Chronic stress during prepubertal development: immediate and long-lasting effects on arterial blood pressure and anxiety-related behavior.
The present work was undertaken to study the immediate and long-lasting effects of environmental stress during prepubertal life in rats with inherited stress-induced arterial hypertension (ISIAH) and normotensive Wistar rats on blood pressure (BP) levels and anxiety-related behavior. Two models of chronic stress (21-32 postnatal days) were used: repeated handling (HS) and unpredictable stress (US) of daily exposures to a variety of mild physical or psychoemotional stressors. Rats were tested just after the end of the chronic stress period and then at the age of 4 months. Chronic prepubertal stress did not affect the basal or stress-induced BP levels in young or adult Wistar rats. In ISIAH rats, chronic stress during the early phase of hypertension development did not accelerate its formation and did not augment its manifestation in adults. Moreover, the basal BP was decreased in young and adult ISIAH rats exposed to HS or US as compared to the age-matched controls. No long-lasting effect on BP elevation under acute stress in adults was found. Plasma corticosterone levels at resting and acute stress conditions were not changed in adult rats that had experienced prepubertal stress. Hypertensive rats proved to be less anxious in the elevated plus-maze test. The immediate effects of chronic stress were similar in the two rat strains: HS had an anxiolytic action while US stimulated anxiety. Long-lasting consequences depended on the rat strain: the anxiolytic effect of HS was retained in Wistar rats and US caused a greater anxiety in adult ISIAH rats. The data do not evidence that symptoms of anxiety are related to the development and maintenance of stress-sensitive arterial hypertension in ISIAH rats.


High levels of pigment epithelium-derived factor in the retina of a rat model of type 2 diabetes.
Spontaneously diabetic Torii (SDT) rats are a new animal model of diabetes. To investigate the mechanisms controlling diabetic retinopathy, we examined the retinal changes in SDT rats and determined the molecular balance between pigment epithelium-derived factor (PEDF), an angiogenic inhibitor, and vascular endothelial growth factor (VEGF), a major angiogenic stimulator. The retinopathy in SDT rats was characterized by a low incidence of neovascular formation and absence of non-perfused areas, and high levels of both PEDF and VEGF. Proliferative neovascular membranes, that are similar to that in human eyes with proliferative diabetic retinopathy, were found in the eyes of some of the SDT rats at >50-weeks-of-age, Immunoreactivity for VEGF was detected in the retina of SDT rats and the level of VEGF increased with the duration of diabetes. More importantly, immunoreactivity for PEDF was also increased in the retina of diabetic SDT rats. Western blot analysis showed that the level of VEGF in the retina was increased by 2.4 fold at 20-week-old, and by 6.8 fold at >40-week-old compared to that of 10-weeks old SDT rats. The levels of PEDF in the retina at 20-week- and at >40-week-old were significantly higher than that of 10-weeks old SDT rats (20-week-old; 13.5-fold increase, > 40-week-old; 10.3-fold increase). Earlier studies showed that the level of PEDF was decreased and VEGF was increased in proliferative diabetic retinopathy in human eyes. The high levels of PEDF in the retina of SDT rats may contribute to the low incidence of neovascular formation and absence of non-perfused areas that do not match the typical diabetic retinopathy in humans.


The role of PET molecular imaging in immune checkpoint inhibitor therapy in lung cancer: Precision medicine and visual monitoring.
Lung cancer is a malignant tumour originating from the bronchial epithelium or glands of the lung with high morbidity and mortality. For advanced lung cancer, the lack of effective treatment often results in poor prognosis. Immune checkpoint inhibitor (ICI) therapy, as a novel therapeutic method, upregulates immunity by blocking the negative regulation of tumours. In the clinical treatment process, not all lung cancer patients can benefit from ICI treatment. Therefore, screening patients who might potentially benefit from ICI therapy and evaluating the efficacy of ICIs has become an important part of therapy for lung cancer patients. This review has summarized the immune microenvironment of lung cancer, the mechanism of ICI therapy and its current application status. Importantly, we focused on the application of 18F-fluorodeoxyglucose (18F-FDG) and other targeted immune checkpoint tracers based on positron emission tomography (PET) for lung cancer, providing a reference for screening lung cancer candidates suitable for ICI therapy and evaluating the therapeutic effect. Finally, future research directions in PET molecular imaging and their potential application in ICI therapy for lung cancer are presented.


Influence of muscle dimensions on economy of isometric exercise in rat medial gastrocnemius muscles in situ.
The effect of muscle dimensions on economy (force-time integral divided by the amount of energy utilized) was investigated in male rats (body mass range 95-490 g), anaesthetized with pentobarbital. The medial gastrocnemius muscle in situ performed 6 maximal isometric contractions of 350 ms duration (1.s-1) at twitch optimum length at 35 degrees C. The areas under the 6 time-force curves were added to obtain force-time integral of the experiment. Differences of concentrations of ATP, phosphocreatine and lactate between experimental and contralateral (resting) muscles were used to calculate high-energy phosphate consumption due to stimulation. Muscle mass and cross-sectional area increased (approximately +400% and +300%, respectively) over the rat body mass range studied. Muscle length and length of the most distal fibre bundle increased by approximately 17 mm and 4 mm, respectively. Force-time integral (N.s) increased proportional to cross-sectional area whereas high-energy phosphate consumption (mumoles) increased proportional to muscle mass. The relative fraction of the total energy consumption utilized for force-independent processes was independent of rat body mass. The economy of the actomyosin system was unaffected during growth, whereas economy of the whole muscle decreased during growth by approximately 30% (p less than 0.001). The effect of muscle dimensions on economy is discussed with respect to human endurance capacity measured by voluntary isometric contractions.


Influence of glide path kinematics during endodontic treatment on the occurrence and intensity of intraoperative and postoperative pain: a systematic review of randomized clinical trials.
Preliminary canal enlargement (glide path preparation) may play a significant role in the development of pain. The aim of this systematic review of randomized clinical trials was to assess the influence of glide path kinematics during endodontic treatment on the occurrence and intensity of intraoperative and postoperative pain. A search was performed in June 2019 in six electronic databases (PubMed, Scopus, LILACS, SciELO, Embase and Web of Science) and two grey literature databases (OpenGrey and OpenThesis). The bibliographic references of the eligible articles were also hand-searched. The included clinical studies assessed the occurrence and intensity of intraoperative and/or postoperative pain after root canal preparation without glide path preparation (WGP) or with glide path preparation using manual (M-GP), continuous rotary (CR-GP), or reciprocating (R-GP) instruments. The primary outcome was the occurrence and intensity of intraoperative and postoperative pain, while analgesic consumption was the secondary outcome. The full texts of the eligible studies were analyzed by two reviewers who performed calibration exercises to verify the risk of bias and quality of the individual studies using the Joanna Briggs Institute Critical Appraisal tool. From 1283 identified articles, only six studies were included in the qualitative analysis of the results, with a total sample of 884 patients/teeth. Three studies presented a high risk of bias, while three studies presented a moderate risk. Two studies reported that CR-GP causes lower pain levels than M-GP and WGP, and three studies showed no differences between CR-GP and R-GP. Regarding analgesic consumption, two studies found no differences among glide path kinematics, and one study reported lower consumption for CR-GP than for M-GP. Because of the limited number of studies and methodological differences, no statistical analyses were performed for the glide path kinematics comparisons. Compelling evidence indicating a significantly different occurrence and intensity of pain among glide path kinematics is lacking. The systematic review protocol was registered in the PROSPERO database [CRD42020139989].


