Validation of admittance computed left ventricular volumes against real-time three-dimensional echocardiography in the porcine heart.
The admittance and Wei's equation is a new technique for ventricular volumetry to determine pressure-volume relations that addresses traditional conductance-related issues of parallel conductance and field correction factor. These issues with conductance have prevented researchers from obtaining real-time absolute ventricular volumes. Moreover, the time-consuming steps involved in processing conductance catheter data warrant the need for a better catheter-based technique for ventricular volumetry. We aimed to compare the accuracy of left ventricular (LV) volumetry between the new admittance catheterization technique and transoesophageal real-time three-dimensional echocardiography (RT3DE) in a large-animal model. Eight anaesthetized pigs were used. A 7 French admittance catheter was positioned in the LV via the right carotid artery. The catheter was connected to an admittance control unit (ADVantage; Transonic Scisense Inc.), and data were recorded on a four-channel acquisition system (FA404; iWorx Systems). Admittance catheterization data and transoesophageal RT3DE (X7-2; Philips) data were simultaneously obtained with the animal ventilated, under neuromuscular blockade and monitored in baseline conditions and during dobutamine infusion. Left ventricular volumes measured from admittance catheterization (Labscribe; iWorx Systems) and RT3DE (Qlab; Philips) were compared. In a subset of four animals, admittance volumes were compared with those obtained from traditional conductance catheterization (MPVS Ultra; Millar Instruments). Of 37 sets of measurements compared, admittance- and RT3DE-derived LV volumes and ejection fractions at baseline and in the presence of dobutamine exhibited general agreement, with mean percentage intermethod differences of 10% for end-diastolic volumes, 14% for end-systolic volumes and 9% for ejection fraction; the respective intermethod differences between admittance and conductance in eight data sets compared were 11, 11 and 12%. Admittance volumes were generally higher than those obtained by RT3DE, especially among the larger ventricles. It is concluded that it is feasible to derive pressure-volume relations using admittance catheterization in large animals. This study demonstrated agreements between admittance and RT3DE to within 10-14% mean intermethod difference in the estimation of LV volumes. Further investigation will be required to examine the accuracy of volumes in largest ventricles, where intermethod divergence is greatest.


What MRI Findings Predict Failure 10 Years After Surgery for Femoroacetabular Impingement?
Magnetic resonance arthrogram (MRA) with radial cuts is presently the best available preoperative imaging study to evaluate chondrolabral lesions in the setting of femoroacetabular impingement (FAI). Existing followup studies for surgical treatment of FAI have evaluated predictors of treatment failure based on preoperative clinical examination, intraoperative findings, and conventional radiography. However, to our knowledge, no study has examined whether any preoperative findings on MRA images might be associated with failure of surgical treatment of FAI in the long term. The purposes of this study were (1) to identify the preoperative MRA findings that are associated with conversion to THA, any progression of osteoarthritis, and/or a Harris hip score of < 80 points after acetabuloplasty and/or osteochondroplasty of the femoral head-neck junction through a surgical hip dislocation (SHD) for FAI at a minimum 10-year followup; and (2) identify the age of patients with symptomatic FAI when these secondary degenerative findings were detected on preoperative radial MRAs. We retrospectively studied 121 patients (146 hips) who underwent acetabuloplasty and/or osteochondroplasty of the femoral head-neck junction through SHD for symptomatic anterior FAI between July 2001 and March 2003. We excluded 35 patients (37 hips) with secondary FAI after previous surgery and 11 patients (12 hips) with Legg-Calvé-Perthes disease. All patients underwent preoperative MRA to further specify chondrolabral lesions except in 19 patients (32 hips) including 17 patients (20 hips) who presented with an MRI from an external institution taken with a different protocol, 10 patients with no preoperative MRA because the patients had already been operated on the contralateral side with a similar appearance, and two patients (two hips) refused MRA because of claustrophobia. This resulted in 56 patients (65 hips) with idiopathic FAI and a preoperative MRA. Of those, three patients (three hips) did not have minimal 10-year followup (one patient died; two hips with followup between 5 and 6 years). The remaining patients were evaluated clinically and radiographically at a mean followup of 11 years (range, 10-13 years). Thirteen pathologic radiographic findings on the preoperative MRA were evaluated for an association with the following endpoints using Cox regression analysis: conversion to THA, radiographic evidence of any progression of osteoarthritis, and/or a Harris hip score of < 80. The age of the patient when each degenerative pattern was found on the preoperative MRA was recorded. The following MRI findings were associated with one or more of our predefined failure endpoints: cartilage damage exceeding 60° of the circumference had a hazard ratio (HR) of 4.6 (95% confidence interval [CI], 3.6-5.6; p = 0.003) compared with a damage of less than 60°, presence of an acetabular rim cyst had a HR of 4.1 (95% CI, 3.1-5.2; p = 0.008) compared with hips without these cysts, and presence of a sabertooth osteophyte had a HR of 3.2 (95% CI, 2.3-4.2; p = 0.013) compared with hips without a sabertooth osteophyte. The degenerative pattern associated with the youngest patient age when detected on preoperative MRA was the sabertooth osteophyte (lower quartile 27 years) followed by cartilage damage exceeding 60° of the circumference (28 years) and the presence of an acetabular rim bone cyst (31 years). Preoperative MRAs with radial cuts reveal important findings that may be associated with future failure of surgical treatment for FAI. Most of these factors are not visible on conventional radiographs or standard hip MRIs. Preoperative MRA evaluation is therefore strongly recommended on a routine basis for patients undergoing these procedures. Findings associated with conversion to arthroplasty, radiographic evidence of any progression of osteoarthritis, and/or a Harris hip score of < 80 points should be incorporated into the decision-making process in patients being evaluated for joint-preserving hip surgery. Level III, therapeutic study.


Signal-transducing adaptor molecules STAM1 and STAM2 are required for T-cell development and survival.
We previously reported that the STAM family members STAM1 and STAM2 are phosphorylated on tyrosine upon stimulation with cytokines through the gammac-Jak3 signaling pathway, which is essential for T-cell development. Mice with targeted mutations in either STAM1 or STAM2 show no abnormality in T-cell development, and mice with double mutations for STAM1 and STAM2 are embryonically lethal; therefore, here we generated mice with T-cell-specific double mutations for STAM1 and STAM2 using the Cre/loxP system. These STAM1(-/-) STAM2(-/-) mice showed a significant reduction in thymocytes and a profound reduction in peripheral mature T cells. In proliferation assays, thymocytes derived from the double mutant mice showed a defective response to T-cell-receptor (TCR) stimulation by antibodies and/or cytokines, interleukin-2 (IL-2) and IL-7. However, signaling events downstream of receptors for IL-2 and IL-7, such as activations of STAT5, extracellular signal-regulated kinase (ERK), and protein kinase B (PKB)/Akt, and c-myc induction, were normal in the double mutant thymocytes. Upon TCR-mediated stimulation, prolonged activations of p38 mitogen-activated protein kinase and Jun N-terminal protein kinase were seen, but activations of ERK, PKB/Akt, and intracellular calcium flux were normal in the double mutant thymocytes. When the cell viability of cultured thymocytes was assessed, the double mutant thymocytes died more quickly than controls. These results demonstrate that the STAMs are indispensably involved in T-cell development and survival in the thymus through the prevention of apoptosis but are dispensable for the proximal signaling of TCR and cytokine receptors.


Neutrophil CD18-dependent arrest on intercellular adhesion molecule 1 (ICAM-1) in shear flow can be activated through L-selectin.
Neutrophil emigration through endothelial cells under shear flow involves several adhesion processes including cell rolling, arrest, and transmigration. Rolling is mediated by selectins, while arrest and transmigration both require activated CD18 integrins. One mode of CD18 activation is via selectins expressed on neutrophils and endothelial cells. We have recently reported that cross-linking of L-selectin (CD62L) resulted in the rapid activation of CD18-dependent adhesion. In the current study, we examine whether binding of E-selectin (CD62E) and L-selectin can activate neutrophil CD18-dependent adhesion under shear flow. Human ICAM-1 (CD54) and E-selectin were co-transfected into L cells. Neutrophil capture, rolling, and arrest on these monolayers were quantitated in a parallel plate flow chamber at a wall shear stress of 2.0 dyne/cm2. Under these conditions, E-selectin supported cell capture and rolling on the monolayer, but did not trigger CD18-mediated cell arrest within 200 microm of rolling. However, when neutrophils were treated with anti-L-selectin mAb and cross-linked with a secondary mAb, approximately 50% of the cells arrested within 54 microm. Cell arrest was also observed in response to IL-8 stimulation. A subthreshold level of IL-8 in combination with L-selectin cross-linking potentiated the level of cell arrest due to either stimulus alone. The transition to cell arrest involved both LFA-1 (CD11a/CD18) and Mac-1 (CD11b/CD18). Blocking either subunit alone failed to reduce arrest, while blocking both molecules with mAbs reduced the number to baseline levels. These data support the conclusion that L-selectin, but not E-selectin, can signal the transition from neutrophil rolling to cell arrest under shear flow.


