Effect of ciprofloxacin combined with sulfamethoxazole-trimethoprim prophylaxis on the incidence of urinary tract infections after kidney transplantation.
Urinary tract infections (UTIs) are common after kidney transplantation, with limited data to guide antibiotic prophylaxis. Retrospective single-center study comparing sulfamethoxazole-trimethoprim 800/160 mg (SMZ/TMP) daily for 30 days followed by Monday, Wednesday, Friday for an additional 5 months (Group 1) versus SMZ/TMP Monday, Wednesday, Friday for 6 months plus ciprofloxacin 250 mg twice daily for 30 days (Group 2) on UTI incidence after kidney transplantation. There were 106 and 130 patients in Groups 1 and 2, respectively. Demographics and transplant characteristics were well matched, except for more patients in Group 2 on corticosteroid maintenance. At 1 year, more patients in Group 1 developed UTIs (23.6% vs. 10.8%; P=0.01) and the mean time to first UTI was shorter (96.6±79.5 vs. 168±89.7 days; P=0.01). UTIs caused by Enterococcus species were higher in Group 2 (28.6% vs. 4%; P=0.047) with enteric gram-negative bacilli accounting for the remaining infections. There was a similar incidence of enteric gram-negative antibiotic resistance to SMZ/TMP (75% vs. 80%; P=1.00) and ciprofloxacin (16.7% vs. 30%; P=0.39) in Groups 1 and 2. For Groups 1 and 2, the proportion of first UTIs requiring hospitalization was 48.9% vs. 40.6%, respectively (P=0.62). Female gender was a UTI risk factor (hazard ratio, 3.5; 95% confidence interval, 1.78-6.8; P=0.0003). The addition of a 30-day course of ciprofloxacin lowered the incidence of UTI; randomized prospective studies are needed to confirm the safety and efficacy of this approach.


No Effect of Transcranial Direct Current Stimulation over Left Dorsolateral Prefrontal Cortex on Temporal Attention.
Selection mechanisms that dynamically gate only relevant perceptual information for further processing and sustained representation in working memory are critical for goal-directed behavior. We examined whether this gating process can be modulated by transcranial direct current stimulation (tDCS) over left dorsolateral prefrontal cortex (lDLPFC)-a region known to play a key role in working memory and conscious access. Specifically, we examined the effects of tDCS on the magnitude of the "attentional blink" (AB), a deficit in identifying the second of two targets presented in rapid succession. Thirty-four participants performed an AB task before (baseline), during and after 20 min of 1-mA anodal and cathodal tDCS in two separate sessions. On the basis of previous reports linking individual differences in AB magnitude to individual differences in DLPFC activity and on the basis of suggestions that effects of tDCS depend on baseline brain activity levels, we hypothesized that anodal tDCS over lDLPFC would modulate the magnitude of the AB as a function of individual baseline AB magnitude. Behavioral results did not provide support for this hypothesis. At the group level, we also did not observe any significant effects of tDCS, and a Bayesian analysis revealed strong evidence that tDCS to lDLPFC did not affect AB performance. Together, these findings do not support the idea that there is an optimal level of prefrontal cortical excitability for cognitive function. More generally, they add to a growing body of work that challenges the idea that the effects of tDCS can be predicted from baseline levels of behavior.


Application of the checkerboard immunoblotting technique to the quantification of host biomarkers in gingival crevicular fluid.
The aim of this study was to describe the development and validation of the checkerboard immunoblotting (CBIB) technique for the high-throughput quantification of multiple inflammatory mediators in gingival crevicular fluid (GCF) samples. Monoclonal antibodies were used to bind GCF interleukin (IL)-1beta and -8 and matrix metalloproteinase (MMP)-8 to the surface of membranes. Biotinylated antibodies were used to detect bound antigens in a checkerboard format. Signals were developed using chemiluminescence, captured on film, and quantified using software for array analysis. The assay was tested for potential cross-reactions among the three pairs of antibodies. Eleven CBIBs were processed to determine the analytical sensitivity of the assay. Forty GCF samples were analyzed using CBIB and enzyme-linked immunosorbent assay (ELISA) in parallel, and the significance of the correlations among the results was tested using the Pearson correlation coefficient. Nine hundred thirty-one GCF samples were collected from 20 periodontally healthy subjects and 20 periodontitis subjects and analyzed using CBIB to test the assay's sensitivity and dynamic ranges using clinical samples. The CBIB was capable of distinguishing among the three analytes. The sensitivity and dynamic ranges of the assay were suitable for the detection of the three targets in the majority of GCF samples. There were highly statistically significant (P <0.0001) positive correlations between CBIB and ELISA data for all three biomarkers. The periodontitis subjects had statistically significantly higher mean levels of IL-1beta and -8 compared to healthy subjects. The CBIB technique is a sensitive and specific assay for the high-throughput quantification of MMP-8 and IL-8 and -1beta in GCF.


Bone healing at implants with different surface configurations: an experimental study in dogs.
To study osseointegration of implants with surface modifications by the use of fluoroboric acid and/or H2 O2 installed in conventional sites or sites with circumferential marginal defects. Four implants with different surfaces were used. One basic surface (ZirTi(®)) was sandblasted with zirconium microspheres and acid etched additionally with hydrofluoric acid. A second surface was treated with fluoroboric acid instead of hydrofluoric acid. The remainder of the other two surfaces was additionally treated with H2O2. The edentulous mandibles of 6 foxhound dogs were used to randomly install 8.5-mm-long implants with the different surfaces and to study the histological healing after 1 and 3 months. To study osteoconductivity, additional four recipient sites were prepared with the coronal region being widened so that a 4 mm deep and 0.85 mm wide marginal defect resulted after the placement of the four implants with different surfaces. No filler material or membranes were used, and a fully submerged healing was allowed for 3 months. At the conventional sites, new bone formation ranged between 68.5% and 74.9% after 1 month. After 3 months, bone-to-implant contact ranged from 72.6% at the ZirTi(®) surface to 84.1% at the fluoroboric acid-treated implants, the difference being statistically significant. At the sites with marginal defects, bone formation ranged from 0.77 mm at the surface treated with fluoroboric acid and H2O2 , to 1.93 mm at the surface treated with fluoroboric acid alone. Fluoroboric acid treatment alone of titanium implant surfaces resulted in improved osseointegration and osteoconductivity after 3 months.


Self-assembly of nanoparticle amphiphiles with adaptive surface chemistry.
We investigate the self-assembly of amphiphilic nanoparticles (NPs) functionalized with mixed monolayers of hydrophobic and hydrophilic ligands in water. Unlike typical amphiphilic particles with "fixed" surface chemistries, the ligands used here are not bound irreversibly but can rearrange dynamically on the particles' surface during their assembly from solution. Depending on the assembly conditions, these adaptive amphiphiles form compact micellar clusters or extended chain-like assemblies in aqueous solution. By controlling the amount of hydrophobic ligands on the particles' surface, the average number of nearest neighbors--that is, the preferred coordination number--can be varied systematically from ∼ 1 (dimers) to ∼ 2 (linear chains) to ∼ 3 (extended clusters). To explain these experimental findings, we present an assembly mechanism in which hydrophobic ligands organize dynamically to form discrete patches between proximal NPs to minimize contact with their aqueous surroundings. Monte Carlo simulations incorporating these adaptive hydrophobic interactions reproduce the three-dimensional assemblies observed in experiment. These results suggest a general strategy based on reconfigurable "sticky" patches that may allow for tunable control over particle coordination number within self-assembled structures.


Techniques of ozone monitoring in a mountain forest region: passive and continuous sampling, vertical and canopy profiles.
Ozone is the most harmful air pollutant for plant ecosystems in the Mediterranean and Alpine areas due to its biological and economic damage to crops and forests. In order to evaluate the relation between ozone exposure and vegetation injury under on-field conditions, suitable ozone monitoring techniques were investigated. In the framework of a 5-year research project aimed at ozone risk assessment on forests, both continuous analysers and passive samplers were employed during the summer seasons (1994-1998) in different sites of a wide mountain region (80 x 40 km2) on the southern slope of the European Alps. Continuous analysers allowed the recording of ozone hourly concentration means necessary both to calculate specific exposure indexes (such as AOT, SUM, W126) and to record daily time-courses. Passive samplers, even though supplied only weekly mean concentration values, made it possible to estimate the altitude concentration gradient useful to correct the altitude dependence of ozone concentrations to be inserted into exposure indexes. In-canopy ozone profiles were also determined by placing passive samplers at different heights inside the forest canopy. Vertical ozone soundings by means of tethered balloons (kytoons) allowed the measurement of the vertical concentration gradient above the forest canopy. They also revealed ozone reservoirs aloft and were useful to explain the ozone advection dynamic in mountain slopes where ground measurement proved to be inadequate. An intercomparison between passive (PASSAM, CH) and continuous measurements highlighted the necessity to accurately standardize all the exposure operations, particularly the pre- and postexposure conservation at cold temperature to avoid dye (DPE) activity. Advantages and disadvantages from each mentioned technique are discussed.


Impact of Common Food Labels on Consumer Liking in Vanilla Yogurt.
As competition on super market shelves is higher than ever, the importance of product concepts, communicated through labels, can dictate a product's success or failure. However, it is possible for labels to affect a consumer's experience, changing the overall response to the product. In this study, we tested samples of vanilla yogurt with one of four commonly used labeling concepts (high-protein, low-fat, made with stevia and all-natural) on sensory perception, consumer liking, expected consumption amount, and willingness to pay (WTP) in a consumer test (n = 108). Each participant evaluated five samples of the same vanilla yogurt identified with one of the labels, or an unlabeled control. Results showed panelists liked the samples labeled with low-fat and high-protein to the greatest degree, with all-natural scoring the lowest. Those more concerned with protein content found the samples less satiating, dependent on sex. Sweetness was also perceived more highly in younger panelists, with panelists WTP dependent on their liking of the labels. Results highlight the importance of labeling as an extrinsic cue affecting liking ratings, with potential ramification for ultimate product success. Understanding consumers' response to labels, as well as their attitudes, has broad implications for food marketing, as well as public health and the study of eating habits.