Infusion of human umbilical cord blood cells ameliorates hind limb dysfunction in experimental spinal cord injury through anti-inflammatory, vasculogenic and neurotrophic mechanisms.
Human umbilical cord blood cells (HUCBCs) were used to investigate the mechanisms underlying the beneficial effects of cord blood cells in spinal cord injury (SCI). Rats were divided into three groups: (1) sham operation (laminectomy only); (2) Laminectomy+SCI+human adult peripheral blood mononucleocytes (PBMCs) (5 x 10(6)/0.3 mL); and (3) Laminectomy+SCi+HUCBCs (5 x 10(6)/0.3 mL). SCI was induced by compressing the spinal cord for 1 minute with an aneurysm clip calibrated to 55 g closing pressure. HUCBCs were infused immediately after SCI via the tail vein. Behavioral function tests measuring the maximal angle at which an animal could hold onto the inclined plane were conducted on days 1, 4 and 7 after SCI. Serum levels of tumor necrosis factor (TNF)-alpha and interleukin (IL)-10, were assayed. Furthermore, to determine if glial cell line-derived neurotrophic factor (GDNF) or vascular endothelial growth factor (VEGF) could be detected in the spinal cord injured area after systemic HUCBC infusion, analysis of these two molecules was conducted by immunofluorescence. Systemic HUCBC infusion significantly attenuated SCI-induced hind limb dysfunction. The serum IL-10 levels were increased, but TNF-alpha levels were decreased after HUCBC infusion. Both VEGF and GDNF could be detected in the injured spinal cord after transplantation of HUCBC, but not PBMC, cells. Our results demonstrate that HUCBC therapy may be beneficial for the recovery of SCI-induced hind limb dysfunction by increasing serum levels of IL-10, VEGF and GDNF in SCI rats.


Escherichia coli O157:H7 suppresses host autophagy and promotes epithelial adhesion via Tir-mediated and cAMP-independent activation of protein kinase A.
Autophagy is a pivotal innate immune response that not only degrades cytosolic components, but also serves as one of the critical antimicrobial mechanisms eliminating intracellular pathogens. However, its role in host defense against extracellular pathogens is largely unknown. Here we showed that E. coli O157:H7 altered autophagy to evade host defense and facilitate adhesion. Enhancing host cell autophagy with tumor necrosis factor (TNF), host starvation or rapamycin reduced the adherence of E. coli O157:H7 to HT-29 cells. As a key regulator of autophagy, protein kinase A (PKA) was activated by E. coli O157:H7 infection. PKA inhibition by H89 abrogated E. coli O157:H7 inhibition of autophagy and prevented bacterial epithelial adhesion. Thus, PKA had a mediatory role in blocking autophagy and E. coli O157:H7 epithelial adhesion. Furthermore, deletion of translocated intimin receptor (tir) prevented PKA activation, whereas ectopic tir expression in a Δtir mutant strain restored its ability to activate PKA and inhibited autophagy in host cells. This indicated that Tir and PKA played pivotal roles in manipulating host autophagy during infection. Consistent with autophagy inhibition, E. coli O157:H7 infection inhibited endoplasmic reticulum (ER) stress in HT-29 cells, which was reversed by TNF, starvation, or H89 treatment. Additionally, E. coli O157:H7-induced PKA activation suppressed extracellular signal-regulated kinase 1/2 (ERK1/2) activation and enhanced phosphatidylinositol 3-kinase/Akt (PI3K/Akt) signaling, thereby repressing autophagic signaling. Conversely, PKA inhibition prevented downregulation of ERK1/2 signaling due to E. coli O157:H7 infection. In summary, E. coli O157:H7 inhibited host autophagy via Tir-mediated PKA activation that favored bacterial persistence on intestinal epithelial cell surfaces.


Local stability identification and the role of key acidic amino acid residues in staphylococcal nuclease unfolding.
Staphylococcal nuclease is a single domain protein with 149 amino acids. It has no disulfide bonds, which makes it a simple model for the study of protein folding. In this study, 20 mutants of this protein were generated each with a single base substitution of glycine for negatively charged glutamic acid or aspartic acid. Using differential scanning microcalorimetry in thermal denaturation experiments, we identified two mutants, E75G and E129G, having approximately 43% and 44%, respectively, lower DeltaH(cal) values than the wild-type protein. Furthermore, two mutants, E75Q and E129Q, were created and the results imply that substitution of the Gly residue has little influence on destabilization of the secondary structure that leads to the large perturbation of the tertiary protein structure stability. Two local stable areas formed by the charge-charge interactions around E75 and E129 with particular positively charged amino acids are thus identified as being significant in maintenance of the three-dimensional structure of the protein.


Influence of Marker Number and Position on Accuracy of Breast Measurement With Three-Dimensional Camera.
The VECTRA H1 three-dimensional (3D) imaging system (Canfield Scientific, Parsippany, NJ) enables easy 3D image construction and measurement. Although the number and positions of markers on the skin for image synthesis might affect accuracy of measurements, few studies have mentioned the possibility. This study investigated the accuracy and reproducibility of distance measurements using VECTRA H1, focusing on the number and positions of markers. A total of 3, 5, or 7 markers were attached to a female breast model including lateral markers 6 cm from the midline and photographed with VECTRA. Five markers were configured in more two ways, with the lateral markers either positioned 3 cm outside the midline (narrow interval) or 9 cm outside the midline (wide interval). 3D models were created three times under each condition, for a total of 15 models. Differences (measurement error) between measured values on 3D models and actual measured values were verified for six distances, such as distance between the nipples. The average difference was 11.1 mm with 3 markers (95% confidence interval (CI), 4.38-17.7 mm, p = 0.0028). In comparison, average difference was -0.395 mm (-0.866 to 0.0763 mm, p = 0.095) with 5 markers, and 0.139 mm (-0186 to 0.465 mm, p = 0.379) with 7 markers, all less than 1 mm. Average difference with narrow interval 5 markers was larger than one with wide interval. In 3D imaging of the breast using VECTRA H1, distance measurements offering clinically satisfactory accuracy can be made by setting appropriate marker conditions. This journal requires that authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors www.springer.com/00266 .