Efficacy of Therapeutic Aquatic Exercise vs Physical Therapy Modalities for Patients With Chronic Low Back Pain: A Randomized Clinical Trial.
Therapeutic aquatic exercise is frequently offered to patients with chronic low back pain, but its long-term benefits are unclear. To assess the long-term effects of therapeutic aquatic exercise on people with chronic low back pain. This 3-month, single-blind randomized clinical trial with a 12-month follow-up period was performed from September 10, 2018, to March 12, 2019, and the trial follow-up was completed March 17, 2020. A total of 113 people with chronic low back pain were included in the experiment. Participants were randomized to either the therapeutic aquatic exercise or the physical therapy modalities group. The therapeutic aquatic exercise group received aquatic exercise, whereas the physical therapy modalities group received transcutaneous electrical nerve stimulation and infrared ray thermal therapy. Both interventions were performed for 60 minutes twice a week for 3 months. The primary outcome was disability level, which was measured using the Roland-Morris Disability Questionnaire; scores range from 0 to 24, with higher scores indicating more severe disability. Secondary outcomes included pain intensity, quality of life, sleep quality, recommendation of intervention, and minimal clinically important difference. Intention-to-treat and per-protocol analyses were performed. Of the 113 participants, 59 were women (52.2%) (mean [SD] age, 31.0 [11.5] years). Participants were randomly allocated into the therapeutic aquatic exercise group (n = 56) or the physical therapy modalities group (n = 57), and 98 patients (86.7%) completed the 12-month follow-up. Compared with the physical therapy modalities group, the therapeutic aquatic exercise group showed greater alleviation of disability, with adjusted mean group differences of -1.77 (95% CI, -3.02 to -0.51; P = .006) after the 3-month intervention, -2.42 (95% CI, -4.13 to -0.70; P = .006) at the 6-month follow-up, and -3.61 (95% CI, -5.63 to -1.58; P = .001) at the 12-month follow-up (P < .001 for overall group × time interaction). At the 12-month follow-up point, improvements were significantly greater in the therapeutic aquatic exercise group vs the physical therapy modalities group in the number of participants who met the minimal clinically important difference in pain (at least a 2-point improvement on the numeric rating scale) (most severe pain, 30 [53.57%] vs 12 [21.05%]; average pain, 14 [25%] vs 11 [19.30%]; and current pain, 22 [39.29%] vs 10 [17.54%]) and disability (at least a 5-point improvement on the Roland-Morris Disability Questionnaire) (26 [46.43%] vs 4 [7.02%]). One of the 56 participants (1.8%) in the therapeutic aquatic exercise group vs 2 of the 57 participants (3.5%) in the physical therapy modalities group experienced low back pain and other pains related to the intervention. The therapeutic aquatic exercise program led to greater alleviation in patients with chronic low back pain than physical therapy modalities and had a long-term effect up to 12 months. This finding may prompt clinicians to recommend therapeutic aquatic exercise to patients with chronic low back pain as part of treatment to improve their health through active exercise rather than relying on passive relaxation. Chinese Clinical Trial Registry: ChiCTR1800016396.


Dynamical characteristics common to neuronal competition models.
Models implementing neuronal competition by reciprocally inhibitory populations are widely used to characterize bistable phenomena such as binocular rivalry. We find common dynamical behavior in several models of this general type, which differ in their architecture in the form of their gain functions, and in how they implement the slow process that underlies alternating dominance. We focus on examining the effect of the input strength on the rate (and existence) of oscillations. In spite of their differences, all considered models possess similar qualitative features, some of which we report here for the first time. Experimentally, dominance durations have been reported to decrease monotonically with increasing stimulus strength (such as Levelt's "Proposition IV"). The models predict this behavior; however, they also predict that at a lower range of input strength dominance durations increase with increasing stimulus strength. The nonmonotonic dependency of duration on stimulus strength is common to both deterministic and stochastic models. We conclude that additional experimental tests of Levelt's Proposition IV are needed to reconcile models and perception.


Long-read sequence assembly of the gorilla genome.
Accurate sequence and assembly of genomes is a critical first step for studies of genetic variation. We generated a high-quality assembly of the gorilla genome using single-molecule, real-time sequence technology and a string graph de novo assembly algorithm. The new assembly improves contiguity by two to three orders of magnitude with respect to previously released assemblies, recovering 87% of missing reference exons and incomplete gene models. Although regions of large, high-identity segmental duplications remain largely unresolved, this comprehensive assembly provides new biological insight into genetic diversity, structural variation, gene loss, and representation of repeat structures within the gorilla genome. The approach provides a path forward for the routine assembly of mammalian genomes at a level approaching that of the current quality of the human genome.


Theoretical comparison of three X-ray phase-contrast imaging techniques: propagation-based imaging, analyzer-based imaging and grating interferometry.
Various X-ray phase-contrast imaging techniques have been developed and applied over the last twenty years in different domains, such as material sciences, biology and medicine. However, no comprehensive inter-comparison exists in the literature. We present here a theoretical study that compares three among the most used techniques: propagation-based imaging (PBI), analyzer-based imaging (ABI) and grating interferometry (GI). These techniques are evaluated in terms of signal-to-noise ratio, figure of merit and spatial resolution. Both area and edge signals are considered. Dependences upon the object properties (absorption, phase shift) and the experimental acquisition parameters (energy, system point-spread function etc.) are derived and discussed. The results obtained from this analysis can be used as the reference for determining the most suitable technique for a given application.


The accessory heads of flexor pollicis longus and flexor digitorum profundus: Incidence and morphology.
Kiloh-Nevin syndrome caused by compressive neuropathy of the anterior interosseous nerve in the forearm is believed to occur because of its compression by the accessory head of flexor pollicis longus (FPLah). Gantzer described two accessory muscles, the more frequent is the FPLah and the less frequently observed is the flexor digitorum profundus accessory head (FDPah). Many studies have reported the prevalence, origin, insertion, nerve supply, and relations of these accessory muscles, most of them focusing on the FPLah. This study was designed to investigate the prevalence, morphology, relation to median and anterior interosseous nerve, and also the coexistence of both the accessory heads. A total of 126 upper limbs of the embalmed cadavers were examined in this study. Fifty-eight limbs (46.03%) showed the presence of the FPLah and 18 limbs (14.28%) had the FDPah. The most common origin of both the accessory muscle bellies was from the under surface of the flexor digitorum superficialis. The FPLah inserted into the FPL muscle at varying levels with 80% inserting into the proximal third of FPL, whereas the FDPah in all cases ended near the level of the wrist joining with one or more tendons of the FDP. Clinical implication of the variation is discussed.


A study to determine the nitroglycerin ointment dose and dosing interval that best promote the healing of chronic anal fissures.
The aim of this study was to determine the optimal dose and dosing interval of nitroglycerin ointment to heal chronic anal fissures. A randomized, double-blind study of intra-anally applied nitroglycerin ointment (Anogesic) was conducted in 17 centers in 304 patients with chronic anal fissures. The patients were randomly assigned to one of eight treatment regimens (0.0, 0.1, 0.2, 0.4 percent nitroglycerin ointment applied twice or three times per day), for up to eight weeks. A dose-measuring device standardized the delivery of 374 mg ointment. Healing of fissures (complete reepithelialization) was assessed by physical examination using an observer unaware of treatment allocation. The subjects assessed pain intensity daily by completing a diary containing a visual analog scale for average pain intensity for the day, the worst pain intensity for the day, and pain intensity at the last defecation. There were no significant differences in fissure healing among any of the treatment groups; all groups, including placebo had a healing rate of approximately 50 percent. This rate of placebo response was inexplicably higher than previously reported in the literature. Treatment with 0.4 percent (1.5 mg) nitroglycerin ointment was associated with a significant (P < 0.0002) decrease in average pain intensity compared with vehicle as assessed by patients with a visual analog scale. The decreases were observed by Day 4 of treatment. At 8 weeks the magnitude of the difference between 0.4 percent nitroglycerin and control was a 21 percent reduction in average pain. Treatment was well tolerated, with only 3.29 percent of patients discontinuing treatment because of headache. Headaches were the primary adverse event and were dose related. Nitroglycerin ointment did not alter healing but significantly and rapidly reduced the pain associated with chronic anal fissures.


Natural head position: An overview.
Cephalometrics has given us a different perspective of interpreting various skeletal problems in the dentofacial complex. Natural head position (NHP) is a reproducible, physiologically determined aspect of function. To determine NHP, a horizontal or vertical reference line outside the crania was used, but preference was given generally to the horizontal. Various intra and extracranial cephalometric horizontal reference planes have been used to formulate diagnosis and plan individualized treatment for an integrated correction of the malocclusion cephalometrics is constantly undergoing refinements in its techniques and analyses to improve the clinical applications. Even though various methods for establishing NHP have been proposed, still it remains a challenge to the clinicians to implement the concept of NHP thoroughly in all the stages of treatment because of practical difficulties in the clinical scenario.


Analysis of a Prophage Gene Frequency Revealed Population Variation of 'Candidatus Liberibacter asiaticus' from Two Citrus-Growing Provinces in China.
Prophages are important genetic elements of bacterial genomes and are involved in lateral gene transfer, pathogenicity, environmental adaptations, and interstrain genetic variability. In this study, the sequence of a prophage terminase gene of 'Candidatus Liberibacter asiaticus', a bacterium associated with citrus Huanglongbing (HLB), was selected as a molecular marker to assess the genetic variation in two 'Ca. L. asiaticus' populations from geographically distinct provinces (Guangdong and Yunnan) in China. The frequency of the prophage terminase gene was 15.8% (19/120) in Guangdong (altitude <500 m) and 97.4% (38/39) in Yunnan (altitude >2,000 m). The difference was highly significant (P < 0.0001) based on χ2 analysis. However, the partial prophage terminase gene sequences obtained from 10 Guangdong strains and 6 Yunnan strains were identical or highly similar, suggesting that at least some bacterial strains in the two locations shared a common recent origin. This is the first report on population variation of 'Ca. L. asiaticus' in China, where HLB was first described. The population variation of 'Ca. L. asiaticus' in the two geographical regions and the related HLB epidemiology were discussed.


Nebulin as a length regulator of thin filaments of vertebrate skeletal muscles: correlation of thin filament length, nebulin size, and epitope profile.
Nebulin, a family of giant proteins with size-variants from 600 to 900 kD in various skeletal muscles, have been proposed to constitute a set of inextensible filaments anchored at the Z line (Wang, K., and J. Wright. 1988. J. Cell Biol. 107:2199-2212). This newly discovered filament of the skeletal muscle sarcomere is an attractive candidate for a length-regulating template of thin filaments. To evaluate this hypothesis, we address the question of coextensiveness of nebulin and the thin filament by searching for a correlation between the size of nebulin variants and the length distribution of the thin filaments in several skeletal muscles. A positive linear correlation indeed exists for a group of six skeletal muscles that display narrow thin filament length distributions. To examine the molecular and architectural differences of nebulin size-variants, we carried out immunoelectron microscopic studies to map out epitope profiles of nebulin variants in these muscles. For this purpose, a panel of mAbs to distinct nebulin epitopes was produced against rabbit nebulin purified by an improved protocol. Epitope profiles of nebulin variants in three skeletal muscles revealed that (a) nebulin is inextensible since nebulin epitopes maintain a fixed distance to the Z line irrespective of the degree of sarcomere stretch; (b) a single nebulin polypeptide spans a minimal distance of 0.9 microns from the Z line; (c) nebulin contains repeating epitopes that are spaced at 40 nm or its multiples; (d) nebulin repeats coincide with thin filament periodicity; (e) nebulin variants differ mainly at either or both ends; and (f) nebulin remains in the sarcomere in actin-free sarcomeres produced by gelsolin treatment. Together, these data suggest that nebulin is an inextensible full-length molecular filament that is coextensive with thin filaments in skeletal muscles. We propose that nebulin acts as a length-regulating template that determines thin filament length by matching its large number of 40-nm repeating domains with an equal number of helical repeats of the actin filaments.


