studies that demonstrate impaired growth of P. falciparum parasites in G6PD-deficient erythrocytes. Attempts to confirm that G6PD deficiency is protective in field studies of malaria have yielded conflicting results, but recent results from large case control studies conducted in East and West Africa provide strong evidence that the most common African G6PD deficiency variant, G6PD A-, is associated with a significant reduction in the risk of severe malaria for both G6PD female heterozygotes and male hemizygotes. The effect of female homozygotes on severe malaria remains unclear but can probably be assumed to be similar to that of comparably deficient male hemizygotes.


Role of calcium in triggering rapid ultrastructural damage in muscle: a study with chemically skinned fibres.
Agents (A23187, caffeine) believed to raise [Ca]i in vertebrate cardiac and skeletal muscles cause rapid and characteristic subcellular damage in vitro and in vivo. By using saponin-skinned amphibian pectoris cutaneous muscle and Ca-EGTA-buffered solutions it is shown that low [Ca] consistently triggers the same rapid (2-20 min), ultrastructural damage. Electron micrographs reveal a close similarity between the damaged intact and skinned preparations, namely loss of myofilament organization, specific Z-line damage, dissolution and hypercontraction bands, characteristic mitochondrial swelling and division. Where both actin and myosin filaments were lost, an underlying cytoskeletal network frequently remained, still attached to the Z-line framework. Ca was effective in skinned preparations from 5 X 10(-7) M to 8 X 10(-6) M, within the concentration range experienced by a contracting muscle. Damage was [Ca]- and time-dependent and it is suggested that it is probably the active movement of Ca ions across key membrane sites that is critical in triggering damage of the myofilament apparatus. Strontium can substitute for Ca at higher concentrations. The action of saponin suggests that the chemically skinned cell is partially activated. Ca-triggering can be bypassed experimentally by membrane-active agents or by sulphydryl agents. Ruthenium Red and trifluoperazine indirectly cause damage in the intact cell by raising [Ca]i. Studies with saponin-skinned cells and protease inhibitors show that changes in pHi, loss of ATP, Ca-activated neutral protease, or release of lysosomal enzymes (cathepsins B, D, L or H), are not involved in characteristic rapid myofilament damage.


Prevalence and associated factors of suicidality in Japanese adolescents: results from a population-based questionnaire survey.
Suicide is the leading cause of death among Japanese adolescents. However, knowledge gaps regarding contemporary demographics and factors associated with suicidality among Japanese adolescents are a major concern. This study examined the prevalence of suicidality among Japanese adolescents and investigated associated factors. A population-based questionnaire survey investigating general health was administered to 22,419 adolescents aged 13-18 years. The 29-item questionnaire covered emotional status, family function, cyberbullying, suicidality, and stressors (e.g., relationships with parents/friends, school performance, and sexual identity). We conducted multiple logistic regression analysis to identify factors associated with suicidality in this population. The prevalence of suicidal ideation was 21.6% in males and 28.5% in females, and that of attempted suicide was 3.5% in males and 6.6% and in females. Bullying and stress related to family relationships had the strongest associations with suicidality. Exposure to cyberbullying had the highest odds ratio for both junior high (3.1, 95% confidence interval [CI] 2.1-4.4) and high school students (3.6, 95% CI 2.5-5.3). Other factors significantly associated with suicidality were sex, emotional status, and stress about relationships with friends, sexual identity, school records, and academic course. Adolescents accessed a variety of resources to cope with stressors, with the Internet being the most common resource consulted. Suicidality is commonly experienced among Japanese adolescents. Although there are many associated risk factors, cyberbullying is of particular concern. Recognition of factors associated with adolescent suicidality will inform further research and suicide prevention efforts for healthcare providers and families.


Catastrophic hyperkalaemia following administration of suxamethonium chloride to a patient with undiagnosed amyotrophic lateral sclerosis.
The depolarising neuromuscular blocking agent suxamethonium chloride, frequently used during endotracheal intubation, is contraindicated in patients with chronic denervation in whom it can cause a life-threatening hyperkalaemic reaction, thought to be mediated through upregulation of nicotinic alpha7 acetylcholine receptors. An underlying neuromuscular disorder should be considered in all patients with acute respiratory insufficiency, and an alternative neuromuscular blocking drug must be used if there is any possibility of widespread denervation.


Intermittent Fasting Alleviates the Increase of Lipoprotein Lipase Expression in Brain of a Mouse Model of Alzheimer's Disease: Possibly Mediated by β-hydroxybutyrate.
Intermittent fasting has been demonstrated to protect against Alzheimer's disease (AD), however, the mechanism is unclear. Histone acetylation and lipoprotein lipase (LPL) are involved in AD progression. Importantly, LPL has been documented to be regulated by histone deacetylases (HDACs) inhibitors (increase histone acetylation level) in adipocyte and mesenchymal stem cells, or by fasting in adipose and muscle tissues. In brain, however, whether histone acetylation or fasting regulates LPL expression is unknown. This study was designed to demonstrate intermittent fasting may protect against AD through increasing β-hydroxybutyrate, a HDACs inhibitor, to regulate LPL. We also investigated microRNA-29a expression associating with regulation of LPL and histone acetylation. The results showed LPL mRNA expression was increased and microRNA-29a expression was decreased in the cerebral cortex of AD model mice (APP/PS1), which were alleviated by intermittent fasting. No significant differences were found in the total expression of LPL protein (brain-derived and located in capillary endothelial cells from peripheral tissues) in the cerebral cortex of APP/PS1 mice. Further study indicated that LPL located in capillary endothelial cells was decreased in the cerebral cortex of APP/PS1 mice, which was alleviated by intermittent fasting. LPL and microRNA-29a expression were separately increased and down-regulated in 2 μM Aβ25-35-exposed SH-SY5Y cells, but respectively decreased and up-regulated in 10 μM Aβ25-35-exposed cells, which were all reversed by β-hydroxybutyrate. The increase of HDAC2/3 expression and the decrease of acetylated H3K9 and H4K12 levels were alleviated in APP/PS1 mice by intermittent fasting treatment, as well in 2 or 10 μM Aβ25-35-exposed cells by β-hydroxybutyrate treatment. These findings above suggested the results from APP/PS1 mice were consistent with those from cells treated with 2 μM Aβ25-35. Interestingly, LPL expression was reduced (0.2-folds) and microRNA-29a expression was up-regulated (1.7-folds) in HDAC2-silenced cells, but respectively increased (1.3-folds) and down-regulated (0.8-folds) in HDAC3-silenced cells. Furthermore, LPL expression was decreased in cells treated with microRNA-29a mimic and increased with inhibitor treatment. In conclusion, intermittent fasting inhibits the increase of brain-derived LPL expression in APP/PS1 mice partly through β-hydroxybutyrate-mediated down-regulation of microRNA-29a expression. HDAC2/3 may be implicated in the effect of β-hydroxybutyrate on microRNA-29a expression.


The Nitric Oxide Synthase Inhibitor l-NAME (Nω-Nitro-L-Arginine Methyl Ester) Does Not Produce Discriminative Stimulus Effects Similar to Ethanol.
N-methyl-d-waspartate (NMDA) antagonists substitute for the discriminative stimulus effects of ethanol, indicating that a component of ethanol's behavioral activity is produced via blockade of NMDA receptor/channel function. Recently, it has been reported that ethanol inhibits NMDA-stimulated nitric oxide synthase (NOS) activity in cortical neurons, thereby decreasing the formation of nitric oxide (NO) in the brain. These findings suggest that some of the behavioral effects of ethanol may be mediated by inactivation of NOS. The present study examined the role of NO formation in mediating the discriminative stimulus effects of ethanol. To address this hypothesis, an NOS inhibitor, Nω-nitro-L-arginine methyl ester (l-NAME) and an NMDA competitive antagonist, (d)-4-(3-phosphonoprop-2-enyl)piperazine-2-carboxylic acid (CPPene), were administered to two groups of rats trained to discriminate 1.5 g/kg of ethanol (n= 6) or 2.0 gkg (n= 7) of ethanol from water. After training, dose ranges of CPPene (3 to 17 mg/kg, ip) and l-NAME (100 to 780 mg/kg, ip) were tested for ethanol-like effects. l-NAME was also tested under a range of pretreatment times (20,60,90, and 120 min). An additional group of rats trained to discriminate 2.0 g/kg (n = 7) of ethanol from water was also tested with CPPene (10 mg/kg, ip) and l-NAME (100 and 300 mg/kg, ip) to verify data gathered from the original 2.0 gkg of ethanol group tested with l-NAME after a 20-minute pretreatment. Although overall, 17 of 20 animals trained to discriminate ethanol from water exhibited complete substitution of CPPene for ethanol, l-NAME, without affecting response rates, did not consistently substitute for either 1.5 g/kg or 20 g/kg of ethanol. These results indicate that inhibition of NO formation is less effective than direct NMDA receptor antagonism in producing ethand-like discriminative stimulus effects.


Feasibility of communication in binary signaling games.
In signaling games the replicator dynamics does not almost always converge to states of perfect communication. A significant portion of the state space converges to components of Nash equilibria that characterize states of partial communication. Since these components consist of non-hyperbolic rest points, the significance of this result will depend on the dynamic behavior of specific perturbations of the replicator equations. In this paper we study selection-mutation dynamics of signaling games, which may be considered as one plausible perturbation of the replicator dynamics. We find that the long term behavior of the dynamics depends on the mutation rates of senders and receivers and on the relevance of communication.