Film thickness and fluidity of various luting cements determined using a trial indentation meter.
The purpose of this study was to evaluate a new trial apparatus which could measure film thickness (T(h)) under a low load, using an indenter. Five commercial luting cements were measured using this apparatus. T(h) was determined using four kinds of indenter, which were 5.0, 10.0, 15.0 and 20.0mm in diameter. For each indenter, the load per contact area of the indenter with the platen equaled 150N per 200 mm2 described in ISO No. 9917. The effects of working time (30, 60, and 90 s) and load (2.86, 6.78, 10.7, and 14.7N) on the fluidity and T(h) were examined using the indenter with a diameter of 5.0mm. The duration of loading was 10 min. The fluidity was defined as the reciprocal of the apparent viscosity and was calculated using Stefan's equation. The T(h) obtained using this apparatus agreed with the film thickness obtained using the test described in ISO No. 9917. For Durelon (DU), T(h) increased 1.58 times and fluidity decreased 0.26 times as the working time increased from 30 to 90 s; T(h) decreased 0.56 times and fluidity increased 1.28 times as loading increased from 2.86 to 14.7N. For Ketac cement radiopaque (KE), Panavia fluoro cement (PA), Scotchbond resin cement (SC), and Vitremer luting cement (VI), although the fluidity and T(h) were not influenced much by duration (30-90 s), T(h) decreased 0.79, 0.74, 0.95, and 0.78 times for KE, PA, SC, and VI, respectively, and fluidity decreased 0.68, 0.51, 0.30, and 0.36 times, respectively, as loading increased from 2.86 to 14.7N. This apparatus was proven effective in elucidating the flow properties of luting cement.


Coordinated incorporation of nascent peptidoglycan and teichoic acid into pneumococcal cell walls and conservation of peptidoglycan during growth.
Choline-containing pneumococcal cell wals are sensitive to autolysin, whereas ethanolamine-containing walls are not. Bacteria were labeled with radioactive peptidoglycan precursors while growing either in choline- or in ethanolaminecontaining media. Subsequently, the labeled cells were allowed to grow for four to five generations in nonradioactive medium supplemented with the alternative amino alcohol source (i.e. cells labeled in choline medium yields ethanolamine; cells labeled in ethanolamine medium yields choline). The autolysin sensitivity of the isotope label in cell walls prepared from such bacteria indicates that nascent peptidoglycan and teichoic acid units that are synthesized at the same time are attached to one another, incorporated into the cell surface at the cellular equator, and remain conserved during growth the division of the bacteria.


Human gastric cancer, Helicobacter pylori and bracken carcinogens: A connecting hypothesis.
Long term infection of Helicobacter pylori (Hp) virulent strains is a key factor in the genesis of human gastric cancer, and so are certain dietary proinflammatory and genotoxic compounds. Carcinogenic bracken fern (Pteridium spp.) is one of these. Toxins from this plant are consumed as bracken culinary preparations, through milk and meat of bracken-exposed livestock, and drain waters from bracken swards. Bracken toxin ptaquiloside (PtQ), a suspected human carcinogen, elicits complex responses in animals leading to death. PtQ and Hp might cooperate in gastric pathologies. This paper presents an hypothesis on PtQ-Hp association leading to the enhancement of carcinogenesis in the human gastric environment that might explain the high gastric cancer incidence and death rates among Hp-infected people living in bracken zones at two levels: (1) The macroscopic scale comprising the flow of PtQ in the human diet. (2) the microscopic scale encompassing (A) gastric luminal medium; (B) gastric mucus structure and mucin degradation elicited by Hp; (C) bacterial pH gradient modification of the gastric mucosa that favors PtQ survival and its penetration into epithelial tissue; (D) combined PtQ/Hp effects on gastric immune and inflammatory responses; (E) PtQ-Hp complementary activity at selected cell signaling cascades and genome disturbance.


Cocaine-induced supersensitivity and arrhythmogenesis.
The mechanism of cocaine-related sudden death is unknown. To test whether cocaine potentiated changes in sinus cycle length, conduction in the atrioventricular node (AH interval) and ventricular effective refractory period induced by infused norepinephrine and ansae subclaviae stimulation, the dose-response curves of sinus cycle length, AH interval and ventricular effective refractory period to infused norepinephrine (0.01 to 0.20 micrograms/kg body weight per min) and the frequency-response curves to ansae subclaviae stimulation (1 to 4 Hz, 2 to 3 mA, 4 ms pulses) were determined before and after intravenous injection of cocaine (5 mg/kg) in 15 anesthetized open chest dogs. Cocaine potentiated shortening of sinus cycle length, AH interval and ventricular effective refractory period induced by norepinephrine infusion and shifted dose-response curves of these variables to the left in eight dogs (supersensitivity). Cocaine did not affect frequency-response curves of sinus cycle length and AH interval to ansae subclaviae stimulation. Ansae subclaviae stimulation shortened the ventricular effective refractory period more after cocaine injection, but frequency-response curves were not shifted to the left in seven dogs (no supersensitivity). Cocaine did not enhance electrical induction of ventricular tachyarrhythmias in 15 dogs without acute myocardial infarction. Acute myocardial infarction was produced by coronary artery ligation in another group of 21 dogs. Of 10 dogs with acute myocardial infarction, spontaneous or electrically induced ventricular tachycardia developed in 1 dog without drugs, in 3 dogs given norepinephrine and in 7 dogs given norepinephrine and cocaine (p less than 0.03 versus without drugs).(ABSTRACT TRUNCATED AT 250 WORDS)


CYP3A4 intron 6 C>T SNP (CYP3A4*22) encodes lower CYP3A4 activity in cancer patients, as measured with probes midazolam and erythromycin.
The CYP3A4*22 allele was recently reported to be associated with reduced CYP3A4 activity. We investigated the impact of this allele on the metabolism of the CYP3A-phenotyping probes, midazolam (MDZ) and erythromycin. Genomic DNA from 108 cancer patients receiving intravenous MDZ and 45 undergoing the erythromycin breath test was analyzed for CYP3A4*22 (rs35599367 C>T) and CYP3A5*3. The MDZ metabolic ratio (1´-OH-MDZ:MDZ) was 20.7% (95% CI: -36.2 to -6.2) lower for CYP3A4*22 carriers compared with CYP3A4*1/*1 patients (p = 0.01). Combining CYP3A4*22 and CYP3A5*3 genotypes showed a 38.7% decrease (95% CI: -50.0 to -27.4; p < 0.001) in 1´-OH-MDZ:MDZ for poor (CYP3A4*22-CYP3A5*3/*3) and 28.0% (95% CI: -33.3 to -22.6; p < 0.001) for intermediate (CYP3A4*1/*1-CYP3A5*3/*3) metabolizers, compared with extensive (CYP3A4*1/*1-CYP3A5*1) CYP3A metabolizers. CYP3A4 erythromycin N-demethylation activity was 40% lower in CYP3A4*22 carriers compared with CYP3A4*1/*1 patients (p = 0.032). The CYP3A4*22 allele is associated with decreased CYP3A4-mediated metabolism, as verified by CYP3A-phenotyping probes.


