Establishing, harmonizing and analyzing critical values in a large academic health center.
No report on establishing critical values (CVs) lists has described a process for harmonizing different lists in a large academic health center or validation on follow-up after 5 years. A definition of a critical value was adopted. CVs in use and reporting times for chemistry, hematology and coagulation (CH&C) tests during a 1-week period at one hospital were analyzed prior to the revision and again 5 years later. CVs lists in use by the different campus hospital laboratories were reviewed for compliance with the definition for a critical value. Lists were harmonized with a total of 37 CH&C tests, five of these included adult and either cord blood or neonatal values. Overall, 26 tests were eliminated, 61 individual values were changed and two tests were added. The revised CVs list reduced the number of calls at one primary teaching hospital by 33%. In the next 5-year period, value thresholds changed (n=2) and one value was re-instated (n=1). When retrospectively examined for impact, one value change was considered appropriate. CVs lists were harmonized among campus hospitals. Tests not considered critical were removed and values adjusted for uniformity. Changes in CVs lists should be evaluated for appropriateness. A process is now in place for periodic review and considerations related to CVs lists.


Use of flow cytometry (Sysmex) UF-100) to screen for positive urine cultures: in search for the ideal cut-off.
Cultures for urinary tract infections (UTI) constitute a large workload in the clinical microbiology laboratory, although up to 80% are usually negative. Several automated methods are available to screen urines for UTI, one being the flow cytometry-based Sysmex((R)) UF-100. The performance of the UF-100 was evaluated over a 16-month period using urine culture as the reference method. During this period, a total of 5356 urine samples were studied (469 children; 3229 women and 1658 men), of which 706 were culture positive (593 grew Gram negative bacilli). Receiver operating characteristics (ROC) curve analysis showed an area under the curve (AUC) of 0.83 for leukocytes and 0.85 for bacterial count. Applying cut-off values reported in the literature gave sensitivities ranging from 75% to 90%, resulting in 73-174 false negatives (FN). Using a logical combination (leukocytes >or=15x10(6)/L OR bacteria >or=500x10(6)/L) gave a sensitivity of 98%. However, the specificity dropped to 25%, resulting in 15 FN. Screening urine samples for UTI detects a large number of culture positive samples. However, the rather large number of FN observed precludes the use of the UF-100 as a routine screening method to exclude urine samples from culture.


Heart rate reveals torpor at high body temperatures in lowland tropical free-tailed bats.
Reduction in metabolic rate and body temperature is a common strategy for small endotherms to save energy. The daily reduction in metabolic rate and heterothermy, or torpor, is particularly pronounced in regions with a large variation in daily ambient temperature. This applies most strongly in temperate bat species (order Chiroptera), but it is less clear how tropical bats save energy if ambient temperatures remain high. However, many subtropical and tropical species use some daily heterothermy on cool days. We recorded the heart rate and the body temperature of free-ranging Pallas' mastiff bats (Molossus molossus) in Gamboa, Panamá, and showed that these individuals have low field metabolic rates across a wide range of body temperatures that conform to high ambient temperature. Importantly, low metabolic rates in controlled respirometry trials were best predicted by heart rate, and not body temperature. Molossus molossus enter torpor-like states characterized by low metabolic rate and heart rates at body temperatures of 32°C, and thermoconform across a range of temperatures. Flexible metabolic strategies may be far more common in tropical endotherms than currently known.


Identification and characterization of peripheral T-cell lymphoma-associated SEREX antigens.
Peripheral T-cell lymphomas (PTCL) are generally less common and pursue a more aggressive clinical course than B-cell lymphomas, with the T-cell phenotype itself being a poor prognostic factor in adult non-Hodgkin lymphoma (NHL). With notable exceptions such as ALK(+) anaplastic large cell lymphoma (ALCL, ALK+), the molecular abnormalities in PTCL remain poorly characterised. We had previously identified circulating antibodies to ALK in patients with ALCL, ALK(+). Thus, as a strategy to identify potential antigens associated with the pathogenesis of PTCL, not otherwise specified (PTCL, NOS), we screened a testis cDNA library with sera from four PTCL, NOS patients using the SEREX (serological analysis of recombinant cDNA expression libraries) technique. We identified nine PTCL, NOS-associated antigens whose immunological reactivity was further investigated using sera from 52 B- and T-cell lymphoma patients and 17 normal controls. The centrosomal protein CEP250 was specifically recognised by patients sera and showed increased protein expression in cell lines derived from T-cell versus B-cell malignancies. TCEB3, BECN1, and two previously uncharacterised proteins, c14orf93 and ZBTB44, were preferentially recognised by patients' sera. Transcripts for all nine genes were identified in 39 cancer cell lines and the five genes encoding preferentially lymphoma-recognised antigens were widely expressed in normal tissues and mononuclear cell subsets. In summary, this study identifies novel molecules that are immunologically recognised in vivo by patients with PTCL, NOS. Future studies are needed to determine whether these tumor antigens play a role in the pathogenesis of PTCL.


Chronic Administration of Pimozide Fails to Attenuate Motor and Pathological Deficits in Two Mouse Models of Amyotrophic Lateral Sclerosis.
Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease which presently does not have any efficient therapeutic approach. Pimozide, a Food and Drug Administration (FDA)-approved neuroepileptic drug, has been recently proposed as a promising treatment for ALS patients based on apparent stabilization of right hand muscles after a short-time administration. A new clinical trial started at the end of 2017 to recruit patients with a prolonged drug delivery schedule. Here, our aim was to investigate the effects of chronic administration of pimozide on disease progression and pathological events in two mouse models of ALS. Pimozide was administered every 2 days to transgenic mice bearing the ALS-linked A315T mutation on the human TAR DNA-binding protein 43 (TDP-43) gene and to mice carrying the human superoxide dismutase 1 (SOD1) gene with the ALS-linked G93A mutation. Chronic administration of pimozide exacerbated motor performances in both animal models and reduced survival in SOD1G93A mice. In TDP-43A315T, it decreased the percentage of innervated neuromuscular junctions (NMJs) and increased the accumulation of insoluble TDP-43. In SOD1G93A mice, pimozide had no effects on NMJ innervation or motoneuron loss, but it increased the levels of misfolded SOD1. We conclude that a chronic administration of pimozide did not confer beneficial effects on disease progression in two mouse models of ALS. In light of a new clinical trial on ALS patients with a chronic regime of pimozide, these results with mouse models suggest prudence and careful monitoring of ALS patients subjected to pimozide treatment.


Elevated plasma high-sensitivity C-reactive protein concentrations in Asian Indians living in the United States.
Proinflammatory state may contribute to the excessive prevalence of type 2 diabetes and cardiovascular disease observed in populations originating from the Indian subcontinent (Asian Indians). This study was conducted to evaluate whether nondiabetic Asian Indian men living in the United States manifest a proinflammatory state when compared with Caucasians of similar age and body fat content. We also compared the relationships between plasma high-sensitivity C-reactive protein (hs-CRP), a marker of low-grade inflammation, and various parameters of body composition and fat distribution and insulin sensitivity in Asian Indians and Caucasians. For this purpose, plasma hs-CRP, oral glucose tolerance test, and anthropometric measurements were conducted in 82 Asian Indian men and 55 Caucasian men of similar age. The two groups had similar body fat content and truncal skinfolds thickness. Asian Indians had higher insulin areas under the curve during oral glucose tolerance tests, indicating a greater insulin resistance. Asian Indians also manifested a significant elevation of plasma hs-CRP. We conclude that young, overtly healthy Asian Indian men have both greater insulin resistance and higher hs-CRP levels than do Caucasians. This difference cannot be explained by greater adiposity in Asian Indians and suggests that many Asian Indians have an underlying proinflammatory state that may contribute to their increased risk for both type 2 diabetes and cardiovascular disease.


Insulin resistance and cognition among HIV-infected and HIV-uninfected adult women: the Women's Interagency HIV Study.
Cognitive impairment remains prevalent in the era of combination antiretroviral therapy (cART) and may be partially due to comorbidities. We postulated that insulin resistance (IR) is negatively associated with cognitive performance. We completed a cross-sectional analysis among 1547 (1201 HIV(+)) women enrolled in the Women's Interagency HIV Study (WIHS). We evaluated the association of IR with cognitive measures among all WIHS women with concurrent fasting bloods and cognitive testing [Trails A, Trails B, and Symbol Digit Modalities Test (SDMT)] using multiple linear regression models. A smaller subgroup also completed the Stroop test (n=1036). IR was estimated using the Homeostasis Model Assessment (HOMA). Higher HOMA was associated with poorer performance on the SDMT, Stroop Color-Naming (SCN) trial, and Stroop interference trial, but remained statistically significant only for the SCN in models adjusting for important factors [β=3.78 s (95% CI: 0.48-7.08), p=0.025, for highest vs. lowest quartile of HOMA]. HIV status did not appear to substantially impact the relationship of HOMA with SCN. There was a small but statistically significant association of HOMA and reduced neuropsychological performance on the SCN test in this cohort of women.


A pressure-driven gas-diffusion/permeation micropump for self-activated sample transport in an extreme micro-environment.
The micropump is the most important functional unit of a micro total analysis system (μTAS). An ideal microfluidics system should adopt simple, stable, robust, inexpensive, and integrated on-chip strategies to transport samples for downstream applications, with little or no external energy consumption and limited manual intervention. Nevertheless, it remains a key challenge for traditional micropumps to be directly integrated into self-contained and disposable μTAS for velocity-stable and passive sample transport. The best way to assess the capability of passive micropumps is to evaluate their pumping performance in extreme environments, e.g. a 3D configurated microchannel instead of a 2D configuration, high temperature conditions instead of at room temperature, a long microchannel instead of short microchannel, a complex topological microsystem (e.g. a microvascular network interconnecting multiple inlets and outlets) instead of a simple topological microsystem (e.g. a one-directional microchannel connecting only one inlet and one outlet), and multi-phase microdroplet transport instead of single-phase plug transport. In this review, a novel micropumping methodology - a pressure-driven gas-diffusion/permeation micropump - is described, which is the first review paper dedicated to this subject. A comprehensive overview is provided for comparison between this novel micropumping methodology and traditional passive micropumps, especially for applications in stable velocity control in the aforementioned extreme environments. Compared with mainstream conventional micropumps, we confirm that pressure-driven gas-diffusion/permeation micropumps combine a number of superior properties all into one device, such as small size, simple structure, without the need for microfabrication procedures or external power consumption, strong transport capacity, homogeneous flow velocity, delivery capacity for both multi-phase microdroplets and single-phase plugs, long-distance transport, persistent pumping for both 3D microchannels and complex topological microsystems (e.g. a biomimetic microvasculature), low cost, ease of microdevice integration, bubble suppression and amazing stability at high temperatures. An advanced outlook and perspectives for the future development of this novel micropump are also discussed, which may serve as a starting point for researchers in the microfluidics fields to harness pressure-driven gas-diffusion/permeation micropumps for downstream applications.


