Ultrasensitive chemosensory responses by a protozoan to epinephrine and other neurochemicals.
A behavioral assay was developed based on differential tendency of a protozoan to attach to an agar gel containing the test substance. The heterotrophic marine dinoflagellate Crypthecodinium (Gyrodinium) cohnii responded negatively (less tendency to attach) to epinephrine at concentrations above 5 X 10(-15)M and to norepinephrine at concentrations above 5 X 10(-9)M. Response to choline as choline H2 citrate, choline bitartrate, and choline chloride was negative above 10(-7)M, but response to the choline analog carbachol was positve (greater tendency to attach) in the range 5 X 10(-6) to 5 X 10(-4)M. Other responses to neurochemicals at comparable concentrations were: dopa, betaine, and glycine--positive; L-glutamic acid, tryptophan, putrescine, and taurine--negative. Serotonin was inert, responses to tyrosine and gamma-aminobutyric acid were variable, and phenylalanine (6 X 10(-3)M) and 5-hydroxytryptophan (5 X 10(-4)M) were negative only at the highest concentrations tested.


Biosilica-coated kappa-carrageenan microspheres for yeast alcohol dehydrogenase encapsulation.
In this study, a novel polysaccharide/inorganic hybrid biocomposite was prepared through biomineralization-inspired process for efficient immobilization of yeast alcohol dehydrogenase (YADH). YADH-encapsulated kappa-carrageenan microspheres (KCM) were first coated with chitosan, which was used to guide and catalyze the biomimetic formation of silica, and then coated with silica derived from tetraethoxysiliane (TEOS). Scanning electron microscopy (SEM) equipped with a energy dispersive X-ray spectrometer (EDX) was employed to investigate the composition and thickness of silica film. Compared with KCM, the silica-coated kappa-carrageenan microspheres (SKCM) containing YADH exhibited improved anti-swelling and catalytic properties. Enzyme leakage of YADH in KCM was detected to be 63.9% after 1 h, while the enzyme leakage in SKCM was as low as 18.2%. The KCM adsorbed water promptly and after 1 h maximum water uptake can be as high as 1576 wt%, while the water uptake of SKCM was only 143 wt% even after 48 h. The optimum pH and temperature for encapsulated YADH were pH 6.5 and 25 degrees C, which were just the same as those for free YADH, but the encapsulated YADH exhibited broader pH and temperature ranges for high activity. Furthermore, the relative activity of YADH in KCM declined almost to zero after 8 recycles, while the relative activity of YADH in SKCM still maintained more than 50%. The significantly increased recycling stability of YADH in SKCM may be attributed to the effective inhibition of enzyme leakage by the compact biosilica layer.


Predicted climate changes for the years to come and implications for disease impact studies.
The paper presents a review of the current ability of the climate modelling community to produce predictions of future climate change. Predictions for the next few decades are reasonably robust, whereas predictions for later time periods depend on uncertainties in climate model structure and on the unknown future course of greenhouse gas emissions. Some regional features are noticeable; however, meaningful interpretation of these can only presently be made at spatial scales that are considerably larger than those required for making sound estimates of the effects of future climate change on animal health. The implication is that current climate change predictions should be considered indicative rather than accurate.


Evaluating melanoma drug response and therapeutic escape with quantitative proteomics.
The evolution of cancer therapy into complex regimens with multiple drugs requires novel approaches for the development and evaluation of companion biomarkers. Liquid chromatography-multiple reaction monitoring mass spectrometry (LC-MRM) is a versatile platform for biomarker measurement. In this study, we describe the development and use of the LC-MRM platform to study the adaptive signaling responses of melanoma cells to inhibitors of HSP90 (XL888) and MEK (AZD6244). XL888 had good anti-tumor activity against NRAS mutant melanoma cell lines as well as BRAF mutant cells with acquired resistance to BRAF inhibitors both in vitro and in vivo. LC-MRM analysis showed HSP90 inhibition to be associated with decreased expression of multiple receptor tyrosine kinases, modules in the PI3K/AKT/mammalian target of rapamycin pathway, and the MAPK/CDK4 signaling axis in NRAS mutant melanoma cell lines and the inhibition of PI3K/AKT signaling in BRAF mutant melanoma xenografts with acquired vemurafenib resistance. The LC-MRM approach targeting more than 80 cancer signaling proteins was highly sensitive and could be applied to fine needle aspirates from xenografts and clinical melanoma specimens (using 50 μg of total protein). We further showed MEK inhibition to be associated with signaling through the NFκB and WNT signaling pathways, as well as increased receptor tyrosine kinase expression and activation. Validation studies identified PDGF receptor β signaling as a potential escape mechanism from MEK inhibition, which could be overcome through combined use of AZD6244 and the PDGF receptor inhibitor, crenolanib. Together, our studies show LC-MRM to have unique value as a platform for the systems level understanding of the molecular mechanisms of drug response and therapeutic escape. This work provides the proof-of-principle for the future development of LC-MRM assays for monitoring drug responses in the clinic.


Iron metabolism in thalassemia intermedia.
Iron overload is frequently present in patients with thalassemia intermedia, and it becomes evident mainly after the second and third decades of life. The degree of the iron load is heterogeneous ranging from mild to severe. In this study we evaluated the iron status of 38 adult patients with thalassemia intermedia and we looked for factors possibly related to the observed heterogeneity of the iron status. The levels of transferrin saturation (TS), serum ferritin (SF) and desferrioxamine-induced urinary iron excretion (DFU) were spread in a wide range from normal to markedly increased. These indices did not correlate with other parameters such as age, hemoglobin levels and entity of the erythropoietic status. A significant difference in the degree of iron overload was observed between patients who underwent splenectomy and non-splenectomized patients. TS, SF and DFU were significantly higher in splenectomized than in non- splenectomized patients, indicating that the spleen could have a role in the regulation of iron metabolism in these patients.


HbA1c and Hypoglycemia Reductions at 24 and 52 Weeks With Sotagliflozin in Combination With Insulin in Adults With Type 1 Diabetes: The European inTandem2 Study.
The objective of this study was to evaluate the efficacy and safety of the dual sodium-glucose cotransporter 1 and 2 inhibitor sotagliflozin compared with placebo when combined with optimized insulin in adults with type 1 diabetes (T1D). In a double-blind, 52-week, international phase 3 trial, adults with T1D were randomized to placebo (n = 258) or once-daily oral sotagliflozin 200 mg (n = 261) or 400 mg (n = 263) after 6 weeks of insulin optimization. The primary outcome was change in HbA1c from baseline to 24 weeks. The first secondary end point was a composite of the proportion of patients with HbA1c <7.0%, no episode of severe hypoglycemia, and no episode of diabetic ketoacidosis (DKA) at week 24. Fasting glucose, weight, insulin dose, and safety end points were assessed through 52 weeks. At 24 weeks, placebo-adjusted changes in HbA1c from baseline (7.8%) were -0.37% and -0.35% with sotagliflozin 200 and 400 mg, respectively (P < 0.001), and differences were maintained at 52 weeks. At 52 weeks, greater proportions of sotagliflozin-treated patients (200 mg: 25.67%; 400 mg: 26.62%) than placebo-treated patients (14.34%; P ≤ 0.001) met the composite end point, and sotagliflozin 400 mg reduced fasting plasma glucose (-0.87 mmol/L; P = 0.008), weight (-2.92 kg; P < 0.001), and total daily insulin dose (-8.2%; P = 0.001). In a 24-week continuous glucose monitoring (CGM) substudy, postprandial glucose decreased (P ≤ 0.009) and CGM demonstrated up to 3 h more time in the target range of 3.9-10.0 mmol/L with sotagliflozin. Treatment satisfaction increased and diabetes distress decreased with sotagliflozin (P < 0.05 vs. placebo). The frequency of documented hypoglycemia was lower with sotagliflozin, and severe hypoglycemia occurred by week 52 in 13 patients (5.0%), 13 patients (5.0%), and 6 patients (2.3%) treated with placebo and sotagliflozin 200 and 400 mg, respectively. DKA occurred in 0 of 258 patients, 6 of 261 patients (2.3%), and 9 of 263 patients (3.4%) in these respective groups. In a 1-year study, sotagliflozin was associated with statistically significant HbA1c reductions. More episodes of DKA and fewer episodes of documented and severe hypoglycemia were observed in patients using sotagliflozin relative to those receiving placebo (ClinicalTrials.gov, NCT02421510).


[Diversity of Coccinellidae (Coleoptera) using aromatic plants (Apiaceae) as survival and reproduction sites in agroecological system].
Studies show that Apiaceae may provide concentrated vital resources for predator insects, stimulating their abundance, diversity and persistence in agricultural systems, thereby increasing their efficiency as biological control agents. Among the predatory insects, Coccinellidae (Coleoptera) on many different species both as larvae and adults, complementing their diet with pollen and/or nectar. This study aimed to determine the diversity and relative abundance of Coccinellidae species visiting plants of Anethum graveolens (dill), Coriandrum sativum (coriander) and Foeniculum vulgare (sweet fennel) (all Apiaceae), particularly in their blooming seasons, and to evaluate the potential of these aromatic species for providing the resources for survivorship and reproduction of coccinelids. Coccinellids were collected by removal of samplings from September to October, 2007. Besides one unidentified species of Chilocorinae, five species of Coccinellinae were collected: Coleomegilla maculata DeGeer, Coleomegilla quadrifasciata (Schönherr), Cycloneda sanguinea (L.), Eriopis connexa (Germar) and Hippodamia convergens Guérin-Meneville. Dill provided a significant increase in the abundance of coccinellids as compared to coriander and sweet fennel. These aromatic species were used by coccinellids as survival and reproduction sites, providing food resources (pollen and/or prey), shelter for larvae, pupae and adults, and mating and oviposition sites as well.


A cottontail rabbit papillomavirus strain (CRPVb) with strikingly divergent E6 and E7 oncoproteins: An insight in the evolution of papillomaviruses.
We previously observed that warts induced by an isolate of cottontail rabbit papillomavirus (CRPV) showed incomplete instead of systemic regression in some domestic rabbits. We report that the viral isolate contained, as a major component, a CRPV strain (CRPVb) showing an unexpectedly high divergence in the E6 and E7 open reading frames (ORFs), compared to the prototype CRPVa present in the isolate as a minor component. The E6 and E7 oncoproteins of CRPVa and -b disclosed only 87.5% identical amino acids and differed in size by three and two amino acids, respectively. This divergence involved (i) a great number (4.4%) of nucleotide substitutions and a high rate (83.3%) of nonsynonymous mutations; (ii) mutations changing the E6 and E7 stop codons; and (iii) in-frame sequence insertions in the E6 ORF (18 nucleotides) and downstream of the mutated E7 stop codon (6 nucleotides), both likely to result from a duplication of adjacent sequences. These extensive differences could account for distinct biological and antigenic properties. Strikingly, only four (0.8%) amino acids of the L1 major capsid protein were variable. Thus, it seems likely that sequence duplications and mutations affecting stop codons exert a strong selection pressure on the fixation of nonsynonymous mutations and that phylogenetic calculations based only on point mutations may misevaluate the time scale of the evolution of papillomaviruses.