Vanadate is a potent (Na,K)-ATPase inhibitor found in ATP derived from muscle.
A potent (Na,K)-ATPase inhibitor purified from "Sigma Grade* ATP has been identified as vanadium using electron probe microanalysis and confirmed by microwave-induced emission spectroscopy and electron paramagnetic resonance spectroscopy. Sodium orthovanadate (Na3 VO4) is identical with the purified inhibitor with respect to ultraviolet absorbance, migration on thin layer chromatography, and inhibition of (Na,K)-ATPase. The (Na,K)-ATPase is in-inhibited 50% by 40 nM Na3 VO4 under optimal conditions (28 mM Mg2+) and the inhibition is 100% reversible by millimolar concentrations of norepinephrine. The physiological significance of this inhibition is discussed in relation to vanadium concentrations in vivo.


Laparoscopic-Assisted Live Donor Nephrectomy: A Comparison of Conventional and Transvaginal Routes for Kidney Extraction.
Laparoscopic approach has become the standard procedure for living donor nephrectomy in many transplant centers. Because the conventional approach results in cosmetic problems and pain during laparoscopic live donor nephrectomy, transvaginal extraction of an intact kidney has been recently introduced as a minimally invasive technique. Here, we aimed to investigate whether transvaginal extraction of an intact kidney during laparoscopic live donor nephrectomy is associated with decreased postoperative pain, nausea and vomiting, and morphine consumption. This prospective data analysis included a total of 27 female donors who underwent laparoscopic removal of a single kidney for living donor nephrectomy through conventional or transvaginal route. Data collected included age, body mass index, ASA scores, histocompatibility, additional medical disorders, peri- and postoperative complications, postoperative pain scores with visual analogue pain scores (VAS), length of postoperative stay, morphine consumption, degree of nausea and vomiting, level of sedation, and pruritus. No significant differences between the transvaginal and conventional groups were observed in VAS scores and morphine consumption at postoperative 1, 3, 6, 12, and 24 hours. Although not reaching statistical significance, according to analysis of morphine consumption, there was a trend toward decreasing analgesic requirements in the transvaginal group at postoperative 12 and 24 hours. There were no significant differences between the groups in terms of degree of nausea or vomiting, or length of postoperative hospital stay. We suggest that with a more desirable cosmetic result, transvaginal natural orifice transluminal endoscopic surgery-assisted living donor nephrectomy (TVNALDN) is a suitable new minimally invasive laparoscopic technique associated with reduced postoperative pain and analgesic requirements in select women.


Speed-up collisions in strong-field double ionization.
We compare quantum and classical models of double ionization (DI) for aligned-electron helium in strong laser fields, considering specifically the role of recollision processes in which the returning electron travels in the direction of the laser force. Quantum studies show that for the knee region in our model a small but persistent portion of the total DI occurs through these speed-up collisions.We show that classical modeling displays similar collisions and reveals that with-the-force doubly ionizing collisions typically involve two-particle trajectories in which both electrons can be said to have been bound or very nearly bound at the zero of the laser field just before the collision. Trajectories leading to the with-the-force doubly ionizing collisions can be classified into two categories-direct excitation, in which there is no unambiguous single ionization before the doubly ionizing collision, and recapture, in which an ionized electron returns to the core and is recaptured prior to the speed-up collision. Comparison of the classical and quantum situations for our laser parameters yields evidence that for our parameters the quantum system favors the direct-excitation pathway over the reattachment pathway.


A spherical cavity model for quadrupolar dielectrics.
The dielectric properties of a fluid composed of molecules possessing both dipole and quadrupole moments are studied based on a model of the Onsager type (molecule in the centre of a spherical cavity). The dielectric permittivity ε and the macroscopic quadrupole polarizability αQ of the fluid are related to the basic molecular characteristics (molecular dipole, polarizability, quadrupole, quadrupolarizability). The effect of αQ is to increase the reaction field, to bring forth reaction field gradient, to decrease the cavity field, and to bring forth cavity field gradient. The effects from the quadrupole terms are significant in the case of small cavity size in a non-polar liquid. The quadrupoles in the medium are shown to have a small but measurable effect on the dielectric permittivity of several liquids (Ar, Kr, Xe, CH4, N2, CO2, CS2, C6H6, H2O, CH3OH). The theory is used to calculate the macroscopic quadrupolarizabilities of these fluids as functions of pressure and temperature. The cavity radii are also determined for these liquids, and it is shown that they are functions of density only. This extension of Onsager's theory will be important for non-polar solutions (fuel, crude oil, liquid CO2), especially at increased pressures.


Use Rate and Outcome in Bilateral Internal Thoracic Artery Grafting: Insights From a Systematic Review and Meta-Analysis.
This meta-analysis was designed to assess whether center experience affects the short- and long-term results and the relative benefits of bilateral internal thoracic artery grafting (BITA) for coronary artery bypass grafting. MEDLINE and EMBASE were searched to identify all articles reporting the outcome of BITA in patients undergoing coronary artery bypass grafting. The BITA center experience was gauged according to the percentage use of BITA in the institutional overall coronary artery bypass grafting population (%BITA). The primary outcome was long-term all-cause mortality. Secondary outcomes were operative mortality, perioperative myocardial infarction, perioperative stroke, deep sternal wound infections (DSWIs), and major postoperative adverse event. The rates of the primary and secondary outcomes were calculated after adjusting for %BITA. Primary and secondary outcomes were also compared between the BITA and the single internal thoracic artery arms in the adjusted studies. Meta-regression was used to evaluate the effect of %BITA on the primary and secondary outcomes. Thirty-four studies (27 894 patients undergoing BITA) were included. In the pooled analysis, the incidence rate for long-term mortality was 2.83% (95% confidence interval, 2.21%-3.61%). %BITA was significantly and inversely associated with long-term mortality and the rate of DSWI. In the pairwise comparison, %BITA was significantly and inversely associated with the risk of long-term mortality and DSWI in the group undergoing BITA. BITA series with higher %BITA report significantly lower long-term mortality and DSWI rate as well as higher long-term survival advantage and lower relative risk of DSWI in their BITA cohort. These findings suggest that a specific volume-outcome relationship exists for BITA grafting.


Patient rights and healthcare-associated infection.
The Universal Declaration of Human Rights was adopted by the United Nations in 1948, and since that time, human rights have become widely recognized and legally enforceable in many countries. Patient rights are now included in healthcare constitutions, such as that of the English National Health Service, and in professional codes of practice. Patient rights have a number of implications for the control of healthcare-associated infections (HCAI), including: (1) justification for infection control over and above economic benefit; (2) focus and emphasis on the individual patient experience; (3) identification of some of the actions taken to control infection as breaches of rights; (4) bridging professional, infection control and public health ethics; (5) a requirement to specify the conditions under which rights can be breached; and (6) grounds for those seeking compensation for HCAI. Assuring patient rights has the potential to improve the patient experience, and in so doing, improve public confidence in healthcare provision and providers.


Productivity and patient satisfaction in primary care--conflicting or compatible goals?
Following recent reforms in Swedish primary care, providers are accountable to both citizens and county councils, in their role as payers. Productivity and quality measurement is fundamental for ensuring health care providers accountability to payers and that resources are spent as intended. The purpose was to study productivity and patient satisfaction in Swedish primary care. One measure of productivity capturing volume of visits and one measure capturing individual's judgment about the quality of services in relation to allocated resources was estimated. The potential conflict between the two measures and variation with respect to different factors was analyzed. There was a great variation in both measures of productivity. No conflict between the two measures of productivity was found. Thus, most providers could increase their volume of services without adverse effects for the quality and vice versa. Providers are however faced with different conditions. Traditional productivity measures are not enough to assess whether allocated resources are used according to set priorities and generates value for money. Information about the length and content of visits and the distribution of services produced is also needed, in particular to assess if resources allocated based on expected great needs among certain groups actually benefits those individuals. Effects of services produced are also needed. This is particularly important to assess if resources allocated based on expected great needs among certain groups actually benefits those individuals.


Comparative aspects of the endotoxin- and cytokine-induced endocrine cascade influencing neuroendocrine control of growth and reproduction in farm animals.
Disease in animals is a well-known inhibitor of growth and reproduction. Earlier studies were initiated to determine the effects of endotoxin on pituitary hormone secretion. These studies found that in sheep, growth hormone (GH) concentration was elevated, whereas insulin-like growth factor-I (IGF-I) was inhibited, as was luteinizing hormone (LH). Examination of the site of action of endotoxin in sheep determined that somatotropes expressed the endotoxin receptor (CD14) and that both endotoxin and interleukin-I beta activated GH secretion directly from the pituitary. In the face of elevated GH, there is a reduction of IGF-I in all species examined. As GH cannot activate IGF-I release during disease, there appears to be a downregulation of GH signalling at the liver, perhaps related to altered nitration of Janus kinase (JAK). In contrast to GH downregulation, LH release is inhibited at the level of the hypothalamus. New insights have been gained in determining the mechanisms by which disease perturbs growth and reproduction, particularly with regard to nitration of critical control pathways, with this perhaps serving as a novel mechanism central to lipopolysaccharide suppression of all signalling pathways. This pathway-based analysis is critical to the developing novel strategies to reverse the detrimental effect of disease on animal production.


Long-term catheterization: current approaches in the diagnosis and treatment of port-related infections.
Since the first description in 1982, totally implanted venous access ports have progressively improved patients' quality of life and medical assistance when a medical condition requires the use of long-term venous access. Currently, they are part of the standard medical care for oncohematologic patients. However, apart from mechanical and thrombotic complications, there are also complications associated with biofilm development inside the catheters. These biofilms increase the cost of medical assistance and extend hospitalization. The most frequently involved micro-organisms in these infections are gram-positive cocci. Many efforts have been made to understand biofilm formation within the lumen catheters, and to resolve catheter-related infection once it has been established. Apart from systemic antibiotic treatment, the use of local catheter treatment (ie, antibiotic lock technique) is widely employed. Many different antimicrobial options have been tested, with different outcomes, in clinical and in in vitro assays. The stability of antibiotic concentration in the lock solution once instilled inside the catheter lumen remains unresolved. To prevent infection, it is mandatory to perform hand hygiene before catheter insertion and manipulation, and to disinfect catheter hubs, connectors, and injection ports before accessing the catheter. At present, there are still unresolved questions regarding the best antimicrobial agent for catheter-related bloodstream infection treatment and the duration of concentration stability of the antibiotic solution within the lumen of the port.


