Theoretical model for an MRI radio frequency resonator.
A theoretical model is described for a magnetic resonance imaging (MRI) radio-frequency resonator (an MRI "coil") that is useful at ultrahigh frequencies. The device is a "TEM resonator," which is based on a concept originally proposed by Röschmann (1988). The coil comprises a circular cavity-like structure containing several coaxial transmission lines operating in a transverse electromagnetic (TEM) mode. The model developed herein treats the empty coil and is based on multiconductor transmission line theory. This work generalizes and extends similar analyses of the device by Röschmann (1995) and Chingas and Zhang (1996). The model employs explicit calculation of per-unit-length parameters for TEM lines having arbitrary geometries. Calculations of the resonator's frequency response are found to compare well with measurements. Fields produced by linear (single-point) and quadrature drive are also computed and compared to images of low-permittivity phantoms.


Adverse effects of the common treatments for polycystic ovary syndrome: a systematic review and meta-analysis.
Polycystic ovary syndrome (PCOS) is common among women of childbearing age and the available pharmacological therapies have different side-effect profiles. We summarized the evidence about the side effects of oral contraceptive pills, metformin, and anti-androgens in women with PCOS. Sources included Ovid Medline, OVID EMBASE, OVID Cochrane Library, Web of Science, Scopus, PsycInfo, and CINAHL from inception through April 2011. We included comparative observational studies enrolling women with PCOS who received the agents of choice for at least 6 months and reported adverse effects. Using a standardized, piloted, and Web-based data extraction form and working in duplicate, we abstracted data from each study and performed meta-analysis when possible. We found 22 eligible studies of which 20 were randomized. No study reported severe side effects (eg, lactic acidosis, thromboembolic episodes, liver toxicity, cancer incidence, or pregnancy loss). Meta-analysis demonstrated no significant change in weight in oral contraceptive pills or flutamide users. Indirect evidence from populations without PCOS demonstrated no increased risk of lactic acidosis with metformin, only case reports of liver toxicity with flutamide (no comparative evidence), and increased relative risk difference of venous thromboembolism with oral contraceptive pills but very low absolute risk. Evidence on mortality, cardiovascular mortality, and cancer was inconclusive. Drugs commonly used to treat PCOS appear to be associated with very low risk of severe adverse effects although data are extrapolated from other populations.


Maternal diet-induced obesity alters mitochondrial activity and redox status in mouse oocytes and zygotes.
The negative impact of obesity on reproductive success is well documented but the stages at which development of the conceptus is compromised and the mechanisms responsible for the developmental failure still remain unclear. Recent findings suggest that mitochondria may be a contributing factor. However to date no studies have directly addressed the consequences of maternal obesity on mitochondria in early embryogenesis.Using an established murine model of maternal diet induced obesity and a live cell dynamic fluorescence imaging techniques coupled with molecular biology we have investigated the underlying mechanisms of obesity-induced reduced fertility. Our study is the first to show that maternal obesity prior to conception is associated with altered mitochondria in mouse oocytes and zygotes. Specifically, maternal diet-induced obesity in mice led to an increase in mitochondrial potential, mitochondrial DNA content and biogenesis. Generation of reactive oxygen species (ROS) was raised while glutathione was depleted and the redox state became more oxidised, suggestive of oxidative stress. These altered mitochondrial properties were associated with significant developmental impairment as shown by the increased number of obese mothers who failed to support blastocyst formation compared to lean dams. We propose that compromised oocyte and early embryo mitochondrial metabolism, resulting from excessive nutrient exposure prior to and during conception, may underlie poor reproductive outcomes frequently reported in obese women.


Neuropathologies in transgenic mice expressing human immunodeficiency virus type 1 Tat protein under the regulation of the astrocyte-specific glial fibrillary acidic protein promoter and doxycycline.
The human immunodeficiency virus type 1 (HIV-1) Tat protein is a key pathogenic factor in a variety of acquired immune deficiency syndrome (AIDS)-associated disorders. A number of studies have documented the neurotoxic property of Tat protein, and Tat has therefore been proposed to contribute to AIDS-associated neurological diseases. Nevertheless, the bulk of these studies are performed in in vitro neuronal cultures without taking into account the intricate cell-cell interaction in the brain, or by injection of recombinant Tat protein into the brain, which may cause secondary stress or damage to the brain. To gain a better understanding of the roles of Tat protein in HIV-1 neuropathogenesis, we attempted to establish a transgenic mouse model in which Tat expression was regulated by both the astrocyte-specific glial fibrillary acidic protein promoter and a doxycycline (Dox)-inducible promoter. In the present study, we characterized the phenotypic and neuropathogenic features of these mice. Both in vitro and in vivo assays confirmed that Tat expression occurred exclusively in astrocytes and was Dox-dependent. Tat expression in the brain caused failure to thrive, hunched gesture, tremor, ataxia, and slow cognitive and motor movement, seizures, and premature death. Neuropathologies of these mice were characterized by breakdown of cerebellum and cortex, brain edema, astrocytosis, degeneration of neuronal dendrites, neuronal apoptosis, and increased infiltration of activated monocytes and T lymphocytes. These results together demonstrate that Tat expression in the absence of HIV-1 infection is sufficient to cause neuropathologies similar to most of those noted in the brain of AIDS patients, and provide the first evidence in the context of a whole organism to support a critical role of Tat protein in HIV-1 neuropathogenesis. More importantly, our data suggest that the Dox inducible, brain-targeted Tat transgenic mice offer an in vivo model for delineating the molecular mechanisms of Tat neurotoxicity and for developing therapeutic strategies for treating HIV-associated neurological disorders.


Mutation Spectrum of the ABCA4 Gene in a Greek Cohort with Stargardt Disease: Identification of Novel Mutations and Evidence of Three Prevalent Mutated Alleles.
To evaluate the frequency and pattern of disease-associated mutations of ABCA4 gene among Greek patients with presumed Stargardt disease (STGD1). A total of 59 patients were analyzed for ABCA4 mutations using the ABCR400 microarray and PCR-based sequencing of all coding exons and flanking intronic regions. MLPA analysis as well as sequencing of two regions in introns 30 and 36 reported earlier to harbor deep intronic disease-associated variants was used in 4 selected cases. An overall detection rate of at least one mutant allele was achieved in 52 of the 59 patients (88.1%). Direct sequencing improved significantly the complete characterization rate, that is, identification of two mutations compared to the microarray analysis (93.1% versus 50%). In total, 40 distinct potentially disease-causing variants of the ABCA4 gene were detected, including six previously unreported potentially pathogenic variants. Among the disease-causing variants, in this cohort, the most frequent was c.5714+5G>A representing 16.1%, while p.Gly1961Glu and p.Leu541Pro represented 15.2% and 8.5%, respectively. By using a combination of methods, we completely molecularly diagnosed 48 of the 59 patients studied. In addition, we identified six previously unreported, potentially pathogenic ABCA4 mutations.


Individual differences in fear potentiated startle in behaviorally inhibited children.
Behavioral inhibition (BI) is a temperament characterized during early childhood by increased fearfulness to novelty, social reticence to unfamiliar peers, and heightened risk for the development of anxiety. Heightened startle responses to safety cues have been found among behaviorally inhibited adolescents who have an anxiety disorder suggesting that this measure may serve as a biomarker for the development of anxiety amongst this risk population. However, it is unknown if these aberrant startle patterns emerge prior to the manifestation of anxiety in this temperament group. The current study examined potentiated startle in 7-year-old children characterized with BI early in life. High behaviorally inhibited children displayed increased startle magnitude to safety cues, particularly during the first half of the task, and faster startle responses compared to low behaviorally inhibited children. These findings suggest that aberrant startle responses are apparent in behaviorally inhibited children during early childhood prior to the onset of a disorder and may serve as a possible endophenotype for the development of anxiety.


Kv2 channels oppose myogenic constriction of rat cerebral arteries.
By hyperpolarizing arterial smooth muscle, voltage-gated, Ca2+-independent K+ (Kv) channels decrease calcium influx and thus oppose constriction. However, the molecular nature of the Kv channels function in arterial smooth muscle remains controversial. Recent investigations have emphasized a predominant role of Kv1 channels in regulating arterial tone. In this study, we tested the hypothesis Kv2 channels may also significantly regulate tone of rat cerebral arteries. We found that Kv2.1 transcript and protein are present in cerebral arterial smooth muscle. In addition, our analysis indicates that a substantial component (approximately 50%) of the voltage dependencies and kinetics of Kv currents in voltage-clamped cerebral arterial myocytes is consistent with Kv2 channels. Accordingly, we found that stromatoxin, a specific inhibitor of Kv2 channels, significantly decreased Kv currents in these cells. Furthermore, stromatoxin enhanced myogenic constriction of pressurized arterial segments. We also found that during angiotensin II-induced hypertension, Kv2 channel function was reduced in isolated myocytes and in intact arteries. This suggests that impaired Kv2 channel activity may contribute to arterial dysfunction during hypertension. On the basis of these novel observations, we propose a new model of Kv channel function in arterial smooth muscle in which Kv2 channels (in combination with Kv1 channels) contribute to membrane hyperpolarization and thus oppose constriction.


Ubiquitin C-terminal hydrolase-L1 is a key regulator of tumor cell invasion and metastasis.
Ubiquitin C-terminal hydrolase-L1 (UCH-L1) catalyses the hydrolysis of ubiquitin ester and amide mainly in neuronal cells. Recently it was proposed as a marker with a potential role in carcinogenesis. However, the molecular mechanism underlying the biological function of UCH-L1 in tumor cells is poorly understood. We found that UCH-L1 is highly expressed in non-small lung cancer cell line H157, having high invasive potential, and that the expression of UCH-L1 in tumor cells enhances their invasive potential in vitro and in vivo. UCH-L1 changes cell morphology by regulating cell adhesion through Akt-mediated pathway. Suppressing UCH-L1 expression by RNAi significantly suppressed the invasion in vitro and in vivo, and the activation of Akt and downstream mitogen activated protein kinases c-Jun N-terminal kinases and p38, but not ERK. In Akt-negative mutants, overexpression of UCH-L1 does not affect the invasion and migration capability of H157 cells. These results suggest that UCH-L1 is a key molecule to regulate tumor-cell invasion by upstream activation of Akt.