Manometric evidence of earlier recovery of fasting gastric motility after antecolic duodenojejunostomy than after retrocolic duodenojejunostomy following PPPD.
Gastric stasis is a unique complication of pylorus-preserving pancreatoduodenectomy (PPPD). Although some studies reported less prevalence of gastric stasis after antecolic duodenojejunostomy, there have been no reports on detailed comparison of gastric motility after antecolic vs. retrocolic duodenojejunostomy after PPPD. Thirty-six patients underwent PPPD with the modified Child reconstruction. Retrocolic duodenojejunostomy was utilized in initial 13 patients (retrocolic group). For comparison, antecolic duodenojejunostomy was employed in subsequent 23 patients (antecolic group). A manometric tube assembly was inserted into the gastric antrum and jejunum during PPPD. Gastrointestinal motility was recorded for 3 hours a day, starting on 6 to 14 days after surgery and repeated at a weekly interval until the first appearance of phase 3 gastric motility. Various clinical parameters were also assessed. Recovery of gastric phase 3 was identified in 19 of 36 patients. Recovery of phase 3 was faster in antecolic group than in retrocolic group (p<0.01). The amount of the gastric juice output during 14 postoperative days was larger in retrocolic group than in antecolic group (p<0.01). Resumption of water intake and food intake was earlier and the length of intravenous hyperalimentation and hospital stay was shorter in antecolic group than in retrocolic group (p<0.05). Antecolic duodenojejunostomy contributes to early recovery of gastric phase 3 motility in patients after PPPD, leading to prevention of early gastric stasis.


Presenting Critical Realist Discourse Analysis as a Tool for Making Sense of Service Users' Accounts of Their Mental Health Problems.
Making sense of service users' accounts of their mental health problems requires a method able to deal with complexity. Yet the different underlying epistemological and ontological positions of the methods researchers use, based, for example, on biomedicine or social constructionism, produce highly partial analyses. Addressing this problem, this article offers a method of Critical Realist Discourse Analysis (CRDA) that employs a synthesized discourse analysis, informed by critical realism, to examine the discursive, material, embodied, and institutional factors that might inform how mental health service users make sense of their mental health problems and associated service use. The article describes the epistemological/ontological underpinnings of CRDA and its three-phase methodology, before showcasing the method using, as examples, two data sets from care leavers and mothers. With our CRDA, we demonstrate a method for analyzing the complexity of interacting factors informing service users' understanding of their mental health problems.


Hemodynamics analysis of patient-specific carotid bifurcation: a CFD model of downstream peripheral vascular impedance.
The study of cardiovascular models was presented in this paper based on medical image reconstruction and computational fluid dynamics. Our aim is to provide a reality platform for the purpose of flow analysis and virtual intervention outcome predication for vascular diseases. By connecting two porous mediums with transient permeability at the downstream of the carotid bifurcation branches, a downstream peripheral impedance model was developed, and the effect of the downstream vascular bed impedance can be taken into consideration. After verifying its accuracy with a healthy carotid bifurcation, this model was implemented in a diseased carotid bifurcation analysis. On the basis of time-averaged wall shear stress, oscillatory shear index, and the relative residence time, fractions of abnormal luminal surface were highlighted, and the atherosclerosis was assessed from a hemodynamic point of view. The effect of the atherosclerosis on the transient flow division between the two branches because of the existence of plaque was also analysed. This work demonstrated that the proposed downstream peripheral vascular impedance model can be used for computational modelling when the outlets boundary conditions are not available, and successfully presented the potential of using medical imaging and numerical simulation to provide existing clinical prerequisites for diagnosis and therapeutic treatment.


Neuroproteomic Analysis after SARS-CoV-2 Infection Reveals Overrepresented Neurodegeneration Pathways and Disrupted Metabolic Pathways.
Besides respiratory illness, SARS-CoV-2, the causative agent of COVID-19, leads to neurological symptoms. The molecular mechanisms leading to neuropathology after SARS-CoV-2 infection are sparsely explored. SARS-CoV-2 enters human cells via different receptors, including ACE-2, TMPRSS2, and TMEM106B. In this study, we used a human-induced pluripotent stem cell-derived neuronal model, which expresses ACE-2, TMPRSS2, TMEM106B, and other possible SARS-CoV-2 receptors, to evaluate its susceptibility to SARS-CoV-2 infection. The neurons were exposed to SARS-CoV-2, followed by RT-qPCR, immunocytochemistry, and proteomic analyses of the infected neurons. Our findings showed that SARS-CoV-2 infects neurons at a lower rate than other human cells; however, the virus could not replicate or produce infectious virions in this neuronal model. Despite the aborted SARS-CoV-2 replication, the infected neuronal nuclei showed irregular morphology compared to other human cells. Since cytokine storm is a significant effect of SARS-CoV-2 infection in COVID-19 patients, in addition to the direct neuronal infection, the neurons were treated with pre-conditioned media from SARS-CoV-2-infected lung cells, and the neuroproteomic changes were investigated. The limited SARS-CoV-2 infection in the neurons and the neurons treated with the pre-conditioned media showed changes in the neuroproteomic profile, particularly affecting mitochondrial proteins and apoptotic and metabolic pathways, which may lead to the development of neurological complications. The findings from our study uncover a possible mechanism behind SARS-CoV-2-mediated neuropathology that might contribute to the lingering effects of the virus on the human brain.


Vibration-related extrusion of capillary blood from the calf musculature depends upon directions of vibration of the leg and of the gravity vector.
In this study, we investigated the effects of vibration of the whole lower leg on the content and the oxygenation of hemoglobin in the unloaded relaxed lateral gastrocnemius muscle. Vibration was applied orthogonal to and in parallel with leg axis to examine whether the extrusion of blood depends on an alignment of main vessel direction, axis of vibration and gravity. The blood volume in the muscles was altered by horizontal and 30° upright body posture. Fifteen male subjects were exposed to 4 sets of experiments with both vibration directions and both tilt angles applied in permutated order. The absence of voluntary muscular activity and the potential occurrence of compound action potentials by stretch reflexes were monitored using electromyography. Total hemoglobin and tissue saturation index were measured with near infrared spectroscopy. Changes of lower leg circumference were measured with strain gauge system placed around the calf. Vibration caused decrease in tHb and increase in TSI indicating extrusion of predominantly venous blood from the muscle. In 30° tilted position, muscles contained more blood at baseline and vibration ejected more blood from the muscle compared with horizontal posture (p < 0.01). At 30° tilting deeper drop in tHb and steeper increase in TSI (p < 0.01) were observed when vibration was applied in parallel with the length axis of muscle. It is concluded that the vibration extrudes more blood in 30° head up posture and the vibration applied in parallel with the length axis of the muscle is more effective than orthogonal vibration.


Separation of Solid Stress From Interstitial Fluid Pressure in Pancreas Cancer Correlates With Collagen Area Fraction.
Elevated total tissue pressure (TTP) in pancreatic adenocarcinoma is often associated with stress applied by cellular proliferation and hydrated hyaluronic acid osmotic swelling; however, the causal roles of collagen in total tissue pressure have yet to be clearly measured. This study illustrates one direct correlation between total tissue pressure and increased deposition of collagen within the tissue matrix. This observation comes from a new modification to a conventional piezoelectric pressure catheter, used to independently separate and quantify total tissue pressure, solid stress (SS), and interstitial fluid pressure (IFP) within the same tumor location, thereby clarifying the relationship between these parameters. Additionally, total tissue pressure shows a direct correlation with verteporfin uptake, demonstrating the impediment of systemically delivered molecules with increased tissue hypertension.


Interaction Time with Electronic Health Records: A Systematic Review.
The amount of time that health care clinicians (physicians and nurses) spend interacting with the electronic health record is not well understood. This study aimed to evaluate the time that health care providers spend interacting with electronic health records (EHR). Data are retrieved from Ovid MEDLINE(R) and Epub Ahead of Print, In-Process and Other Non-Indexed Citations and Daily, (Ovid) Embase, CINAHL, and SCOPUS. Peer-reviewed studies that describe the use of EHR and include measurement of time either in hours, minutes, or in the percentage of a clinician's workday. Papers were written in English and published between 1990 and 2021. All physicians and nurses involved in inpatient and outpatient settings. A narrative synthesis of the results, providing summaries of interaction time with EHR. The studies were rated according to Quality Assessment Tool for Studies with Diverse Designs. Out of 5,133 de-duplicated references identified through database searching, 18 met inclusion criteria. Most were time-motion studies (50%) that followed by logged-based analysis (44%). Most were conducted in the United States (94%) and examined a clinician workflow in the inpatient settings (83%). The average time was nearly 37% of time of their workday by physicians in both inpatient and outpatient settings and 22% of the workday by nurses in inpatient settings. The studies showed methodological heterogeneity. This systematic review evaluates the time that health care providers spend interacting with EHR. Interaction time with EHR varies depending on clinicians' roles and clinical settings, computer systems, and users' experience. The average time spent by physicians on EHR exceeded one-third of their workday. The finding is a possible indicator that the EHR has room for usability, functionality improvement, and workflow optimization.


Cross-talk between inflammation and angiotensin II: studies based on direct transfection of cardiomyocytes with AT1R and AT2R cDNA.
Ischemic myocardium exhibits inflammation, local angiotensin II (Ang II) generation and up-regulation of LOX-1, a lectin-like ox-LDL receptor. To define the inter-active roles of Ang II and inflammation in furthering tissue injury, cultured HL-1 cardiomyocytes were treated with Ang II. Ang II treatment up-regulated the expression of Ang II type 1 (AT1R) and type 2 (AT2R) receptors as well as LOX-1. Ang II also activated p44/42MAPK, p38MAPK, c-Jun and NF-κB, and increased the expression of inflammation-related genes (interleukins-6, interleukins-10, tumor necrosis factor-α, intercellular adhesion molecule-1). To study how inflammation per se might affect expression of Ang II receptors and LOX-1, cultured, cardiomyocytes were treated with lipopolysaccharide (LPS). Like Ang II, LPS increased the expression of AT1R, AT2R and LOX-1. LPS also activated mitogen-acticated protein kinase (MAPKs), c-Jun and NF-κB, and pro-inflammatory genes. The selective inhibitors of MAPKs, c-Jun and NF-κB each blocked the transcription of LOX-1 and pro-inflammatory genes in response to Ang II as well as LPS. These observations suggested a positive feedback between Ang II and inflammation. To delineate the role of AT1R and AT2R in LOX-1 expression, another set of cardiomyocytes were transfected with AT1R or AT2R cDNA. Forced over-expression of AT1R resulted in activation of MAPKs, c-Jun and NF-κB, up-regulation of inflammatory genes and LOX-1; on the other hand forced AT2R over-expression induced up-regulation of pro-apoptotic signals (pro-IL-1β and IL-1β), and decreased LOX-1 expression. These studies show that both Ang II and inflammation mediator LPS up-regulate AT1R, AT2R and LOX-1 expression. Up-regulation of AT1R promotes inflammation and LOX-1 expression, whereas up-regulation of AT2R promotes apoptosis signals and decreases LOX-1 expression.