Field studies of drug-resistant cattle trypanosomes in Kénédougou Province, Burkina Faso.
Field studies were conducted to assess the occurrence of resistance to isometamidium chloride and diminazene aceturate in trypanosomes infecting cattle in Kénédougou Province of Burkina Faso. Forty-five of the 166 villages in Kénédougou were randomly sampled and visited to assess livestock numbers, trypanosomosis risk, and tsetse challenge. The proportion of cattle infections associated with drug-resistant trypanosomes was assessed in the nine villages with the highest trypanosome infection prevalence and one village with a confirmed history of drug-resistant infections. These studies showed that resistance to both isometamidium and diminazene was widespread. However, there was considerable variation between villages in drug-resistance parameters, with the proportion of treated cattle with trypanosome infections 3 months after isometamidium prophylaxis varying from 6.9 to 63.8% and the proportion of cattle having infections 2 weeks after treatment with diminazene varying from 0 to 36.8%. The demonstration of widespread resistance to both isometamidium and diminazene has important implications, as administration of trypanocides is the most commonly employed method to control trypanosomosis in this area.


Multiple Simultaneous Gastrointestinal Parasitic Infections in a Patient with Human Immunodeficiency Virus.
Patients with the human immunodeficiency virus (HIV) infection are at high risk for gastrointestinal infections causing diarrhea, particularly when those infections are parasitic in nature. This propensity is more pronounced in AIDS, where opportunistic parasitic infections may cause severe diarrhea, marked absorptive dysfunction, and significant risk of mortality. There are scant data regarding parasitic infections among HIV patients in the developed world; most studies and research come from povertystricken areas of South Africa, India, Iran, and the South Pacific. Although multiple infections with the same or different parasites have been reported, simultaneous infections are rare. We present the case of a 35-year-old man who developed a co-infection with Giardia, Cryptosporidium, and Strongyloides, simultaneously, the diagnosis being made after the judicious evaluation of a stool sample. Given the associated morbidity, prompt diagnosis and treatment are needed to avoid further complications in patients with HIV. To our knowledge this is the first reported case of triple parasitic infection in a patient with HIV.


A Hybrid Constant and Oscillatory Field Ion Mobility Analyzer Using Structures for Lossless Ion Manipulations.
Here we explore the combination of constant and oscillatory fields applied in a single device to affect the continuous separation and filtering of ions based on their mobilities. The device explored allows confining and manipulating ions utilizing a combination of radio frequency (rf), direct current (DC) fields, and traveling waves (TW) in a structures for lossless ion manipulations (SLIM) module. We have investigated theoretically and experimentally a concept for continuous filtering of ions based on their mobilities where ions are mobility separated and selected by passage through two regions, both of which incorporated combined TW and constant fields providing opposing forces on the ions. The SLIM module was composed of two surfaces with mirror-image arrays of electrodes and had two regions where the different TW and opposing DC fields could be applied. The filtering capabilities are determined by the applied DC gradient and the TW parameters, such as speed, amplitude, and the TW sequence (i.e., the duty cycle of the traveling wave). The effects of different parameters on the sensitivity and the ion mobility (IM) resolution of the device have been investigated. By appropriately choosing the DC gradient and TW parameters for the two sections, it is possible to transmit ions of a selected mobility while filtering out others of both higher and lower mobility. The novel device described here provides a basis for the targeted analysis of compounds based upon the continuous selection of ions according to their mobility and without the need for high electric fields or pulsed injection. Graphical abstract .


Ultrafast laser-induced microstructure/nanostructure replication and optical properties.
This paper demonstrates replication of ultrafast laser-induced micro/nano surface textures on poly(dimethylsiloxane) (PDMS). The surface texture replication process reduces the processing steps for microtexturing while improving light trapping. Two methods are demonstrated to replicate surface microtexture, a simple mold method and an embossing method. The laser microtextured silicon and titanium surfaces with micro to nanoscale features have been successfully replicated. Optical characterization of the replicated microtextured PDMS surfaces is performed and the results agree with model predictions. The replicated microtextured PDMS film is applied on a silicon surface and optical characterization shows that surface reflectance can be suppressed over 55% compared to the control value.


Terahertz spectroscopy of 2,4-dinitrotoluene over a wide temperature range (7-245 K).
Previous THz spectroscopy of the TNT explosive precursor, 2,4-dinitrotoluene (DNT), has been restricted to room temperature (apart from one set of data at 11 K). Here, for the first time, we investigate the spectrum as the temperature is systematically varied, from 7 to 245 K. Many new features appear in the spectrum on cooling below room temperature. As well as the five absorption lines observed previously, we observe five additional lines. In addition, a new room-temperature line at 8.52 THz (281 cm(-1)) is observed. Six of the lines red-shift with temperature and four of them blue-shift. The blue shift is explained by interplay between intramolecular and intermolecular hydrogen bonds. The variation in line width and line intensity with temperature is not systematic, although a conspicuous decrease in line intensity with temperature is observed in all cases. Modeling with hybrid PBE0 and TPSSh functionals helps identify absorption modes.


Nanoplasmonic probes of RNA folding and assembly during pre-mRNA splicing.
RNA splicing plays important roles in transcriptome and proteome diversity. Herein, we describe the use of a nanoplasmonic system that unveils RNA folding and assembly during pre-mRNA splicing wherein the quantification of mRNA splice variants is not taken into account. With a couple of SERS-probes and plasmonic probes binding at the boundary sites of exon-2/intron-2 and intron-2/exon-3 of the pre-mature RNA of the β-globin gene, the splicing process brings the probes into the plasmonic bands. For plasmonic probes, a plasmon shift increase of ∼29 nm, corresponding to intron removal and exon-2 and exon-3 connection to form the mRNA molecule, is measured by plasmonic coupling. The increased scattering intensity and surface-enhanced Raman scattering (SERS) fingerprinting reveal the clear dynamics of pre-mRNA splicing. Moreover, a time-resolved experiment of individual RNA molecules exhibited a successful splicing and an inhibited splicing event by 33 μM biflavonoid isoginkgetin, a general inhibitor of RNA splicing. The results suggest that the RNA splicing is successfully monitored with the nanoplasmonic system. Thus, this platform can be useful for studying RNA nanotechnology, biomolecular folding, alternative splicing, and maturation of microRNA.


Modes of operation: A topographic neural gradient supporting stimulus dependent and independent cognition.
Human cognition is flexible - drawing on both sensory input, and representations from memory, to successfully navigate complex environments. Contemporary accounts suggest this flexibility is possible because neural function is organized into a hierarchy. Neural regions are organized along a macroscale gradient, anchored at one end by unimodal systems involved with perception and action, and at the other by transmodal systems, including the default mode network, supporting cognition less directly tied to immediate stimulus input. The current study tested whether this cortical hierarchy captures modes of behaviour that depend on immediate input, as well as those that depend on representations from memory. Participants made decisions regarding the location or identity of shapes using information in the environment (0-back) or from a prior trial (1-back). Using task based imaging we established that, regardless of the nature of the decision, medial and lateral visual cortex were recruited when decisions rely on immediate input, while transmodal regions were recruited when judgments depend on information from the prior trial. Using principal components analysis, we demonstrated that shifting decision-making from perception to memory altered the focus of neural activity from unimodal to transmodal regions (and vice versa). Notably, the more pronounced these shifts in neural activity from unimodal to transmodal regions when decisions relied on memory, the more efficiently individuals performed this task. These data illustrate how the macroscale organization of neural function into a hierarchy allows cognition to rely on input, or information from memory, in a flexible and efficient manner.


Factors influencing the effectiveness of malaria control in Bioko Island, equatorial Guinea.
The Bioko Island Malaria Control Project (BIMCP) has carried out intensive interventions since early 2004 to reduce malaria transmission through indoor residual spraying (IRS) and case management. Annual parasite prevalence surveys have been carried out to monitor the effectiveness of the program. Significant overall reductions in prevalence of infection have been observed, with 42% fewer infections occurring in 2006 compared with baseline. Nevertheless, there is evidence of considerable heterogeneity in impact of the intervention. Prevalence of infection was significantly associated with spray status of the child's house, spray coverage with effective insecticide of the neighborhood of the house, bed net use, and time elapsed since last spray. Careful scheduling of spray coverage is therefore essential to maximize the effectiveness of IRS and to ensure consistent reductions in parasite prevalence. This can only be achieved if comprehensive monitoring systems are in place for both the management and evaluation of the intervention.


Biomolecular pleiomorphism probed by spatial interpolation of coarse models.
In low resolution structures of biological assemblies one can often observe conformational deviations that require a flexible rearrangement of structural domains fitted at the atomic level. We are evaluating interpolation methods for the flexible alignment of atomic models based on coarse models. Spatial interpolation is well established in image-processing and visualization to describe the overall deformation or warping of an object or an image. Combined with a coarse representation of the biological system by feature vectors, such methods can provide a flexible approximation of the molecular structure. We have compared three well-known interpolation techniques and evaluated the results by comparing them with constrained molecular dynamics. One method, inverse distance weighting interpolation, consistently produced models that were nearly indistinguishable on the alpha carbon level from the molecular dynamics results. The method is simple to apply and enables flexing of structures by non-expert modelers. This is useful for the basic interpretation of volumetric data in biological applications such as electron microscopy. The method can be used as a general interpretation tool for sparsely sampled motions derived from coarse models.