Outcome analysis of donor gender in heart transplantation.
Several studies have shown a detrimental effect of female donor gender on the survival of solid-organ transplant recipients, including heart, kidney and liver. We evaluated our own experience in heart transplantation in the cyclosporine era, since 1980, to determine the effect of donor gender on survival. We retrospectively reviewed 869 consecutive patients who underwent primary heart transplantation at Stanford University Medical Center between December 1980 and March 2004. Actuarial life-table data were calculated for survival and freedom from rejection and compared between groups. Multivariate Cox proportional hazard analysis was used to identify predictors of reduced long-term survival. One-year mortality in male recipients who received a female donor heart (24%) was higher than in male recipients who received male donor heart (13%) (p = 0.009). Actuarial survival rates for male recipients at 1, 5 and 10 years were 86%, 69% and 50% (with male donor), and 76%, 59% and 45% (with female donor) (p = 0.01), respectively. Donor gender had no effect on long-term survival in male recipients < 45 years of age and female recipients. Female donor gender was identified as an independent risk factor for death by multivariate analysis, with an odds ratio of 2.3 (95% confidence interval 1.5 to 3.4, p < 0.001). In heart transplantation the detrimental effect of female donor gender on recipient survival is significant but limited to male recipients > 45 years of age. These findings should be considered in the process of donor-recipient matching.


Auditory Comprehension Deficits in Post-stroke Aphasia: Neurologic and Demographic Correlates of Outcome and Recovery.
Introduction: One of the most challenging symptoms of aphasia is an impairment in auditory comprehension. The inability to understand others has a direct impact on a person's quality of life and ability to benefit from treatment. Despite its importance, limited research has examined the recovery pattern of auditory comprehension and instead has focused on aphasia recovery more generally. Thus, little is known about the time frame for auditory comprehension recovery following stroke, and whether specific neurologic and demographic variables contribute to recovery and outcome. Methods: This study included 168 left hemisphere chronic stroke patients stroke patients with auditory comprehension impairments ranging from mild to severe. Univariate and multivariate lesion-symptom mapping (LSM) was used to identify brain regions associated with auditory comprehension outcomes on three different tasks: Single-word comprehension, yes/no sentence comprehension, and comprehension of sequential commands. Demographic variables (age, gender, and education) were also examined for their role in these outcomes. In a subset of patients who completed language testing at two or more time points, we also analyzed the trajectory of recovery in auditory comprehension using survival curve-based time compression. Results: LSM analyses revealed that poor single-word auditory comprehension was associated with lesions involving the left mid- to posterior middle temporal gyrus, and portions of the angular and inferior-middle occipital gyri. Poor yes/no sentence comprehension was associated almost exclusively with the left mid-posterior middle temporal gyrus. Poor comprehension of sequential commands was associated with lesions in the left posterior middle temporal gyrus. There was a small region of convergence between the three comprehension tasks, in the very posterior portion of the left middle temporal gyrus. The recovery analysis revealed that auditory comprehension scores continued to improve beyond the first year post-stroke. Higher education was associated with better outcome on all auditory comprehension tasks. Age and gender were not associated with outcome or recovery slopes. Conclusions: The current findings suggest a critical role for the posterior left middle temporal gyrus in the recovery of auditory comprehension following stroke, and that spontaneous recovery of auditory comprehension can continue well beyond the first year post-stroke.


[Implementation of an insertion bundle for preventing central line-associated bloodstream infections in an Intensive Care Unit in Colombia].
Central line-associated bloodstream infections (CLABSI) related to insertion and device care in intensive care units are frequent and preventable events. To evaluate the reduction in the rate of CLABSI through implementation of an insertion bundle. A study was conducted in the Adult-ICU at the University Hospital of Neiva comparing a pre-interventional period with an interventional one, each lasting 6 months; the intervention consisting of implementing a bundle of measures for the insertion of central venous catheters (CVC). In the pre-intervention period (2010) the rate of CLABSI and the population's characteristics were evaluated. The bundle for the insertion of the CVC consisted in: hands hygiene, use of 2% clorhexidine, maximum sterile barriers and avoiding femoral access. The rate of CLABSI decreased from 5.56 to 3.26 per 1000 catheter days. The length of ICU stay and catheter duration were associated with a higher risk of infection associated to these devices (p < 0.05). Compliance with the bundle is a protective factor against the development of CLABSI (OR 0.45, p = 0.615). The staff adherence to the bundle was over 80%. Implementing a Central Line Insertion Bundle proved to be a useful measure in prevention of CLABSI in our hospital. This strategy could be implemented in other hospitals of similar complexity.


Laser-induced breakdown spectroscopy of ammonia gas with resonant vibrational excitation.
In this work, laser-induced breakdown spectroscopy (LIBS) of gaseous ammonia (NH3) molecules on- and off-resonant vibrational excitation was studied in open air. A wavelength-tunable, continuous wave (CW), carbon dioxide (CO2) laser tuned at a resonant absorption peak (9.219 µm) within the infrared radiation (IR) range was used to resonantly excite the vibration of the N-H wagging mode of ammonia molecules. A pulsed Nd:YAG laser (1064 nm, 15 ns) was used to break down the ammonia gas for plasma imaging and spectral measurements. In this study, plasmas generated with the ammonia molecules without additional CO2 laser beam irradiation and with additional CO2 laser beam irradiation with the wavelengths on- and off-resonant vibrational excitation of ammonia molecules were investigated and referred as LIBS, LIBS-RE-ON and LIBS-RE-OFF, respectively. The experimental results showed that the temporal and spatial evolution as well as electron temperature and density of plasmas induced with LIBS and LIBS-RE-OFF were consistent but differed from LIBS-RE-ON. Compared with LIBS and LIBS-RE-OFF, plasmas in LIBS-RE-ON showed larger spatial expansion and enhanced emission after a delay time of 1 µs in this study, as well as significantly enhanced electron temperature by ∼ 64%. Time-resolved electron temperatures and densities showed that the emission signal enhancement in LIBS-RE-ON can be primarily attributed to the electron temperature enhancement. Signal enhancement in LIBS indicated improved detection sensitivity. This study could inspire future works on LIBS for gas detection with improved sensitivity and selectivity probably by using ultrafast/intense laser-induced molecular breakdown/ionization with resonant vibrational excitation of molecules.


Optimizing Analytical Depth and Cost Efficiency of IEF-LC/MS Proteomics.
IEF LC-MS/MS is an analytical method that incorporates a two-step sample separation prior to MS identification of proteins. When analyzing complex samples this preparatory separation allows for higher analytical depth and improved quantification accuracy of proteins. However, cost and analysis time are greatly increased as each analyzed IEF fraction is separately profiled using LC-MS/MS. We propose an approach that selects a subset of IEF fractions for LC-MS/MS analysis that is highly informative in the context of a group of proteins of interest. Specifically, our method allows a significant reduction in cost and instrument time as compared to the standard protocol of running all fractions, with little compromise to coverage. We develop algorithmics to optimize the selection of the IEF fractions on which to run LC-MS/MS. We translate the fraction optimization task to Minimum Set Cover, a well-studied NP-hard problem. We develop heuristic solutions and compare them in terms of effectiveness and running times. We provide examples to demonstrate advantages and limitations of each algorithmic approach. Finally, we test our methodology by applying it to experimental data obtained from IEF LC-MS/MS analysis of yeast and human samples. We demonstrate the benefit of this approach for analyzing complex samples with a focus on different protein sets of interest.


Recovery Rate of Cells of the Seven Regulated Serogroups of Shiga Toxin-Producing Escherichia coli from Raw Veal Cutlets, Ground Veal, and Ground Beef from Retail Stores in the Mid-Atlantic Region of the United States.
A total of 482 veal cutlet, 555 ground veal, and 540 ground beef samples were purchased from retail establishments in the mid-Atlantic region of the United States over a noncontiguous 2-year period between 2014 and 2017. Samples (325 g each) were individually enriched and screened via real-time PCR for all seven regulated serogroups of Shiga toxin-producing Escherichia coli (STEC). Presumptive STEC-positive samples were subjected to serogroup-specific immunomagnetic separation and plated onto selective media. Up to five isolates typical for STEC from each sample were analyzed via multiplex PCR for both the virulence genes (i.e., eae, stx1 and/or stx2, and ehxA) and serogroup-specific gene(s) for the seven regulated STEC serogroups. The recovery rates of non-O157 STEC from veal cutlets (3.94%, 19 of 482 samples) and ground veal (7.03%, 39 of 555 samples) were significantly higher (P < 0.05) than that from ground beef (0.93%, 5 of 540 samples). In contrast, only a single isolate of STEC O157:H7 was recovered; this isolate originated from 1 (0.18%) of 555 samples of ground veal. Recovery rates for STEC were not associated with state, season, packaging type, or store type (P > 0.05) but were associated with brand and fat content (P < 0.05). Pulsed-field subtyping of the 270 viable and confirmed STEC isolates from the 64 total samples testing positive revealed 78 pulsotypes (50 to 80% similarity) belonging to 39 pulsogroups, with ≥90% similarity among pulsotypes within pulsogroups. Multiple isolates from 43 (67.7%) of 64 samples testing positive had an indistinguishable pulsotype. STEC serotypes O26 and O103 were the most prevalent serogroups in beef and veal, respectively. These findings support related findings from regulatory sampling studies over the past decade and confirm that recovery rates for the regulated STEC serogroups are higher for raw veal than for raw beef samples, as was observed in the present study of meat purchased at food retailers in the mid-Atlantic region of the United States.


Color and depth priors in natural images.
Natural scene statistics have played an increasingly important role in both our understanding of the function and evolution of the human vision system, and in the development of modern image processing applications. Because range (egocentric distance) is arguably the most important thing a visual system must compute (from an evolutionary perspective), the joint statistics between image information (color and luminance) and range information are of particular interest. It seems obvious that where there is a depth discontinuity, there must be a higher probability of a brightness or color discontinuity too. This is true, but the more interesting case is in the other direction--because image information is much more easily computed than range information, the key conditional probabilities are those of finding a range discontinuity given an image discontinuity. Here, the intuition is much weaker; the plethora of shadows and textures in the natural environment imply that many image discontinuities must exist without corresponding changes in range. In this paper, we extend previous work in two ways--we use as our starting point a very high quality data set of coregistered color and range values collected specifically for this purpose, and we evaluate the statistics of perceptually relevant chromatic information in addition to luminance, range, and binocular disparity information. The most fundamental finding is that the probabilities of finding range changes do in fact depend in a useful and systematic way on color and luminance changes; larger range changes are associated with larger image changes. Second, we are able to parametrically model the prior marginal and conditional distributions of luminance, color, range, and (computed) binocular disparity. Finally, we provide a proof of principle that this information is useful by showing that our distribution models improve the performance of a Bayesian stereo algorithm on an independent set of input images. To summarize, we show that there is useful information about range in very low-level luminance and color information. To a system sensitive to this statistical information, it amounts to an additional (and only recently appreciated) depth cue, and one that is trivial to compute from the image data. We are confident that this information is robust, in that we go to great effort and expense to collect very high quality raw data. Finally, we demonstrate the practical utility of these findings by using them to improve the performance of a Bayesian stereo algorithm.