A Survey of Mechanical Ventilator Practices Across Burn Centers in North America.
Burn injury introduces unique clinical challenges that make it difficult to extrapolate mechanical ventilator (MV) practices designed for the management of general critical care patients to the burn population. We hypothesize that no consensus exists among North American burn centers with regard to optimal ventilator practices. The purpose of this study is to examine various MV practice patterns in the burn population and to identify potential opportunities for future research. A researcher designed, 24-item survey was sent electronically to 129 burn centers. The χ, Fisher's exact, and Cochran-Mantel-Haenszel tests were used to determine if there were significant differences in practice patterns. We analyzed 46 questionnaires for a 36% response rate. More than 95% of the burn centers reported greater than 100 annual admissions. Pressure support and volume assist control were the most common initial MV modes used with or without inhalation injury. In the setting of Berlin defined mild acute respiratory distress syndrome (ARDS), ARDSNet protocol and optimal positive end-expiratory pressure were the top ventilator choices, along with fluid restriction/diuresis as a nonventilator adjunct. For severe ARDS, airway pressure release ventilation and neuromuscular blockade were the most popular. The most frequently reported time frame for mechanical ventilation before tracheostomy was 2 weeks (25 of 45, 55%); however, all respondents reported in the affirmative that there are certain clinical situations where early tracheostomy is warranted. Wide variations in clinical practice exist among North American burn centers. No single ventilator mode or adjunct prevails in the management of burn patients regardless of pulmonary insult. Movement toward American Burn Association-supported, multicenter studies to determine best practices and guidelines for ventilator management in burn patients is prudent in light of these findings.


The time-course of the inflammatory response to major burn injury and its relation to organ failure and outcome.
Burn injury causes major inflammatory activation and cytokine release, however, the temporal resolution of the acute and sub-acute inflammatory response has not yet been fully delineated. To this end, we have quantified 20 inflammatory mediators in plasma from 44 adult patients 0-21 days after burn injury and related the time course of these mediators to % total body surface area (TBSA) burned, clinical parameters, organ failure and outcome. Of the cytokines analyzed in these patients, interleukin 6 (IL-6), IL-8, IL-10 and monocyte chemoattractant protein 1 (MCP-1) correlated to the size of the injury at 24-48h after burn injury. In our study, the concentration of IL-10 had prognostic value in patients with burn injury both measured at admission and at 24-48h after injury. However, simple demographic data such as age, % burned TBSA, inhalation injury and their combination, the Baux score and modified Baux score, outperform most of the cytokines, with the exception of IL-8 and MCP-1 levels on admission, in predicting death.


The acute physiological status of white sharks (Carcharodon carcharias) exhibits minimal variation after capture on SMART drumlines.
Drumlines incorporating SMART (Shark-Management-Alert-in-Real-Time) technology are a new tool used in several bather protection programmes globally. In New South Wales (NSW), Australia, the white shark (Carcharodon carcharias) is a target species for SMART drumlines because they are often involved in attacks on humans. To understand white shark sensitivity to capture and to establish protocols around acceptable timeframes for responding to alerts, 47 juvenile and subadult white sharks were caught on SMART drumlines at five locations off the east coast of Australia. There was no at-vessel mortality during the sampling period. After capture, blood was sampled from each shark to assess its acute physiological status. Of the 18 metabolites investigated, only lactate and aspartate aminotransferase exhibited significant positive relationships with the capture duration on SMART drumlines. These results indicate that the capture process is relatively benign and that the current response times used here are appropriate to minimize long-term negative impacts on released white sharks. Where white sharks are likely to interact negatively with beachgoers, SMART drumlines can therefore be a useful addition to bather protection programmes that also aim to minimize harm to captured animals. Other shark species captured on SMART drumlines should also be investigated to gain broader understanding of potential physiological consequences of using this new technology.


Peripheral Insulin Regulates a Broad Network of Gene Expression in Hypothalamus, Hippocampus, and Nucleus Accumbens.
The brain is now recognized as an insulin-sensitive tissue; however, the role of changing insulin concentrations in the peripheral circulation in gene expression in the brain is largely unknown. Here, we performed a hyperinsulinemic-euglycemic clamp on 3-month-old male C57BL/6 mice for 3 h. We show that, in comparison with results in saline-infused controls, increases in peripheral insulin within the physiological range regulate expression of a broad network of genes in the brain. Insulin regulates distinct pathways in the hypothalamus (HTM), hippocampus, and nucleus accumbens. Insulin shows its most robust effect in the HTM and regulates multiple genes involved in neurotransmission, including upregulating expression of multiple subunits of GABA-A receptors, Na+ and K+ channels, and SNARE proteins; differentially modulating glutamate receptors; and suppressing multiple neuropeptides. Insulin also strongly modulates metabolic genes in the HTM, suppressing genes in the glycolysis and pentose phosphate pathways, while increasing expression of genes regulating pyruvate dehydrogenase and long-chain fatty acyl-CoA and cholesterol biosynthesis, thereby rerouting of carbon substrates from glucose metabolism to lipid metabolism required for the biogenesis of membranes for neuronal and glial function and synaptic remodeling. Furthermore, based on the transcriptional signatures, these changes in gene expression involve neurons, astrocytes, oligodendrocytes, microglia, and endothelial cells. Thus, peripheral insulin acutely and potently regulates expression of a broad network of genes involved in neurotransmission and brain metabolism. Dysregulation of these pathways could have dramatic effects in normal physiology and diabetes.


Beyond the 'raw' and the 'cooked': a history of fortified blended foods.
This paper offers a history of fortified blended foods, a humanitarian product that first emerged in the middle of the twentieth century. Tracing its emergence and development, the paper argues that this food was the product of four key historical trends: (i) the search for a compact and efficient diet in the wake of the Second World War; (ii) the high modernist movement that saw science and technology as a way to improve on traditional foods; (iii) the state-led industrialisation of the development decades oriented around the notion of a worldwide 'protein gap'; and (iv) the legacy of 'productivist' agriculture in the United States, generating massive surpluses in certain crops that had to be adapted creatively for a multitude of uses. The paper positions fortified blended foods in these broader historical processes, and asserts that humanitarian techniques are very much rooted in cultural, political, and social conditions.


Effects of Ruscus extract on the internal diameter of arterioles and venules of the hamster cheek pouch microcirculation.
In the present study, we investigated (a) the effects of the extract of Ruscus aculeatus, which is used to increase peripheral venous tone, on the diameter of arterioles (ID range 10-70 microns) and venules (ID range 20-135 microns) of hamster cheek pouch microvasculature in vivo and (b) the influence of temperature on the observed effects. For microcirculatory measurements, the preparations were placed under an intravital microscope and coupled to a closed-circuit TV (ccTV) system. The TV monitor display was used to obtain arteriolar and venular ID recordings (always at the same site) by an image shearing device. For systemic intravenous (i.v.) administration, the measurements were performed every 10 min, before (control) and after injection of the extract (5 mg/kg). During topical application, the extract was tested, in different concentrations, at 25 degrees, 36.5 degrees, and 40 degrees C. Systemic i.v. administration of Ruscus extract evoked venular constriction and did not affect the arteriolar diameter or mean arterial pressure (MAP). Topical application of Ruscus extract elicited concentration- and temperature-dependent responses in the vessels. At 25 degrees C, arterioles and venules dilated; at 36.5 degrees C, the arterioles remained unchanged while the venules constricted, and at 40 degrees C, the arterioles remained unchanged or constricted depending on the concentration used while the venules further constricted. The effects of Ruscus extract observed in vivo at the microcirculatory level further support the data previously reported on larger vessels and on patients with venous insufficiency.


Meta-Analysis of Cell-based CaRdiac stUdiEs (ACCRUE) in patients with acute myocardial infarction based on individual patient data.
The meta-Analysis of Cell-based CaRdiac study is the first prospectively declared collaborative multinational database, including individual data of patients with ischemic heart disease treated with cell therapy. We analyzed the safety and efficacy of intracoronary cell therapy after acute myocardial infarction (AMI), including individual patient data from 12 randomized trials (ASTAMI, Aalst, BOOST, BONAMI, CADUCEUS, FINCELL, REGENT, REPAIR-AMI, SCAMI, SWISS-AMI, TIME, LATE-TIME; n=1252). The primary end point was freedom from combined major adverse cardiac and cerebrovascular events (including all-cause death, AMI recurrance, stroke, and target vessel revascularization). The secondary end point was freedom from hard clinical end points (death, AMI recurrence, or stroke), assessed with random-effects meta-analyses and Cox regressions for interactions. Secondary efficacy end points included changes in end-diastolic volume, end-systolic volume, and ejection fraction, analyzed with random-effects meta-analyses and ANCOVA. We reported weighted mean differences between cell therapy and control groups. No effect of cell therapy on major adverse cardiac and cerebrovascular events (14.0% versus 16.3%; hazard ratio, 0.86; 95% confidence interval, 0.63-1.18) or death (1.4% versus 2.1%) or death/AMI recurrence/stroke (2.9% versus 4.7%) was identified in comparison with controls. No changes in ejection fraction (mean difference: 0.96%; 95% confidence interval, -0.2 to 2.1), end-diastolic volume, or systolic volume were observed compared with controls. These results were not influenced by anterior AMI location, reduced baseline ejection fraction, or the use of MRI for assessing left ventricular parameters. This meta-analysis of individual patient data from randomized trials in patients with recent AMI revealed that intracoronary cell therapy provided no benefit, in terms of clinical events or changes in left ventricular function. URL: http://www.clinicaltrials.gov. Unique identifier: NCT01098591.


Cognitive and perceptual responses during passive heat stress in younger and older adults.
We tested the hypothesis that attention, memory, and executive function are impaired to a greater extent in passively heat-stressed older adults than in passively heat-stressed younger adults. In a randomized, crossover design, 15 older (age: 69 ± 5 yr) and 14 younger (age: 30 ± 4 yr) healthy subjects underwent passive heat stress and time control trials. Cognitive tests (outcomes: accuracy and reaction time) from the CANTAB battery evaluated attention [rapid visual processing (RVP), choice reaction time (CRT)], memory [spatial span (SSP), pattern recognition memory (PRM)], and executive function [one touch stockings of Cambridge (OTS)]. Testing was undertaken on two occasions during each trial, at baseline and after internal temperature had increased by 1.0 ± 0.2°C or after a time control period. For tests that measured attention, reaction time during RVP and CRT was slower (P ≤ 0.01) in the older group. During heat stress, RVP reaction time improved (P < 0.01) in both groups. Heat stress had no effect (P ≥ 0.09) on RVP or CRT accuracy in either group. For tests that measured memory, accuracy on SSP and PRM was lower (P < 0.01) in the older group, but there was no effect of heat stress (P ≥ 0.14). For tests that measured executive function, overall, accuracy on OTS was lower, and reaction time was slower in the older group (P ≤ 0.05). Reaction time generally improved during heat stress, but there was no effect of heat stress on accuracy in either group. These data indicate that moderate increases in body temperature during passive heat stress do not differentially compromise cognitive function in younger and older adults.


