Graded Variation in T1w/T2w Ratio during Adolescence: Measurement, Caveats, and Implications for Development of Cortical Myelin.
Adolescence is characterized by the maturation of cortical microstructure and connectivity supporting complex cognition and behavior. Axonal myelination influences brain connectivity during development by enhancing neural signaling speed and inhibiting plasticity. However, the maturational timing of cortical myelination during human adolescence remains poorly understood. Here, we take advantage of recent advances in high-resolution cortical T1w/T2w mapping methods, including principled correction of B1+ transmit field effects, using data from the Human Connectome Project in Development (HCP-D; N = 628, ages 8-21). We characterize microstructural changes relevant to myelination by estimating age-related differences in T1w/T2w throughout the cerebral neocortex from childhood to early adulthood. We apply Bayesian spline models and clustering analysis to demonstrate graded variation in age-dependent cortical T1w/T2w differences that are correlated with the sensorimotor-association (S-A) axis of cortical organization reported by others. In sensorimotor areas, T1w/T2w ratio measures start at high levels at early ages, increase at a fast pace, and decelerate at later ages (18-21). In intermediate multimodal areas along the S-A axis, T1w/T2w starts at intermediate levels and increases linearly at an intermediate pace. In transmodal/paralimbic association areas, T1w/T2w starts at low levels and increases linearly at the slowest pace. These data provide evidence for graded variation of the T1w/T2w ratio along the S-A axis that may reflect cortical myelination changes during adolescence underlying the development of complex information processing and psychological functioning. We discuss the implications of these results as well as caveats in interpreting magnetic resonance imaging (MRI)-based estimates of myelination.SIGNIFICANCE STATEMENT Myelin is a lipid membrane that is essential to healthy brain function. Myelin wraps axons to increase neural signaling speed, enabling complex neuronal functioning underlying learning and cognition. Here, we characterize the developmental timing of myelination across the cerebral cortex during adolescence using a noninvasive proxy measure, T1w/T2w mapping. Our results provide new evidence demonstrating graded variation across the cortex in the timing of T1w/T2w changes during adolescence, with rapid T1w/T2w increases in lower-order sensory areas and gradual T1w/T2w increases in higher-order association areas. This spatial pattern of microstructural brain development closely parallels the sensorimotor-to-association axis of cortical organization and plasticity during ontogeny.


Redox-regulated peptide transfer from the transporter associated with antigen processing to major histocompatibility complex class I molecules by protein disulfide isomerase.
Most antigenic peptides are generated by proteasomes in the cytosol and are transported by the transporter associated with antigen processing (TAP) into the endoplasmic reticulum, where they bind with nascent major histocompatibilitiy complex class I molecule (MHC-I). Although the overall process of peptide-MHC-I complex assembly is well studied, the mechanism by which free peptides are delivered from TAP to MHC-I is unknown. In this study, we investigated the possible role of protein disulfide isomerase (PDI) as a peptide carrier between TAP and MHC-I. Analysis of PDI-peptide complexes reconstituted in vitro showed that PDI exhibits some degree of specificity for peptides corresponding to antigenic ligands of various human leukocyte antigen (HLA) alleles. Mutations of either anchor residues of the peptide ligand or the peptide-binding site of PDI inhibited the PDI-peptide interaction. The PDI-peptide interaction increased under reducing conditions, whereas binding of the peptide to PDI decreased under oxidizing conditions. TAP-associated PDI was predominantly present in the reduced form, whereas the MHC-I-associated PDI was present in the oxidized form. Further, upon binding of optimal peptides, PDI was released from TAP and sequentially associated with HLA-A2.1. Our data revealed a redox-regulated chaperone function of PDI in delivering antigenic peptides from TAP to MHC-I.


Methicillin-resistant Staphylococcus aureus isolates from surfaces and personnel at a hospital laundry facility.
Examine a clinical laundry facility for the presence of methicillin-resistant Staphylococcus aureus (MRSA) on environmental surfaces and among personnel. Nasal and face samples along with surface samples were collected four times in 2015. MRSA isolates were confirmed using standardized biochemical assays and molecular characterization. MRSA was identified in 33/120 (28%) samples from the dirty and 3/120 (3%) samples from the clean environmental areas. MRSA isolates included: (dirty) ST5 SCCmec type II, ST8 SCCmec type IV, ST231 SCCmec type II, ST239 SCCmec type III, ST239 SCCmec type IV, ST256 SCCmec type IV and (clean) ST5 SCCmec type II and ST8 SCCmec type IV. Five different employees were MRSA positive, 4/8 (50%) from the dirty: and 1/15 (6·7%) from the clean, but there was a 10-fold higher MRSA carriage 6/22 (27%) dirty vs 1/38 (2·6%) clean when all 50 human samples were combined. MRSA prevalence was significantly higher (28 vs 3%) in dirty vs clean areas within the laundry facility suggesting a greater risk for personnel on the dirty side. This is the first report of isolation and characterization of MRSA from surfaces and personnel from a clinical laundry facility.


Pollen limitation as a main driver of fruiting dynamics in oak populations.
In many perennial wind-pollinated plants, the dynamics of seed production is commonly known to be highly fluctuating from year to year and synchronised among individuals within populations. The proximate causes of such seeding dynamics, called masting, are still poorly understood in oak species that are widespread in the northern hemisphere, and whose fruiting dynamics dramatically impacts forest regeneration and biodiversity. Combining long-term surveys of oak airborne pollen amount and acorn production over large-scale field networks in temperate areas, and a mechanistic modelling approach, we found that the pollen dynamics is the key driver of oak masting. Mechanisms at play involved both internal resource allocation to pollen production synchronised among trees and spring weather conditions affecting the amount of airborne pollen available for reproduction. The sensitivity of airborne pollen to weather conditions might make oak masting and its ecological consequences highly sensitive to climate change.


Multicenter study verifying a method of noninvasive continuous cardiac output measurement using pulse wave transit time: a comparison with intermittent bolus thermodilution cardiac output.
Many technologies have been developed for minimally invasive monitoring of cardiac output. Estimated continuous cardiac output (esCCO) measurement using pulse wave transit time is one noninvasive method. Because it does not require any additional sensors other than those for conducting 3 basic forms of monitoring (electrocardiogram, pulse oximeter wave, and noninvasive (or invasive) arterial blood pressure measurement), esCCO measurement is potentially useful in routine clinical circulatory monitoring for any patient including low-risk patients. We evaluated the efficacy of noninvasive esCCO using pulse wave transit time in this multicenter study. We compared esCCO and intermittent bolus thermodilution cardiac output (TDCO) in 213 patients, 139 intensive care units (ICUs), and 74 operating rooms (ORs), at 7 participating institutions. We performed electrocardiogram, pulse oximetry, TDCO, and arterial blood pressure measurements in patients in ICUs and ORs; a single calibration was performed to measure esCCO continuously. TDCO measurement was performed once daily for ICU patients and every hour for OR patients, and just before the removal of the pulmonary arterial catheter from patients in both the ICU and OR. We evaluated esCCO against TDCO with correlation analysis and Bland and Altman analysis and also assessed the change of bias over time. Furthermore, we inspected the impact of change in systemic vascular resistance (SVR) on change in bias because abnormal SVR was assumed to be a factor contributing to the change of the bias. From among 588 esCCO and TDCO datasets (excluding calibration points), 587 datasets were analyzed for 213 patients. The analysis results show a correlation coefficient of 0.79 (P < 0.0001, 95% confidence limits of 0.756-0.819), a bias (mean difference between esCCO and TDCO) of 0.13 L/min (95% confidence interval of bias 0.04-0.22 L/min), and a precision (1 SD) of 1.15 L/min (95% prediction interval was -2.13 to 2.39 L/min). There were no significant differences among 3 defined time intervals over 48 hours after calibration (repeated-measures analysis of variance P = 0.781) in the ICU. The influence of SVR on esCCO analysis showed a correlation coefficient between SVR and an error of 0.37 (P < 0.0001, 95% confidence interval 0.298-0.438). The efficacy of noninvasive esCCO technology was compared with TDCO in 213 cases. Five hundred eighty-seven datasets comparing esCCO and TDCO showed close correlation and small bias and precision, which were comparable to current arterial waveform analysis technologies.


Lokiarchaeon is hydrogen dependent.
The nature of the host that acquired the mitochondrion at the eukaryote origin is an important microbial evolutionary issue. Modern phylogenetics indicates that the host was an archaeon. The metagenome sequence of Candidatus Lokiarchaeon has identified it as being the closest relative of the host yet known. Here, we report comparative genomic evidence indicating that Lokiarchaeon is hydrogen dependent, as one theory for the eukaryote origin-the hydrogen hypothesis-predicts for the host lineage.


Ultrasound evaluation of the distal migration of the long head of biceps tendon following tenotomy in patients undergoing arthroscopic repair of tears of the rotator cuff.
This study evaluates the position of the long head of biceps tendon using ultrasound following simple tenotomy, in patients with arthroscopically repaired rotator cuff tears. In total, 52 patients with a mean age of 60.7 years (45 to 75) underwent arthroscopic repair of the rotator cuff and simple tenotomy of the long head of biceps tendon. At two years post-operatively, ultrasound revealed that the tendon was inside the bicipital groove in 43 patients (82.7%) and outside in nine (17.3%); in six of these it was lying just outside the groove and in the remaining three (5.8%) it was in a remote position with a positive Popeye Sign. A dynamic ultrasound scan revealed that the tenotomised tendons had adhered to the surrounding tissues (autotenodesis).The initial condition of the tendon influenced its final position (p < 0.0005). The presence of a Popeye sign was statistically influenced by the pre-operative co-existence of supraspinatus and subscapularis tears (p < 0.0001). It appears that the natural history of the tenotomised long head of biceps tendon is to tenodese itself inside or just outside the bicipital groove, while its pre-operative condition and coexistent subscapularis tears play a significant role in the occurrence of a Popeye sign.


Syndrome X and family practitioners.
Increased incidence of hypertension, non-insulin dependent diabetes (NIDDM) and coronary heart disease often cluster in the same individuals and there have been speculations that a common mechanism may be responsible for all of these pathological conditions. This risk factor constellation, which is associated with an enhanced risk for cardiovascular disease, is sometimes referred to as the "Insulin Resistance Syndrome", "Syndrome X", or the "Metabolic Syndrome". To find out the prevalence of Syndrome X in the population of patients coming to a preventive health check clinic at a tertiary care teaching hospital in a megacity of the developing world. A total of 270 patients, above the age of 40 years, who attended preventive health check clinics of 2 Family Physicians at the Aga Khan University from January 1996 to July 1997 were selected. Patients below 40 years were excluded from the study. The prevalence of Syndrome X, defined as association of obesity, NIDDM, hypertension, raised LDL and raised triglycerides is 2.6% in patients above 40 years, who were screened in this study. The significant prevalence of Syndrome X is alarming and we need to strengthen our existing educational programs for prevention of obesity, increased physical activity and better control of hypertension. When drugs are selected for pharmacological treatment, priority should be given to those, which improve the insulin sensitivity index or are at least neutral in this respect.