Adenoid cystic carcinoma of the nasal cavity and paranasal sinuses: a meta-analysis.
Objectives To identify independent predictors of outcome in patients with adenoid cystic carcinoma (ACC) of the paranasal sinuses and skull base. Design Meta-analysis of the literature and data from the International ACC Study Group. Setting University-affiliated medical center. Participants The study group consisted of 520 patients, 99 of them from the international cohort. The median follow-up period was 60 months (range, 32 to 100 months). Main Outcome Measures Overall survival (OS) and disease-specific survival (DSS). Results The 5-year OS and DSS of the entire cohort were 62% and 67%, respectively. The local recurrence rate was 36.6%, and the regional recurrence rate was 7%. Distant metastasis, most commonly present in the lung, was recorded in 106 patients (29.1%). In the international cohort, positive margins and ACC of the sphenoid or ethmoidal sinuses were significant predictors of outcome (p < 0.001). Perineural invasion and adjuvant treatment (radiotherapy or chemoradiation) were not associated with prognosis. Conclusion Tumor margin status and tumor site are associated with prognosis in ACC of the paranasal sinuses, whereas perineural invasion is not. Adjuvant treatment apparently has no impact on outcome.


Chemical factors affecting the interpretation of blood cyanide concentrations in fire victims.
The purpose of this study was to examine the effects of methemoglobinemia caused by fire gases on blood cyanide concentrations in fire victims. Twenty-two fire victims with postmortem intervals of 8-48 h were involved. Blood cyanide concentrations at the time of death (C(0)) were estimated using the formula: C(0)=Ce(0.046 t) (C=blood cyanide concentration detected at autopsy, 0.046=first-order rate constant of cyanide disappearing from blood in corpses, and t=postmortem interval). Total (free and combined with cyanide) methemoglobin (MetHb) content was used to estimate the maximum capacity of MetHb for combining cyanide. Blood cyanide concentrations at the time of death were very high (5.32-6.47 mg/l) in five victims. Three showed high saturation (54.7-63.0%) of carboxyhemoglobin (CO-Hb) and elevated total MetHb contents (2.6-5.0%). MetHb at these levels is capable of scavenging up to 8.6-11.4 mg/l of blood cyanide. Thus, blood cyanide might have been completely combined with MetHb at the time of their death. In the remaining two victims, CO-Hb saturation was not high (30.9 and 37.9%) and no free MetHb was detected. As a result they may have exhibited severe toxic effects of cyanide at the time of their death. Our results indicate that MetHb contents and CO-Hb saturation should be determined to evaluate the toxic effects of cyanide in fire victims.


The Potential of Human Stem Cells for the Study and Treatment of Glaucoma.
Currently, the only available and approved treatments for glaucoma are various pharmacologic, laser-based, and surgical procedures that lower IOP. Although these treatments can be effective, they are not always sufficient, and they cannot restore vision that has already been lost. The goal of this review is to briefly assess current developments in the application of stem cell biology to the study and treatment of glaucoma and other forms of optic neuropathy. A combined literature review and summary of the glaucoma-related discussion at the 2015 "Sight Restoration Through Stem Cell Therapy" meeting that was sponsored by the Ocular Research Symposia Foundation (ORSF). Ongoing advancements in basic and eye-related developmental biology have enabled researchers to direct murine and human stem cells along specific developmental paths and to differentiate them into a variety of ocular cell types of interest. The most advanced of these efforts involve the differentiation of stem cells into retinal pigment epithelial cells, work that has led to the initiation of several human trials. More related to the glaucoma field, there have been recent advances in developing protocols for differentiation of stem cells into trabecular meshwork and retinal ganglion cells. Additionally, efforts are being made to generate stem cell-derived cells that can be used to secrete neuroprotective factors. Advancing stem cell technology provides opportunities to improve our understanding of glaucoma-related biology and develop models for drug development, and offers the possibility of cell-based therapies to restore sight to patients who have already lost vision.


Olive oil bioactives protect pigs against experimentally-induced chronic inflammation independently of alterations in gut microbiota.
Subclinical chronic inflammation (SCI) is associated with impaired animal growth. Previous work has demonstrated that olive-derived plant bioactives exhibit anti-inflammatory properties that could possibly counteract the growth-depressing effects of SCI. To test this hypothesis and define the underlying mechanism, we conducted a 30-day study in which piglets fed an olive-oil bioactive extract (OBE) and their control counterparts (C+) were injected repeatedly during the last 10 days of the study with increasing doses of Escherichia coli lipopolysaccharides (LPS) to induce SCI. A third group of piglets remained untreated throughout the study and served as a negative control (C-). In C+ pigs, SCI increased the circulating concentration of interleukin 1 beta (p < 0.001) and decreased feed ingestion (p < 0.05) and weight gain (p < 0.05). These responses were not observed in OBE animals. Although intestinal inflammation and colonic microbial ecology was not altered by treatments, OBE enhanced ileal mRNA abundance of tight and adherens junctional proteins (p < 0.05) and plasma recovery of mannitol (p < 0.05) compared with C+ and C-. In line with these findings, OBE improved transepithelial electrical resistance (p < 0.01) in TNF-α-challenged Caco-2/TC-7 cells, and repressed the production of inflammatory cytokines (p < 0.05) in LPS-stimulated macrophages. In summary, this work demonstrates that OBE attenuates the suppressing effect of SCI on animal growth through a mechanism that appears to involve improvements in intestinal integrity unrelated to alterations in gut microbial ecology and function.


The human MUC2 mucin apoprotein appears to dimerize before O-glycosylation and shares epitopes with the 'insoluble' mucin of rat small intestine.
Rabbit antiserum against a synthetic peptide corresponding to a tandemly repeated amino acid sequence in the human intestinal mucin apoprotein MUC2 was used in immunoprecipitation to study the biosynthesis of MUC2 in the colon-carcinoma cell line LS 174T. Under non-reducing conditions, two bands were precipitated, the smaller with an apparent size of about 700 kDa on SDS/PAGE. When analysed by two-dimensional electrophoresis after reduction, the larger band migrated to the same position as the smaller band and was interpreted as a putative disulphide-bond-stabilized dimer. Pulse-chase experiments showed only the monomer after 5 min and the appearance of the putative dimer after 30 min. The MUC2 apoprotein was also precipitated by antisera against the HF-deglycosylated peptides of the two highly glycosylated domains of the 'insoluble' mucin complex of rat small intestine [Carlstedt, Herrmann, Karlsson, Sheehan, Fransson and Hansson (1993) J. Biol. Chem. 268, [18771-18781]. Endoprotease Lys-C cleavage of the immunopurified apoprotein gave a large fragment of about 250 kDa that was detected by both the antiserum against the MUC2 tandem repeat and one of the glycopeptide antisera. This supports the view that the 'insoluble' mucin of rat small intestine is encoded by the Muc2 gene, as recently indicated by a partial cDNA sequence [Hansson, Baeckström, Carlstedt and Klinga-Levan (1994) Biochem. Biophys. Res. Commun. 198, 181-190] and that parts of the apoprotein are conserved between the species. A lectin from the snail Helix pomatia that detects terminal alpha-GalNAc residues did not bind to the monomer or putative dimer, suggesting that O-glycosylation starts after dimerization. The results indicate that the biosynthetic pathway of the MUC2 mucin may be similar to that of the von Willebrand factor with which MUC2 shares sequence similarities at its C- and N-termini.


The effect of chiropractic treatment on infantile colic: study protocol for a single-blind randomized controlled trial.
Infantile colic is a common condition during early childhood affecting around one of six newborns. The condition is characterized by inconsolable crying and fussing in otherwise healthy and thriving infants. The most used definition is excessive crying for at least three hours a day for at least three days for at least three weeks. The cause of colic is still unknown although many hypotheses and thereby many different treatment modalities have been investigated. Chiropractic care is used increasingly in treatment of infants, including for infantile colic, although the evidence worldwide is sparse. A randomized, controlled trial was designed to evaluate the effect of chiropractic treatment on infantile colic. This paper describes the protocol as well as results from a pilot study examining the acceptability and feasibility of the intervention. The study is designed as a single-blind randomized, controlled trial. The invited families are residents on the Island of Funen and information about the project is distributed from the maternity wards and health visitors. Children at the age of 2-14 weeks with unexplained excessive crying are screened for eligibility and recruited by the primary investigator through home visits. Eligible children are then randomized to chiropractic treatment or control. All children attend in the chiropractor clinic two times a week for two weeks. The parents are unaware of their child's allocation during the project period. The primary outcome measure is change in daily hours of crying based on the parental diaries.The study intends to include 200 children, and the intervention has, during a pilot study, been found acceptable and feasible among families with newborns. In a single-blind randomized controlled design we will evaluate the effectiveness of chiropractic treatment on infantile colic. The study will contribute to determine the effect of chiropractic treatment on infantile colic in an area where limited evidence exists. Furthermore, the study aims to explore if subgroups of children with suspected musculoskeletal problems will benefit more from the intervention than others. If they obtain better results, this could imply the need for stratified care. Clinicaltrials.gov and Identifier: NCT02595515 (registered 2 November 2015).