Serum IF1 concentration is independently associated to HDL levels and to coronary heart disease: the GENES study.
HDL is strongly inversely related to cardiovascular risk. Hepatic HDL uptake is controlled by ecto-F1-ATPase activity, and potentially inhibited by mitochondrial inhibitor factor 1 (IF1). We recently found that IF1 is present in serum and correlates with HDL-cholesterol (HDL-C). Here, we have evaluated the relationship between circulating IF1 and plasma lipoproteins, and we determined whether IF1 concentration is associated with the risk of coronary heart disease (CHD). Serum IF1 was measured in 648 coronary patients ages 45-74 and in 669 matched male controls, in the context of a cross-sectional study on CHD. Cardiovascular risk factors were documented for each participant, including life-style habits and biological and clinical markers. In controls, multivariate analysis demonstrated that IF1 was independently positively associated with HDL-C and apoA-I (r = 0.27 and 0.28, respectively, P < 0.001) and negatively with triglycerides (r = -0.23, P < 0.001). Mean IF1 concentration was lower in CHD patients than in controls (0.43 mg/l and 0.53 mg/l, respectively, P < 0.001). In multivariate analyses, following adjustments on cardiovascular risk factors or markers, IF1 was negatively related to CHD (P < 0.001). This relationship was maintained after adjustment for HDL-C or apoA-I. This study identifies IF1 as a new determinant of HDL-C that is inversely associated with CHD.


Renal Denervation in Resistant Hypertension and Obstructive Sleep Apnea: Randomized Proof-of-Concept Phase II Trial.
It has been postulated that catheter-based renal denervation (RDN) may lower blood pressure (BP) and improve severity of obstructive sleep apnea (OSA) in resistant hypertensive patients. The aim of our study (NCT01366625) was to investigate in a prospective randomized trial the effect of RDN on BP and clinical course of OSA. Sixty patients with true resistant hypertension coexisting with moderate-to-severe OSA (apnea/hypopnea index, ≥15) were randomly allocated to RDN group (30 patients) and to control group (30 patients). The primary end point was reduction in office systolic BP at 3 months. Secondary end points included reduction in diastolic office and ambulatory BP, change in apnea/hypopnea index and biochemical measurements at 3 months, and change in echocardiographic measurements at 6 months. There were no differences in clinical characteristics between the groups. At 3 months in the RDN group, both office and ambulatory BP were significantly reduced, and a significant decrease in OSA severity (apnea/hypopnea index, 39.4 versus 31.2 events per hour; P=0.015) was observed. Between-group difference in apnea/hypopnea index change was significant at 0.05. At 6 months in the RDN group, reductions in office and ambulatory BP were sustained and were accompanied by significant improvement in echocardiographic measures of global longitudinal strain. There were no differences in metabolic variables in follow-up in both groups. In a randomized controlled trial, RDN lowered both office and ambulatory BP in patients with resistant hypertension and OSA. This was accompanied by improvement of the clinical severity of OSA. URL: http://www.clinicaltrials.gov. Unique identifier: NCT01366625.


Reasons for self-reported unmet healthcare needs in Canada: a population-based provincial comparison.
In this study, we compare self-perceived unmet need across Canadian provinces and assess how the reasons for unmet need - problems with availability, accessibility and acceptability - vary. This cross-sectional study uses data from the Canadian Community Health Survey (2.1) conducted in 2003. Overall, 11.7% perceived having had unmet healthcare needs in the previous 12 months. The adjusted provincial rates varied from 13.3% in Manitoba to 7.8% in Prince Edward Island. Among those reporting unmet health service needs, the leading reason was problems of availability of services (54.9%), followed by acceptability (42.8%) and accessibility related to cost or transportation (12.7%). Unmet need due to problems of availability was most likely in Quebec, Newfoundland and Manitoba, while Alberta and British Columbia had the highest likelihood of unmet need due to accessibility problems. Those in British Columbia, Saskatchewan and Manitoba were more likely to report problems of acceptability. The reasons for unmet need vary across provinces, with each reason having different policy implications.


Blood pressure changes as predictors of future mortality in the seven countries study.
Twelve cohorts of men aged 40-59 at entry, enrolled in six countries (Finland, The Netherlands, Italy, Yugoslavia, Greece and Japan), giving a total of 8,287 subjects, were examined for the measurement of cardiovascular risk factors and then followed-up for 20 years. Changes of systolic blood pressure (SBP) occurred over the first 10 years in 6,767 men and these values, computed by an integral-like procedure (Delta-SBP), were used as possible predictors of fatal events recorded in the second 10 years of follow-up. Men who had a relative increase of SBP in the first 10 years showed an excess risk of death as compared with those who had a relative decrease of SBP, after adjustment for age and entry levels of SBP. Such relative risks were greater than 1 in the cohorts pooled within each of the six countries, ranging from 1.07 to 1.79 for all causes of death and from 1.12 to 2.15 for atherosclerotic cardiovascular disease deaths (coronary, stroke and peripheral atherosclerotic disease). The Cox model was solved using the same two end-points as dependent variables and, as coviariates, six risk factors measured at entry examination (age, cigarettes smoked per day, body mass index, serum cholesterol, physical activity at work and systolic blood pressure). By adding Delta-SBP the predictive power of the models was significantly improved and the coefficients of Delta-SBP proved to be statistically significant.


Mussel-inspired copolymer-coated polypropylene mesh with anti-adhesion efficiency for abdominal wall defect repair.
Polypropylene (PP) meshes are one of the most commonly used prosthesis materials in repairing abdominal wall defects. However, their application is usually limited due to possible serious abdominal adhesions between the mesh and the viscera. Instilling PP meshes with excellent anti-adhesion characteristics is still a formidable challenge. In this work, in order to prevent intestinal adhesion to the PP mesh, an effective method was developed to prepare anti-adhesive PP meshes, which was inspired by mussel adhesive proteins. A functional monomer, namely, dopamine methacrylamide, was first synthesized. Then, it was copolymerized with poly(ethylene glycol) methacrylate on the surface of O2-plasma-treated PP (OPP) meshes to form comb-like copolymer poly[poly(ethylene glycol) methacrylate-co-dopamine methacrylamide] (PEDMA), which was simultaneously grafted in situ on the OPP mesh surface through the catechol group of PEDMA, subsequently yielding an anti-adhesive PP mesh (OPP-g-PEDMA). The properties of PEDMA and OPP-g-PEDMA meshes were characterized by NMR, GPC, TGA, FTIR, XPS, SEM, and water contact angle measurements. NIH-3T3 cells were employed to assess the cytocompatibility of OPP-g-PEDMA in vitro. Furthermore, the rat abdominal wall defect model was used to evaluate the efficacy of adhesion prevention. The results show that OPP-g-PEDMA not only possesses fantastic biocompatibility but also satisfactory anti-adhesion property involving minimal chronic inflammation, as well as lower adhesion formation rate and adhesion tenacity scores (less than 1.0). This type of OPP-g-PEDMA mesh is a promising candidate in effectively preventing peritoneal adhesion during abdominal wall defect repair.


The role of methylation in the copper(ii) coordination properties of a His-containing decapeptide.
N-Methylation of the peptide amide bond has proven to be a powerful strategy to fine-tune the conformation and properties of peptides. In this context and for the first time, we show that N-methylation can also be used to control the copper(ii) coordination properties of peptides and stabilize at high pH values the copper(ii) species lacking amidate coordination. Namely, we have prepared a derivative of the O-Asp peptide where the copper(ii) coordinating amino acids, i.e. Asp and His residues, were N-methylated (ONMe-Asp). A combined study using potentiometric and spectroscopic (UV-Vis, CD, EPR and NMR) techniques indicates the formation of the wanted major species, [CuH(ONMe-Asp)]2+, where copper(ii) is bound to His4(Nε), His7(Nε), His9(Nε) and Asp2(COO-). With respect to the parent non-methylated O-Asp peptide, [CuH(ONMe-Asp)]2+ is stable at higher pH values but has lower affinity for copper(ii). Additionally, electrochemical studies reveal a Cu(ii) ⇌ Cu(i) redox process with a larger cathodic and anodic peak separation. Species containing copper(ii) coordinating amidates were not observed for this ONMe-Asp peptide.


Control of myogenic differentiation by fibroblast growth factor is mediated by position in the G1 phase of the cell cycle.
We have used the expression of the muscle form of creatine phosphokinase (M-CPK) to assay myogenic differentiation in the cloned muscle cell line BC3Hl. BC3Hl cells express M-CPK when arrested in the G0 portion of the cell cycle. Addition of the anionic form of brain fibroblast growth factor (B-FGF) rapidly represses synthesis of M-CPK with a half-time of 7 h. Even though B-FGF is not mitogenic for the cells, it causes quiescent BC3Hl cells to exit from the G0 portion of the cell cycle, and to accumulate at a new restriction point approximately 4 to 6 h in the G1 portion of the cell cycle. The repression of M-CPK synthesis by B-FGF is reversible upon removal of B-FGF, and cells which have re-initiated expression of M-CPK have also returned to the G0 portion of the cell cycle. The primary control of M-CPK expression by B-FGF appears to be at the level of gene transcription. We conclude that arrest of cells at G0 but not at other positions in the G1 phase of the cell cycle provides permissive conditions for the expression of muscle-specific proteins, and that defined polypeptide growth factors, in this case B-FGF, are important in the control of the expression of muscle-specific proteins.


Diagnostic approach to platelet function disorders.
Platelet disorders are common bleeding disorders, with a variety of congenital and acquired causes. The diagnostic evaluation of platelet disorders challenges both clinicians and clinical laboratories, as testing for these conditions is complex, not well standardized and time consuming. An understanding of normal platelet function has provided insights on the pathogenesis of many platelet function disorders. Knowledge of the key features of platelet disorders aids their diagnostic assessment. Tests for aggregation, secretion and dense granule defects continue to be the most helpful for the evaluation of suspected platelet function disorders.