Splenic sarcoidosis without focal nodularity: a case of 1,25-dihydroxyvitamin D-mediated hypercalcemia localized with FDG PET/CT.
To report an uncommon cause of 1,25-dihydroxyvitamin D (1,25[OH]2D)-mediated hypercalcemia associated with splenic sarcoidosis and illustrate the evaluation and potential role of fluorodeoxyglucose (FDG) positron emission tomography (PET)/computed tomography (CT) in such patients. We present detailed clinical features, laboratory results, imaging results, and pathology results for this rare entity, discuss evaluation and management options, and review previous literature. A 65-year-old male presented with symptomatic hypercalcemia, with a serum calcium level of 14.1 mg/dL 3 months after being initiated on ergocalciferol for vitamin D deficiency. He was found to have a suppressed parathyroid hormone level, normal 25-hydroxyvitamin D (25[OH]D) level, and elevated 1,25(OH)2D level. Extensive evaluation did not yield a definitive diagnosis. His calcium levels normalized and symptoms resolved on prednisone then recurred when prednisone was discontinued. FDG PET/CT showed intense uptake in the spleen. Splenectomy was performed, which resulted in resolution of hypercalcemia and yielded a diagnosis of splenic sarcoidosis. Splenic sarcoidosis causing hypercalcemia has been rarely reported. Our case is unique in that the spleen lacked typical focal nodularity on cross-sectional CT imaging, which is expected in sarcoid involvement of the spleen. Our case adds to an emerging literature documenting the potential value of FDG PET/CT in localizing otherwise occult 1,25(OH)2D-mediated hypercalcemia.


An open trial of valproate in borderline personality disorder.
Target symptoms in pharmacotherapy of borderline personality disorder include mood instability, anxiety, and impulsivity. Valproate appears useful for the treatment of these target symptoms in several disorders, and carbamazepine has been found effective for such symptoms in borderline personality disorder. We therefore conducted a preliminary open-label trial of valproate in borderline personality disorder. Eleven patients who met DSM-III-R criteria for borderline personality disorder were entered into an 8-week study of valproate. Exclusion criteria included current major depression or major medical disorder. All patients were in psychotherapy at least once a week for a minimum of 8 weeks prior to starting medication. Valproate was increased as tolerated to reach blood levels of 50 to 100 micrograms/mL. Clinician- and self-rated scales were completed each week. Three patients did not complete the study. Of completers, 4 of 8 patients were responders ("much less" or "less") on clinician-rated change scores for overall pathology and for mood. Three of 8 patients were responders on change scores for anxiety, anger, impulsivity, and rejection sensitivity. There was a significant (p = .03) decrease in total Symptom Checklist-90 scores between the start and end of the trial. On the Overt Aggression Scale (Modified), total other-directed assault did not significantly decrease, but there was a significant (p = .02) decrease in global subjective irritability. Valproate led to overall improvement in 50% of a small sample of borderline personality disorder patients who completed an 8-week open trial. The medication was modestly helpful for mood and irritability as well as for anxiety, anger, rejection sensitivity, and impulsivity, but specific therapeutic effects varied from patient to patient. More extensive controlled trials of anticonvulsants for impulsive personality disorders are warranted.


Mitotic activity of survivin is regulated by acetylation at K129.
Survivin is a cancer-associated protein regulated by multiple factors, including acetylation at K129 within its C-terminal α-helical tail. Acetylation of survivin is being pursued as a potential prognostic marker in breast cancer. This modification at K129 may cause nuclear accumulation of survivin in interphase cells; however, whether this affects its essential role during mitosis has not been addressed. We posited whether mimicking acetylation of survivin at K129 alters its activity during mitosis. Fluorescence microscopy and time-lapse imaging showed that, mutating this site to an alanine to act as a constitutive acetyl mimetic, K129A, causes defects in chromosome segregation and cytokinesis. As a non-acetylatable version, K129R, also has difficulty during mitotic exit, we conclude that cyclical acetylation and deacetylation is required for fully functional survivin during mitosis.


Protective effect of peroxisome proliferator activator receptor (PPAR)-α and -γ ligands against methotrexate-induced nephrotoxicity.
The anticancer drug methotrexate (MTX) may cause multi-organ toxicities, including nephrotoxicity. To investigate effects of peroxisome proliferator activator receptor (PPAR)-α and -γ agonists; fenofibrate (FEN) and pioglitazone (PIO), in MTX-induced nephrotoxicity in rats. Rats were given FEN or PIO (150 or 5 mg/kg/day, respectively) orally for 15 days. MTX was injected as a single dose of 20 mg/kg, i.p. at day 11 of experiment, with or without either PPAR agonists. MTX induced renal toxicity, assessed by increase in serum urea and creatinine as well as histopathological alterations. MTX caused renal oxidative/nitrosative stress, indicated by decrease in GSH and catalase with increase in malondialdehyde and nitric oxide (NOx) levels. In addition, MTX increased renal level of the pro-inflammatory cytokine; tumor necrosis factor (TNF)-α and up-regulated the expression of both the inflammatory and apoptotic markers; NF-κB and caspase 3. Pre-administration of FEN or PIO to MTX-treated rats improved renal function and reversed oxidative/nitrosative parameters. Interestingly, pre-administration of PIO, but not FEN, decreased renal TNF-α level and NF-κB expression compared to MTX alone. Furthermore, PIO had more significant effect than FEN on reversing MTX-induced renal caspase 3 expression. Both FEN and PIO conferred protection against MTX-induced nephrotoxicity through comparable amelioration of oxidative/nitrosative stress. FEN lacked any effect on TNF-α/NF-κB, which was reflected on its less improvement on renal histopathology and apoptosis. At indicated dosage, PPAR-γ ligand; PIO shows better improvement of MTX-induced nephrotoxicity compared to PPAR-α ligand; FEN due to differential effect on TNF-α/NF-κB inflammatory pathway.


The effect of tendon stem/progenitor cell (TSC) sheet on the early tendon healing in a rat Achilles tendon injury model.
Tissue-engineering approaches have a great potential to improve the treatment of tendon injuries that affect millions of people. The present study tested the hypothesis that introduction of a tendon derived stem/progenitor cell (TSC) sheet accelerates tendon healing and tendon regeneration in a rat model. TSC sheets were produced on temperature-responsive culture dishes. Then, they were grafted on unwounded Achilles tendons and at sites of a 3mm of Achilles tendon defect. At 2 and 4weeks after implantation tendons were examined by histology, immunohistochemistry, transmission electron microscopy (TEM) and mechanical testing. The results showed that the implanted TSC sheet remained stably attached on the tendon surface at 4 weeks after implantation. Moreover, in the tendon defect model, tendon defect area where TSC sheet was implanted was well regenerated and had better organized collagen fibers with elongated spindle shaped cells, compared to relatively disorganized collagen fibers and round shaped cells in the control group. TEM observations revealed longitudinally aligned collagen fibers and thick collagen fibrils in the TSC sheet implanted group. Finally, at 4weeks mechanical property of the TSC sheet implanted tendon had better ultimate load than the control. In conclusion, this study demonstrates the feasibility of implanting TSC sheets on tendons in vivo. Introduction of the cell sheets into a tendon defect significantly improved histological properties and collagen content at both 2 and 4 weeks after implantation, indicating that TSC sheets may effectively promote tendon remodeling in the early stages of tendon healing. Tendon injury is a highly prevalent clinical problem that debilitates millions of people worldwide in both occupational and athletic settings. It also costs billions of healthcare dollars in treatment every year. In this study, we showed the feasibility of using tendon derived stem cell sheet to deliver biologically active tenogenic-constructs and promote tendon regeneration. This work has the potential to impact the orthopaedic surgery and sports medicine fields in the treatment of tendon injury.


Imputation Match Bias in Immigrant Wage Convergence.
Although immigrants to the United States earn less at entry than their native-born counterparts, an extensive literature has found that immigrants have faster earnings growth that results in rapid convergence to native-born earnings. However, recent evidence based on U.S. Census data indicates a slowdown in the rate of earnings assimilation. We find that the pace of immigrant wage convergence based on recent data may be understated in the literature as a result of the method used by the census to impute missing information on earnings, which does not use immigration status as a match characteristic. Because both the share of immigrants in the workforce and earnings imputation rates have risen over time, imputation match bias for recent immigrants is more consequential than in earlier periods and may lead to an underestimate of the rate of immigrant wage convergence.


Novel insights into diminished cardiac reserve in non-obstructive hypertrophic cardiomyopathy from four-dimensional flow cardiac magnetic resonance component analysis.
Hypertrophic cardiomyopathy (HCM) is characterized by hypercontractility and diastolic dysfunction, which alter blood flow haemodynamics and are linked with increased risk of adverse clinical events. Four-dimensional flow cardiac magnetic resonance (4D-flow CMR) enables comprehensive characterization of ventricular blood flow patterns. We characterized flow component changes in non-obstructive HCM and assessed their relationship with phenotypic severity and sudden cardiac death (SCD) risk. Fifty-one participants (37 non-obstructive HCM and 14 matched controls) underwent 4D-flow CMR. Left-ventricular (LV) end-diastolic volume was separated into four components: direct flow (blood transiting the ventricle within one cycle), retained inflow (blood entering the ventricle and retained for one cycle), delayed ejection flow (retained ventricular blood ejected during systole), and residual volume (ventricular blood retained for >two cycles). Flow component distribution and component end-diastolic kinetic energy/mL were estimated. HCM patients demonstrated greater direct flow proportions compared with controls (47.9 ± 9% vs. 39.4 ± 6%, P = 0.002), with reduction in other components. Direct flow proportions correlated with LV mass index (r = 0.40, P = 0.004), end-diastolic volume index (r = -0.40, P = 0.017), and SCD risk (r = 0.34, P = 0.039). In contrast to controls, in HCM, stroke volume decreased with increasing direct flow proportions, indicating diminished volumetric reserve. There was no difference in component end-diastolic kinetic energy/mL. Non-obstructive HCM possesses a distinctive flow component distribution pattern characterised by greater direct flow proportions, and direct flow-stroke volume uncoupling indicative of diminished cardiac reserve. The correlation of direct flow proportion with phenotypic severity and SCD risk highlight its potential as a novel and sensitive haemodynamic measure of cardiovascular risk in HCM.