Association between several clinical and radiological determinants with long-term clinical progression and good prognosis of lower limb osteoarthritis.
To investigate the factors associated with clinical progression and good prognosis in patients with lower limb osteoarthritis (OA). Cohort study of 145 patients with OA in either knee, hip or both. Progression was defined as 1) new joint prosthesis or 2) increase in WOMAC pain or function score during 6-years follow-up above pre-defined thresholds. Patients without progression with decrease in WOMAC pain or function score lower than pre-defined thresholds were categorized as good prognosis. Relative risks (RRs) for progression and good prognosis with 95% confidence interval (95% CI) were calculated by comparing the highest tertile or category to the lowest tertile, for baseline determinants (age, sex, BMI, WOMAC pain and function scores, pain on physical examination, total range of motion (tROM), osteophytes and joint space narrowing (JSN) scores), and for worsening in WOMAC pain and function score in 1-year. Adjustments were performed for age, sex, and BMI. Follow-up was completed by 117 patients (81%, median age 60 years, 84% female); 62 (53%) and 31 patients (26%) showed progression and good prognosis, respectively. These following determinants were associated with progression: pain on physical examination (RR 1.2 (1.0 to 1.5)); tROM (1.4 (1.1 to 1.6); worsening in WOMAC pain (1.9 (1.2 to 2.3)); worsening in WOMAC function (2.4 (1.7 to 2.6)); osteophytes 1.5 (1.0 to 1.8); and JSN scores (2.3 (1.5 to 2.7)). Worsening in WOMAC pain (0.1 (0.1 to 0.8)) and function score (0.1 (0.1 to 0.7)), were negatively associated with good prognosis. Worsening of self-reported pain and function in one year, limited tROM and higher osteophytes and JSN scores were associated with clinical progression. Worsening in WOMAC pain and function score in 1- year were associated with lower risk to have good prognosis. These findings help to inform patients with regard to their OA prognosis.


Mono- and dinuclear oxidovanadium(v) complexes of an amine-bis(phenolate) ligand with bromo-peroxidase activities: synthesis, characterization, catalytic, kinetic and computational studies.
The mono- and dinuclear oxidovanadium(v) complexes [VVO(L1)(Cl)] (1) and [L1VVO(μ2-O)VO(L1)] (2) of ONNO donor amine-bis(phenolate) ligand (H2L1) were readily synthesized by the reaction between H2L1 and VCl3.(THF)3 or VO(acac)2 in MeOH or MeCN, respectively, and then characterized through mass spectroscopy, 1H-NMR and FTIR techniques. Both the complexes possess distorted octahedral geometry around each V centre. Upon the addition of 1 equivalent or more acid to a MeCN solution of complex 1, it immediately turned into the protonated form, which might be in equilibrium as: [L1ClVV[double bond, length as m-dash]OH]+ ↔ [L1ClVV-OH]+ (in the case of [L1ClVV[double bond, length as m-dash]OH]+ oxo-O is just protonated, whereas in [L1ClVV-OH]+ it is a hydroxo species), with the shift in λmax from 610 nm to 765 nm. Similar was the case for complex 2. The complexes 1 and 2 could efficiently catalyze the oxidative bromination of salicylaldehyde in the presence of H2O2 to produce 5-bromo salicylaldehyde as the major product with TONs of 405 and 450, respectively, in the mixed solvent system (H2O : MeOH : THF = 4 : 3 : 2, v/v). The kinetic analysis of the bromide oxidation reaction indicated a first-order mechanism in the protonated peroxidovanadium complex and a bromide ion and limiting first-order mechanism on [H+]. The evaluated kBr and kH values were 5.78 ± 0.20 and 11.01 ± 0.50 M-1 s-1 for complex 1 and 6.21 ± 0.13 and 20.14 ± 0.72 M-1 s-1 for complex 2, respectively. The kinetic and thermodynamic acidities of the protonated oxido species of complexes 1 and 2 were pKa = 2.55 (2.35) and 2.16 (2.19), respectively, which were far more acidic than those reported by Pecoraro et al. for peroxido-protonation instead of oxido protonation. On the basis of the chemistry observed for these model compounds, a mechanism of halide oxidation and a detailed catalytic cycle are proposed for the vanadium haloperoxidase enzyme and these were substantiated by detailed DFT calculations.


Difference in appearance between prone and supine myocardial perfusion images obtained on a high-efficiency cadmium zinc telluride SPECT camera.
The recent introduction of high-efficiency solid-state gamma cameras for myocardial perfusion single photon emission computed tomography has enabled lower patient radiation dose, faster imaging, and improved image quality. However, artifacts still complicate interpretation. Prone imaging is a common maneuver to reduce artifacts and increase accuracy for detection of coronary artery disease, but its effect on imaging relative to supine imaging has not been fully characterized in these new systems. In this IRB-approved, HIPAA-compliant retrospective study, 30 patients were reviewed, who underwent prone and supine imaging on the GE 530c multipinhole cadmium zinc telluride camera under both rest and stress conditions. Informed consent was waived. Perfusion was scored visually by two readers on a five-point scale according to the 17-segment model. Differences were assessed for significance using a multivariate linear effects model and restricted maximum likelihood method. Prone positioning resulted in increased activity in the basal inferior (P<0.001), basal inferolateral (P=0.009), basal inferoseptal (P<0.001), and mid-inferior (P<0.001) segments when taking into account factors such as stress versus rest, perfusion scores of other segments, and reader. Prone imaging on the GE 530c camera increases measured tracer activity in the basal inferior, basal inferolateral, basal inferoseptal, and mid-inferior segments. Caution is advised when diagnosing myocardial ischemia in these territories, particularly if clinical data are unavailable.


An active biopolymer network controlled by molecular motors.
We describe an active polymer network in which processive molecular motors control network elasticity. This system consists of actin filaments cross-linked by filamin A (FLNa) and contracted by bipolar filaments of muscle myosin II. The myosin motors stiffen the network by more than two orders of magnitude by pulling on actin filaments anchored in the network by FLNa cross-links, thereby generating internal stress. The stiffening response closely mimics the effects of external stress applied by mechanical shear. Both internal and external stresses can drive the network into a highly nonlinear, stiffened regime. The active stress reaches values that are equivalent to an external stress of 14 Pa, consistent with a 1-pN force per myosin head. This active network mimics many mechanical properties of cells and suggests that adherent cells exert mechanical control by operating in a nonlinear regime where cell stiffness is sensitive to changes in motor activity. This design principle may be applicable to engineering novel biologically inspired, active materials that adjust their own stiffness by internal catalytic control.


A comprehensive assessment of the precision and agreement of anterior corneal power measurements obtained using 8 different devices.
To comprehensively assess the precision and agreement of anterior corneal power measurements using 8 different devices. Thirty-five eyes from 35 healthy subjects were included in the prospective study. In the first session, a single examiner performed on each subject randomly measurements with the RC-5000 (Tomey Corp., Japan), KR-8000 (Topcon, Japan), IOLMaster (Carl Zeiss Meditec, Germany), E300 (Medmont International, Australia), Allegro Topolyzer (Wavelight AG, Germany), Vista (EyeSys, TX), Pentacam (Oculus, Germany) and Sirius (CSO, Italy). Measurements were repeated in the second session (1 to 2 weeks later). Repeatability and reproducibility of corneal power measurements were assessed based on the intrasession and intersession within-subject standard deviation (Sw), repeatability (2.77Sw), coefficient of variation (COV), and intraclass correlation coefficient (ICC). Agreement was evaluated by 95% limits of agreement (LoA). All devices demonstrated high repeatability and reproducibility of the keratometric values (2.77Sw<0.36D, COV<0.3%, ICC>0.98). Repeated-measures analysis of variance with Bonferroni post test showed statistically significant differences (P<0.01) among mean keratometric values of most instruments; the largest differences were observed between the EyeSys Vista and Medmont E300. Good agreement (i.e., 95%LoA within ± 0.5D) was found between most instruments for flat, steep and mean keratometry, except for EyeSys and Medmont. Repeatability and reproducibility of vectors J(0) and J(45) was good, as the ICCs were higher than 0.9, except J(45) of Medmont and Pentacam. For the 95% LoAs of J(0) and J(45), they were all ≤ ± 0.31 among any two paired devices. The 8 devices showed excellent repeatability and reproducibility. The results obtained using the RC-5000, KR-8000, IOLMaster, Allegro Topolyzer, Pentacam and Sirius were comparable, suggesting that they could be used interchangeably in most clinical settings. Caution is warranted with the measurements of the EyeSys Vista and Medmont E300, which should not be used interchangeably with other devices due to lower agreement. ClinicalTrials.gov NCT01587287.


Polyamine transport by the polyspecific organic cation transporters OCT1, OCT2, and OCT3.
Polyamines are ubiquitous organic cations implicated in many physiological processes. Because they are positively charged at physiological pH, carrier-mediated systems are necessary for effective membrane permeation, but the identity of specific polyamine transporter proteins in eukaryotic cells remains unclear. Polyspecific organic cation transporters (OCTs) interact with many natural and xenobiotic monovalent cations and have been reported to transport dicationic compounds, including the short polyamine putrescine. In this study, we used Xenopus oocytes expressing mammalian OCT1 (SLC22A1), OCT2 (SLC22A2), or OCT3 (SLC22A3) to assess binding and transport of longer-chain polyvalent polyamines. In OCT-expressing oocytes, [(3)H]MPP(+) uptake rates were 15- to 35-fold higher than in noninjected oocytes, whereas those for [(3)H]spermidine increased more modestly above the background, up to 3-fold. This reflected up to 20-fold lower affinity for spermidine than for MPP(+); thus, K(0.5) for MPP(+) was ~50 μM in OCT1, ~170 μM in OCT2, and ~60 μM in OCT3, whereas for spermidine, K(0.5) was ~1 mM in OCT1, OCT2, and OCT3. J(max) values for MPP(+) and spermidine were within the same range, suggesting that both compounds are transported at a similar turnover rate. To gain further insight into OCT substrate specificity, we screened a selection of structural polyamine analogues for effect on [(3)H]MPP(+) uptake. In general, blocking potency increased with overall hydrophobic character, which indicates that, as for monovalent cations, hydrophobicity is a major requirement for recognition in polyvalent OCT substrates and inhibitors. Our results demonstrate that the natural polyamines are low affinity, but relatively high turnover, substrates for OCTs. The identification of OCTs as polyamine transport systems may contribute to further understanding of the mechanisms involved in polyamine homeostasis and aid in the design of polyamine-like OCT-targeted drugs.