Thromboembolism in Patients with Metastatic Urothelial Cancer Treated with Immune Checkpoint Inhibitors.
Immunotherapy has become one of the mainstays for metastatic urothelial carcinoma treatment. Whether immune checkpoint inhibitor therapy increases thromboembolism (TE) risk is unknown. We investigated the incidence of arterial thromboembolism (ATE) and venous thromboembolism (VTE) events and its associated outcomes in patients with metastatic urothelial cancer treated with immune checkpoint inhibitors. Patients with urothelial cancer treated with immune checkpoint inhibitors at the Cleveland Clinic from 1/1/2015 to 12/31/2019 were identified. The Kaplan-Meier method estimated overall survival and Cox proportional hazards regression evaluated the impact of TE on overall survival. Of 279 patients, 72% were men with pure urothelial cancer (62%) who started atezolizumab (40%), nivolumab (3%), or pembrolizumab (57%). At a median follow-up of 5.6 months (range 0.3-51.6), 42 patients developed a TE (VTE n = 37, 13%, ATE n = 5, 2%). The cumulative incidence of TE after immune checkpoint inhibitor therapy was 9.1% (95% confidence interval 6.0-13.0) at 6 months and 13.6% (95% confidence interval 9.6-18.4) at 12 months. Most TE (VTE 62%, ATE 100%) occurred within 6 months of immune checkpoint inhibitor initiation (median doses 5, range 1-59), and the majority (VTE 81%, ATE 100%) resulted in hospitalization (median: 5 days, 4 days, respectively). Thromboembolism (hazard ratio 2.296, p = 0.0004), Bajorin score 1 or 2 (hazard ratio 1.490, p = 0.0315), and Bajorin score 2 (hazard ratio 3.50, p < 0.0001) were associated with worse overall survival. Immune checkpoint inhibitors are associated with a high TE risk. Thromboembolism is associated with worsened survival, among other poor outcomes. Further investigation into the mechanism behind immune checkpoint inhibitor-associated TE is needed.


Long-Term Benefits of Rapid Antiretroviral Therapy Initiation in Reducing Medical and Overall Health Care Costs Among Medicaid-Covered Patients with Human Immunodeficiency Virus.
New guidelines for the treatment of human immunodeficiency virus (HIV) suggest that morbidity and mortality could be reduced if antiretroviral therapy (ART) was initiated immediately after diagnosis, regardless of CD4 cell count. To assess real-world time to ART initiation and describe medical, pharmacy, and total health care costs in the 6-, 12-, 24-, and 36-month periods after HIV diagnosis based on time to ART initiation among Medicaid-covered patients. Multistate Medicaid data (January 2012-March 2017) was used to identify adults with HIV-1 initiating ART ≤ 360 days of initial HIV-1 diagnosis. People living with HIV (PLWH) were sorted into mutually exclusive cohorts based on time from diagnosis to ART initiation (≤ 14 days, > 14 to ≤ 60 days, > 60 to ≤ 180 days, and > 180 to ≤ 360 days). ART regimen had to include a protease inhibitor, an integrase strand transfer inhibitor, or a non-nucleoside reverse transcriptase inhibitor, with ≥ 2 nucleoside reverse transcriptase inhibitors. Medical, pharmacy, and total health care costs in the 6, 12, 24, and 36 months following HIV diagnosis were stratified by timeliness of ART initiation. Of 974 patients, 347 (35.6%) initiated ART > 360 days after diagnosis and were excluded. Among the remaining 627 eligible patients, mean age was 39.9 years, 42.7% were female, and 53.9% were black. Among them, 128 (20.4%) were treated ≤ 14 days, 228 (36.4%) between > 14 and ≤ 60 days, 163 (26.0%) between > 60 and ≤ 180 days, and 108 (17.2%) between > 180 and ≤ 360 days. Among patients treated ≤ 180 days, 4.6% had ≥ 1 opportunistic infection in the 6-month period before ART initiation; this proportion reached 5.6% for patients treated >180 and ≤ 360 days. Over the 6-, 12-, 24-, and 36-month periods after diagnosis, per-patient-per-month (PPPM) medical costs were lower for patients who initiated ART ≤ 14 days than for those who initiated > 180 and ≤ 360 days after diagnosis (6 months: $1,611 [≤ 14 days] vs. $3,008 [> 180 and ≤ 360 days]; 12 months: $1,188 vs. $2,110; 24 months: $754 vs. $1,368; 36 months: $651 vs. $1,196). Over the same periods, medical costs generally accounted for > 50% of total health care costs for patients who initiated ART between > 60 and ≤ 180 days and > 180 and ≤ 360 days and for 30%-40% of total health care costs for patients treated ≤ 14 days and between > 14 and ≤ 60 days. Total PPPM health care costs increased with delay of ART initiation in the 36-month period after diagnosis ($2,058 [treated ≤ 14 days] vs. $2,310 [treated between > 180 and ≤ 360 days]). In this study from 2012 to 2017 of Medicaid PLWH treated with ART, 20.4% initiated ART ≤14 days of HIV diagnosis. Patients with delayed ART initiation accumulated more total health care costs in the 36-month period after HIV diagnosis than those initiated within 14 days, highlighting the long-term benefit of rapid ART initiation. An important opportunity remains to engage PLWH in care more rapidly. This study was supported by Janssen Scientific Affairs, which was involved in the study design, interpretation of results, manuscript preparation, and publication decisions. Emond, Romdhani, Lefebvre, and Côté-Sergent are employees of Analysis Group, a consulting company that was contracted by Janssen Scientific Affairs to conduct this study and develop the manuscript. Shohoudi was an employee of Analysis Group at the time the study was conducted. Benson, Tandon, Chow, and Dunn are employees and stockholders of Johnson & Johnson. Parts of the material in this study have been presented at the HIV Drug Therapy Meeting; October 28-31, 2018; Glasgow, UK, and the AMCP Annual Meeting; March 25-28, 2019; San Diego, CA.