Detection of Poinsettia mosaic virus Infecting Poinsettias (Euphorbia pulcherrima) in Venezuela.
Poinsettia mosaic virus (PnMV), a putative member of the tymoviruses, was detected in several cultivars of vegetatively propagated poinsettias grown in commercial nurseries in Estado Miranda, Venezuela. Symptoms associated with the affected plants consisted of severe mottling and distortion of leaves and bracteoles. The suspect virus was mechanically transmitted to Nicotiana benthamiana. Leaf extracts and thin sections of affected leaf tissue were analyzed by transmission electron microscopy. Spherical virus particles (30 nm diameter) were observed in samples from symptomatic poinsettia plants. Ultrastructural analyses of virus-infected cells revealed aggregates of virus particles in the cytoplasm and central vacuole. The virus was purified twice from infected N. benthamiana, resulting in yields as high as 12 mg/100 g. Dissociated coat protein contained a single 24-kDa protein species. The virus was not serologically related to Carnation mottle, Bean rugose mosaic, Cowpea mosaic, Cucumber mosaic, Pea enation mosaic, Prunus necrotic ringspot, Apple mosaic, Tobacco streak, Maize rayado fino, Tomato ringspot, Bean southern mosaic, Sowbane mosaic, Andean potato latent, Belladona mottle, Scrophularia or Turnip yellow mosaic viruses, but did react positively in enzyme-linked immunosorbent assay and western blot analysis with antiserum (ATCC PVAS-476) to PnMV. Based on these results, the virus is considered to be PnMV. To our knowledge, this is the first report of PnMV infecting poinsettias in Venezuela.


Network pharmacology strategies toward multi-target anticancer therapies: from computational models to experimental design principles.
Polypharmacology has emerged as novel means in drug discovery for improving treatment response in clinical use. However, to really capitalize on the polypharmacological effects of drugs, there is a critical need to better model and understand how the complex interactions between drugs and their cellular targets contribute to drug efficacy and possible side effects. Network graphs provide a convenient modeling framework for dealing with the fact that most drugs act on cellular systems through targeting multiple proteins both through on-target and off-target binding. Network pharmacology models aim at addressing questions such as how and where in the disease network should one target to inhibit disease phenotypes, such as cancer growth, ideally leading to therapies that are less vulnerable to drug resistance and side effects by means of attacking the disease network at the systems level through synergistic and synthetic lethal interactions. Since the exponentially increasing number of potential drug target combinations makes pure experimental approach quickly unfeasible, this review depicts a number of computational models and algorithms that can effectively reduce the search space for determining the most promising combinations for experimental evaluation. Such computational-experimental strategies are geared toward realizing the full potential of multi-target treatments in different disease phenotypes. Our specific focus is on system-level network approaches to polypharmacology designs in anticancer drug discovery, where we give representative examples of how network-centric modeling may offer systematic strategies toward better understanding and even predicting the phenotypic responses to multi-target therapies.


Photophobia and corneal crystal density in nephropathic cystinosis: an in vivo confocal microscopy and anterior-segment optical coherence tomography study.
To analyze the correlation between photophobia and corneal crystal density in nephropathic cystinosis using in vivo confocal microscopy (IVCM) and anterior-segment optical coherence tomography (AS-OCT). Forty eyes of 20 patients with nephropathic cystinosis aged 7 to 37 years were included in this study. Ophthalmologic investigations included clinician-assessed and self-assessed evaluations of photophobia, slit-lamp biomicroscopy analysis, the depth of crystal deposition (DCD) and the central corneal thickness (CCT) in the central cornea measured with AS-OCT, and IVCM analysis of the crystal density score (IVCM-CysS), inflammatory cell density (IVCM-inf), and nerve damage (IVCM-N). Age, sex, intraleukocyte cystine concentrations (ICC), and the need for renal transplantation were also recorded. The average subjective and objective photophobia scores were 2.10 ± 1.28 and 1.70 ± 1.41, respectively. Using AS-OCT, the average percentage of crystal infiltration (OCT-CysP) and was 49.56 ± 27.31% (range, 11.45%-95.81%). The mean IVCM-CysS was 8.84 ± 4.34, the mean density of inflammatory cells (IVCM-inf) was 178.28 ± 173.00 cells/mm2, and the mean IVCM-N score was 3.11 ± 2.11. Clinician- and self-assessed estimations of photophobia were correlated (R2 = 0.61). No significant correlation was observed between clinician- and self-assessed photophobia scores and ICC or sex. There were significant correlations between clinician- and self-assessed photophobia scores and age, OCT-CysP, IVCM-CysS, IVCM-inf, and IVCM-N. The IVCM-CysS was also correlated with OCT-CysP (R2 = 0.27), IVCM-inf (R2 = 0.37), and IVCM-N (R2 = 0.56). In vivo confocal microscopy and AS-OCT are reliable tools to quantify cystinosis corneal crystals. In patients with nephropathic cystinosis, the intensity of photophobia is associated with the density of crystals, infiltration of inflammatory cells, and nerve damage within the cornea.


Temperature-sensitive hydrogels by graft polymerization of chitosan and N-isopropylacrylamide for drug release.
Thermo-responsive polysaccharidic hydrogels were designed and synthesized by a free radical induced grafting procedure. Chitosan was chosen as biopolymer to impart biocompatibility and biodegradability to the macromolecular systems, while N-isopropylacrylamide (NIPAAm) was selected as co-monomer responsive for the thermo-sensitive properties. Ammonium persulfate was the initiator system and different polymeric networks have been synthesized by modulating the amount of NIPAAm in the polymerization feed. The resulting hydrogels were proposed as drug delivery devices and their performance was evaluated by using Diclofenac sodium salt as a model drug. Hydrogels were carefully characterized by FT-IR spectrophotometry, calorimetric analyses and swelling behavior in a temperature range of 15-45°C. Finally, to verify the suitability of these hydrogels as thermo-responsive devices, the drug release profiles were studied performing in vitro experiments around the swelling-shrinking transition temperatures of the macromolecular systems.


Low agreement between radio binding assays in analyzing glutamic acid decarboxylase (GAD65Ab) autoantibodies in patients classified with type 2 diabetes.
Autoantibodies against glutamic acid decarboxylase (GAD65Ab) are used in the classification of diabetes in adults. We assessed the concordance in GAD65 autoantibody levels within subjects between three different GAD65Ab radio binding assays (RBA). Plasma samples from 112 diabetes patients (median age 50 years) initially classified with type 2 diabetes was randomly selected from a local diabetes registry. Coded samples were analyzed with two RBA employing (35)S-labeled GAD65. The first used the pEx9 plasmid (pEx9 RBA), the second employed the pThGAD65 plasmid (pThGAD65 RBA) to label GAD65 by in vitro transcription translation. We also used a commercial kit employing plasmid pGAD17 labelled with (125)I (pGAD17 RBA). Subsequent analyses followed standard procedures. Two different cut-offs for GAD65Ab positivity were used in all three assays. We calculated the correlation, concordance, and agreement between the assays. The proportion of GAD65Ab positivity differed between assays when low cut-offs were used (pEx9 RBA 25%, pThGAD65 RBA 17.9%, and pGAD17 RBA 12.5%, respectively). When high cut-offs were applied, the concordance between the pEx9 RBA and the pThGAD65 RBA was 97.3 while their concordance to the pGAD17 RBA was lower (88.4 and 87.4, respectively). There was a low agreement between both pEx9 RBA and pGAD17 RBA (0.45, 95% CI 0.20-0.70) and between pThGAD65 RBA and pGAD17 RBA (0.43, 95% CI 0.18-0.68). We found discrepancies in determining the GAD65Ab positivity, which constitutes a problem when GAD65Ab are used clinically. Further methodological GAD65Ab assays studies are warranted.


An event-based hydrologic simulation model for bioretention systems.
Bioretention systems are designed to treat stormwater and provide attenuated drainage between storms. Bioretention has shown great potential at reducing the volume and improving the quality of stormwater. This study introduces the bioretention hydrologic model (BHM), a one-dimensional model that simulates the hydrologic response of a bioretention system over the duration of a storm event. BHM is based on the RECARGA model, but has been adapted for improved accuracy and integration of pollutant transport models. BHM contains four completely-mixed layers and accounts for evapotranspiration, overflow, exfiltration to native soils and underdrain discharge. Model results were evaluated against field data collected over 10 storm events. Simulated flows were particularly sensitive to antecedent water content and drainage parameters of bioretention soils, which were calibrated through an optimisation algorithm. Temporal disparity was observed between simulated and measured flows, which was attributed to preferential flow paths formed within the soil matrix of the field system. Modelling results suggest that soil water storage is the most important short-term hydrologic process in bioretention, with exfiltration having the potential to be significant in native soils with sufficient permeability.


Crucial role of estrogen for the mammalian female in regulating semen coagulation and liquefaction in vivo.
Semen liquefaction changes semen from a gel-like to watery consistency and is required for sperm to gain mobility and swim to the fertilization site in the Fallopian tubes. Kallikrein-related peptidases 3 (KLK3) and other kallikrein-related peptidases from male prostate glands are responsible for semen liquefaction by cleaving gel-forming proteins (semenogelin and collagen). In a physiological context, the liquefaction process occurs within the female reproductive tract. How seminal proteins interact with the female reproductive environment is still largely unexplored. We previously reported that conditional genetic ablation of Esr1 (estrogen receptor α) in the epithelial cells of the female reproductive tract (Wnt7aCre/+;Esr1f/f) causes female infertility, partly due to a drastic reduction in the number of motile sperm entering the oviduct. In this study, we found that post-ejaculated semen from fertile wild-type males was solidified and the sperm were entrapped in Wnt7aCre/+;Esr1f/f uteri, compared to the watery semen (liquefied) found in Esr1f/f controls. In addition, semenogelin and collagen were not degraded in Wnt7aCre/+;Esr1f/f uteri. Amongst multiple gene families aberrantly expressed in the absence of epithelial ESR1, we have identified that a lack of Klks in the uterus is a potential cause for the liquefaction defect. Pharmacological inhibition of KLKs in the uterus replicated the phenotype observed in Wnt7aCre/+;Esr1f/f uteri, suggesting that loss of uterine and seminal KLK function causes this liquefaction defect. In human cervical cell culture, expression of several KLKs and their inhibitors (SPINKs) was regulated by estrogen in an ESR1-dependent manner. Our study demonstrates that estrogen/ESR1 signaling in the female reproductive tract plays an indispensable role in normal semen liquefaction, providing fundamental evidence that exposure of post-ejaculated semen to the suboptimal microenvironment in the female reproductive tract leads to faulty liquefaction and subsequently causes a fertility defect.