Atrial fibrillation and sinus node dysfunction in human ankyrin-B syndrome: a computational analysis.
Ankyrin-B is a multifunctional adapter protein responsible for localization and stabilization of select ion channels, transporters, and signaling molecules in excitable cells including cardiomyocytes. Ankyrin-B dysfunction has been linked with highly penetrant sinoatrial node (SAN) dysfunction and increased susceptibility to atrial fibrillation. While previous studies have identified a role for abnormal ion homeostasis in ventricular arrhythmias, the molecular mechanisms responsible for atrial arrhythmias and SAN dysfunction in human patients with ankyrin-B syndrome are unclear. Here, we develop a computational model of ankyrin-B dysfunction in atrial and SAN cells and tissue to determine the mechanism for increased susceptibility to atrial fibrillation and SAN dysfunction in human patients with ankyrin-B syndrome. Our simulations predict that defective membrane targeting of the voltage-gated L-type Ca(2+) channel Cav1.3 leads to action potential shortening that reduces the critical atrial tissue mass needed to sustain reentrant activation. In parallel, increased fibrosis results in conduction slowing that further increases the susceptibility to sustained reentry in the setting of ankyrin-B dysfunction. In SAN cells, loss of Cav1.3 slows spontaneous pacemaking activity, whereas defects in Na(+)/Ca(2+) exchanger and Na(+)/K(+) ATPase increase variability in SAN cell firing. Finally, simulations of the intact SAN reveal a shift in primary pacemaker site, SAN exit block, and even SAN failure in ankyrin-B-deficient tissue. These studies identify the mechanism for increased susceptibility to atrial fibrillation and SAN dysfunction in human disease. Importantly, ankyrin-B dysfunction involves changes at both the cell and tissue levels that favor the common manifestation of atrial arrhythmias and SAN dysfunction.


Axillary temperature measurement: a less stressful alternative for hospitalised cats?
Rectal temperature measurement (RTM) can promote stress and defensive behaviour in hospitalised cats. The aim of this study was to assess if axillary temperature measurement (ATM) could be a reliable and less stressful alternative for these animals. In this prospective study, paired rectal and axillary temperatures were measured in 42 cats, either by a veterinarian or a student. To assess the impact of these procedures on the cat's stress state, their heart rate was checked and a cat stress score (CSS) was defined and graded from 1 (relaxed) to 5 (terrified). A moderate correlation was found between RTM and ATM (r=0.52; P<0.0001). RTM was on average 0.9 °C (1.6 °F) higher than ATM (P<0.0001), although a wide variation was found in the difference between these two measurements (-2.1 °C to 3.6 °C (-3.8 °F to 6.5 °F)). ATM failed to identify hypothermia in 25 per cent of the cases and hyperthermia in 19 per cent of the cases but may be considered less stressful than RTM. Indeed, RTM induced a mildly greater increase in heart rate (+6 bpm; P=0.01) and in CSS (+0.2; P=0.001) than ATM. The results were not affected by operator type. In conclusion, RTM should remain the standard method to obtain accurate temperatures in cats.


Adequate prenatal care reduces the risk of adverse pregnancy outcomes in women with history of infertility: a nationwide population-based study.
To investigate the effects of various measures of prenatal care on adverse pregnancy outcomes in women with a history of infertility. A retrospective cohort study. Data were derived by linking 2 large nationwide population-based datasets, the National Health Insurance Research Database and Taiwan Birth Certificate Registry. The study sample included 15,056 women with an infertility diagnosis and 60,224 randomly selected women without infertility matched to the study sample by maternal age. A conditional logistic regression analysis was performed for the analysis. Women diagnosed with infertility respectively had 1.39 (95% CI, 1.06~1.83), 1.15 (95% CI, 1.08~1.24), 1.13 (95% CI, 1.08~1.18), and 1.08 (95% CI, 1.05~1.12) higher odds of having very low birth weight (VLBW) babies, preterm births, labor complications, and cesarean sections (CSs) compared to women without infertility. Inadequate numbers of total and major prenatal visits and late initiation of prenatal care increased the risks of adverse pregnancy outcomes in women with infertility, especially the risk of a VLBW baby. However, no significant associations were found for the risks of adverse birth outcomes in infertile women with adequate prenatal care compared to fertile women with adequate care. Study findings suggest that adequate prenatal care can reduce the risk of adverse pregnancy outcomes in women with infertility.


The two-year progression of structural and functional cerebral MRI in amyotrophic lateral sclerosis.
MRI has emerged as one of several urgently needed candidate disease progression biomarkers for the neurodegenerative disorder amyotrophic lateral sclerosis (ALS), not least due to its unique ability to non-invasively assess structural and functional cerebral pathology. We sought to identify the extent of detectable change in cerebral MRI metrics over a more prolonged period. Analysis of multi-modal MRI data was performed in a cohort of sixteen patients (13 ALS and 3 with primary lateral sclerosis) in whom it was possible to acquire six-monthly images over two years. Structural brain changes were assessed using voxel-based morphometry of grey matter and shape analysis of sub-cortical grey matter structures, tract-based spatial statistics of diffusion tensor imaging (DTI) metrics optimized for longitudinal analysis in the white matter, as well as whole brain voxel-wise statistics of DTI metrics. Changes in resting state functional MRI (rs-fMRI) were investigated via independent component and dual regression analyses of functional connectivity (FC), controlled for confounding effects of grey matter decline. Both linear changes with time and brain changes correlated with revised ALS functional rating score (ALSFRS-R) decline were studied. Widespread and progressive reductions in grey matter were observed in the precentral gyri and posterior cingulate cortex, as well as progressive local atrophy of the thalamus, caudate, and pallidum bilaterally, and right putamen, hippocampus and amygdala. The most prominent DTI tract-based changes were in the superior longitudinal fasciculi and corpus callosum. More widespread areas of DTI changes included the thalami and caudate nuclei, hippocampi and parahippocampal gyri, insular cortices, anterior and posterior cingulate gyri, frontal operculum and cerebellum. FC decreases were noted between the sensorimotor resting state network and the frontal pole, between a network comprising both thalami and an area in the visual cortex, in relation to both time from baseline and ALSFRS-R decline. FC increases between the left primary motor cortex and left fronto-parietal network were seen for both statistical approaches. A longer period of follow-up, though necessarily involving more slowly-progressive cases, demonstrated widespread changes in both grey and white matter structural MRI measures. The mixed picture of regional decreases and increases in FC is compatible with compensatory change, in what should be viewed as a brain-based disease characterised by larger-scale disintegration of motor and frontal projection cerebral networks.


Evaluation of a two dimensional analysis method as a screening and evaluation tool for anterior cruciate ligament injury.
Increased knee valgus predicts the risk of anterior cruciate ligament (ACL) injury, particularly in women. Reducing injury rates thus relies on detecting and continually evaluating people with relatively large valgus motions. To examine the potential of a two dimensional (2D) video analysis method for screening for excessive valgus. Ten female and 10 male National Collegiate Athletic Association basketball players had three dimensional (3D) knee valgus and two dimensional (2D) frontal plane knee angle quantified during side step, side jump, and shuttle run tasks. 3D valgus was quantified from external marker coordinates using standard techniques, and 2D data were obtained from both the frontal plane projections of these coordinates (2D-Mot) and manual digitization of digital video footage (2D-Cam). A root mean square (RMS) error was calculated between 2D-Mot and 2D-Cam data to evaluate the reliability of the latter. Correlations between 2D-Cam and 3D data (intersubject and intrasubject) were also conducted, and regression slope and r2 values obtained. 2D-Cam and 2D-Mot data were consistent for side step (RMS = 1.7 degrees) and side jump (RMS = 1.5 degrees) movements. Between subjects, 2D-Cam and 3D data correlated well for the side step (r2 = 0.58) and side jump (r2 = 0.64). Within subjects, 2D-Cam and 3D data correlated moderately for the side step (r2 = 0.25 (0.19)) and side jump (r2 = 0.36 (0.27)). The 2D-Cam method can be used to screen for excessive valgus in elite basketball players, particularly for movements occurring primarily in the frontal plane. This method may also be a useful training evaluation tool when large reductions in dynamic valgus motions are required.


Correlation between subfoveal choroidal thickness and the severity or progression of nonexudative age-related macular degeneration.
To investigate the correlation between subfoveal choroidal thickness (SFChT) and the severity or progression of nonexudative AMD. One hundred seventy-six eyes of 114 patients with nonexudative AMD were included in this study. These eyes were divided into stages I through IV, based on the Age-Related Eye Disease Study (AREDS) classification of fundus findings. Using enhanced depth imaging from spectralis domain optical coherence tomography (SD-OCT), the central retinal thickness (CRT), SFChT, and parafoveal choroidal thickness (PFChT) were measured. The area of geographic atrophy (GA) was measured from fundus autofluorescence (FAF) images, and the progression of GA was calculated using RegionFinder software. The age-adjusted SFChT levels were lower at later stages of nonexudative AMD. These measurements were as follows: 266.68 ± 12.60 (stage I: 28 eyes), 263.34 ± 9.87 (stage II: 48 eyes), 200.55 ± 8.83 (stage III: 71 eyes), and 188.34 ± 13.72 (stage IV: 29 eyes) (P = 0.0028). The age-adjusted SFChT was also negatively correlated with the best corrected visual acuity (BCVA) (estimate, -0.001; P = 0.0006). Among 16 eyes with GA at baseline, SFChT showed a negative correlation with the baseline area of GA (r = 0.5521, P = 0.0133). In addition, GA progressed more rapidly during the mean follow up of 22.19 ± 9.08 months when the SFChT was lower at baseline (r = 0.5658, P = 0.0112). Subfoveal choroidal thickness is closely related to the BCVA, the severity of nonexudative AMD, as well as the rate of GA progression. Subfoveal choroidal thickness may be a predictor of disease progression in GA cases.


