Sulfate but not thiosulfate reduces calculated and measured urinary ionized calcium and supersaturation: implications for the treatment of calcium renal stones.
Urinary sulfate (SO4(2-)) and thiosulfate (S2O3(2-)) can potentially bind with calcium and decrease kidney stone risk. We modeled the effects of these species on the concentration of ionized calcium (iCa) and on supersaturation (SS) of calcium oxalate (CaOx) and calcium phosphate (CaP), and measured their in vitro effects on iCa and the upper limit of stability (ULM) of these salts. Urine data from 4 different types of stone patients were obtained from the Mayo Nephrology Clinic (Model 1). A second data set was obtained from healthy controls and hypercalciuric stone formers in the literature who had been treated with sodium thiosulfate (STS) (Model 2). The Joint Expert Speciation System (JESS) was used to calculate iCa and SS. In Model 1, these parameters were calculated as a function of sulfate and thiosulfate concentrations. In Model 2, data from pre- and post STS urines were analyzed. ULM and iCa were determined in human urine as a function of sulfate and thiosulfate concentrations. Calculated iCa and SS values for all calcium salts decreased with increasing sulfate concentration. Thiosulfate had no effect on these parameters. In Model 2, calculated iCa and CaOx SS increased after STS treatment, but CaP SS decreased, perhaps due to a decrease in pH after STS treatment. In confirmatory in vitro experiments supplemental sulfate, but not thiosulfate, significantly increased the calcium needed to achieve the ULM of CaP and tended to increase the oxalate needed to reach the ULM of CaOx. Sulfate also significantly decreased iCa in human urine, while thiosulfate had no effect. Increasing urinary sulfate could theoretically reduce CaOx and CaP stone risk. Although STS may reduce CaP stone risk by decreasing urinary pH, it might also paradoxically increase iCa and CaOx SS. As such, STS may not be a viable treatment option for stone disease.


The association of visceral adiposity index with the risk of kidney stone and kidney stone recurrence.
Our aim in this study was primarily to assess the relationship between visceral adiposity index (VAI) and the risk of kidney stones and kidney stone recurrence in US adults. We used data from the National Health and Nutrition Examination Survey (NHANES) 2007-2014 for our analysis. VAI was calculated from waist circumference (WC), body mass index (BMI), triglycerides (TG), and high-density lipoprotein-cholesterol (HDL-C). Kidney stones and recurrence of kidney stones were obtained from questionnaire interview data. We used multivariate logistic regression analysis to explore the correlation between VAI and the risk of kidney stone and kidney stone recurrence. In addition, we performed subgroup analysis, interaction tests, and restricted cubic spline (RCS) analysis. A total of 9886 participants were included in this study, with a prevalence of 9.24% for kidney stones and 2.97% for recurrence of kidney stones. The prevalence of kidney stones and kidney stone recurrence increased with higher quartiles of VAI. We observed a significantly positive correlation between VAI and the risk of kidney stone and kidney stone recurrence. Participants with the highest VAI quartiles had a 48% (OR: 1.48, 95%CI: 1.08-2.02) and 52% (OR: 1.52, 95%CI: 0.86-2.71) increased risk of kidney stones and kidney stone recurrence, respectively, compared to participants with the lowest VAI quartiles. Subgroup analysis and interaction tests demonstrated this positive association independent of different subgroup factors. Visceral fat accumulation may be associated with an increased risk of kidney stones and kidney stone recurrence.


Two-Dimensional Cellular and Three-Dimensional Bio-Printed Skin Models to Screen Topical-Use Compounds for Irritation Potential.
Assessing skin irritation potential is critical for the safety evaluation of topical drugs and other consumer products such as cosmetics. The use of advanced cellular models, as an alternative to replace animal testing in the safety evaluation for both consumer products and ingredients, is already mandated by law in the European Union (EU) and other countries. However, there has not yet been a large-scale comparison of the effects of topical-use compounds in different cellular skin models. This study assesses the irritation potential of topical-use compounds in different cellular models of the skin that are compatible with high throughput screening (HTS) platforms. A set of 451 topical-use compounds were first tested for cytotoxic effects using two-dimensional (2D) monolayer models of primary neonatal keratinocytes and immortalized human keratinocytes. Forty-six toxic compounds identified from the initial screen with the monolayer culture systems were further tested for skin irritation potential on reconstructed human epidermis (RhE) and full thickness skin (FTS) three-dimensional (3D) tissue model constructs. Skin irritation potential of the compounds was assessed by measuring tissue viability, trans-epithelial electrical resistance (TEER), and secretion of cytokines interleukin 1 alpha (IL-1α) and interleukin 18 (IL-18). Among known irritants, high concentrations of methyl violet and methylrosaniline decreased viability, lowered TEER, and increased IL-1α secretion in both RhE and FTS models, consistent with irritant properties. However, at low concentrations, these two compounds increased IL-18 secretion without affecting levels of secreted IL-1α, and did not reduce tissue viability and TEER, in either RhE or FTS models. This result suggests that at low concentrations, methyl violet and methylrosaniline have an allergic potential without causing irritation. Using both HTS-compatible 2D cellular and 3D tissue skin models, together with irritation relevant activity endpoints, we obtained data to help assess the irritation effects of topical-use compounds and identify potential dermal hazards.


Statins and the risk of gastric cancer in diabetes patients.
Several studies have suggested a cancer risk reduction in statin users although the evidence remains weak for stomach cancer. The purpose of this study was to use an exact-matching case-control design to examine the risk of gastric cancer associated with the use of statins in a cohort of patients with diabetes. Cases were defined as patients with incident gastric cancer identified by International Classification of Diseases 16.0 ~ 16.9 recorded at Samsung Medical Center database during the period of 1999 to 2008, at least 6 months after the entry date of diabetes code. Each gastric cancer case patient was matched with one control patient from the diabetes patient registry in a 1:1 fashion, blinded to patient outcomes. A total of 983 cases with gastric cancer and 983 controls without gastric cancer, matched by age and sex, were included in the analysis. The presence of prescription for any statin was inversely associated with gastric cancer risk in the unadjusted conditional logistic regression model (OR: 0.18; 95% CI: 0.14 - 0.24; P < .0001). Multivariate analysis using conditional logistic regression with Bonferroni's correction against aspirin indicated a significant reduction in the risk of gastric cancer in diabetes patients with statin prescriptions (OR: 0.21; 95% CI: 0.16 - 0.28; P < .0001). After adjustment for aspirin use, a longer duration of statin use was associated with reduced risk of gastric cancer, with statistical significance (P<.0001). A strong inverse association was found between the risk of gastric adenocarcinoma and statin use in diabetic patients.


Early distal axonopathy of the visual pathway in experimental diabetes.
Diabetic retinopathy is a leading cause of acquired blindness. Visual function disorders have been observed in diabetic patients with very early retinopathy or even before the onset of retinopathy. The aim of the present work was to analyze the visual pathway in an early stage of experimental diabetes. Diabetes was induced in Wistar rats by an i.p. injection of streptozotocin. A deficit in anterograde transport from the retina to the superior colliculus was observed 6 weeks after streptozotocin injection. At this time point, morphologic studies did not reveal retinal ganglion cell loss or substantial alterations in the superior colliculus. The optic nerve was morphometrically evaluated at intraorbital (unmyelinated and myelinated) and intracranial sections. In animals that had been diabetic for 6 weeks, a large increase in astrocyte reactivity occurred in the distal (but not the intraorbital) portion, which coincided with significant axon loss. Moreover, profound myelin alterations and altered morphologic features of oligodendrocyte lineage were observed at the distal (but not the proximal) optic nerve portion. The present results suggest that axoglial alterations at the distal portion of the optic nerve could be the first structural change in the diabetic visual pathway.


Evaluation of Project P.A.T.H.S. in Hong Kong: utilization of student weekly diary.
Four schools participating in the experimental implementation phase of the Project P.A.T.H.S. (Positive Adolescent Training through Holistic Social Programmes) (Secondary 1 level) were randomly selected and invited to join this research study. After completion of the Tier 1 Program, Secondary 1 students in the participating schools were invited to write a reflective journal in the form of a weekly diary in order to reveal their perceptions and feelings regarding the Tier 1 Program and the related benefits. Results of the qualitative data analyses showed that most of the respondents (a) had positive views on the program, (b) had positive views on the instructors, and (c) stated that they had acquired competencies at societal, familial, interpersonal, and personal levels after joining the program. The present qualitative findings based on students' weekly diaries provide additional support for the effectiveness of the Tier 1 Program of P.A.T.H.S. in Hong Kong.


The mechanisms of perineuronal net abnormalities in contributing aging and neurological diseases.
The perineuronal net (PNN) is a highly latticed extracellular matrix in the central nervous system, which is composed of hyaluronic acid, proteoglycan, hyaluronan and proteoglycan link protein (Hapln), and tenascin. PNN is predominantly distributed in GABAergic interneurons expressing Parvalbumin (PV) and plays a critical role in synaptic function, learning and memory, oxidative stress, and inflammation. In addition, PNN's structure and function are also modulated by a variety of factors, including protein tyrosine phosphatase σ (PTPσ), orthodenticle homeo-box 2 (Otx2), and erb-b2 receptor tyrosine kinase 4 (ErbB4). Glycosaminoglycan (GAG), a component of proteoglycan, also influences PNN through its sulfate mode. PNN undergoes abnormal changes during aging and in various neurological diseases, such as Alzheimer's disease, Parkinson's disease, schizophrenia, autism spectrum disorder, and multiple sclerosis. Nevertheless, there is limited report on the relationship between PNN and aging or age-related neurological diseases. This review elaborates on the mechanisms governing PNN regulation and summarizes how PNN abnormalities contribute to aging and neurological diseases, offering insights for potential treatments.


Neonatal Cardio-pulmonary Arrest: Emergency Catheterization of Umbilical Vein.
In an emergency, the physician responsible for neonatal care must be skilled in umbilical catheterization. Several drugs can be given through an endotracheal tube, but some require intravenous administration. The umbilical vein is a better route of administration than peripheral veins because it is easily located and can be entered readily. It allows immediate access to the central circulation, enhancing drug distribution. The authors outline the procedure in a step-by-step description. This pictorial article can be used as a handy reference by physicians needing to administer fluids and drugs during cardio-pulmonary arrest in neonates.