Cognitive impairment in patients with multiple system atrophy and progressive supranuclear palsy.
This article reports the severity and profile of neuropsychological impairment on a prevalent cohort of patients with a clinical diagnosis of either multiple system atrophy (n=372) or progressive supranuclear palsy (n=311) from the Neuroprotection and Natural History in Parkinson Plus Syndromes cohort. The Dementia Rating Scale and Frontal Assessment Battery were used to assess global cognition and executive dysfunction. For the Dementia Rating Scale impairment was observed in approximately 57% of the progressive supranuclear palsy group and 20% of the multiple system atrophy group. In the former, impairment in a single cognitive domain was observed in 40%, with the same number showing impairment in multiple domains, while in the latter the figures were 28.6 and 13.5%, respectively. On the Frontal Assessment Battery, impairment was observed in 62.0% of patients with progressive supranuclear palsy and 31.8% of those with multiple system atrophy. Although the progressive supranuclear palsy group performed worse overall, the cognitive profiles of the two groups on the Dementia Rating Scale subscales were identical, with the main impairment of the Initiation and Perseveration subscale. The impaired patients in the two groups were largely indistinguishable, qualitatively and quantitatively. Impairment was associated with greater age and clinical disability in both groups and was evident even in the early stages (22% in multiple system atrophy and 50% in progressive supranuclear palsy). Where a pathological diagnosis was available, the original clinical diagnosis was confirmed in the majority of cases, including those with significant cognitive impairment. The rate of impairment in those with a confirmed pathological diagnosis was comparable to that of the sample as a whole. These results demonstrate, in the largest prospectively recruited cohort of patients with progressive supranuclear palsy and multiple system atrophy studied to date, the existence of a cognitive profile similar to that previously reported in idiopathic Parkinson's disease. The results indicate a high level of cognitive impairment associated with progressive supranuclear palsy, but also point to comparable dysfunction in a substantial proportion of the patients with multiple system atrophy. Significant cognitive impairment appears consistent with a diagnosis of multiple system atrophy, even early in the disease, with important implications for diagnosis, research and management.


Omega-3 fatty acids and cardiovascular disease: new developments and applications.
The omega-3 fatty acids (FA) found in fish oils, eicosapentaenoic and docosahexaenoic acids (EPA and DHA, respectively), have been extensively studied therapeutically in a wide variety of disease conditions, but in none more than cardiovascular disease (CVD). Our review summarizes mechanisms of action, recent meta-analyses of CVD outcome trials, sources (fish and supplements), and recommendations for use of omega-3 FA in clinical practice. With the ability to now measure the omega-3 FA biostatus through blood tests, patients can achieve cardioprotective levels by either taking fish oil supplements or simply eating more oily fish. Two omega-3 FA formulations (both in the ethyl ester form) have been approved by the US Food and Drug Administration (FDA) for the treatment of patients with very high triglyceride levels (> 500 mg/dL); one contains both EPA and DHA, whereas the other contains only EPA. The agents have been extensively tested in 2 patient populations, those with very high triglycerides and those with triglycerides between 200 and 500 mg/dL while on background statin therapy. In general, treatment with EPA+DHA appears to lower patient triglycerides more effectively, but in those patients with very high triglyceride levels, use of EPA+DHA also raised low-density lipoprotein cholesterol levels, whereas EPA alone did not. Both formulations, at doses that do not lower triglycerides, have been shown to reduce CVD events in some, but not all, studies. Given the favorable risk-to-benefit ratio for these essentially nutritional agents, use is expected to continue to expand.


Investigating drug induced changes in single, living lymphocytes based on Raman micro-spectroscopy.
Raman spectroscopy is a powerful tool for label-free, single cell characterization. In many reported studies, a Raman spectrum is acquired from a fraction of the cell volume and used as a representative signature of the whole cell to identify and discriminate between cell populations. It has remained an open question whether this is the most suitable approach since the spectra may not truly represent the cell as a whole and critical biochemical information could therefore be lost. To address this question, we developed a line-scan Raman microscope to acquire Raman images of single lymphocytes exposed to the chemotherapeutic drug doxorubicin for 24 to 96 hours. Principal component analysis was able to separate cells based on their drug-exposure times. Difference spectra on the mean data for the different time-points revealed that changes are related to a decrease in mean nucleic acid content and an increase in mean protein and lipid content. Vertex component analysis was used to extract the pure component spectra of lipids, nucleic acids, and proteins. Quantitative analysis of the data revealed that biochemical changes occurred at both local subcellular (i.e. molecular density) and global cellular (i.e. total observable molecular content) levels. However, significant differences between the trends in the local and global changes were observed. While local nucleic acid content decreased with increasing drug exposure time, the total cellular nucleic acid content remained relatively constant. For protein, local content remained relatively constant for all exposure times while the total protein content in the cell increased ∼3 fold. Lipid content in the entire cell increased ∼5 fold, compared to a smaller increase in lipid at the local level. These results show that valuable information about the biochemical changes throughout the entire cell can be missed if only Raman spectra of localized cell regions are used. These findings are expected to have a major impact on the future development of Raman spectroscopy for cytometry applications.


No evidence for the induction of brown algal chemical defense by the phytohormones jasmonic acid and methyl jasmonate.
Induced chemical defense reactions are widespread in marine brown algae. Despite the evidence that the biosynthesis of defense metabolites can be up-regulated upon herbivory, we do not know how this regulation of biosynthetic pathways to secondary metabolites is achieved in brown algae. In higher plants, the phytohormone jasmonic acid (JA) is crucial for the mediation of induced chemical defenses, and several findings of this metabolite from marine sources have been reported. We tested the hypothesis that JA or related metabolites play a role in induced brown algal defense. Quantification of oxylipins with a detection limit around 20 ng g(-1) algal tissue did not reveal the presence of JA in the seven examined brown algal species Dictyota dichotoma, Colpomenia peregrina, Ectocarpus fasciculatus, Fucus vesiculosus, Himanthalia elongata, Saccharina latissima (formerly Laminaria saccharina), and Sargassum muticum. Moreover, treatment with ecologically relevant concentrations of JA and methyl jasmonate did not lead to a significant change in the profile of medium- and non-polar metabolites of the tested algae. Only when high concentrations of > or =500 microg ml(-1) medium of the phytohormones were applied that a metabolic response which could be attributed to unspecific stress was observed. Bioassays with D. dichotoma that focused on medium- and non-polar compounds confirmed the lack of a biological role of JA and methyl jasmonate in the induction of algal induced chemical defenses. The phytohormone-treated samples did not exhibit any increased defense potential towards the amphipod Ampithoe longimana and the isopod Paracerceis caudata. JA and related phytohormones, known to be active in higher plants, thus appear to play no role in brown algae for induction of the defense chemicals studied here.


Composting for Biocontained Cattle Mortality Disposal and Associated Greenhouse Gas and Leachate Emissions.
Composting can be an effective means of biodegrading livestock mortalities in emergency disposal situations, such as disease outbreaks. Within the past decade, our knowledge detailing composting has increased substantially. However, research data linking the environmental impact of composting to atmospheric and terrestrial systems are limited. We investigated composting efficacy, greenhouse gas emissions, and leachate properties from two static compost piles, each containing 16 cattle mortalities, built with either beef manure (BM) or wood shavings (WS) as envelope material. Wood shavings achieved a greater maximum temperature than BM (60 vs. 50°C) and maintained higher temperatures over 200 d ( < 0.001). Greenhouse gas emissions were evaluated using a static chamber and gas chromatography. Emissions of NO ( < 0.001), CH ( < 0.01), and CO ( < 0.05) were lower from WS than BM, resulting in 3-fold lower total CO equivalent emissions. After 250 d of composting, piles were relocated, and soil cores were taken (i) from beneath the piles, (ii) adjacent to the piles where leachate had accumulated, and (iii) in a control zone without compost exposure. Elevated concentrations of ammonium ( < 0.05) and chloride ( < 0.05) were found in soil beneath both BM and WS. Microbial DNA profiles suggested that leachate from BM compost increased bacterial diversity in soil, maintaining a biological soil impact after pile removal. Degradation of bovine mitochondrial DNA fragments was monitored by polymerase chain reaction. Limited migration of genetic bovine material from compost into soil was observed. Based on the mortalities decomposition and leachate contents, both BM and WS are suitable envelope materials for composting.


Reliability and criterion-related validity of a new repeated agility test.
The study aimed to assess the reliability and the criterion-related validity of a new repeated sprint T-test (RSTT) that includes intense multidirectional intermittent efforts. The RSTT consisted of 7 maximal repeated executions of the agility T-test with 25 s of passive recovery rest in between. Forty-five team sports players performed two RSTTs separated by 3 days to assess the reliability of best time (BT) and total time (TT) of the RSTT. The intra-class correlation coefficient analysis revealed a high relative reliability between test and retest for BT and TT (>0.90). The standard error of measurement (<0.50) showed that the RSTT has a good absolute reliability. The minimal detectable change values for BT and TT related to the RSTT were 0.09 s and 0.58 s, respectively. To check the criterion-related validity of the RSTT, players performed a repeated linear sprint (RLS) and a repeated sprint with changes of direction (RSCD). Significant correlations between the BT and TT of the RLS, RSCD and RSTT were observed (p<0.001). The RSTT is, therefore, a reliable and valid measure of the intermittent repeated sprint agility performance. As this ability is required in all team sports, it is suggested that team sports coaches, fitness coaches and sports scientists consider this test in their training follow-up.