Antigenic heterogeneity of Qa-2 antigens in C57BL/6.
The Qa-2 antigens are class I-like molecules encoded by genes mapped telomeric to the H-2D region on chromosome 17 in the mouse. A panel of 8 new monoclonal anti-Qa-2 antibodies derived from a C3H.KBR anti-C3H. SW immunization was studied. Immunoprecipitation of 125I-labeled C57BL/6 splenocyte antigens showed that all of these antibodies precipitated 40 kDa molecules which could be completely precleared by the monoclonal antibody 20-8-4, which had previously been shown to crossreact with Qa-2. One of the monoclonal antibodies (1-12-1), however, was found not to completely preclear Qa-2 antigens precipitable by the other 7 antibodies or by 20-8-4, suggesting the existence of at least two different species of Qa-2 molecules. Cell lines transfected with Q7 or Q9 genes were reactive with all 9 antibodies and the Qa-2 antigens expressed on surface membranes of these cells were completely precleared by both 20-8-4 and 1-12-1. Therefore, the observed heterogeneity of these molecules cannot be explained by an antigenic difference between the Q7 and Q9 gene products. 2D gel analyses showed identical pI spectra between Qa-2 molecules precipitated with 20-8-4 and 1-12-1. In addition, all of the monoclonal antibodies reacted with labeled antigen preparations following treatment with Endo F or neuraminidase, indicating that carbohydrate moieties are probably not responsible for the antigenic difference between the two species of Qa-2 antigen.


Affine kinematics in planar fibrous connective tissues: an experimental investigation.
The affine transformation hypothesis is usually adopted in order to link the tissue scale with the fibers scale in structural constitutive models of fibrous tissues. Thanks to the recent advances in imaging techniques, such as multiphoton microscopy, the microstructural behavior and kinematics of fibrous tissues can now be monitored at different stretching within the same sample. Therefore, the validity of the affine hypothesis can be investigated. In this paper, the fiber reorientation predicted by the affine assumption is compared to experimental data obtained during mechanical tests on skin and liver capsule coupled with microstructural imaging using multiphoton microscopy. The values of local strains and the collagen fibers orientation measured at increasing loading levels are used to compute a theoretical estimation of the affine reorientation of collagen fibers. The experimentally measured reorientation of collagen fibers during loading could not be successfully reproduced with this simple affine model. It suggests that other phenomena occur in the stretching process of planar fibrous connective tissues, which should be included in structural constitutive modeling approaches.


A dedicated microcomputer-based instrument for interval analysis of multicomponent wave forms in single fibre EMG.
We have developed a self-contained microprocessor-based instrument compatible with conventional EMG equipment for the analysis of multicomponent SFEMG wave forms suitable for single operator use. Intervals between 4 components of a MUAP can be analysed using 3 types of threshold or window triggers. The amplitude, duration and polarity of each of these triggers can be varied independently. The instrument is portable and useful in the clinical setting.


Hazards of the limiting-dilution method of cloning hybridomas.
Three hybridoma clones, which were shown to change the characteristics of their antibody specificities when grown under different culturing conditions, are described in detail. This phenomenon was shown to be due to the persistence of mixed clones, even under conditions where standard statistical treatment indicated a high probability of monoclonality. Such mixed clones persisted, sometimes undetected, through repeated cycles of re-cloning. It was shown that the assumption that every viable clone has the same random chance of monoclonality, is invalid, and can lead to misleadingly high estimates for the probability of monoclonality. Verification of seeding of individual wells with single cells is recommended and the relative merits of this versus repeated limiting-dilution cloning are discussed.


Japanese Encephalitis Vaccines.
As an eminently vaccine-preventable disease, encephalitis caused by Japanese encephalitis virus (JEV) has attracted an unusually high degree of attention from those seeking to develop viral vaccines. Since the 1950s, all types of JEV vaccines including inactivated, recombinant and live attenuated ones have been licensed. As an example of an extremely successful endeavour, the time is ripe for reviewing the development of JEV vaccines and probing the reasons behind their uniform success. Vaccines against JEV have come a long way since the first licensing in the mid-1950s of the mouse brain-grown-inactivated virus preparations, to the present day live-attenuated virus vaccines. A survey of the various inactivated and live vaccines developed against JEV provides a striking insight into the impressive safety and efficacy of all the vaccines available to prevent encephalitis from JEV. This review juxtaposes studies to understand naturally acquired immunity against JEV that have mostly been published post-2000, compares these with those elicited by vaccines and highlights the paucity of data on cell-mediated immune responses elicited by JEV vaccines. This article not only seeks to make available the immense salient literature on this endeavour in one collection, but also queries the basis for the remarkable success of JEV vaccines, not least of which may be the ease of protecting against encephalitis caused by JEV. To conclude, the true test of the ingenuity of those dedicated to the pursuit of viral vaccines would be success against viral diseases such as HIV-AIDS and dengue that pose a far greater challenge to scientists.


Anatomic repair of anomalies of ventriculoarterial connection associated with ventricular septal defect. I. Criteria of surgical decision.
The feasibility of anatomic repair (defined as the reconstruction of normal ventriculoarterial connection) was investigated in 104 patients who underwent an operation for anomalies of ventriculoarterial connection associated with ventricular septal defect. Three types of anatomic repair were used: intraventricular rerouting, REV (association of intraventricular rerouting with translocation of the pulmonary arterial trunk on the right ventricle), and arterial switch associated with closure of the ventricular septal defect. Intraventricular repair was considered to be the best and simplest method when possible. In the other cases, REV was indicated if pulmonary outflow tract obstruction was present, and arterial switch was performed when the tract was patent. The feasibility of intraventricular repair was related to the distances between the tricuspid valve and the semilunar valves. Preoperative measurement of these distances is an essential criterion to choose the appropriate repair of anomalies of ventriculoarterial connection associated with ventricular septal defect.


Genetic characterization of porcine circovirus type 2 in captive wild boars in southern Brazil.
Porcine circovirus type 2 (PCV2) has been identified in pig population in Brazil since 2000, but scarce studies involving wild boars with PCV2 infection are reported in the country. This study aimed to perform the genetic characterization of PCV2 detected in clinically healthy captive wild boars from farms located in Southern Brazil. Bronchial and mesenteric lymph nodes from 129 clinically healthy captive wild boars were tested by nested PCR for PCV2 detection. Six out of 38 positive samples (29.5%) were submitted to a quantitative real time PCR (qPCR) and genetic sequencing. Viral load up to 1.19 × 109 viral DNA copies/uL was detected in lymph nodes samples by qPCR. According to the ORF2 gene sequence analysis, all PCV2 samples were classified into PCV2b genotype. Comparisons based on a 702 nt region of the ORF2 of all six isolates revealed a high degree of similarity between these isolates. The ORF2 sequences characterized here share 97.1-100% of nucleotide identity and 95.7-100% of amino acid identity with other PCV2b isolated in Brazil from wild boars and feral pigs. This study reports the first detection and genetic characterization of PCV2b in captive wild boars in Brazil and provides important information on PCV2 infection in this domesticated species.