The importance of the leader sequence for directing lanthionine formation in lacticin 481.
Lantibiotics are post-translationally modified peptide antimicrobial agents that are synthesized with an N-terminal leader sequence and a C-terminal propeptide. Their maturation involves enzymatic dehydration of Ser and Thr residues in the precursor peptide to generate unsaturated amino acids, which react intramolecularly with nearby cysteines to form cyclic thioethers termed lanthionines and methyllanthionines. The role of the leader peptide in lantibiotic biosynthesis has been subject to much speculation. In this study, mutations of conserved residues in the leader sequence of the precursor peptide for lacticin 481 (LctA) did not inhibit dehydration and cyclization by lacticin 481 synthetase (LctM) showing that not one specific residue is essential for these transformations. These amino acids may therefore be conserved in the leader sequence of class II lantibiotics to direct other biosynthetic events, such as proteolysis of the leader peptide or transport of the active compound outside the cell. However, introduction of Pro residues into the leader peptide strongly affected the efficiency of dehydration, consistent with recognition of the secondary structure of the leader peptide by the synthetase. Furthermore, the presence of a hydrophobic residue at the position of Leu-7 appears important for enzymatic processing. Based on the data in this work and previous studies, a model for the interaction of LctM with LctA is proposed. The current study also showcases the ability to prepare other lantibiotics in the class II lacticin 481 family, including nukacin ISK-1, mutacin II, and ruminococcin A using the lacticin 481 synthetase. Surprisingly, a conserved Glu located in a ring that appears conserved in many class II lantibiotics, including those not belonging to the lacticin 481 subgroup, is not essential for antimicrobial activity of lacticin 481.


The dual role of cyclin C connects stress regulated gene expression to mitochondrial dynamics.
Following exposure to cytotoxic agents, cellular damage is first recognized by a variety of sensor mechanisms. Thenceforth, the damage signal is transduced to the nucleus to install the correct gene expression program including the induction of genes whose products either detoxify destructive compounds or repair the damage they cause. Next, the stress signal is disseminated throughout the cell to effect the appropriate changes at organelles including the mitochondria. The mitochondria represent an important signaling platform for the stress response. An initial stress response of the mitochondria is extensive fragmentation. If the damage is prodigious, the mitochondria fragment (fission) and lose their outer membrane integrity leading to the release of pro-apoptotic factors necessary for programmed cell death (PCD) execution. As this complex biological process contains many moving parts, it must be exquisitely coordinated as the ultimate decision is life or death. The conserved C-type cyclin plays an important role in executing this molecular Rubicon by coupling changes in gene expression to mitochondrial fission and PCD. Cyclin C, along with its cyclin dependent kinase partner Cdk8, associates with the RNA polymerase holoenzyme to regulate transcription. In particular, cyclin C-Cdk8 repress many stress responsive genes. To relieve this repression, cyclin C is destroyed in cells exposed to pro-oxidants and other stressors. However, prior to its destruction, cyclin C, but not Cdk8, is released from its nuclear anchor (Med13), translocates from the nucleus to the cytoplasm where it interacts with the fission machinery and is both necessary and sufficient to induce extensive mitochondria fragmentation. Furthermore, cytoplasmic cyclin C promotes PCD indicating that it mediates both mitochondrial fission and cell death pathways. This review will summarize the role cyclin C plays in regulating stress-responsive transcription. In addition, we will detail this new function mediating mitochondrial fission and PCD. Although both these roles of cyclin C are conserved, this review will concentrate on cyclin C's dual role in the budding yeast Saccharomyces cerevisiae.


The herpes simplex virus type 1 cleavage/packaging protein, UL32, is involved in efficient localization of capsids to replication compartments.
Six genes, including UL32, have been implicated in the cleavage and packaging of herpesvirus DNA into preassembled capsids. We have isolated a UL32 insertion mutant which is capable of near-wild-type levels of viral DNA synthesis; however, the mutant virus is unable to cleave and package viral DNA, consistent with the phenotype of a previously isolated temperature-sensitive herpes simplex virus type 1 mutant, tsN20 (P. A. Schaffer, G. M. Aron, N. Biswal, and M. Benyesh-Melnick, Virology 52:57-71, 1973). A polyclonal antibody which recognizes UL32 was previously used by Chang et al. (Y. E. Chang, A. P. Poon, and B. Roizman, J. Virol. 70:3938-3946, 1996) to demonstrate that UL32 accumulates predominantly in the cytoplasm of infected cells. In this report, a functional epitope-tagged version of UL32 showed that while UL32 is predominantly cytoplasmic, some nuclear staining which colocalizes with the major DNA binding protein (ICP8, UL29) in replication compartments can be detected. We have also used a monoclonal antibody (5C) specific for the hexon form of major capsid protein VP5 to study the distribution of capsids during infection. In cells infected with wild-type KOS (6 and 8 h postinfection), 5C staining patterns indicate that capsids are present in nuclei within replication compartments. These results suggest that cleavage and packaging occur in replication compartments at least at 6 and 8 h postinfection. Cells infected with the UL32 mutant exhibit a hexon staining pattern which is more diffusely distributed throughout the nucleus and which is not restricted to replication compartments. We propose that UL32 may play a role in "bringing" preassembled capsids to the sites of DNA packaging and that the failure to localize to replication compartments may explain the cleavage/packaging defect exhibited by this mutant. These results suggest that the UL32 protein is required at a step distinct from those at which other cleavage and packaging proteins are required and may be involved in the correct localization of capsids within infected cells.


Influence of aspirin and dipyridamole on patency of coronary artery bypass grafts.
A prospective randomized trial was performed to determine if the administration of inhibitors of platelet function would improve the patency of coronary artery bypass grafts. Patients were operated on for intractable angina with angiographically demonstrable lesions. The left internal mammary artery (IMA) was used for bypass of lesions of the left anterior descending coronary artery (LAD). Saphenous vein grafts were used for the LAD if the IMA was inadequate and for all other vessels. Treated patients received 1,300 mg of aspirin and 100 mg of dipyridamole (Persantine) orally each day. Control patients received neither drug. Patients returned 3 to 6 months after operation for repeat angiography. Results were analyzed by chi-square. One hundred seventy-four patients entered the study from June, 1973, through December, 1975, and 113 were analyzed. In the control group, 66 patients had 27 IMA-LAD grafts and 93 saphenous vein grafts. In the treatment group, 47 patients underwent 18 IMA-LAD grafts and 75 saphenous vein grafts. Ninety-eight of the 120 grafts (82%) were patent in the control group, and 87 of 93 grafts (94%) were patent in the treatment group (x2 = 6.34, p less than 0.02). Of the 45 IMA-LAD grafts in both groups, only 1 was occluded, a patency of 98%. In the control group, 72 of 93 saphenous vein grafts (77%) were patent. In the treatment group, 69 of 75 (92%) were patent (x2 = 6.54, p less than 0.02). The results of the study show a 15% difference between the two groups in the early patency of saphenous vein grafts. We continue to use aspirin and dipyridamole to improve the patency of saphenous vein bypass grafts.


A preliminary study on self-care telemonitoring of dysarthria in spinal muscular atrophy.
Spinal muscular atrophy (SMA) is a rare neuromuscular disease which may cause impairments in oro-facial musculature. Most of the individuals with SMA present bulbar signs such as flaccid dysarthria which mines their abilities to speak and, as consequence, their psychic balance. To support clinicians, recent work has demonstrated the feasibility of video-based techniques for assessing the oro-facial functions in patients with neurological disorders such as amyotrophic lateral sclerosis. However, no work has so far focused on automatic and quantitative monitoring of dysarthria in SMA. To overcome limitations this work's aim is to propose a cloud-based store-and-forward telemonitoring system for automatic and quantitative evaluation of oro-facial muscles in individuals with SMA. The system integrates a convolutional neural network (CNN) aimed at identifying the position of facial landmarks from video recordings acquired via a web application by an SMA patient.Clinical relevance- The proposed work is in the preliminary stage, but it represents the first step towards a better understanding of the bulbar-functions' evolution in patients with SMA.


Effect of collagenase and ouabain on renal cell volume in hypotonic media.
Proximal straight tubules (S2 segments) swell rapidly in hypotonic media, but within a few minutes their volume returns toward control levels due to extrusion of K, Na, Cl, and water from the cytoplasm. In the present studies we determined the extent to which hydrostatic pressure (derived from the elastic tubule basement membrane (TBM) as the tubule enlarged in hypotonic medium) contributed to the regulation of cell volume. Removal of the TBM by collagenase had no effect on cell volume regulation in otherwise normal tubules. By contrast, tubules treated with ouabain, though they appeared to regulate their volumes in hypotonic media, were unable to do so in the presence of glycoside if the TBM had been removed with collagenase. This latter result is interpreted to show that hydrostatic pressure generated by extension of the TBM can cause "apparent" volume regulation when the sodium pump is blocked by ouabain. We conclude that normal proximal renal tubules regulate cell volume in hypotonic solutions by mechanisms that are dependent on the normal operation of the classical sodium pump.


Ertapenem Versus Meropenem for the Treatment of Extended Spectrum Beta-Lactamase-Producing Enterobacterales Bacteremia in Critically Ill Patients.
The preferred carbapenem for treatment of infections caused by extended spectrum beta-lactamase-producing Enterobacterales (ESBL-E) in critically ill patients is debated. The purpose of this study was to evaluate the difference in clinical failure between ertapenem and meropenem for treatment of ESBL-E bacteremia in critically ill patients. Of concern is ertapenem use in hypoalbuminemia given the potential for higher drug clearance. This retrospective, matched cohort study compared critically ill patients treated with ertapenem or meropenem for ESBL-E bacteremia between October 2016 and August 2022. Patients were matched on age, sex, lowest albumin, and in a 1:2 ratio of ertapenem to meropenem. The primary outcome, clinical failure, was a composite of 30-day mortality, antibiotic escalation, and microbiological failure. Secondary outcomes included all-cause readmission and development of superinfection. Of 54 patients, 18 received ertapenem and 36 meropenem. Most had a urinary infection source (55.6% vs 41.7%, P = 0.393). There was no difference in clinical failure (50.0% vs 38.9%, P = 0.436). Ertapenem patients had antibiotic escalation more often (33.3% vs 2.8%, P = 0.002). There was no difference in 30-day mortality (11.1% vs 27.8%, P = 0.298), microbiological failure (27.8% vs 11.1%, P = 0.142), all-cause readmission (22.2% vs 13.9%, P = 0.461), or development of superinfection (11.1% vs 13.9%, P = 1.000). There was no difference in clinical failure in a small, retrospective cohort of critically ill patients receiving ertapenem or meropenem for ESBL-E bacteremia. Ertapenem may be appropriate in some critically ill and hypoalbuminemic patients, though additional data are needed.