The cortisol awakening response - normal values and confounds.
In several recent investigations it could be demonstrated that the free cortisol response to awakening can serve as an useful index of the adrenocortical activity. When measured with strict reference to the time of awakening the assessment of this endocrine response is able to uncover subtle changes in hypothalamus-pituitary-adrenal (HPA) axis activity, which are, for instance, related to persisting pain, burnout and chronic stress. Furthermore, it has been suggested that the HPA axis might serve as an indicator of allostatic load in subjects exposed to prolonged environmental noise. In the present paper four separate studies with a total of 509 adult subjects were combined in order to provide reliable information on normal values for the free cortisol response to awakening. Corresponding with earlier findings, a mean cortisol increase of about 50% within the first 30 minutes after awakening was observed. The intraindividual stability over time was shown to be remarkably high with correlations up to r=.63 (for the area under the response curve). Furthermore, the cortisol rise after awakening is rather consistent, with responder rates of about 75%. Gender significantly influenced early morning free cortisol levels. Although women showed a virtually identical cortisol increase after awakening compared to men, a significantly delayed decrease was observed. Confirming and extending previous findings, the present study strongly suggests that neither age, nor the use of oral contraceptives, habitual smoking, time of awakening, sleep duration or using / not using an alarm clock have a considerable impact on free cortisol levels after awakening. The cortisol awakening response can be assessed under a wide variety of clinical and field settings, since it is non-invasive, inexpensive and easy-to-employ. The present data provide normal values and information on potential confounds which should facilitate investigations into the endocrine consequences of prolonged exposure to environmental noise.


A review of the management of two common clinical problems found in patients with cystic fibrosis: cystic fibrosis-related diabetes and poor growth.
Cystic fibrosis-related diabetes (CFRD) and glucose intolerance often occur in teens and adults with CF. The initial deficiency is an impaired first-phase insulin response; as patients age, peak insulin response is delayed and less robust than normal. Decreased insulin sensitivity (insulin resistance) is also present in patients with CF. Insulin is the only currently recommended therapy for all types of CFRD, and many clinicians find that basal/bolus regimens are optimal. Another common finding in children with CF is poor linear growth and inadequate weight gain. Recombinant human growth hormone (rhGH) is being explored in this patient population; studies overall show improvements in height and weight, without development of glucose intolerance. rhGH may be a useful growth-promoting therapy in children with CF.


Variability in Submaximal Self-Paced Exercise Bouts of Different Intensity and Duration.
Rating of perceived exertion (RPE) as a training-intensity prescription has been extensively used by athletes and coaches. However, individual variability in the physiological response to exercise prescribed using RPE has not been investigated. Twenty well-trained competitive cyclists (male = 18, female = 2, maximum oxygen consumption = 55.07 [11.06] mL·kg-1·min-1) completed 3 exercise trials each consisting of 9 randomized self-paced exercise bouts of either 1, 4, or 8 minutes at RPEs of 9, 13, and 17. Within-athlete variability (WAV) and between-athletes variability (BAV) in power and physiological responses were calculated using the coefficient of variation. Total variability was calculated as the ratio of WAV to BAV. Increased RPEs were associated with higher power, heart rate, work, volume of expired oxygen (VO2), volume of expired carbon dioxide (VCO2), minute ventilation (VE), deoxyhemoglobin (ΔHHb) (P < .001), and lower tissue saturation index (ΔTSI%) and ΔO2Hb (oxyhaemoglobin; P < .001). At an RPE of 9, shorter durations resulted in lower VO2 (P < .05) and decreased ΔTSI%, and the ΔHHb increased as the duration increased (P < .05). At an RPE of 13, shorter durations resulted in lower VO2, VE, and percentage of maximum oxygen consumption (P < .001), as well as higher power, heart rate, ΔHHb (P < .001), and ΔTSI% (P < .05). At an RPE of 17, power (P < .001) and ΔTSI% (P < .05) increased as duration decreased. As intensity and duration increased, WAV and BAV in power, work, heart rate, VO2, VCO2, and VE decreased, and WAV and BAV in near-infrared spectroscopy increased. Self-paced intensity prescriptions of high effort and long duration result in the greatest consistency on both a within- and between-athletes basis.


Anemia as a clinical marker of stable chronic obstructive pulmonary disease in the Korean obstructive lung disease cohort.
Anemia is a major co-morbidity in chronic obstructive pulmonary disease (COPD). However, the mechanism of development for anemia and the impact of anemia on the prognosis of COPD remain poorly understood. Therefore, this study attempted to evaluate the prognostic role of anemia on the clinical course of COPD and investigate the factors linked with the serum hemoglobin level in COPD. We analyzed 407 COPD patients enrolled in the Korean obstructive lung disease (KOLD) cohort at 16 hospitals in Korea recruited over 9 years. Multivariate Cox regression analysis was performed to find independent predictors of survival and multivariate logistic regression analyses were done to find independent factors. Anemic COPD were older with lower body mass index (BMI) (P<0.001), lower serum cholesterol level (P=0.001), lower serum albumin level (P<0.001), and shorter 6-minute walking distance (P=0.046) compared to non-anemic COPD. A multivariate Cox regression analysis revealed that age (P=0.002), BMI (P=0.001), post-bronchodilator forced expiratory volume in 1 second (FEV1) (P=0.007), 6-minute walk distance (P=0.008), anemia (P=0.025) were significant predictors for all-cause mortality. In multivariate regression analysis, older age (P<0.001), female gender (P=0.001), lower BMI (P=0.016), and lower serum albumin level (P<0.001) were independent factors associated with lower serum hemoglobin level. Our data showed that anemia was an independent risk factor for mortality in COPD, and aging, lower serum albumin level, and lower BMI were independent factors associated with lower serum hemoglobin level.


A scoping review of the evidence for efficacy of acupuncture in companion animals.
Acupuncture has become increasingly popular in veterinary medicine. Within the scientific literature there is debate regarding its efficacy. Due to the complex nature of acupuncture, a scoping review was undertaken to identify and categorize the evidence related to acupuncture in companion animals (dogs, cats, and horses). Our search identified 843 relevant citations. Narrative reviews represented the largest proportion of studies (43%). We identified 179 experimental studies and 175 case reports/case series that examined the efficacy of acupuncture. Dogs were the most common subjects in the experimental trials. The most common indication for use was musculoskeletal conditions, and the most commonly evaluated outcome categories among experimental trials were pain and cardiovascular parameters. The limited number of controlled trials and the breadth of indications for use, outcome categories, and types of acupuncture evaluated present challenges for future systematic reviews or meta-analyses. There is a need for high-quality randomized controlled trials addressing the most common clinical uses of acupuncture, and using consistent and clinically relevant outcomes, to inform conclusions regarding the efficacy of acupuncture in companion animals.


[Prevention and pain management in term and preterm infants].
Pain in the neonatal period is frequently experienced by 6-10% of newly born infants, preterm and term, who require neonatal intensive care. Repetitive painful procedures without adequate analgesia provided by the medical staff may bear long-term or even life-long adverse consequences. The use of pharmacological and non-pharmacological modalities in the management of pain may change this undesirable situation. The use of opioid analgesia for very painful procedures and the use of non-opioid medications in combination with opioids are essential. A change in the sensory environment of the sick infant is an important additional analgesic effect. In addition to pain management in the neonatal intensive care units, neonatal circumcision is the most frequent surgical procedure performed in males, and is frequently conducted without appropriate analgesia. The simple available methods of analgesia for neonatal circumcision are discussed and should be employed in order to avoid painful circumcision. Many pediatric medical associations in the developed world consider failure to provide proper routine analgesia for neonatal circumcision to be an unethical and sub-optimal medical practice.


The CB1 cannabinoid receptor mediates glutamatergic synaptic suppression in the hippocampus.
Cannabinoids have profound effects on synaptic function and behavior. Of the two cloned cannabinoid receptors, cannabinoid receptor 1 (CB1) is widely distributed in the CNS and accounts for most of the neurological effects of cannabinoids, while cannabinoid receptor 2 (CB2) expression in the CNS is very limited. The presence of additional receptors [i.e. cannabinoid receptor 3 (CB3)] is suggested by growing evidence of cannabinoid effects that are not mediated by CB1 or CB2. The most direct functional evidence for a CB3 comes from a study in hippocampus where deletion of CB1 was shown to have no effect on cannabinoid-mediated suppression of the excitatory synapse between Schaffer collateral/commissural fibers and CA1 pyramidal cells [Novel cannabinoid-sensitive receptor mediates inhibition of glutamatergic synaptic transmission in the hippocampus. Neuroscience 106:1-4]. In contrast, we report here that in extracellular field recordings, the cannabinoid agonist WIN 55,212-2 (5 microM) had no effect on Schaffer collateral/commissural fiber-CA1 pyramidal cell (Sch-CA1) synaptic transmission in slices from two independently made cannabinoid receptor 1-/- lines [Zimmer et al 1999 and Ledent et al 1999] while strongly suppressing Sch-CA1 synaptic transmission in CB1+/+ mice of the background strains. Also, we observed robust cannabinoid-mediated suppression of the Sch-CA1 synapse in pure C57BL/6 mice, contradicting a recent report that cannabinoid suppression of this synapse is absent in this strain [Hoffman AF, Macgill AM, Smith D, Oz M, Lupica CR (2005) Species and strain differences in the expression of a novel glutamate-modulating cannabinoid receptor in the rodent hippocampus. Eur J Neurosci 22:2387-2391]. Our results strongly suggest that cannabinoid-induced suppression of the Sch-CA1 synapse is mediated by CB1. Non-canonical cannabinoid receptors do not seem to play a major role in inhibiting transmitter release at this synapse.