Motives for smoking in movies affect future smoking risk in middle school students: an experimental investigation.
Exposure to smoking in movies has been linked to adolescent smoking uptake. However, beyond linking amount of exposure to smoking in movies with adolescent smoking, whether the way that smoking is portrayed in movies matters for influencing adolescent smoking has not been investigated. This study experimentally examined how motivation for smoking depicted in movies affects self-reported future smoking risk (a composite measure with items that assess smoking refusal self-efficacy and smoking intentions) among early adolescents. A randomized laboratory experiment was used. Adolescents were exposed to movie scenes depicting one of three movie smoking motives: social smoking motive (characters smoked to facilitate social interaction); relaxation smoking motive (characters smoked to relax); or no smoking motive (characters smoked with no apparent motive, i.e., in neutral contexts and/or with neutral affect). Responses to these movie scenes were contrasted (within subjects) to participants' responses to control movie scenes in which no smoking was present; these control scenes matched to the smoking scenes with the same characters in similar situations but where no smoking was present. A total of 358 adolescents, aged 11-14 years, participated. Compared with participants exposed to movie scenes depicting characters smoking with no clear motive, adolescents exposed to movie scenes depicting characters smoking for social motives and adolescents exposed to movie scenes depicting characters smoking for relaxation motives had significantly greater chances of having increases in their future smoking risk. Exposure to movies that portray smoking motives places adolescents at particular risk for future smoking.


Bicarbonate reabsorption and electrophysiology of proximal tubules in uninephrectomized rats.
1. The kinetics of acidification of luminal fluid in hypertrophied proximal tubules after unilateral nephrectomy was studied by stationary microperfusion and continuous measurement of luminal pH with antimony microelectrodes. 2. Trans-epithelial and basolateral membrane electrical potential differences were measured in order to detect modifications in electrogenic transport mechanisms under these conditions. 3. The values of stationary pH and HCO3- concentration were significantly lower, the mean acidification half-time was not different and net reabsorptive HCO3- fluxes in proximal tubules were significantly increased in uninephrectomized rats. According to an electrical analogue model, these results suggest (a) a reduction in the internal series resistance of the H+ pump, caused perhaps by an increased density of pump sites, and (b) an increase in the protonmotive force of the pump. 4. The trans-epithelial electrical potential difference measured in free flow conditions was significantly more lumen-positive in uninephrectomized rats. The trans-epithelial electrical potential difference measured during intraluminal perfusion with Ringer solution containing 30 mmol/l HCO3- was significantly more negative in all groups studied. In uninephrectomized rats treated with acetazolamide, the trans-epithelial electrical potential difference was more lumen-negative than that in untreated uninephrectomized rats. These results are compatible with a steeper transepithelial Cl- gradient as well as with electrogenic, active H+ secretion. 5. There was no significant difference in the basolateral electrical potential difference between control and uninephrectomized rats. 6. In conclusion, our data show an increase in the transport rates of HCO3- in the proximal tubule of uninephrectomized rats, which may be due to an increase in the density of transporters in the brush-border membrane, and an increased ability of the transport mechanism to create H+ gradients.


Fluoride effects: the two faces of janus.
The behavior of fluoride ions in the human organism is a classic example of double-edged sword. On the one hand the daily supplementation with fluoride is undoubtedly an important preventing factor in protecting teeth from caries, and, as an important mitogenic stimulus for osteoblasts, it may enhance mineral deposition in bone, but on the other hand fluoride, above a threshold concentration, has been demonstrated to be toxic. We present here a brief review of fluoride metabolism and exposure, its use in caries prevention and its effects on bone, followed by an updating about the main hypotheses concerning its mechanism of action and toxicity. The effects of fluoride have been related mainly to its ability to evoke the activation of G proteins and the inhibition of phosphotyrosine phosphatases, leading to an intracellular increase of tyrosine phosphorylation and activation of the mitogen-activated protein kinase pathway, and its capacity to cause generation of reactive oxygen species. We present also a unifying hypothesis accounting for these apparently different effects, although the available experimental models and conditions are highly variable in the literature. A lot of experiments still need to be performed to clarify the positive and negative effects of fluoride. Finding the mechanisms accounting for fluoride toxicity is an important point: indeed, the use of fluoride has been proposed in the preparation of new biomaterials to be inserted in the bone, in order to improve their stable and safe integration.


TRPV1 and TRPA1 Channels Are Both Involved Downstream of Histamine-Induced Itch.
Two histamine receptor subtypes (HR), namely H1R and H4R, are involved in the transmission of histamine-induced itch as key components. Although exact downstream signaling mechanisms are still elusive, transient receptor potential (TRP) ion channels play important roles in the sensation of histaminergic and non-histaminergic itch. The aim of this study was to investigate the involvement of TRPV1 and TRPA1 channels in the transmission of histaminergic itch. The potential of TRPV1 and TRPA1 inhibitors to modulate H1R- and H4R-induced signal transmission was tested in a scratching assay in mice in vivo as well as via Ca2+ imaging of murine sensory dorsal root ganglia (DRG) neurons in vitro. TRPV1 inhibition led to a reduction of H1R- and H4R- induced itch, whereas TRPA1 inhibition reduced H4R- but not H1R-induced itch. TRPV1 and TRPA1 inhibition resulted in a reduced Ca2+ influx into sensory neurons in vitro. In conclusion, these results indicate that both channels, TRPV1 and TRPA1, are involved in the transmission of histamine-induced pruritus.


A series of 3D lanthanide coordination polymers decorated with a rigid 3,5-pyridinedicarboxylic acid linker: syntheses, structural diversity, DFT study, Hirshfeld surface analysis, luminescence and magnetic properties.
Single crystal X-ray diffraction studies reveal the formation of six new coordination polymers (CPs) with the general formulas [Dy(3,5-pdc)(3,5-pdcH)(H2O)2]n·nH2O (1), [Pr2(3,5-pdc)3(H2O)2]n·2n(H2O) (2), [Sm2(3,5-pdc)3(H2O)3]n·nH2O (3), {[Eu2(3,5-pdc)3(H2O)3(CH3CHO)]n·n[2(H2O)(DMF)]} (4), {[Gd2(3,5-pdc)3 (H2O)2]n·2nH2O} (5) and [Er(3,5-pdc)(adip)0.5(H2O)]n (6) (where 3,5-pdc2- = fully deprotonated; 3,5-pdcH- = partially deprotonated 3,5-pyridinedicarboxylic acid; adip2- = fully deprotonated adipic acid; and DMF = dimethylformamide) by solvothermal self-assembly of lanthanide ions with rigid 3,5-pyridinedicarboxylic acid as a linker and adipic acid as an auxiliary flexible spacer (only coordinated in CP 6). CPs 1 and 2 crystallize in the triclinic P1[combining macron] space group, whereas CPs 3, 4 and 6 crystallize in the monoclinic P21/n, P21/c and C2/c space groups, respectively. CP 5 exhibits the trigonal R3 space group. The 3,5-pdc ligand exhibits eight diverse coordination modes in CPs 1-6, whereas the adipic acid spacer in CP 6 shows only one coordination mode (μ4-κO:κO,O:κO:κO,O). The organic ligands interconnect with metal ions to generate 3D metal-organic frameworks with a variety of intriguing topologies. Theoretical studies, DFT calculations and Hirshfeld surface analysis support the structures adopted by the various CPs. CPs 3 (Sm) and 4 (Eu) emit strong ligand-sensitized characteristic f-f luminescence. Weak ferromagnetic interactions have been studied at low temperatures for CP 1 and CP 5.


The role of microbiota in immunotherapy outcomes in colorectal cancer patients: A protocol for a systematic review.
In the human gut, there are many microbes, including bacteria, viruses and parasites. The imbalance in the numbers of each type of these microbes can translate into gastrointestinal disorders. Lately, different microbiota patterns have been associated with the levels of efficacy of immunotherapy in multiple cancer conditions. Studies have shown that patients with a more diverse gut microbiome respond better to immunotherapy than those with a homogeneous microbiome. This systematic review aims to identify and assess the available evidence on the efficacy of immunotherapy in treating colorectal cancer (CRC) patients and the effect of their microbiota on their treatment outcomes. The researchers will study the literature regarding CRC and immunotherapy outcomes to survey the different approaches employed to assess the treatment outcomes. A systematic search will be performed in five biomedical databases (PubMed, Scopus, Web of Science, Embase, and the Cochrane Library) in June-July, 2022. Also, open-access registers of clinical trials will be trawled. The search will be conducted without geographical or publication date restrictions; however, only papers published in the English language will be sought. Details regarding patients' diets, lifestyles, and characteristics will be assessed. We will define the primary outcome to compare CRC patients' immunotherapy responses with their gut microbiota composition. The systematic review methodology does not require ethics approval due to the nature of the study design. The systematic review results will be published in an open-access peer-reviewed journal. PROSPERO ID: CRD42021277691.


Cerebellar Dentate Connectivity across Adulthood: A Large-Scale Resting State Functional Connectivity Investigation.
Cerebellar contributions to behavior in advanced age are of interest and importance, given its role in motor and cognitive performance. There are differences and declines in cerebellar structure in advanced age and cerebellar resting state connectivity is lower. However, the work on this area to date has focused on the cerebellar cortex. The deep cerebellar nuclei provide the primary cerebellar inputs and outputs to the cortex, as well as the spinal and vestibular systems. Dentate networks can be dissociated such that the dorsal region is associated with the motor cortex, whereas the ventral aspect is associated with the prefrontal cortex. However, whether dentato-thalamo-cortical networks differ across adulthood remains unknown. Here, using a large adult sample (n = 590) from the Cambridge Center for Ageing and Neuroscience, we investigated dentate connectivity across adulthood. We replicated past work showing dissociable resting state networks in the dorsal and ventral aspects of the dentate. In both seeds, we demonstrated that connectivity is lower with advanced age, indicating that connectivity differences extend beyond the cerebellar cortex. Finally, we demonstrated sex differences in dentate connectivity. This expands our understanding of cerebellar circuitry in advanced age and underscores the potential importance of this structure in age-related performance differences.