Itaconate and derivatives reduce interferon responses and inflammation in influenza A virus infection.
Excessive inflammation is a major cause of morbidity and mortality in many viral infections including influenza. Therefore, there is a need for therapeutic interventions that dampen and redirect inflammatory responses and, ideally, exert antiviral effects. Itaconate is an immunomodulatory metabolite which also reprograms cell metabolism and inflammatory responses when applied exogenously. We evaluated effects of endogenous itaconate and exogenous application of itaconate and its variants dimethyl- and 4-octyl-itaconate (DI, 4OI) on host responses to influenza A virus (IAV). Infection induced expression of ACOD1, the enzyme catalyzing itaconate synthesis, in monocytes and macrophages, which correlated with viral replication and was abrogated by DI and 4OI treatment. In IAV-infected mice, pulmonary inflammation and weight loss were greater in Acod1-/- than in wild-type mice, and DI treatment reduced pulmonary inflammation and mortality. The compounds reversed infection-triggered interferon responses and modulated inflammation in human cells supporting non-productive and productive infection, in peripheral blood mononuclear cells, and in human lung tissue. All three itaconates reduced ROS levels and STAT1 phosphorylation, whereas AKT phosphorylation was reduced by 4OI and DI but increased by itaconate. Single-cell RNA sequencing identified monocytes as the main target of infection and the exclusive source of ACOD1 mRNA in peripheral blood. DI treatment silenced IFN-responses predominantly in monocytes, but also in lymphocytes and natural killer cells. Ectopic synthesis of itaconate in A549 cells, which do not physiologically express ACOD1, reduced infection-driven inflammation, and DI reduced IAV- and IFNγ-induced CXCL10 expression in murine macrophages independent of the presence of endogenous ACOD1. The compounds differed greatly in their effects on cellular gene homeostasis and released cytokines/chemokines, but all three markedly reduced release of the pro-inflammatory chemokines CXCL10 (IP-10) and CCL2 (MCP-1). Viral replication did not increase under treatment despite the dramatically repressed IFN responses. In fact, 4OI strongly inhibited viral transcription in peripheral blood mononuclear cells, and the compounds reduced viral titers (4OI>Ita>DI) in A549 cells whereas viral transcription was unaffected. Taken together, these results reveal itaconates as immunomodulatory and antiviral interventions for influenza virus infection.


Generation of an iPSC line (UMGWi001-B) from a patient with Floating-Harbor Syndrome (FLHS) carrying a heterozygous SRCAP mutation (p.Arg2444).
Floating-Harbor syndrome (FLHS) is a rare genetic disease caused by mutations in the SRCAP gene. Here, we generated an induced pluripotent stem cell line from gingival fibroblasts of a male patient with a heterozygous mutation in exon 34 of the SRCAP gene (c.7330C > T, p.Arg2444*). The iPSC colonies have an atypical morphology with diffuse borders and disintegrate quickly upon touch. Still, the cell line expresses pluripotency markers and differentiates into three germ layers. The cell line can be used as patient-specific disease model and help elucidate the molecular mechanisms involving SRCAP in the context of FLHS.


Anaesthetic management of obstetric emergencies.
Obstetric emergencies are a challenge both for the obstetrician and the anaesthesiologist. The incidence of caesarean sections as per the National Family Health Survey published in 2015-16 was 17.2%. In 7.6% of cases, the decision to conduct a caesarean section was taken after the onset of labour pains. Caesarean sections are classified depending on the urgency into four categories. The target decision to delivery interval for category 1 caesarean section is less than 30 min. This is used as an audit tool for the efficiency of an obstetric service. The management of these emergencies involves a rapid assessment, with minimal investigations. Although general anaesthesia is considered to have higher morbidity and mortality, category 1 caesarean sections may still warrant this technique. Rapid sequence spinal anaesthesia is replacing general anaesthesia for many of the category 1 indications. In category 2 and 3 caesarean sections, spinal anaesthesia still remains the technique of choice. Failed intubation, failed neuraxial block, extensive neuraxial block, awareness under anaesthesia, thromboembolism, amniotic fluid embolism, haemorrhage and maternal collapse are some of the complications. Haemorrhage is said to be the leading cause of mortality worldwide.


Preparation and characterization of polypseudorotaxanes based on block-selected inclusion complexation between poly(propylene oxide)-poly(ethylene oxide)-poly(propylene oxide) triblock copolymers and alpha-cyclodextrin.
A series of new polypseudorotaxanes were synthesized in high yields when the middle poly(ethylene oxide) (PEO) block of poly(propylene oxide)-poly(ethylene oxide)-poly(propylene oxide) (PPO-PEO-PPO) triblock copolymers was selectively recognized and included by alpha-cyclodextrin (alpha-CD) to form crystalline inclusion complexes (ICs), although the middle PEO block was flanked by two thicker PPO blocks, and a PPO chain had been previously thought to be impenetrable to alpha-CD. X-ray diffraction studies demonstrated that the IC domains of the polypseudorotaxanes assumed a channel-type structure similar to the necklace-like ICs formed by alpha-CD and PEO homopolymers. Solid-state CP/MAS (13)C NMR studies showed that the alpha-CD molecules in the polypseudorotaxanes adopted a symmetrical conformation due to the formation of ICs. The compositions and stoichiometry of the polypseudorotaxanes were studied using (1)H NMR, and a 2:1 (ethylene oxide unit to alpha-CD) stoichiometry was found for all polypseudorotaxanes although the PPO-PEO-PPO triblock copolymers had different compositions and block lengths, suggesting that only the PEO block was closely included by alpha-CD molecules, whereas the PPO blocks were uncovered. The hypothesis was further supported by the differential scanning calorimetry (DSC) studies of the polypseudorotaxanes. The glass transitions of the PPO blocks in the polypseudorotaxanes were clearly observed because they were uncovered by alpha-CD and remained amorphous, whereas the glass-transition temperatures increased, because the molecular motion of the PPO blocks was restricted by the hard crystalline phases of the IC domains formed by alpha-CD and the PEO blocks. The thermogravimetric analysis (TGA) revealed that the polypseudorotaxanes had better thermal stability than their free components due to the inclusion complexation. Finally, the kinetics of the threading process of alpha-CD onto the copolymers was also studied. The findings reported in this article suggested interesting possibilities in designing other cyclodextrin ICs and polypseudorotaxanes with block structures.


Serotonergic innervation and serotonin receptor expression of NPY-producing neurons in the rat lateral and basolateral amygdaloid nuclei.
Pharmacobehavioral studies in experimental animals, and imaging studies in humans, indicate that serotonergic transmission in the amygdala plays a key role in emotional processing, especially for anxiety-related stimuli. The lateral and basolateral amygdaloid nuclei receive a dense serotonergic innervation in all species studied to date. We investigated interrelations between serotonergic afferents and neuropeptide Y (NPY)-producing neurons, which are a subpopulation of inhibitory interneurons in the rat lateral and basolateral nuclei with particularly strong anxiolytic properties. Dual light microscopic immunolabeling showed numerous appositions of serotonergic afferents on NPY-immunoreactive somata. Using electron microscopy, direct membrane appositions and synaptic contacts between serotonin-containing axon terminals and NPY-immunoreactive cellular profiles were unequivocally established. Double in situ hybridization documented that more than 50 %, and about 30-40 % of NPY mRNA-producing neurons, co-expressed inhibitory 5-HT1A and excitatory 5-HT2C mRNA receptor subtype mRNA, respectively, in both nuclei with no gender differences. Triple in situ hybridization showed that individual NPY mRNA-producing interneurons co-express both 5-HT1A and 5-HT2C mRNAs. Co-expression of NPY and 5-HT3 mRNA was not observed. The results demonstrate that serotonergic afferents provide substantial innervation of NPY-producing neurons in the rat lateral and basolateral amygdaloid nuclei. Studies of serotonin receptor subtype co-expression indicate a differential impact of the serotonergic innervation on this small, but important, population of anxiolytic interneurons, and provide the basis for future studies of the circuitry underlying serotonergic modulation of emotional stimulus processing in the amygdala.


Influences on the drinking of heavier drinkers: Interactional realities in seeking to 'change drinking cultures'.
'Changing drinking culture' is a prominent goal in the Australian state of Victoria's current alcohol strategy-seeking a shift so that 'excessive drinking isn't seen as the norm'. As a social activity, there is a strong collective aspect to drinking and associated behaviour: customs within the drinking group and at the level of social worlds of drinking operate both to increase and to control drinking patterns and associated behaviours. The paper considers how risky drinkers and those in social worlds of heavy drinking experience others' expectations about drinking. Using Victorian population survey responses (n = 2092 adults who had consumed alcohol in previous year) to identify those in a social world of group drinking, and a subcategory who are also risky drinkers, the paper explores pressures on those in these categories both to drink more and to drink less, whether from family members, from work colleagues, or from friends. Those who are both risky and social drinkers are much more likely than other drinkers to report pressures to drink more from friends and workmates, and even from family members, although they more often report pressures from family members to drink less than to drink more. Efforts to change a drinking culture, it is argued, must take account of the collective nature of drinking and of the interplay of influences at interpersonal and subcultural levels if they are to be effective in reducing rates of heavy drinking and alcohol problems. [Room R, Callinan S, Dietze P. Influences on the drinking of heavier drinkers: Interactional realities in seeking to 'change drinking cultures'. Drug Alcohol Rev 2015].


Patterns and predictors of persistence of suicide ideation: Results from the Army Study to Assess Risk and Resilience in Servicemembers (Army STARRS).
Persistent suicide ideation (SI) is known to be a risk factor for subsequent suicidal behaviors. Reducing SI persistence among people with a history of SI consequently might be a useful target for preventive intervention; however, basic information is lacking about patterns and predictors of SI persistence. We report preliminary retrospective data on annual SI persistence in a representative sample of 3,501 U.S. Army soldiers with lifetime SI from the Army Study to Assess Risk and Resilience in Servicemembers (Army STARRS). Reports about age-of-onset and number of years with SI were used to estimate two definitions of persistence: persistence beyond year-of-onset and proportional annual persistence (i.e., percentage of years with SI since year-of-onset). Results revealed that for 47.8% of respondents with lifetime SI, their SI did not persist beyond the year-of-onset. For the 52.2% whose SI did persist beyond the year-of-onset, the median (interquartile range) proportional annual persistence was 33% (17-67%). Significant predictors of increased persistence were different for respondents with preenlistment SI onset (prior histories of attention-deficit/hyperactivity disorder [ADHD], bipolar disorder, and panic disorder) and postenlistment SI onset (male, combat support military occupation specialty, prior histories of ADHD, panic disorder, and posttraumatic stress disorder). These predictors of persistence are different from the predictors of SI onset, suggesting that secondary preventive interventions to reduce SI persistence may need to focus on different factors than primary preventive interventions to reduce SI onset. (PsycINFO Database Record (c) 2018 APA, all rights reserved).