The global impact and cost-effectiveness of a melioidosis vaccine.
Every year, 90,000 people may die from melioidosis. Vaccine candidates have not proceeded past animal studies, partly due to uncertainty around the potential market size. This study aims to estimate the potential impact, cost-effectiveness and market size for melioidosis vaccines. Age-structured decision tree models with country-specific inputs were used to estimate net costs and health benefits of vaccination, with health measured in quality-adjusted life years (QALYs). Four target groups of people living in endemic regions were considered: (i) people aged over 45 years with chronic renal disease, (ii) people aged over 45 years with diabetes, (iii) people aged over 45 years with diabetes and/or chronic renal disease, (iv) everyone aged over 45 years. Melioidosis risk was estimated using Bayesian evidence synthesis of 12 observational studies. In the base case, vaccines were assumed to have 80% efficacy, to have 5-year mean protective duration and to cost USD10.20-338.20 per vaccine. Vaccination could be cost-effective (with incremental cost-effectiveness ratio below GDP per capita) in 61/83 countries/territories with local melioidosis transmission. In these 61 countries/territories, vaccination could avert 68,000 lost QALYs, 8300 cases and 4400 deaths per vaccinated age cohort, at an incremental cost of USD59.6 million. Strategy (ii) was optimal in most regions. The vaccine market may be worth USD268 million per year at its threshold cost-effective price in each country/territory. There is a viable melioidosis vaccine market, with cost-effective vaccine strategies in most countries/territories with local transmission.


The mitochondrial permeability transition pore.
The mitochondrial permeability transition pore (PTP) is a high conductance channel of the inner membrane whose opening leads to an increase of permeability to solutes with molecular masses up to about 1500Da, the 'permeability transition'. This potentially catastrophic event has long been known, yet the molecular bases for its occurrence remain unsolved despite its established importance in several in vivo models of pathology. Recent studies based on inactivation of genes encoding putative pore components (such as the adenine nucleotide translocators and the voltage-dependent anion channel) have raised major questions about the involvement of these proteins in PTP formation, yet they have conclusively demonstrated the role of matrix cyclophilin D as the mitochondrial receptor for the desensitizing effects of cyclosporin A. While the nature of the components forming the PTP remains controversial, the identification of novel inhibitors that can be used as affinity labels is offering new perspectives towards the molecular definition of the PTP.


Two-year outcomes after percutaneous coronary intervention of calcified lesions with drug-eluting stents.
Percutaneous coronary intervention (PCI) of lesions with coronary arterial calcification (CAC) is common and has been historically associated with an increased risk of adverse events. Whether the association between target lesion calcification (CAC) and outcomes differ across drug-eluting stent generation or between patients with high vs. low residual platelet reactivity (PR) remains unknown. We assessed the association of CAC with adverse ischemic and bleeding events among patients undergoing contemporary PCI with drug-eluting stents (DES). We included all 8582 patients who underwent successful PCI with DES in the prospective ADAPT-DES study. Patients were grouped according to whether or not they had CAC. We used a multivariable logistic regression analysis to determine independent predictors of CAC. We assessed the 2-year risk of major adverse cardiac events (MACE: Death, myocardial infarction, or stent thrombosis) and bleeding by constructing Kaplan-Meier curves and fitting unadjusted and adjusted Cox proportional hazards models. We assessed the influence of DES generation and PR on the effect of CAC on outcomes by including interaction terms in the models. CAC was present in 2644 (30.8%) patients. Age, smoking, hypertension, hyperlipidemia, insulin-treated diabetes, hemodialysis, and peripheral artery disease were independent predictors of CAC. Having a CAC was associated with increased unadjusted and adjusted hazards for 2-year MACE and bleeding. The association between CAC and ischemic outcomes was consistent across DES generations and PR (pinteraction>0.05). Contemporary DES PCI of calcified lesions is common and is associated with an increased risk of ischemic and bleeding complications.


The BAH domain of ORC1 links H4K20me2 to DNA replication licensing and Meier-Gorlin syndrome.
The recognition of distinctly modified histones by specialized 'effector' proteins constitutes a key mechanism for transducing molecular events at chromatin to biological outcomes. Effector proteins influence DNA-templated processes, including transcription, DNA recombination and DNA repair; however, no effector functions have yet been identified within the mammalian machinery that regulate DNA replication. Here we show that ORC1--a component of ORC (origin of replication complex), which mediates pre-DNA replication licensing--contains a bromo adjacent homology (BAH) domain that specifically recognizes histone H4 dimethylated at lysine 20 (H4K20me2). Recognition of H4K20me2 is a property common to BAH domains present within diverse metazoan ORC1 proteins. Structural studies reveal that the specificity of the BAH domain for H4K20me2 is mediated by a dynamic aromatic dimethyl-lysine-binding cage and multiple intermolecular contacts involving the bound peptide. H4K20me2 is enriched at replication origins, and abrogating ORC1 recognition of H4K20me2 in cells impairs ORC1 occupancy at replication origins, ORC chromatin loading and cell-cycle progression. Mutation of the ORC1 BAH domain has been implicated in the aetiology of Meier-Gorlin syndrome (MGS), a form of primordial dwarfism, and ORC1 depletion in zebrafish results in an MGS-like phenotype. We find that wild-type human ORC1, but not ORC1-H4K20me2-binding mutants, rescues the growth retardation of orc1 morphants. Moreover, zebrafish depleted of H4K20me2 have diminished body size, mirroring the phenotype of orc1 morphants. Together, our results identify the BAH domain as a novel methyl-lysine-binding module, thereby establishing the first direct link between histone methylation and the metazoan DNA replication machinery, and defining a pivotal aetiological role for the canonical H4K20me2 mark, via ORC1, in primordial dwarfism.


A Latent Source Model for Patch-Based Image Segmentation.
Despite the popularity and empirical success of patch-based nearest-neighbor and weighted majority voting approaches to medical image segmentation, there has been no theoretical development on when, why, and how well these nonparametric methods work. We bridge this gap by providing a theoretical performance guarantee for nearest-neighbor and weighted majority voting segmentation under a new probabilistic model for patch-based image segmentation. Our analysis relies on a new local property for how similar nearby patches are, and fuses existing lines of work on modeling natural imagery patches and theory for nonparametric classification. We use the model to derive a new patch-based segmentation algorithm that iterates between inferring local label patches and merging these local segmentations to produce a globally consistent image segmentation. Many existing patch-based algorithms arise as special cases of the new algorithm.


Multisystemic Inflammatory Syndrome in Children Associated With SARS-CoV-2 Infection: A Case Series Report in a Pediatric Center in Mexico.
We report four cases of patients with multisystem inflammatory syndrome in children (MIS-C) associated with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, of which three patients presented characteristics of Kawasaki disease (KD). All presented fever of more than 3 days, and gastrointestinal involvement, significant increase in C-reactive protein (CRP), polymorphonuclear cells, procalcitonin, D-dimer, fibrinogen and troponin, lymphopenia and hypoalbuminemia. Myocardial involvement was observed in two patients. All were treated with fluids resuscitation and vasoactive therapy, 75% received intravenous immunoglobulin (IVIG) and systemic steroids. Two patients developed a transient acute kidney injury, one patient presented as acute appendicitis and developed a bilateral pleural effusion. One patient required a second dose of IVIG and boluses of methylprednisolone. None required mechanical ventilation and there were no deaths.


Tumour necrosis factor-alpha augments the expression of Fc IgE receptor (Fc epsilon RII/CD23) on human monocytic cell lines and down-regulates interleukin-4-driven Fc epsilon RII expression on monocytes.
We investigated the expression of the low affinity Fc IgE receptor (Fc epsilon RII/CD23) on the human monocytic cell lines U937, THP-1, Mono-Mac-6, and cultured human peripheral blood monocytes under stimulation with human tumour necrosis factor-alpha (TNF-alpha) and other cytokines. Fc epsilon RII was demonstrated by flow cytometry analysis employing the anti-Fc epsilon RII monoclonal antibody 3-5. TNF-alpha alone had a weak but significant stimulating effect on the Fc epsilon RII expression on the cell lines U937 and THP-1, and very modestly on Mono-Mac-6 cells. TNF-alpha strongly synergized with interferon-gamma (IFN-gamma) and interleukin-4 (IL-4). IFN-alpha per se was ineffectual, but was able to increase the TNF-alpha effect. Furthermore, the action of TNF-alpha was slightly augmented by human IL-6. Similar effects were noted with TNF-beta alone or in combination with other cytokines. Interestingly, on human monocytes TNF-alpha weakly reduced the basal level of Fc epsilon RII, and markedly diminished the IL-4-induced Fc epsilon RII expression. Our results indicate that several cytokines may interact in a cytokine network to modulate Fc epsilon RII expression on monocytic cell lines. On human blood monocytes, TNF-alpha, like IFN-gamma or IL-6, counteracts the IL-4-induced Fc epsilon RII expression. These data suggest different regulatory pathways of Fc epsilon RII expression on blood monocytes and myelomonocytic cell lines.


Streptococcus pneumoniae ClpL modulates adherence to A549 human lung cells through Rap1/Rac1 activation.
Caseinolytic protease L (ClpL) is a member of the HSP100/Clp chaperone family, which is found mainly in Gram-positive bacteria. ClpL is highly expressed during infection for refolding of stress-induced denatured proteins, some of which are important for adherence. However, the role of ClpL in modulating pneumococcal virulence is poorly understood. Here, we show that ClpL impairs pneumococcal adherence to A549 lung cells by inducing and activating Rap1 and Rac1, thus increasing phosphorylation of cofilin (inactive form). Moreover, infection with a clpL mutant (ΔclpL) causes a greater degree of filopodium formation than D39 wild-type (WT) infection. Inhibition of Rap1 and Rac1 impairs filopodium formation and pneumococcal adherence. Therefore, ClpL can reduce pneumococcal adherence to A549 cells, likely via modulation of Rap1- and Rac1-mediated filopodium formation. These results demonstrate a potential role for ClpL in pneumococcal resistance to host cell adherence during infection. This study provides insight into further understanding the interactions between hosts and pathogens.