Non-vitamin K oral anticoagulants for coronary or peripheral artery disease: a systematic review and meta-analysis of mortality and major bleeding.
Several high quality randomized controlled studies were recently published on non-vitamin K oral anticoagulants (NOACs) in patients with or at risk for coronary artery (CAD) or peripheral artery disease (PAD). While a reduction on cardiovascular event is known and an increase in moderate bleeding is expected, the effect of this strategy on survival is currently unknown. Accordingly, we performed a comprehensive systematic review and meta-analysis of randomized controlled trials to investigate the effect of NOAC on survival. We searched Pubmed, EMBASE, Cochrane Central Register, and Clinicaltrials.gov (last updated March 31st 2019). The primary endpoint was all-cause mortality at the longest reported follow-up. Coprimary endpoint was major bleeding according to the International Society on Thrombosis and Hemostasis (ISTH) criterion. We included ten randomized controlled trials comparing NOACs versus control treatment (placebo, single platelet or dual antiplatelet therapy) enrolling 66665 patients with or at risk for CAD or PAD. NOACs were associated with a decreased risk of mortality (825/41655 [4.4%] versus 405/25010 [5.6%] RR 0.93 [95% CI: 0.87-1.00], P=0.04), and an increased risk for major bleeding (RR 1.62 [95% CI: 1.23-2.13], P=0.0005) when compared to control. Findings were robust to trial sequential, subgroup, and sensitivity analyses. Low doses NOACs were associated with a reduced mortality when compared to standard dose NOACs. NOACs reduced all-cause mortality in patients with or at risk for CAD or PAD, even though they increased the risk of major bleeding. Future studies regarding the best doses of NOACs are warranted.


Use of the progesterone (P4) receptor antagonist aglepristone to characterize the role of P4 withdrawal for parturition and placental release in cows.
In late pregnant cows, progesterone (P(4)) is mainly of luteal origin. However, the trophoblast may provide high local P(4) concentrations in the uterus. To test for the importance of a complete P(4) withdrawal for parturition-related processes and placental release, the P(4) receptor (PGR) blocker aglepristone (Ap) was administered to three cows on days 270 and 271 of pregnancy. A complete opening of the cervix was observed 46.5±7.3 h after the start of treatment. However, expulsion of the calves was impaired obviously because of insufficient myometrial activity, and placental membranes were retained for at least 10 days. Measurement of P(4) concentrations indicated that PGR blockage induced luteolysis. To investigate the role of P(4) withdrawal for the prepartal tissue remodeling of the placentomes, the caruncular epithelium was evaluated by morphometry, and the percentage of trophoblast giant cells (TGCs) relative to the total number of trophoblast cells were assessed. Caruncular epithelium in Ap-treated cows (D272+Ap) was immature (30.5±3.3%) and not different from untreated controls (elected cesarean section (CS) on day 272; D272-CS; 31.5±1.4%), whereas it was significantly reduced at normal term (D280.5±1.3; 21.0±6.1%; P=0.011). Correspondingly, the percentage of TGCs were 20.1±1.4 in D272+Ap, 22.1±4.8 in D272-CS, and 9.8±3.9 at term (P=0.001). No effect was detected on placental estrogen synthesis. The results showed that in late pregnant cows, P(4) withdrawal only induces a limited spectrum of the processes related to normal parturition and is not a crucial factor for the prepartal tissue remodeling in placentomes and the timely release of the placenta.


[Comparative characteristics of 24-hour blood pressure profile and heart rate variability in indigenous and non-indigenous patients with chronic coronary heart disease and hypertension from the Yamal-Nenets Autonomic District].
To investigate the specific features of a 24-hour blood pressure (BP) profile and heart rate variability (HRV) in the indigenous peoples (Nenets, Khanty, Selcups, and Komis) and newcomers with chronic coronary heart disease (CHD) and hypertension, who lived in the Yamal-Nenets Autonomic District. Two hundred male and females patients aged 21 to 55 years (mean age 48.2 +/- 0.7 years) with chronic CHD and hypertension, who resided in the Far North, were examined. All the patients were divided into 4 groups: (1) 50 aboriginal patients with hypertension only; (2) 50 newcomers with hypertension only; 3) 50 natives with chronic CHD and hypertension; (4) 50 non-natives with the above conditions. The groups were matched for gender, age, and the duration of hypertension and CHD. To study the nature of changes in the 24-hour BP profile, all the patients underwent 24-hour ambulatory BP monitoring (ABPM) and HRV examination. The HRV analysis revealed that all the groups had increases in sympathetic autonomic nervous system (ANS) activity (88% in Group 1; 96% in Group 2; 94% in Group 3, and 92% in Group 4) and decreases in parasympathetic ANS activity (76% in Group 1; 74% in Group 2; 78% in Group 3; and 72% in Group 4), which was suggestive of neurocardiopathy. Analyzing the data of 24-hour ABPM showed that among the natives, there were more patients with increased systolic and diastolic BP (SBP and DBP) variability and higher nocturnal SBP time index (TI). These groups also showed a preponderance of patients with abnormal 24-hour BP profiles as compared to the groups of newcomers (p = 0.034). Among the latter, there were more patients with higher SBP and DBP variability and increased daytime DBP TI and also more patients with a normal nocturnal BP reduction (p = 0.012). The group of indigenous populations displayed a predominance of non-dippers and night-pickers and higher nocturnal SBP and DBP whereas the group of non-indigenous ones exhibited a preponderance of dippers and higher daytime SBP and DBP variability.


From speciation to introgressive hybridization: the phylogeographic structure of an island subspecies of termite, Reticulitermes lucifugus corsicus.
Although much research has been carried out into European Reticulitermes taxonomy in recent years, there is still much discussion about phylogenetic relationships. This study investigated the evolution from intra- to interspecific phylogeny in the island subspecies Reticulitermes lucifugus corsicus and threw new light on this phenomenon. An integrative approach based on microsatellites and mitochondrial and nuclear DNA sequences was used to analyze samples taken from a wide area around the Tyrrhenian sea and showed how the subspecies evolved from its origins to its most recent form on continental coasts. According to mitochondrial phylogeny and molecular clock calculations, island and continental taxa diverged significantly by vicariance in the Pleistocene glacial period. However, more recently, numerous migrations, certainly human-mediated, affected the structure of the populations. This study provided evidence of direct hybridization and multiple introgressions which occurred in several hybrid areas. Analysis using STRUCTURE based on microsatellite data identified a population in Provence (France) which differed considerably (Fst = 0.477) from populations on the island of Corsica and in Tuscany in the Italian peninsula. This new population, principally distributed in urban areas, is highly heterogeneous especially within the ITS2 regions where homogenization by concerted evolution does not appear to have been completed. This study provides an unusual picture of genetic interaction between termite populations in the Tyrrhenian area and suggests that more attention should be paid to the role of introgression and human impact on the recent evolution of European termites.


Glycation-induced inactivation and loss of antigenicity of catalase and superoxide dismutase.
Oxidative mechanisms are thought to have a major role in several biological phenomena, including cataract formation and diabetic complications. Here we investigate the inactivation of catalase and superoxide dismutase, both powerful antioxidant enzymes, by sugars of different glycating abilities, and the loss of antigenicity that was monitored by the loss of activity after immunoprecipitation with monospecific antibodies. The antigenicity of non-glycated or glycated enzymes separated by affinity chromatography were determined by dot-blotting. Incubation with sugars resulted in a time-dependent inactivation of the enzymes. Ribose and fructose inactivated them more rapidly than glucose and glucose 6-phosphate. Glycation induced losses of antigenicity and inactivation simultaneously. The glycated enzymes had entirely lost their antigenicity compared with non-glycated enzyme. These results further support the idea that inactivation of enzyme and loss of antigenicity are simultaneous. This might occur in the pathogenesis of diabetic complications and aging.


Evaluation of a Conceptual Model to Guide Health Care Providers in Promoting Exercise Among Persons With Multiple Sclerosis.
Fewer than 20% of persons with multiple sclerosis (MS) engage in enough exercise to manage MS symptoms and improve function. To address this problem, the authors developed a conceptual model to promote exercise among persons with MS through the patient-provider interaction within health care settings. The current qualitative study evaluated and refined the conceptual model based on 32 semistructured interviews involving persons with MS. The data were subject to inductive, semantic thematic analysis. Participants highlighted that the conceptual model was a necessary addition to current MS care and noted multiple strengths regarding its design (e.g., structure) and content (e.g., patient-provider interaction). Furthermore participants noted areas of the conceptual model that could be improved (e.g., less focus on neurologists as exercise promoters). This comprehensive evaluation yielded a refined conceptual model for exercise promotion in MS through the patient-provider interaction.


A receptor tyrosine kinase, Sky, and its ligand Gas 6 are expressed in gonads and support primordial germ cell growth or survival in culture.
Although a number of growth factors and their receptors are involved in the proliferation and differentiation of primordial germ cells (PGCs), the only factor that has been shown to be active in vivo is Steel factor, a ligand for c-Kit. To identify new growth factor receptors that may be required for PGCs function in vivo, we used an reverse transcription-polymerase chain reaction-based strategy to screen for protein kinase genes expressed in PGC-derived embryonic germ cells. We report here that one such gene encoding the receptor tyrosine kinase, Sky, is expressed in both PGCs and their supporting cells in male genital ridges after 11.5 dpc. Interestingly, Sky expression was not detected in female genital ridges, although transcripts were detected in supporting cells in the developing ovary at later stages. Gas 6, a ligand for Sky, was also expressed in interstitial cells which surround Sky positive cells in genital ridges, and, in addition, it supported PGC growth or survival in culture. After birth, Sky expression in testis was restricted to Sertoli cells, and Gas 6 was detected around peritubular cells and Leydig cells. These results suggest that Gas 6-Sky signaling plays a role in PGC growth, sexual differentiation, and Sertoli cell functions in vivo. Sky expression in Sertoli cells diminished by 3 weeks of age, when haploid germ cells first appear. On the other hand, the expression in Sertoli cells was markedly upregulated in the testis of germ cell-deficient W/Wv and jsd/jsd mice. The results suggest that signals from differentiated germ cells suppress Sky gene expression in Sertoli cells. High-resolution chromosomal mapping of Sky is also reported.


Organic-Inorganic Copper(II)-Based Material: A Low-Toxic, Highly Stable Light Absorber for Photovoltaic Application.
Lead halide perovskite solar cells have recently emerged as a very promising photovoltaic technology due to their excellent power conversion efficiencies; however, the toxicity of lead and the poor stability of perovskite materials remain two main challenges that need to be addressed. Here, for the first time, we report a lead-free, highly stable C6H4NH2CuBr2I compound. The C6H4NH2CuBr2I films exhibit extraordinary hydrophobic behavior with a contact angle of ∼90°, and their X-ray diffraction patterns remain unchanged even after 4 h of water immersion. UV/vis absorption spectrum shows that C6H4NH2CuBr2I compound has an excellent optical absorption over the entire visible spectrum. We applied this copper-based light absorber in printable mesoscopic solar cell for the initial trial and achieved a power conversion efficiency of ∼0.5%. Our study represents an alternative pathway to develop low-toxic and highly stable organic-inorganic hybrid materials for photovoltaic application.