[Prostate cancer and disseminated intravascular coagulation: review of the literature].
Disseminated intravascular coagulation is a rare complication of prostatic cancer evolution. Occurring on hormonorefractory phase, it remains most often infraclinic. Cases of acute, severe intravascular disseminated coagulation at first presentation are life-threatening because of hemorragic and thrombotic complications, justifying emergency medical treatment. In the light of a review of literature, we insist on epidemiological features, physiopathology and therapeutics of intravascular disseminated coagulation. In spite of a pejorative prognosis, this could help to achieve a period of remission.


Dysphagia and dysmotility of the pharynx and oesophagus in patients with primary Sjögren's syndrome.
To assess the prevalence of pharyngeal and oesophageal symptoms and dysmotility in patients with primary Sjögren's syndrome (pSS) and relate these to autonomic nervous function. Twenty consecutive pSS patients, according to the American-European Consensus Criteria (AECC), and 30 age- and sex-matched controls from the Swedish general population registry were studied. All subjects completed a pharyngeal and oesophageal symptoms questionnaire and were examined by pharyngeal and oesophageal video radiography. In addition, the pSS patients were examined by two different autonomic nervous function tests, the deep breathing test [calculating the expiration/inspiration (E/I) ratio] and the finger skin blood flow test [the vasoconstriction (VAC) index]. pSS patients experienced significantly more dysphagia compared with controls (65% vs. 3%; p<0.001). Pharyngeal (45% vs. 7%; p<0.01), oesophageal (80% vs. 7%; p<0.001) and gastro-oesophageal reflux symptoms (60% vs. 23%; p<0.01) were also more prevalent in pSS patients compared with controls while pharyngeal (15% vs. 17%; p = NS) and oesophageal dysmotility (40% vs. 30%; p = NS) were not. Dysphagia was not associated with dysmotility but was found to be associated with a decreased E/I ratio [-1.05 (-1.51 to -0.40) in patients with dysphagia vs. -0.21 (-0.39 to 0.65) in patients without dysphagia; p<0.01]. Subjective swallowing difficulties were more common in pSS patients than in controls while objective signs of pharyngeal and oesophageal dysmotility were not. Dysphagia in pSS patients does not seem to be related to video radiographical signs of dysmotility but may be related to an impaired parasympathetic function.


Barriers and facilitators to implementing a continuing medical education intervention in a primary health care setting.
Continuing medical education (CME), as a systematic attempt to facilitate change in General Practitioners' (GPs) practices, is considered crucial, assuming that if physicians are up-to-date, they will change and improve their practice, resulting in better performance and ultimately better patient care. However, studies continue to demonstrate considerable gaps between the real and ideal performance and patient-related outcomes. The objective of this study was to explore GP's perception of the factors affecting the implementation of a CME digital platform in a primary health care setting in Portugal. Our work is framed in a larger effectiveness-implementation hybrid type 1 study, where a Digital Behaviour Change Intervention (DBCI), called ePrimaPrescribe, was developed and implemented with the aim of changing benzodiazepines (BZD) prescribing patterns. Our design used mixed methodologies to obtain an enriched knowledge on GPs' perspectives on the facilitators and barriers to implementing a Digital Behaviour Change Intervention (DBCI) applied to CME. To do so, we used data coming from an onsite questionnaire, an adapted version of the Barriers and Facilitators Assessment Instrument (BaFAI) and in-depth interviews. From the 47 GPs successfully included in the intervention arm of our cluster-randomized effectiveness study, we collected 37 onsite questionnaires, 24 BaFAIs, and performed 12 in-depth interviews. GPs reported as the main barriers to CME a lack of time, a perception of work overload, a lack of digital competence, a lack of digital infrastructure, and motivational and emotional factors. They reported as facilitators to CME delivered through a DBCI the convenience of the delivery method, the practical and pragmatic characteristics of the content, and the possibility for CME to be mandatory. The perceptions of the barriers and facilitators reported by GPs represent an important contribution to improving knowledge regarding the factors influencing the implementation of CME in primary health care settings. We consider that our study might bring useful insights to other countries where primary health care plays a central role in the provision of care. ClinicalTrials.gov number NCT04925596 .


Effect of tranexamic acid on endothelial von Willebrand factor/ADAMTS-13 response to in vitro shock conditions.
Traumatic/hemorrhagic shock, sepsis and other inflammatory processes lead to endothelial activation and a loss of the endothelial glycocalyx. von Willebrand factor (vWF) is an acute phase reactant that is released from endothelial cells and megakaryocytes. Stimulated but not basal vWF leads to significant formation of ultralarge multimers (ultralarge vWF [ULvWF]) and risk for thrombotic complications. Ultralarge vWF is cleaved by a disintegrin and metalloproteinase with a thrombospondin type motif 13 (ADAMTS 13); alterations in ULvWF/ADAMTS 13 ratio may contribute to trauma-induced coagulopathy. Salutary effects of tranexamic acid (TXA) on trauma-induced coagulopathy have been described. These effects appear apart from antifibrinolytic actions of TXA and include protection of the endothelial glycocalyx. Ultralarge vWF is in part anchored to the glycocalyx layer of the endothelium. Tranexamic acid protected the endothelial glycocalyx layer from degradation using a microfluidic model of the microcirculation subjected to hypoxia-reoxygenation and catecholamine excess. We hypothesized that TXA administration following shock conditions would impact the vWF-ADAMTS-13 axis by protecting the glycocalyx from degradation. This was studied in a endothelial microfluidic flow study. Human umbilical vein endothelial cells were established under flow conditions and subjected to biomimetic shock. Tranexamic acid was added after 90 minutes of perfusion. von Willebrand factor antigen and ADAMTS-13 activity were measured. Western blot analysis was performed for vWF characterization from perfusion media. Shock conditions increased vWF antigen and decreased ADAMTS 13 activity. Tranexamic acid ameliorated shock induced cleavage in the ADAMTS 13-vWF axis with a reduction of the thrombogenic ULvWF. These results suggest another mechanism whereby administration of TXA early following traumatic/hemorrhagic shock mitigates microvascular perfusion abnormalities and subsequent organ failure. The resultant effects on platelet adhesion and aggregation require further study.