Polymerization on the rocks: negatively-charged alpha-amino acids.
Oligomers of the negatively-charged amino acids, glutamic acid, aspartic acid, and O-phospho-L-serine are adsorbed by hydroxylapatite and illite with affinities that increase with oligomer length. In the case of oligo-glutamic acids adsorbed on hydroxylapatite, addition of an extra residue results in an approximately four-fold increase in the strength of adsorption. Oligomers much longer than the 7-mer are retained tenaciously by the mineral. Repeated incubation of short oligo-glutamic acids adsorbed on hydroxylapatite or illite with activated monomer leads to the accumulation of oligomers at least 45 units long. The corresponding reactions of aspartic acid and O-phospho-L-serine on hydroxylapatite are less effective in generating long oligomers, while illite fails to accumulate substantial amounts of long oligomers of aspartic acid or of O-phospho-L-serine.


Variation for resistance to kernel infection and toxin accumulation in winter wheat infected with Fusarium graminearum.
Host resistance is the main way to control Fusarium head blight (FHB) in wheat. Despite improved levels of resistance to infection and spread in vegetative tissue, the toxin deoxynivalenol (DON) can still accumulate to unacceptable concentration levels. In this study, our objectives were to assess the genetic variation for resistance to kernel infection (RKI) and resistance to toxin accumulation (RTA) and their role in controlling DON. We collected spikes with different levels of visual symptoms from each of 32 wheat genotypes and at four environments and determined DON and fungal biomass (FB) from each sample. We assessed RKI by regressing FB on the level of visual symptoms and RTA by regressing DON on FB for each genotype. Significant genetic effects were found for RKI and RTA. Some genotypes consistently had low FB in their grain despite increasing visual symptoms suggesting RKI. Additionally, some genotypes consistently had low DON in their grain despite increasing FB levels suggesting a higher RTA in these genotypes. The variation for RKI and RTA explained a significant fraction of the variation for DON among genotypes with moderate visual symptoms using independent grain samples. Although RKI and RTA were significantly correlated (r = 0.58, P = 0.05), RTA was more predictive of DON accumulation because it modeled 32 to 44% of the genotype sum of squares for DON, while only 9 to 10% were predicted using RKI. Thus, variation for RTA was important in explaining variation for DON among genotypes with acceptable levels of resistance to fungal infection and spread. This work indicates that there is a need to develop a better understanding of RTA and rapid screening methods for this trait.


Implant overdentures: recommendations and analysis of the clinical benefits.
Due to the progress made in implantology, in recent years the interest in prosthetic rehabilitation in edentulous mouths using overdentures has increased considerably. Indications to the treatment of implant supported overdenture could be classified in three groups: the first group consists of younger members of the elderly population who have an edentulous upper jaw rehabilitated with a conventional complete denture but experience discomfort with it and therefore desire a stable prosthesis and greater comfort in the mouth; the second group, for which the use of implant overdentures is recommended, consists of older patients who require greater stability from a complete mandibular denture; the third group consists of compromised patients and those with acquired or congenital maxillofacial conditions. Moreover, advantages of overdentures supported by implants are analyzed; in fact, they allow a lower bone reabsorption, a better retention and stability of the prosthesis than the traditional complete denture, an increased masticatory effectiveness, a reduction of pain during mastication tanks to the higher stability, a better sensory perception, a considerable patient satisfaction, and the option of making an immediate prosthetic rehabilitation with implants through immediate load.


Genes controlling spread of breast cancer to lung "gang of 4".
Cancer-related mortality is caused in a large part by the metastasis of primary tumor. Each cancer has a particular way of spreading cancerous cells. Recently, genetic and pharmacological analysis identified the set of genes, such as epidermal growth factor receptor ligand epiregulin (EREG), cyclooxygenase-2 (COX2) and matrix metalloproteinases 1 and 2 (MMP-1 and MMP-2) that have been found to be associated with metastasis of breast cancer to lung. Inhibition of EGFR and COX2 could minimize lung metastasis of breast cancer in a clinical setting. In this review, we summarized the current knowledge on EREG, COX2, MMP-1 and MMP-2 in tumor development and metastasis.


Zymographic and ultrastructural evaluations after low-level laser irradiation on masseter muscle of HRS/J strain mice.
Low-level laser therapy (LLLT) has been widely used in the treatment of the stomatognathic system dysfunction; however, its biological effect remains poorly understood. This study evaluated the effect of LLLT (GaAlAs, 780 nm, 20 J/cm(2), 40 mW) on masseter muscle of HRS/J mice after different numbers of laser irradiations (three, six, and ten) for 20 s in alternate days. Three experimental groups were defined according to the number of laser irradiations and three control groups (n=5) were used. On the third day after the last irradiation, all animals were killed and the masseter muscle was removed and processed for the following analysis: (a) transmission electron microscopy, (b) zymography, (c) immunohistochemistry for vascular endothelial growth factor (VEGF) and VEGFR-2. The results showed: (a) with six laser applications, a dilation of T tubules, and sarcoplasmic reticulum cistern, increased pinocytosed vesicles in the endothelium; with ten laser applications, few pinocytic vesicles in the endothelium and condensed mitochondria. (b) Under the conditions of this study, the synthesis of other matrix metalloproteinases was not observed, only the MMP-2 and -9. (c) After ten laser irradiations, immunostaining was observed only for VEGFR-2. We conclude that after six laser applications, ultrastructural changes may facilitate the Ca(+2) transfer to cytosol and increase the fluid transport from one surface to another. The ultrastructural changes and no immunostaining for VEGF with ten applications may decrease the metabolic activity as well as damage the angiogenic process, suggesting that an effective number of laser applications may be less than ten, associating to this therapy a better cost-benefit.


1,25(OH)2D3 and dexamethasone additively suppress synovial fibroblast activation by CCR6+ T helper memory cells and enhance the effect of tumor necrosis factor alpha blockade.
Despite recent improvements in the treatment of rheumatoid arthritis (RA), an insufficient treatment response and the development of treatment resistance in many patients illustrates the need for new therapeutic strategies. Chronic synovial inflammation could be suppressed by targeting RA synovial fibroblast (RASF) activation by, for example, interleukin (IL)-17A-producing CCR6+ T helper memory (memTh) cells. Here, we modulated this interaction by combining the active vitamin D metabolite 1,25(OH)2D3 with dexamethasone (DEX) and explored the potential therapeutic applications. CCR6+ memTh cells from peripheral blood mononuclear cells (PBMCs) of healthy donors or treatment-naive early RA patients were cultured alone or with RASF from established RA patients for 3 days and treated with or without 1,25(OH)2D3, DEX, or etanercept. Treatment effects were assessed using enzyme-linked immunosorbent assay (ELISA) and flow cytometry. 1,25(OH)2D3, and to lesser extent DEX, reduced production of the pro-inflammatory cytokines IL-17A, IL-22, and interferon (IFN)γ in CCR6+ memTh cells. Tumor necrosis factor (TNF)α was only inhibited by the combination of 1,25(OH)2D3 and DEX. In contrast, DEX was the strongest inhibitor of IL-6, IL-8, and tissue-destructive enzymes in RASF. As a result, 1,25(OH)2D3 and DEX additively inhibited inflammatory mediators in CCR6+ memTh-RASF cocultures. Interestingly, low doses of mainly DEX, but also 1,25(OH)2D3, combined with etanercept better suppressed synovial inflammation in this coculture model compared with etanercept alone. This study suggests that 1,25(OH)2D3 and DEX additively inhibit synovial inflammation through targeting predominantly CCR6+ memTh cells and RASF, respectively. Furthermore, low doses of DEX and 1,25(OH)2D3 enhance the effect of TNFα blockade in inhibiting RASF activation, thus providing a basis to improve RA treatment.


Triazolo[4,5-d]pyrimidin-5-amines based ERK3 inhibitors fail to demonstrate selective effects on adipocyte function.
Extracellular signal-regulated kinase 3 (ERK3 also designated MAPK6 - mitogen-activated protein kinase 6) is a ubiquitously expressed kinase participating in the regulation of a broad spectrum of physiological and pathological processes. Targeted inhibition of the kinase may allow the development of novel treatment strategies for a variety of types of cancer and somatic pathologies, as well as preserving metabolic health, combat obesity and diabetes. We chose and synthesized three triazolo [4,5-d]pyrimidin-5-amines proposed previously as putative ERK3 inhibitors to assess their selectivity and biological effects in terms of metabolic state impact in living cells. As it was previously shown that ERK3 is a major regulator of lipolysis in adipocytes, we focused on this process. Our new results indicate that in addition to the previously identified lipolytic enzyme ATGL, ERK3 also regulates hormone-sensitive lipase (HSL) and monoglyceride lipase (MGL). Moreover, this kinase also promotes the abundance of fatty acid synthase (FASN) as well as protein kinase cAMP-activated catalytic subunit alpha (PKACα). To investigate various effects of putative ERK3 inhibitors on lipolysis, we utilized different adipocyte models. We demonstrated that molecules exhibit lipolysis-modulating effects; however, the effects of triazolo [4,5-d]pyrimidin-5-amines based inhibitors on lipolysis are not dependent on ERK3. Subsequently, we revealed a wide range of the compounds' possible targets using a machine learning-based prediction. Therefore, the tested compounds inhibit ERK3 in vitro, but the biological effect of this inhibition is significantly overlapped and modified by some other molecular events related to the non-selective binding to other targets.


Gradual correction of idiopathic genu varum deformity using the Ilizarov technique.
Proximal tibial osteotomy is an effective treatment option for genu varum deformity among the many other described techniques. The purpose of this study is to evaluate the clinical and radiological outcomes and the complications in gradual correction of idiopathic genu varum deformity using Ilizarov frame. Proximal tibial medial opening wedge osteotomy was performed in 21 lower limbs of 11 patients, with whom the Ilizarov external fixator was used for gradual correction of the varus deformity. The mean age of the patients was 24.8 years (SD, 5.3). Deformity measurements of conventional mechanical axis deviation, mechanical medial proximal tibial angle, mechanical lateral distal femoral angle, posterior proximal tibial angle, joint conversion angle, tibio-femoral angle and tibial slope were compared. The mean time for removal of the Ilizarov fixator was 24.7 weeks. At the last follow-up, the mean of Hospital for Special Surgery knee score increased, and the mean mechanical medial proximal tibial angle, tibio-femoral angle and conventional mechanical axis deviation improved. The differences between preoperative and postoperative posterior proximal tibial angle, mechanical lateral distal femoral angle, joint conversion angle and tibial slope were not significant. Ten complications were observed, of which 8 were minor complications and 2 were minor complications. With a few complications, normal alignment and orientation of lower extremity can be established in patients with idiopathic genu varum deformity through gradual correction using a Ilizarov fixator. Retrospective case series, Level IV.