Comparison of human rotaviruses isolated in Mexico City and in Santiago, Chile, by electrophoretic migration of their double-stranded ribonucleic acid genome segments.
During the period October to December 1979, rotaviruses were obtained from infants and young children hospitalized with acute gastroenteritis in Mexico City and were compared by analysis of the migration of their double-stranded ribonucleic acid (RNA) genome segments in gel electrophoresis. Comparison of the results of this analysis and of those of similar studies carried out in 1977 and 1978 showed that the two rotavirus electropherotypes designated 2s and 21 have been continuously present and that the proportion in which these two types have been found in hospitalized patients has varied greatly year to year. The RNAs from rotaviruses 2s and 21 differed in the electrophoretic migraton of at least eight genome segments. However, RNAs from virus assigned to the same electrophoreotypes were not necessarily identical: on the basis of small but significant differences in the migration of segment 7, 8, or 9, isolates of types 2s and 21 could be assigned to two and three different subtypes, respectively. Human rotaviruses obtained in a distant geographical region, Santiago, Chile, in July 1979 had RNA electrophoretic patterns similar to that of electropherotype 21 but different from it in the migration of one or two of the larger RNA segments.


Emergence of selectivity and specificity in a coarse-grained model of the nuclear pore complex with sequence-agnostic FG-Nups.
The role of hydrophobicity of phenylalanine-glycine nucleoporins (FG-Nups) in determining the transport of receptor-bound cargo across the nuclear pore complex (NPC) is investigated using Langevin dynamics simulations. A coarse-grained, minimal model of the NPC, comprising a cylindrical pore and hydrophobic-hydrophilic random copolymers for FG-Nups was employed. Karyopherin-bound receptor-cargo complexes (Kaps) were modeled as rigid, coarse-grained spheres without (inert) and with (patchy) FG-binding hydrophobic domains. With a sequence-agnostic description of FG-Nups and the absence of any anisotropies associated with either NPC or cargo, the model described tracer transport only as a function of FG-Nup hydrophobicity, f. The simulations showed the emergence of two important features of cargo transport, namely, NPC selectivity and specificity. NPC selectivity to patchy tracers emerged due to hydrophobic Kap-FG interactions and despite the sequence-agnostic description of FG-Nups. Furthermore, NPC selectivity was observed only in a specific range of FG-hydrophobic fraction, 0.05 ≤ f ≤ 0.20, resulting in specificity of NPC transport with respect to f. Significantly, this range corresponded to the number fraction of FG-repeats observed in both S. cerevisiae and H. sapiens NPCs. This established the central role of the FG-hydrophobic fraction in determining NPC transport, and provided a biophysical basis for conservation of the FG-Nup hydrophobic fraction across evolutionarily distant NPCs. Specificity in NPC transport emerged from the formation of a hydrogel-like network inside the pore with a characteristic mesh size dependent on f. This network rejected cargo for f > 0.2 based on size exclusion, which resulted in enhanced translocation probability for 0.05 ≤ f ≤ 0.20. Extended brush configurations outside the pore resulted in entropic repulsion and exclusion of inert cargo in this range. Thus, our minimal NPC model exhibited a hybrid cargo translocation mechanism, with aspects of both virtual gate and selective-phase models, in this range of FG-hydrophobic fraction.


Neonatal amygdala volumes and the development of self-regulation from early infancy to toddlerhood.
Objective: At the broadest level, self-regulation (SR) refers to a range of separate, but interrelated, processes (e.g., working memory, inhibition, and emotion regulation) central for the regulation of cognition, emotion, and behavior that contribute to a plethora of health and mental health outcomes. SR skills develop rapidly in early childhood, but their neurobiological underpinnings are not yet well understood. The amygdala is one key structure in negative emotion generation that may disrupt SR. In the current study, we investigated the associations between neonatal amygdala volumes and mother-reported and observed child SR during the first 3 years of life. We expected that larger neonatal amygdala volumes would be related to poorer SR in children. Method: We measured amygdala volumes from magnetic resonance imaging (MRI) performed at age M = 3.7 ± 1.0. We examined the associations between the amygdala volumes corrected for intracranial volume (ICV) and (a) parent-reported indicators of SR at 6, 12, and 24 months (N = 102) and (b) observed task-based indicators of SR (working memory and inhibitory control) at 30 months of age in a smaller subset of participants (N = 80). Results: Bilateral neonatal amygdala volumes predicted poorer working memory at 30 months in girls, whereas no association was detected between amygdalae and inhibitory control or parent-reported SR. The left amygdala by sex interaction survived correction for multiple comparisons. Conclusions: Neonatal amygdala volume is associated with working memory, particularly among girls, and the association is observed earlier than in prior studies. Moreover, our findings suggest that the neural correlates for parent-reported, compared to observed early life SR, may differ. (PsycInfo Database Record (c) 2021 APA, all rights reserved).


Degradation of glutathione in Aspergillus nidulans - Short communication.
Relative transcriptions of Aspergillus nidulans dug1-3 (orthologes of Saccharomyces cerevisiae DUG - deficient in utilization of glutathione - pathway genes) and ggtA encoding γ-glutamyl transpeptidase were studied under conditions inducing glutathione degradation. GgtA was induced in all cases when glutathione levels decreased, but addition of yeast extract, which moderated glutathione degradation, enhanced its induction. Although dug2 showed constitutive transcription, dug1 and dug3 were induced by carbon and nitrogen starvation and yeast extract did not caused significant changes in their relative transcription. The in silico reconstructed DUG pathway of A. nidulans is a promising candidate for cytosolic GSH degradation induced by carbon/nitrogen stress.


The Efficacy of Novel Commercial Tourniquet Designs for Extremity Hemorrhage Control: Implications for Spontaneous Responder Every Day Carry.
Tourniquets (TQs) save lives. Although military-approved TQs appear more effective than improvised TQs in controlling exsanguinating extremity hemorrhage, their bulk may preclude every day carry (EDC) by civilian lay-providers, limiting availability during emergencies. The purpose of the current study was to compare the efficacy of three novel commercial TQ designs to a military-approved TQ. Nine Emergency Medicine residents evaluated four different TQ designs: Gen 7 Combat Application Tourniquet (CAT7; control), Stretch Wrap and Tuck Tourniquet (SWAT-T), Gen 2 Rapid Application Tourniquet System (RATS), and Tourni-Key (TK). Popliteal artery flow cessation was determined using a ZONARE ZS3 ultrasound. Steady state maximal generated force was measured for 30 seconds with a thin-film force sensor. Success rates for distal arterial flow cessation were 89% CAT7; 67% SWAT-T; 89% RATS; and 78% TK (H 0.89; P = .83). Mean (SD) application times were 10.4 (SD = 1.7) seconds CAT7; 23.1 (SD = 9.0) seconds SWAT-T; 11.1 (SD = 3.8) seconds RATS; and 20.0 (SD = 7.1) seconds TK (F 9.71; P <.001). Steady state maximal forces were 29.9 (SD = 1.2) N CAT7; 23.4 (SD = 0.8) N SWAT-T; 33.0 (SD = 1.3) N RATS; and 41.9 (SD = 1.3) N TK. All novel TQ systems were non-inferior to the military-approved CAT7. Mean application times were less than 30 seconds for all four designs. The size of these novel TQs may make them more conducive to lay-provider EDC, thereby increasing community resiliency and improving the response to high-threat events.


Number of initial symptoms of SARS-CoV-2 infection is associated with the risk of otological symptoms: a retrospective study.
The characteristics of otological symptoms in patients with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection are lacking. Almost no research has been conducted to explore the emergence of otological symptoms after coronavirus disease 2019 infection. The aims of this study were to investigate the prevalence and specific clinical characteristics of and risk factors for otological symptoms among patients with SARS-CoV-2 infection. We included two groups to investigate the prevalence and clinical characteristics of otological symptoms among patients with SARS-CoV-2 infection. The first sample (S1) was drawn retrospectively from four communities via questionnaires, and the second sample (S2) from an outpatient clinic. A total of 189 participants were included in S1 (124 women [65.6%]; mean [standard deviation (SD)] age, 33.66 [13.56] years), and 47 in S2 (25 women [53.2%]; mean [SD] age, 45.28 [14.64] years). The most prevalent otological symptoms in S1 were dizziness (15.9%), tinnitus (7.9%), aural fullness (6.9%), otalgia (5.3%), hearing loss (1.6%), and otopyorrhoea (1.1%). Moreover, for each additional typical symptom of SARS-CoV-2 infection, the risk (odds ratio) of otological symptoms increased by 1.33 (95% confidence interval: 1.10-1.61, p = 0.003). The prevalence of aural fullness was higher in the unvaccinated group than that in the group receiving two or three vaccinations (p = 0.018). Various otological symptoms may occur in patients with SARS-CoV-2 infection. The number of typical symptoms of SARS-CoV-2 infection is positively associated with the probability of otological symptoms. However, vaccination may reduce the probability of certain otological symptoms.


Poorly Differentiated Clusters Predict a Poor Prognosis for External Auditory Canal Carcinoma.
Squamous cell carcinoma (SCC) of the external auditory canal (EAC) is rare and offers a poor prognosis; more accurate prognostic biomarkers are required. Our laboratory recently demonstrated that tumor budding, characterized by tumor cell clusters (< 5 cells), and laminin 5-γ2 staining of SCC of the EAC are associated with shorter survival. However, clusters composed of ≥ 5 tumor cells are also found in the stroma. Previous reports of colorectal cancer suggest that poorly differentiated clusters (PDCs) are a negative prognostic indicator. Here, we report on the association between PDCs and prognosis in SCC of the EAC. PDCs and tumor budding were histopathologically and immunohistochemically (cytokeratin AE1/AE3) analyzed in 31 cases of pre-treatment biopsy SCC of the EAC. Clusters in the stroma composed of < or ≥ 5 cancer cells were defined as tumor budding or PDCs, respectively. Entire tumors were initially scanned to identify greatest PDC density. Tumors with low or high PDC density were classified as low- and high-grade, respectively. Patients with high-grade PDCs had a significantly poorer outcome than those with low-grade. Even in cases of low-grade tumor budding, those with high-grade PDCs had a poor prognosis. Multivariate analysis results indicated that high-grade PDCs were associated with poor prognosis. PDC grade can provide a more accurate prognosis than tumor budding in SCC of the EAC.