Splanchnic perfusion during delayed, hypotensive, or aggressive fluid resuscitation from uncontrolled hemorrhage.
The purpose of this study was to determine the effect of three different fluid resuscitation strategies on splanchnic perfusion in a clinically relevant model of uncontrolled hemorrhage after liver trauma. Anesthetized swine were instrumented with a gastric near-infrared spectroscopy probe (GStO2), a jejunal tonometer (PrCO2), a portal vein catheter (SpvO2, lactate), and an ultrasonic blood flow probe on the superior mesenteric artery. The liver was lacerated to produce uncontrolled hemorrhage and a shock state characterized by a 40-60% decrease in cardiac output and a decrease in mean arterial pressure (MAP) to 42 +/- 1 mmHg. Animals were randomly assigned to either delayed resuscitation (n = 6); hypotensive resuscitation with lactated Ringer's infusion to MAP = 60 mmHg (n = 6); or aggressive resuscitation with LR to MAP >/= 75 mmHg (n = 6). For the remainder of the protocol, the treatment was identical. The data showed that blood loss (47 +/- 7 and 45 +/- 10 mL/kg) and total fluid requirements (118 +/- 73 and 171 +/- 85 mL/kg) were similar with either hypotensive or aggressive resuscitation. In contrast, with delayed resuscitation, both values were lower (27 +/- 2 mL/kg and 87 +/- 33 mL/kg, both P < 0.05). Despite aggressive resuscitation, SpvO2 and GstO2 were about 10% lower (both P < 0.05 within group) and PrCO2 was about 20 mmHg higher (P < 0.05 within group) than the corresponding values in the other two groups. Thus, delayed resuscitation minimized the blood loss but did not restore tissue oxygenation, whereas aggressive resuscitation was associated with maximal blood loss and splanchnic hypoperfusion. For this reason, it is reasonable to conclude that hypotensive resuscitation might be an effective strategy to maintain splanchnic perfusion after blunt abdominal trauma and uncontrolled hemorrhage.


Hands on the future: facilitation of cortico-spinal hand-representation when reading the future tense of hand-related action verbs.
Reading action-related verbs brings about sensorimotor neural activity, suggesting that the linguistic representation of actions impinges upon neural structures largely overlapping with those involved in actual action execution. While studies of direct action observation indicate that motor mirroring is inherently anticipatory, no information is currently available on whether deriving action-related knowledge from language also takes into account the temporal deployment of actions. Using transcranial magnetic stimulation, here we sought to determine whether reading action verbs conjugated in the future induced higher cortico-spinal activity with respect to when the same verbs were conjugated in the past tense. We recorded motor-evoked potentials (MEPs) from relaxed hand and leg muscles of healthy subjects who were reading silently hand- or leg-related action, sensorial (non-somatic) and abstract verbs conjugated either in future or past tense. The amplitude of MEPs recorded from the hand was higher during reading hand-related action verbs conjugated in the future than in the past. No future-related modulation of leg muscles activity was found during reading leg-related action verbs. In a similar vein, no future-related change of hand or leg muscles reactivity was found for abstract or sensorial verbs. These results indicate that the anticipatory mirroring of hand actions may be triggered by linguistic representations and not only by direct action observation.


A novel function for the haemopoietic supportive murine bone marrow MS-5 mesenchymal stromal cell line in promoting human vasculogenesis and angiogenesis.
The bone marrow contains specific microenvironmental stem cell niches that maintain haemopoiesis. CXCL12-expressing mesenchymal stromal cells are closely associated with the bone marrow sinusoidal endothelia, forming key elements of the haemopoietic stem cell niche, yet their ability to regulate endothelial function is not clearly defined. Given that the murine nestin(+) cell line, MS-5, provides a clonal surrogate bone marrow stromal niche capable of regulating both murine and human primitive haemopoietic stem/progenitor cell (HSC/HPC) fate in vitro, we hypothesized that MS-5 cells might also support new blood vessel formation and function. Here, for the first time, we demonstrate that this is indeed the case. Using proteome arrays, we identified HSC/HPC active angiogenic factors that are preferentially secreted by haemopoietic supportive nestin(+) MS-5 cells, including CXCL12 (SDF-1), NOV (CCN3), HGF, Angiopoietin-1 and CCL2 (MCP-1). Concentrating on CXCL12, we confirmed its presence in MS-5 conditioned media and demonstrated that its antagonist in receptor binding, AMD-3100, which mobilizes HSC/HPCs and endothelial progenitors from bone marrow, could significantly reduce MS-5 mediated human vasculogenesis in vitro, principally by regulating human endothelial cell migration. Thus, the clonal nestin(+) MS-5 murine bone marrow stromal cell line not only promotes human haemopoiesis but also induces human vasculogenesis, with CXCL12 playing important roles in both processes.


Current challenges of gene therapy for prostate cancer.
Gene therapy for prostate cancer faces hurdles similar to those being encountered for other cancers and nonmalignant processes. The greatest obstacle is the identification of efficient delivery systems, since numerous animal models and cell culture systems have shown potential efficacy when most cells express the introduced genetic material. Early prostate cancers are easily accessible to gene vector introduction, and the predictable metastatic patterns of this cancer may offer additional advantages for gene therapy. This article reviews gene vectors and gene products, as well as ongoing trials of gene therapy that have recently begun in prostate cancer.


Pediatric sudden cardiac arrest.
Pediatric sudden cardiac arrest (SCA), which can cause sudden cardiac death if not treated within minutes, has a profound effect on everyone: children, parents, family members, communities, and health care providers. Preventing the tragedy of pediatric SCA, defined as the abrupt and unexpected loss of heart function, remains a concern to all. The goal of this statement is to increase the knowledge of pediatricians (including primary care providers and specialists) of the incidence of pediatric SCA, the spectrum of causes of pediatric SCA, disease-specific presentations, the role of patient and family screening, the rapidly evolving role of genetic testing, and finally, important aspects of secondary SCA prevention. This statement is not intended to address sudden infant death syndrome or sudden unexplained death syndrome, nor will specific treatment of individual cardiac conditions be discussed. This statement has been endorsed by the American College of Cardiology, the American Heart Association, and the Heart Rhythm Society.


Effects of neuropeptide Y on cell length and membrane currents in isolated guinea pig ventricular myocytes.
Direct effects of neuropeptide Y were studied in left ventricular myocytes isolated from guinea pigs. Contraction was measured as the change in unloaded cell length using a photodiode array. Action potentials were elicited at 1 Hz in current-clamp mode, and membrane currents were measured using a switch-clamp amplifier with 2 M-KCl microelectrodes. At concentrations of 10(-6) M and above, neuropeptide Y reduced contraction in a concentration-dependent fashion. The reduction in contraction by the peptide was proportionately greater in the presence of isoproterenol, and the increase in contraction caused by isoproterenol was completely inhibited by 10(-6) M neuropeptide Y. In response to neuropeptide Y, action potential duration was shortened, and the time course of the shortening was similar to that of the reduction in contraction. Under voltage clamp, 1 x 10(-5) M neuropeptide Y reduced peak L-type calcium current by 32% and shifted the myocyte current-voltage relation during a slow ramp in a manner that suggested a reduction in the background rectifier K+ current. The effects of the peptide on membrane currents were greatly attenuated by preincubation of the cells with pertussis toxin (100 ng/ml). We conclude that neuropeptide Y reduces developed shortening, action potential duration, L-type calcium current, and background rectifier current in single guinea pig ventricular myocytes and that these effects are mediated, at least in part, via membrane G proteins.


Analyzing functional connectivity using a network likelihood model of ensemble neural spiking activity.
Analyzing the dependencies between spike trains is an important step in understanding how neurons work in concert to represent biological signals. Usually this is done for pairs of neurons at a time using correlation-based techniques. Chornoboy, Schramm, and Karr (1988) proposed maximum likelihood methods for the simultaneous analysis of multiple pair-wise interactions among an ensemble of neurons. One of these methods is an iterative, continuous-time estimation algorithm for a network likelihood model formulated in terms of multiplicative conditional intensity functions. We devised a discrete-time version of this algorithm that includes a new, efficient computational strategy, a principled method to compute starting values, and a principled stopping criterion. In an analysis of simulated neural spike trains from ensembles of interacting neurons, the algorithm recovered the correct connectivity matrices and interaction parameters. In the analysis of spike trains from an ensemble of rat hippocampal place cells, the algorithm identified a connectivity matrix and interaction parameters consistent with the pattern of conjoined firing predicted by the overlap of the neurons' spatial receptive fields. These results suggest that the network likelihood model can be an efficient tool for the analysis of ensemble spiking activity.


Mutations of mitochondrial DNA in atherosclerosis and atherosclerosis-related diseases.
Atherosclerosis, the primary cause of cardiovascular disease, is a complex and multifactorial pathology resulted from the harmful interactions between genetic and environmental factors. There is a growing body of evidence in support of the role of mitochondrial factors in the pathogenesis of atherosclerosis. Impaired mitochondrial function and structural and qualitative changes in mitochondrial components such as mitochondrial DNA (mtDNA) damage may be directly involved in the development of multiple mechanisms of atherogenesis. Recent findings show that several heteroplasmic mutations of mtDNA are related to atherosclerosis, coronary heart disease and several atherosclerosis-related diseases such as arterial hypertension and diabetes mellitus. Therefore, heteroplasmic mtDNA mutations could represent a promising molecular biomarker of genetic susceptibility to atherosclerosis and related pathologies. This review is focused on the latest findings in the studies of mutations of mitochondrial genome, which are associated with atherosclerosis and atherosclerosis- related diseases.


Knockdown of RNA interference pathway genes in western corn rootworm, Diabrotica virgifera virgifera, identifies no fitness costs associated with Argonaute 2 or Dicer-2.
The use of transgenic crops that induce silencing of essential genes using double-stranded RNA (dsRNA) through RNA interference (RNAi) in western corn rootworm, Diabrotica virgifera virgifera, is likely to be an important component of new technologies for the control of this important corn pest. Previous studies have demonstrated that the dsRNA response in D. v. virgifera depends on the presence of RNAi pathway genes including Dicer-2 and Argonaute 2, and that downregulation of these genes limits the lethality of environmental dsRNA. A potential resistance mechanism to lethal dsRNA may involve loss of function of RNAi pathway genes. Howver, the potential for resistance to evolve may depend on whether these pathway genes have essential functions such that the loss of function of core proteins in the RNAi pathway will have fitness costs in D. v. virgifera. Fitness costs associated with potential resistance mechanisms have a central role in determining how resistance can evolve to RNAi technologies in western corn rootworm. We evaluated the effect of dsRNA and microRNA pathway gene knockdown on the development of D. v. virgifera larvae through short-term and long-term exposures to dsRNA for Dicer and Argonaute genes. Downregulation of Argonaute 2, Dicer-2, Dicer-1 did not significantly affect larval survivorship or development through short and long-term exposure to dsRNA. However, downregulation of Argonaute 1 reduced larval survivorship and delayed development. The implications of these results as they relate to D. v. virgifera resistance to lethal dsRNA are discussed.