Hawthorn extract for treating chronic heart failure: meta-analysis of randomized trials.
The aim of this meta-analysis was to assess the evidence from rigorous clinical trials of the use of hawthorn extract to treat patients with chronic heart failure. We searched the literature using MEDLINE, EMBASE, the Cochrane Library, CINAHL, CISCOM, and AMED. Experts on and manufacturers of commercial preparations containing hawthorn extract were asked to contribute published and unpublished studies. There were no restrictions about the language of publication. Two reviewers independently performed the screening of studies, selection, validation, data extraction, and the assessment of methodological quality. To be included, studies were required to state that they were randomized, double-blind, and placebo controlled, and used hawthorn extract monopreparations. Thirteen trials met all inclusion criteria. In most of the studies, hawthorn was used as an adjunct to conventional treatment. Eight trials including 632 patients with chronic heart failure (New York Heart Association classes I to III) provided data that were suitable for meta-analysis. For the physiologic outcome of maximal workload, treatment with hawthorn extract was more beneficial than placebo (weighted mean difference, 7 Watt; 95% confidence interval [CI]: 3 to 11 Watt; P < 0.01; n = 310 patients). The pressure-heart rate product also showed a beneficial decrease (weighted mean difference, -20; 95% CI: -32 to -8; n = 264 patients) with hawthorn treatment. Symptoms such as dyspnea and fatigue improved significantly with hawthorn treatment as compared with placebo. Reported adverse events were infrequent, mild, and transient; they included nausea, dizziness, and cardiac and gastrointestinal complaints. In conclusion, these results suggest that there is a significant benefit from hawthorn extract as an adjunctive treatment for chronic heart failure.


Influenza vaccine with squalene adjuvant: new preparation. No better than available products.
(1) Injectable influenza vaccines reduce morbidity and mortality in people over 65 years. (2) A new influenza vaccine, with an adjuvant (MF59C.1) based on squalene, is now marketed in France for people over 65, and especially those with chronic conditions at risk of influenza complications. (3) The clinical evaluation dossier contains data from about twenty immunogenicity studies in more than 4000 elderly subjects. According to a meta-analysis of these studies, there is no firm evidence that the MF59C.1 adjuvant vaccine is any better than other vaccines at inducing immunity in elderly people with chronic conditions. (4) A retrospective analysis of mortality among subjects enrolled in immunogenicity studies showed no significant difference between groups receiving the squalene adjuvant vaccine and groups receiving another influenza vaccine, either in the general population or in subsets of patients with relevant chronic conditions. (5) Local adverse effects (pain, rash, induration) and systemic adverse effects (malaise, myalgia, headache) were significantly more common after the squalene adjuvant vaccine than after other influenza vaccines. Pharmacovigilance data collected by the company show no unexpected adverse events. (6) In practice, there is no reason to prefer the squalene adjuvant vaccine to existing vaccines for elderly people, whether or not they have underlying chronic conditions.


Individual preferences for physical exercise as secondary prevention for non-specific low back pain: A discrete choice experiment.
Exercise is effective in improving non-specific low back pain (LBP). Certain components of physical exercise, such as the type, intensity and frequency of exercise, are likely to influence participation among working adults with non-specific LBP, but the value and relative importance of these components remain unknown. The study's aim was to examine such specific components and their influence on individual preferences for exercise for secondary prevention of non-specific LBP among working adults. In a discrete choice experiment, working individuals with non-specific LBP answered a web-based questionnaire. Each respondent was given ten pairs of hypothetical exercise programs and asked to choose one option from each pair. The choices comprised six attributes of exercise (i.e., type of training, design, intensity, frequency, proximity and incentives), each with either three or four levels. A conditional logit regression that reflected the random utility model was used to analyze the responses. The final study population consisted of 112 participants. The participants' preferred exercise option was aerobic (i.e., cardiovascular) rather than strength training, group exercise with trainer supervision, rather than individual or unsupervised exercise. They also preferred high intensity exercise performed at least once or twice per week. The most popular types of incentive were exercise during working hours and a wellness allowance rather than coupons for sports goods. The results show that the relative value of some attribute levels differed between young adults (age ≤ 44 years) and older adults (age ≥ 45 years) in terms of the level of trainer supervision required, exercise intensity, travel time to exercise location and financial incentives. For active study participants, exercise frequency (i.e., twice per week, 1.15; CI: 0.25; 2.06) influenced choice of exercise. For individuals with more than one child, travel time (i.e., 20 minutes, -0.55; CI: 0.65; 3.26) was also an influential attribute for choice of exercise, showing that people with children at home preferred to exercise close to home. This study adds to our knowledge about what types of exercise working adults with back pain are most likely to participate in. The exercise should be a cardiovascular type of training carried out in a group with trainer supervision. It should also be of high intensity and preferably performed twice per week during working hours. Coupons for sports goods do not appear to motivate physical activity among workers with LBP. The findings of the study could have a substantial impact on the planning and development of exercise provision and promotion strategies to improve non-specific LBP. Providers and employers may be able to improve participation in exercise programs for adults with non-specific LBP by focusing on the exercise components which are the most attractive. This in turn would improve satisfaction and adherence to exercise interventions aimed at preventing recurrent non-specific LBP.


Relationship of childhood abuse and household dysfunction to many of the leading causes of death in adults. The Adverse Childhood Experiences (ACE) Study.
The relationship of health risk behavior and disease in adulthood to the breadth of exposure to childhood emotional, physical, or sexual abuse, and household dysfunction during childhood has not previously been described. A questionnaire about adverse childhood experiences was mailed to 13,494 adults who had completed a standardized medical evaluation at a large HMO; 9,508 (70.5%) responded. Seven categories of adverse childhood experiences were studied: psychological, physical, or sexual abuse; violence against mother; or living with household members who were substance abusers, mentally ill or suicidal, or ever imprisoned. The number of categories of these adverse childhood experiences was then compared to measures of adult risk behavior, health status, and disease. Logistic regression was used to adjust for effects of demographic factors on the association between the cumulative number of categories of childhood exposures (range: 0-7) and risk factors for the leading causes of death in adult life. More than half of respondents reported at least one, and one-fourth reported > or = 2 categories of childhood exposures. We found a graded relationship between the number of categories of childhood exposure and each of the adult health risk behaviors and diseases that were studied (P < .001). Persons who had experienced four or more categories of childhood exposure, compared to those who had experienced none, had 4- to 12-fold increased health risks for alcoholism, drug abuse, depression, and suicide attempt; a 2- to 4-fold increase in smoking, poor self-rated health, > or = 50 sexual intercourse partners, and sexually transmitted disease; and 1.4- to 1.6-fold increase in physical inactivity and severe obesity. The number of categories of adverse childhood exposures showed a graded relationship to the presence of adult diseases including ischemic heart disease, cancer, chronic lung disease, skeletal fractures, and liver disease. The seven categories of adverse childhood experiences were strongly interrelated and persons with multiple categories of childhood exposure were likely to have multiple health risk factors later in life. We found a strong graded relationship between the breadth of exposure to abuse or household dysfunction during childhood and multiple risk factors for several of the leading causes of death in adults.


Crossover from semi-dilute to densely packed thin polymer films at the air-water interface and structure formation at thin film breakup.
A series of poly(n-butyl acrylate) (PnBA, 5 to 32 kg mol-1) homopolymers and diblock copolymers with poly(ethylene glycol) (PEG, constant molecular weight of 0.3 kg mol-1) is synthesized for the purpose of the investigation of quasi-2D polymer films at the air-water interface. The presented compression isotherms show a transition from θ solvent behavior for PnBA homopolymers to good solvent conditions when the volume fraction of the PEG in the block copolymers is increased by decreasing the molecular weight of PnBA. A transition from a semi-dilute regime to a densely packed layer is observed in the pressure isotherms for all the polymers. In the densely packed films we found first evidence for thin film breakup of a thin polymer film directly at the air-water interface. Combination of results from Brewster-Angle-Microscopy and Surface X-ray scattering provide a consistent picture of the film breakup. Our results suggest a preferred length scale of 2.5 μm. This scenario is analogous to a spinodal mechanism driven by thermal fluctuations of the film height.


Acute Visual Field Defect following Vitrectomy Determined to Originate from Optic Nerve by Electrophysiological Tests.
To present our findings on the cause of an acute visual field defect (VFD) that developed in a patient on the day after vitrectomy for proliferative diabetic retinopathy. A 50-year-old man complained of a blind area in the superior visual field that developed one day after vitrectomy. The patient had undergone uncomplicated vitrectomy for a long-duration vitreous hemorrhage associated with proliferative diabetic retinopathy. Residual vitreous hemorrhage hampered a clear view of the fundus. Goldmann perimetry showed a horizontal VFD in the superior field. The area corresponding to the VFD was examined by multifocal electroretinograms (mfERGs) and multifocal visual evoked potentials (mfVEPs). The amplitudes of the mfVEPs were reduced with prolonged implicit times especially when the superior hemifield was stimulated, while the amplitudes and implicit times were within the normal range when other parts of the visual field were stimulated. In addition, the full-field photopic ERGs and photopic negative responses were attenuated in the right eye. These findings suggested that the VFD did not originate from alterations in the retinal inner and middle layer but in the ganglion cells. The visual acuity improved to 1.2 but his optic disc became pale and the VFD remained unchanged more than 12 years after the surgery. We suggest that vitrectomy can cause ischemic optic neuropathy by interfering with the circulation associated with diabetes mellitus. Evaluations by mfERGs, mfVEPs, and full-field photopic ERGs were helpful in making the diagnosis.


Effectiveness and prognosis of covered stents with different diameters in transjugular intrahepatic portosystemic shunt: a meta-analysis.
This meta-analysis was designed to evaluate the clinical outcomes of transjugular intrahepatic portosystemic shunt (TIPS) conducted utilizing stents of different diameters, thus providing recommendations for more logical selections of covered stents for patients with portal hypertension, in particular for the Asian population. Web of Science, PubMed, Embase, Cochrane Library, Chinese National Knowledge Infrastructure and Wan Fang were searched for randomized controlled trials and cohort studies from inception until February 2023. The meta-analysis was carried out using Revman 5.4 Software. Heterogeneity between researches was assessed by the χ2 test and I2 index. The outcomes evaluated were the incidence of post-TIPS hepatic encephalopathy (HE), variceal rebleeding, shunt dysfunction, 1-year overall survival and decrease in portal pressure gradient (PPG). Eight appropriate clinical trials with 1246 patients were selected (638 and 608 patients in the experimental and control groups, respectively). In regards to preoperative PPG reduction, there was no discernible difference between the two groups [mean difference = 1.15, 95% confidence interval (CI) = -0.29-2.58, P = 0.12]. The rate of post-TIPS HE was significantly higher in patients in the 8 mm stent group than in the 6-7 mm stent group [odds ratio (OR) = 0.54, 95% CI = 0.42-0.70, P < 0.00001, I2 = 46%]. There were no significant differences in the rates of variceal rebleeding (OR = 1.05, 95% CI = 0.67-1.65, P = 0.84, I2 = 0%), shunt dysfunction (OR = 0.88, 95% CI = 0.53-1.47, P = 0.64, I2 = 0%) and 1-year overall survival (OR = 0.86, 95% CI = 0.50-1.50, P = 0.61, I2 = 0%). Asian populations with portal hypertension may benefit more from TIPS with 6-7 mm covered stents because they can reduce the risk of postoperative HE while offering similar efficacy when compared to 8 mm covered stents.