[Homeostasis model assessment (HOMA) values in Chilean elderly subjects].
The homeostasis assessment model for insulin resistance (HOMA-IR) estimates insulin resistance using basal insulin and glucose values and has a good concordance with values obtained with the euglycemic clamp. However it has a high variability that depends on environmental, genetic and physiologic factors. Therefore it is imperative to establish normal HOMA values in different populations. To report HOMA-IR values in Chilean elderly subjects and to determine the best cutoff point to diagnose insulin resistance. Cross sectional study of 1003 subjects older than 60 years of whom 803 (71% women) did not have diabetes. In 154 subjects, an oral glucose tolerance test was also performed. Insulin resistance (IR) was defined as the HOMA value corresponding to percentile 75 of subjects without over or underweight. The behavior of HOMA-IR in metabolic syndrome was studied and receiver operating curves (ROC) were calculated, using glucose intolerance defined as a blood glucose over 140 mg/dl and hyperinsulinemia, defined as a serum insulin over 60 microU/ml, two hours after the glucose load. Median HOMA-IR values were 1.7. Percentile 75 in subjects without obesity or underweight was 2.57. The area under the ROC curve, when comparing HOMA-IR with glucose intolerance and hyperinsulinemia, was 0.8 (95% confidence values 0.72-0.87), with HOMA-IR values ranging from 2.04 to 2.33. HOMA-IR is a useful method to determine insulin resistance in epidemiological studies. The HOMA-IR cutoff point for insulin resistance defined in thi spopulation was 2.6.


Transintestinal cholesterol efflux.
Regulation of cholesterol homeostasis is a complex interplay of a multitude of metabolic pathways situated in different organs. The liver plays a central role and has received most attention of the research community. In this review, we discuss recent progress in the understanding of the emerging role of the intestine in cholesterol transport. In recent years, insight in the transport systems that mediate intestinal cholesterol excretion has deepened considerably. Evidence is emerging that the proximal part of the small intestine is able to secrete cholesterol actively, a pathway called transintestinal cholesterol efflux (TICE). In mice, TICE accounts for up to 70% of fecal neutral sterol excretion. The small intestine plays a significant role in the regulation of body cholesterol homeostasis. Active processes control both absorption and excretion of the sterol and the pathways involved are being elucidated. TICE might provide an attractive target for therapy aiming at reduction of atherosclerosis.


Adaptive detection and removal of non-gaussian spikes from gaussian data.
A nonlinear adaptive method is presented for filtering a signal which is corrupted by spikes which take discrete values Mi with probability Pi at random points in time. An unsupervised learning technique is used to estimate the unknown parameters Mi, Pi, and oi. The spikes are then removed using a Bayes classifier. A theoretical and experimental comparison with the MMSE linear filter is presented.


Serious misdiagnosis-related harms in malpractice claims: The "Big Three" - vascular events, infections, and cancers.
Background Diagnostic errors cause substantial preventable harm, but national estimates vary widely from 40,000 to 4 million annually. This cross-sectional analysis of a large medical malpractice claims database was the first phase of a three-phase project to estimate the US burden of serious misdiagnosis-related harms. Methods We sought to identify diseases accounting for the majority of serious misdiagnosis-related harms (morbidity/mortality). Diagnostic error cases were identified from Controlled Risk Insurance Company (CRICO)'s Comparative Benchmarking System (CBS) database (2006-2015), representing 28.7% of all US malpractice claims. Diseases were grouped according to the Agency for Healthcare Research and Quality (AHRQ) Clinical Classifications Software (CCS) that aggregates the International Classification of Diseases diagnostic codes into clinically sensible groupings. We analyzed vascular events, infections, and cancers (the "Big Three"), including frequency, severity, and settings. High-severity (serious) harms were defined by scores of 6-9 (serious, permanent disability, or death) on the National Association of Insurance Commissioners (NAIC) Severity of Injury Scale. Results From 55,377 closed claims, we analyzed 11,592 diagnostic error cases [median age 49, interquartile range (IQR) 36-60; 51.7% female]. These included 7379 with high-severity harms (53.0% death). The Big Three diseases accounted for 74.1% of high-severity cases (vascular events 22.8%, infections 13.5%, and cancers 37.8%). In aggregate, the top five from each category (n = 15 diseases) accounted for 47.1% of high-severity cases. The most frequent disease in each category, respectively, was stroke, sepsis, and lung cancer. Causes were disproportionately clinical judgment factors (85.7%) across categories (range 82.0-88.8%). Conclusions The Big Three diseases account for about three-fourths of serious misdiagnosis-related harms. Initial efforts to improve diagnosis should focus on vascular events, infections, and cancers.


Patient Safety and Quality Improvement in Otolaryngology Education: A Systematic Review.
Objective The breadth and depth of patient safety/quality improvement (PS/QI) research dedicated to otolaryngology-head and neck surgery (OHNS) education remains unknown. This systematic review aims to define this scope and to identify knowledge gaps as well as potential areas of future study to improved PS/QI education and training in OHNS. Data Sources A computerized Ovid/Medline database search was conducted (January 1, 1965, to May 15, 2015). Similar computerized searches were conducted using Cochrane Database, PubMed, and Google Scholar. Review Methods The study protocol was developed a priori using the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA). Articles were classified by year, subspecialty, Institute of Medicine (IOM) Crossing the Chasm categories, and World Health Organization (WHO) subclass. Results Computerized searches yielded 8743 eligible articles, 267 (3.4%) of which met otolaryngology PS/QI inclusion criteria; 51 (19%) were dedicated to resident/fellow education and training. Simulation studies (39%) and performance/competency evaluation (23.5%) were the most common focus. Most projects involved general otolaryngology (47%), rhinology (18%), and otology (16%). Classification by the IOM included effective care (45%), safety/effective care (41%), and effective and efficient care (7.8%). Most research fell into the WHO category of "identifying solutions" (61%). Conclusion Nineteen percent of OHNS PS/QI articles are dedicated to education, the majority of which are simulation and focus on effective care. Knowledges gaps for future research include facial plastics PS/QI and the WHO category of "studies translating evidence into safer care."


Evaluation of choroidal thickness using spectral-domain optical coherence tomography in migraine patients during acute migraine attacks: a comparative study.
The purpose of this study was to assess choroidal thickness in migraine patients during acute migraine attacks and compare them with healthy controls, using spectral domain optical coherence tomography (OCT). In this prospective case-control study, choroidal thicknesses of 46 migraine patients during acute migraine attacks and 46 age- and sex-matched healthy subjects were measured using a high-speed, high-resolution frequency domain-OCT device. All patients underwent a complete ophthalmic examination before the measurements. OCT measurements were taken at the same time of day (0900 hours), in order to minimize the effects of diurnal variation. There was a statistically significant difference in mean choroidal thickness between the migraine patients during acute migraine attacks (356.3±21.46 μm) and the controls (302.3±18.34 μm; P=0.000). There were significant differences at all measurement points (P<0.001 for all). The increased choroidal thickness of the migraine patients during acute migraine attacks might be related to the vascular pathology of the disease. Further studies are needed to evaluate the etiopathologic relationship between choroidal thickness and acute migraine attack.


New species of insect trypanosomatids from Costa Rica and the proposal for a new subfamily within the Trypanosomatidae.
Several new species of trypanosomatids (Euglenozoa, Kinetoplastea, Trypanosomatidae), isolated from the intestines of Neotropical insects (Heteroptera), were genotyped on the basis of spliced leader RNA, and also defined phylogenetically using gene sequences of small subunit ribosomal RNA and glycosomal glyceraldehyde phosphate dehydrogenase. The taxonomic descriptions also included characterization using morphometry and electron microscopy. Our phylogenetic analyses placed the new species within the clade, previously designated "SE" for "Slowly Evolving" sequences of ribosomal RNA genes, a clade that also includes numerous monoxenous parasites of insects from the genera Crithidia, Leptomonas, and Wallaceina, as well as the dixenous genus Leishmania. Based on the high phylogenetic support for this clade, which is consistently recovered in all recent phylogenetic reconstructions, a proposal is put forward to recognize this natural taxon as a new subfamily, Leishmaniinae, within the family Trypanosomatidae.


Current evidence and future directions for targeting HIV entry: therapeutic and prophylactic strategies.
Great strides have been made in developing potent antiretroviral regimens that block human immunodeficiency virus (HIV) transcription and assembly. Despite these therapeutic advances, problems of drug resistance, latent viral reservoirs, and drug-induced toxic effects that compromise effective viral control point to the need for new classes of anti-HIV drugs with different modes of action. One promising approach involves blocking HIV entry into human cells, a complex process that involves multiple protein interactions. The process of HIV entry begins with binding of the viral envelope glycoprotein to both the CD4 receptor and one of several chemokine receptors and ends with fusion of viral and cell membranes. Conceptually, there are 3 steps in the HIV entry process that could serve as therapeutic targets: binding of the viral envelope glycoprotein with the CD4 receptor, binding of the envelope-CD4 complex to chemokine receptors, and fusion of the viral and cell membranes. Preclinical and clinical assessment of these entry inhibitors is ongoing and will determine if they possess properties required for drug licensure. Moreover, the worldwide epidemic is largely occurring in developing countries that cannot afford these drugs: a prophylactic vaccine is necessary and urgent. New knowledge of the HIV-envelope glycoprotein has also provided insight into possibilities for the design of novel HIV vaccines. JAMA. 2000;284:215-222


No evidence of an association between tyrosine hydroxylase gene polymorphisms and suicide victims.
Functional alternations of noradrenergic and dopaminergic neurotransmission have been implicated in suicidal behavior. A tetranucleotide repeat polymorphism in the first intron of the tyrosine hydroxylase (TH) gene, encoding a rate-limiting enzyme for the synthesis of catecholamines, is reported to have the potential to control expression of the gene and to be associated with suicidal behavior in patients with adjustment disorders. To test the hypothesis that TH gene polymorphisms are involved in suicide through an alteration of TH function, this tetranucleotide repeat polymorphism and the other two SNPs that cause a change in amino acid sequence were examined in suicide victims who completed suicide and control subjects. No significant differences in genotype distribution or allele frequencies were found between the two groups in the three polymorphisms. These findings suggest that these functional polymorphisms are not involved in a biological susceptibility to suicide.


Consecutive DNA terminator sequencing by using enzymatically generated primers.
An improved strategy for the dideoxy chain termination sequencing of M13 recombinant DNA using enzymatically generated primers is presented. It involves synchronous extension of the universal primer with the Klenow fragment of DNA polymerase I at an average rate of 200 deoxynucleoside triphosphates per minute to the immediate downstream region of a preselected restriction enzyme site. Subsequent cleavage with the restriction enzyme generates the short primers with homogeneous 5' ends which can be used for further sequencing. The next restriction sites are selected in the newly sequenced regions of DNA by means of a microcomputer. By repeating this primer extension-cleavage-sequencing strategy sequences altogether about 6 kb long from several recombinant single-stranded M13 DNAs have been determined by using twenty restriction enzymes with different specificities.