The role of community health workers in cervical cancer screening in low-income and middle-income countries: a systematic scoping review of the literature.
Community-based screening for cervical cancer and task sharing to community health workers (CHWs) have been suggested as a potential way to increase screening coverage in low- and middle-income countries (LMICs). The aims of the scoping review were to understand the following: (i) where and how CHWs are currently deployed in screening in LMIC settings; (ii) the methods used to train and support CHWs in screening, and (iii) The evidence on the cost-effectiveness of using CHWs to assist in screening. A scoping literature search of 11 major databases and the grey literature was performed between 1978 and 2018. We included comprehensive search terms for 'CHWs' and 'Cervical Cancer', and used the World Bank criteria to define LMICs. Of the 420 articles screened, 15 met the inclusion criteria for review. Studies were located in Africa (n=5), Asia (n=5), and South and Central America (n=5). CHWs played a role in community education and raising awareness (n=14), conducting or assisting in cervical screening (n=5), or follow-up (n=1). 11 studies described CHW training activities. Only one study provided a formal cost analysis. The roles of CHWs in cervical cancer screening in LMICs have largely to date focused on education, outreach, and awareness programmes. Community-based approaches to cervical cancer screening are feasible, although the sociocultural context plays an important role in the acceptability of these interventions. Further in-depth contextually grounded studies exploring the acceptability of such interventions are required, as well as studies exploring the cost-effectiveness of involving CHWs in cervical cancer screening activities.


Metal free direct C(sp2)-H arylaminations using nitrosoarenes to 2-hydroxy-di(het)aryl amines as multifunctional Aβ-aggregation modulators.
An unprecedented metal free arylamination reaction involving nitrosoarenes as the electrophilic aminating agents is reported. The direct arylamination of a broad range of substrates, such as naphthols, hydroxyquinolines, hydroxyquinones, coumarins and 1,3-cyclohexadienones was achieved under operationally simple and mild conditions without the aid of additional reagents/steps for N-O bond reduction. Interestingly, novel 2-hydroxydiaryl amines were found to act as Aβ-aggregation inhibitors.


A randomized controlled trial of intra-articular triamcinolone and/or physiotherapy in shoulder capsulitis.
To assess the effectiveness of intra-articular triamcinolone injection and physiotherapy singly or combined in the treatment of adhesive capsulitis of the shoulder. Eighty patients with adhesive capsulitis of less than 6 months duration were randomized to one of four groups: Group A, injection of triamcinolone 20 mg and eight sessions of standardized physiotherapy; Group B, injection of triamcinolone 20 mg alone; Group C, placebo injection and eight sessions of standardized physiotherapy; or Group D, placebo injection alone. All subjects were given an identical home exercise programme. Outcome measures were assessed at 6 weeks and 16 weeks. The primary outcome measure was Shoulder Disability Questionnaire (SDQ) score. Secondary outcomes were measurement of pain using a visual analogue scale (VAS), global disability using VAS and range of passive external rotation. A two-way analysis of variance was used to explore the effects of corticosteroid injection and physiotherapy. At 6 weeks, the SDQ had improved significantly more in the groups receiving corticosteroid injection (P = 0.004). Physiotherapy improved passive external rotation at 6 weeks (P = 0.02) and corticosteroid injection improved self-assessment of global disability at 6 weeks (P = 0.04). There was no interaction effect between injection and physiotherapy. At 16 weeks, all groups had improved to a similar degree with respect to all outcome measures. Corticosteroid injection is effective in improving shoulder-related disability, and physiotherapy is effective in improving the range of movement in external rotation 6 weeks after treatment.


Cognitive Enhancement and Social Mobility: Skepticism from India.
Cognitive enhancement (CE) covers a broad spectrum of methods, including behavioral techniques, nootropic drugs, and neuromodulation interventions. However, research on their use in children has almost exclusively been carried out in high-income countries with limited understanding of how experts working with children view their use in low- and middle- income countries (LMICs). This study examines perceptions on cognitive enhancement, their techniques, neuroethical issues about their use from an LMICs perspective.Seven Indian experts were purposively sampled for their expertise in bioethics, child development and child education. In-depth interviews were conducted using a semi-structured topic guide to examine (1) understanding of CE, (2) which approaches were viewed as cognitive enhancers, (3) attitudes toward different CE techniques and (4) neuroethical issues related to CE use within the Indian context. All interviews were audio recorded and transcribed before thematic analysis.Findings indicate Indian experts view cognitive enhancement as a holistic positive impact on overall functioning and well-being, rather than improvement in specific cognitive abilities. Exogenous agents, and neuromodulation were viewed with skepticism, whereas behavioral approaches were viewed more favorably. Neuroethical concerns included equitable access to CE, limited scientific evidence and over-reliance on technology to address societal problems. This highlights the need for more contextually relevant neuroethics research in LMICs.


Predictors of Pathologic Complete Response in Rectal Cancer Patients Undergoing Total Mesorectal Excision After Preoperative Chemoradiation.
Preoperative chemoradiotherapy (CRT) is the standard of care for patients with stage II and III rectal cancer. This strategy leads to pathologic complete response (pCR) in a significant number of patients. Factors predictive of pCR are currently being extensively investigated. The aim of this study was to analyze clinical factors that might be predictive of pCR.This study was a retrospective analysis of rectal cancer patients from January 2004 through December 2012. A total of 332 stage II and III patients with middle and low rectal cancer (≤10 cm) who received CRT and underwent curative total mesorectal excision were eligible. The median radiation dose was 50.4 Gy, and 72.6% of patients received infusional 5-fluorouracil with leucovorin, whereas 19.6% of patients received TS-1 with irinotecan, and 7.8% of patients received xeloda only. Pathologic complete response was confirmed by using pathologic specimens and analyzed based on predictive clinical factors.Among the 332 patients, 27.4% (n = 91) achieved pCR. Age, sex, body mass index, clinical T and N stages, tumor differentiation, the chemotherapy agent for CRT, and the time interval between CRT and surgery did not differ between the pCR and non-pCR groups. Carcinoembryogenic antigen (CEA) levels before CRT were 4.61 ± 7.38 ng/mL in the pCR group and 10.49 ± 23.83 ng/mL in the non-pCR group (P = 0.035). Post-CRT CEA levels were 1.4 ± 1.07 ng/mL in the pCR group and 2.16 ± 2.8 ng/mL in the non-pCR group (P = 0.014), and the proportion of middle rectal cancer patients was higher in pCR group (54.9%, P = 0.028). The results from multivariate logistic regression analysis indicated that higher tumor location (odds ratio 2.151; P = 0.003) and low post-CRT CEA level (odds ratio 0.789; P = 0.04) were independent predictive factors for pCR.Tumor location and post-CRT CEA level were predictive factors in pCR for rectal cancer patients. Therefore, these factors may be important determinants in achieving pCR, and may also be used to predict oncologic outcomes.


Altered near-infrared spectroscopy response to breath-holding in patients with fibromyalgia.
Fibromyalgia (FM) is a complex syndrome characterized by chronic widespread pain and a heightened response to pressure. Most medical researches pointed out that FM patients with endothelial dysfunction and arterial stiffness. A continuous-wave near-infrared spectroscopy (NIRS) system is used in present study to measure the hemodynamic changes elicited by breath-holding task in patients with FM. Each patient completed a questionnaire survey including demographics, characteristics of body pain, associated symptoms, headache profiles and Hospital Anxiety and Depression Scale. A total of 27 FM patients and 26 health controls were enrolled. In comparison with healthy controls, patients with FM showed lower maximal and averaged change of oxyhemoglobin concentration in both the left (1.634 ±0.890 and 0.810 ±0.525 μM) and the right (1.576 ±0.897 and 0.811 ±0.601 μM) prefrontal cortex than healthy controls (P < .05 for both sides) during the breath-holding task. In conclusion, FM is associated with altered cerebrovascular reactivity measured by NIRS and breath-holding task, which may reflect endothelial dysfunction or arterial stiffness. Oxygenated hemoglobin concentration changes of healthy controls and FM patients.


Bcl-2 stabilization by paxillin confers 5-fluorouracil resistance in colorectal cancer.
5-Fluorouracil (5-FU) is chemotherapeutic agent widely used for the treatment of colorectal cancer. Unfortunately, advanced colorectal cancer is often resistance to such chemotherapy and poor outcome. An adaptor protein paxillin (PXN) is phosphorylated at Y31/Y118 (pPXN-Y31/Y118) by Src contributes to cell mobility and Ser (S)272 of PXN in LD4 domain is important to the interaction between PXN and Bcl-2. We thus hypothesized that pPXN-Y31/Y118 may be required for Bcl-2 protein stability via PXN interacting with Bcl-2 to confer 5-FU resistance in colorectal cancer. Mechanistically, pPXN-S272 is phosphorylated through pPXN-Y31/Y118-mediated p21 protein-activated kinase 1 (PAK1) activation and pPXN-S272 is required for PXN to interact with Bcl-2. The interaction between PXN and Bcl-2 is essential for Bcl-2 protein stability through phosphorylation of Bcl-2 at S87 (pBcl-2-S87) by pPXN-Y31/Y118-mediated ERK activation. An increase in Bcl-2 expression by PXN is responsible for resistance to 5-FU. The resistance to 5-FU can be abolished by inhibitor of Src and PAK1 or Bcl-2 antagonist in cell and animal models. Among patients, Bcl-2 expression is positively correlated with expression of PXN and pPXN-S272, respectively. Patients with high PXN/high Bcl-2 or high pPXN-S272/high Bcl-2 tumors are commonly to have an unfavorable response to 5-FU-based chemotherapy, compared with patients who have high PXN, high pPXN-S272 or high Bcl-2 tumors alone. Therefore, we suggest that Src, PAK1 or Bcl-2 inhibitor may potentially overcome the resistance of 5-FU-based chemotherapy and consequently to improve outcomes in patients with PXN/Bcl-2 and pPXN-S272/Bcl-2-positive tumors.