Effects of oral potassium supplementation on acid-base status and plasma ion concentrations of horses during endurance exercise.
To compare effects of oral supplementation with an experimental potassium-free sodium-abundant electrolyte mixture (EM-K) with that of oral supplementation with commercial potassium-rich mixtures (EM+K) on acid-base status and plasma ion concentrations in horses during an 80-km endurance ride. 46 healthy horses. Blood samples were collected before the ride; at 21-, 37-, 56-, and 80-km inspection points; and during recovery (ie, 30-minute period after the ride). Consumed electrolytes were recorded. Blood was analyzed for pH, PvCO2, and Hct, and plasma was analyzed for Na+, K+, Cl-, Ca2+, Mg2+, lactate, albumin, phosphate, and total protein concentrations. Plasma concentrations of H+ and HCO3-, the strong ion difference (SID), and osmolarity were calculated. 34 (17 EM-K and 17 EM+K treated) horses finished the ride. Potassium intake was 33 g less and Na+ intake was 36 g greater for EM-K-treated horses, compared with EM+K-treated horses. With increasing distance, plasma osmolarity; H+, Na+, K+, Mg2+, phosphate, lactate, total protein, and albumin concentrations; and PvCO2 and Hct were increased in all horses. Plasma HCO3-, Ca2+, and Cl- concentrations were decreased. Plasma H+ concentration was significantly lower in EM-K-treated horses, compared with EM+K-treated horses. Plasma K+ concentrations at the 80-km inspection point and during recovery were significantly less in EM-K-treated horses, compared with EM+K-treated horses. Increases in plasma H+ and K+ concentrations in this endurance ride were moderate and unlikely to contribute to signs of muscle fatigue and hyperexcitability in horses.


Systematic identification of signaling pathways with potential to confer anticancer drug resistance.
Cancer cells can activate diverse signaling pathways to evade the cytotoxic action of drugs. We created and screened a library of barcoded pathway-activating mutant complementary DNAs to identify those that enhanced the survival of cancer cells in the presence of 13 clinically relevant, targeted therapies. We found that activation of the RAS-MAPK (mitogen-activated protein kinase), Notch1, PI3K (phosphoinositide 3-kinase)-mTOR (mechanistic target of rapamycin), and ER (estrogen receptor) signaling pathways often conferred resistance to this selection of drugs. Activation of the Notch1 pathway promoted acquired resistance to tamoxifen (an ER-targeted therapy) in serially passaged breast cancer xenografts in mice, and treating mice with a γ-secretase inhibitor to inhibit Notch signaling restored tamoxifen sensitivity. Markers of Notch1 activity in tumor tissue correlated with resistance to tamoxifen in breast cancer patients. Similarly, activation of Notch1 signaling promoted acquired resistance to MAPK inhibitors in BRAF(V600E) melanoma cells in culture, and the abundance of Notch1 pathway markers was increased in tumors from a subset of melanoma patients. Thus, Notch1 signaling may be a therapeutic target in some drug-resistant breast cancers and melanomas. Additionally, multiple resistance pathways were activated in melanoma cell lines with intrinsic resistance to MAPK inhibitors, and simultaneous inhibition of these pathways synergistically induced drug sensitivity. These data illustrate the potential for systematic identification of the signaling pathways controlling drug resistance that could inform clinical strategies and drug development for multiple types of cancer. This approach may also be used to advance clinical options in other disease contexts.


Genomic landscape of extended-spectrum β-lactamase resistance in Escherichia coli from an urban African setting.
Efforts to treat Escherichia coli infections are increasingly being compromised by the rapid, global spread of antimicrobial resistance (AMR). Whilst AMR in E. coli has been extensively investigated in resource-rich settings, in sub-Saharan Africa molecular patterns of AMR are not well described. In this study, we have begun to explore the population structure and molecular determinants of AMR amongst E. coli isolates from Malawi. Ninety-four E. coli isolates from patients admitted to Queen's Hospital, Malawi, were whole-genome sequenced. The isolates were selected on the basis of diversity of phenotypic resistance profiles and clinical source of isolation (blood, CSF and rectal swab). Sequence data were analysed using comparative genomics and phylogenetics. Our results revealed the presence of five clades, which were strongly associated with E. coli phylogroups A, B1, B2, D and F. We identified 43 multilocus STs, of which ST131 (14.9%) and ST12 (9.6%) were the most common. We identified 25 AMR genes. The most common ESBL gene was bla CTX-M-15 and it was present in all five phylogroups and 11 STs, and most commonly detected in ST391 (4/4 isolates), ST648 (3/3 isolates) and ST131 [3/14 (21.4%) isolates]. This study has revealed a high diversity of lineages associated with AMR, including ESBL and fluoroquinolone resistance, in Malawi. The data highlight the value of longitudinal bacteraemia surveillance coupled with detailed molecular epidemiology in all settings, including low-income settings, in describing the global epidemiology of ESBL resistance.


Epidemiology of Autosomal Dominant Polycystic Kidney Disease in Olmsted County.
The prevalence of autosomal dominant polycystic kidney disease (ADPKD) remains controversial. Incidence rates in Olmsted County, Minnesota, during 1935-1980 were previously reported. The current work extends this study to 2016. The Rochester Epidemiology Project and radiology databases of Mayo Clinic and Olmsted Medical Center (healthcare providers for Olmsted County) were searched to identify all subjects meeting diagnostic criteria for definite, likely, and possible ADPKD. Annual incidence rates were calculated using incident cases during 1980-2016 as numerator and age- and sex-specific estimates of the population of Olmsted County as denominator. Point prevalence was calculated using prevalence cases as numerator and age- and sex-specific estimates of the population of Olmsted County on January 1, 2010 as denominator. Survival curves from the time of diagnosis were compared with expected survival of the Minnesota population. The age- and sex-adjusted annual incidence of definite and likely ADPKD diagnosis during 1980-2016 was 3.06 (95% CI, 2.52 to 3.60) per 100,000 person-years, which is 2.2 times higher than that previously reported for 1935-1980 (1.38 per 100,000 person-years). The point prevalence of definite or likely ADPKD on January 1, 2010 was 68 (95% CI, 53.90 to 82.13) per 100,000 population. Much higher incidence rates and point prevalence were obtained when possible ADPKD cases were included. Contrary to the previous Olmsted County study, patient survival in this study was not different from that in the general population. The point prevalence of definite and likely ADPKD observed in this study is higher than those reported in the literature, but lower than genetic prevalence based on estimates of disease expectancy or on analysis of large population-sequencing databases.


Gamma Knife Central Lateral Thalamotomy for Chronic Neuropathic Pain: A Single-Center, Retrospective Study.
Chronic neuropathic pain can be severely disabling and is difficult to treat. The medial thalamus is believed to be involved in the processing of the affective-motivational dimension of pain, and lesioning of the medial thalamus has been used as a potential treatment for neuropathic pain. Within the medial thalamus, the central lateral nucleus has been considered as a target for stereotactic lesioning. To study the safety and efficacy of central lateral thalamotomy using Gamma Knife radiosurgery (GKRS) for the treatment of neuropathic pain. We retrospectively reviewed all patients with neuropathic pain who underwent central lateral thalamotomy using GKRS. We report on patient outcomes, including changes in pain scores using the Numeric Pain Rating Scale and Barrow Neurological Institute pain intensity score, and adverse events. Twenty-one patients underwent central lateral thalamotomy using GKRS between 2014 and 2021. Meaningful pain reduction occurred in 12 patients (57%) after a median period of 3 months and persisted in 7 patients (33%) at the last follow-up (the median follow-up was 28 months). Rates of pain reduction at 1, 2, 3, and 5 years were 48%, 48%, 19%, and 19%, respectively. Meaningful pain reduction occurred more frequently in patients with trigeminal deafferentation pain compared with all other patients (P = .009). No patient had treatment-related adverse events. Central lateral thalamotomy using GKRS is remarkably safe. Pain reduction after this procedure occurs in a subset of patients and is more frequent in those with trigeminal deafferentation pain; however, pain recurs frequently over time.


'A mastectomy for something that wasn't even truly invasive cancer'. Women's understandings of having a mastectomy for screen-detected DCIS: a qualitative study.
To explore women's understandings of having a mastectomy for screen-detected ductal carcinoma in situ (DCIS). Participants recruited throughout the United Kingdom and interviewed in their own homes by an anthropologist. Qualitative study using semi-structured interviews and thematic analysis. Thirty-five women with screen-detected DCIS were interviewed, of whom twenty had a mastectomy. A qualitative thematic analysis of women's understandings of having a mastectomy for DCIS identified four key themes: understandings of routine breast screening; uncertainty about DCIS and its natural progression; uncertainty about whether a mastectomy is justified for DCIS; information gaps and treatment decisions. Women were often concerned that a mastectomy for screen-detected DCIS was a 'drastic' treatment for an asymptomatic, precancerous condition of which they had been previously unaware. Some questioned why they were treated with such urgency, even suspecting that their clinicians were responding to targets. Given the uncertainties about DCIS and its complexity, it is important that women have the information they need to make treatment decisions. Better information about the uncertainties and the rationale for using mastectomy as a treatment may help women to make better informed choices and feel more comfortable about their decisions.


Reactive species formed on proteins exposed to singlet oxygen.
Singlet oxygen ((1)O(2)) is believed to be generated in biological systems by a range of endogenous processes (e.g. enzymatic and chemical reactions) and exogenous stimuli (e.g. UV or visible light in the presence of a sensitiser). Kinetic data is consistent with proteins being a major target for (1)O(2), with damage occurring preferentially at Trp, His, Tyr, Met, and Cys side-chains. Reaction with each of these residues gives rise to further reactive species. In the case of Trp and Tyr, initial poorly characterised endoperoxides are believed to undergo ring-opening reactions to give hydroperoxides, which can be reduced to the corresponding alcohols; other products arising from radical intermediates can also be generated, particularly in the presence of UV light and metal ions. With His side-chains, poorly characterised peroxides are also formed. Reaction with Met and Cys has been proposed to occur via zwitterionic peroxy intermediates. Peroxides are also generated on isolated proteins, and protein within intact cells, via(1)O(2)-mediated reactions. The peroxides formed on Trp, Tyr, and His peptides, as well as on proteins, have been shown to induce damage to other targets, with molecular oxidation of thiol residues an important reaction. This can result in the inactivation of cellular enzymes and the oxidation of other biological targets. Protein cross-linking and aggregation can also be induced by reactive species formed on photo-oxidised proteins, though the nature of the species that participate in such reactions is poorly understood. These secondary reactions, and particularly those involving hydroperoxides, may play a key role in the induction of secondary damage (bystander effects) in systems subject to photo-oxidation.