Caspofungin resistant disseminated candidiasis in a 7-year-old girl with T cell lymphoma: a case report.
Immunocompromised patients are at increased risk of disseminated candidiasis. Guidelines for the treatment of invasive candidiasis were last published in 2009, but resistance to the recommended treatment has recently been described in the literature. Here we present the case of an immunocompromised child with T-cell lymphoma who died secondary to disseminated candidiasis despite prolonged antifungal therapy. Awareness of the increasing resistance patterns of Candida when caring for immunocompromised patients, especially pediatric patients, may improve treatment and create better patient outcomes.


Mutations in ANKH cause chondrocalcinosis.
Chondrocalcinosis (CC) is a common cause of joint pain and arthritis that is caused by the deposition of calcium-containing crystals within articular cartilage. Although most cases are sporadic, rare familial forms have been linked to human chromosomes 8 (CCAL1) or 5p (CCAL2) (Baldwin et al. 1995; Hughes et al. 1995; Andrew et al. 1999). Here, we show that two previously described families with CCAL2 have mutations in the human homolog of the mouse progressive ankylosis gene (ANKH). One of the human mutations results in the substitution of a highly conserved amino acid residue within a predicted transmembrane segment. The other creates a new ATG start site that adds four additional residues to the ANKH protein. Both mutations segregate completely with disease status and are not found in control subjects. In addition, 1 of 95 U.K. patients with sporadic CC showed a deletion of a single codon in the ANKH gene. The same change was found in a sister who had bilateral knee replacement for osteoarthritis. Each of the three human mutations was reconstructed in a full-length ANK expression construct previously shown to regulate pyrophosphate levels in cultured cells in vitro. All three of the human mutations showed significantly more activity than a previously described nonsense mutation that causes severe hydroxyapatite mineral deposition and widespread joint ankylosis in mice. These results suggest that small sequence changes in ANKH are one cause of CC and joint disease in humans. Increased ANK activity may explain the different types of crystals commonly deposited in human CCAL2 families and mutant mice and may provide a useful pharmacological target for treating some forms of human CC.


Preparing to Stop Action Increases Beta Band Power in Contralateral Sensorimotor Cortex.
How do we prepare to stop ourselves in the future? Here, we used scalp EEG to test the hypothesis that people prepare to stop by putting parts of their motor system (specifically, here, sensorimotor cortex) into a suppressed state ahead of time. On each trial, participants were cued to prepare to stop one hand and then initiated a bimanual movement. On a minority of trials, participants were instructed to stop the cued hand while continuing quickly with the other. We used a guided multivariate source separation method to examine oscillatory power changes in presumed sensorimotor cortical areas. We observed that, when people prepare to stop a hand, there were above-baseline beta band power increases (12-24 Hz) in contralateral cortex up to a second earlier. This increase in beta band power in the proactive period was functionally relevant because it predicted, trial by trial, the degree of selectivity with which participants subsequently stopped a response but did not relate to movement per se. Thus, preparing to stop particular response channels corresponds to increased beta power from contralateral (sensorimotor) cortex, and this relates specifically to subsequent stopping. These results provide a high temporal resolution and frequency-specific electrophysiological signature of the preparing-to-stop state that is pertinent to future studies of mitigating provocation, including in clinical disorders. The results also highlight the utility of guided multivariate source separation for revealing the cortical dynamics underlying both movement and response suppression.


Expansion of epitope cross-reactivity by anti-idiotype modulation of the primary humoral response.
The primary humoral response produces antigen-specific antibodies so to clear the initial infection, and generates a population of corresponding memory cells to prevent infection by future encounters with the same pathogen. The continuous genetic modification of a pathogen's exterior, however, is one mechanism used to evade the immune defenses of its host. Here we describe a novel means, involving anti-idiotypic antibodies, by which the host can counteract such pathogen genetic alterations by modulation of its primary humoral response. An autoimmune response against primary antibodies, Ab1's, creates anti-idiotypic antibodies (Ab2's), some of which (designated Ab2alpha) are able to bind the Ab1/antigen complex. We have discovered that binding of Ab2alpha to its corresponding Ab1 can expand Ab1's ability to bind variations of its antigen. This expanded epitope cross-reactivity is shown not only to increase the binding activity of Ab1 but also its ability to neutralize a variant infectious virus. MAb M77 is an Ab1, which is highly strain-specific for the HIV-1 envelope protein gp120(IIIB). This Ab1 can be rendered cross-reactive and neutralizing for an otherwise resistant HIV strain by its interaction with a unique anti-idiotypic Ab2alpha (GV12). Furthermore, molecular characterization of this expanded cross-reactivity was accomplished using combinatorial phage display peptide libraries.


Identification of homing receptors that mediate the recruitment of CD4 T cells to the genital tract following intravaginal infection with Chlamydia trachomatis.
Murine genital infection induced with the mouse pneumonitis biovar of Chlamydia trachomatis (MoPn) elicits a short-lived protective immunity mediated primarily by Th1 CD4 cells. To understand the development of local cell-mediated immunity against C. trachomatis infection, we investigated the mechanism(s) which mediates CD4 lymphocyte migration to the genital mucosa by identifying molecules that could support this process. We found that primarily CD4 cells were recruited to the genital tract (GT) during primary and challenge MoPn infection. Peak levels were found 21 days after primary inoculation (15.4% +/- 2.7%) and 7 days (31.3% +/- 8.5%) after challenge but diminished after resolution of infection. The CD4 cells appeared to be recruited to the GT in response to infection since these cells expressed the profile of activated, or memory, cells. We also observed up-regulation of homing receptors containing LFA-1 (CD11a) and alpha4 (CD49d) on GT CD4 cells over the course of infection. Furthermore, the mucosal homing receptor chain, beta7, but not the peripheral homing receptor chain beta1 (CD29), was detected on GT CD4 cells. MoPn-infected GT tissue expressed the endothelial cell ligands vascular cell adhesion molecule 1 (VCAM-1), intracellular adhesion molecule 1 (ICAM-1), and mucosal vascular addressin cell adhesion molecule 1 (MAdCAM-1), which correspond to the homing receptors on GT CD4 cells. Interestingly, VCAM-1 and MAdCAM-1 were not expressed in the GTs of uninfected mice but were temporarily induced following infection, indicating that expression of endothelial ligands in the GT are regulated by chlamydial infection. These data suggest that recruitment of CD4 cells to the GT is mediated through LFA-1:ICAM-1 and alpha4beta7:MAdCAM-1-VCAM-1 interactions.


Pharmacological Targeting of STK19 Inhibits Oncogenic NRAS-Driven Melanomagenesis.
Activating mutations in NRAS account for 20%-30% of melanoma, but despite decades of research and in contrast to BRAF, no effective anti-NRAS therapies have been forthcoming. Here, we identify a previously uncharacterized serine/threonine kinase STK19 as a novel NRAS activator. STK19 phosphorylates NRAS to enhance its binding to its downstream effectors and promotes oncogenic NRAS-mediated melanocyte malignant transformation. A recurrent D89N substitution in STK19 whose alterations were identified in 25% of human melanomas represents a gain-of-function mutation that interacts better with NRAS to enhance melanocyte transformation. STK19D89N knockin leads to skin hyperpigmentation and promotes NRASQ61R-driven melanomagenesis in vivo. Finally, we developed ZT-12-037-01 (1a) as a specific STK19-targeted inhibitor and showed that it effectively blocks oncogenic NRAS-driven melanocyte malignant transformation and melanoma growth in vitro and in vivo. Together, our findings provide a new and viable therapeutic strategy for melanomas harboring NRAS mutations.


Cleavage of disulfide bonds leads to inactivation and degradation of the type IIa, but not type IIb sodium phosphate cotransporter expressed in Xenopus laevis oocytes.
Tris(2-carboxyethyl)phosphine (TCEP) reduces (cleaves) disulfide bonds of the renal proximal tubule type IIa Na/Pi- cotransporter (rat NaPi IIa) and thereby inhibits its function. We tested the effect of TCEP on the murine type IIa Na/P(i)-cotransporter and the corresponding IIb intestinal isoform both expressed in Xenopus laevis oocytes. After incubation with TCEP the function of NaPi IIa was inhibited and protein amount was decreased. Injection of the lysosomal inhibitor leupeptin prevented degradation of the protein. Exposure of oocytes to TCEP at 0 degrees C led to a reduction in transport function without concomitant loss in Na/Pi IIa protein. In contrast to NaPi type IIa, the type IIb isoform was neither inhibited, nor degraded after incubation with TCEP. These results suggest that cleavage of disulfide bonds led to changes within the confirmation of the type IIa transporter that result in (i) inhibition of the transport activity and (ii) internalization and subsequent lysosomal degradation of transporter protein. Sequence comparisons suggest the involvement/presence of different disulfide bonds in type IIa and type IIb Na/P(i)-cotransporters.


Entropy-induced microphase separation in hard diblock copolymers.
Whereas entropy can induce phase behavior that is as rich as seen in energetic systems, microphase separation remains a very rare phenomenon in entropic systems. In this paper, we present a density functional approach to study the possibility of entropy-driven microphase separation in diblock copolymers. Our model system consists of copolymers composed of freely jointed slender hard rods. The two types of monomeric segments have comparable lengths, but a significantly different diameter, the latter difference providing the driving force for the phase separation. At the same time this system can also exhibit liquid crystalline phases. We treat this system in the appropriate generalization of the Onsager approximation to chain-like particles. Using a linear stability (bifurcation) analysis, we analytically determine the onset of the microseparated and the nematic phases for long chains. We find that for very long chains the microseparated phase always pre-empts the nematic. In the limit of infinitely long chains, the correlations within the chain become Gaussian and the approach becomes exact. This allows us to define a Gaussian limit in which the theory strongly simplifies and the competition between microphase separation and liquid crystal formation can be studied essentially analytically. Our main results are phase diagrams as a function of the remaining model parameters: i.e., the diameter ratio, the length ratio, and the number ratio of the two types of segments. We also determine the amplitude of the inhomogeneous order as a function of position along the chain at the onset of the microphase separation instability. Finally, we give suggestions as to how this type of entropy-induced microphase separation could be observed experimentally.