Strategic adjustment of parental care in tree swallows: life-history trade-offs and the role of glucocorticoids.
Life-history theory predicts that optimal strategies of parental investment will depend on ecological and social factors, such as current brood value and offspring need. Parental care strategies are also likely to be mediated in part by the hypothalamic-pituitary-adrenal axis and glucocorticoid hormones. Here, we present an experiment in tree swallows (Tachycineta bicolor), a biparental songbird with wide geographical distribution, asking whether parental care is strategically adjusted in response to signals of offspring need and brood value and if so, whether glucocorticoids are involved in these adjustments. Using an automated playback system, we carried out playbacks of nestling begging calls specifically to females in two populations differing in their brood value: a northern population in Ontario, Canada (relatively higher brood value) and a southern population in North Carolina, USA (relatively lower brood value). We quantified female offspring provisioning rates before and during playbacks and plasma corticosterone levels (cort) once during late incubation and once immediately after playbacks. Females in both populations increased feeding rates temporarily during the first 2 h of playback but the increase was not sustained for the entire duration of playback (6 h). Cort levels from samples at the end of the playback did not differ between control females and females that received playbacks. However, females that had higher increases in cort between the incubation and nestling period had greater fledging success. These results suggest that females are able to strategically respond to offspring need, although the role of glucocorticoids in this strategic adjustment remains unclear.


Biological monitoring for depleted uranium exposure in U.S. Veterans.
As part of an ongoing medical surveillance program for U.S. veterans exposed to depleted uranium (DU), biological monitoring of urine uranium (U) concentrations is offered to any veteran of the Gulf War and those serving in more recent conflicts (post-Gulf War veterans). Since a previous report of surveillance findings in 2004, an improved methodology for determination of the isotopic ratio of U in urine ((235)U:(238)U) has been developed and allows for more definitive evaluation of DU exposure. This report updates previous findings. Veterans provide a 24-hr urine specimen and complete a DU exposure questionnaire. Specimens are sent to the Baltimore Veterans Affairs Medical Center for processing. Uranium concentration and isotopic ratio are measured using ICP-MS at the Armed Forces Institute of Pathology. Between January 2003 and June 2008, we received 1,769 urine specimens for U analysis. The mean urine U measure was 0.009 microg U/g creatinine. Mean urine U concentrations for Gulf War and post-Gulf War veterans were 0.008 and 0.009 microg U/g creatinine, respectively. Only 3 of the 1,700 (0.01%) specimens for which we completed isotopic determination showed evidence of DU. Exposure histories confirmed that these three individuals had been involved in "friendly fire" incidents involving DU munitions or armored vehicles. No urine U measure with a "depleted" isotopic signature has been detected in U.S. veterans without a history of retained DU embedded fragments from previous injury. These findings suggest that future DU-related health harm is unlikely in veterans without DU fragments.


Bluetongue virus entry into cells.
Bluetongue virus (BTV) is a member of the Orbivirus genus within the Reoviridae family. Like those of other members of the family, BTV particles are nonenveloped and contain two distinct capsids, namely, an outer capsid and an inner capsid or core. The two outer capsid proteins, VP2 and VP5, are involved in BTV entry into cells and in the delivery of the transcriptionally active core to the target cell cytoplasm. However, very little is known about the precise mechanism of BTV entry. In this report, using RNA interference, we demonstrate that inhibition of the clathrin-dependent endocytic pathway correlates with reduced BTV internalization and subsequent replication. Furthermore, by using the ATPase inhibitor bafilomycin A1, we show that exposure of the virus to acidic pH is required for productive infection. Moreover, microscopic analysis of cells incubated with BTV indicated that the virus is internalized into early endosomes, where separation of the outer capsid and inner core occurs. Together, our data indicate that BTV undergoes low-pH-induced penetration in early endosomes following clathrin-mediated endocytosis from the plasma membrane, supporting a stepwise model for BTV entry and penetration.


Embryo cryopreservation and preeclampsia risk.
To determine whether assisted reproductive technology (ART) cycles involving cryopreserved-warmed embryos are associated with the development of preeclampsia. Retrospective cohort study. IVF clinics and hospitals. A total of 15,937 births from ART: 9,417 singleton and 6,520 twin. We used linked ART surveillance, birth certificate, and maternal hospitalization discharge data, considering resident singleton and twin births from autologous or donor eggs from 2005-2010. We compared the frequency of preeclampsia diagnosis for cryopreserved-warmed versus fresh ET and used multivariable logistic regression to adjust for confounders. Among pregnancies conceived with autologous eggs resulting in singletons, preeclampsia was greater after cryopreserved-warmed versus fresh ET (7.51% vs. 4.29%, adjusted odds ratio = 2.17 [95% CI 1.67-2.82]). Preeclampsia without and with severe features, preeclampsia with preterm delivery, and chronic hypertension with superimposed preeclampsia were more frequent after cryopreserved-warmed versus fresh ET (3.99% vs. 2.55%; 2.95% vs. 1.41%; 2.76 vs. 1.48%; and 0.95% vs. 0.43%, respectively). Among pregnancies from autologous eggs resulting in twins, the frequency of preeclampsia with severe features (9.26% vs. 5.70%) and preeclampsia with preterm delivery (14.81% vs. 11.74%) was higher after cryopreserved versus fresh transfers. Among donor egg pregnancies, rates of preeclampsia did not differ significantly between cryopreserved-warmed and fresh ET (10.78% vs. 12.13% for singletons and 28.0% vs. 25.15% for twins). Among ART pregnancies conceived using autologous eggs resulting in live births, those involving transfer of cryopreserved-warmed embryos, as compared with fresh ETs, had increased risk for preeclampsia with severe features and preeclampsia with preterm delivery.


Distinct roles of non-canonical poly(A) polymerases in RNA metabolism.
Trf4p and Trf5p are non-canonical poly(A) polymerases and are part of the heteromeric protein complexes TRAMP4 and TRAMP5 that promote the degradation of aberrant and short-lived RNA substrates by interacting with the nuclear exosome. To assess the level of functional redundancy between the paralogous Trf4 and Trf5 proteins and to investigate the role of the Trf4-dependent polyadenylation in vivo, we used DNA microarrays to compare gene expression of the wild-type yeast strain of S. cerevisiae with either that of trf4Delta or trf5Delta mutant strains or the trf4Delta mutant expressing the polyadenylation-defective Trf4(DADA) protein. We found little overlap between the sets of transcripts with altered expression in the trf4Delta or the trf5Delta mutants, suggesting that Trf4p and Trf5p target distinct groups of RNAs for degradation. Surprisingly, most RNAs the expression of which was altered by the trf4 deletion were restored to wild-type levels by overexpression of TRF4(DADA), showing that the polyadenylation activity of Trf4p is dispensable in vivo. Apart from previously reported Trf4p and Trf5p target RNAs, this analysis along with in vivo cross-linking and RNA immunopurification-chip experiments revealed that both the TRAMP4 and the TRAMP5 complexes stimulate the degradation of spliced-out introns via a mechanism that is independent of the polyadenylation activity of Trf4p. In addition, we show that disruption of trf4 causes severe shortening of telomeres suggesting that TRF4 functions in the maintenance of telomere length. Finally, our study demonstrates that TRF4, the exosome, and TRF5 participate in antisense RNA-mediated regulation of genes involved in phosphate metabolism. In conclusion, our results suggest that paralogous TRAMP complexes have distinct RNA selectivities with functional implications in RNA surveillance as well as other RNA-related processes. This indicates widespread and integrative functions of TRAMP complexes for the coordination of different gene expression regulatory processes.


Peroral endoscopic myotomy: procedural complications and pain management for the perioperative clinician.
Achalasia refers to the lack of smooth muscle relaxation of the distal esophagus. Although nonsurgical treatments such as pneumatic dilatation of the distal esophagus and botulinum toxin injections have been performed, these procedures have limited duration. Similarly, surgical treatment with Heller myotomy is associated with complications. At our institution, we perform the peroral endoscopic myotomy (POEM) in qualified patients. Briefly, POEM involves endoscopic creation of a mid-esophageal submucosal bleb, creation of a submucosal tunnel with the endoscope, and then a distal myotomy, resulting in relaxation of the distal esophagus. The aim of our study is to document perioperative pain and associated pain management for our initial patients undergoing POEM and to review the literature for perioperative complications of this procedure. Therefore, anesthetic and pain management for our initial eleven patients undergoing POEM were reviewed. Patient demographics, pre-POEM pain medication history, perioperative pain medication requirements, and post-POEM pain scores were examined. We found post-POEM pain was usually in the mild-moderate range; a combination of medications was effective (opioids, nonsteroidal anti-inflammatory drugs, acetaminophen). Our literature search revealed a wide frequency range of complications such as pneumoperitoneum and subcutaneous emphysema, with rare serious events such as capnopericardium leading to cardiac arrest. In conclusion, our experience with POEM suggests pain and can be managed adequately with a combination of medications; the procedure appears to be safe and reasonable to perform in an outpatient endoscopy unit.


The calf model of immunity for development of a vaccine against tuberculosis.
Tuberculosis (TB) remains a major threat to public health. The identification of safe TB vaccine candidates beyond Mycobacterium bovis BCG, is an exciting prospect for control of human TB and necessary in the context of the human immunodeficiency virus (HIV) pandemic. Selection of vaccine candidates for human trials which are ultimately targeted for use in children less than 5 years of age or in newborns will require an animal model that closely approximates immune function and disease. We propose that the bovine neonate and adolescent is a robust animal model for preclinical safety and efficacy evaluation of TB candidate vaccines targeting this special human population. Parallel studies conducted in bovine neonates and non-human primates with a leading auxotrophic mutant with demonstrated efficacy/safety in a rodent TB model of TB demonstrated similar findings with respect to gross pathology scoring relative to BCG. The findings indicated more numerous and severe lesions in the lung in addition to higher levels of IFN-gamma producing cells. BCG vaccinates demonstrated higher levels of FoxP3 transcripts and lower levels of IL-4 mRNA.