A covalent modification of NADP+ revealed by the atomic resolution structure of FprA, a Mycobacterium tuberculosis oxidoreductase.
FprA is a mycobacterial oxidoreductase that catalyzes the transfer of reducing equivalents from NADPH to a protein acceptor. We determined the atomic resolution structure of FprA in the oxidized (1.05 A resolution) and NADPH-reduced (1.25 A resolution) forms. The comparison of these FprA structures with that of bovine adrenodoxin reductase showed no significant overall differences. Hence, these enzymes, which belong to the structural family of the disulfide oxidoreductases, are structurally conserved in very distant organisms such as mycobacteria and mammals. Despite the conservation of the overall fold, the details of the active site of FprA show some peculiar features. In the oxidized enzyme complex, the bound NADP+ exhibits a covalent modification, which has been identified as an oxygen atom linked through a carbonylic bond to the reactive C4 atom of the nicotinamide ring. Mass spectrometry has confirmed this assignment. This NADP+ derivative is likely to form by oxidation of the NADP+ adduct resulting from nucleophilic attack by an active-site water molecule. A Glu-His pair is well positioned to activate the attacking water through a mechanism analogous to that of the catalytic triad in serine proteases. The NADP+ nicotinamide ring exhibits the unusual cis conformation, which may favor derivative formation. The physiological significance of this reaction is presently unknown. However, it could assist with drug-design studies in that the modified NADP+ could serve as a lead compound for the development of specific inhibitors.


Early combination therapy with etanercept and methotrexate in JIA patients shortens the time to reach an inactive disease state and remission: results of a double-blind placebo-controlled trial.
Remission is the primary objective of treating juvenile idiopathic arthritis (JIA). It is still debatable whether early intensive treatment is superior in terms of earlier achievement of remission. The aim of this study was to evaluate the effectiveness of early etanercept+methotrexate (ETA+MTX) combination therapy versus step-up MTX monotherapy with ETA added in refractory disease. A multi-centre, double-blind, randomized study in active polyarticular JIA patients treated with either ETA+MTX (n = 35) or placebo+MTX (n = 33) for up to 24 weeks, followed by a 24-week open-label phase. The efficacy endpoints included pedACR30 criteria improvement at week 12, inactive disease at week 24, and remission at week 48. Patients who failed to achieve the endpoints at week 12 or at week 24 escaped to open-label ETA+MTX. Safety was assessed at each visit. By intention-to-treat analysis, more patients in the ETA+MTX group reached the pedACR30 response at week 12 (33 (94.3%)) than in the placebo+MTX group (20 (60.6%); p = 0.001). At week 24, comparable percentages of patients reached inactive disease (11 (31.4%) vs 11 (33.3%)). At week 48, 11 (31.4%) and eight (24.2%) patients achieved remission. The median (+/-IQR) times to achieve an inactive disease state in the ETA+MTX and placebo+MTX groups were 24 (14-32) and 32 (24-40) weeks, respectively. Forty-four (74/100 patient-years) adverse events (AEs) were reported, leading to treatment discontinuation in 6 patients. Early combination therapy with ETA+MTX proved to be highly effective compared to the standard step-up regimen. Compared to those treated with the standard regimen, more patients treated with a combination of ETA+MTX reached the pedACR30 response and achieved inactive disease and remission more rapidly.


Some epidemiological aspects of cutaneous leishmaniasis in northern khorasan province, iran.
Cutaneous leishmaniasis (CL) is a widespread tropical infection which has a high incidence rate in Iran. The aim of this study was to determine some epidemiological aspects of disease in Northern Khorasan Province, Iran. From 2005 to 2008, data concerning 1453 patients with CL were collected and analyzed from the different districts of health service registry of the province. The statistical analyses were carried out with SPSS version 12.0 for windows. The highest number of patients was in 2005 with 555 cases in this year. 19.3% of patients aged younger than 5-year and 57.5% were older than 15 year. 37.8% had only one lesion, and 40.5% had at least three lesions. The highest incidence of disease was observed in Jajarm district in 2005 (381.1 per 100,000), and the lowest incidence rate was in Farouj district in the same year. The disease was observed in all months of the year with the highest incidence rate from September to November. Although Jajrm is a known foci in Iran, based on our knowledge there is no report in the literature on assessing the prevalence of CL in this region in recent years. We also found that the disease is endemic in Northern Khorasan Province.


One Electron Multiple Proton Transfer in Model Organic Donor-Acceptor Systems: Implications for High Frequency EPR.
EPR spectroscopy is an important spectroscopic method for identification and characterization of radical species involved in many biological reactions. The tyrosyl radical is one of the most studied amino acid radical intermediates in biology. Often in conjunction with histidine residues, it is involved in many fundamental biological electron and proton transfer processes, such as in the water oxidation in photosystem II. As biological processes are typically extremely complicated and hard to control, molecular bio-mimetic model complexes are often used to clarify the mechanisms of the biological reactions. Here we present theoretical calculations to investigate the sensitivity of magnetic resonance parameters to proton-coupled electron transfer events, as well as conformational substates of the molecular constructs which mimic the tyrosine-histidine (Tyr-His) pairs found in a large variety of proteins. Upon oxidation of the phenol, the Tyr analogue, these complexes can perform not only one-electron one-proton transfer (EPT), but also one-electron two-proton transfers (E2PT). It is shown that in aprotic environment the gX-components of the electronic g-tensor are extremely sensitive to the first proton transfer from the phenoxyl oxygen to the imidazole nitrogen (EPT product), leading to a significant increase of the gX-value of up to 0.003, but are not sensitive to the second proton transfer (E2PT product). In the latter case the change of the gX-value is much smaller (ca. 0.0001), which is too small to be distinguished even by high frequency EPR. The 14N hyperfine values are also too similar to allow differentiation between the different protonation states in EPT and E2PT. The magnetic resonance parameters were also calculated as a function of the rotation angles around single bonds. It was demonstrated that rotation of the phenoxyl group results in large positive changes (>0.001) in the gX-values. Analysis of the data reveals that the main source of these changes is related to the strength of the H-bond between phenoxyl oxygen and the proton(s) on N1 and N2 positions of the imidazole.


Neuroblast senescence in the aged brain augments natural killer cell cytotoxicity leading to impaired neurogenesis and cognition.
Normal aging is accompanied by escalating systemic inflammation. Yet the potential impact of immune homeostasis on neurogenesis and cognitive decline during brain aging have not been previously addressed. Here we report that natural killer (NK) cells of the innate immune system reside in the dentate gyrus neurogenic niche of aged brains in humans and mice. In situ expansion of these cells contributes to their abundance, which dramatically exceeds that of other immune subsets. Neuroblasts within the aged dentate gyrus display a senescence-associated secretory phenotype and reinforce NK cell activities and surveillance functions, which result in NK cell elimination of aged neuroblasts. Genetic or antibody-mediated depletion of NK cells leads to sustained improvements in neurogenesis and cognitive function during normal aging. These results demonstrate that NK cell accumulation in the aging brain impairs neurogenesis, which may serve as a therapeutic target to improve cognition in the aged population.


Pseudoceramide for childhood eczema: does it work?
Atopic eczema is a chronic relapsing skin disease associated with atopy, and characterised by reduced skin hydration, impaired skin integrity (transepidermal water loss), and poor quality of life. Proper emollient usage is an important facet of its management. This study aimed to establish an approach to evaluate the efficacy of using an emollient over a 4-week period. Prospective observational study. A paediatric dermatology out-patient clinic of a university teaching hospital in Hong Kong. Consecutive new patients aged 5 to 18 years with atopic eczema diagnosed according to Hanifin and Rajka's criteria were recruited from March to August 2009. They or their parents were instructed to liberally apply the test emollient to the flexures and areas affected with eczema, twice daily. Outcome assessments were repeated 2 and 4 weeks later. Skin hydration and transepidermal water loss in the right forearm (2 cm below antecubital flexure), and disease severity (SCORing Atopic Dermatitis index) and Children's Dermatology Life Quality Index. At the end of the study period, a global assessment of treatment was recorded. Thirty-three patients with atopic eczema were recruited and treated with applications of a pseudoceramide-containing cream (Curel, Kao, Japan). The mean age of the patients (16 males and 17 females) was 12 (standard deviation, 4) years. Four weeks following the use of the cream, skin hydration improved significantly and fewer patients were using topical corticosteroids. In these patients, there was no deterioration in transepidermal water loss, eczema severity, or quality of life. The pseudoceramide cream improved skin hydration but not severity or quality of life over a 4-week usage.


Change and Regulation of Nutritional Metabolism in Silver Pomfret During Compensatory Growth.
Compensatory growth (CG) in fish is heavily influenced by nutrient metabolism. However, there are limited studies examining how nutrient metabolism is regulated during this process. For silver pomfret, an important commercial marine fish, it's crucial to establish effective starvation and re-feeding strategies to ensure good water quality and fast growth. To identify the complete compensatory growth model of silver pomfret, we conducted an experiment with a control group (normal feeding) and three starvation/re-feeding groups. We observed that the recovery of weight and condition factor in the 14-day starvation and 14-day re-feeding groups was significantly faster than other groups, indicating full compensatory growth. Thus, we selected this group for the next experiment. We performed untargeted metabolomics and transcriptome analysis of muscle tissue on Day 14, 21 and 28 (CG process), and examined the key regulatory genes of nutrient metabolism on Day 0, 7, 14, 21 and 28 (starvation and re-feeding process). Our data revealed that during starvation, silver pomfret first utilized carbohydrates and short-chain lipids, followed by proteins and long-chain lipids. After re-feeding, lipids accumulated first, resulting in rapid growth, followed by the recovery of protein content in muscle. During starvation, the expression of anabolic-related genes such as TER and CALR decreased, and catabolic-related genes such as TSC2 and MLYCD increased, promoting the AMPK pathway. During re-feeding, anabolic-related gene expression increased without AMPK inhibition. Our findings provide insights into the energy utilization strategies of fish and molecular regulation during compensatory growth in fish.