Self-administered tuberculosis treatment outcomes in a tribal population on the indo-myanmar border, Nagaland, India.
Multiple strategies are being adopted by national tuberculosis (TB) programmes to achieve universal coverage of tuberculosis treatment. However, populations living in 'hard-to-reach' areas of north-east India have poor access to health services. Our study aimed to detail treatment outcomes in TB program supported by Médecins Sans Frontières (MSF) and using an alternative model of TB treatment delivery in Mon district, Nagaland, India. This was a retrospective cohort study of TB patients, initiated on self-administered therapy (SAT) through Mon District Hospital, Nagaland, India between April 2012 and March 2013. A total of 238 tuberculosis patients had final TB treatment outcomes during the study period, including 82 and 156 from semi-urban and rural areas respectively. The majority of patients (62%, 147/238) were suffering from pulmonary, smear-positive tuberculosis. Overall, 74% of patients (175/238) had successful outcomes, being cured or having completed their treatment. Females (81%), pulmonary TB patients (75%) and those on a Category I regimen (79%) had better treatment success rates than males (67%), extra-pulmonary TB patients (62%) and patients on a Category II regimen (61%). The univariate and bivariate analyses found age, sex and TB treatment regimen significantly associated with unsuccessful TB treatment outcomes (defined as death, loss-to-follow-up and failure). However, only older age showed significance in a multivariate binary logistic regression model. Our study suggests that self-administered TB treatment is feasible for patients living in areas with limited or no access to health services. The relatively low number of patients with adverse outcomes suggests that SAT models are safe; other advantages include the need for fewer resources and less frequent movements by patients. National TB programmes should consider allowing SAT strategies for delivery of TB treatment to 'hard-to-reach' populations, which could in turn help to achieve universal coverage and contribute to global TB elimination by 2050.


Relation between heel position and the distribution of forefoot plantar pressures and skin callosities in rheumatoid arthritis.
To investigate the relation between the position of the rearfoot and the distribution of forefoot plantar pressures and skin callosities in rheumatoid arthritis. Plantar pressures and callosity patterns were measured in 102 rheumatoid arthritis patients (120 feet with normal heel alignment and 84 feet with valgus heel alignment measured by goniometry) and in 42 (84 feet) age matched healthy adults. Peak pressures (kPa) were measured across the metatarsal heads in-shoe using an FScan system and the distribution of plantar callosities was visually mapped for each foot. Peak pressures were significantly greater at all but the first metatarsal head in the rheumatoid normal heel alignment and healthy adult groups than in the rheumatoid valgus heel group. The feet of both the rheumatoid normal heel group and the healthy adult group behaved the same, the highest peak pressures registering on the central metatarsal heads. However, only in the rheumatoid group were plantar callosities found at these sites. In the rheumatoid valgus heel group, lateral metatarsal heads were frequently non-weightbearing, producing gross loading patterns with a dominant medial distribution. Peak pressures were shifted to the medial fore-foot accompanied by a higher prevalence of callosities. The results, however, failed to establish clearly an association between peak pressures and callus formation. In rheumatoid arthritis there is an important interrelation between the rearfoot position and forefoot pressure sites.


Refined structures of substrate-bound and phosphate-bound thymidylate synthase from Lactobacillus casei.
Crystal structures of two crystal forms of the complex of Lactobacillus casei (TS) with its substrate dUMP have been solved and refined at 2.55 A resolution. The two crystal forms differ by approximately 5% in the c-axis length. The TS-dUMP complexes are symmetric dimers with dUMP bound equivalently in both active sites. dUMP is non-covalently bound in the same conformation as in ternary complexes of TS with dUMP and cofactor or cofactor analogs. The same hydrogen bonds are made between TS and substrate in the binary and ternary complexes. We have also determined the 2.36 A crystal structure of phosphate-bound L. casei TS. This structure has been refined to an R-factor of 19.3% with highly constrained geometry. Refinement has revealed the locations of all residues in the protein, including the disordered residues 90 to 119, which are part of an insert found only in the L. casei and Staphylococcus aureus transposon Tn4003 TS sequences. The 2.9 A multiple isomorphous replacement (MIR) structure of L. casei TS in a complex with its substrate dUMP has been refined to a crystallographic R-factor of 15.5%. Reducing agents were withheld from crystallization solutions during MIR structure determination to allow heavy-metal labeling of the cysteine residues. Therefore, the active-site cysteine residue in this structure is oxidized and the dUMP is found at half-occupancy in the active site. No significant conformational difference was found between the phosphate-bound and dUMP-bound structures. The TS-dUMP structures were better ordered than the phosphate-bound TS or the oxidized TS-dUMP, particularly Arg23, which is clearly hydrogen-bonded to the phosphate group of dUMP. A large and a small P6(1)22 crystal form are observed for both phosphate-bound and dUMP-bound L. casei TS. The small cell forms of the phosphate-bound and dUMP-bound enzyme are isomorphous, whereas the cell constants of the larger cell form change slightly when dUMP is bound (c = 240 A versus c = 243 A). For both liganded and unliganded enzyme, conversion from the small to the large crystal form sometimes occurs spontaneously, and the crystal packing changes at a single interface. Conversion may be the result of a small change in pH in the mother liquor surrounding the crystal. A single intermolecular contact between symmetry-related Asp287 residues is disrupted on going from the small to the large crystal form.


Cannabidiol inhibits cancer cell invasion via upregulation of tissue inhibitor of matrix metalloproteinases-1.
Although cannabinoids exhibit a broad variety of anticarcinogenic effects, their potential use in cancer therapy is limited by their psychoactive effects. Here we evaluated the impact of cannabidiol, a plant-derived non-psychoactive cannabinoid, on cancer cell invasion. Using Matrigel invasion assays we found a cannabidiol-driven impaired invasion of human cervical cancer (HeLa, C33A) and human lung cancer cells (A549) that was reversed by antagonists to both CB(1) and CB(2) receptors as well as to transient receptor potential vanilloid 1 (TRPV1). The decrease of invasion by cannabidiol appeared concomitantly with upregulation of tissue inhibitor of matrix metalloproteinases-1 (TIMP-1). Knockdown of cannabidiol-induced TIMP-1 expression by siRNA led to a reversal of the cannabidiol-elicited decrease in tumor cell invasiveness, implying a causal link between the TIMP-1-upregulating and anti-invasive action of cannabidiol. P38 and p42/44 mitogen-activated protein kinases were identified as upstream targets conferring TIMP-1 induction and subsequent decreased invasiveness. Additionally, in vivo studies in thymic-aplastic nude mice revealed a significant inhibition of A549 lung metastasis in cannabidiol-treated animals as compared to vehicle-treated controls. Altogether, these findings provide a novel mechanism underlying the anti-invasive action of cannabidiol and imply its use as a therapeutic option for the treatment of highly invasive cancers.


Modes of Brassinosteroid Activity in Cold Stress Tolerance.
Cold stress is a significant environmental factor that negatively affects plant growth and development in particular when it occurs during the growth phase. Plants have evolved means to protect themselves from damage caused by chilling or freezing temperatures and some plant species, in particular those from temperate geographical zones, can increase their basal level of freezing tolerance in a process termed cold acclimation. Cold acclimation improves plant survival, but also represses growth, since it inhibits activity of the growth-promoting hormones gibberellins (GAs). In addition to GAs, the steroid hormones brassinosteroids (BRs) also take part in growth promotion and cold stress signaling; however, in contrast to Gas, BRs can improve cold stress tolerance with fewer trade-offs in terms of growth and yields. Here we summarize our current understanding of the roles of BRs in cold stress responses with a focus on freezing tolerance and cold acclimation pathways.


PR_b-targeted PEGylated liposomes for prostate cancer therapy.
In recent years, there has been considerable effort in designing improved delivery systems by including site-directed surface ligands to further enhance their selective targeting. The goal of this study is to engineer alpha5beta1-targeted stealth liposomes (nanoparticles covered with poly(ethylene glycol) (PEG)) that will bind to alpha5beta1-expressing LNCaP human prostate cancer cells and efficiently release the encapsulated load intracellularly. For this purpose, liposomes (with and without PEG2000) were functionalized with a fibronectin-mimetic peptide (PR_b) and delivered to LNCaPs. The amount of PEG2000 and other liposomal components were characterized by 1H NMR, and the amount of peptide by the bicinchoninic acid protein assay. Fibronectin is the natural ligand for alpha5beta1, and a promising design for a fibronectinmimetic peptide includes both the primary binding site (RGD) and the synergy site (PHSRN) connected by a linker and extended off a surface by a spacer. We have previously designed a peptide-amphiphile, PRb, that employed a hydrophobic tail, connected to the N-terminus of a peptide headgroup composed of a spacer, the synergy site sequence, a linker mimicking both the distance and hydrophobicity/hydrophilicity present in the native protein fibronectin (thus presenting an overall "neutral" linker), and finally the primary binding sequence. We have examined different liposomal formulations, functionalized only with PR_b or with PR_b and PEG2000. For PR_b-targeted PEGylated liposomes, efficient cell binding was observed for peptide concentrations of 2 mol % and higher. When compared to GRGDSP-targeted stealth liposomes, PR_b functionalization was superior to that of GRGDSP as shown by increased LNCaP binding, internalization efficiency, as well as cytotoxicity after incubation of LNCaPs with tumor necrosis factor-alpha (TNFalpha)-encapsulated liposomes. More importantly, PR_b is alpha5beta1-specific, whereas many integrins bind to small RGD peptides. Thus, the proposed PR_b-targeted delivery system has the potential to deliver a therapeutic payload to prostate cancer cells in an efficient and specific manner.


A population of gamma-ray millisecond pulsars seen with the Fermi Large Area Telescope.
Pulsars are born with subsecond spin periods and slow by electromagnetic braking for several tens of millions of years, when detectable radiation ceases. A second life can occur for neutron stars in binary systems. They can acquire mass and angular momentum from their companions, to be spun up to millisecond periods and begin radiating again. We searched Fermi Large Area Telescope data for pulsations from all known millisecond pulsars (MSPs) outside of globular clusters, using rotation parameters from radio telescopes. Strong gamma-ray pulsations were detected for eight MSPs. The gamma-ray pulse profiles and spectral properties resemble those of young gamma-ray pulsars. The basic emission mechanism seems to be the same for MSPs and young pulsars, with the emission originating in regions far from the neutron star surface.