Bleeding esophagogastric varices from extrahepatic portal hypertension: 40 years' experience with portal-systemic shunt.
This article discusses the largest and longest experience reported to date of the use of portal-systemic shunt (PSS) to treat recurrent bleeding from esophagogastric varices caused by extrahepatic portal hypertension associated with portal vein thrombosis (PVT). Two hundred consecutive children and adults with extrahepatic portal hypertension caused by PVT who were referred between 1958 and 1998 after recovering from at least two episodes of bleeding esophagogastric varices requiring blood transfusions were managed according to a well-defined and uniformly applied protocol. All but 14 of the 200 patients were eligible for and received 5 or more years of regular followup (93%); 166 were eligible for and received 10 or more years of regular followup (83%). The etiology of PVT was unknown in 65% of patients. Identifiable causes of PVT were neonatal omphalitis in 30 patients (15%), umbilical vein catheterization in 14 patients (7%), and peritonitis in 14 patients (7%). The mean number of bleeding episodes before PSS was 5.4 (range 2 to 18). Liver biopsies showed normal morphology in all patients. The site of PVT was the portal vein alone in 134 patients (76%), the portal vein and adjacent superior mesenteric vein in 10 patients (5%), and the portal and splenic veins in 56 patients (28%). Postoperative survival to leave the hospital was 100%. Actuarial 5-year, 10-year, and 15-year survival rates were 99%, 97%, and 95%, respectively. Five patients (2.5%), all with central end-to-side splenorenal shunts, developed thrombosis of the PSS, and these were the only patients who had recurrent variceal bleeding. During 10 or more years of followup, 97% of the eligible patients were shown to have a patent shunt and were free of bleeding. No patient developed portal-systemic encephalopathy, liver function tests remained normal, liver biopsies in 100 patients showed normal architecture, hypersplenism was corrected. PSS is the only consistently effective therapy for bleeding esophagogastric varices from PVT and extrahepatic portal hypertension, resulting in many years of survival, freedom from recurrent bleeding, normal liver function, and no encephalopathy.


[The evaluation of oxidative modification of proteins in patients with chronic disseminated dermatosis].
The analysis was made concerning oxidative modification of proteins of blood serum and erythrocytes in patients with chronic disseminated dermatosis. The high degree of total oxidative modification of proteins was established in patients with psoriasis and atopic dermatitis. The increase of level of oxidized derivatives of apoproteins in compound of lipoproteins of low density under psoriasis, atopic dermatitis and pemphigus was detected The increase of amount of carbonyl derivative of oligopeptids under psoriasis was revealed. In patients with resistance to applied therapy the statistically significant decrease of total oxidative modification of proteins of blood serum and erythrocytes was detected. This occurrence is possibly related to derangement of process of proteolytic destruction of proteins.


Suggested improvements to the standard filter paper assay used to measure cellulase activity.
Two suggestions can be found in the literature to improve the reproducibility of the Mandels' filter paper assay: add supplemental cellobiase and increase the boiling time for color development. Here we provide data that strongly supports adding supplemental cellobiase. Adding supplemental cellobiase increased assay response by 56%. Cellulases from different sources have different cellobiase activities, which would cause significant variation in the assay response. There is no need for additional boiling time-5 minutes is sufficient. For maximum reproducibility, it is essential that the water bath vigorously boil so that temperature excursions are minimized.


(Iso)flav(an)ones, chalcones, catechins, and theaflavins as anticarcinogens: mechanisms, anti-multidrug resistance and QSAR studies.
Flavonoids have shown anticarcinogenic activity in cancer cell lines, animal models, and some human studies. Quantitative structure-activity relationship (QSAR) models have become useful tools for identification of promising lead compounds in anticancer drug development. However, epidemiological and clinical studies are still scarce. Compounds with flavonoid scaffold have been the subject of many mechanistic studies in cells, but information on human chemopreventive properties is still missing. The knowledge of the mechanisms of action, anti-multidrug resistance, and QSAR studies on flavonoids and related compounds may help to enhance research on these compounds and their bioactivity. Therefore, once the issue is introduced, the mechanisms involved, and QSAR studies developed to predict the activity and toxicity of these chemicals to biological systems are discussed. QSAR studies on flavonoids as inhibitors of breast cancer resistance protein (BCRP/ABCG2), 17β-hydroxysteroid dehydrogenase (17β-HSD), PIM-1 kinase and cyclin-dependent kinases (CDKs) are analyzed. Combined treatment of flavonoids with TRAIL and current chemotherapy agents is also discussed as a promising cancer chemoprevention and/or therapy.


Screening Papaveraceae as Novel Antibiofilm Natural-Based Agents.
The antimicrobial properties of herbs from Papaveraceae have been used in medicine for centuries. Nevertheless, mutual relationships between the individual bioactive substances contained in these plants remain poorly elucidated. In this work, phytochemical composition of extracts from the aerial and underground parts of five Papaveraceae species (Chelidonium majus L., Corydalis cava (L.) Schweigg. and Körte, C. cheilanthifolia Hemsl., C. pumila (Host) Rchb., and Fumaria vaillantii Loisel.) were examined using LC-ESI-MS/MS with a triple quadrupole analyzer. Large differences in the quality and quantity of all analyzed compounds were observed between species of different genera and also within one genus. Two groups of metabolites predominated in the phytochemical profiles. These were isoquinoline alkaloids and, in smaller amounts, non-phenolic carboxylic acids and phenolic compounds. In aerial and underground parts, 22 and 20 compounds were detected, respectively. These included: seven isoquinoline alkaloids: protopine, allocryptopine, coptisine, berberine, chelidonine, sanguinarine, and chelerythrine; five of their derivatives as well as non-alkaloids: malic acid, trans-aconitic acid, quinic acid, salicylic acid, trans-caffeic acid, p-coumaric acid, chlorogenic acid, quercetin, and kaempferol; and vanillin. The aerial parts were much richer in phenolic compounds regardless of the plant species. Characterized extracts were studied for their antimicrobial potential against planktonic and biofilm-producing cells of S. aureus, P. aeruginosa, and C. albicans. The impact of the extracts on cellular metabolic activity and biofilm biomass production was evaluated. Moreover, the antimicrobial activity of the extracts introduced to the polymeric carrier made of bacterial cellulose was assessed. Extracts of C. cheilanthifolia were found to be the most effective against all tested human pathogens. Multiple regression tests indicated a high antimicrobial impact of quercetin in extracts of aerial parts against planktonic cells of S. aureus, P. aeruginosa, and C. albicans, and no direct correlation between the composition of other bioactive substances and the results of antimicrobial activity were found. Conclusively, further investigations are required to identify the relations between recognized and unrecognized compounds within extracts and their biological properties.


Oral contraceptive causing renal artery thrombosis.
A young female presented with acute left lower quadrant pain followed by nausea and vomiting. She was found to have haematuria and elevated serum creatine. CT scan revealed a wedge-shaped hypodensity along with an intraluminal filling defect on the left kidney. Renal artery duplex showed no evidence for stenosis and MRI was negative for any atherosclerotic disease. Technetium scan confirmed the diagnosis of left renal infarct. Following day the patient became febrile and was noted to have leucocytosis and elevated serum lactate dehydrogenase. She was started on enoxaparin and low-dose aspirin. Blood cultures were negative. The oral contraceptive was stopped. Fever and leucocytosis resolved in the following 3 days. Extensive thrombophilic work-up was negative. No recurrence of thrombosis was found during a 6-month follow-up period. To the best of our knowledge, this is the first report of renal artery thrombosis leading to acute renal infarction associated with oral contraceptive use.


Temporal Bayesian Network modeling approach to evaluating the emotional cascade model of borderline personality disorder.
Theoretical models of personality disorders can be complex and multifaceted, making it difficult to validate such models in a comprehensive, empirical fashion. One such model of borderline personality disorder (BPD) is the emotional cascade model (Selby & Joiner, 2009), which has garnered empirical support in piecemeal fashion but has not been examined in a gestalt fashion. One way to test comprehensive models of personality pathology is with Temporal Bayesian Network (TBN) modeling, in which the relations between multiple subcomponents of a model can be specified and examined over a dynamic time frame, allowing for the modeling of positive feedback processes in addition to comprehensive model utility. In this study, we applied TBN modeling to examine the emotional cascade model in a sample of adolescents and young adults who actively self-injure, including those with BPD. TBN modeling was applied to ecological momentary assessment data provided via participant smartphone assessments for a period of 2 weeks. TBN analysis suggested that the emotional cascade model has considerable predictive utility, demonstrating substantial accuracy in predicting BPD diagnosis (with accuracy estimates around 90%) and momentary prediction of rumination, negative emotion, and dysregulated behaviors (with accuracy estimates consistently above 70% and reaching up to 100%, depending on the level of momentary prediction specificity). These findings provide support and validity to the notion that BPD may emerge from a dynamic interplay between emotional cascades and dysregulated behaviors. Implications of TBN modeling of BPD and personality disorders, in general, are discussed. (PsycInfo Database Record (c) 2021 APA, all rights reserved).


Bayesian clinical trial designs: Another option for trauma trials?
Conducting clinical trials in trauma care is challenging. As new treatments become available, we are faced with the dilemma of how to confirm their effectiveness and strengthen the evidence base. Randomized controlled trials are the criterion standard, but target groups in trauma care are often small and specialized, making the classic approach to trial design difficult. Bayesian designs represent an innovative means of increasing trial efficiency and conducting trials with more realistic sample sizes. This article examines the design of such trials, using the UK-REBOA Trial as an example.