Impact of tacrine and 7-methoxytacrine on gastric myoelectrical activity assessed using electrogastrography in experimental pigs.
Tacrine was the first acetylcholinesterase inhibitor approved for therapy of Alzheimer's disease. It has currently been withdrawn in some countries mostly due to the risk of hepatotoxicity and might be replaced by its derivate 7-methoxytacrine (7-MEOTA). The aim of this study was to assess the impact of these two compounds on gastric myoelectrical activity by means of surface cutaneous electrogastrography (EGG). Twelve pigs (Sus scrofa f. domestica, weighing 30-35 kg) entered the study. A single dose of tacrine (200 mg i.m., n=6) or 7-MEOTA (200 mg i.m., n=6) was administrated. All EGG recordings were performed under general anaesthesia in the morning after 24 hours of fasting. Basal (30 minutes) and study recordings (150 minutes) were accomplished using an EGG stand (MMS, Enschede, the Netherlands). Results were expressed as dominant frequency of gastric slow waves, power analysis (areas of amplitudes) and power ratio assessment (ratio of the areas of amplitudes after and before study drug administration). Tacrine decreased EGG dominant frequency 10 minutes after its administration (from basal 3.1±0.6 to 2.8±0.6 cycles per minute; p=0.014). Tacrine induced a non-significant 60-minute increase of the power (with maximal value 493±533 μV2 at 20 minutes) and power ratio (with maximal value 2.04±3.4 at 10 minutes). Tacrine caused substantial gastric arrhythmia. 7-MEOTA did not influence dominant frequency of gastric slow waves significantly. 7-MEOTA caused a short-term late increase of the power ratio at 60 minutes (6.3±11.2; p=0.003). Blood cholinesterase activity did not correlate with any EGG parameter either after tacrine or 7-MEOTA at any time. Tacrine and 7-MEOTA have different impacts on EGG. Tacrine decreased dominant frequency and induced long-lasting gastric arrhythmia. 7-MEOTA caused a short-term late increase of the EGG power in experimental pigs.


Longitudinal effects of swimming on bone in adolescents: a pQCT and DXA study.
The aims of the present study were, firstly, to evaluate areal bone mineral density (aBMD), bone strength and structure during a swimming season and compare them to those of normo-active controls (CG), and secondly to ascertain whether practising an additional weight-bearing sport other than swimming might improve bone. Twenty-three swimmers who only swam (SWI-PURE; 14 males, 9 females), 11 swimmers who combined swimming with an additional weight-bearing sport (SWI-SPORT; 8 males, 3 females) and 28 controls (CG; 16 males, 12 females) participated in the present study. aBMD was assessed with dual energy X-ray (DXA). Bone mass, area, structure and strength of the non-dominant tibia and radius were measured with peripheral quantitative computed tomography (pQCT). Measurements were performed at the beginning of the swimming season and 8 months later. The only difference among groups for DXA and pQCT variables was found for arm aBMD, which was higher in the SWI-SPORT than in the CG group at both pre- and post-evaluation. Group by time interactions (GxT) were found for trochanter aBMD when comparing SWI-SPORT to CG and SWI-SPORT to SWI-PURE, favouring in both cases SWI-SPORT. No GxT were found for the radius. For the tibia, GxT were found between SWI-SPORT and CG and between SWI-PURE and CG, in both cases favouring the swimmers. A season of swimming does not confer any additional benefits to aBMD, but may confer minor benefits to structure and mass. Complementing swimming with a weight-bearing activity is beneficial to bone.


Relationship between Activities of Daily Living and Readmission within 90 Days in Hospitalized Elderly Patients with Heart Failure.
To examine the relationship between activities of daily living (ADL) and readmission within 90 days and assess the cutoff value of ADL to predict readmission in hospitalized elderly patients with heart failure (HF). This cohort study comprised 589 consecutive patients with HF aged ≥65 years, who underwent cardiac rehabilitation from May 2012 to May 2016 and were discharged home. We investigated patients' characteristics, basic attributes, and ADL (motor and cognitive Functional Independence Measure [FIM]). We analyzed the data using the unpaired t-test, χ2 test, Cox proportional hazard model, receiver operating characteristic (ROC) curve, and Kaplan-Meier method. Of 589 patients, 113 met the criteria, and they were divided into the nonreadmission (n = 90) and readmission groups (n = 23). Age, body mass index, New York Heart Association class, hemoglobin level, and motor FIM score were significantly different between the two groups (p < 0.05). The body mass index (hazard ratio [HR]: 0.87; p < 0.05) and motor FIM score (HR: 0.94; p < 0.01) remained statistically significant. The cutoff value for the motor FIM score determined by ROC curve analysis was 74.5 points (area under the curve = 0.78; p < 0.001). The motor FIM score in elderly patients with HF was an independent predictor of rehospitalization within 90 days.


Disease course of inflammatory bowel disease unclassified in a European population-based inception cohort: An Epi-IBD study.
A definitive diagnosis of Crohn's disease (CD) or ulcerative colitis (UC) is not always possible, and a proportion of patients will be diagnosed as inflammatory bowel disease unclassified (IBDU). The aim of the study was to investigate the prognosis of patients initially diagnosed with IBDU and the disease course during the following 5 years. The Epi-IBD study is a prospective population-based cohort of 1289 IBD patients diagnosed in centers across Europe. Clinical data were captured prospectively throughout the follow-up period. Overall, 476 (37%) patients were initially diagnosed with CD, 701 (54%) with UC, and 112 (9%) with IBDU. During follow-up, 28 (25%) IBDU patients were changed diagnoses to either UC (n = 20, 71%) or CD (n = 8, 29%) after a median of 6 months (interquartile range: 4-12), while 84 (7% of the total cohort) remained IBDU. A total of 17 (15%) IBDU patients were hospitalized for their IBD during follow-up, while 8 (7%) patients underwent surgery. Most surgeries (n = 6, 75%) were performed on patients whose diagnosis was later changed to UC; three of these colectomies led to a definitive diagnosis of UC. Most patients (n = 107, 96%) received 5-aminosalicylic acid, while 11 (10%) patients received biologicals, of whom five remained classified as IBDU. In a population-based inception cohort, 7% of IBD patients were not given a definitive diagnosis of IBD after 5 years of follow-up. One in four patients with IBDU eventually was classified as CD or UC. Overall, the disease course and medication burden in IBDU patients were mild.


Relationship of spinal curvature, mobility, and low back pain in women with and without urinary incontinence
Background/aim: This study aimed to investigate the relationship of sagittal spinal curvature, mobility, and low back pain (LBP) in women with and without urinary incontinence (UI). Materials and methods: Thirty-two women with UI (incontinence group) and 41 women without UI (control group) were included in this study. The sagittal spinal curvature and mobility were assessed with a Spinal Mouse device (IDIAG, Fehraltorf, Switzerland). Urogenital symptom distress, LBP, and disability caused by LBP were assessed using the Urogenital Distress Inventory-6 (UDI-6), a visual analog scale (VAS), and the Oswestry Disability Index (ODI), respectively. Results: It was seen that the sagittal thoracic curvature, lumbar curvature, and pelvic tilt were increased in the incontinence group in comparison to the control group (P < 0.05). An increase in sagittal lumbar mobility and pelvic mobility was found in the incontinence group (P < 0.05). It was observed that 71.9% of the women with UI and 12.2% of the women without UI had LBP. There were positive correlations of the UDI-6 with the VAS (r = 0.363, P = 0.041) and the ODI (r = 0.511, P = 0.003). Conclusion: The sagittal spinal alignment and lumbopelvic hypermobility should be taken into consideration in the existence of UI.


Loss of Bmal1 leads to uncoupling and impaired glucose-stimulated insulin secretion in β-cells.
The circadian clock has been shown to regulate metabolic homeostasis. Mice with a deletion of Bmal1, a key component of the core molecular clock, develop hyperglycemia and hypoinsulinemia, suggesting β-cell dysfunction. However, the underlying mechanisms are not fully known. In this study, we investigated the mechanisms underlying the regulation of β-cell function by Bmal1. We studied β-cell function in global Bmal1-/- mice, in vivo and in isolated islets ex vivo, as well as in rat insulinoma cell lines with shRNA-mediated Bmal1 knockdown. Global Bmal1-/- mice develop diabetes secondary to a significant impairment in glucose-stimulated insulin secretion (GSIS). There is a blunting of GSIS in both isolated Bmal1-/- islets and in Bmal1 knockdown cells, as compared to controls, suggesting that this is secondary to a loss of cell-autonomous effect of Bmal1. In contrast to previous studies, in these Bmal1-/- mice on a C57Bl/6 background, the loss of stimulated insulin secretion, interestingly, is with glucose but not to other depolarizing secretagogues, suggesting that events downstream of membrane depolarization are largely normal in Bmal1-/- islets. This defect in GSIS occurs as a result increased mitochondrial uncoupling with consequent impairment of glucose-induced mitochondrial potential generation and ATP synthesis, due to an upregulation of Ucp2. Inhibition of Ucp2, in isolated islets, leads to a rescue of the glucose-induced ATP production and insulin secretion in Bmal1-/- islets. Thus, Bmal1 regulates mitochondrial energy metabolism to maintain normal GSIS and its disruption leads to diabetes due to a loss of GSIS.


Three-Dimensional Chiral Lattice Fermion in Floquet Systems.
We show that the Nielsen-Ninomiya no-go theorem still holds on a Floquet lattice: there is an equal number of right-handed and left-handed Weyl points in a three-dimensional Floquet lattice. However, in the adiabatic limit, where the time evolution of the low-energy subspace is decoupled from the high-energy subspace, we show that the bulk dynamics in the low-energy subspace can be described by Floquet bands with extra left- or right-handed Weyl points, despite the no-go theorem. Assuming adiabatic evolution of two bands, we show that the difference of the number of right-handed and left-handed Weyl points equals twice the winding number of the adiabatic Floquet operator over the Brillouin zone. Based on these findings, we propose a realization of purely left- or right-handed Weyl particles on a 3D lattice using a Hamiltonian obtained through dimensional reduction of a four-dimensional quantum Hall system. We argue that the breakdown of the adiabatic approximation on the surface facilitates unusual closed orbits of wave packets in an applied magnetic field, which traverse alternatively through the low-energy and high-energy sector of the spectrum.