Transcriptomics resources of human tissues and organs.
Quantifying the differential expression of genes in various human organs, tissues, and cell types is vital to understand human physiology and disease. Recently, several large-scale transcriptomics studies have analyzed the expression of protein-coding genes across tissues. These datasets provide a framework for defining the molecular constituents of the human body as well as for generating comprehensive lists of proteins expressed across tissues or in a tissue-restricted manner. Here, we review publicly available human transcriptome resources and discuss body-wide data from independent genome-wide transcriptome analyses of different tissues. Gene expression measurements from these independent datasets, generated using samples from fresh frozen surgical specimens and postmortem tissues, are consistent. Overall, the different genome-wide analyses support a distribution in which many proteins are found in all tissues and relatively few in a tissue-restricted manner. Moreover, we discuss the applications of publicly available omics data for building genome-scale metabolic models, used for analyzing cell and tissue functions both in physiological and in disease contexts.


An automated screening system for tuberculosis.
Automated screening systems are commonly used to detect some agent in a sample and take a global decision about the subject (e.g., ill/healthy) based on these detections. We propose a Bayesian methodology for taking decisions in (sequential) screening systems that considers the false alarm rate of the detector. Our approach assesses the quality of its decisions and provides lower bounds on the achievable performance of the screening system from the training data. In addition, we develop a complete screening system for sputum smears in tuberculosis diagnosis, and show, using a real-world database, the advantages of the proposed framework when compared to the commonly used count detections and threshold approach.


Exercise physiology of normal development, sex differences, and aging.
The scientific study of human development has evolved from studies of children to studies of the full lifespan. Many physiological changes occur throughout the lifespan and unique changes occur during normal development compared to healthy aging. An enlarging body of data supports the idea that there exist critical periods of development during which physiological perturbations to the internal milieu (e.g., disease or physical activity) can alter the overall programming of developmental processes. Although different physiological functions decline with age with widely varying rates, the aging changes accumulated throughout the physiological systems reduce the capacity to cope with the stress and maintain homeostasis. The understanding of this process of development and aging is complicated by important physiologic sex differences with regard to nearly all physiological systems. Regular physical activity can favorably modulate this developmental and aging process and can have important health benefits. However, a physically inactive lifestyle can markedly impair normal development and lead to numerous diseases. Life-long physical activity is essential for preserving or delaying the onset of functional disability and chronic cardiovascular and metabolic diseases.


Chaperonins facilitate KNOTTED1 cell-to-cell trafficking and stem cell function.
Cell-to-cell communication in plants includes the selective trafficking of transcription factors and other signals through plasmodesmata. The KNOTTED1 (KN1) homeobox (KNOX) family transcription factors, which use this pathway, are essential for stem cell establishment and/or maintenance. Here we show that KN1 trafficking requires the chaperonin complex, which belongs to a group of cytosolic chaperones that fold specific substrate proteins. Genetic and physical interaction data show a functional relevance for chaperonins in KNOX family-dependent stem cell maintenance. Furthermore, tissue-specific complementation assays indicate a mechanistic basis for chaperonin function during the posttranslocational refolding process. Our study shows that chaperonins are essential for the cell-to-cell trafficking of a subset of mobile transcription factors and demonstrates the importance of chaperonin-dependent protein trafficking for plant stem cell function.


Complementary and alternative medicine use by osteoporosis clinic patients.
We describe complementary and alternative medicine use (CAM) in 360 patients attending osteoporosis clinics. Of these patients, 57% were CAM users. Predictors of CAM use included lower mental quality of life, younger age and higher education. Less than half of CAM use was disclosed to physicians, despite potential adverse interactions. The prevalence of complementary and alternative medicine (CAM) use in osteoporosis clinics is not known. The objective of this study was to describe the pattern of CAM use in this population. We performed a cross-sectional study of 360 patients attending academic osteoporosis clinics in Toronto, Canada in 2001. Subjects completed a self-administered questionnaire on CAM use. Health-related quality of life (HQL) was measured with the Short-Form 36v2. Comparative statistics and logistic regression were performed to identify sociodemographic, HQL and clinical correlates of CAM use. More than 80% of participants were women, Caucasian and had at least a high school education. Of subjects, 57% used CAM in the previous year. Only 44% of CAM use was disclosed to a medical doctor. CAM users and non-users did not differ in clinical characteristics such as bone mineral density, level of comorbidity and fracture history. In univariate analysis, CAM users were less satisfied with conventional medicine. However, when we explored patient satisfaction, comorbidities and sociodemographic as predictors for CAM use, the multivariable analyses showed that lower mental HQL, younger age, and post-secondary education were the only significant predictors. We identified 35 cases in which the utilization of CAM supplements could possibly exacerbate existing medical conditions. Patients attending osteoporosis clinics frequently use CAM. Conceptually, the predictors of use identified in this study may fit into a socio-behavioral model that helps explain why people turn to CAM. Physicians may need to elicit a history of CAM use more vigilantly so as to better screen for possible adverse clinical interactions.


Lewy Body Dementia: The Under-Recognized but Common FOE.
After Alzheimer's disease, Lewy body dementia (LBD) is the most prevalent progressive dementia of the many cognitive disorders wreaking unspeakable havoc on millions of lives. LBD is characterized by the presence of Lewy bodies, which are abnormal aggregates of a protein called alpha-synuclein, and are found in regions of the brain that regulate behavior, memory, movement, and personality. Many of the symptoms of Alzheimer's, Parkinson's, and LBD overlap, but LBD is more difficult to diagnose. Underdiagnosis is just part of the reason why LBD is unknown to the public and many health-care providers, and why funding for research lags far behind that for almost every other cognitive disorder.


Artefacts in continuous ECG recordings--provoking and preventing manoeuvres.
A systematic estimation of the effects of some clinically important artefact provoking and artefact-preventing manoeuvres. A test protocol for the evaluation of technical modifications of continuous ECG recordings was tested in 17 patients. The programme comprised ECG recordings during five artefact-provoking manoeuvres (slight shaking of the ECG cables, rotating shoulders, slight electrode touching, washing, teeth-brushing) and two simple artefact-preventing manoeuvres (taping ECG cables and covering electrodes with paper cups). The artefact-provoking manoeuvres induced a substantial increase in artefactual ECG. The artefact-preventing manoeuvres only incompletely prevented this increase. There is a great need of technical improvements to reduce the distortion of ECG by artefacts. The test protocol developed by us exposes a broad spectrum of different categories of ECG qualities and is therefore suitable for evaluating technical improvements concerning artefactual ECG.


Features of mammalian microRNA promoters emerge from polymerase II chromatin immunoprecipitation data.
MicroRNAs (miRNAs) are short, non-coding RNA regulators of protein coding genes. miRNAs play a very important role in diverse biological processes and various diseases. Many algorithms are able to predict miRNA genes and their targets, but their transcription regulation is still under investigation. It is generally believed that intragenic miRNAs (located in introns or exons of protein coding genes) are co-transcribed with their host genes and most intergenic miRNAs transcribed from their own RNA polymerase II (Pol II) promoter. However, the length of the primary transcripts and promoter organization is currently unknown. We performed Pol II chromatin immunoprecipitation (ChIP)-chip using a custom array surrounding regions of known miRNA genes. To identify the true core transcription start sites of the miRNA genes we developed a new tool (CPPP). We showed that miRNA genes can be transcribed from promoters located several kilobases away and that their promoters share the same general features as those of protein coding genes. Finally, we found evidence that as many as 26% of the intragenic miRNAs may be transcribed from their own unique promoters. miRNA promoters have similar features to those of protein coding genes, but miRNA transcript organization is more complex.


Regulation of aflatoxin B1-metabolizing aldehyde reductase and glutathione S-transferase by chemoprotectors.
Ingestion of aflatoxin B1 (AFB1) represents a major risk factor in the aetiology of human hepatocellular carcinoma. In the rat, the harmful effects of AFB1 can be prevented by the administration of certain drugs which induce hepatic detoxification enzymes. We have previously shown that treatment of rats with the chemoprotector ethoxyquin (EQ) results in a marked increase in expression of the Alpha-class glutathione S-transferase (GST) Yc2 subunit which has high activity towards AFB1-8,9-epoxide [Hayes, Judah, McLellan, Kerr, Peacock and Neal (1991) Biochem. J. 279, 385-398]. To allow an assessment of whether the increased expression of GST Yc2 represents a general adaptive resistance mechanism to chemical stress, that is invoked by both chemoprotectors and carcinogens, we have examined the effects of EQ, butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), phenobarbital (PB), AFB1, 3-methylcholanthrene (3-MC) and clofibrate on the AFB1-glutathione-conjugating activity and the GST subunit levels in rat liver. In addition, the effect of these drugs on the hepatic levels of an aldehyde reductase (AFB1-AR) that metabolizes the cytotoxic dialdehydic form of AFB1 has been studied as this enzyme also appears to be important in chemoprotection. Administration of the antioxidants EQ, BHA or BHT, as well as PB, led to a marked increase in levels of the GST Yc2 subunit in rat liver, and this increase coincided with a substantial rise in the GST activity towards AFB1-8,9-epoxide; neither AFB1, 3-MC nor clofibrate caused induction of Yc2 or any of the GST subunits examined. Among the xenobiotics studied, EQ was found to be the most effective inducing agent for the Yc2 subunit as well as Yc1, Yb1 and Yf. However, PB was equally as effective as EQ in increasing levels of the Ya-type subunits, although it was not found to be as potent an inducer of the other GST subunits, including Yc2. In addition to induction of GST, EQ caused a substantial increase in the hepatic content of AFB1-AR. Both BHA and BHT were also able to induce this enzyme but, by contrast, PB was found to be a poor inducer of AFB1-AR. AFB1, 3-MC and clofibrate were unable to serve as inducers of this reductase. The presence of Alpha-class GST, including the Yc2 subunit, was examined in various rat tissues. Constitutive expression of Yc2 was found in the epididymis at levels comparable with that observed in the liver from EQ-treated rats.(ABSTRACT TRUNCATED AT 400 WORDS)


Transplantation of human hairy cell leukemia in radiation-preconditioned nude mice: characterization of the model by histological, histochemical, phenotypic, and tumor kinetic studies.
Two cell lines (EH and HK) with hairy cell leukemia (HCL) immunophenotypes were recently derived from two HCL patients. Both cell lines were transplanted subcutaneously (2 x 10(5) or 2 x 10(6)/mouse) in male BALB/c nu/nu mice (n = 128) with a 97% success rate when coimplanted with nonproliferative HT-1080 fibrosarcoma cells (2 x 10(6)/mouse) in recipients preconditioned with total-body irradiation (200 R weekly for 3 weeks). Tumors appeared five to ten days postimplant and reached up to 25% of body weight after a mean survival of 8 weeks (range, 30 to 90 days). Tumor histology suggested large cell lymphoma. Cytochemically and immunophenotypically, tumor cells were indistinguishable from their parent cells. Species and lineage derivation of tumor cells was confirmed by antibody probes against the mouse histocompatibility antigen H-2, human T and B lymphocyte antigens, and the HCL-associated common chronic lymphocytic leukemia antigen (cCLLa). In order of decreasing frequency, metastases occurred in the spleen, lungs, pleura, lymph nodes, bone marrow, and kidneys. Up to 12% of circulating lymphoid cells in mice were cCLLa-positive, which suggested hematogenous tumor dissemination. This HCL xenotransplantation model might be useful in preclinical studies for exploring novel experimental therapies for the management of human HCL.