Enhanced Electrocatalytic Stability of Platinum Nanoparticles Supported on Sulfur-Doped Carbon using in-situ Solution Plasma.
The metal-air battery is a form of renewable energy generation technology that produces energy electrochemically and can address energy concerns in the near future. However, state-of-the-art Pt electrocatalysts often suffer from agglomeration or detachment from carbon supports under prolonged operation, eventually limiting the long-term utilization of metal-air batteries. In this work, Pt nanoparticles were deposited on sulfur-doped nanocarbon to increase its stability. We first synthesized sulfur-doped (S-doped) and pristine carbon as support materials via a plasma process, and thereafter loaded platinum (Pt) nanoparticles onto the S-doped and pristine carbon matrix. From a sintering test at 600 °C, the Pt nanoparticles supported on pristine carbon increased from 2.4 to 5.2 nm; meanwhile, the average size of Pt NPs supported on S-doped carbon only increased from 2.2 to 2.51 nm. From the electrochemical analyses, the mass activity of Pt on pristine and S-doped carbon supports decreased by 25% and 10%, respectively, after 1500 cycles. The results proposed that the sulfide C-S-C bond provided a strong platinum-S-doped carbon support interaction between the support materials and the loaded Pt nanoparticles. Thus, S-doped carbon supports can serve as a stabilizer of Pt nanoparticles to enhance their durability in the application of metal-air batteries and other electrochemical devices.


Jet and accretion-disk emission untangled in 3C 273.
A long-term spectral variability study of 3C 273 on data obtained by BeppoSAX allows us to decouple the beamed nonthermal (jet) and unbeamed thermal (accretion flow) radiation produced in the inner region of a radio-loud active galactic nucleus. Jet power, when compared with unbeamed radiation, increases with energy. The thermal component is generally overwhelmed by the nonthermal radiation, by a factor of 1.2 to 3 in the 2- to 10-keV range and up to a factor of 7 above 20 keV. In only one case, the accretion flow overcomes the jet, allowing the K(alpha) iron line to emerge clearly over the continuum.


Protein aggregation: pathways, induction factors and analysis.
Control and analysis of protein aggregation is an increasing challenge to pharmaceutical research and development. Due to the nature of protein interactions, protein aggregation may occur at various points throughout the lifetime of a protein and may be of different quantity and quality such as size, shape, morphology. It is therefore important to understand the interactions, causes and analyses of such aggregates in order to control protein aggregation to enable successful products. This review gives a short outline of currently discussed pathways and induction methods for protein aggregation and describes currently employed set of analytical techniques and emerging technologies for aggregate detection, characterization and quantification. A major challenge for the analysis of protein aggregates is that no single analytical method exists to cover the entire size range or type of aggregates which may appear. Each analytical method not only shows its specific advantages but also has its limitations. The limits of detection and the possibility of creating artifacts through sample preparation by inducing or destroying aggregates need to be considered with each method used. Therefore, it may also be advisable to carefully compare analytical results of orthogonal methods for similar size ranges to evaluate method performance.


Interobserver reliability in the histopathological diagnosis of cartilaginous tumors in patients with multiple osteochondromas.
The distinction between benign and malignant cartilaginous tumors located peripherally in the bone may be a challenging task in surgical pathology. The aim of this study was to investigate interobserver reliability in histological diagnosis of cartilaginous tumors in the setting of multiple osteochondromas and to evaluate possible histological parameters that could differentiate among osteochondroma, low- and high-grade secondary peripheral chondrosarcoma. Interobserver reliability was assessed by 12 specialized bone-tumor pathologists in a set of 38 cases. Substantial agreement on diagnosis among all the reviewers was observed (intraclass correlation coefficient=0.78). Our study confirmed that mitotic figures and nuclear pleomorphism are hallmarks of high-grade secondary peripheral chondrosarcoma. However, despite the substantial agreement, we demonstrated that histology alone cannot distinguish osteochondroma from low-grade secondary peripheral chondrosarcoma in the setting of multiple osteochondromas, as nodularity, the presence of binucleated cells, irregular calcification, cystic/mucoid changes and necrosis were not helpful to indicate malignant transformation of an osteochondroma. On the other hand, among the concordant cases, the cartilage cap in osteochondroma was significantly less thicker than in low- and high-grade secondary peripheral chondrosarcoma. Therefore, our study showed that a multidisciplinary approach integrating clinical and radiographical features and the size of the cartilaginous cap in combination with a histological assessment are crucial to the diagnosis of cartilaginous tumors.


METT-10, a putative methyltransferase, inhibits germ cell proliferative fate in Caenorhabditis elegans.
Germ-line stem cells are unique because they either self-renew through mitosis or, at a certain frequency, switch to meiosis and produce gametes. The switch from proliferation to meiosis is tightly regulated, and aberrations in switching result in either too little or too much proliferation. To understand the genetic basis of this regulation, we characterized loss-of-function mutations and a novel tumorous allele of Caenorhabditis elegans mett-10, which encodes a conserved putative methyltransferase. We show that METT-10 is a nuclear protein that acts in the germ line to inhibit the specification of germ-cell proliferative fate. METT-10 also promotes vulva, somatic gonad, and embryo development and ensures meiotic development of those germ cells that do differentiate. In addition, phenotypic analysis of a mett-10 null allele reveals that METT-10 enables mitotic cell cycle progression. The finding that METT-10 functions to inhibit germ-cell proliferative fate, despite promoting mitotic cell cycle progression of those germ cells that do proliferate, separates the specification of proliferative fate from its execution.


Suramin and radiotherapy in newly diagnosed glioblastoma: phase 2 NABTT CNS Consortium study.
Suramin is a polysulfonated naphthylurea that inhibits the function of growth factors and growth factor receptors implicated in glioma progression, angiogenesis, and radioresistance. The safety and benefits of combining inhibitors of angiogenesis and growth factors with cytotoxic therapies in patients with neoplasms of the central nervous system remain unclear. The objectives of this phase 2 study were to determine the safety of administering suramin with standard cranial radiotherapy (RT) and to estimate survival using this approach in patients with newly diagnosed glioblastoma multiforme (GBM). Fifty-five patients with newly diagnosed GBM (Karnofsky performance status >or= 60) were enrolled in this multicenter phase 2 study. Patients received suramin by a conventional intermittent fixed-dosing regimen for 1 week prior to and during cranial RT (60 Gy in 30 fractions, weeks 2-7). Patients with stable or responsive disease at week 18 received an additional 4 weeks of suramin (weeks 19-22). The median survival for suramin-treated patients was 11.6 months, with 1-year and 18-month survival rates of 49% (95% confidence interval [CI], 36%-62%) and 18% (95% CI, 8%-28%), respectively. Overall, 55% of the patients (30/55) had greater than grade 2 toxicity at least possibly related to suramin therapy. Two patients died of possibly related neurologic events (i.e., stroke, elevated intracranial pressure). Otherwise, toxicities were generally transient and self-limited. Administration of suramin using an intermittent fixed-dosing regimen during cranial RT was generally well tolerated. However, overall survival is not significantly improved when compared with the New Approaches to Brain Tumor Therapy GBM database or other comparable patient populations.


Expression of a novel high-affinity purine nucleobase transport function in mutant mammalian T lymphoblasts.
The single nucleoside transport function of mouse S49 lymphoblasts also transports purine bases (B. Aronow and B. Ullman, J. Biol. Chem. 261:2014-2019, 1986). This transport of purine bases by S49 cells is sensitive to inhibition by dipyridamole (DPA) and 4-nitrobenzylthioinosine, two potent inhibitors of nucleoside transport. Therefore, wild-type S49 cells cannot salvage low hypoxanthine concentrations in the presence of 10 microM DPA and 11 microM azaserine; the latter is a potent inhibitor of purine biosynthesis. Among a mutagenized wild-type population, a cell line, JPA2, was isolated which could proliferate in 50 microM hypoxanthine-11 microM azaserine-10 microM DPA. The basis for the survival of JPA2 cells under these selective conditions was expression of a unique, high-affinity purine nucleobase transport function not present in wild-type cells. JPA2 cells could transport 5 microM concentrations of hypoxanthine, guanine, and adenine 15- to 30-fold more efficiently than parental cells did. Kinetic analyses revealed that the affinity of the JPA2 transporter for all three purine bases was much greater than that of the wild-type nucleobase transport system. Moreover, nucleobase transport in JPA2 cells, unlike that in parental cells, was insensitive to inhibition by DPA, 4-nitrobenzylthioinosine, sulfhydryl reagents, and nucleosides. No alterations in nucleoside transport capability, phosphoribosylpyrophosphate levels, or purine phosphoribosyltransferase enzymes were detected in JPA2 cells. Thus, JPA2 cells express a novel nucleobase transport capability which can be distinguished from the nucleoside transport function by multiple biochemical parameters.


NS reassortment of an H7-type highly pathogenic avian influenza virus affects its propagation by altering the regulation of viral RNA production and antiviral host response.
Highly pathogenic avian influenza viruses (HPAIV) with reassorted NS segments from H5- and H7-type avian virus strains placed in the genetic background of the A/FPV/Rostock/34 HPAIV (FPV; H7N1) were generated by reverse genetics. Virological characterizations demonstrated that the growth kinetics of the reassortant viruses differed from that of wild-type (wt) FPV and depended on whether cells were of mammalian or avian origin. Surprisingly, molecular analysis revealed that the different reassortant NS segments were not only responsible for alterations in the antiviral host response but also affected viral genome replication and transcription as well as nuclear ribonucleoprotein (RNP) export. RNP reconstitution experiments demonstrated that the effects on accumulation levels of viral RNA species were dependent on the specific NS segment as well as on the genetic background of the RNA-dependent RNA polymerase (RdRp). Beta interferon (IFN-β) expression and the induction of apoptosis were found to be inversely correlated with the magnitude of viral growth, while the NS allele, virus subtype, and nonstructural protein NS1 expression levels showed no correlation. Thus, these results demonstrate that the origin of the NS segment can have a dramatic effect on the replication efficiency and host range of HPAIV. Overall, our data suggest that the propagation of NS reassortant influenza viruses is affected at multiple steps of the viral life cycle as a result of the different effects of the NS1 protein on multiple viral and host functions.