Chriz, a chromodomain protein specific for the interbands of Drosophila melanogaster polytene chromosomes.
Polytene interphase chromosomes are compacted into a series of bands and interbands reflecting their organization into independent chromosomal domains. In order to understand chromosomal organization, we set out to study the role of proteins that are selective for interbands. Here we describe the Drosophila melanogaster chromodomain protein Chriz that is coimmunoprecipitated with the zinc finger protein Z4. Both proteins colocalize exclusively to the interbands on Drosophila polytene chromosomes. Like Z4, Chriz is ubiquitously expressed throughout development and is associated with chromatin in all interphase nuclei. Following dissociation from chromatin, early in mitosis Chriz binds to the centrosomes and to the mitotic spindle. Newly induced amorphic Chriz alleles are early lethal, and ubiquitous overexpression of Chriz is lethal as well. Available Chriz hypomorphs which survive until pupal stage have a normal chromosomal phenotype. Reducing Z4 protein does not affect Chriz binding to polytene chromosomes and vice versa. Z4 is still chromosomally bound when Chriz protein is depleted by RNA interference.


The total carbon column observing network.
A global network of ground-based Fourier transform spectrometers has been founded to remotely measure column abundances of CO(2), CO, CH(4), N(2)O and other molecules that absorb in the near-infrared. These measurements are directly comparable with the near-infrared total column measurements from space-based instruments. With stringent requirements on the instrumentation, acquisition procedures, data processing and calibration, the Total Carbon Column Observing Network (TCCON) achieves an accuracy and precision in total column measurements that is unprecedented for remote-sensing observations (better than 0.25% for CO(2)). This has enabled carbon-cycle science investigations using the TCCON dataset, and allows the TCCON to provide a link between satellite measurements and the extensive ground-based in situ network.


Influence of wood species on toxicity of log-wood stove combustion aerosols: a parallel animal and air-liquid interface cell exposure study on spruce and pine smoke.
Wood combustion emissions have been studied previously either by in vitro or in vivo models using collected particles, yet most studies have neglected gaseous compounds. Furthermore, a more accurate and holistic view of the toxicity of aerosols can be gained with parallel in vitro and in vivo studies using direct exposure methods. Moreover, modern exposure techniques such as air-liquid interface (ALI) exposures enable better assessment of the toxicity of the applied aerosols than, for example, the previous state-of-the-art submerged cell exposure techniques. We used three different ALI exposure systems in parallel to study the toxicological effects of spruce and pine combustion emissions in human alveolar epithelial (A549) and murine macrophage (RAW264.7) cell lines. A whole-body mouse inhalation system was also used to expose C57BL/6 J mice to aerosol emissions. Moreover, gaseous and particulate fractions were studied separately in one of the cell exposure systems. After exposure, the cells and animals were measured for various parameters of cytotoxicity, inflammation, genotoxicity, transcriptome and proteome. We found that diluted (1:15) exposure pine combustion emissions (PM1 mass 7.7 ± 6.5 mg m- 3, 41 mg MJ- 1) contained, on average, more PM and polycyclic aromatic hydrocarbons (PAHs) than spruce (PM1 mass 4.3 ± 5.1 mg m- 3, 26 mg MJ- 1) emissions, which instead showed a higher concentration of inorganic metals in the emission aerosol. Both A549 cells and mice exposed to these emissions showed low levels of inflammation but significantly increased genotoxicity. Gaseous emission compounds produced similar genotoxicity and a higher inflammatory response than the corresponding complete combustion emission in A549 cells. Systems biology approaches supported the findings, but we detected differing responses between in vivo and in vitro experiments. Comprehensive in vitro and in vivo exposure studies with emission characterization and systems biology approaches revealed further information on the effects of combustion aerosol toxicity than could be achieved with either method alone. Interestingly, in vitro and in vivo exposures showed the opposite order of the highest DNA damage. In vitro measurements also indicated that the gaseous fraction of emission aerosols may be more important in causing adverse toxicological effects. Combustion aerosols of different wood species result in mild but aerosol specific in vitro and in vivo effects.


Immunoaffinity purification of bovine factor VII.
Factor VII has been purified to homogeneity from bovine plasma by a procedure that includes affinity purification on an immunoadsorbent column. Recovery was determined by both coagulant assay and liquid scintillation counting, using 3H-factor VII as an internal standard. The purification factor calculated by both methods was approximately 120,000-fold, with a final yield of approximately 18%. Homogeneity was assessed by sodium dodecyl sulfate (SDS) polyacrylamide gel electrophoresis. The material migrated as a single polypeptide chain of 53,000 daltons, and following activation by factor Xa, the one-chain zymogen was quantitatively converted to two-chain factor VIIa. Conversion of affinity-purified factor VII to factor VIIa resulted in up to a 119-fold activation of the coagulant activity, which is 2.7-4 times greater than the activatability reported for factor VII prepared by other methods. Zur et al. calculated that pure factor VII, uncontaminated by traces of factor VIIa, would be activated 123-fold upon conversion to factor VIIa. The close agreement between observed activatability of affinity-purified factor VII and the theoretical prediction suggests that we have isolated factor VII essentially free of factor VIIa. The purification data from three lots of bovine plasma yield an estimate for the plasma concentration of factor VII from 10.1 nM to 18.5 nM.


The effect of internal DC shocks on the atrial fibrillation frequency.
The objective of this study, was to investigate the effect of internal DC shocks on the atrial fibrillation frequency (AFF). AFF has previously been shown to predict the success and energy requirements in patients undergoing internal cardioversion (IC) of atrial fibrillation (AF). However the possibility that unsuccessful shocks during IC may influence the AFF has not been before studied. Thirty eight patients with AF, suggested for DC cardioversion at the Royal Victoria Hospital in Belfast, were included in our study. Two catheters were positioned in the right atrial appendage (RAA) and the coronary sinus (CS), to deliver a biphasic shock waveform, synchronized with the R wave of the electrocardiogram (ECG) signal. A voltage step-up protocol (50-300 V) was used for patient cardioversion. The ECG was analyzed for a mean of 52,8+/-10.1 seconds (corresponding to segments before and after nonsuccessful shocks). Atrial fibrillatory activity was extracted by means of bandpass filtering and ventricular activity (QRST) cancellation. QRST complexes were cancelled using a recursive least squared (RLS) adaptive filter. FFT was applied to the residual atrial fibrillatory signal. AFF was estimated from the dominant frequency within the 3-12 Hz band of the power spectrum. R-R intervals during the segments were also analyzed. A total of 26 patients were successfully cardioverted, employing 167 shocks (141 nonsuccessful). AFF, computed with 10 s of signal, showed significant reduction (mean 0.3052 +/- 1.1055 Hz, P=0.028) comparing segments immediately before and after shocks, and AFF significantly increases (mean 0.2582 +/- 0.609 Hz, P=0.007) between segments immediately after shocks and those 35 s after. AFF showed distinct behavior according to the energy level of the shocks. In conclusion, intracardiac electric shocks could cause transitory changes in the AFF of patients with atrial fibrillation.


Comparison of hamstring strain injury rates between male and female intercollegiate soccer athletes.
Hamstring strains are common among soccer athletes, and they have a high incidence of recurrence. Among American collegiate soccer players, men have an overall higher incidence rate of hamstring strains than women. This research compares the hamstring strain injury rates in event and athlete characteristics between male and female college soccer athletes. Descriptive epidemiology study. Data describing partial and complete hamstring strains were obtained from the National Collegiate Athletic Association (NCAA) Injury Surveillance System (ISS) for men's and women's soccer from 2004 to 2009. Incidence rate ratios (IRRs) comparing the incidence of hamstring strains between the sexes as well as during games versus practices and the preseason versus the in-season were calculated. χ(2) tests were used to compare the occurrence of hamstring strains across different event and athlete characteristics. Men were 64% more likely than women to sustain a hamstring strain (IRR, 1.64; 95% CI, 1.37-1.96). Men had significantly higher rates of hamstring strains than women during both games (IRR, 2.42; 95% CI, 1.82-3.23) and practices (IRR, 1.34; 95% CI, 1.06-1.68). There were no differences between men and women in injury rates during the preseason, but men were significantly more likely to sustain a hamstring strain during the in-season (IRR, 1.98; 95% CI, 1.56-2.52). Men had a significantly higher proportion of recurrent hamstring strains compared with women (men, 22%; women, 12%; P = .003). There were no significant differences in the distribution of strains in event or athlete characteristics between men and women for first-time or recurrent hamstring strains. In collegiate soccer, men have significantly higher rates of hamstring strains than women, and regardless of the recurrence status, the event and athlete characteristics were similar for both sexes. Identifying common characteristics may assist in the targeted development of preventive and rehabilitative programs as well as continued research on hamstring strains among collegiate soccer players.


Dietary protein and bone health: a systematic review and meta-analysis.
There has been a resurgence of interest in the controversial relation between dietary protein and bone health. This article reports on the first systematic review and meta-analysis of the relation between protein and bone health in healthy human adults. The MEDLINE (January 1966 to September 2007) and EMBASE (1974 to July 2008) databases were electronically searched for all relevant studies of healthy adults; studies of calcium excretion or calcium balance were excluded. In cross-sectional surveys, all pooled r values for the relation between protein intake and bone mineral density (BMD) or bone mineral content at the main clinically relevant sites were significant and positive; protein intake explained 1-2% of BMD. A meta-analysis of randomized placebo-controlled trials indicated a significant positive influence of all protein supplementation on lumbar spine BMD but showed no association with relative risk of hip fractures. No significant effects were identified for soy protein or milk basic protein on lumbar spine BMD. A small positive effect of protein supplementation on lumbar spine BMD in randomized placebo-controlled trials supports the positive association between protein intake and bone health found in cross-sectional surveys. However, these results were not supported by cohort study findings for hip fracture risk. Any effects found were small and had 95% CIs that were close to zero. Therefore, there is a small benefit of protein on bone health, but the benefit may not necessarily translate into reduced fracture risk in the long term.