Evaluation of atrial electromechanical delay and left atrial mechanical function in patients with obstructive sleep apnea : Cardiac involvement in patients with OSA.
The aim of this study was to evaluate atrial electromechanical delay measured by tissue Doppler imaging and left atrial mechanical function in patients with obstructive sleep apnea (OSA). Fourty-seven moderate-to-severe OSA patients who were newly diagnosed by polysomnography (Apnea-hypopnea index ≥ 15 events/h, 32 males, mean age 49.4 ± 11.5) and 30 patients who had no OSA in polysomnography (Apnea-hypopnea index < 5 events/h, 21 males, mean age 45.4 ± 9.1) were included in the study. Using tissue Doppler, diastolic functions, atrial electromechanical coupling were measured from the lateral mitral, septal, and tricuspid annulus. Inter, intra, and left atrial electromechanical delay were calculated (lateral-tricuspid, septum-tricuspid, lateral-septal). Left atrial volumes (maximal, minimal, and presystolic) were measured by the method of discs in the apical four-chamber view and were indexed to body surface area. Mechanical function parameters of the left atrium were also calculated. Interatrial, intraatrial, and left atrial electromechanical delays were significantly higher in the OSA group compared to the control group. Passive emptying fraction was significantly decreased, volume at the beginning of atrial systole and active emptying volume were significantly increased in OSA patients compared to the controls. The apnea-hypopnea index was significantly associated with interatrial and intraatrial electromechanical delay, passive emptying fraction, and conduit volume. Electromechanical delay was markedly prolonged and left atrial electromechanical function was impaired in untreated OSA patients. These impairments worsen with increasing severity of OSA.


SERMs and cardiovascular disease in women. How do these agents affect risk?
The beneficial effects of SERMs, specifically tamoxifen in the treatment and prevention of breast cancer and raloxifene in the prevention of osteoporosis, are well established. In addition, numerous groups of investigators have reported that these agents have a positive impact on cardiovascular health, possibly as a result of their cholesterol-lowering and anticoagulation actions. Although studies clearly showed that tamoxifen therapy improved the levels of some types of lipids, the changes did not appear to translate into a decreased risk of cardiovascular disease. However, the risk of thromboembolic events (as well as endometrial cancer) was increased with the use of tamoxifen, which is often prescribed for breast cancer prevention in healthy women. Similarly, raloxifene treatment had modest positive effects on cardiovascular risk factors but was associated with an increased risk of thromboembolism. When viewed as a whole, study results dictate that the benefits of SERM use for the prevention of cardiovascular disease be carefully weighed against the potential risks.


In vitro establishment of lytic and nonproductive infection by herpes simplex virus type 1 in three-dimensional keratinocyte culture.
The F strain of herpes simplex virus type 1 (HSV-1) was tested for its ability to produce lytic or nonproductive infection in squamous epithelial cells cultured in a three-dimensional organotypic tissue culture. For the tissue culture, we used HaCat cells (immortalized skin keratinocytes) and normal fibroblasts derived from the skin. The cultures were infected with HSV-1 (5 PFU) either when the epithelial cells had grown as a monolayer with a confluence of 80% on the collagen fibroblast gel or 30 min after lifting of the epithelial cells into the air-liquid interface. The cultures were collected 1 week after inoculation. Typical cytopathic effects of HSV infection (ballooning and reticular degeneration with multinucleate giant cells) were seen only in those cultures in which the epithelial cells were infected before lifting. The presence of HSV was confirmed by DNA and RNA in situ hybridization and PCR. No morphological changes were found in cultures infected after lifting into the air-liquid interface. No infectious virus was recovered either from cells or culture supernatant. However, these cultures were positive for HSV DNA on PCR and showed expression of the LAT gene by in situ hybridization and Northern blot (RNA) hybridization. The present results indicate that both nonproductive and lytic HSV infection can be produced in vitro and the outcome of the infection depends on the time of viral inoculation in relation to epithelial maturation.


Genomics detects population structure within and between ocean basins in a circumpolar seabird: The white-chinned petrel.
The Southern Ocean represents a continuous stretch of circumpolar marine habitat, but the potential physical and ecological drivers of evolutionary genetic differentiation across this vast ecosystem remain unclear. We tested for genetic structure across the full circumpolar range of the white-chinned petrel (Procellaria aequinoctialis) to unravel the potential drivers of population differentiation and test alternative population differentiation hypotheses. Following range-wide comprehensive sampling, we applied genomic (genotyping-by-sequencing or GBS; 60,709 loci) and standard mitochondrial-marker approaches (cytochrome b and first domain of control region) to quantify genetic diversity within and among island populations, test for isolation by distance, and quantify the number of genetic clusters using neutral and outlier (non-neutral) loci. Our results supported the multi-region hypothesis, with a range of analyses showing clear three-region genetic population structure, split by ocean basin, within two evolutionary units. The most significant differentiation between these regions confirmed previous work distinguishing New Zealand and nominate subspecies. Although there was little evidence of structure within the island groups of the Indian or Atlantic oceans, a small set of highly-discriminatory outlier loci could assign petrels to ocean basin and potentially to island group, though the latter needs further verification. Genomic data hold the key to revealing substantial regional genetic structure within wide-ranging circumpolar species previously assumed to be panmictic.


Identification of newborns at risk for autism using electronic medical records and machine learning.
Current approaches for early identification of individuals at high risk for autism spectrum disorder (ASD) in the general population are limited, and most ASD patients are not identified until after the age of 4. This is despite substantial evidence suggesting that early diagnosis and intervention improves developmental course and outcome. The aim of the current study was to test the ability of machine learning (ML) models applied to electronic medical records (EMRs) to predict ASD early in life, in a general population sample. We used EMR data from a single Israeli Health Maintenance Organization, including EMR information for parents of 1,397 ASD children (ICD-9/10) and 94,741 non-ASD children born between January 1st, 1997 and December 31st, 2008. Routinely available parental sociodemographic information, parental medical histories, and prescribed medications data were used to generate features to train various ML algorithms, including multivariate logistic regression, artificial neural networks, and random forest. Prediction performance was evaluated with 10-fold cross-validation by computing the area under the receiver operating characteristic curve (AUC; C-statistic), sensitivity, specificity, accuracy, false positive rate, and precision (positive predictive value [PPV]). All ML models tested had similar performance. The average performance across all models had C-statistic of 0.709, sensitivity of 29.93%, specificity of 98.18%, accuracy of 95.62%, false positive rate of 1.81%, and PPV of 43.35% for predicting ASD in this dataset. We conclude that ML algorithms combined with EMR capture early life ASD risk as well as reveal previously unknown features to be associated with ASD-risk. Such approaches may be able to enhance the ability for accurate and efficient early detection of ASD in large populations of children.


Ultrastructural comparison of Bonamia spp. (Haplosporidia) infecting ostreid oysters.
The ultrastructure of Bonamia from Ostrea angasi from Australia, Crassostrea ariakensis from the USA, O. puelchana from Argentina and O. edulis from Spain was compared with described Bonamia spp. All appear conspecific with B. exitiosa. The Bonamia sp. from Chile had similarities to the type B. exitiosa from New Zealand (NZ), but less so than the other forms recognized as B. exitiosa. Two groups of ultrastructural features were identified; those associated with metabolism (mitochondrial profiles, lipid droplets and endoplasmic reticulum), and those associated with haplosporogenesis (Golgi, indentations in the nuclear surface, the putative trans-Golgi network, perinuclear granular material and haplosporosome-like bodies). Metabolic features were regarded as having little taxonomic value, and as the process of haplosporogenesis is not understood, only haplosporosome shape and size may be of taxonomic value. However, the uni-nucleate stages of spore-forming haplosporidians are poorly known and may be confused with Bonamia spp. uni-nucleate stages. The many forms of NZ B. exitiosa have not been observed in other hosts, which may indicate that it has a plastic life cycle. Although there are similarities between NZ B. exitiosa and Chilean Bonamia in the development of a larger uni-nucleate stage and the occurrence of cylindrical confronting cisternae, the clarification of the identity of Chilean Bonamia must await molecular studies.


Sézary T-cell activating factor is a Chlamydia pneumoniae-associated protein.
We previously identified a protein that was stimulatory for malignant Sézary T cells, termed Sézary T-cell activating factor (SAF). However, the identity of this protein has not been fully elucidated, nor has it's role been determined in the pathogenesis of cutaneous T-cell lymphoma (CTCL). The basis for epidermotropism and proliferation of malignant cells in the skin of patients with CTCL is unknown. Using a monoclonal antibody inhibitory for SAF activity, we demonstrated that SAF is present in the skin of 16 of 27 samples from patients with mycosis fungoides, the predominant form of CTCL. In this report, the SAF determinant is demonstrated to be associated with Chlamydia pneumoniae bacteria by immunohistochemistry, immunoelectron microscopy, and culture analysis. Reactivity of antibodies against an outer membrane protein of C. pneumoniae or against the lipopolysaccharide of Chlamydiae spp. demonstrated that these determinants are coexpressed in 90% of the SAF-positive samples. We confirmed the presence of C. pneumoniae DNA and RNA in the skin by PCR and reverse transcription-PCR and by sequence analysis of the PCR products. The expression of the C. pneumoniae antigens and SAF appears to be associated with active disease in that C. pneumoniae antigens were absent or greatly diminished in the skin of three patients examined after Psoralen and long-wave UVA radiation treatment. Our results suggest that SAF is a Chlamydia-associated protein and that further investigation is warranted to determine whether SAF and C. pneumoniae play a role in the pathogenesis of CTCL.


Blood pressure control in acute cerebrovascular disease.
Acute cerebrovascular diseases (ischemic stroke, intracerebral hemorrhage, and subarachnoid hemorrhage) affect 780,000 Americans each year. Physicians who care for patients with these conditions must be able to recognize when acute hypertension requires treatment and should understand the principles of cerebral autoregulation and perfusion. Physicians should also be familiar with the various pharmacologic agents used in the treatment of cerebrovascular emergencies. Acute ischemic stroke frequently presents with hypertension, but the systemic blood pressure should not be treated unless the systolic pressure exceeds 220 mm Hg or the diastolic pressure exceeds 120 mm Hg. Overly aggressive treatment of hypertension can compromise collateral perfusion of the ischemic penumbra. Hypertension associated with intracerebral hemorrhage can be treated more aggressively to minimize hematoma expansion during the first 3 to 6 hours of illness. Subarachnoid hemorrhage is usually due to aneurysmal rupture; systolic blood pressure should be kept <150 mm Hg to prevent re-rupture of the aneurysm. Nicardipine and labetalol are recommended for rapidly treating hypertension during cerebrovascular emergencies. Sodium nitroprusside is not recommended due to its adverse effects on cerebral autoregulation and intracranial pressure. Hypoperfusion of the injured brain should be avoided at all costs.