Opioid receptors modulate diverse types of calcium channels in the nucleus tractus solitarius of the rat.
We have investigated the coupling between opioid receptors and different types of Ca2+ channels in neurons acutely isolated from the nucleus tractus solitarius (NTS) of the rat. Using fura-2-based imaging we found that Ca2+ transients evoked by depolarization with 50 mM KCl were suppressed by the mu-opioid receptor agonist D-Ala2,N-MePhe4,Gly5-ol-enkephalin (DAMGO) and less effectively by the kappa-receptor agonist U-69,593. The delta-receptor agonist D-Pen2,D-Pen5-enkephalin (DPDPE) was ineffective. In whole-cell voltage-clamp recordings from these neurons, depolarizing voltage steps elicited high-threshold Ca2+ currents that could be distinguished pharmacologically into different components. Part of the current could be blocked by dihydropyridines, part by omega-conotoxin-GVIA and part by omega-agatoxin-IVA. This suggests that the neurons contained L-, N-, and P/Q-type Ca2+ channels. DAMGO and U-69,593 both blocked part of the Ca2+ current but DPDPE was ineffective. Perfusion of GTP-gamma-S into the cells produced a rapid rundown of the Ca2+ current and occluded further effects of the opioid agonists, suggesting the involvement of a G-protein in the coupling mechanism. Inhibition of L-channels did not alter the effect of DAMGO. On the other hand inhibition of N-channels occluded about 80% of the effect of DAMGO. Inhibition of the P/Q-current occluded the remainder of the DAMGO effect. Thus, it appears that activation of opioid receptors can inhibit N- and P/Q-type Ca2+ channels but not L-channels in these cells. It is likely that such effects are important in opioid-mediated inhibition of transmitter release in the brain.


Right-wing authoritarianism predicts prejudice equally toward "gay men and lesbians" and "homosexuals".
Two recent experiments found evidence for what we term the social category label (SCL) effect-that the relationship between right-wing authoritarianism (RWA) and prejudice against gay men and lesbians can be reduced or even eliminated when the target group is labeled "gay men and lesbians" rather than "homosexuals" (Rios, 2013). Although this appears a promising approach to reduce self-reported sexual prejudice, with both theoretical implications for the meaning of RWA itself and practical implications for question wording for assessing these attitudes, there are several reasons to further examine these findings, including (a) inconsistencies with extant evidence, (b) small sample sizes in the original 2 experiments, and (c) concerns with the RWA measures used in the 2 experiments. We tested the SCL hypothesis with a nationally representative sample (Study 1) and close and conceptual replications of Rios' (2013) 2 studies (Studies 2-5) using multiple measures of RWA and prejudice. Across 23 tests of the SCL hypothesis, we obtained 1 statistically significant and 1 marginally significant effect consistent with the hypothesis, 2 significant effects opposite the hypothesis, and 19 nonsignificant effects. A meta-analysis of evidence reported here and in Rios (2013) indicates that RWA strongly predicts antigay prejudice, with no significant variation by label. This confirms the typically robust association between RWA and antigay prejudice and confirms that the SCL effect is not robust. We discuss potential limitations of these studies, theoretical, methodological, and practical implications for our failures to replicate the original SCL studies, and future directions for examining social category label effects. (PsycINFO Database Record


Coordinated effects of sequence variation on DNA binding, chromatin structure, and transcription.
DNA sequence variation has been associated with quantitative changes in molecular phenotypes such as gene expression, but its impact on chromatin states is poorly characterized. To understand the interplay between chromatin and genetic control of gene regulation, we quantified allelic variability in transcription factor binding, histone modifications, and gene expression within humans. We found abundant allelic specificity in chromatin and extensive local, short-range, and long-range allelic coordination among the studied molecular phenotypes. We observed genetic influence on most of these phenotypes, with histone modifications exhibiting strong context-dependent behavior. Our results implicate transcription factors as primary mediators of sequence-specific regulation of gene expression programs, with histone modifications frequently reflecting the primary regulatory event.


Robot-Assisted Training Early After Cardiac Surgery.
To assess feasibility and safety of a robot-assisted gait therapy with the Lokomat® system in patients early after open heart surgery. Within days after open heart surgery 10 patients were subjected to postoperative Lokomat® training (Intervention group, IG) whereas 20 patients served as controls undergoing standard postoperative physiotherapy (Control group, CG). All patients underwent six-minute walk test and evaluation of the muscular strength of the lower limbs by measuring quadriceps peak force. The primary safety end-point was freedom from any device-related wound healing disturbance. Patients underwent clinical follow-up after one month. Both training methods resulted in an improvement of walking distance (IG [median, interquartile range, p-value]: +119 m, 70-201 m, p = 0.005; CG: 105 m, 57-152.5m, p < 0.001) and quadriceps peak force (IG left: +5 N, 3.8 7 N, p = 0.005; IG right: +3.5 N, 1.5-8.8 N, p = 0.011; CG left: +5.5 N, 4-9 N, p < 0.001; CG right: +6 N, 4.3-9.8 N, p < 0.001) in all participants. Results with robot-assisted training were comparable to early postoperative standard in hospital training (median changes in walking distance in percent, p = 0.81; median changes in quadriceps peak force in percent, left: p = 0.97, right p = 0.61). No deep sternal wound infection or any adverse event occurred in the robot-assisted training group. Robot-assisted gait therapy with the Lokomat® system is feasible and safe in patients early after median sternotomy. Results with robot-assisted training were comparable to standard in hospital training. An adapted and combined aerobic and resistance training intervention with augmented feedback may result in benefits in walking distance and lower limb muscle strength (ClinicalTrials.gov number, NCT 02146196).


The inference of phased haplotypes for the immunoglobulin H chain V region gene loci by analysis of VDJ gene rearrangements.
The existence of many highly similar genes in the lymphocyte receptor gene loci makes them difficult to investigate, and the determination of phased "haplotypes" has been particularly problematic. However, V(D)J gene rearrangements provide an opportunity to infer the association of Ig genes along the chromosomes. The chromosomal distribution of H chain genes in an Ig genotype can be inferred through analysis of VDJ rearrangements in individuals who are heterozygous at points within the IGH locus. We analyzed VDJ rearrangements from 44 individuals for whom sufficient unique rearrangements were available to allow comprehensive genotyping. Nine individuals were identified who were heterozygous at the IGHJ6 locus and for whom sufficient suitable VDJ rearrangements were available to allow comprehensive haplotyping. Each of the 18 resulting IGHV│IGHD│IGHJ haplotypes was unique. Apparent deletion polymorphisms were seen that involved as many as four contiguous, functional IGHV genes. Two deletion polymorphisms involving multiple contiguous IGHD genes were also inferred. Three previously unidentified gene duplications were detected, where two sequences recognized as allelic variants of a single gene were both inferred to be on a single chromosome. Phased genomic data brings clarity to the study of the contribution of each gene to the available repertoire of rearranged VDJ genes. Analysis of rearrangement frequencies suggests that particular genes may have substantially different yet predictable propensities for rearrangement within different haplotypes. Together with data highlighting the extent of haplotypic variation within the population, this suggests that there may be substantial variability in the available Ab repertoires of different individuals.


Glycation of LDL by methylglyoxal increases arterial atherogenicity: a possible contributor to increased risk of cardiovascular disease in diabetes.
To study whether modification of LDL by methylglyoxal (MG), a potent arginine-directed glycating agent that is increased in diabetes, is associated with increased atherogenicity. Human LDL was isolated and modified by MG in vitro to minimal extent (MG(min)-LDL) as occurs in vivo. Atherogenic characteristics of MG(min)-LDL were characterized: particle size, proteoglycan-binding, susceptibility to aggregation, LDL and non-LDL receptor-binding, and aortal deposition. The major site of modification of apolipoprotein B100 (apoB100) modification was investigated by mass spectrometric peptide mapping. MG(min)-LDL contained 1.6 molar equivalents of MG modification-mostly hydroimidazolone-as found in vivo. MG(min)-LDL had decreased particle size, increased binding to proteoglycans, and increased aggregation in vitro. Cell culture studies showed that MG(min)-LDL was bound by the LDL receptor but not by the scavenger receptor and had increased binding affinity for cell surface heparan sulfate-containing proteoglycan. Radiotracer studies in rats showed that MG(min)-LDL had a similar fractional clearance rate in plasma to unmodified LDL but increased partitioning onto the aortal wall. Mass spectrometry peptide mapping identified arginine-18 as the hotspot site of apoB100 modification in MG(min)-LDL. A computed structural model predicted that MG modification of apoB100 induces distortion, increasing exposure of the N-terminal proteoglycan-binding domain on the surface of LDL. This likely mediates particle remodeling and increases proteoglycan binding. MG modification of LDL forms small, dense LDL with increased atherogenicity that provides a new route to atherogenic LDL and may explain the escalation of cardiovascular risk in diabetes and the cardioprotective effect of metformin.


Loss of transcriptional control over endogenous retroelements during reprogramming to pluripotency.
Endogenous retroelements (EREs) account for about half of the mouse or human genome, and their potential as insertional mutagens and transcriptional perturbators is suppressed by early embryonic epigenetic silencing. Here, we asked how ERE control is maintained during the generation of induced pluripotent stem cells (iPSCs), as this procedure involves profound epigenetic remodeling. We found that all EREs tested were markedly up-regulated during the reprogramming of either mouse embryonic fibroblasts, human CD34(+) cells, or human primary hepatocytes. At the iPSC stage, EREs of some classes were repressed, whereas others remained highly expressed, yielding a pattern somewhat reminiscent of that recorded in embryonic stem cells. However, variability persisted between individual iPSC clones in the control of specific ERE integrants. Both during reprogramming and in iPS cells, the up-regulation of specific EREs significantly impacted on the transcription of nearby cellular genes. While transcription triggered by specific ERE integrants at highly precise developmental stages may be an essential step toward obtaining pluripotent cells, the broad and unspecific unleashing of the repetitive genome observed here may contribute to the inefficiency of the reprogramming process and to the phenotypic heterogeneity of iPSCs.


Function of the CRISPR-Cas System of the Human Pathogen Clostridium difficile.
Clostridium difficile is the cause of most frequently occurring nosocomial diarrhea worldwide. As an enteropathogen, C. difficile must be exposed to multiple exogenous genetic elements in bacteriophage-rich gut communities. CRISPR (clustered regularly interspaced short palindromic repeats)-Cas (CRISPR-associated) systems allow bacteria to adapt to foreign genetic invaders. Our recent data revealed active expression and processing of CRISPR RNAs from multiple type I-B CRISPR arrays in C. difficile reference strain 630. Here, we demonstrate active expression of CRISPR arrays in strain R20291, an epidemic C. difficile strain. Through genome sequencing and host range analysis of several new C. difficile phages and plasmid conjugation experiments, we provide evidence of defensive function of the CRISPR-Cas system in both C. difficile strains. We further demonstrate that C. difficile Cas proteins are capable of interference in a heterologous host, Escherichia coli. These data set the stage for mechanistic and physiological analyses of CRISPR-Cas-mediated interactions of important global human pathogen with its genetic parasites. Clostridium difficile is the major cause of nosocomial infections associated with antibiotic therapy worldwide. To survive in bacteriophage-rich gut communities, enteropathogens must develop efficient systems for defense against foreign DNA elements. CRISPR-Cas systems have recently taken center stage among various anti-invader bacterial defense systems. We provide experimental evidence for the function of the C. difficile CRISPR system against plasmid DNA and bacteriophages. These data demonstrate the original features of active C. difficile CRISPR system and bring important insights into the interactions of this major enteropathogen with foreign DNA invaders during its infection cycle.