Neuropsychological functioning in children with early-treated phenylketonuria: impact of white matter abnormalities.
Impact of white matter abnormalities (WMAs) on neuropsychological functioning in children with early-treated phenylketonuria (ETPKU) was examined. Children with ETPKU (20 males, 12 females, mean age 11 years 2 months, SD 3 years 6 months) and controls (20 males, 14 females, mean age 10 years 4 months, SD 3 years 1 month) aged 7 to 18 years were assessed using tests of attention, processing speed, memory and learning, executive function, and academic achievement. Those with ETPKU, exhibiting WMAs extending into subcortical/frontal regions (n=14), displayed significant impairments in a number of domains. Children with ETPKU but no WMAs (n=6), or pathology restricted to the posterior periventricular region (n=12), displayed only mild deficits. Concurrent phenylalanine levels correlated weakly with cognitive parameters, whereas lifetime phenylalanine levels were associated with deficits in several cognitive domains. Impairments in children with extensive WMAs are consistent with compromised neural transmission, which is characterized by dysmyelination. However, children with no detectable, or mild WMAs, also displayed cognitive problems, indicating that neuropsychological functioning in children with ETPKU is determined by a complex interaction of biological and environmental factors.


How a regional collaborative of hospitals and physicians in Michigan cut costs and improved the quality of care.
There is evidence that collaborations between hospitals and physicians in particular regions of the country have led to improvements in the quality of care. Even so, there have not been many of these collaborations. We review one, the Michigan regional collaborative improvement program, which was paid for by a large private insurer, has yielded improvements for a range of clinical conditions, and has reduced costs in several important areas. In general and vascular surgery alone, complications from surgery dropped almost 2.6 percent among participating Michigan hospitals-a change that translates into 2,500 fewer Michigan patients with surgical complications each year. Estimated annual savings from this one collaborative are approximately $20 million, far exceeding the cost of administering the program. Regional collaborative improvement programs should become increasingly attractive to hospitals and physicians, as well as to national policy makers, as they seek to improve health care quality and reduce costs.


Viral clearance is associated with improved insulin resistance in genotype 1 chronic hepatitis C but not genotype 2/3.
Genotype-specific associations between hepatitis C virus (HCV) and insulin resistance (IR) have been described, but a causal relationship remains unclear. This study investigated the association between a sustained virological response (SVR) and IR after chronic HCV therapy. 2255 treatment-naive patients with chronic HCV genotype 1 or 2/3 were enrolled in two phase 3 trials of albinterferon alpha-2b versus pegylated interferon alpha-2a for 48 or 24 weeks, respectively. IR was measured before treatment and 12 weeks after treatment using homeostasis model assessment (HOMA)-IR. Paired HOMA-IR measurements were available in 1038 non-diabetic patients (497 with genotype 1; 541 with genotype 2/3). At baseline the prevalence of HOMA-IR >3 was greater in patients with genotype 1 than 2/3 (33% vs 27%; p=0.048). There was a significant reduction in the prevalence of IR in patients with genotype 1 achieving SVR (δ 10%; p<0.001), but not in genotype 1 non-responders or those with genotype 2/3. Multivariate analysis indicated that SVR was associated with a significant reduction in mean HOMA-IR in patients with genotype 1 (p=0.004), but not in those with genotype 2/3, which was independent of body mass index, alanine transaminase, γ-glutamyl transpeptidase and lipid level changes. SVR is associated with a reduction in HOMA-IR in patients with HCV genotype 1 but not in those with genotype 2/3. Genotype 1 may have a direct effect on the development of IR, independent of host metabolic factors, and may be partially reversed by viral eradication.


Characteristics, Properties and Analytical/Bioanalytical Methods of 5-Aminosalicylic Acid: A Review.
Five-aminosalicylic acid (5-ASA) is an anti-inflammatory drug indicated in the treatment of inflammatory bowel diseases such as ulcerative colitis and Crohn's disease. Among the analytical methods of quantification of 5-ASA described in the literature, the High Efficiency Liquid Chromatography stands out, a sensitive technique but with a high cost. In recent years, alternative methods have been developed, presenting efficiency and reduced cost, such as UV/visible spectrophotometric, spectrofluorescent, and electrochemical methods, techniques recommended for the application in quality control and quantification of 5-ASA in pharmaceutical forms and biological fluids. This article aims to review the physicochemical characteristics, pharmacokinetics, mechanisms of action, controlled release systems, and the different analytical and bioanalytical methods for the quantification of 5-ASA.


New anti-thrombotic drugs for stroke prevention.
Ischemic stroke is the third most common cause of death and of long-term disability and exhibits a high recurrence rate. Therefore, appropriate primary and secondary prevention is mandatory. In non-cardioembolic stroke, in addition to lifestyle changes and to targeted treatments, current guidelines recommend antiplatelet treatment. In cardioembolic stroke, Vitamin K antagonists (VKAs) are recommended. Although a favorable risk/benefit ratio of both treatments has also been demonstrated in elderly patients, registry data emphasize that such interventions are often under-used, especially in patients with atrial fibrillation (AF). Furthermore, variability in the inter-individual response to drugs has been recognized as a leading cause of event recurrence. Thus, in addition to poor adherence, efficacy and safety issues appear to be involved in the recurrence rate of stroke. In this review, we report main Registries data on adherence to stroke prevention treatment schedule. We also discuss the major limitations of "traditional" antithrombotic drugs and report Phase III study results on safety and efficacy of new antiplatelet and anticoagulant drugs, with emphasis on stroke prevention.


A virus responds instantly to the presence of the vector on the host and forms transmission morphs.
Many plant and animal viruses are spread by insect vectors. Cauliflower mosaic virus (CaMV) is aphid-transmitted, with the virus being taken up from specialized transmission bodies (TB) formed within infected plant cells. However, the precise events during TB-mediated virus acquisition by aphids are unknown. Here, we show that TBs react instantly to the presence of the vector by ultra-rapid and reversible redistribution of their key components onto microtubules throughout the cell. Enhancing or inhibiting this TB reaction pharmacologically or by using a mutant virus enhanced or inhibited transmission, respectively, confirming its requirement for efficient virus-acquisition. Our results suggest that CaMV can perceive aphid vectors, either directly or indirectly by sharing the host perception. This novel concept in virology, where viruses respond directly or via the host to the outside world, opens new research horizons, that is, investigating the impact of 'perceptive behaviors' on other steps of the infection cycle.DOI:http://dx.doi.org/10.7554/eLife.00183.001.


Analysis and characterization of herpes simplex virus after its persistence in a lymphoblastoid cell line for 15 months.
Infection of a human lymphoblastoid cell line (F-365 line containing Epstein-Barr viral capsid antigen, derived from an individual without overt signs of lymphoma, infectious mononucleosis, or leukemia) with herpes simplex virus (HSV), maintained and observed for 15 months, was characterized by the continuous production of infectious extracellular virus. By the 5th day postinfection 75% of the cells produced HSV antigen as detected by fluorescent antibody, and by the 10th day 90% did so; production continued through the 15th month. Only 11% of single isolated cells produced detectable infectious virus. HSV produced after the 3rd month formed smaller plaque in monolayer cell culture than did the parental virus. No antigenic or polypeptide change in the HSV was detected by crossed immunoelectrophoresis and sodium dodecyl sulfate-polyacrylamide gel electrophoresis analysis over the 15-month cultivation in F-365 cells. Cell susceptibility and HSV virulence did not appear to change. The HSV-lymphoblastoid cell culture provided a useful model in which to study long-term virus-cell interactions.


A cluster of aspartic residues in the extracellular loop II of PAR 4 is important for thrombin interaction and activation of platelets.
Thrombin activates platelets via proteolytic cleavage of protease-activated receptors (PARs) 1 and 4. The two PARs have distinct but complementary roles. The mechanisms responsible for PAR1 activation by thrombin have been extensively studied. However, much less is known regarding thrombin activation of PAR4, especially the potential involvement of regions of PAR4 other than the N-terminal, which is bound to the catalytic site of thrombin. We have studied PAR4 in S. cerevisiae strain MMY12, an expression system in which the GPCR receptors are connected to a Lac Z reporter gene resulting in increased β-galactosidase activity. This approach was used to assess PAR4 mutants to evaluate the contribution of different aspartic residues in facilitating PAR4 activation. Furthermore, peptides mimicking parts of the PAR4 N-terminal and the second extracellular loop (ECLII) were tested for their ability to inhibit platelet activation by thrombin. Binding of these peptides to γ-thrombin was studied by monitoring the decrease in tryptophan fluorescence intensity of thrombin. We conclude that not only the N-terminal but also the electronegative aspartic residues D224, D230 and D235 (located in ECLII) are be important for PAR4 binding to thrombin. We further suggest that they play a role for the tethered ligand binding to the receptor, as mutations also affected activation in response to a PAR4-activating peptide mimicking the new N-terminal formed after cleavage. This agrees with previous results on PAR1 and thrombin binding. We suggest that the ECLII of PAR4 could be a potential target for antithrombotic drug development.


Transcriptional Analysis and Subcellular Protein Localization Reveal Specific Features of the Essential WalKR System in Staphylococcus aureus.
The WalKR two-component system, controlling cell wall metabolism, is highly conserved among Bacilli and essential for cell viability. In Staphylococcus aureus, walR and walK are followed by three genes of unknown function: walH, walI and walJ. Sequence analysis and transcript mapping revealed a unique genetic structure for this locus in S. aureus: the last gene of the locus, walJ, is transcribed independently, whereas transcription of the tetra-cistronic walRKHI operon occurred from two independent promoters located upstream from walR. Protein topology analysis and protein-protein interactions in E. coli as well as subcellular localization in S. aureus allowed us to show that WalH and WalI are membrane-bound proteins, which associate with WalK to form a complex at the cell division septum. While these interactions suggest that WalH and WalI play a role in activity of the WalKR regulatory pathway, deletion of walH and/or walI did not have a major effect on genes whose expression is strongly dependent on WalKR or on associated phenotypes. No effect of WalH or WalI was seen on tightly controlled WalKR regulon genes such as sle1 or saouhsc_00773, which encodes a CHAP-domain amidase. Of the genes encoding the two major S. aureus autolysins, AtlA and Sle1, only transcription of atlA was increased in the ΔwalH or ΔwalI mutants. Likewise, bacterial autolysis was not increased in the absence of WalH and/or WalI and biofilm formation was lowered rather than increased. Our results suggest that contrary to their major role as WalK inhibitors in B. subtilis, the WalH and WalI proteins have evolved a different function in S. aureus, where they are more accessory. A phylogenomic analysis shows a striking conservation of the 5 gene wal cluster along the evolutionary history of Bacilli, supporting the key importance of this signal transduction system, and indicating that the walH and walI genes were lost in the ancestor of Streptococcaceae, leading to their atypical 3 wal gene cluster, walRKJ.