Mechanisms of translational regulation in Drosophila.
Translational regulation plays an essential role in many phases of the Drosophila life cycle. During embryogenesis, specification of the developing body pattern requires co-ordination of the translation of oskar, gurken and nanos mRNAs with their subcellular localization. In addition, dosage compensation is controlled by Sex-lethal-mediated translational regulation while dFMR1 (the Drosophila homologue of the fragile X mental retardation protein) controls translation of various mRNAs which function in the nervous system. Here we describe some of the mechanisms that are utilized to regulate these various processes. Our review highlights the complexity that can be involved with multiple factors employing different mechanisms to control the translation of a single mRNA.


An unusual hemoglobin anomaly and its relation to alpha-thalassemia and hemoglobin-H disease.
A Chinese family with hemoglobin H in the propositus has been reinvestigated. Although the original propositus is now deceased, a sister has the same hematological manifestations. Her hemoglobin, like that of the deceased sister, contains hemoglobins A, H, and Bart's. In addition, however, two minor components have been detected. These minor components appear to have abnormal alpha-chains and are also present in the maternal grandmother, the mother, a maternal aunt, and three other siblings but only in about one-tenth the amount. One of the minor components may be the same as Hb-Thai (25). The father has the characteristics of classical alpha-thalassemia. These results are discussed in relation to current concepts of alpha-thalassemia as they relate to "silent" and "classical" alpha-thalassemia and to possible multiple alpha-chain loci.


Effects of persistent luminescence decay on mechanoluminescence phenomena of SrAl2O4:Eu2+, Dy3+ materials.
This Letter reveals for the first time, to the best of our knowledge, the effects of stress-free persistent luminescence (PL) decay on the mechanoluminescence (ML) phenomena and the effects of stresses and strain rates on the PL decay of SrAl(2)O(4):Eu(2+), Dy(3+) (SAOED) materials. Previous research on ML phenomena in this material has focused on the effects of strain rates and stress variations on ML light intensity. However, experimental evidence provided herein shows that the ML light emission is also related to the PL decay time elapsed until the onset of stressing and the PL decay rate is dependent on the stress, strain rate, and the stress-free PL decay time interval. For quantitative stress measurements using SAOED materials, understanding of ML light sensitivity and its dependence on critical factors (strain rate, stress-free PL decay time interval, photoexcitation time, instantaneous PL decay rate, etc.) is crucially important. This Letter provides new and important perspectives that are essential for developing predictive models and/or calibration procedures for ML stress sensors.


'A field for private members': The Wolfenden committee and Scottish homosexual law reform, 1950-67.
The proceedings and report of the Wolfenden Committee on Prostitution and Homosexual Offences (1954-7) figure prominently in the historiography of homosexuality in later twentieth-century Britain. However, in the main, research has centred on the social politics of the Committee and its implications for sexual law reform in England, and there is a notable lack of regional studies. Using a range of government archives, this article focuses on the written and oral evidence of Scottish witnesses to the Committee. It documents the pre-existing legal and medical provisions for the treatment of 'homosexual offences' in Scotland, and surveys the Scottish evidence for and against the decriminalization of homosexual practices. Thereafter, it examines the views of the Scottish members of the Committee in the context of the Wolfenden Report. The article then surveys the wide-ranging opposition to homosexual law reform within Scotland in the period 1957-67, culminating in its exclusion from the 1967 Sexual Offences Act. Finally, it evaluates the implications of the Scottish experience and concludes that, in some important respects, it does not conform to the innovative and transitional picture advanced in many previous interpretations of the Wolfenden Committee and its aftermath.


Safety Assessment of a Hemp Extract using Genotoxicity and Oral Repeat-Dose Toxicity Studies in Sprague-Dawley Rats.
Cannabinoids are extracted from Cannabis sativa L. and are used for a variety of medicinal purposes. Recently, there has been a focus on the cannabinoid Cannabidiol (CBD) and its potential benefits. This study investigated the safety of a proprietary extract of C. sativa, consisting of 9% hemp extract (of which 6.27% is CBD) and 91% olive oil. The mutagenic potential of the hemp extract was evaluated with the AMES assay inclusive of a hepatic drug metabolizing mix (S9) rich in CYP enzymes. The test article did not elicit evidence of bacterial mutagenicity. GLP compliant 14-day and a 90-day toxicity study were conducted. Olive oil was used as a control. The 90-day study had a 28-day recovery period. Treatments for the 14-day non-recovery range-finding study were 0, 1000, 2000 and 4000 mg test article/kg body weight (bw)/day for 14 days. There was a non-statistically significant (p > 0.05) decrease in body weights for the male and female rats receiving the test article. Hypoactivity, hyperactivity, reduced food consumption and piloerection were observed in the rats receiving 4000 mg test article/kg bw. Histopathology showed an increase in the size of liver cells (hypertrophy) around the central vein (centrilobular) in Groups 3 (3/10) and 4 (5/10) that correlated with increased liver weights. In the 90-day study, 8 groups of rats were dosed with 0, 200, 400 and 800 mg test article/kg bw/day. Groups 5 to 8 had a 28-day recovery. There were no test article-linked changes in clinical observations, physical examinations, Functional Observation Battery, ophthalmology, Motor Activity Assessment, hematology, clinical chemistries and macropathology (all groups). With the exception of the liver and adrenal gland, no test article-linked pathology was observed. For all rats receiving the test article, histopathology showed hypertrophy of liver cells around the central vein. The increase of liver weight is most likely caused by hypertrophy due to up-regulation of the hepatic drug metabolizing enzymes. The hepatocellular hypertrophy was completely reversed in 28 days and was not considered to be an adverse effect. Vacuolization of the adrenal zona fasciculata was observed in the control and 800 mg test article/kg bw groups. The vacuolization of the zona fasciculata was of the same incidence and severity in treatment and control male rats and correlated with an increased in the weights of the adrenal glands. In addition, a statistically significant increase (p<0.05) in adrenal-to-body weight ratios was observed for females receiving 800 mg test article/kg bw. This increase in adrenal-to-body weight ratio did not correlate with any of the pathology findings. The NOAEL for the test article is 800 mg/kg bw/day for female and 400 mg/kg bw/day for male Sprague Dawley rats.


Quality and Quantity of the Elbow Arthroscopy Literature: A Systematic Review and Meta-Analysis.
The purpose of this article is to perform a systematic review and meta-analysis of elbow arthroscopy literature to answer the following questions: "Across the world, what demographic of patients are undergoing elbow arthroscopy, what are the most common indications for elbow arthroscopy, and how good is the evidence?" The authors hypothesized that patients who undergo elbow arthroscopy will be chiefly age <40 years, the most common indication for elbow arthroscopy will be a release/débridement, and the evidence regarding elbow arthroscopy will be poor. Also, no significant differences will exist in elbow arthroscopy publications, subjects, outcomes, and techniques based on continent/country of publication. A systematic review was registered with the International Prospective Register of Ongoing Systematic Reviews (PROSPERO) and performed with Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines using 3 publicly available databases. Therapeutic clinical outcome investigations reporting arthroscopic elbow outcomes with levels of evidence I-IV were eligible for inclusion. All study, subject, and surgical technique demographics were analyzed and compared between continents and countries. Statistics were calculated using 1-way analysis of variance (ANOVA) to compare between continents and Pearson's correlation coefficients to evaluate changes over time. In total, 112 studies were included (3093 subjects; 3168 elbows; 64% male; mean 34.9 ± 14.68 years. Mean 33.4 ± 26.02 months follow-up. Most studies were level IV evidence (94.6%) and had a low Modified Coleman Methodology Score (MCMS) (mean 28.1 ± 8.06). From 1985 through 2013, the number of publications significantly increased with time (P = .004) in all continents. The 3 most common indications for elbow arthroscopy were osteochondritis dissecans (OCD), lateral epicondylitis, and release and débridement. The number of reported cases for the 3 most common indications significantly increased over time but did not differ between regions (P > .05 in all cases). Thirty-two studies (28.6%) reported clinical outcomes, the most common of which was the Mayo Elbow Performance Score, reported in 9.8% of studies. The quantity, but not the quality, of arthroscopic elbow publications has significantly increased over time. Most patients undergo elbow arthroscopy for lateral epicondylitis, OCD, and release and débridement. Pathology and indications do not appear to differ geographically with more men undergoing elbow arthroscopy than women.


Three-dimensional coherent transfer function for a confocal microscope with two D-shaped pupils.
The three-dimensional coherent transfer function for D-shaped pupils in reflection-mode confocal scanning microscopy is analytically derived under the paraxial approximation. Three-dimensional numerical plots are presented, showing the dependence of the transfer functions on the width of a central divider. The applications in fiber-optical confocal scanning microscopy are also discussed.


Regulation of the secondary antibody response in vitro. Enhancement by actinomycin D and inhibition by a macromolecular product of stimulated lymph node cultures.
Two opposite effects of actinomycin D on antibody synthesis have been studied in organ cultures of rabbit lymph node fragments. These cultures were prepared from previously primed rabbits and stimulated with antigen(s) on day 0 to yield a secondary response, whose inductive phase extended to about day 9 and whose productive phase may last for several months in the serum-free medium described here. Concentrations of actinomycin D above 0.01 microM (0.012 microg/ml) produce inhibition of antibody synthesis during both phases of the response. However, antibody synthesis is about 10 times more sensitive to inhibition by this drug when it is added during the inductive phase than during the productive phase. During the latter phase, synthesis is more rapidly terminated as the drug level approaches 10 /microM (12.5 microg/ml). At this level the 50% synthesis time is about 2.8 hr, which is identical with that found when 5-10 microM puromycin is added to the medium of parallel cultures. Transient enhancement of antibody synthesis is frequently produced by a brief exposure to low levels of actinomycin D (generally less than 0.01 microM). Enhancement appears in precise temporal association with actinomycin pulses added for 2 days or less only between days 6 and 16. This apparent enhancement of antibody synthesis resembles the increased enzyme synthesis described by Garren et al. (6) and led to a search for an antibody-inhibitory material (AIM) whose synthesis might be stopped preferentially by low levels of the drug. Stimulated lymph node cultures produce between days 6 and 15 a nondialyzable material which inhibits antibody synthesis during the productive phase of heterologous antigen-antibody culture systems. Just as enhancement with low levels of actinomycin D appears within 2 hr after the drug has been added to cultures, so inhibition occurs within 4 hr of adding AIM to cultures during their productive phase. These observations suggest that AIM is analogous to the translational "repressor" postulated by Garren et al. (6). AIM has relevance in two areas of immunology: (a) it may be the explanation for many examples of antigenic competition, and (b) it may represent a normal control mechanism for the productive phase.