Cost-effectiveness of niraparib, rucaparib, and olaparib for treatment of platinum-resistant, recurrent ovarian carcinoma.
Olaparib was approved on December 19, 2014 by the US FDA as 4th-line therapy (and beyond) for patients with germline BRCA1/2 mutations; rucaparib was approved on December 19, 2016 as 3rd-line therapy (and beyond) for germline or somatic BRCA1/2-mutated recurrent disease. On October 23, 2019, niraparib was approved for treatment of women with damaging mutations in BRCA1/2 or other homologous recombination repair genes who had been treated with three or more prior regimens. We compared the cost-effectiveness of PARPi(s) with intravenous regimens for platinum-resistant disease. Median progression-free survival (PFS) and toxicity data from regulatory trials were incorporated in a model which transitioned patients through response, hematologic complications, non-hematologic complications, progression, and death. Using TreeAge Pro 2017, each PARPi(s) was compared separately to non‑platinum-based and bevacizumab-containing regimens. Costs of IV drugs, managing toxicities, infusions, and supportive care were estimated using 2017 Medicare data. Incremental cost-effectiveness ratios (ICERs) were calculated and PFS was reported in quality adjusted life months for platinum-resistant populations. Non‑platinum-based intravenous chemotherapy was most cost effective ($6,412/PFS-month) compared with bevacizumab-containing regimens ($12,187/PFS-month), niraparib ($18,970/PFS-month), olaparib ($16,327/PFS-month), and rucaparib ($16,637/PFS-month). ICERs for PARPi(s) were 3-3.5× times greater than intravenous non‑platinum-based regimens. High costs of orally administered PARPi(s) were not mitigated or balanced by costs of infusion and managing toxicities of intravenous regimens typically associated with lower response and shorter median PFS. Balancing modest clinical benefit with costs of novel therapies remains problematic and could widen disparities among those with limited access to care.


The illusion of mental health.
It is argued that researchers' reliance on "objective" mental health scales and disregard for clinical judgment has led to many mistaken conclusions. Specifically, standard mental health scales appear unable to distinguish between genuine mental health and the facade or illusion of mental health created by psychological defenses. Evidence is presented indicating that (a) many people who look healthy on standard mental health scales are not psychologically healthy, and (b) illusory mental health (based on defensive denial of distress) has physiological costs and may be a risk factor for medical illness. Clinical judges could distinguish genuine from illusory mental health, whereas "objective" mental health scales could not. The findings call into question the conclusions of many previous studies that rest on standard mental health scales. They suggest new ways of understanding how psychological factors may influence health. Finally, they suggest that clinical methods (which researchers often malign) may have an important role to play in meaningful mental health research.


Effects of Far-Infrared Radiation-Lamp Therapy on Recovery From Simulated Soccer Match Running Activities in Elite Soccer Players.
The authors investigated whether far-infrared radiation (FIR) lamp therapy would reduce muscle damage and enhance recovery from multiple soccer-match-related running activities. Twenty-four elite female soccer players (20-24 y) were assigned into a FIR or a sham treatment group (n = 12/group). They performed a daily 90-minute Loughborough Intermittent Shuttle Test (LIST) for 6 consecutive days. Maximal voluntary contraction torque of the knee extensors (KEs) and flexors, muscle soreness, plasma creatine kinase activity, countermovement jump, and several other performance measures (eg, 30-m dash, Yo-Yo Intermittent Recovery Test Level 1) were taken before the first LIST, 1 hour after each LIST, and 24, 48, 72, 96, and 120 hours after the last LIST. All participants received a 30-minute FIR or sham treatment on KEs and knee flexors, respectively, at 2 hour after each LIST and 25, 49, 73, and 97 hours after the last LIST. All measures changed significantly (P < .05) at 1 hour after the first LIST without difference (P > .05) between groups. Maximal voluntary contraction torque (eg, the largest decrease of KE for FIR: 13% [4%], sham: 25% [5%]), countermovement jump height (4% [3%] vs 14% [4%]), and other performance measures (eg, Yo-Yo Intermittent Recovery Test: 11% [5%] vs 26% [5%]) decreased less, and peak muscle soreness (eg, KE: 26 [9] vs 51 [18] mm) and plasma creatine kinase activity (172 [32] vs 1289 [610] IU/L) were smaller for the FIR than for the sham group (P < .05), and they returned to the baseline earlier (P < .05) for the FIR group. These results suggest that the FIR therapy provided potent effects on reducing accumulated muscle damage and enhancing recovery.


Perivascular epithelioid cell tumor of the retroperitoneum in a young woman resulting in an abdominal chyloma.
Perivascular epithelioid cell tumor (PEComa) is an extremely rare neoplasm which appears to have predominancy for young, frequently Asian, women. The neoplasm is composed chiefly of HMB-45-positive epithelioid cells with clear to granular cytoplasm and usually showing a perivascular distribution. These tumors have been reported in various organs under a variety of designations. Malignant PEComas exist but are very rare. The difficulty in determining optimal therapy, owing to the sparse literature available, led us to present this case. We report a retroperitoneal PEComa discovered during emergency surgery for abdominal pain in a 28-year-old Asian woman. The postoperative period was complicated by chylous ascites that was initially controlled by a wait-and-see policy with total parenteral nutrition. However, the chyle production gradually increased to more than 4 l per day. The development of a bacterial peritonitis resulted in cessation of production of abdominal fluid permitting normal nutrition without chylous leakage. Effective treatment for this rare complication of PEComa is not yet known; therefore, we have chosen to engage in long-term clinical follow-up.


Fetal and neonatal alloimmune thrombocytopenia: recommendations for evidence-based practice, an international approach.
Fetal and neonatal alloimmune thrombocytopenia (FNAIT) may result in severe bleeding, particularly fetal and neonatal intracranial haemorrhage (ICH). As a result, FNAIT requires prompt identification and treatment; subsequent pregnancies need close surveillance and management. An international panel convened to develop evidence-based recommendations for diagnosis and management of FNAIT. A rigorous approach was used to search, review and develop recommendations from published data for: antenatal management, postnatal management, diagnostic testing and universal screening. To confirm FNAIT, fetal human platelet antigen (HPA) typing, using non-invasive methods if quality-assured, should be performed during pregnancy when the father is unknown, unavailable for testing or heterozygous for the implicated antigen. Women with a previous child with an ICH related to FNAIT should be offered intravenous immunoglobulin (IVIG) infusions during subsequent affected pregnancies as early as 12 weeks gestation. Ideally, HPA-selected platelets should be available at delivery for potentially affected infants and used to increase the neonatal platelet count as needed. If HPA-selected platelets are not immediately available, unselected platelets should be transfused. FNAIT studies that optimize antenatal and postnatal management, develop risk stratification algorithms to guide management and standardize laboratory testing to identify high risk pregnancies are needed.


Neuropeptide S inhibits gastrointestinal motility and increases mucosal permeability through nitric oxide.
Neuropeptide S (NPS) receptor (NPSR1) polymorphisms are associated with enteral dysmotility and inflammatory bowel disease (IBD). This study investigated the role of NPS in conjunction with nitrergic mechanisms in the regulation of intestinal motility and mucosal permeability. In rats, small intestinal myoelectric activity and luminal pressure changes in small intestine and colon, along with duodenal permeability, were studied. In human intestine, NPS and NPSR1 were localized by immunostaining. Pre- and postprandial plasma NPS was measured by ELISA in healthy and active IBD humans. Effects and mechanisms of NPS were studied in human intestinal muscle strips. In rats, NPS 100-4,000 pmol·kg(-1)·min(-1) had effects on the small intestine and colon. Low doses of NPS increased myoelectric spiking (P < 0.05). Higher doses reduced spiking and prolonged the cycle length of the migrating myoelectric complex, reduced intraluminal pressures (P < 0.05-0.01), and increased permeability (P < 0.01) through NO-dependent mechanisms. In human intestine, NPS localized at myenteric nerve cell bodies and fibers. NPSR1 was confined to nerve cell bodies. Circulating NPS in humans was tenfold below the ∼0.3 nmol/l dissociation constant (Kd) of NPSR1, with no difference between healthy and IBD subjects. In human intestinal muscle strips precontracted by bethanechol, NPS 1-1,000 nmol/l induced NO-dependent muscle relaxation (P < 0.05) that was sensitive also to tetrodotoxin (P < 0.01). In conclusion, NPS inhibits motility and increases permeability in neurocrine fashion acting through NO in the myenteric plexus in rats and humans. Aberrant signaling and upregulation of NPSR1 could potentially exacerbate dysmotility and hyperpermeability by local mechanisms in gastrointestinal functional and inflammatory reactions.


An intermediate in the phage lambda site-specific recombination reaction is revealed by phosphorothioate substitution in DNA.
It has been proposed that phage lambda site-specific recombination proceeds via two independent strand exchanges: the first exchange forming a Holliday-structure which is then converted into complete recombinant products by the second strand exchange. If this hypothesis is correct, one should be able to trap the putative Holliday intermediate by preventing the second strand exchange. In this paper, we show that substitution of phosphorothioate for phosphate in one strand of a recombination site is an effective way to block recombination while permitting the accumulation of a novel structure. This effect is seen only when phosphorothioate is positioned at a point of potential cleavage by Int recombinase, demonstrating that the inhibition of strand exchange is highly specific. Analysis of the novel structure that accumulates in these reactions proves that it contains a Holliday joint. Holliday-structures can also be detected in unblocked recombinations but are present at very low levels. The characteristics of Holliday-structure formation that we describe substantiate the proposed recombination pathway.


Cotton GhCKI disrupts normal male reproduction by delaying tapetum programmed cell death via inactivating starch synthase.
Anther infertility under high temperature (HT) conditions is a critical factor contributing to yield loss in cotton (Gossypium hirsutum). Using large-scale expression profile sequencing, we studied the effect of HT on cotton anther development. Our analysis revealed that altered carbohydrate metabolism or disrupted tapetal programmed cell death (PCD) underlie anther sterility. Expression of the Gossypium hirsutum casein kinase I (GhCKI) gene, which encodes a homolog of casein kinase I (CKI), was induced in an HT-sensitive cotton line after exposure to HT. As mammalian homologs of GhCKI are involved in inactivation of glycogen synthase and the regulation of apoptosis, GhCKI may be considered a target gene for improving anther fertility under HT conditions. Our studies suggest that GhCKI exhibits starch synthase kinase activity, increases glucose content in early-stage buds and activates the accumulation of abscisic acid, thereby disturbing the balance of reactive oxygen species and eventually disrupting tapetal PCD, leading to anther abortion or indehiscence. These results indicate that GhCKI may be a key regulator of tapetal PCD and anther dehiscence, with the potential to facilitate regulation of HT tolerance in crops.