Hydrolytic and Biological Degradation of Bulk-fill and Self-adhering Resin Composites.
This study aimed to evaluate the hydrolytic degradation (in vitro) and biodegradation (in situ) of different resin composites: bulk-fill (XTra Fill, XTF/VOCO; Tetric EvoCeram Bulk Fil, TBF/ Ivoclar Vivadent), self-adhering (Vertise Flow, VTF/ Kerr; Fusio Liquid Dentin, FUS/ Pentron Clinical), and a conventional resin composite (Filtek Z250, Z250/ 3M ESPE), which was used as a control. Seventy-five cylindrical specimens (7 × 1 mm) were desiccated and immersed into distilled water (DW), artificial saliva (AS), and 0.1 M lactic acid (LA) (n=5) for 180 days. Specimens were weighed after 180 days, after which they were desiccated again. The sorption (μg/mm3) and solubility (μg/mm3) were calculated based on ISO 4049. For the in situ phase, an intraoral palatal device containing five cylindrical specimens (5 × 1.5 mm) was used by 20 volunteers for seven days. Surface roughness was evaluated before and after this period to analyze the superficial biodegradation. Sorption and solubility data were submitted to Kruskal-Wallis and Mann-Whitney tests. The Wilcoxon signed-rank test was used to compare roughness at different observation times. The statistical significance for all tests was considered α=0.05. For in vitro, self-adhering resin composites (VTF and FUS) showed, respectively, higher sorption values independent of the solution (62.55 and 50.81 μg/mm3 in DW, 67.26 and 50.46 μg/mm3 in AS, and 64.98 and 59.86 μg/mm3 in LA). Self-adhering VTF also had a greater solubility value in DW (22.18 μg/mm3) and FUS in LA (65.87 μg/mm3). In AS, the bulk-fill resin composite XTF showed higher solubility (22.13 μg/mm3). All resins were biodegraded, but the XTF specimens were more resistant (p=0.278) to chemical attack. The self-adhering resin composites showed the highest hydrolytic degradation, and the bulk-fill resin composites exhibited comparable or superior results to the conventional resin composites. Not all resin composites underwent biodegradation in the in situ environment. The storage environment influenced the final characteristics of each material tested.


Local Anesthetic Delivered with a Dual Action Ring and Injection Applicator Reduces the Acute Pain Response of Lambs during Tail Docking.
Docking the tail of lambs is a standard husbandry procedure and is achieved through several techniques including clamps, hot or cold knives and latex rings, the last of which is the most popular. All tail docking methods cause acute pain which can be reduced by application of local anesthetic, however precise anatomical injection for optimal efficacy requires considerable skill. This pen trial evaluated the ability of local anesthetic (LA) delivered with a dual function ring applicator/injector to alleviate acute tail docking pain. Thirty ewe lambs were assigned to one of three treatment groups (n = 10 per group): ring plus local anesthetic (Ring LA), ring only (Ring) and sham handled control (Sham). Lambs were videoed and their behavior categorized every five minutes for the first hour and every 10 min for the subsequent two hours after treatment. There was a significant effect (p < 0.001) of treatment on total active pain related behaviors in the first hour, with Ring lambs showing higher counts compared to Ring LA or Sham. Ring lambs also displayed a significantly higher count of combined abnormal postures (p < 0.001) than Ring LA or Sham lambs. Delivery of 1.5 mL of 2% lignocaine via the dual action device abolished abnormal behaviors and signs of pain in Ring LA lambs. However, lambs in the Ring LA group spent less time attempting to suckle compared to Ring and Sham lambs, suggesting that some residual discomfort remained.


Biological behavior of tumors and associated retroviremia in cats inoculated with Snyder-Theilen fibrosarcoma virus and the phenomenon of tumor recurrence after primary regression.
The fate of tumors and associated retroviremia was studied in 111 cats infected with the Snyder-Theilen strain of feline sarcoma virus (FeSV). Tumors appeared at the site of inoculation within 7 to 10 days. A retroviremia, due mainly to the associated feline leukemia virus helper virus (FeLV-helper), developed at the same time as tumors. Of the cats, 44 developed progressively growing tumors and therefore had to be killed, and 67 developed tumors that regressed. There was a strong correlation between the persistence of the accompanying retroviremia and the growth of the tumors. The 44 cats with progressively growing fibrosarcomas remained retroviremic until death. Conversely, 53 of the 67 cats with solitary, regressing tumors were only transiently retroviremic. Tumor regression in these cats paralleled the disappearance of retrovirus from the blood. The fate of tumors and retroviremia was not always the same, however. Twelve cats remained persistently retroviremic after all signs of gross tumors disappeared. Two other kittens became nonviremic within 20 days after inoculation, yet tumors continued to grow and even metastasize for another 3 to 5 weeks before regressing. Fibrosarcomas recurred 3 weeks to 8 months later in 8 of 12 persistently retroviremic cats with regressed tumors. Although the blood and bone marrow from these cats contained predominantly FeLV-helper, tumor cells yielded both FeSV and FeLV-helper. Of 53 animals, 3 developed recurrent fibrosarcomas 5 weeks to 8 months after all signs of tumors and retroviremia had disappeared. Cells cultured from these tumors appeared initially like normal fibroblasts and were virus nonproducers. After one to three passages in culture, however, cells became malignantly transformed and replicated both FeSV and FeLV-helper. Cultures of the bone marrow from these and other nonviremic cats with regressed tumors yielded only FeLV-helper.


Development of a patient-reported questionnaire for collecting toxicity data following prostate brachytherapy.
To improve a questionnaire used to collect patient-reported outcomes from patients with early stage prostate cancer treated with brachytherapy. A secondary aim was to adapt the Late Effects of Normal Tissue (LENT) subjective toxicity questionnaire for use to collect Common Terminology Criteria for Adverse Events (CTCAE) data, the current preferred platform for assessing radiation toxicity. Three hundred and seventy-seven patients were treated with permanent iodine-125 seed implant brachytherapy for early prostate cancer. Toxicity data were collected before and at nine time points post-treatment (0-36 months). Compliance rates for patients completing individual items and item-subsection correlation coefficients were calculated. A factor analysis was carried out to analyse responses to the questionnaire and identify less informative questions, which could be removed. Cronbach's α coefficient was used to measure reliability. Two thousand one hundred and eighty-eight questionnaires were analysed. There was poor compliance for questions specifically relating to operations and bowel medication. We found that the division of the questionnaire into subsections based on anatomical site was reasonable and that certain items could be safely removed. The high mean value for Cronbach's α across all questionnaires (0.752; 95% CI: 0.726-0.779) indicated that the questionnaire was reliable. Fifteen of the 44 questions were removed from the original questionnaires. Questions on urinary incontinence severity, management of urinary and bowel incontinence, effects of reduced flow of urine and the effects of symptoms on activity of daily living and change in sexual function were required to adapt the LENT subjective questionnaire for use to collect CTCAE data. A questionnaire, validated over 6 years to collect LENT subjective data were adapted and is a reliable approach for collecting CTCAE data after prostate brachytherapy.


Functional P-gp expression in multiple myeloma patients at primary diagnosis and relapse or progressive disease.
In this study, 25 multiple myeloma (MM) patients at primary diagnosis and 18 MM patients at relapse or progressive disease (PD) were examined in order to investigate the incidence of P-glycoprotein (P-gp) expression at initial diagnosis and relapse or PD. Furthermore, P-gp expression in relation to VAD regimen response was determined. P-gp expression in the myeloma cells was determined using monoclonal antibody 4E3.16 and the rhodamine 123 functional test. The percentage of patients with P-gp overexpression at primary diagnosis ranged between 0 and 41% in the literature vs 32% in our study. The percentage of P-gp positive patients at relapse or PD ranged between 29 and 59% in the literature vs 33% in this analysis. All P-gp positive patients had a functional P-gp, ie a pumping P-gp. A significant difference concerning response (50 vs 58.3%) to VAD treatment and median survival (10 vs 12.5 months) between P-gp positive and P-gp negative patients could not be determined. Six of 12 P-gp negative MM patients at relapse or PD developed after VAD therapy a relapse combined with P-gp overexpression. These results do not confirm the suggestions that P-gp overexpression influences response to VAD treatment. However, the results described in the literature and our own emphasize the need for careful accompanying research programmes aimed at detecting the complexity of chemotherapy resistance in the light of developing a risk-adapting therapy for MM patients.


The HALO submaximal treadmill protocol to measure cardiorespiratory fitness in obese children and youth: a proof of principle study.
Many limitations exist with completing cardiorespiratory fitness testing in obese children. The aim of this study was to determine if the new Healthy Active Living and Obesity Research Group's (HALO's) submaximal cardiorespiratory fitness testing protocol for obese children and youth provides a comparable estimate of peak oxygen uptake to that measured using validated maximal and submaximal, equation-based protocols in the obese pediatric population. A group of obese children (n = 21; all ≥95th body mass index percentile; aged 10-17 years) completed 3 exercise testing protocols. Testing was completed as part of an ongoing cohort study and 2 submaximal cardiorespiratory fitness tests were completed, in randomized order, during a second visit. Significant correlations were found between observed peak oxygen uptake (mL·min(-1)) and predicted peak oxygen uptake for both the HALO (r = 0.75, p = 0.001) and Nemeth (r = 0.66, p = 0.001) submaximal protocols. A similar correlation was found, after accounting for body mass, between measured and predicted HALO peak oxygen uptake (mL·kg(-1)·min(-1)) values (r = 0.54, p = 0.01). HALO predicted peak oxygen uptake values showed a significant correlation when plotted against the measured values (r = 0.99). A Bland-Altman analysis found agreement between the maximal and HALO submaximal protocols (mean bias = -201.75 mL·min(-1)). The significant relationships found between estimates of peak oxygen uptake from the HALO submaximal protocol and measures of peak oxygen uptake during maximal cardiorespiratory testing support the use of the HALO submaximal protocol as a valid measure to estimate maximal cardiorespiratory fitness within the obese pediatric population. Given the proof of principle goal of this study, future research in the obese, pediatric population is encouraged to confirm the generalizability of the protocol.


Review of fullerene toxicity and exposure--appraisal of a human health risk assessment, based on open literature.
Fullerenes have gained considerable attention due to their anti-oxidant and radical scavenging properties. Their current applications include targeted drug delivery, energy application, polymer modifications and cosmetic products. The production of fullerenes and their use in consumer products is expected to increase in future. This study aims to investigate the feasibility and challenges associated with conducting a human health risk assessment for fullerenes based on the open literature, utilising an approach similar to that of a classical regulatory risk assessment. Available data relates to different types of fullerenes (with varying size, surface chemistry, solubility, aggregation/agglomeration) and care should therefore be taken when drawing general conclusions across the parameters. Pristine fullerenes have shown low toxicity and there is probably no risks expected for humans exposed to fullerenes in the workplace under good hygiene conditions. The main concern for consumers is exposure via direct dermal application of fullerenes present in cosmetics. Available studies do not indicate a short term risk from the tested fullerene types, however no extrapolation to all fullerene types and to chronic exposure can be made. In conclusion, the current dataset on fullerenes in relation to both, human exposure and hazard is limited and does not allow reaching any definite conclusions suitable for regulatory decision making. Main future work should focus on generating occupational and consumer exposure data, as well as suitable data on toxicokinetics and potential toxic effects following repeated inhalation and dermal exposure allowing to determine a NOAEL. It seems also relevant to clarify whether certain fullerene types may potentially induce genotoxic and/or carcinogenic effects via physiologically relevant routes.