PsyPad: a platform for visual psychophysics on the iPad.
This article introduces PsyPad, a customizable, open-source platform for configuring and conducting visual psychophysics experiments on iPads without the need for any code development for the iPad. Stimuli for experiments are created off-line as a library of images. The PsyPad app (obtainable from the Apple App Store) presents the images according to either built-in, customizable staircase or method of constant stimuli procedures, mapping stimuli levels to images based on the image file names. On-screen buttons for responses are configurable and matched to "correct" using the image file name of any given stimulus. All actions are logged into a text file and sent to a specified server at the end of the test if an Internet connection is available. If the iPad is not connected, the results are uploaded the next time the iPad is online. We provide a secure server for this purpose, but the server-side software is also open source if researchers choose to run their own server.


Differential accumulation of pelargonidin glycosides in petals at three different developmental stages of the orange-flowered gentian (Gentiana lutea L. var. aurantiaca).
Corolla color in Gentiana lutea L. exhibits a yellow/orange variation. We previously demonstrated that the orange petal color of G. lutea L. var. aurantiaca is predominantly caused by newly synthesized pelargonidin glycosides that confer a reddish hue to the yellow background color, derived from the carotenoids. However, the anthocyanin molecules of these pelargonidin glycosides are not yet fully identified and characterized. Here, we investigated the regulation, content and type of anthocyanins determining the petal coloration of the orange-flowered G. lutea L. var. aurantiaca. Anthocyanins from the petals of G. lutea L. var. aurantiaca were characterized and quantified by HPLC-ESI-MS/MS (High-performance liquid chromatography-electrospray ionization-tandem mass spectrometry) coupled with a diode array detector in flowers at three different stages of development (S1, S3 and S5). Eleven pelargonidin derivatives were identified in the petals of G. lutea L. var. aurantiaca for the first time, but quantitative and qualitative differences were observed at each developmental stage. The highest levels of these pelargonidin derivatives were reached at the fully open flower stage (S5) where all anthocyanins were detected. In contrast, not all the anthocyanins were detected at the budlet stage (S1) and mature bud stage (S3) and those corresponded to more complex pelargonidin derivatives. The major pelargonidin derivatives found at all the stages were pelargonidin 3-O-glucoside, pelargonidin 3,5-O-diglucoside and pelargonidin 3-O-rutinoside. Furthermore, the expression of DFR (dihydroflavonol 4-reductase), ANS (anthocyanidin synthase), 3GT (UDP-glucose:flavonoid 3-O-glucosyltransferase), 5GT (UDP-glucose:flavonoid 5-O-glucosyltransferase) and 5AT (anthocyanin 5-aromatic acyltransferase) genes was analyzed in the petals of three developmental stages, showing that the expression level of DFR, ANS and 3GT parallels the accumulation of the pelargonidin glucosides. Overall, this study enhances the knowledge of the biochemical basis of flower coloration in Gentiana species, and lays a foundation for breeding of flower color and genetic variation studies on Gentiana varieties.


Recent horizontal transmission of plasmids between natural populations of Escherichia coli and Salmonella enterica.
Seventy-one natural isolates obtained from a Salmonella reference collection were examined for the presence of plasmids closely related to the Escherichia coli F plasmid. The collection consists of several serovars of the S. enterica Typhimurium complex, subspecies I, to which 99% of pathogenic salmonellae belong. Molecular genetic techniques of DNA hybridization, along with PCR and DNA sequencing, were used to examine the occurrence, distribution, and genetic diversity of F-like plasmids among Salmonella strains. The F plasmid genes examined were finO, traD, traY, and repA, which map at dispersed positions on the F plasmid of E. coli. Comparative sequence analysis of each of the four genes in Salmonella plasmids showed them to be homologous (in some cases, virtually identical) to those found in F plasmids of E. coli natural isolates. Furthermore, the frequency of F-like plasmids in Salmonella strains was approximately the same as that observed in the E. coli Reference Collection. However, in Salmonella, the distribution was confined predominately to the serovars Typhimurium and Muenchen. The unexpected finding of a shared pool of F-like plasmids between S. enterica and E. coli demonstrates the significant role of conjugation in the histories of these important bacterial species.


Robust and broadband frequency conversion in composite crystals with tailored segment widths and χ(2) nonlinearities of alternating signs.
We propose an efficient, robust, and broadband nonlinear optical frequency conversion technique, which uses segmented crystals constructed in analogy with the composite pulses in nuclear magnetic resonance and quantum optics. The composite crystals are made of several macroscopic segments of nonlinear susceptibilities of opposite signs and specific thicknesses, which are determined from the condition to maximize the conversion efficiency with respect to variations in the experimental parameters. These crystals deliver broadband operation for significantly lower pump intensities than single bulk crystals. We demonstrate this technique by numerical simulation of sum-frequency generation in MgO:LiNbO3 crystal.


Antibodies against Stachybotrys chartarum extract and its antigenic components, Stachyhemolysin and Stachyrase-A: a new clinical biomarker.
IgG and IgE antibodies against Stachybotrys extract have been reported in allergic patients and residents of water-damaged buildings. Detection of these antibodies in blood was partially attributed to cross-reacting proteins from other fungi. There is a need for a specific method to detect antibodies against characteristic components of S. chartarum. We measured IgG and IgE antibodies against Stachybotrys hemolysin and proteinase-Stachyrase-A by ELISA and ELISA-inhibition techniques. Of 50 reference sera with IgE greater than 500 IU ml and positive against different mold extracts used in this study, significant elevation in IgG or IgE antibodies against S. chartarum extract was present in 25 and 21 specimens. Of these specimens 20 (80%) and 10 (40%) were positive for IgG anti-Stachybotrys hemolysin and anti-Stachyrase-A, while 8 out of 21 sera (38%) and 17 out of 21 (81%) specimens were positive for IgE anti-Stachybotrys hemolysin and anti-Stachyrase-A respectively. Inhibition studies using Stachybotrys hemolysin and Stachyrase-A at a concentration of 50 microg/ml prevented binding of anti-Stachybotrys to S. chartarum extract. Detection of IgG as well as IgE antibodies against Stachybotrys hemolysin and Stachyrase-A and inhibition of anti-Stachybotrys binding to Stachybotrys antigens indicate that Stachybotrys hemolysin and Stachyrase-A are two major antigenic components of S. chartarum extract, which can be used in antibody assays. Measurement of antibodies against these characteristic components of S. chartarum may be considered for demonstration of exposure and possibly allergy to the fungus.


Sonographically Detected Non Alcoholic Fatty Liver Disease in Apparently Healthy Adults and Associated Factors.
This hospital-based study was done to see the prevalence of sonologically detected non alcoholic fatty liver disease and associated factors in the apparently healthy adults. Apparently healthy and non alcoholic companions of the patients visiting the Centre of Nuclear Medicine and Ultrasound, Sylhet were subjected to abdominal ultrasonography to see the presence of fatty liver. Demographic features and other relevant data were collected in a semi structured questionnaire to find out the associated factors for non alcoholic fatty liver disease (NAFLD). Total 1019 persons with mean age of 37.23 years were included in the study. Among them 703 (69%) were female and 316 (31%) were male. Out of them 189 (18.5%) persons had sonologically detectable nonalcoholic fatty liver disease. NAFLD was more prevalent in male than female (25.6% vs. 15.4%, p=0.000). In univariate analysis NAFLD were more in male (25.6%) 41-50 years age group (29.3%, p=0.000), over weight (32.3%)/obese subjects (51.4%), businessmen (24.0%), service holders (28.7%), high income group, diabetics (27.0% vs. 18.0%, p=0.000) and hypertensive subjects (43.3% vs. 15.24%, p=0.000). In multivariate analysis, BMI over 23kg/m² (OR 6.683, p=0.000), age >30 years (OR 1.787, p=0.006) and higher income (OR 1.788, 95% CI 0.970-3.293) were independent factors associated with NAFLD. Sonologically detected nonalcoholic fatty liver disease (18.5%) is common in our apparently healthy adults. BMI over 23kg/m² was the most important predictor for NAFLD.


Influence of muscle oxygenation and nitrate-rich beetroot juice supplementation on O2 uptake kinetics and exercise tolerance.
We tested the hypothesis that acute supplementation with nitrate (NO3-)-rich beetroot juice (BR) would improve quadriceps muscle oxygenation, pulmonary oxygen uptake (V˙O2) kinetics and exercise tolerance (Tlim) in normoxia and that these improvements would be augmented in hypoxia and attenuated in hyperoxia. In a randomised, double-blind, cross-over study, ten healthy males completed two-step cycle tests to Tlim following acute consumption of 210 mL BR (18.6 mmol NO3-) or NO3--depleted beetroot juice placebo (PL; 0.12 mmol NO3-). These tests were completed in normobaric normoxia [fraction of inspired oxygen (FIO2): 21%], hypoxia (FIO2: 15%) and hyperoxia (FIO2: 40%). Pulmonary V˙O2 and quadriceps tissue oxygenation index (TOI), derived from multi-channel near-infrared spectroscopy, were measured during all trials. Plasma [nitrite] was higher in all BR compared to all PL trials (P < 0.05). Quadriceps TOI was higher in normoxia compared to hypoxia (P < 0.05) and higher in hyperoxia compared to hypoxia and normoxia (P < 0.05). Tlim was improved after BR compared to PL ingestion in the hypoxic trials (250 ± 44 vs. 231 ± 41 s; P = 0.006; d = 1.13), with the magnitude of improvement being negatively correlated with quadriceps TOI at Tlim (r = -0.78; P < 0.05). Tlim was not improved following BR ingestion in normoxia (BR: 364 ± 98 vs. PL: 344 ± 78 s; P = 0.087, d = 0.61) or hyperoxia (BR: 492 ± 212 vs. PL: 472 ± 196 s; P = 0.273, d = 0.37). BR ingestion increased peak V˙O2 in hypoxia (P < 0.05), but not normoxia or hyperoxia (P > 0.05). These findings indicate that BR supplementation is more likely to improve Tlim and peak V˙O2 in situations when skeletal muscle is more hypoxic.