Distribution of ClC-2 chloride channel in rat and human epithelial tissues.
The ubiquitous ClC-2 Cl(-) channel is thought to contribute to epithelial Cl(-) secretion, but the distribution of the ClC-2 protein in human epithelia has not been investigated. We have studied the distribution of ClC-2 in adult human and rat intestine and airways by immunoblotting and confocal microscopy. In the rat, ClC-2 was present in the lateral membranes of villus enterocytes and was predominant at the basolateral membranes of luminal colon enterocytes. The expression pattern of ClC-2 in the human intestine differed significantly, because ClC-2 was mainly detected in a supranuclear compartment of colon cells. We found significant expression of ClC-2 at the apex of ciliated cells in both rat and human airways. These results show that the distribution of ClC-2 in airways is consistent with participation of ClC-2 channels in Cl(-) secretion and indicate that extrapolation of results from studies of ClC-2 function in rat intestine to human intestine is not straightforward.


Measurement Techniques to Resolve and Control Population Dynamics of Mixed-Culture Processes.
Microbial mixed cultures are gaining increasing attention as biotechnological production systems, since they offer a large but untapped potential for future bioprocesses. Effects of secondary metabolite induction and advantages of labor division for the degradation of complex substrates offer new possibilities for process intensification. However, mixed cultures are highly complex, and, consequently, many biotic and abiotic parameters are required to be identified, characterized, and ideally controlled to establish a stable bioprocess. In this review, we discuss the advantages and disadvantages of existing measurement techniques for identifying, characterizing, monitoring, and controlling mixed cultures and highlight promising examples. Moreover, existing challenges and emerging technologies are discussed, which lay the foundation for novel analytical workflows to monitor mixed-culture bioprocesses.


Evaluation of collagen in connective tissue walls of odontogenic cysts--a histochemical study.
The purpose of this study was to evaluate the nature of collagen in the connective tissue walls of odontogenic cysts, like the odontogenic keratocyst (OKC), dentigerous cyst and radicular cyst using picrosirius red stained sections. Furthermore, it was intended to assess if the capsular connective tissue can affect the nature of overlying epithelium, thus emphasizing the role of epithelial-mesenchymal interactions in biological behaviour of the cysts. The material for the study included 51 formalin-fixed paraffin-embedded tissue blocks (15 odontogenic keratocyst, 15 dentigerous cysts, 15 radicular cysts and four normal mucosa and two dental follicular tissue as controls), retrieved from the Department of Oral Pathology and Microbiology, MCODS, Manipal. Tissue blocks were sectioned at 5-μm thickness, stained with picrosirius red stain and observed with polarization and light microscopy. Few sections of OKC and dentigerous cyst exhibited greenish-yellow birefringence in sub-epithelial region, whereas others showed a yellowish-orange birefringence under polarization microscopy. Most radicular cysts had yellowish-orange to orange birefringence. Shift in colour in case OKC and dentigerous cyst was attributed to the presence of inflammation in those sections. These regions also exhibited either a change in phenotype or thickness of overlying epithelium. This technique can be used to study the nature of collagen fibres in odontogenic cyst walls. Further studies with an increased sample size and using various epithelial and mesenchymal markers and ssDNA antibodies should be carried out to confirm the effect of epithelial-mesenchymal interactions on the nature of epithelium of odontogenic cysts.


Post-Exercise Rehydration: Effect of Consumption of Beer with Varying Alcohol Content on Fluid Balance after Mild Dehydration.
The effects of moderate beer consumption after physical activity on rehydration and fluid balance are not completely clear. Therefore, in this study, we investigated the effect of beer consumption, with varying alcohol content, on fluid balance after exercise-induced dehydration. Eleven healthy males were included in this cross over study (age 24.5 ± 4.7 years, body weight 75.4 ± 3.3 kg, VO2max 58.3 ± 6.4 mL kg min-1). Subjects exercised on a cycle ergometer for 45 min at 60% of their maximal power output (Wmax) until mild dehydration (1% body mass loss). Thereafter, in random order, one of five experimental beverages was consumed, in an amount equal to 100% of their sweat loss: non-alcoholic beer (0.0%), low-alcohol beer (2.0%), full-strength beer (5.0%), an isotonic sports drink, and water. Fluid balance was assessed up till 5 h after rehydration. After 1 h, urine production was significantly higher for 5% beer compared to the isotonic sports drink (299 ± 143 vs. 105 ± 67 mL; p < 0.01). At the end of the 5-h observation period, net fluid balance (NFB) was negative for all conditions (p = 0.681), with the poorest fluid retention percentage for 5% beer (21% fluid retention) and the best percentage for the isotonic sports drink (42%). Non-alcoholic beer, low-alcoholic beer, and water resulted in fluid retention of 36, 36, and 34%, respectively (p = 0.460). There was no difference in NFB between the different beverages. Only a short-lived difference between full-strength beer and the isotonic sports drink in urine output and NFB was observed after mild exercise-induced dehydration. Fluid replacement - either in the form of non-alcoholic beer, low-alcoholic beer, full-strength beer, water, or an isotonic sports drink of 100% of body mass loss was not sufficient to achieve full rehydration. The combination of a moderate amount of beer, with varying alcohol content, enough water or electrolyte- and carbohydrate beverages, and salty foods might improve rehydration, but more research is needed.


A pragmatic trial to improve adherence with scheduled appointments in an inner-city pain clinic by human phone calls in the patient's preferred language.
We investigated if human reminder phone calls in the patient's preferred language increase adherence with scheduled appointments in an inner-city chronic pain clinic. We hypothesized that language and cultural incongruence is the underlying mechanism to explain poor attendance at clinic appointments in underserved Hispanic populations. Pragmatic randomized controlled clinical trial SETTING: Innercity academic chronic pain clinic with a diverse, predominantly African-American and Hispanic population PATIENTS: All (n=963) adult patients with a scheduled first appointment between October 2014 and October 2015 at the Montefiore Pain Center in the Bronx, New York were enrolled. Patients were randomized to receive a human reminder call in their preferred language before their appointment, or no contact. We recorded patients' demographic characteristics and as primary outcome attendance as scheduled, failure to attend and/or cancellation calls. We fit Bayesian and classical multinomial logistic regression models to test if the intervention improved adherence with scheduled appointments. Among the 953 predominantly African American and Hispanic/Latino patients, 475 patients were randomly selected to receive a language-congruent, human reminder call, while 478 were assigned to receive no prior contact, (after we excluded 10 patients, scheduled for repeat appointments). In the experimental group, 275 patients adhered to their scheduled appointment, while 84 cancelled and 116 failed to attend. In the control group, 249 patients adhered to their scheduled appointment, 31 cancelled and 198 failed to attend. Human phone reminders in the preferred language increased adherence (RR 1.89, CI95% [1.42, 1.42], (p<0.01). The intervention seemed particularly effective in Hispanic patients, supporting our hypothesis of cultural congruence as possible underlying mechanism. Human reminder phone calls prior in the patient's preferred language increased adherence with scheduled appointments. The intervention facilitated access to much needed care in an ethnically diverse, resource poor population, presumably by overcoming language barriers.


Structural and dynamic independence of isopeptide-linked RanGAP1 and SUMO-1.
Although sumoylation regulates a diverse and growing number of recognized biological processes, the molecular mechanisms by which the covalent attachment of the ubiquitin-like protein SUMO can alter the properties of a target protein remain to be established. To address this question, we have used NMR spectroscopy to characterize the complex of mature SUMO-1 with the C-terminal domain of human RanGAP1. Based on amide chemical shift and 15N relaxation measurements, we show that the C terminus of SUMO-1 and the loop containing the consensus sumoylation site in RanGAP1 are both conformationally flexible. Furthermore, the overall structure and backbone dynamics of each protein remain unchanged upon the covalent linkage of Lys524 in RanGAP1 to the C-terminal Gly97 of SUMO-1. Therefore, SUMO-1 and RanGAP1 behave as "beads-on-a-string," connected by a flexible isopeptide tether. Accordingly, the sumoylation-dependent interaction of RanGAP1 with the nucleoporin RanBP2 may arise through the bipartite recognition of both RanGAP1 and SUMO-1 rather than through a new binding surface induced in either individual protein upon their covalent linkage. We hypothesize that this conformational flexibility may be a general feature contributing to the recognition of ubiquitin-like modified proteins by their downstream effector machineries.


Genomic organization and splicing evolution of the doublesex gene, a Drosophila regulator of sexual differentiation, in the dengue and yellow fever mosquito Aedes aegypti.
In the model system Drosophila melanogaster, doublesex (dsx) is the double-switch gene at the bottom of the somatic sex determination cascade that determines the differentiation of sexually dimorphic traits. Homologues of dsx are functionally conserved in various dipteran species, including the malaria vector Anopheles gambiae. They show a striking conservation of sex-specific regulation, based on alternative splicing, and of the encoded sex-specific proteins, which are transcriptional regulators of downstream terminal genes that influence sexual differentiation of cells, tissues and organs. In this work, we report on the molecular characterization of the dsx homologue in the dengue and yellow fever vector Aedes aegypti (Aeadsx). Aeadsx produces sex-specific transcripts by alternative splicing, which encode isoforms with a high degree of identity to Anopheles gambiae and Drosophila melanogaster homologues. Interestingly, Aeadsx produces an additional novel female-specific splicing variant. Genomic comparative analyses between the Aedes and Anopheles dsx genes revealed a partial conservation of the exon organization and extensive divergence in the intron lengths. An expression analysis showed that Aeadsx transcripts were present from early stages of development and that sex-specific regulation starts at least from late larval stages. The analysis of the female-specific untranslated region (UTR) led to the identification of putative regulatory cis-elements potentially involved in the sex-specific splicing regulation. The Aedes dsx sex-specific splicing regulation seems to be more complex with the respect of other dipteran species, suggesting slightly novel evolutionary trajectories for its regulation and hence for the recruitment of upstream splicing regulators. This study led to uncover the molecular evolution of Aedes aegypti dsx splicing regulation with the respect of the more closely related Culicidae Anopheles gambiae orthologue. In Aedes aegypti, the dsx gene is sex-specifically regulated and encodes two female-specific and one male-specific isoforms, all sharing a doublesex/mab-3 (DM) domain-containing N-terminus and different C-termini. The sex-specific regulation is based on a combination of exon skipping, 5' alternative splice site choice and, most likely, alternative polyadenylation. Interestingly, when the Aeadsx gene is compared to the Anopheles dsx ortholog, there are differences in the in silico predicted default and regulated sex-specific splicing events, which suggests that the upstream regulators either are different or act in a slightly different manner. Furthermore, this study is a premise for the future development of transgenic sexing strains in mosquitoes useful for sterile insect technique (SIT) programs.