Psychosocial profile of institutionalised street children in Alexandria, Egypt: a comparative study with school children.
The phenomenon of street children in Egypt constitutes a public health concern. This study aimed to investigate the characteristics of institutionalised street children in Alexandria, to compare the prevalence of substance abuse and conduct disorder between street children and school children, and to identify predictors of these mental health outcomes among street children. Institutionalised street children (n = 102) participated in a cross-sectional comparative study with a matched group of school children (n = 156). An interviewing questionnaire was used to assess demographic characteristics and substance use. Conduct disorder was measured using the Revised Ontario Child Health study scale. Poverty, family breakdown, and domestic violence were the main reasons for street children having left home. Street children recorded significantly higher rates of substance use (9.8%) and conduct disorder (35.3%) compared to school children. In street children, smoking was a significant predictor of substance use and conduct disorder. Other predictors of conduct disorder included physical illness and having 5 to 7 siblings. Substance abuse and conduct disorder were present among institutionalised street children at higher rates than school children. Absence of basic life needs and disrupted families constituted the main reasons for leaving home. Interventions at the governmental and non-governmental levels are needed.


Aberrant methylation of the Human Hedgehog interacting protein (HHIP) gene in pancreatic neoplasms.
Hedgehog pathway overactivity has been implicated in the development of a variety of human cancers. The Human Hedgehog interacting protein (HHIP), a negative regulator of hedgehog signaling, has been shown to be underexpressed in pancreatic cancers. In this study we determined if the HHIP gene is a target for genetic and epigenetic alterations. While no mutations of HHIP were identified, we found complete methylation of the HHIP promoter CpG island in three pancreatic cancer cell lines, and partial hypermethylation in 13/17 (80%) pancreatic cancer cell lines, 35/75 (46%) primary pancreatic cancers and 14/18 (78%) pancreatic cancer xenografts, but no methylation in 13 normal pancreata. In pancreatic cancer cell lines, complete methylation was associated with absent or reduced HHIP expression by real-time RT-PCR. HHIP expression could be restored in methylated cell lines using epigenetic modifier drugs. Restoring the expression of HHIP in pancreatic cancer cells by 5-aza-2'-deoxycytidine led to a decrease in Gli reporter activity, consistent with downregulation of Hedgehog signaling. These results indicate in some pancreatic adenocarcinomas that HHIP is epigenetically inactivated by promoter methylation, and its silencing could contribute to the increased Hedgehog signaling observed in pancreatic neoplasms.


Tobacco Quitlines May Help Exclusive Vapers Quit: An Analysis of Data From an Employer-Sponsored Quitline.
Numerous studies have supported the effectiveness and cost-effectiveness of quitlines for cigarette smoking cessation, but how effective they are for vaping cessation has not been established. Our secondary analysis examined quitline data on participants in employer-sponsored quitlines in the US run by Optum, Inc to compare quit rates among callers who were exclusive vapers (n = 1,194) with those who were exclusive smokers (n = 22,845). We examined data from the time of quitline enrollment, January 2017, through October 2020. Before adjusting for differences in demographics, quitline treatment engagement, and unadjusted quit rates, the quit rates for vapers were significantly higher. However, after adjusting for demographic and treatment engagement variables, 6-month quit rates among vapers did not differ significantly from rates among smokers.


Antibiotics and the nervous system: More than just the microbes?
The use of antibiotics has recently risen to prominence in neuroscience due to their potential value in studying the microbiota-gut-brain axis. In this context they have been largely employed to illustrate the many influences of the gut microbiota on brain function and behaviour. Much of this research is bolstered by the abnormal behaviour seen in germ-free animals and other well-controlled experiments. However, this literature has largely failed to consider the neuroactive potential of antibiotics themselves, independent from, or in addition to, their microbicidal effects. This is problematic, as clinical as well as experimental literature, largely neglected through the past decade, has clearly demonstrated that broad classes of antibiotics are neuroactive or neurotoxic. This is true even for some antibiotics that are widely regarded as not absorbed in the intestinal tract, and is especially concerning when considering the highly-concentrated and widely-ranging doses that have been used. In this review we will critically survey the clinical and experimental evidence that antibiotics may influence a variety of nervous system functions, from the enteric nervous system through to the brain and resultant behaviour. We will discuss substantial evidence which clearly suggests neuro-activity or -toxicity by most classes of antibiotics. We will conclude that, while evidence for the microbiota-gut-brain axis remains strong, clinical and experimental studies which employ antibiotics to probe it must consider this potential confound.


Q fever: an under-reported reportable communicable disease.
The objective of this study was to provide real-world clinical laboratory-based data to supplement Centers for Disease Control and Prevention (CDC) reporting of Q fever. We analysed titre results of specimens submitted to a large US clinical laboratory for Coxiella burnetii IgG antibody testing from 2010 through 2016. Presumptive Q fever was defined as acute (phase II IgG titre ⩾1:128, phase I titre <1:1024) or chronic (phase I IgG titre ⩾1:1024), based on the results from a single serum specimen. During 2010-2016, an average of 328 presumptive acute Q fever cases were identified at Quest each year, nearly three times the annual average reported to the CDC (122). During the same period, the number of chronic cases identified annually at Quest Diagnostics (34) was similar to that reported to the CDC (29). These findings suggest that CDC data may underestimate the incidence of acute Q fever.


Omega-3 therapeutic supplementation in a patient with metastatic adenocarcinoma of the pancreas with muscle mass depletion.
Pancreatic adenocarcinoma has an extremely poor prognosis. With the best available treatments, the median overall survival duration is still less than 1 year. Most patients develop anorexia and major muscle mass loss that interfere with chemotherapy tolerance and survival. In this paper, we present a case in which these problems were a major concern. A multidisciplinary approach with chemotherapy and close nutritional support permitted better control of the disease and longer survival. We also review the literature on nutritional interventions that show an improvement in quality of life and survival in these patients.


Nucleosomal histone proteins of L. donovani: a combination of recombinant H2A, H2B, H3 and H4 proteins were highly immunogenic and offered optimum prophylactic efficacy against Leishmania challenge in hamsters.
The present study includes cloning and expression of recombinant Leishmania donovani histone proteins (rLdH2B, rLdH3, rLdH2A and rLdH4), assessment of their immunogenicity in Leishmania infected cured patients/endemic contacts as well as in cured hamsters and finally evaluation of their prophylactic efficacy in hamsters against L. donovani challenge. All recombinant proteins were expressed and purified from the heterologous bacterial host system. Leishmania infected cured patients/endemic contacts as well as cured hamsters exhibited significantly higher proliferative responses to individual recombinant histones and their pooled combination (rLdH2B+rLdH3+rLdH2A+rLdH4) than those of L.donovani infected hosts. The L.donovani soluble antigens (SLD) stimulated PBMCs of cured/exposed and Leishmania patients to produce a mixed Thl/Th2-type cytokine profile, whereas rLdH2B, rLdH3, rLdH2A, rLdH4 and pooled combination (rLdH2-4) stimulated the production of Th1 cytokines IFN-γ, IL-12 and TNF-α but not Th2 cytokines IL-4 or IL-10. The immunogenicity of these histone proteins along with their combination was also checked in cured hamsters where they stimulated higher lymphoproliferation and Nitric oxide production in lymphocytes of cured hamsters than that of infected controls. Moreover, significantly increased IgG2 response, an indicative of cell mediated immunity, was observed in cured hamsters against these individual proteins and their combination as compared to infected hamsters. Further, it was demonstrated that rLdH2B, rLdH3, rLdH2A and rLdH4 and pooled combination were able to provide considerable protection for hamsters against L. donovani challenge. The efficacy was supported by the increased inducible Nitric Oxide Synthase (iNOS) mRNA transcripts and Th1-type cytokines--IFN-γ, IL-12 and TNF-α and down-regulation of IL-4, IL-10 and TGF-β. Hence, it is inferred that pooled rLdH2-4 elicits Thl-type of immune responses exclusively and confer considerable protection against experimental Visceral Leishmaniasis.


Pharmaconutrition administration on outcomes of elective oncological surgery for gastrointestinal malignancies: is timing everything?-a review of published meta-analyses until the end of 2016.
The last 25 years have seen an increasing number of publications attesting the benefits of pharmaconutrition in the management of patients undergoing elective oncological gastrointestinal surgery. A number of randomized controlled trials and meta-analyses suggest the use of pharmaconutrition in this group of patients produces superior outcomes to standard nutritional formulations in terms of postoperative infective complications, anastomotic breakdown and length of hospital stay. The use of pharmaconutrition products, therefore, has gained increasing acceptance for use in elective gastrointestinal oncological surgical populations and been incorporated into practice guidelines. However, there remains doubts as to the robustness of such data supporting these recommendation. This is because studies reporting improved outcomes with pharmaconutrition (I) frequently compare this intervention with non-equivalent control groups; (II) do not report on the actual nutritional provision received by study participants; (III) overlook the potential impact of industry funding on research conducted and (IV) do not adopt a multi-disciplinary approach to the research undertaken. For these reasons, a critical re-appraisal of the use and recommendations of pharmaconutrition in this group of patients is urgently warranted to resolve some of the above mentioned issues. The aim of this review was to analyse meta-analyses published until the end of 2016 in this area to highlight the strengths and weakness of the present research and prioritize certain areas which will benefit from future research.


The role of mental health professionals in political asylum processing.
Applying for asylum in the United States can be a strenuous process for both applicants and immigration attorneys. Mental health professionals with expertise in asylum law and refugee trauma can make important contributions to such cases. Not only can mental health professionals provide diagnostic information that may support applicants' claims, but they can evaluate how culture and mental health symptoms relate to perceived deficits in credibility or delays in asylum application. They can define mental health treatment needs and estimate the possible effects of repatriation on mental health. Mental health professionals can also provide supportive functions for clients as they prepare for testimony. Finally, in a consultative role, mental health experts can help immigration attorneys to improve their ability to elicit trauma narratives from asylum applicants safely and efficiently and to enhance their resilience in response to vicarious trauma and burnout symptoms arising from work with asylum seekers.