Fbxw7 regulates tumor apoptosis, growth arrest and the epithelial-to-mesenchymal transition in part through the RhoA signaling pathway in gastric cancer.
F-box and WD repeat domain-containing7 (Fbxw7), a member of the F-box family of proteins, which are components of an E3 ubiquitin ligase complex, plays an important role as a general tumor suppressor in regulating the effects of various oncoproteins. Recently, accumulating studies have shown that Fbxw7 plays an important role in tumor cell motility, invasion and cancer metastasis. However, little is known about the signaling mechanisms that regulate tumor apoptosis, growth arrest and the epithelial-to-mesenchymal transition (EMT) in gastric cancer. In our study, we confirmed that Fbxw7 expression was decreased in gastric cancer tissues, and that Fbxw7 inhibited gastric cancer progression by inducing apoptosis and growth arrest. Furthermore, gastric cancer migration and invasion were decreased or increased following Fbxw7 overexpression or knockdown, respectively, and the expressions of various EMT markers, such as E-cadherin, N-cadherin and vimentin, were altered after Fbxw7 inhibition or overexpression. Furthermore, we demonstrated that Fbxw7 inhibits the EMT via the down-regulation of Snail 1 and ZEB 1, which are upstream transcription factors that promote this process. Additionally, RhoA showed higher expression in the same gastric cancer tissues than in normal tumor-adjacent samples. We found that Fbxw7 expression was negatively correlated with RhoA protein expression in gastric cancer tissues based on Pearson's correlation coefficient analysis. Moreover, we found that RhoA protein abundance was regulated by Fbxw7 via ubiquitination and proteasomal degradation in gastric cancer. We further demonstrated the effects of RhoA re-expression or inhibition on stable Fbxw7-overexpressing or Fbxw7-silenced cell lines in vitro and in vivo. These results suggest that Fbxw7 induces apoptosis and growth arrest and inhibits the EMT in part by down-regulating the RhoA signaling pathway.


Bacterial contamination and growth in two defined formula diets of different pH.
We inoculated partially hydrolysed protein feed of low pH and an intact protein feed of neutral pH with various pathogenic bacteria, and showed that the low pH feed restricted bacterial growth. To study this effect in a clinical setting, 20 malnourished in-patients were randomised prospectively to receive one or other of these feeds. Both formulae were given as a continuous feed via a nasogastric tube, 1,000 ml over 12 h twice daily, using routine hygienic measures. On two occasions significant contamination was demonstrated (Erwinia herbicola and Acinetobacter Iwoffi), both occurring in the intact protein diet. When the bacteria were isolated and transferred to the hydrolysed protein diet, their growth was inhibited. The contamination did not cause clinical complications. The study demonstrates inhibition of microbial growth in a partially hydrolysed protein formula of low pH. This effect may reduce the risk of contamination, and limit infectious complications.


Chronopharmacological dependence of antihypertensive effects of the imidazoline-like drugs in stroke-prone spontaneously hypertensive rats.
In the present study we investigated the chronopharmacological dependence of dose-dependent hypotensive and cardiochronotropic effects of the imidazoline-like drugs (clonidine, rilmenidine and moxonidine) in stroke-prone spontaneously hypertensive rats (SHR-SP), using radio-telemetric system (Data Sciences, USA). The 24-h blood pressure, heart rate and locomotor activity profiles showed peak values during the rats' active phase during the night period. The degree of hypotensive and bradycardic effects of all drugs were most evident at this time and occurred in the absence of a change in locomotor activity. These studies show that clonidine, rilmenidine and moxonidine decrease blood pressure and heart rate in a time-dependent manner in SHR-SP. It was demonstrated that the degree and duration of hypotensive action of imidazoline-like drugs vary with the time of drug administration.


Differential effects of acute morphine administrations on polymorphonuclear cell metabolism in various mouse strains.
This paper shows that an acute morphine treatment dose-dependently alters the energetic and oxidative metabolism of polymorphonuclear leukocytes obtained from BALB/c and DBA/2 mice, while phagocytic cells from C57BL/6 were not affected. In sensitive mouse strains, i.e. BALB/c and DBA/2, morphine decreased both ATP concentration and energy charge potential. At the same time, ATP catabolic products, i.e. nucleosides (inosine+adenosine) and oxypurines (hypoxanthine+xanthine+uric acid), significantly increased, indicating an imbalance between energy production and consumption. Morphine treatment also induced malondialdehyde and superoxide anions production in leukocyte cells from sensitive mice. The opiate antagonist naloxone blocked morphine-induced modifications by the lower morphine dose. The same parameters in cells from C57BL/6 mice were not affected. These findings confirm that: i) the phagocytic cells are an important target for the in vivo effects of morphine, and ii) the genotype-dependent variation influences the immunological responsiveness to opiates.


Iron transport machinery of human cells: players and their interactions.
Organisms, like cells, maintain tight control of iron. In humans as well as other mammals, control is achieved through the regulation of iron uptake into the body rather than through the excretion of iron. The mechanisms by which humans and mice regulate both iron uptake and the distribution of iron within the body and cells are reviewed. Special emphasis is given to the iron transporters involved in this process.


Loratadine.
Loratadine, 4-(8-Chloro-5,6-dihydro-11H-benzo[5,6]cyclohepta[1,2-b]pyridin-11-ylidene)-1-piperidinecarboxylic acid ethyl ester, is an antihistamine drug with long-acting effects and has limited selectivity for peripheral H1 receptors. It is widely used for the prevention of allergic diseases such as rhinitis chronic urticaria, and asthma. This chapter discusses, by a critical extensive review of the literature, the description of loratadine in terms of its names, formulae, elemental composition, appearance, methods of preparation. The profile contains physicochemical properties of Loratadine, including pKa value, solubility and X-ray powder diffraction. In addition, it involves Fourier transform infrared spectrometry, nuclear magnetic resonance spectroscopy and mass spectroscopy for functional groups and structural confirmation of. The chapter also includes methods of analysis of the drug such as compendial, titrimetric, electrochemical, spectroscopic, chromatographic and capillary electrophoretic methods. The chapter also covers clinical applications of the drug such as its uses, doses, ADME profiles and mechanism of action.


Inhibition of microRNA-143-3p attenuates myocardial hypertrophy by inhibiting inflammatory response.
MicroRNA-143-3p (miR-143-3p) is involved in the initiation of inflammatory response and the progression of cardiovascular diseases. Myocardial hypertrophy is a common symptom in numerous cardiovascular diseases. In the current study, we attempted to demonstrate the role of miR-143-3p in the development of myocardial hypertrophy by focusing on its association with inflammation. Myocardial hypertrophy was induced by transverse aortic constriction (TAC) method in vivo and by H2 O2 administration in vitro. The expression status of miR-143-3p and downstream effectors were detected in animal heart tissues and H9c2 cells. Furthermore, the effect of miR-143-3p inhibition on H2 O2 -induced changes in ERK5/PPARδ/NF-κB axis was assessed. TAC induced oxidative stress and inflammation in rat heart tissues, which was associated with the increased expressions of miR-143-3p and p-ERK5. However, the up-regulated expression of miR-143-3p had no effect on the expression of ERK5, which was a direct target of miR-143-3p. The results of in vitro assays showed that H2 O2 administration increased the levels of miR-143-3p and p-EKR5 and induced the activation of NF-κB pathway. After the inhibition of miR-143-3p, the activation of EKR5 and NF-κB pathway was suppressed, whereas the expression of PPARδ was up-regulated. The current study demonstrated that miR-143-3p is crucial to the initiation of inflammatory response induced by myocardial hypertrophy. The activation of ERK5 following miR-143-3p up-regulation appears to be a complementary response to induce the subsequent anti-inflammatory signaling transduction, which needed further exploration.