Self-bias modulates saccadic control.
We present novel data on the role of attention in eliciting enhanced processing of stimuli associated with self. Participants were required to make pro- or anti-saccades according to whether learned shape-label pairings matched or mismatched. When stimuli matched participants were required to make an anti-saccade, and when the stimuli mismatched a pro-saccade was required. We found that anti-saccades were difficult to make to stimuli associated with self when compared to stimuli associated with a friend and a stranger. In contrast, anti-saccades to friend-stimuli were easier to make than anti-saccades to stranger-stimuli. In addition, a correct anti-saccade to a self-associated stimulus disrupted subsequent pro-saccade trials, relative to when the preceding anti-saccade was made to other stimuli. The data indicate that self-associated stimuli provide a strong cue for explicit shifts of attention to them, and that correct anti-saccades to such stimuli demand high levels of inhibition (which carries over to subsequent pro-saccade trials). The self exerts an automatic draw on attention.


FGAP: an automated gap closing tool.
The fast reduction of prices of DNA sequencing allowed rapid accumulation of genome data. However, the process of obtaining complete genome sequences is still very time consuming and labor demanding. In addition, data produced from various sequencing technologies or alternative assemblies remain underexplored to improve assembly of incomplete genome sequences. We have developed FGAP, a tool for closing gaps of draft genome sequences that takes advantage of different datasets. FGAP uses BLAST to align multiple contigs against a draft genome assembly aiming to find sequences that overlap gaps. The algorithm selects the best sequence to fill and eliminate the gap. FGAP reduced the number of gaps by 78% in an E. coli draft genome assembly using two different sequencing technologies, Illumina and 454. Using PacBio long reads, 98% of gaps were solved. In human chromosome 14 assemblies, FGAP reduced the number of gaps by 35%. All the inserted sequences were validated with a reference genome using QUAST. The source code and a web tool are available at http://www.bioinfo.ufpr.br/fgap/.


High-grade dysplasia and intramucosal adenocarcinoma in Barrett's esophagus: the role of esophagectomy in the era of endoscopic eradication therapy.
The aim of this review is to evaluate the role of esophagectomy for high-grade dysplasia (HGD) and intramucosal adenocarcinoma (IMC) in light of recent advances in endoscopic therapy for Barrett's esophagus. Radiofrequency ablation (RFA) and endoscopic mucosal resection (EMR) are proven well tolerated and effective, at least in midterm follow-up. The application of these techniques has opened a new road for the local treatment of esophageal HGD and IMC. To safely employ these techniques, reliable and accurate staging of the esophageal neoplasm is essential. EMR has taken a central role, as it allows the pathologist to provide tumor-staging information necessary for an appropriate clinical management decision process. Unfortunately, both RFA and EMR have limitations that preclude their universal use in the treatment of early esophageal cancer. In some cases, esophagectomy still remains the best treatment option. The evolution of the minimally invasive approach to esophagectomy may improve outcomes of this major operation. A better understanding of the indications and limitations of endoscopic therapy for HGD and IMC permits a tailored approach to the management of patients with early esophageal adenocarcinoma. When indicated, the selection of a less morbid surgical technique has the potential to improve overall surgical and oncological outcomes.


Structural and chemical basis for glucosamine 6-phosphate binding and activation of the glmS ribozyme.
The glmS ribozyme is the first naturally occurring catalytic RNA that relies on an exogenous, nonnucleotide cofactor for reactivity. From a biochemical perspective, the glmS ribozyme derived from Bacillus anthracis is the best characterized. However, much of the structural work to date has been done on a variant glmS ribozyme, derived from Thermoanaerobacter tengcongensis. Here we present structures of the B. anthracis glmS ribozyme in states before the activating sugar, glucosamine 6-phosphate (GlcN6P), has bound and after the reaction has occurred. These structures show an active site preorganized to bind GlcN6P that retains some affinity for the sugar even after cleavage of the RNA backbone. A structure of an inactive glmS ribozyme with a mutation distal from the ligand-binding pocket highlights a nucleotide critical to the reaction that does not affect GlcN6P binding. Structures of the glmS ribozyme bound to a naturally occurring inhibitor, glucose 6-phosphate (Glc6P), and a nonnatural activating sugar, mannosamine 6-phosphate (MaN6P), reveal a binding mode similar to that of GlcN6P. Kinetic analyses show a pH dependence of ligand binding that is consistent with titration of the cofactor's phosphate group and support a model in which the major determinant of activity is the sugar amine independent of its stereochemical presentation.


Switching Gears, Structuring the Right Search Strategy.
Nematodes can use local and global search strategies to find food. In this issue of Neuron, López-Cruz et al. (2019) unravel a neural circuit mechanism that allows worms to select and switch between these search modes depending on recent experience of food.


Validation of the Self-Efficacy for Managing Chronic Disease Scale: A Scleroderma Patient-Centered Intervention Network Cohort Study.
Self-management programs for patients with chronic illnesses, including rheumatic diseases, seek to enhance self-efficacy for performing health management behaviors. No measure of self-efficacy has been validated for patients with systemic sclerosis (SSc; scleroderma). The objective of this study was to assess the validity and internal consistency reliability of the Self-Efficacy for Managing Chronic Disease (SEMCD) scale in SSc. English-speaking SSc patients enrolled in the Scleroderma Patient-centered Intervention Network Cohort who completed the SEMCD scale at their baseline assessment between March 2014 and June 2015 were included. Patients were enrolled from 21 sites in Canada, the US, and the UK. Confirmatory factor analysis (CFA) was used to evaluate the factor structure of the SEMCD scale. Cronbach's alpha was calculated to assess internal consistency reliability. Hypotheses on the direction and magnitude of Pearson's correlations with psychological and physical outcome measures were formulated and tested to examine convergent validity. A total of 553 patients were included. CFA supported the single-factor structure of the SEMCD scale (Tucker Lewis Index = 0.99, comparative fit index = 0.99, root mean square error of approximation = 0.10). Internal consistency was high (α = 0.93), and correlations with measures of psychological and physical functioning were moderate to large (|r| = 0.48-0.67, P < 0.001), confirming study hypotheses. Scores from the SEMCD scale are valid for measuring self-efficacy in patients with SSc, and results support using the scale as an outcome measure to evaluate the effectiveness of self-management programs in SSc.


Genomic and evolutionary analyses of Tango transposons in Aedes aegypti, Anopheles gambiae and other mosquito species.
Tango is a transposon of the Tc1 family and was originally discovered in the African malaria mosquito, Anopheles gambiae. Here we report a systematic analysis of the genome sequence of the yellow fever mosquito, Aedes aegypti, which uncovered three distinct Tango transposons. We name the only An. gambiae Tango transposon AgTango1 and the three Ae. aegypti Tango elements AeTango1-3. Like AgTango1, AeTango1 and AeTango2 elements both have members that retain characteristics of autonomous elements such as intact open reading frames and terminal inverted repeats (TIRs). AeTango3 is a degenerate transposon with no full-length members. All full-length Tango transposons contain subterminal direct repeats within their TIRs. AgTango1 and AeTango1-3 form a single clade among other Tc1 transposons. Within this clade, AgTango1 and AeTango1 are closely related and share approximately 80% identity at the amino acid level, which exceeds the level of similarity of the majority of host genes in the two species. A survey of Tango in other mosquito species was carried out using degenerate PCR. Tango was isolated and sequenced in all members of the An. gambiae species complex, Aedes albopictus and Ochlerotatus atropalpus. Oc. atropalpus contains a rich diversity of Tango elements, while Tango elements in Ae. albopictus and the An. gambiae species complex all belong to Tango1. No Tango was detected in Culex pipiens quinquefasciatus, Anopheles stephensi, Anopheles dirus, Anopheles farauti or Anopheles albimanus using degenerate PCR. Bioinformatic searches of the Cx. p. quinquefasciatus (~10 x coverage) and An. stephensi (0.33 x coverage) databases also failed to uncover any Tango elements. Although other evolutionary scenarios cannot be ruled out, there are indications that Tango1 underwent horizontal transfer among divergent mosquito species.


Genetic models in applied physiology: selected contribution: effects of spaceflight on immunity in the C57BL/6 mouse. I. Immune population distributions.
There are several aspects of the spaceflight environment that may lead to changes in immunity: mission-related psychological stress, radiation, and changes in gravity. On December 5, 2001, the space shuttle Endeavor launched for a 12-day mission to examine these effects on C57BL/6 mice for the first time. On their return, assays were performed on the spleen, blood, and bone marrow. In response to flight, there were no significant differences in the general circulating leukocyte proportions. In contrast, there was an increase in splenic lymphocyte percentages, with a corresponding decrease in granulocytes. There was an overall shift in splenic lymphocytes away from T cells toward B cells, and a decrease in the CD4-to-CD8 ratios due to a decrease in T helpers. In contrast, there were proportional increases in bone marrow T cells, with decreases in B cells. Although the blast percentage and count were decreased in flight mice, the CD34(+) population was increased. The data were more consistent with a shift in bone marrow populations rather than a response to changes in the periphery. Many of the results are similar to those using other models. Clearly, spaceflight can influence immune parameters ranging from hematopoiesis to mature leukocyte mechanisms.


Development and validation of a three-dimensional finite element model of the face.
A detailed three-dimensional finite element model of the face is presented in this paper. Bones, muscles, skin, fat, and superficial muscoloaponeurotic system were reconstructed from magnetic resonance images and modeled according to anatomical, plastic, and reconstructive surgery literature. The finite element mesh, composed of hexahedron elements, was generated through a semi-automatic procedure with an effective compromise between the detailed representation of anatomical parts and the limitation of the computational time. Nonlinear constitutive equations are implemented in the finite element model. The corresponding model parameters were selected according to previous work with mechanical measurements on soft facial tissue, or based on reasonable assumptions. Model assumptions concerning tissue geometry, interactions, mechanical properties, and the boundary conditions were validated through comparison with experiments. The calculated response of facial tissues to gravity loads, to the application of a pressure inside the oral cavity and to the application of an imposed displacement was shown to be in good agreement with the data from corresponding magnetic resonance images and holographic measurements. As a first application, gravimetric soft tissue descent was calculated from the long time action of gravity on the face in the erect position, with tissue aging leading to a loss of stiffness. Aging predictions are compared with the observations from an "aging database" with frontal photos of volunteers at different age ranges (i.e., 20-40 years and 50-70 years).