Relationship between the use of electronic devices and susceptibility to multiple sclerosis.
Multiple sclerosis (MS) is an autoimmune condition influenced by both genetic and environmental factors. Dirty electricity generated by electronic equipment is one of the environmental factors that may directly or indirectly impact MS susceptibility. The current Study aimed to evaluate the relationship between the usage time of electronic equipment and susceptibility to MS in North-West Iranian people. This approach was carried out upon 471 MS-diagnosed patients and 453 healthy participants as control group in East Province of Azerbaijan. By utilizing structured questionnaires, the information of all participants about usage status of some electronic devices was obtained. Data were analyzed by IBM SPSS Statistics version 18.0 and the quantitative variables were analyzed by Chi Square and Independent sample t tests. P values below or equal to 0.05 were considered as significant. Among the evaluated items in this approach, the utilization of cell phones and satellite television dishes were significantly higher in MS patients (p < 0.001, p = 0.07). Furthermore, a correlation was observed between sleeping with cell phone and/or laptop under the pillow (p = 0.011) and MS disease; however, there was no significant differences between MS patients and controls in computer using and television watching. Our study reinforces the concept that the utilization of some electronic devices and the continuous exposure to dirty electricity would increase the risk of MS disease thereupon by enhancing the cognizance of adverse effects of dirty electricity and reducing the time spent over electronic devices during adolescence and adulthood the occurrence probability of MS could be declined.


Identification and characterization of a second polygalacturonase gene of Aspergillus niger.
The filamentous fungus Aspergillus niger produces several endopolygalacturonases that are involved in the degradation of pectin. PGI, the enzyme representing the second most abundant activity in a commercial enzyme preparation, was further characterized and the corresponding gene was isolated. The nucleotide sequence of the pgaI gene was determined and the protein coding region was found to be interrupted by two short introns, one of which has a unusual donor splice site. The deduced 368 amino acids long protein with a putative prepropeptide of 31 amino acids shows 60% sequence identity to PGII in the mature protein. PGI overproducing A. niger strains were obtained by cotransformation with the cloned gene.


Infected cell protein (ICP)47 enhances herpes simplex virus neurovirulence by blocking the CD8+ T cell response.
The herpes simplex virus (HSV) infected cell protein (ICP)47 blocks CD8+ T cell recognition of infected cells by inhibiting the transporter associated with antigen presentation (TAP). In vivo, HSV-1 replicates in two distinct tissues: in epithelial mucosa or epidermis, where the virus enters sensory neurons; and in the peripheral and central nervous system, where acute and subsequently latent infections occur. Here, we show that an HSV-1 ICP47- mutant is less neurovirulent than wild-type HSV-1 in mice, but replicates normally in epithelial tissues. The reduced neurovirulence of the ICP47- mutant was due to a protective CD8+ T cell response. When compared with wild-type virus, the ICP47- mutant expressed reduced neurovirulence in immunologically normal mice, and T cell-deficient nude mice after reconstitution with CD8+ T cells. However, the ICP47- mutant exhibited normal neurovirulence in mice that were acutely depleted of CD8+ T cells, and in nude mice that were not reconstituted, or were reconstituted with CD4+ T cells. In contrast, CD8+ T cell depletion did not increase the neurovirulence of an unrelated, attenuated HSV-1 glycoprotein (g)E- mutant. ICP47 is the first viral protein shown to influence neurovirulence by inhibiting CD8+ T cell protection.


Magnetic resonance imaging of renal abnormalities in patients with congenital osseous anomalies of the spine.
Patients with congenital osseous anomalies of the spine are known to have a high prevalence of abnormalities in the renal system and of the spinal cord. Today, the screening tools of choice to detect these abnormalities include ultrasonography of the kidneys and collecting system and magnetic resonance imaging of the spine. A single screening tool that can identify both renal and intraspinal anomalies would be ideal. Imaging studies of all patients with a congenital osseous anomaly of the spine seen at our institution during a ten-year period were retrospectively reviewed. Only patients who had had both a sonogram of the renal system and a magnetic resonance imaging study of the entire spine were included in the investigation. All studies were reviewed blindly by a pediatric radiologist for this study. One hundred and fifty-three patients met the criteria for inclusion in the study. Forty-one patients (27%) had a total of forty-seven renal abnormalities noted on both the sonogram and the magnetic resonance imaging scan. In no instance was a renal anomaly seen on one study and not on the other. When properly performed, screening magnetic resonance imaging scans of the spine can show renal abnormalities, thus obviating the need for a separate screening renal ultrasound study.


Early diagnosis of mucosal squamous cell carcinoma of the esophagus: including two interesting cases of superficial spreading-type and multicentric-type squamous cell carcinomas.
We reviewed 10 patients with esophageal mucosal carcinoma in order to improve the early diagnosis of the disease. Histologically seven of the 14 lesions were carcinomas in situ (epithelial cancer), and the other seven lesions were carcinomas confined to the mucosa other than epithelial cancer (muscularis mucosae cancer), all 14 lesions were squamous cell carcinomas (SCC). One of these seven mucosal SCC, which demonstrated an extensive spreading-type SCC in which the size of the SCC was 7 cm long while extending entirely around the esophageal lumen in circumferential spread, is described in detail, and multiple epithelial cancers existed separately in one case. Eleven lesions diagnosed before operation showed abnormal findings on conventional endoscopy regardless of the size and depth of transmural invasion. An additional lesion was visible with dye endoscopy as an unstained area, but it was not visible with radiography or conventional endoscopy. Dye endoscopy using Lugol solution is very important because it allows detection and evaluation of the extent of esophageal mucosal cancer.


The eclectic and multiple therapy of a shoe fetishist.
This case history presents not only the therapists' point of view but also the client's. Four critical periods during therapy with a shoe fetishist were described by the two therapists and the client. The results of this procedure suggest that it is a facilitating method of gaining insight into the therapeutic process.


Characterization of plaque components with intravascular ultrasound elastography in human femoral and coronary arteries in vitro.
The composition of plaque is a major determinant of coronary-related clinical syndromes. Intravascular ultrasound (IVUS) elastography has proven to be a technique capable of reflecting the mechanical properties of phantom material and the femoral arterial wall. The aim of this study was to investigate the capability of intravascular elastography to characterize different plaque components. Diseased human femoral (n=9) and coronary (n=4) arteries were studied in vitro. At each location (n=45), 2 IVUS images were acquired at different intraluminal pressures (80 and 100 mm Hg). With the use of cross-correlation analysis on the high-frequency (radiofrequency) ultrasound signal, the local strain in the tissue was determined. The strain was color-coded and plotted as an additional image to the IVUS echogram. The visualized segments were stained on the presence of collagen, smooth muscle cells, and macrophages. Matching of elastographic data and histology were performed with the use of the IVUS echogram. The cross sections were segmented in regions (n=125) that were based on the strain value on the elastogram. The dominant plaque types in these regions (fibrous, fibro-fatty, or fatty) were obtained from histology and correlated with the average strain and echo intensity. The strain for the 3 plaque types as determined by histology differed significantly (P=0.0002). This difference was mainly evident between fibrous and fatty tissue (P=0.0004). The plaque types did not reveal echo-intensity differences in the IVUS echogram (P=0.882). Different strain values are found between fibrous, fibro-fatty, and fatty plaque components, indicating the potential of intravascular elastography to distinguish different plaque morphologies.


Performance comparison between k-tuple distance and four model-based distances in phylogenetic tree reconstruction.
Phylogenetic tree reconstruction requires construction of a multiple sequence alignment (MSA) from sequences. Computationally, it is difficult to achieve an optimal MSA for many sequences. Moreover, even if an optimal MSA is obtained, it may not be the true MSA that reflects the evolutionary history of the underlying sequences. Therefore, errors can be introduced during MSA construction which in turn affects the subsequent phylogenetic tree construction. In order to circumvent this issue, we extend the application of the k-tuple distance to phylogenetic tree reconstruction. The k-tuple distance between two sequences is the sum of the differences in frequency, over all possible tuples of length k, between the sequences and can be estimated without MSAs. It has been traditionally used to build a fast 'guide tree' to assist the construction of MSAs. Using the 1470 simulated sets of sequences generated under different evolutionary scenarios, the neighbor-joining trees and BioNJ trees, we compared the performance of the k-tuple distance with four commonly used distance estimators including Jukes-Cantor, Kimura, F84 and Tamura-Nei. These four distance estimators fall into the category of model-based distance estimators, as each of them takes account of a specific substitution model in order to compute the distance between a pair of already aligned sequences. Results show that trees constructed from the k-tuple distance are more accurate than those from other distances most time; when the divergence between underlying sequences is high, the tree accuracy could be twice or higher using the k-tuple distance than other estimators. Furthermore, as the k-tuple distance voids the need for constructing an MSA, it can save tremendous amount of time for phylogenetic tree reconstructions when the data include a large number of sequences.


Wave kinetics of random fibre lasers.
Traditional wave kinetics describes the slow evolution of systems with many degrees of freedom to equilibrium via numerous weak non-linear interactions and fails for very important class of dissipative (active) optical systems with cyclic gain and losses, such as lasers with non-linear intracavity dynamics. Here we introduce a conceptually new class of cyclic wave systems, characterized by non-uniform double-scale dynamics with strong periodic changes of the energy spectrum and slow evolution from cycle to cycle to a statistically steady state. Taking a practically important example-random fibre laser-we show that a model describing such a system is close to integrable non-linear Schrödinger equation and needs a new formalism of wave kinetics, developed here. We derive a non-linear kinetic theory of the laser spectrum, generalizing the seminal linear model of Schawlow and Townes. Experimental results agree with our theory. The work has implications for describing kinetics of cyclical systems beyond photonics.