Genetic and physical interaction between the NPHP5 and NPHP6 gene products.
Nephronophthisis (NPHP) is an autosomal recessive cystic kidney disease, caused by mutations of at least nine different genes. Several extrarenal manifestations characterize this disorder, including cerebellar defects, situs inversus and retinitis pigmentosa. While the clinical manifestations vary significantly in NPHP, mutations of NPHP5 and NPHP6 are always associated with progressive blindness. This clinical finding suggests that the gene products, nephrocystin-5 and nephrocystin-6, participate in overlapping signaling pathways to maintain photoreceptor homeostasis. To analyze the genetic interaction between these two proteins in more detail, we studied zebrafish embryos after depletion of NPHP5 and NPHP6. Knockdown of zebrafish zNPHP5 and zNPHP6 produced similar phenotypes, and synergistic effects were observed after the combined knockdown of zNPHP5 and zNPHP6. The N-terminal domain of nephrocystin-6-bound nephrocystin-5, and mapping studies delineated the interacting site from amino acid 696 to 896 of NPHP6. In Xenopus laevis, knockdown of NPHP5 caused substantial neural tube closure defects. This phenotype was copied by expression of the nephrocystin-5-binding fragment of nephrocystin-6, and rescued by co-expression of nephrocystin-5, supporting a physical interaction between both gene products in vivo. Since the N- and C-terminal fragments of nephrocystin-6 engage in the formation of homo- and heteromeric protein complexes, conformational changes seem to regulate the interaction of nephrocystin-6 with its binding partners.


Escherichia coli of Ready-to-Eat (RTE) Meats Origin Showed Resistance to Antibiotics Used by Farmers.
Bacterial foodborne infections, including meat-derived infections, are globally associated with diseases and some deaths. Antibiotics are sometimes used to treat bacterial infections. The use of antibiotics by farmers contributes to the development of resistance by foodborne pathogens. This study aimed to investigate the antibiotics used by farmers and the occurrence of antibiotic-resistant Escherichia coli in ready-to-eat (RTE) meat sources. Data was obtained from livestock farmers through the administration of semistructured questionnaires (n = 376) to obtain information on their demographics, knowledge and antibiotic usage. The procedure in the USA Food and Drug Administration (FDA)'s Bacteriological Analytical Manual was used for E. coli detection. Antibiotic resistance test was performed using the disk diffusion method. The findings revealed that most of the farmers were male (74.5%), were aged 30-39 years (28.5%), had tertiary education (30.3%) and had 6-10 years of experience in livestock husbandry. Sheep (65.7%) were the most reared livestock, and antibiotics were mostly used to treat sick animals (36.7%). Tetracycline (27.7%) was the most common antibiotic used by farmers, followed by amoxicillin/clavulanic acid (18.6%) and trimethoprim/sulfamethoxazole (11.7%). Most farmers (56.1%) said they had knowledge of antibiotic usage. The prevalence of E. coli in RTE meats was lowest in pork (6.0%) and highest in chevon (20.0%). E. coli isolates from RTE meats were highly resistant to teicoplanin (96.77%), tetracycline (93.55%), amoxicillin/clavulanic (70.97%), azithromycin (70.97%) and trimethoprim/sulfamethoxazole (58.06%) but was susceptible to chloramphenicol (93.55%), ciprofloxacin (61.29%) and ceftriaxone (58.06%). The multiple antibiotic index ranged from 0.22 to 0.78. Multidrug resistance (93.55%) was high among the E. coli isolates. The resistance pattern AmcAzmTecTeSxt (amoxicillin/clavulanic acid-azithromycin-telcoplanin-tetracycline-trimethoprim/sulfamethoxazole) was the most common. The use of antibiotics by farmers must be well regulated. Sellers of RTE meats also ought to take hygiene practices seriously to keep meat safe and healthy for public consumption.


Secreted Frizzled-related protein 1 (Sfrp1) regulates the progression of renal fibrosis in a mouse model of obstructive nephropathy.
Renal fibrosis is responsible for progressive renal diseases that cause chronic renal failure. Sfrp1 (secreted Frizzled-related protein 1) is highly expressed in kidney, although little is known about connection between the protein and renal diseases. Here, we focused on Sfrp1 to investigate its roles in renal fibrosis using a mouse model of unilateral ureteral obstruction (UUO). In wild-type mice, the expression of Sfrp1 protein was markedly increased after UUO. The kidneys from Sfrp1 knock-out mice showed significant increase in expression of myofibrobast markers, α-smooth muscle actin (αSMA). Sfrp1 deficiency also increased protein levels of the fibroblast genes, vimentin, and decreased those of the epithelial genes, E-cadherin, indicated that enhanced epithelial-to-mesenchymal transition. There was no difference in the levels of canonical Wnt signaling; rather, the levels of phosphorylated c-Jun and JNK were more increased in the Sfrp1(-/-) obstructed kidney. Moreover, the apoptotic cell population was significantly elevated in the obstructed kidneys from Sfrp1(-/-) mice following UUO but was slightly increased in those from wild-type mice. These results indicate that Sfrp1 is required for inhibition of renal damage through the non-canonical Wnt/PCP pathway.


Suicide in the medical setting.
Little is known about suicide in the hospital setting. Although suicide is a major public health concern, the literature on suicide in the medical setting is limited, and accurate data on hospital-based suicides are unavailable. Consequently, the prevalence, demographic characteristics, and risk factors for suicide in this population are unknown. The literature on completed suicides in medical or surgical wards of a general hospital was summarized to generate hypotheses for further investigation regarding in-hospital suicides. MEDLINE, PsycINFO, IndexCat, and Scopus were queried for English-language articles on inpatient suicides in a general hospital. These data were compared with reports of suicide by psychiatric inpatients and the annual suicide statistics from the U.S. general population. Twelve articles detailing 335 suicides in the medical setting were included. Published data on hospital-based suicides are limited by selection bias, incomplete reporting, and a small number of completed suicides. Consequently, no significant setting-specific findings emerge from the existing literature. Reported cases suggest that inpatients who commit suicide in the medical setting may have a different demographic profile and employ different methods of suicide in comparison with individuals who commit suicide in psychiatric settings or the general population. Given the absence of systematic data collection and the highly variable nature of reported suicides, it could not be determined if clinically relevant distinctions exist between suicides in different health care settings. Prospective and more detailed data collection are needed because a more complete characterization of suicide in medical inpatients may be useful in both prevention approaches and institutional policies with respect to hospital-based suicides.


Inhibition of gastric cancer by camptothecin involves apoptosis and multiple cellular pathways.
The prognosis for gastric cancer remains dismal; novel agents that target specific molecular pathways are needed as adjuvant therapy. Camptothecin (CPT), on inhibitor of topoisomerase I, is effective in the treatment of certain solid tumors; its effects on gastric cancer are largely undefined. The purpose of this study was to (1) characterize the effects of CPT on the growth of a human gastric cancer and (2) assess potential cellular mechanisms responsible for CPT-mediated growth inhibition. The human gastric cancer SIIA was transplanted subcutaneously into athymic nude mice. After tumors reached approximately 100 mm2, mice were randomized into 3 groups to receive either CPT (5 or 10 mg/kg) or vehicle (control) intraperitoneally 3 days per week for 3 weeks; tumor size was measured biweekly. To assess potential mechanisms of CPT-mediated inhibition, SIIA cells were treated with CPT (20 mumol/L) and cells were counted over a time course; apoptosis was assessed by Hoechst stain and DNA laddering. Expression of p53 (a tumor suppressor), p21Waf1 and p27Kip1 (cell cycle inhibitors), and Bcl-2 and Bcl-XL (antiapoptotic proteins) was determined. CPT (5 and 10 mg/kg) significantly inhibited tumor growth of SIIA gastric cancers compared with controls. CPT-mediated inhibition of SIIA cell proliferation was associated with an increase in apoptosis. Moreover, CPT treatment resulted in induction of p53, p21Waf1, and p27Kip1 and a decrease in Bcl-2 and Bcl-XL RNA and protein levels. Treatment with CPT effectively inhibited the growth of the human gastric cancer SIIA; the mechanism involved was induction of apoptosis mediated by up-regulation of p53, p21Waf1/Cip1, and p27Kip1 and the down-regulation of Bcl-2 and Bcl-XL. Novel agents such as CPT, which target specific molecular pathways, may prove clinically useful in the adjuvant treatment of gastric cancers.


Antibiotic therapy for ventilator-associated tracheobronchitis: a standard of care to reduce pneumonia, morbidity and costs?
The present review draws our attention to ventilator-associated tracheobronchitis (VAT) as a distinct clinical entity that has been associated with progression to ventilator-associated pneumonia (VAP) and worse patient outcomes. In contrast to VAP, which has been extensively investigated for over the past 30 years, most VAT studies have been conducted in the past decade. There are ample data which demonstrate that VAT may progress to VAP, have more ventilator days, and have longer ICU stay that may translate into higher healthcare costs. The article focuses on the diagnostic criteria for VAT, causative agents, and studies analyzing associations between VAT and patient outcomes in relation to early, appropriate intravenous, and/or aerosolized antibiotic therapy. Aerosolized antibiotic treatment delivered by improved device technology is a novel approach that has proved to be effective for the treatment and eradication of multidrug-resistant bacterial pathogens. Aerosolized antibiotics are effective in decreasing the use of systemic antibiotics, reducing bacterial resistance, and may also facilitate clinical resolution of infection. Evidence presented in this review supports treatment of VAT with early and appropriate antibiotic therapy as a standard of care to reduce VAP, ventilator days, and duration of ICU stay in high-risk patient population.


Anticonvulsant-induced aplastic anemia: increased susceptibility to toxic drug metabolites in vitro.
A 53-yr-old man sequentially developed aplastic anemia from phenytoin and carbamazepine. Both compounds undergo metabolism to potentially toxic arene oxide intermediates. We tested the hypothesis that the patient's adverse reactions were due to a defect in detoxification of such metabolites by challenging his peripheral lymphocytes with drug metabolites generated by a murine hepatic microsomal system in vitro. The patient's cell viability was normal in the absence of drugs. However, his cells showed greater toxicity from both phenytoin and carbamazepine metabolites than did controls. Toxicity was dependent on microsomes and NADPH. Intermediate toxicity was noted in cells from the patient's mother. The results provide the first evidence for a role of arene oxide drug metabolites in aplastic anemia in humans and suggest that enhanced susceptibility to toxicity may be based on an inherited abnormality in metabolite detoxification.