Modelling the relative abundance of the primary African vectors of malaria before and after the implementation of indoor, insecticide-based vector control.
Malaria remains a heavy burden across sub-Saharan Africa where transmission is maintained by some of the world's most efficient vectors. Indoor insecticide-based control measures have significantly reduced transmission, yet elimination remains a distant target. Knowing the relative abundance of the primary vector species can provide transmission models with much needed information to guide targeted control measures. Moreover, understanding how existing interventions are impacting on these relative abundances highlights where alternative control (e.g., larval source management) is needed. Using the habitat suitability probabilities generated by predictive species distribution models combined with data collated from the literature, a multinomial generalized additive model was applied to produce relative abundance estimates for Anopheles arabiensis, Anopheles funestus and Anopheles gambiae/Anopheles coluzzii. Using pre- and post-intervention abundance data, estimates of the effect of indoor insecticide-based interventions on these relative abundances were made and are illustrated in post-intervention maps. Conditional effect plots and relative abundance maps illustrate the individual species' predicted habitat suitability and how they interact when in sympatry. Anopheles arabiensis and An. funestus show an affinity in habitat preference at the expense of An. gambiae/An. coluzzii, whereas increasing habitat suitability for An. gambiae/An. coluzzii is conversely less suitable for An. arabiensis but has little effect on An. funestus. Indoor insecticide-based interventions had a negative impact on the relative abundance of An. funestus, and a lesser effect on An. arabiensis. Indoor residual spraying had the greatest impact on the relative abundance of An. funestus, and a lesser effect on An. gambiae/An. coluzzii. Insecticide-treated bed nets reduced the relative abundance of both species equally. These results do not indicate changes in the absolute abundance of these species, which may be reduced for all species overall. The maps presented here highlight the interactions between the primary vector species in sub-Saharan Africa and demonstrate that An. funestus is more susceptible to certain indoor-based insecticide interventions than An. gambiae/An. coluzzii, which in turn, is more susceptible than An. arabiensis. This may provide An. arabiensis with a competitive advantage where it is found in sympatry with other more endophilic vectors, and potentially increase the need for outdoor-based vector interventions to deal with any residual transmission barring the way to malaria elimination.


Child Poverty and the Promise of Human Capacity: Childhood as a Foundation for Healthy Aging.
The effect of child poverty and related early life experiences on adult health outcomes and patterns of aging has become a central focus of child health research and advocacy. In this article a critical review of this proliferating literature and its relevance to child health programs and policy are presented. This literature review focused on evidence of the influence of child poverty on the major contributors to adult morbidity and mortality in the United States, the mechanisms by which these associations operate, and the implications for reforming child health programs and policies. Strong and varied evidence base documents the effect of child poverty and related early life experiences and exposures on the major threats to adult health and healthy aging. Studies using a variety of methodologies, including longitudinal and cross-sectional strategies, have reported significant findings regarding cardiovascular disorders, obesity and diabetes, certain cancers, mental health conditions, osteoporosis and fractures, and possibly dementia. These relationships can operate through alterations in fetal and infant development, stress reactivity and inflammation, the development of adverse health behaviors, the conveyance of child chronic illness into adulthood, and inadequate access to effective interventions in childhood. Although the reviewed studies document meaningful relationships between child poverty and adult outcomes, they also reveal that poverty, experiences, and behaviors in adulthood make important contributions to adult health and aging. There is strong evidence that poverty in childhood contributes significantly to adult health. Changes in the content, financing, and advocacy of current child health programs will be required to address the childhood influences on adult health and disease. Policy reforms that reduce child poverty and mitigate its developmental effects must be integrated into broader initiatives and advocacy that also attend to the health and well-being of adults.


Systematic versus opportunistic risk assessment for the primary prevention of cardiovascular disease.
Screening programmes can potentially identify people at high cardiovascular risk and reduce cardiovascular disease (CVD) morbidity and mortality. However, there is currently not enough evidence showing clear clinical or economic benefits of systematic screening-like programmes over the widely practised opportunistic risk assessment of CVD in primary care settings. The primary objective of this review was to assess the effectiveness, costs and adverse effects of systematic risk assessment compared to opportunistic risk assessment for the primary prevention of CVD. We searched the Cochrane Central Register of Controlled Trials (CENTRAL) on the Cochrane Library, MEDLINE, EMBASE on 30 January 2015, and Web of Science Core Collection and additional databases on the Cochrane Library on 4 December 2014. We also searched two clinical trial registers and checked reference lists of relevant articles. We applied no language restrictions. We selected randomised controlled trials (RCTs) that assessed the effects of systematic risk assessment, defined as a screening-like programme involving a predetermined selection process of people, compared with opportunistic risk assessment which ranged from no risk assessment at all to incentivised case finding of CVD and related risk factors. Participants included healthy adults from the general population, including those who are at risk of CVD. Two review authors independently selected studies. One review author extracted data and assessed them for risk of bias and a second checked them. We assessed evidence quality using the GRADE approach and present this in a 'Summary of findings' table. Nine completed RCTs met the inclusion criteria, of which four were cluster-randomised. We also identified five ongoing trials. The included studies had a high or unclear risk of bias, and the GRADE ratings of overall quality were low or very low. The length of follow-up varied from one year in four studies, three years in one study, five or six years in two studies, and ten years in two studies. Eight studies recruited participants from the general population, although there were differences in the age ranges targeted. One study recruited family members of cardiac patients (high risk assessment). There were considerable differences between the studies in the interventions received by the intervention and control groups. There was insufficient evidence to stratify by the types of risk assessment approaches.Limited data were available on all-cause mortality (risk ratio (RR) 0.97, 95% confidence interval (CI) 0.92 to 1.02; 3 studies,103,571 participants, I² = 0%; low-quality evidence) and cardiovascular mortality (RR 1.00, 95% CI 0.90 to 1.11; 2 studies, 43,955 participants, I² = 0%), and suggest that screening has no effect on these outcomes. Data were also limited for combined non-fatal endpoints; overall, evidence indicates no difference in total coronary heart disease (RR 1.01, 95% CI 0.95 to 1.07; 4 studies, 5 comparisons, 110,168 participants, I² = 0%; low-quality evidence), non-fatal coronary heart disease (RR 0.98, 95% CI 0.89 to 1.09; 2 studies, 43,955 participants, I² = 39%), total stroke (RR 0.99, 95% CI 0.90 to 1.10; 2 studies, 79,631 participants, I² = 0%, low-quality evidence), and non-fatal stroke (RR 1.17, 95% CI 0.94 to 1.47; 1 study, 20,015 participants).Overall, systematic risk assessment appears to result in lower total cholesterol levels (mean difference (MD) -0.11 mmol/l, 95% CI -0.17 to -0.04, 6 studies, 7 comparisons, 12,591 participants, I² = 57%; very low-quality evidence), lower systolic blood pressure (MD -3.05 mmHg, 95% CI -4.84 to -1.25, 6 studies, 7 comparisons, 12,591 participants, I² = 82%; very low-quality evidence) and lower diastolic blood pressure (MD -1.34 mmHg, 95% CI -1.76 to -0.93, 6 studies, 7 comparisons, 12,591 participants, I² = 0%; low-quality evidence). One study assessed adverse effects and found no difference in psychological distress at five years (1126 participants). The results are limited by the heterogeneity between trials in terms of participants recruited, interventions and duration of follow-up. Limited data suggest that systematic risk assessment for CVD has no statistically significant effects on clinical endpoints. There is limited evidence to suggest that CVD systematic risk assessment may have some favourable effects on cardiovascular risk factors. The completion of the five ongoing trials will add to the evidence base.


Regional dynamics of amyloid-β deposition in healthy elderly, mild cognitive impairment and Alzheimer's disease: a voxelwise PiB-PET longitudinal study.
Amyloid-β deposition in Alzheimer's disease is thought to start while individuals are still cognitively unimpaired and it is hypothesized that after an early phase of fast accumulation, a plateau is reached by the time of cognitive decline. However, few longitudinal Pittsburgh compound B-positron emission tomography studies have tested this hypothesis, and with conflicting results. The purpose of this work is to further our understanding of the dynamics of amyloid-β deposition in a large longitudinal cohort. A total of 32 patients with Alzheimer's disease, 49 subjects with mild cognitive impairment and 103 healthy controls underwent two Pittsburgh compound B-positron emission tomography scans 18 months apart. For each participant, a parametric map of Pittsburgh compound B-positron emission tomography rate of change was created [(follow-up scan - baseline scan)/follow-up duration] and entered in a voxelwise three-way analysis of covariance, with clinical status (healthy controls, mild cognitive impairment or Alzheimer's disease), disease progression (clinical conversion from healthy controls to mild cognitive impairment or Alzheimer's disease, or from mild cognitive impairment to Alzheimer's disease) and Pittsburgh compound B status (positive versus negative) as independent factors. Only a significant effect of the Pittsburgh compound B status was found: both Pittsburgh compound B-positive and -negative subjects showed a significant increase in amyloid-β deposition, with this increase being significantly higher in Pittsburgh compound B-positive individuals. This finding suggests either that Pittsburgh compound B-negative individuals have slower rates of amyloid-β accumulation than positive, or that the proportion of individuals showing significant increase in amyloid-β deposition, termed 'Pittsburgh compound B accumulators', is higher within the Pittsburgh compound B-positive group than within the Pittsburgh compound B-negative group. The bimodal distribution of the individual rates of neocortical amyloid-β accumulation observed support the existence of 'Pittsburgh compound B non-accumulators' and 'Pittsburgh compound B accumulators' and different clustering analyses led to a consistent threshold to separate these two subgroups (0.014-0.022 standardized uptake value ratio(pons)/year). The voxelwise three-way analysis of covariance was thus recomputed with the 'Pittsburgh compound B accumulators' only and the results were almost unchanged, with the Pittsburgh compound B-positive group showing higher accumulation than the Pittsburgh compound B-negative group. Finally, a significant negative correlation was found between Pittsburgh compound B rate of change and Pittsburgh compound B baseline burden, but only in the Pittsburgh compound B-positive group (r= -0.24; P=0.025). Higher rates of amyloid-β deposition are associated with higher amyloid-β burden suggesting that amyloid-β deposition does not reach a plateau when cognitive impairments manifest but is instead an ongoing process present even at the Alzheimer's disease stage. amyloid-β accumulation also seems to slow down at the latest stages of the process, i.e. in participants with the highest amyloid burden. Furthermore, this study identified the existence of Pittsburgh compound 'accumulators' and 'non-accumulators', notably within the Pittsburgh compound B-negative group, which may be a relevant concept for future studies.