Role of airway lactoperoxidase in scavenging of hydrogen peroxide damage in asthma.
Hydrogen peroxide (H(2)O(2)) that is mainly generated by neutrophils and eosinophils in asthma is known to be damaging to the airway and to contribute to airway inflammation. The purpose of the present study was to determine the contribution and the role of lactoperoxidase in scavenging airway hydrogen peroxide, in order to propose a therapeutic approach for asthma. The study was an open clinical trial. Twenty-five nonsmoking asthmatic patients were included in the study. Of them, 16 patients (64%) were male and 9 (36%) were female, with age ranging from 29 to 48 years (45.13 +/- 4.6). Of the 25 patients included in the study, only 16 patients completed the study; and they were eligible for analyses. Exhaled breath condensate was collected from all patients at the time of entering the study; and 2, 4 and 8 weeks later. All patients received dapson as a lactoperoxidase inhibitor at a dose of 50 mg daily for 8 weeks. The study was conducted during the period from January 2006 to end of October 2006. H(2)O(2) concentration was determined by an enzymatic assay. Determination of exhaled breath condensate for hydrogen peroxide concentration after 8 weeks of dapson usage indicated an increase (1.05 +/- 0.36 microM; 95% CI, 0.89-1.21) as compared to that at baseline (P < 0.0001), 2 weeks (P < 0.001) and 4 weeks (P > 0.05). The increase in hydrogen peroxide concentration in exhaled breath condensate after inhibition of lactoperoxidase by dapson advocates a potential role for lactoperoxidase in scavenging of hydrogen peroxide in asthmatic airway.


Antihyperlipidemic effects of Citrus sinensis, Citrus paradisi, and their combinations.
Hyperlipidemia, extensively contributes in the progression of coronary heart diseases and atherosclerosis, but may be managed through alterations in the nutritional pattern. Several studies show that diet rich in polyphenols and antioxidants have antiatherogenic effects. Citrus sinensis and Citrus paradisi are widely known for health benefits and have found to produce antioxidant, anti-inflammatory, and hypolipidemic effects, hence current research was planned to determine the hypolipidemic effects of C. sinensis and C. paradisi in rats receiving diet rich in cholesterol. All rats were divided into 11 groups each comprising 10 animals: Normal control group and hyperlipidemic control. C. sinensis treated three groups, C. paradisi treated three groups, C. sinensis and C. paradisi combination treated two groups, and group treated atorvastatin. All rats in the respective groups were treated orally with sterile water, juices, and standard drug for 8 weeks and lipid profile was estimated at the end of dosing. Cholesterol, triglycerides (TGs), and low-density lipoprotein (LDL) were decreased at all the three doses of C. sinensis and C. paradisi but rise in high-density lipoprotein (HDL) was only significant at 8 ml/kg, and 0.3 ml/kg, respectively. Animals received the combination doses of C. sinensis and C. paradisi also showed a highly significant fall in cholesterol, LDL, and TGs, however HDL level was significantly elevated by SPJ-2 combination. Results suggest that C. sinensis and C. paradisi possess antihyperlipidemic activity due to phytochemicals and other essential nutrients, hence may serve as cardioprotective by preventing thrombosis.


Infrequent breakfast consumption is associated with higher body adiposity and abdominal obesity in Malaysian school-aged adolescents.
Unhealthy dietary pattern increases the risk of obesity and metabolic disorders in growing children and adolescents. However, the way the habitual pattern of breakfast consumption influences body composition and risk of obesity in adolescents is not well defined. Thus, the aim of the present study was to assess any associations between breakfast consumption practices and body composition profiles in 236 apparently healthy adolescents aged 12 to 19 years. A self-administered questionnaire on dietary behaviour and lifestyle practices and a dietary food frequency questionnaire were used. Body composition and adiposity indices were determined using standard anthropometric measurement protocols and dual energy χ-ray absorptiometry (DXA). Mean age of the participants was 15.3±1.9 years. The majority of participants (71.2%) fell in the normal body mass index (BMI) ranges. Breakfast consumption patterns showed that only half of the participants (50%) were consuming breakfast daily. Gender-specific multivariate analyses (ANCOVA) showed that in both boys and girls, those eating breakfast at least 5 times a week had significantly lower body weight, body mass index (BMI), BMI z-scores, waist circumference, body fat mass and percent body fat (%BF) compared to infrequent breakfast eaters, after adjustment for age, household income, pubertal status, eating-out and snacking practices, daily energy intakes, and daily physical activity levels. The present findings indicate that infrequent breakfast consumption is associated with higher body adiposity and abdominal obesity. Therefore, daily breakfast consumption with healthy food choices should be encouraged in growing children and adolescents to prevent adiposity during these critical years of growth.


The Role of Mindfulness in Reducing the Adverse Effects of Childhood Stress and Trauma.
Research suggests that many children are exposed to adverse experiences in childhood. Such adverse childhood exposures may result in stress and trauma, which are associated with increased morbidity and mortality into adulthood. In general populations and trauma-exposed adults, mindfulness interventions have demonstrated reduced depression and anxiety, reduced trauma-related symptoms, enhanced coping and mood, and improved quality of life. Studies in children and youth also demonstrate that mindfulness interventions improve mental, behavioral, and physical outcomes. Taken together, this research suggests that high-quality, structured mindfulness instruction may mitigate the negative effects of stress and trauma related to adverse childhood exposures, improving short- and long-term outcomes, and potentially reducing poor health outcomes in adulthood. Future work is needed to optimize implementation of youth-based mindfulness programs and to study long-term outcomes into adulthood.


Effect of change in vaccine schedule on pertussis epidemiology in France: a modelling and serological study.
In April-May, 2013, France modified its pertussis vaccination schedule, which uses the acellular pertussis vaccine, from three primary doses at 2, 3, and 4 months of age and a first booster at 16-18 months of age (former schedule) to two primary doses at 2 and 4 months of age and a first booster at 11 months of age (new schedule). We aimed to assess the subsequent effect of the vaccine schedule change on pertussis epidemiology in France. In this modelling study, using data collected between Jan 1, 2012, and Dec 31, 2019, from French national surveillance sources, we analysed the PCR test results of nasopharyngeal swabs collected from symptomatic outpatients aged 2-20 years with suspected pertussis. We developed a negative binomial regression model for the number of confirmed pertussis cases by year and age to assess the relative risks of pertussis depending on vaccine schedule. The linear predictor included the year, the age group, the population size, and a proxy of waning immunity. We tested different models in which waning immunity could vary with vaccine schedule and type of primary vaccine. The models were fitted to the 2012-18 data via Bayesian Markov chain Monte Carlo sampling, and the 2019 data were left out for external model validation. We also compared the anti-pertussis toxin (PT) antibody concentrations in leftover sera from children not tested for pertussis or recent respiratory tract infection aged 2-5 years born before and after the vaccine schedule change. We collected data on 7493 confirmed cases of pertussis. The model that best fitted the 2012-18 epidemiological data supported a faster waning of immunity following vaccination with the new vaccine schedule. 3 years after vaccination, the risk of developing pertussis was 1·7 (95% CI 1·4-2·0) times higher for children vaccinated according to the new schedule than those vaccinated according to the former schedule. The model correctly predicted the age distribution of cases in 2019. Geometric mean concentrations (GMC) of anti-PT IgG were 50% lower in children aged 2 years vaccinated with the new schedule (GMC=5·85 IU/mL [95% CI 4·08-8·39]) than in children of the same age vaccinated with the former schedule (GMC=11·62 IU/mL [95% CI 9·05-14·92]; p=0·0016), and 43% lower in children aged 3 years vaccinated with the new schedule (GMC=3·88 IU/mL [95% CI 2·82-5·34]) than those with the former schedule (GMC=6·80 IU/mL [95% CI 4·77-9·70]; p=0·026). A shorter-lived protection induced by the new vaccine schedule recommended in France since 2013 is associated with an increase of pertussis cases in children aged 2-5 years. If similar findings are observed in other countries and clinical trials, these findings should be considered in future pertussis vaccination policies. INCEPTION, Labex-IBEID, Institut Pasteur, and Santé Publique France.


Resorbable Nanocomposites with Bone-Like Strength and Enhanced Cellular Activity.
Bone cements for treatment of fractures at weight-bearing sites are subjected to dynamic physiological loading from daily activities. An ideal bone cement rapidly sets after injection, exhibits bone-like strength, stimulates osteogenic differentiation of endogenous cells, and resorbs at a rate aligned with patient biology. However, currently available materials fall short of these targeted properties. Nanocrystalline hydroxyapatite (nHA) enhances osteogenic differentiation, new bone formation, and osteoclast differentiation activity compared to amorphous or micron-scale crystalline hydroxyapatite. However, the brittle mechanical properties of nHA precludes its use in treatment of weight-bearing bone defects. In this study, we report settable nHA-poly(ester urethane) (PEUR) nanocomposites synthesized from nHA, lysine triisocyanate (LTI), and poly(caprolactone) triol via a solvent-free process. The nanocomposites are easily mixed and injected using a double-barrel syringe, exhibit mechanical properties exceeding those of conventional bone cements, enhance mineralization of osteoprogenitor cells in vitro, and undergo osteoclast-mediated degradation in vitro. This combination of properties cannot be achieved using other technologies, which underscores the potential of nHA-PEUR nanocomposites as a new approach for promoting bone healing at weight-bearing sites.


High fish density delays wound healing in Atlantic salmon (Salmo salar).
In this study, we look closer at how high fish densities influence wound repair mechanisms in post-smolt Atlantic salmon. The fish were wounded with a 5 mm skin punch biopsy needle and stocked at two different densities, a high fish density (100 kg/m3) treatment and a low fish density treatment (20 kg/m3) serving as the control. The healing wounds were followed for 57 days with samples taken 1, 3, 7, 14, 36, 43 and 57 days post wounding. The transcriptomic analysis suggests that high fish density enhance inflammation and represses cell proliferation, tissue secretion and collagen synthesis in the healing wounds. The histological analysis further showed delayed epidermal and dermal repair in the high fish density treatment compared to control. The overall wound contraction was also altered by the treatment. In conclusion, high fish density enhances immune responses and delay tissue repair, which ultimately results in delayed wound healing.