Achieving pregnancy safely for HIV-serodiscordant couples: a social ecological approach.
The recognition and fulfilment of the sexual and reproductive health and rights (SRHR) of all individuals and couples affected by HIV, including HIV-serodiscordant couples, requires intervention strategies aimed at achieving safe and healthy pregnancies and preventing undesired pregnancies. Reducing risk of horizontal and vertical transmission and addressing HIV-related infertility are key components of such interventions. In this commentary, we present challenges and opportunities for achieving safe pregnancies for serodiscordant couples through a social ecological lens. At the individual level, knowledge (e.g. of HIV status, assisted reproductive technologies) and skills (e.g. adhering to antiretroviral therapy or pre-exposure prophylaxis) are important. At the couple level, communication between partners around HIV status disclosure, fertility desires and safer pregnancy is required. Within the structural domain, social norms, stigma and discrimination from families, community and social networks influence individual and couple experiences. The availability and quality of safer conception and fertility support services within the healthcare system remains essential, including training for healthcare providers and strengthening integration of SRHR and HIV services. Policies, legislation and funding can improve access to SRHR services. A social ecological framework allows us to examine interactions between levels and how interventions at multiple levels can better support HIV-serodiscordant couples to achieve safe pregnancies. Strategies to achieve safer pregnancies should consider interrelated challenges at different levels of a social ecological framework. Interventions across multiple levels, implemented concurrently, have the potential to maximize impact and ensure the full SRHR of HIV-serodiscordant couples.


Successful treatment with bortezomib and dexamethasone for proliferative glomerulonephritis with monoclonal IgG deposits in multiple myeloma: a case report.
Proliferative glomerulonephritis with monoclonal IgG deposits (PGNMID) is a form of renal involvement by monoclonal IgG deposits that was found in mesangial, subendothelial or subepithelial regions. The distribution of glomerular deposits was completely different from that in monoclonal immunoglobulin deposition disease. PGNMID is reported to be rarely associated with a hematological malignancy. Previously, only five cases of PGNMID with multiple myeloma have been reported. However, the pathogenic relationship between PGNMID and multiple myeloma was unclear because a detailed description was not provided. We report that a patient with PGNMID associated with multiple myeloma was treated with bortezomib and dexamethasone and underwent the second renal biopsy after treatment, showing that chemotherapy was effective for PGNMID clinically and pathologically. A 75-year-old man presented with progressive leg edema, had nephrotic range proteinuria, hypoalbuminemia, moderate renal failure, and occult blood in his urine. Electrophoresis results showed serum and urinary monoclonal spikes of IgGκ type immunoglobulin. A renal biopsy specimen showed lobular mesangial proliferation with mesangiolysis, glomerular micro-aneurysm, and endocapillary hypercellularity. Immunofluorescence results revealed strong granular capillary and mesangial staining for IgG1, C3 and κ light chain in glomeruli without tubular deposits of any immunoglobulin. Electron microscopy also showed dense granular deposits in subendothelial and mesangial areas. PGNMID associated with multiple myeloma (IgGκ type) was diagnosed on the basis of a subsequent bone marrow examination. Bortezomib and dexamethasone therapy significantly reduced proteinuria and elevated serum albumin level. Eight months later, the second renal biopsy showed no active lesions and that the IgG1 and κ light chain deposits had drastically disappeared. This is the first case of PGNMID with multiple myeloma successfully treated with bortezomib and dexamethasone in which comparative renal biopsies were performed before and after treatment. Our findings suggest the pathogenesis of PGNMID and therapeutic options for PGNMID.


PD 404,182 is a virocidal small molecule that disrupts hepatitis C virus and human immunodeficiency virus.
We describe a virucidal small molecule, PD 404,182, that is effective against hepatitis C virus (HCV) and human immunodeficiency virus (HIV). The median 50% inhibitory concentrations (IC(50)s) for the antiviral effect of PD 404,182 against HCV and HIV in cell culture are 11 and 1 μM, respectively. The antiviral activity of PD 404,182 is due to the physical disruption of virions that is accompanied to various degrees (depending on the virus and exposure temperature/time) by the release of viral nucleic acids into the surrounding medium. PD 404,182 does not directly lyse liposomal membranes even after extended exposure, and it shows no attenuation in antiviral activity when preincubated with liposomes of various lipid compositions, suggesting that the compound inactivates viruses through interaction with a nonlipid structural component of the virus. The virucidal activity of PD 404,182 appears to be virus specific, as little to no viral inactivation was detected with the enveloped Dengue and Sindbis viruses. PD 404,182 effectively inactivates a broad range of primary isolates of HIV-1 as well as HIV-2 and simian immunodeficiency virus (SIV), and it does not exhibit significant cytotoxicity with multiple human cell lines in vitro (50% cytotoxic concentration, >300 μM). The compound is fully active in cervical fluids, although it exhibits decreased potency in the presence of human serum, retains its full antiviral potency for 8 h when in contact with cells, and is effective against both cell-free and cell-associated HIV. These qualities make PD 404,182 an attractive candidate anti-HIV microbicide for the prevention of HIV transmission through sexual intercourse.


Neutral Cyclometalated Iridium(III) Complexes Bearing Substituted N-Heterocyclic Carbene (NHC) Ligands for High-Performance Yellow OLED Application.
The synthesis, crystal structure, and photophysics of a series of neutral cyclometalated iridium(III) complexes bearing substituted N-heterocyclic carbene (NHC) ancillary ligands ((C∧N)2Ir(R-NHC), where C∧N and NHC refer to the cyclometalating ligand benzo[h]quinoline and 1-phenylbenzimidazole, respectively) are reported. The NHC ligands were substituted with electron-withdrawing or -donating groups on C4' of the phenyl ring (R = NO2 (Ir1), CN (Ir2), H (Ir3), OCH3 (Ir4), N(CH3)2 (Ir5)) or C5 of the benzimidazole ring (R = NO2 (Ir6), N(CH3)2 (Ir7)). The configuration of Ir1 was confirmed by a single-crystal X-ray diffraction analysis. The ground- and excited-state properties of Ir1-Ir7 were investigated by both spectroscopic methods and time-dependent density functional theory (TDDFT) calculations. All complexes possessed moderately strong structureless absorption bands at ca. 440 nm that originated from the C∧N ligand based 1π,π*/1CT (charge transfer)/1d,d transitions and very weak spin-forbidden 3MLCT (metal-to-ligand charge transfer)/3LLCT (ligand-to-ligand charge transfer) transitions beyond 500 nm. Electron-withdrawing substituents caused a slight blue shift of the 1π,π*/1CT/1d,d band, while electron-donating substituents induced a red shift of this band in comparison to the unsubstituted complex Ir3. Except for the weakly emissive nitro-substituted complexes Ir1 and Ir6 that had much shorter lifetimes (≤160 ns), the other complexes are highly emissive in organic solutions with microsecond lifetimes at ca. 540-550 nm at room temperature, with the emitting states being predominantly assigned to 3π,π*/3MLCT states. Although the effect of the substituents on the emission energy was insignificant, the effects on the emission quantum yields and lifetimes were drastic. All complexes also exhibited broad triplet excited-state absorption at 460-700 nm with similar spectral features, indicating the similar parentage of the lowest triplet excited states. The highly emissive Ir2 was used as a dopant for organic light-emitting diode (OLED) fabrication. The device displayed a yellow emission with a maximum current efficiency (ηc) of 71.29 cd A-1, a maximum luminance (Lmax) of 32747 cd m-2, and a maximum external quantum efficiency (EQE) of 20.6%. These results suggest the potential of utilizing this type of neutral Ir(III) complex as an efficient yellow phosphorescent emitter.


Cerebral Autoregulation during Orthostatic Challenge in Congenital Central Hypoventilation Syndrome.
Rationale: Congenital central hypoventilation syndrome (CCHS) is a rare autonomic disorder with altered regulation of breathing, heart rate (HR), and blood pressure (BP). Aberrant cerebral oxygenation in response to hypercapnia/hypoxia in CCHS raises the concern that altered cerebral autoregulation may contribute to CCHS-related, variably impaired neurodevelopment. Objectives: To evaluate cerebral autoregulation in response to orthostatic challenge in CCHS cases versus controls. Methods: CCHS and age- and sex-matched control subjects were studied with head-up tilt (HUT) testing to induce orthostatic stress. Fifty CCHS and 100 control HUT recordings were included. HR, BP, and cerebral oxygen saturation (regional oxygen saturation) were continuously monitored. The cerebral oximetry index (COx), a real-time measure of cerebral autoregulation based on these measures, was calculated. Measurements and Main Results: HUT resulted in a greater mean BP decrease from baseline in CCHS versus controls (11% vs. 6%; P < 0.05) and a diminished increase in HR in CCHS versus controls (11% vs. 18%; P < 0.01) in the 5 minutes after tilt-up. Despite a similar COx at baseline, orthostatic provocation within 5 minutes of tilt-up caused a 50% greater increase in COx (P < 0.01) and a 29% increase in minutes of impaired autoregulation (P < 0.02) in CCHS versus controls (4.0 vs. 3.1 min). Conclusions: Cerebral autoregulatory mechanisms appear to be intact in CCHS, but the greater hypotension observed in CCHS consequent to orthostatic provocation is associated with greater values of COx/impaired autoregulation when BP is below the lower limits of autoregulation. Effects of repeated orthostatic challenges in everyday living in CCHS necessitate further study to determine their influence on neurodevelopmental disease burden.


Vibrational spectra of methane clathrate hydrates from molecular dynamics simulation.
Molecular dynamics simulations were performed on methane clathrate hydrates at ambient conditions. Thermal expansion results over the temperature range 60-300 K show that the unit cell volume increases with temperature in agreement with experiment. Power spectra were obtained at 273 K from velocity autocorrelation functions for selected atoms, and normal modes were assigned. The spectra were further classified according to individual atom types, allowing the assignment of contributions from methane molecules located in small and large cages within the structure I unit cell. The symmetric C-H stretch of methane in the small cages occurs at a higher frequency than for methane located in the large cages, with a peak separation of 14 cm(-1). Additionally, we determined that the symmetric C-H stretch in methane gas occurs at the same frequency as methane in the large cages. Results of molecular dynamics simulations indicate the use of power spectra obtained from the velocity autocorrelation function is a reliable method to investigate the vibrational behavior of guest molecules in clathrate hydrates.


Health care: development of data for a marketing approach.
Marketing in health care is a relatively new process. It is a business tool that can serve a very useful purpose. Health care management has become aware of the usefulness of marketing in long-range planning. Through a well-thought-out marketing plan, the provider will not be leaving the future to chance. A well-conceived, patient-oriented, competitor-aware marketing plan should place the medical practice at a strategic advantage as the health care industry joins other industries in the competitive marketplace for the consumer's dollar.The ever-increasing political and regulatory environment that the health care field is undergoing emphasizes the need for the inclusion of marketing skills, such as cost containment, in the medical curriculum. It should be the obligation of the training facilities as well as medical societies to respond to this need by providing the education that will enable black providers to survive in this competitive environment.