Enhanced dye-sensitized solar cell photocurrent and efficiency using a Y-shaped, pyrazine-containing heteroaromatic sensitizer linkage.
A new sensitizer motif for dye sensitized solar cells (DSSC) has been developed. A heteroaromatic moiety containing a pyrazine ring links two porphyrin chromophores to the metal oxide surface via two carboxylic acid attachment groups. A test DSSC sensitized with the new molecule was 3.5 times more efficient than a similar cell sensitized by a single porphyrin model compound. The open circuit photovoltage was increased by a modest factor of 1.3, but the photocurrent increased by a factor of 2.7. Most of the increase is attributed to a reduced rate of charge recombination of the charge separated state formed by photoinduced electron transfer from the excited sensitizer to the TiO2, although some of the difference is due to increased light absorption resulting from more dye on the photoanode. Increased light absorption due to the pyrazine-containing group may also play a role. The design illustrated here could also be used to link complementary sensitizers or antenna moieties in order to increase spectral coverage.


Systematic review and meta-analysis of algorithms used to identify drug-induced liver injury (DILI) in health record databases.
Drug induced liver injury (DILI) is largely underreported, leading to underestimation of its burden. Electronic detection of DILI in healthcare databases shows promise to overcome the issues of spontaneous reporting. The performance of detection algorithms may vary because of inconsistent DILI definition and detection criteria. We performed a systematic review and meta-analysis to identify the DILI detection criteria used in health record databases and determine the performance characteristics of the detection algorithms. We searched PubMed, EMBASE and Scopus for studies that utilized laboratory threshold criteria to identify DILI cases. Validation studies were included in the meta-analysis. Data were abstracted using standardized forms and quality was assessed using modified Quality Assessment of Diagnostic Accuracy Studies 2 (QUADAS-2) criteria. We evaluate the performance characteristics of the detection algorithm by obtaining the pooled estimate of the positive predictive value (PPV) assuming a random effects model. A total of 29 studies met the inclusion criteria for the systematic review; 25 of these studies (n = 35 948) had PPV estimates for performing the meta-analysis. The PPV of DILI detection algorithms was low, ranging from 1.0% to 40.2%, with a pooled estimate of 14.6% (95% CI 10.7-18.9). Algorithms that performed better had prespecified exclusion diagnoses as well as drugs of interest to minimize false positives. Algorithm performance varied with different case definitions of DILI attributed to different laboratory threshold criteria, diagnosis codes, and study drugs.


Support for linkage of familial combined hyperlipidemia to chromosome 1q21-q23 in Chinese and German families.
We examined familial combined hyperlipidemia (FCHL) families from nonisolated regions in Germany and China to see if we could corroborate support for a chromosome 1q FCHL locus in more general populations. We recruited 24 German families with 137 members, 92 of whom met the criteria of affected in terms of the low density lipoprotein (LDL) and triglyceride levels in excess of the 90th percentile for age and gender. In China, we recruited 12 families with a total of 81 members. All affected persons had total cholesterol concentrations >240 mg/dl and triglyceride concentrations >250 mg/dl. We examined the markers APOA2, D1S1677, D1S104, D1S194, D1S426, and D1S196. Two-point linkage analysis allowing for heterogeneity gave a maximum linkage of disorder score (HLOD) of 2.60 right over D1S194, estimating the proportion of linked families at 36%. This marker is adjacent to D1S104. The evidence for linkage was roughly the same both in the German (HLOD 1.40) and Chinese families (HLOD 1.52). Marker D1S194 is close to the retinoid X receptor (RXR) gene locus, which was found to be linked to triglyceride levels in an earlier twin study from our laboratory. We interpret our observations as encouraging support for the recent findings indicating the presence of a gene for FCHL on chromosome 1q. Furthermore, since DIS194 is adjacent to the gene for the RXR, we suggest that RXR is an attractive candidate for involvement in FCHL.


Aberrant cGMP signaling persists during recovery in mice with oxygen-induced pulmonary hypertension.
Bronchopulmonary dysplasia (BPD), a common complication of preterm birth, is associated with pulmonary hypertension (PH) in 25% of infants with moderate to severe BPD. Neonatal mice exposed to hyperoxia for 14d develop lung disease similar to BPD, with evidence of associated PH. The cyclic guanosine monophosphate (cGMP) signaling pathway has not been well studied in BPD-associated PH. In addition, there is little data about the natural history of hyperoxia-induced PH in mice or the utility of phosphodiesterase-5 (PDE5) inhibition in established disease. C57BL/6 mice were placed in room air or 75% O2 within 24h of birth for 14d, followed by recovery in room air for an additional 7 days (21d). Additional pups were treated with either vehicle or sildenafil for 7d during room air recovery. Mean alveolar area, pulmonary artery (PA) medial wall thickness (MWT), RVH, and vessel density were evaluated at 21d. PA protein from 21d animals was analyzed for soluble guanylate cyclase (sGC) activity, PDE5 activity, and cGMP levels. Neonatal hyperoxia exposure results in persistent alveolar simplification, RVH, decreased vessel density, increased MWT, and disrupted cGMP signaling despite a period of room air recovery. Delayed treatment with sildenafil during room air recovery is associated with improved RVH and decreased PA PDE5 activity, but does not have significant effects on alveolar simplification, PA remodeling, or vessel density. These data are consistent with clinical studies suggesting inconsistent effects of sildenafil treatment in infants with BPD-associated PH.


Voltage opens unopposed gap junction hemichannels formed by a connexin 32 mutant associated with X-linked Charcot-Marie-Tooth disease.
The X-linked form of Charcot-Marie-Tooth disease (CMTX) is an inherited peripheral neuropathy that arises in patients with mutations in the gene encoding the gap junction protein connexin 32 (Cx32), which is expressed by Schwann cells. We recently showed that Cx32 containing the CMTX-associated mutation, Ser-85-Cys (S85C), forms functional cell-cell channels in paired Xenopus oocytes. Here, we describe that this mutant connexin also shows increased opening of hemichannels in nonjunctional surface membrane. Open hemichannels may damage the cells through loss of ionic gradients and small metabolites and increased influx of Ca(2+), and provide a mechanism by which this and other mutant forms of Cx32 may damage cells in which they are expressed. Evidence for open hemichannels includes: (i) oocytes expressing the Cx32(S85C) mutant show greatly increased conductance at inside positive potentials, significantly larger than in oocytes expressing wild-type Cx32 (Cx32WT); and (ii) the induced currents are similar to those previously described for several other connexin hemichannels, and exhibit slowly developing increases with increasing levels of positivity and reversible reduction when intracellular pH is decreased or extracellular Ca(2+) concentration is increased. Although increased currents are seen, oocytes expressing Cx32(S85C) have lower levels of the protein in the surface and in total homogenates than do oocytes expressing Cx32WT; thus, under the conditions examined here, hemichannels in the surface membrane formed of the Cx32(S85C) mutant have a higher open probability than hemichannels formed of Cx32WT. This increase in functional hemichannels may damage Schwann cells and ultimately lead to loss of function in peripheral nerves of patients harboring this mutation.


The linkage between the four-step binding of oxygen and the binding of heterotropic anionic ligands in hemoglobin.
The linkage between the four-step binding of oxygen and the binding of heterotropic anionic ligands in hemoglobin was investigated by accurately measuring and analyzing the oxygen equilibrium curves of human adult hemoglobin in the presence and absence of various concentrations of one or two of the following materials: chloride (Cl-), 2,3-diphosphoglycerate (DPG), and inositol hexaphosphate (IHP). Each equilibrium curve was analyzed according to the Adair equation to evaluate the four-step oxygen equilibrium constants (Adair constants) and the median oxygen pressure. The binding constants of the anions for the molecular species of hemoglobin carrying j oxygen molecules, Hb(O2)j(j=0,1,...,4), were evaluated from the dependences of the Adair constants and the median oxygen pressure on the anion concentration by introducing a model which takes the competitive binding of Cl- and DPG or IHP into account. Assumptions made in the model are: (a) the hemoglobin molecule has two oxygen-linked binding sites for Cl- which are equivalent and independent and (b) no Cl- can be bound to hemoglobin to which DPG or IHP is already bound and vice versa. Thus, we could obtain values for the intrinsic binding constants of Cl- and DPG, i.e., the constants in the absence of other competitive anions. For IHP, only the binding constants and apparent binding constants for Hb and Hb(O2)2 were obtained. Values of the Cl- binding constants and apparent binding constants for DPG and IHP, i.e., the binding constants in the presence of Cl- for Hb and Hb(O2)4, were in reasonable agreement with literature values. From the binding constants we calculated anion binding curves for Hb(O2)j(J=0,1,...,4), the number of anions bound to Hb(O2)J, And the relationship between fractional anion saturation of hemoglobin and fractional oxygen saturation. The numbers of released anions are not uniform with respect to oxygenation step. This non-uniformity is the reason for the changes in the shape of the oxygen equilibrium curve with anion concentration changes and for the non-uniform dependences of the Adair constants on anion concentration, and also results in non-linear relations between anion saturation and oxygen saturation. The anion binding constants and various binding properties of the anions derived from those constants are consistent with those observed by other investigators using different techniques, indicating that the present model describes the oxygen-linked competitive anion binding well.