Vulvovestibular Syndrome and Vaginal Microbiome: A Simple Evaluation.
The vulvovestibular syndrome (VVS) is a chronic, inflammatory, multifactorial, chronic inflammation of the female urogenital access. The aim of this anecdotal, observational, retrospective, case-control study was to comparatively evaluate the most common bacterial strains (Lactobacillus spp., Klebsiella spp., Gardnerella spp., and Streptococcus spp.) and fungi (Candida spp., Pennicillum spp., and Aspergillus spp.) in vulvodinic women, and in women without gynecological symptoms (control group). We found that vulvodinic patients had statistically lower Lactobacilli and higher total Fungi concentration. Our preliminary study is useful to further clarify the etiopathology of vulvodynia and suggest new therapeutic strategies for approaching the VVS.


Preassigned-time synchronization for complex-valued memristive neural networks with reaction-diffusion terms and Markov parameters.
This study addresses the preassigned-time synchronization for complex-valued memristive neural networks with reaction-diffusion terms and Markov parameters. Employing a preassigned-time stable control strategy, two distinct controllers with varying power exponent parameters are designed to ensure that synchronization can be achieved within a predefined time frame. Unlike existing finite/fixed-time results, a priori specification of the settling time is addressed. Furthermore, Green's formula and boundary conditions are efficiently applied to overcome potential symmetry loss. Additionally, the activation function's constraint range is more lenient compared to existing constraints. Finally, the effectiveness of the presented methods are demonstrated through two examples.


[Research progress on substitutes for autogenous soft tissue grafts in mucogingival surgery].
Mucogingival surgery is a general term for periodontal surgeries that correct aberrant periodontal soft tissues. Conventional mucogingival surgeries with pedicle flap or autologous soft tissue graft for treatment of gingival recession and insufficient keratinized tissues are always related to disadvantages such as need for a second surgery site, limited supplies, and complaints for postoperative discomfort. In this regard, research and application of soft tissue substitutes have gained increasing attention. Various kinds of soft tissue substitutes, including acellular dermal matrix and xenogeneic collagen matrix, have been developed and applied to clinical treatment. This review aims to summarize advances in research of the characteristics and clinical effectiveness of several soft tissue substitutes and provide references for clinical application.


MLH1 -93G>A promoter polymorphism and risk of mismatch repair deficient colorectal cancer.
Rare inherited mutations in the mutL homolog 1 (MLH1) DNA mismatch repair gene can confer an increased susceptibility to colorectal cancer (CRC) with high penetrance where disease frequently develops in the proximal colon. The core promoter of MLH1 contains a common single nucleotide polymorphism (SNP) (-93G>A, dbSNP ID:rs1800734) located in a region essential for maximum transcriptional activity. We used logistic regression analysis to examine the association between this variant and risk of CRC in patients in the United Kingdom. All statistical tests were 2 sided. In an analysis of 1,518 patients with CRC, homozygosity for the MLH1 -93A variant was associated with a significantly increased 3-fold risk of CRC negative for MLH1 protein by immunohistochemistry (odds ratio (OR): AA vs GG = 3.30, 95% CI 1.46-7.47, n = 1392, p = 0.004, MLH1 negative vs MLH1 positive CRC) and with a 68% excess of proximal CRC (OR: AA vs GG=1.68, 95% confidence interval (CI) 1.00-2.83, n = 1,518, p = 0.05, proximal vs distal CRC). These findings suggest that the MLH1 -93G>A polymorphism defines a low penetrance risk allele for CRC.


Academics as Agentic Superheroes: Female academics' lack of fit with the agentic stereotype of success limits their career advancement.
Gender gaps in academia persist with women being less likely to attain leadership, earning lower salaries, and receiving less research funding and resources compared to their male peers. The current research demonstrates yet another, more intangible gender gap in academia called lack of fit, whereby compared to male academics, female academics perceive higher misfit between their professional self-concept and the agentic 'superhero' stereotype of the successful academic. The entire population of Dutch academics (i.e., assistant, associate, and full professors from 14 universities) was approached to participate in a nationwide survey. Results from this unique dataset (N = 3978) demonstrate that academics perceive agency (e.g., self-confident, self-focused, competitive) as more descriptive of the stereotypical successful academic than communality (e.g., team-oriented, good teacher, collegial). Importantly, early career female academics perceived highest lack of fit with this narrowly-defined agentic occupational stereotype, which was correlated with lower work engagement, professional identification and career efficacy, and higher work exhaustion and exit intentions. Thus, lack of fit seems yet another barrier contributing to pervasive gender gaps in academia. Implications for building more inclusive academic cultures, where not only agentic but also communal academic practice is recognized and rewarded are discussed.


Sex and gender differences in lung cancer.
Each year more than 400,000 Americans die from diseases directly related to smoking, and lung cancer is now the leading cause of death from neoplasia in U.S. men and women. Cancer of the lung and bronchus was responsible for one-quarter of all cancer deaths among U.S. women last year, killing approximately 67,000 women. This is related both to the demographics of smoking among women and the poor survival rate for persons with lung cancer. Epidemiologic evidence from a number of studies suggests that women are more susceptible to tobacco-induced carcinogenesis than men, taking into account baseline exposure, body weight, body height, and body mass index. More recently, there has been increasing biochemical and genetic data to support this male-female difference in susceptibility. Patients with lung cancer currently have few therapeutic options. Understanding these new genetic developments may pave the road for innovative therapeutic approaches for women and new screening methods to determine those at greatest risk for developing lung cancer. Clearly, smoking-related disease among women is a major public health issue that will require effective programs for smoking prevention and cessation among females. Both sex and gender differences in smoking-related disease will be discussed in this review.


Sex ratio adjustment in relation to paternal attractiveness in a wild bird population.
When the relative fitness of sons and daughters differs, sex-allocation theory predicts that it would be adaptive for individuals to adjust their investment in different sexes of offspring. Sex ratio adjustment by females in response to the sexual attractiveness of their mate would be an example of this. In vertebrates the existence of this form of sex ratio adjustment is controversial and may be confounded with sex-biased mortality, particularly in sexually size-dimorphic species. Here we use PCR amplification of a conserved W-chromosome-linked gene to show that the sex ratio within broods of a natural population of sexually size-monomorphic collared flycatchers Ficedula albicollis is related to the size of their father's forehead patch, a heritable secondary sexual character implicated in female choice. Experimental manipulations of paternal investment, which influence the size of his character in future breeding attempts, result in corresponding changes in the sex ratio of offspring born to males in those breeding attempts. In contrast, manipulations of maternal investment have no effect on future sex ratios, and there is no relationship between variables predicting the reproductive value of the brood and nestling sex ratio. Analysis of recruitment of offspring reveals similar patterns of sex ratio bias. The results suggest that female collared flycatchers be able to adjust the sex ratio of eggs ovulated in response to the phenotype of their mate. This finding is most consistent with "genetic quality" models of sexual selection.


Stepwise Bose-Einstein Condensation in a Spinor Gas.
We observe multistep condensation of sodium atoms with spin F=1, where the different Zeeman components m_{F}=0,±1 condense sequentially as the temperature decreases. The precise sequence changes drastically depending on the magnetization m_{z} and on the quadratic Zeeman energy q (QZE) in an applied magnetic field. For large QZE, the overall structure of the phase diagram is the same as for an ideal spin-1 gas, although the precise locations of the phase boundaries are significantly shifted by interactions. For small QZE, antiferromagnetic interactions qualitatively change the phase diagram with respect to the ideal case, leading, for instance, to condensation in m_{F}=±1, a phenomenon that cannot occur for an ideal gas with q>0.


Comparing the osteogenic capacities of bone substitutes: hydroxyapatite, high-density porous polyethylene, and bone collagen: a biochemical and histological analysis.
Several inorganic materials have been shown previously to hold some osteogenic capacity. The purpose of this study is to compare the bone-forming abilities of hydroxyapatite ceramic, high-density porous polyethylene, and bone collagen within the periosteal island flap of rabbit tibia using histological and biochemical analysis. With this goal, four discrete experimental groups were formed, each comprising 22 New Zealand male rabbits. A sac was created on each rabbit tibial periosteum flap in each of the groups, and each of the previously mentioned materials was placed within this sac separately. One of these groups was thought as a control group without any material being placed inside the periosteal sac. Biopsies were taken at weeks 1, 2, 4, and 8 for biochemical analysis and at weeks 2 and 8 for histological evaluation. Neo-osteogenesis was evaluated quantitatively by determination of alkaline phosphatase and osteocalcin levels biochemically as well as by the percentage of new bone formation inside the periosteal sac histologically. Results show statistically that the osteogenic effect of high-density porous polyethylene is greater than that of the other materials used in this study (P < 0.05).


Cell surface expression of the ROMK (Kir 1.1) channel is regulated by the aldosterone-induced kinase, SGK-1, and protein kinase A.
The Kir1.1 (ROMK) subtypes of inward rectifier K+ channels mediate potassium secretion and regulate sodium chloride reabsorption in the kidney. The density of ROMK channels on the cortical collecting duct apical membrane is exquisitely regulated in concert with physiological demands. Although protein kinase A-dependent phosphorylation of one of the three phospho-acceptors in Kir1.1, Ser-44, also a canonical serum-glucocorticoid-regulated kinase (SGK-1) phosphorylation site, controls the number of active channels, it is unknown whether this involves activating dormant channels already residing on the plasma membrane or recruiting new channels to the cell surface. Here we explore the mechanism and test whether SGK-1 phosphorylation of ROMK regulates cell surface expression. Removal of the phosphorylation site by point mutation (Kir1.1, S44A) dramatically attenuated the macroscopic current density in Xenopus oocytes. As measured by antibody binding of external epitope-tagged forms of Kir1.1, surface expression of Kir1.1 S44A was inhibited, paralleling the reduction in macroscopic current. In contrast, surface expression and macroscopic current density was augmented by a phosphorylation mimic mutation, Kir1.1 S44D. In vitro phosphorylation assays revealed that Ser-44 is a substrate of SGK-1 phosphorylation, and expression of SGK-1 with the wild type channel increased channel density to the same level as the phosphorylation mimic mutation. Moreover, the stimulatory effect of SGK-1 was completely abrogated by mutation of the phosphorylation site. In conclusion, SGK-1 phosphorylation of Kir1.1 drives expression on the plasmalemma. Because SGK-1 is an early aldosterone-induced gene, our results suggest a possible molecular mechanism for aldosterone-dependent regulation of the secretory potassium channel in the kidney.