Impaired integration of disambiguating evidence in delusional schizophrenia patients.
It has been previously demonstrated that a cognitive bias against disconfirmatory evidence (BADE) is associated with delusions. However, small samples of delusional patients, reliance on difference scores and choice of comparison groups may have hampered the reliability of these results. In the present study we aimed to improve on this methodology with a recent version of the BADE task, and compare larger groups of schizophrenia patients with/without delusions to obsessive-compulsive disorder (OCD) patients, a population with persistent and possibly bizarre beliefs without psychosis. A component analysis was used to identify cognitive operations underlying the BADE task, and how they differ across four groups of participants: (1) high-delusional schizophrenia, (2) low-delusional schizophrenia, (3) OCD patients and (4) non-psychiatric controls. As in past studies, two components emerged and were labelled 'evidence integration' (the degree to which disambiguating information has been integrated) and 'conservatism' (reduced willingness to provide high plausibility ratings when justified), and only evidence integration differed between severely delusional patients and the other groups, reflecting delusional subjects giving higher ratings for disconfirmed interpretations and lower ratings for confirmed interpretations. These data support the finding that a reduced willingness to adjust beliefs when confronted with disconfirming evidence may be a cognitive underpinning of delusions specifically, rather than obsessive beliefs or other aspects of psychosis such as hallucinations, and illustrates a cognitive process that may underlie maintenance of delusions in the face of counter-evidence. This supports the possibility of the BADE operation being a useful target in cognitive-based therapies for delusions.


Directionally Interacting Spheres and Rods Form Ordered Phases.
The structures formed by mixtures of dissimilarly shaped nanoscale objects can significantly enhance our ability to produce nanoscale architectures. However, understanding their formation is a complex problem due to the interplay of geometric effects (entropy) and energetic interactions at the nanoscale. Spheres and rods are perhaps the most basic geometrical shapes and serve as convenient models of such dissimilar objects. The ordered phases formed by each of these individual shapes have already been explored, however, when mixed, spheres and rods have demonstrated only limited structural organization to date. Here, we show using experiments and theory that the introduction of directional attractions between rod ends and isotropically interacting spherical nanoparticles (NPs) through DNA base pairing leads to the formation of ordered three-dimensional lattices. The spheres and rods arrange themselves in a complex alternating manner, where the spheres can form either a face-centered cubic (FCC) or hexagonal close-packed (HCP) lattice, or a disordered phase, as observed by in situ X-ray scattering. Increasing NP diameter at fixed rod length yields an initial transition from a disordered phase to the HCP crystal, energetically stabilized by rod-rod attraction across alternating crystal layers, as revealed by theory. In the limit of large NPs, the FCC structure is instead stabilized over the HCP by rod entropy. We, therefore, propose that directionally specific attractions in mixtures of anisotropic and isotropic objects offer insight into unexplored self-assembly behavior of noncomplementary shaped particles.


Prepolymers of hexamethylene diisocyanate as a cause of occupational asthma.
Occupational asthma (OA) caused by products that contain hexamethylene diisocyanate (HDI) has been ascribed to the highly volatile monomer of HDI. Most two-component paints are now made up primarily of nonvolatile prepolymers of HDI (30% to 60%) with only trace amounts (< 0.1%) of the monomer. The respective role of the two chemical forms of HDI in causing OA has never been investigated. Twenty workers who were consecutively referred for possible OA that resulted from exposure to spray paints underwent inhalation challenges on separate days with pure HDI monomer and the commercial formulation of HDI prepolymers to which they had been exposed at work. Specific inhalation challenges elicited a positive asthmatic reaction in 10 of the 20 subjects. Among these subjects, four had positive bronchial reactions (two early, one late, and one dual) to both the monomer and the prepolymers. Four other subjects had asthmatic reactions (two early, one late, and one dual) after exposure to the prepolymers but not after exposure to the monomer. The discordance in bronchial response elicited by the monomer and the prepolymers could not be due to differences in the level of baseline nonspecific bronchial reactivity or in HDI concentrations during the tests. One subject showed an atypical progressive reaction after exposure to the monomer but not after exposure to the prepolymer. In this case, the discordant response could be explained by differences in HDI concentration. These observations show that, although they are nonvolatile, the prepolymers of HDI can induce OA and that asthmatic reactions as a result of exposure to prepolymers but not the monomer is not a rare occurrence.


Bacterial Zoonoses Transmitted by Household Pets: State-of-the-Art and Future Perspectives for Targeted Research and Policy Actions.
The close contact between household pets and people offers favourable conditions for bacterial transmission. In this article, the aetiology, prevalence, transmission, impact on human health and preventative measures are summarized for selected bacterial zoonoses transmissible by household pets. Six zoonoses representing distinct transmission routes were selected arbitrarily based on the available information on incidence and severity of pet-associated disease caused by zoonotic bacteria: bite infections and cat scratch disease (physical injuries), psittacosis (inhalation), leptospirosis (contact with urine), and campylobacteriosis and salmonellosis (faecal-oral ingestion). Antimicrobial resistance was also included due to the recent emergence of multidrug-resistant bacteria of zoonotic potential in dogs and cats. There is a general lack of data on pathogen prevalence in the relevant pet population and on the incidence of human infections attributable to pets. In order to address these gaps in knowledge, and to minimize the risk of human infection, actions at several levels are recommended, including: (1) coordinated surveillance of zoonotic pathogens and antimicrobial resistance in household pets, (2) studies to estimate the burden of human disease attributable to pets and to identify risk behaviours facilitating transmission, and (3) education of those in charge of pets, animal caretakers, veterinarians and human medical healthcare practitioners on the potential zoonotic risks associated with exposure to pets. Disease-specific recommendations include incentives to undertake research aimed at the development of new diagnostic tests, veterinary-specific antimicrobial products and vaccines, as well as initiatives to promote best practices in veterinary diagnostic laboratories and prudent antimicrobial usage.


Radiographic Assessment of Shoulder Position in 619 Idiopathic Scoliosis Patients: Can T1 Tilt Be Used as an Intraoperative Proxy to Determine Postoperative Shoulder Balance?
The purpose of this study is to assess radiographic shoulder measures from the preoperative to the postoperative time period, specifically to determine whether T1 tilt could be used as an intraoperative proxy for shoulder balance determination. This study focused on radiographic shoulder measures of 619 adolescent idiopathic scoliosis patients who underwent spinal deformity surgery. A prospective, multicenter database of adolescent idiopathic scoliosis was queried to identify all patients who had undergone spinal deformity surgery with >2 years of follow-up postoperatively. Radiographic analysis focused on measures of shoulder balance: T1 tilt, clavicle angle, and radiographic shoulder height. A total of 619 patients were included in this analysis. Mean age at surgery was 14.8 years with 83% female. Mean preoperative curve size was 58.0 degrees. Mean T1 tilt preoperatively was -0.10 degrees and postoperatively 2.42 degrees. Mean clavicle angle preoperatively was -1.39 degrees and postoperatively 0.79 degrees. Mean radiographic shoulder height preoperatively was -7.04 mm and postoperatively 1.63 mm. All 3 radiographic parameters demonstrated reasonable correlation preoperatively and postoperatively to each other. To assess the viability of T1 tilt as an intraoperative proxy for shoulder balance, standardized ratios between the variables were created. Analysis of these ratios demonstrated little or no relationship preoperatively to postoperatively, hence the relationship of T1 tilt to radiographic shoulder height does not remain constant. Analysis of the relationship of T1 tilt to radiographic shoulder height from preoperative to postoperative did not demonstrate consistency. Lenke 3 and 6 curve patterns demonstrated preoperative to postoperative correlation, both with nonstructural proximal thoracic curves; however, for the remaining curve patterns T1 tilt cannot be used as an intraoperative proxy for shoulder balance. Level IV.


Knee pain, knee osteoarthritis, and the risk of fracture.
Patients with osteoarthritis (OA) have increased bone mineral density; however, the association between knee OA and fracture is controversial. Few data exist on the association between knee pain and fracture. We examined the association of knee OA and knee pain with fracture and falls in elderly men and women. The study group comprised 6,641 men and women ages > or =75 years who participated in a 3-year randomized controlled trial of intramuscular vitamin D therapy. Patients completed a questionnaire about knee pain and OA. Fracture and fall data were collected prospectively every 6 months. Knee pain prevalence and a clinician diagnosis of knee OA were 35.2% and 6.8%, respectively. A total of 436 incident nonvertebral fractures were reported, and 3,992 patients sustained a fall. Prevalent knee pain was associated with an increased risk of falls (hazard ratio [HR] 1.26, 95% confidence interval [95% CI] 1.17-1.36) and hip fracture (HR 2.0, 95% CI 1.18-3.37). Increasing severity of knee pain was associated with a greater risk of falls and hip fracture. Clinician diagnosis of knee OA was associated with an increased risk of nonvertebral fractures (HR 1.61, 95% CI 1.09-2.36). The increased risk of fracture was not substantially reduced by adjusting for falls, but was attenuated by adjustment for the use of walking aids. Patients with a clinical diagnosis of knee OA and with knee pain have an increased risk of nonvertebral and hip fracture. This is not explained by the increased risk of falls, but is more likely to be due to the severity of falls sustained. Knee pain and OA should be regarded as independent risk factors for fracture.


Which Malpositioned Pedicle Screws Should Be Revised?
Up to 10% of free-hand pedicle screws are malpositioned, and 1 in 300 patients may undergo return to surgery for revision of malpositioned screws. The indications for revision of asymptomatic malpositioned screws have not been carefully examined in the literature. We sought to evaluate the threshold among spinal deformity surgeons for revision of malpositioned screws. Twelve experienced spine surgeons reviewed x-ray and computed tomographic images of 32 malpositioned pedicle screws with variable degrees of anterior, medial, and lateral breeches. The surgeons were asked whether based on the image they would revise the screw: (1) intraoperatively before rod placement; (2) intraoperatively after rod placement; (3) in clinic with an asymptomatic patient. For each scenario, we assumed stable neuromonitoring and no neurological changes. Agreement and multirater κ was calculated. There was good agreement as to which screws were malpositioned (80% agreement, κ=0.703). After the rod was placed or postoperatively (scenarios 2 and 3), surgeons less frequently recommended screw revision, and there was greater variability among the surgeons' recommendations. For return to surgery from clinic for asymptomatic screw revision, % agreement was only 65% (κ=0.477). The majority recommended revision surgery for screws which approached the dura (10/12) or the aorta (7/12 surgeons). Half of the surgeons recommended revision surgery for an asymptomatic screw if the entire screw diameter was in the canal. Revision surgery was not recommended for asymptomatic patients with screws partially violating the canal (<½ the screw diameter), malpositioned laterally in the rib head, or with small anterior cortical violations remote from a vascular structure. There is significant variability of opinion among surgeons regarding which malpositioned screws can be safely observed in an asymptomatic patient. Given the frequency of malpositioned screws and morbidity of surgical return to surgery, more long-term data are needed to develop practice guidelines for determining which screws require revision surgery. Level III-retrospective comparative study.