Are antidepressants carcinogenic? A review of preclinical and clinical studies.
Antidepressants are widely prescribed for mood and anxiety disorders, though reports in the oncology and epidemiology literature have suggested these agents may possess tumor initiating and/or promoting properties, raising questions about safe long-term use in patients. The author conducted a review of the preclinical and clinical literature on the connection between antidepressants and carcinogenesis. A MEDLINE search was conducted for English-language articles published from 1966 to 2002 using the search terms antidepressants, tumors, carcinogenesis, and cancer, as well as specific antidepressant names. Additional studies were ascertained through cross-references. Preclinical studies found evidence for both tumor promotion and suppression, though the majority of studies predominantly examined tricyclic antidepressants (TCAs), with 1 report suggesting that TCAs with a nitrogen atom in the central ring are genotoxic. Of 13 clinical studies, 3 found a significant increase, 4 noted a trend increase, and 6 found no increase in risk for cancer with antidepressant (mostly TCA) use. Methodologic differences could account for some of the discrepancies found in the clinical studies, while questions about the validity for humans of the preclinical models raise doubt about the significance of those findings. While there is some suggestive evidence of an association between antidepressant use and cancer, the link is, at this time, questionable but deserving of further study, especially with newer agents. Clinicians should not withhold antidepressant medication when indicated, as the risks of untreated depressive and anxiety disorders exceed the as yet unsubstantiated risk of tumor formation in such patients.


Preferential chemotaxis of activated human CD4+ T cells by extracellular cyclophilin A.
The recruitment and trafficking of leukocytes are essential aspects of the inflammatory process. Although chemokines are thought to be the main regulators of cell trafficking, extracellular cyclophilins have been shown recently to have potent chemoattracting properties for human leukocytes. Cyclophilins are secreted by a variety of cell types and are detected at high levels in tissues with ongoing inflammation. CD147 has been identified as the main signaling receptor for cyclophilin A (CypA) on human leukocytes. It is interesting that the expression of CD147 is elevated on leukocytes from inflamed tissue, suggesting a correlation among the presence of extracellular cyclophilins, CD147 expression, and inflammatory responses. Thus, cyclophilin-CD147 interactions may contribute directly to the recruitment of leukocytes into inflamed tissues. In the current studies, we show that activated human T lymphocytes express elevated levels of CD147, compared with resting T cells and that these activated T cells migrate more readily to CypA than resting cells. Furthermore, we show that unlike resting CD4+ T cells, the cyclophilin-mediated migration of activated T cells does not require interaction with heparan sulfate receptors but instead, is dependent on CD147 interaction alone. Such findings suggest that cyclophilin-CD147 interactions will be most potent when leukocytes are in an activated state, for example, during inflammatory responses. Thus, targeting cyclophilin-CD147 interactions may provide a novel approach for alleviating tissue inflammation.


Traditional/alternative medicines and the right to health: Key elements for a convention on global health.
Little has been done to investigate and promote the importance of non-conventional medicines (NCMs) in the realization of the right to health, yet all over the world people regularly resort to NCMs to secure healing or to prevent or mitigate the occurrence of a wide range of morbidities. This study aims to elucidate the theoretical framework of the role of NCMs in realizing the right to health, to identify the potential manifestations and causes of violations of the right to health in their practice, and to propose the practice of NCMs that could be included in a Framework Convention on Global Health. We use both the documentary analysis and the violation of rights approaches. Through a non-directive review of the literature, we have tried to clarify the concepts and uniqueness of NCMs. We have also tried to unveil the challenges facing NCMs in a context where conventional medicines assume extensive power. The human rights approach has enabled us to bring to light the potential challenges to the rights of the various stakeholders that NCMs create. We argue that NCMs can contribute to realizing the right to health through their availability, accessibility, acceptability, and relative quality. The Framework Convention on Global Health could contribute to the effective realization of this right by integrating basic principles to ensure the recognition, protection, promotion, and conservation of NCMs-at least of those NCMs that have shown evidence of efficacy-as well as catalyzing increased international cooperation in this area.


Linearly Polymerized Benzene Arrays As Intermediates, Tracing Pathways to Carbon Nanothreads.
How might fully saturated benzene polymers of composition [(CH)6]n form under high pressure? In the first approach to answering this question, we examine the stepwise increase in saturation of a one-dimensional stack of benzene molecules by enumerating the partially saturated polymer intermediates, subject to constraints of unit cell size and energy. Defining the number of four-coordinate carbon atoms per benzene formula unit as the degree of saturation, a set of isomers for degree-two and degree-four polymers can be generated by either thinking of the propagation of partially saturated building blocks or by considering a sequence of cycloadditions. There is also one 4 + 2 reaction sequence that jumps directly from a benzene stack to a degree-four polymer. The set of degree-two polymers provides several useful signposts toward achieving full saturation: chiral versus achiral building blocks, certain forms of conformational freedom, and also dead ends to further saturation. These insights allow us to generate a larger set of degree-four polymers and enumerate the many pathways that lead from benzene stacks to completely saturated carbon nanothreads.


Long-term follow-up after comprehensive rehabilitation of persons with epilepsy, with emphasis on participation in employment or education.
The objective of this study was to describe the current situation of patients with epilepsy after rehabilitation with emphasis on employment and education and to investigate if clinical factors at admission were associated with increase in employment or education. All patients that participated in a comprehensive rehabilitation were eligible. Data were collected from medical records at admission, during rehabilitation, at discharge and from a structured telephone interview at follow-up 1-17 years after admission. In total, 124 patients participated in the follow-up. Participation in employment or education improved from admission to follow-up in 38 patients. In univariable analysis, active epilepsy with tonic-clonic seizures at admission was significantly associated with increased participation in employment or education at follow-up, so was decreased frequency of tonic-clonic seizures from admission to follow-up. The significance of the associations disappeared in adjusted multivariable analysis. Participation in employment or education was improved for many patients at follow-up.


Treatment for continuous spikes and waves during sleep (CSWS): survey on treatment choices in North America.
Current literature does not allow an evidence-based approach to the treatment of continuous spikes and waves during sleep (CSWS). The aim of this study was to describe treatment choices made by clinicians caring for patients with CSWS in North America. A 24-question survey on treatment choices for CSWS was distributed to the members of the American Epilepsy Society (AES). The survey presented a clinical vignette of CSWS. The questions addressed treatment choices for that clinical scenario. Surveys were self-administered and collected using an online survey website (www.surveymonkey.com). Two-hundred thirty-two surveys were completed. Prominent sleep-potentiated spiking was considered to warrant treatment by 81% of respondents. The proportion of patients in whom cognitive improvement occurs when sleep-potentiated spiking is effectively treated is in >75% of patients (according to 16% of respondents), in 25-75% of patients (according to 52% of respondents), in <25% of patients (according to 20% of respondents), and no or unclear cognitive changes (according to 12% of respondents). The preferred first choice to reduce sleep-potentiated epileptiform activity was high-dose benzodiazepines (47%), valproate (26%), and corticosteroids (15%). The preferred second-choice was valproate (26%), high-dose benzodiazepines (24%), and corticosteroids (23%). Among high-dose benzodiazepines, the preferred one was diazepam 1 mg/kg for one night followed by 0.5 mg/kg/day. The preferred dose of valproate was 30-49 mg/kg/day. Among corticosteroids the preferred choice was oral prednisone 2 mg/kg/day. The most commonly considered endpoints of treatment efficacy were (in decreasing order): response of epileptiform activity in electroencephalography (EEG), cognitive function, and seizure reduction. Results were consistent among respondents with different levels of training and clinical experience. There were differences in conceptualization and treatment approaches between pediatric and adult neurologists. Most clinicians considered that prominent sleep-potentiated epileptiform activity should be treated. There was no agreement on best treatment, but potential candidates included high-dose benzodiazepines, valproate, levetiracetam, and corticosteroids.


Clinical infection control in gene therapy: a multidisciplinary conference.
Gene therapy is being studied for the treatment of a variety of acquired and inherited disorders. Retroviruses, adenoviruses, poxviruses, adeno-associated viruses, herpesviruses, and others are being engineered to transfer genes into humans. Treatment protocols using recombinant viruses are being introduced into clinical settings. Infection control professionals will be involved in reviewing the safety of these agents in their clinics and hospitals. To date, only a limited number of articles have been written on infection control in gene therapy, and no widely available recommendations exist from federal or private organizations to guide infection control professionals. The goals of the conference were to provide a forum where gene therapy experts could share their perspectives and experience with infection control in gene therapy and to provide an opportunity for newcomers to the field to learn about issues specific to infection control in gene therapy. Recommendations for infection control in gene therapy were proposed.


Invasive behavior of Campylobacter jejuni in immunosuppressed chicken.
Campylobacter jejuni is a predominant cause of gastroenteritis in humans but rather harmless in chickens. The basis of this difference is unknown. We investigated the effect of the chicken immune defense on the behavior of C. jejuni using glucocorticoid (GC)-treated and mock-treated 17-day old Ross 308 chicken bearing in mind that GCs have immunosuppressive effects and dampen the innate immune response. The effect of GC administration on the behavior of C. jejuni was compared with that on infection with Salmonella Enteritidis to address possible microbe-associated differences. Our results revealed that GC treatment fastened the intestinal colonization of C. jejuni (p < 0.001) and enhanced its dissemination to the liver (p = 0.007). The effect of GC on intestinal colonization of S. Enteritidis was less pronounced (p = 0.033) but GC did speed up the spread of this pathogen to the liver (p < 0.001). Cytokine transcript analysis showed an up to 30-fold reduction in baseline levels of IL-8 mRNA in the cecal (but not spleen) tissue at Day 1 after GC treatment (p < 0.005). Challenge with C. jejuni strongly increased intestinal IL-8, IL-6, and iNOS transcript levels in the non-GC treated animals but not in the GC-treated birds (P < 0.005). In vitro assays with chicken macrophages showed that GC dampened the TLR agonist- and C. jejuni induced-inflammatory gene transcription and production of nitric oxide (P < 0.005). Together, the results support the hypothesis that C. jejuni has the intrinsic ability to invade chicken tissue and that an effective innate immune response may limit its invasive behavior.