Transcranial Direct Current Stimulation Over the Primary and Secondary Somatosensory Cortices Transiently Improves Tactile Spatial Discrimination in Stroke Patients.
In healthy subjects, dual hemisphere transcranial direct current stimulation (tDCS) over the primary (S1) and secondary somatosensory cortices (S2) has been found to transiently enhance tactile performance. However, the effect of dual hemisphere tDCS on tactile performance in stroke patients with sensory deficits remains unknown. The purpose of this study was to investigate whether dual hemisphere tDCS over S1 and S2 could enhance tactile discrimination in stroke patients. We employed a double-blind, crossover, sham-controlled experimental design. Eight chronic stroke patients with sensory deficits participated in this study. We used a grating orientation task (GOT) to measure the tactile discriminative threshold of the affected and non-affected index fingers before, during, and 10 min after four tDCS conditions. For both the S1 and S2 conditions, we placed an anodal electrode over the lesioned hemisphere and a cathodal electrode over the opposite hemisphere. We applied tDCS at an intensity of 2 mA for 15 min in both S1 and S2 conditions. We included two sham conditions in which the positions of the electrodes and the current intensity were identical to that in the S1 and S2 conditions except that current was delivered for the initial 15 s only. We found that GOT thresholds for the affected index finger during and 10 min after the S1 and S2 conditions were significantly lower compared with each sham condition. GOT thresholds were not significantly different between the S1 and S2 conditions at any time point. We concluded that dual-hemisphere tDCS over S1 and S2 can transiently enhance tactile discriminative task performance in chronic stroke patients with sensory dysfunction.


Effects of chicken extract on plasma antioxidative status and lipid oxidation in healthy rats.
Chicken extract has been consumed in oriental countries for centuries for improving body conditions such as recovery from fatigue. It is a rich source of antioxidant dipeptides. The in vivo antioxidative abilities were evaluated. Diets mixed with 4 different amounts of chicken extract were investigated for in vivo antioxidation ability using healthy male Sprague-Dawley (SD) rats. Total antioxidant status (TAS), thiobarbituric reactive substances (TBARS), iron content, superoxide dismutase (SOD) activity, glutathion peroxidase (GPx) activity and uric acid content were determined. In healthy rats, most of the indexes were not affected by intake of chicken extract significantly. However, plasma TBARS in the chicken extract-fed groups increased at the end of the experiment, which could be due to some pro-oxidative minerals in the extract. In conclusion, we found no significant or minor changes on the activities of antioxidative enzymes, antioxidant conditions, or lipid oxidation in healthy rats from consuming chicken extract, which may be the result of a balanced body condition. However, because of its high content of dipeptides, we suggest that it should have liver protecting effects if oxidative stresses are introduced.


Drug target optimization in chronic myeloid leukemia using innovative computational platform.
Chronic Myeloid Leukemia (CML) represents a paradigm for the wider cancer field. Despite the fact that tyrosine kinase inhibitors have established targeted molecular therapy in CML, patients often face the risk of developing drug resistance, caused by mutations and/or activation of alternative cellular pathways. To optimize drug development, one needs to systematically test all possible combinations of drug targets within the genetic network that regulates the disease. The BioModelAnalyzer (BMA) is a user-friendly computational tool that allows us to do exactly that. We used BMA to build a CML network-model composed of 54 nodes linked by 104 interactions that encapsulates experimental data collected from 160 publications. While previous studies were limited by their focus on a single pathway or cellular process, our executable model allowed us to probe dynamic interactions between multiple pathways and cellular outcomes, suggest new combinatorial therapeutic targets, and highlight previously unexplored sensitivities to Interleukin-3.


Prothrombin Complex Concentrates for Perioperative Vitamin K Antagonist and Non-vitamin K Anticoagulant Reversal.
Vitamin K antagonist therapy is associated with an increased bleeding risk, and clinicians often reverse anticoagulation in patients who require emergency surgical procedures. Current guidelines for rapid anticoagulation reversal for emergency surgery recommend four-factor prothrombin complex concentrate and vitamin K coadministration. The authors reviewed the current evidence on prothrombin complex concentrate treatment for vitamin K antagonist reversal in the perioperative setting, focusing on comparative studies and in the context of intracranial hemorrhage and cardiac surgery. The authors searched Cochrane Library and PubMed between January 2008 and December 2017 and retrieved 423 English-language papers, which they then screened for relevance to the perioperative setting; they identified 36 papers to include in this review. Prothrombin complex concentrate therapy was consistently shown to reduce international normalized ratio rapidly and control bleeding effectively. In comparative studies with plasma, prothrombin complex concentrate use was associated with a greater proportion of patients achieving target international normalized ratios rapidly, with improved hemostasis. No differences in thromboembolic event rates were seen between prothrombin complex concentrate and plasma, with prothrombin complex concentrate also demonstrating a lower risk of fluid overload events. Overall, the studies the authors reviewed support current recommendations favoring prothrombin complex concentrate therapy in patients requiring vitamin K antagonist reversal before emergency surgery.


Asymmetric regulation of quorum-sensing receptors drives autoinducer-specific gene expression programs in Vibrio cholerae.
Quorum sensing (QS) is a mechanism of chemical communication that bacteria use to monitor cell-population density and coordinate group behaviors. QS relies on the production, detection, and group-wide response to extracellular signal molecules called autoinducers. Vibrio cholerae employs parallel QS circuits that converge into a shared signaling pathway. At high cell density, the CqsS and LuxPQ QS receptors detect the intra-genus and inter-species autoinducers CAI-1 and AI-2, respectively, to repress virulence factor production and biofilm formation. We show that positive feedback, mediated by the QS pathway, increases CqsS but not LuxQ levels during the transition into QS-mode, which amplifies the CAI-1 input into the pathway relative to the AI-2 input. Asymmetric feedback on CqsS enables responses exclusively to the CAI-1 autoinducer. Because CqsS exhibits the dominant QS signaling role in V. cholerae, agonism of CqsS with synthetic compounds could be used to control pathogenicity and host dispersal. We identify nine compounds that share no structural similarity to CAI-1, yet potently agonize CqsS via inhibition of CqsS autokinase activity.


Biomechanical analysis of Brostrom versus Brostrom-Gould lateral ankle instability repairs.
The traditional Brostrom repair and the modified Brostrom-Gould repair are 2 historically reliable procedures used to address lateral ankle instability. The purpose of this study was to evaluate the biomechanical stability conferred by the Brostrom repair as compared to the Brostrom-Gould modification in an unstable cadaveric ankle model. A total of 10 cadaveric specimens were placed in a Telos ankle stress apparatus in an anterior-posterior position and then in a lateral position, while a 170 N load was applied to simulate anterior drawer (AD) and talar tilt (TT) tests, respectively. In both circumstances, the ankle was held in 15 degrees of plantarflexion, neutral, and 15 degrees of dorsiflexion, while the movement of the sensors was measured using a video motion analysis system. Measurement of the translation between the talus and tibia in the AD test and the angle between the tibia and talus in the TT test were calculated for specimens in the (1) intact, (2) sectioned (division of the ATFL and CFL), (3) Brostrom repair and (4) Gould modification states. When compared to both the repaired states and the intact states, the sectioned state demonstrated increased inversion and translation at all ankle positions during TT and AD testing. Furthermore, no significant differences were found between the intact state and either of the repaired states. Finally, no difference in the biomechanical stability could be identified between the traditional Brostrom repair and the modified Brostrom-Gould procedure. Our findings indicate that there is no significant biomechanical difference in initial ankle stability conferred by augmenting the traditional Brostrom repair with the Gould modification in this time-zero cadaveric model. These data suggest that the additional reinforcement of an ankle's lateral ligament complex repair of the ankle with the inferior extensor retinaculum may be marginal at the time of surgery.


Apparent prevention of neural tube defects by periconceptional vitamin supplementation. 1981.
An earlier preliminary paper is expanded. Women who had given birth to one or more infants with a neural tube defect were recruited into a trial of periconceptional vitamin supplementation. Two hundred mothers attending five centres were fully supplemented (FS), 50 were partially supplemented (PS), and 300 were unsupplemented (US). Neural tube defect recurrences in the study pregnancies were 1(0.5%), in FS, none in PS, and 13 (4%) in US mothers. The difference in outcome between FS and US mothers is significant. The most likely explanation is that supplementation has prevented some neural tube defects, but further studies are needed.


Time-resolved searchlight analysis of imagined visual motion using 7 T ultra-high field fMRI: Data on interindividual differences.
Interindividual differences play a crucial role in research on mental imagery. The inherently private nature of imagery does not allow for the same experimental control that is possible in perception research. Even when there are precise instructions subjects will differ in their particular imagery strategy and, hence, show different brain activations. Here, we show results of a time-resolved searchlight analysis for 12 individual subjects who perform a visual motion imagery task. The data show the spatial and temporal extent of brain areas and time windows that allow for a successful decoding of the direction of imagined motion out of four options. Accuracy maps for six different time windows are shown for every individual subject and are made freely available on NeuroVault. These data accompany the findings in the publication "Decoding the direction of imagined visual motion using 7 T ultra-high field fMRI" (Emmerling et al., 2016) [1].


Relationship between white matter fractional anisotropy and other indices of cerebral health in normal aging: tract-based spatial statistics study of aging.
White matter (WM) fractional anisotropy (FA) is thought to be related to WM integrity and decline in FA is often used as an index of decreasing WM health. However, the relationship of FA to other structural indices of cerebral health has not been well studied. We hypothesized that the decline in WM health will be associated with changes in several other indices of cerebral health. In this manuscript we studied the correlation between whole-brain/hemispheric/corpus callosum FA and gray matter (GM) thickness, sulcal span, and the volume of T2-hyperintense WM in a group of 31 healthy aging individuals (12 males/19 females) aged 57-82 years old. Individual subjects' FA measures were calculated from diffusion tracing imaging (DTI) data using tract-based spatial statistics--an approach specifically designed and validated for voxel-wise multi-subject FA analysis. Age-controlled correlation analysis showed that whole-brain average FA values were significantly and positively correlated with the subject's average GM thickness and negatively correlated with hyperintense WM volume. Intra-hemispheric correlations between FA and other measures of cerebral health had generally greater effect sizes than inter-hemispheric correction, with correlation between left FA and left GM thickness being the most significant (r=0.6, p<0.01). Regional analysis of FA values showed that late-myelinating fiber tracts of the genu of corpus callosum had higher association with other cerebral health indices. These data are consistent with the hypothesis that late-myelinating regions of the brain bear the brunt of age-related degenerative changes.