Absence of tapasin alters immunodominance against a lymphocytic choriomeningitis virus polytope.
Tapasin edits the peptide repertoire presented to CD8(+) T cells by favoring loading of slow off-rate peptides on MHC I molecules. To investigate the role of tapasin on T cell immunodominance we used poxvirus viral vectors expressing a polytope of lymphocytic choriomeningitis virus epitopes with different off-rates. In tapasin-deficient mice, responses to subdominant fast off-rate peptides were clearly favored. This alteration of the CD8(+) T cell hierarchy was a consequence of tapasin editing and not a consequence of the alteration of the T cell repertoire in tapasin-deficient mice, because bone marrow chimeric mice (wild-type recipients reconstituted with tapasin knockout bone marrow) showed the same hierarchy as the tapasin knockout mice. Tapasin editing is therefore a contributing factor to the phenomenon of immunodominance. Although tapasin knockout cells have low MHC I surface expression, Ag presentation was efficient and resulted in strong T cell responses involving T cells with increased functional avidity. Therefore, in this model, tapasin-deficient mice do not have a reduced but rather have an altered immune response.


Quercetin effects on weight gain and caloric intake in exercised rats.
Quercetin is a flavonoid which activates oxidative metabolism. Quercetin may reduce weight gain by decreasing feed efficiency. The present study aims to evaluate weight gain, caloric intake and feed efficiency in exercised and sedentary rats supplemented with quercetin. Wistar rats were divided into four groups: quercetin-exercise training (QT), quercetin-sedentary (QS), placebo-exercise training (PT) and placebo-sedentary (PS). Rats were exercised and/or orally supplemented with quercetin (25 mg · kg(-1) on alternate days) during six weeks. Weight gain of the QT group decreased when compared with the PT and PS groups. Exercised groups increased cumulative caloric intake during the experimental period. The QT group rats also reduced their feed efficiency when compared with the QS and PS groups. These results suggest that quercetin is not able to decrease weight gain because no differences were found between placebo and quercetin condition either in the sedentary or in the training condition.


Effects of fasting on patients with chronic kidney disease during Ramadan and practical guidance for healthcare professionals.
There are an estimated 1.8 billion Muslims worldwide, with the majority of them choosing to fast during the month of Ramadan. Fasting, which requires abstinence from food and drink from dawn to sunset can be up to 20 h per day during the summer months in temperate regions. Fasting can be especially challenging in patients on haemodialysis and peritoneal dialysis. Moreover, there is concern that those with chronic kidney disease (CKD) can experience electrolyte imbalance and worsening of renal function. In this article, current literature is reviewed and a decision-making management tool has been developed to assist clinicians in discussing the risks of fasting in patients with CKD, with consideration also given to circumstances such as the coronavirus disease 2019 pandemic. Our review highlights that patients with CKD wishing to fast should undergo a thorough risk assessment ideally within a month before Ramadan, as they may require medication changes and a plan for regular monitoring of renal function and electrolytes in order to fast safely. Recommendations have been based on risk tiers (very high risk, high risk and low-moderate risk) established by the International Diabetes Federation and the Diabetes and Ramadan International Alliance. Patients in the very high risk and high risk categories should be encouraged to explore alternative options to fasting, while those in the low-moderate category may be able to fast safely with guidance from their clinician. Prior to the commencement of Ramadan, all patients must receive up-to-date education on sick-day rules and instructions on when to terminate their fast or abstain from fasting.


Vector integration is nonrandom and clustered and influences the fate of lymphopoiesis in SCID-X1 gene therapy.
Recent reports have challenged the notion that retroviruses and retroviral vectors integrate randomly into the host genome. These reports pointed to a strong bias toward integration in and near gene coding regions and, for gammaretroviral vectors, around transcription start sites. Here, we report the results obtained from a large-scale mapping of 572 retroviral integration sites (RISs) isolated from cells of 9 patients with X-linked SCID (SCID-X1) treated with a retrovirus-based gene therapy protocol. Our data showed that two-thirds of insertions occurred in or very near to genes, of which more than half were highly expressed in CD34(+) progenitor cells. Strikingly, one-fourth of all integrations were clustered as common integration sites (CISs). The highly significant incidence of CISs in circulating T cells and the nature of their locations indicate that insertion in many gene loci has an influence on cell engraftment, survival, and proliferation. Beyond the observed cases of insertional mutagenesis in 3 patients, these data help to elucidate the relationship between vector insertion and long-term in vivo selection of transduced cells in human patients with SCID-X1.


Assessing the effectiveness of a pharmacist-delivered smoking cessation program in the State of Qatar: study protocol for a randomized controlled trial.
It had been reported that up to 37% of the adult male population smokes cigarettes in Qatar. The Global Youth Tobacco Survey also stated that 13.4% of male school students aged 13 to 15 years in Qatar smoke cigarettes. Smoking cessation is key to reducing smoking-related diseases and deaths. Healthcare providers are in an ideal position to encourage smoking cessation. Pharmacists are the most accessible healthcare providers and are uniquely situated to initiate behavior change among patients. Many studies have shown that pharmacists can be successful in helping patients quit smoking. Studies demonstrating the effectiveness of pharmacist-delivered smoking cessation programs are lacking in Qatar. This proposal aims to test the effect of a structured smoking cessation program delivered by trained ambulatory pharmacists in Qatar. A prospective, randomized, controlled trial is conducted at eight ambulatory pharmacies in Qatar. Participants are randomly assigned to receive an at least four-session face-to-face structured patient-specific smoking cessation program conducted by the pharmacist or 5 to 10 min of unstructured brief smoking cessation advice (emulating current practice) given by the pharmacist. Both groups are offered nicotine replacement therapy if feasible. The primary outcome of smoking cessation will be confirmed by an exhaled carbon monoxide test at 12 months. Secondary outcomes constitute quality-of-life adjustment as well as cost analysis of program resources consumed, including per case and patient outcome. If proven to be effective, this smoking cessation program will be considered as a model that Qatar and the region can apply to decrease the smoking burden. Clinical Trials NCT02123329 .


Control of hematopoietic stem cell quiescence by the E3 ubiquitin ligase Fbw7.
Ubiquitination is a posttranslational mechanism that controls diverse cellular processes. We focus here on the ubiquitin ligase Fbw7, a recently identified hematopoietic tumor suppressor that can target for degradation several important oncogenes, including Notch1, c-Myc, and cyclin E. We have generated conditional Fbw7 knockout animals and inactivated the gene in hematopoietic stem cells (HSCs), progenitors, and their differentiated progeny. Deletion of Fbw7 specifically and rapidly affects hematopoiesis in a cell-autonomous manner. Fbw7(-/-) HSCs show defective maintenance of quiescence, leading to impaired self-renewal and a severe loss of competitive repopulating capacity. Furthermore, Fbw7(-/-) progenitors are unable to colonize the thymus, leading to a profound depletion of T cell progenitors. Deletion of Fbw7 in bone marrow (BM) stem cells and progenitors leads to the stabilization of c-Myc, a transcription factor previously implicated in HSC self-renewal. On the other hand, neither Notch1 nor cyclin E is visibly stabilized in the BM of Fbw7-deficient mice. Gene expression studies of Fbw7(-/-) HSCs and hematopoietic progenitors indicate that Fbw7 regulates, through the regulation of HSC cycle entry, the transcriptional "signature" that is associated with the quiescent, self-renewing HSC phenotype.


Delay of transverse rectus abdominis myocutaneous flap reconstruction improves flap reliability in the obese patient.
Since its introduction in 1982, the transverse rectus abdominis musculocutaneous (TRAM) flap has been a mainstay of breast reconstruction. However, in certain high-risk individuals, such as the obese, smokers, and irradiated patients, flap reliability is decreased, which leads to a higher rate of flap complications. The authors hypothesized that although the nonflap complication rate is increased in the obese patient, flap complications are not increased in those who undergo a delayed TRAM procedure. From 1995 to 2003, 107 consecutive patients who underwent a delayed TRAM procedure were examined in a retrospective study. The delayed TRAM procedures were all performed by the senior author (Georgiade) at a single institution. Patients were classified by their body mass index (weight in kilograms and height in square meters). No patient had complete loss of her flap regardless of body mass index. Patients with an index of 30 kg/m2 and under had a partial fat necrosis rate of 11.4 percent (10 of 88 patients), whereas two of 19 patients (10.5 percent) with an index of greater than 30 kg/m2 had partial fat necrosis of their flap (not significant). The average body mass index of the group with flap complications was 27.8 +/- 4.3 kg/m2, whereas that of the group with no flap complications was 26.5 +/- 4.3 kg/m2 (not significant). The rate of non-flap-related complications, such as deep venous thrombosis and pulmonary embolism, was 8 percent (seven of 88 patients) for those with a body mass index of less than 30 kg/m2 and 31.6 percent (six of 19 patients) for those with an index greater than 30 kg/m2 (p = 0.0112). The average body mass index of the group with nonflap complications was 29.9 +/- 4.9 kg/m2, compared with 26.3 +/- 4.0 kg/m2 for the group with no non-flap-related complications (p = 0.031). Of note, patients with a history of smoking and those who had received radiation therapy did not show a statistically significant increase in flap complications. Despite a progressively increasing overall complication rate for patients with a higher body mass index, there was not a similar trend for flap-related complications. The authors' data support the idea that the delayed TRAM procedure is a safe and reliable technique for obese and morbidly obese patients.