Role of calcium in the rate-dependent depression of atrioventricular nodal conduction in the dog heart under vagal influence.
Increase in heart rate may be detrimental to atrioventricular conduction. The effects of such an increase were investigated in the paced intact dog heart, by measuring the conduction time in the atrioventricular node (obtained from the His bundle potential recording) and the effective refractory period in this node as determined by the extrastimulus method. Investigations on atrioventricular nodal conduction were performed with and without vagal influence. After central restoration of vagal tone by dextromoramide in anesthetized animals, both parameters appeared to lengthen as the heart rate rose. This lengthening became considerable at the highest rates. After blockade of cholinergic receptors by atropine, no significant change occurred when the heart rate was raised. The prolongation observed under vagal tone was enhanced by the rise in the plasma calcium concentration to 3.10 mmol X l-1 and reduced by a calcium influx inhibitor, verapamil, in 0.2 mg X kg-1 dose. These effects are related to the calcium intracellular concentration, since the rise in this concentration beyond an optimum has been demonstrated to inhibit the calcium and potassium channel.


DNA polymerase stalling at structured DNA constrains the expansion of short tandem repeats.
Short tandem repeats (STRs) contribute significantly to de novo mutagenesis, driving phenotypic diversity and genetic disease. Although highly diverse, their repetitive sequences induce DNA polymerase slippage and stalling, leading to length and sequence variation. However, current studies of DNA synthesis through STRs are restricted to a handful of selected sequences, limiting our broader understanding of their evolutionary behaviour and hampering the characterisation of the determinants of their abundance and stability in eukaryotic genomes. We perform a comprehensive analysis of DNA synthesis at all STR permutations and interrogate the impact of STR sequence and secondary structure on their genomic representation and mutability. To do this, we developed a high-throughput primer extension assay that allows monitoring of the kinetics and fidelity of DNA synthesis through 20,000 sequences comprising all STR permutations in different lengths. By combining these measurements with population-scale genomic data, we show that the response of a model replicative DNA polymerase to variously structured DNA is sufficient to predict the complex genomic behaviour of STRs, including abundance and mutational constraints. We demonstrate that DNA polymerase stalling at DNA structures induces error-prone DNA synthesis, which constrains STR expansion. Our data support a model in which STR length in eukaryotic genomes results from a balance between expansion due to polymerase slippage at repeated DNA sequences and point mutations caused by error-prone DNA synthesis at DNA structures.


The effect of handedness on electromyographic activity of human shoulder muscles during movement.
The aim of the study was to investigate whether there was a difference in the electromyographic (EMG) activity of human shoulder muscles between the dominant and nondominant side during movement and to explore whether a possible side-difference depends on the specific task. We compared the EMG activity with surface and intramuscular electrodes in eight muscles of both shoulders in 20 healthy subjects whose hand preference was evaluated using a standard questionnaire. EMG signals were recorded during abduction and external rotation. During abduction, the normalized EMG activity was significantly smaller on the dominant side compared to the nondominant side for all the muscles except for infraspinatus and lower trapezius (P <or= 0.002). In contrast, during external rotation, higher EMG activity was seen in the supraspinatus, infraspinatus, lower and upper trapezius and latissimus muscles of the dominant side (P <or= 0.01). We demonstrated a side-difference in shoulder muscle activity, which was dependent on the type of motion carried out, suggesting a qualitative difference in the activation of muscles during the two types of movement. Dynamic abduction has the characteristics of a dominant arm task (i.e., task performed almost exclusively by the dominant arm) and reduced muscle activity for the dominant side during abduction indicates a dominance-related advantage in arm dynamics.


Colorectal cancer in a monoallelic MYH mutation carrier.
Although the literature describes mutY homolog gene (MYH) polyposis as an autosomal recessive syndrome, we report a case of colorectal cancer in a carrier of MYH polyposis. Biallelic mutations in the MYH gene have been shown to increase the risk of colorectal cancer over the lifetime of the mutation carrier.1,2 However, there is no clear consensus in the literature as whether a monoallelic mutation increases the risk for colorectal cancer.3 In this report, we postulate that a single mutation is sufficient to increase the risk of colorectal cancer. We also propose that the G382D MYH mutation may play a dominant rather than a recessive role in polyposis and cancer development.


Cutting Edge: Nonobese Diabetic Mice Deficient in Chromogranin A Are Protected from Autoimmune Diabetes.
T cells reactive to β cell Ags are critical players in the development of autoimmune type 1 diabetes. Using a panel of diabetogenic CD4 T cell clones derived from the NOD mouse, we recently identified the β cell secretory granule protein, chromogranin A (ChgA), as a new autoantigen in type 1 diabetes. CD4 T cells reactive to ChgA are pathogenic and rapidly transfer diabetes into young NOD recipients. We report in this article that NOD.ChgA(-/-) mice do not develop diabetes and show little evidence of autoimmunity in the pancreatic islets. Using tetramer analysis, we demonstrate that ChgA-reactive T cells are present in these mice but remain naive. In contrast, in NOD.ChgA(+/+) mice, a majority of the ChgA-reactive T cells are Ag experienced. Our results suggest that the presence of ChgA and subsequent activation of ChgA-reactive T cells are essential for the initiation and development of autoimmune diabetes in NOD mice.


Culturing hippocampal and cortical neurons.
Primary cultures of rat and mouse hippocampus and cerebral cortex are widely used to study neuronal properties such as axonal extension, synaptic transmission, and excitotoxicity. Short-term culturing of these neurons can be very straightforward and is perhaps easier than culturing cells lines once dissections are made and cell stocks are frozen. Long-term cultures of relatively pure neuronal populations require slightly more effort, but protocols are described that are less complicated than most published protocols. These include simpler ways to clean and coat coverslips, as well as using glia-conditioned medium to eliminate the need to make individual cocultures of neurons and glia. These methods consistently yield hippocampal and cortical cultures expressing dendritic spines and synapses that survive over 3 weeks in culture. For investigators employing biochemical assays where a fairly large amount of protein is necessary, cortical neurons may be especially attractive to use as large amounts of tissue are obtained and available for culture.


Magnetic Ugi-functionalized graphene oxide complexed with copper nanoparticles: Efficient catalyst toward Ullman coupling reaction in deep eutectic solvents.
Herein, we report the direct synthesis of carboxamide-functionalized graphene oxide (carboxamide-f-GO) for the development of new nanocatalysts, with highly dispersed particles, through covalent functionalization with a facile and direct strategy. This surface functionalization was carried out through a one-pot sequential four-component Ugi reaction. Subsequently, the Ugi-ligand decorated on the surface of the graphene oxide sheets coordinated with copper nanoparticles (Cu NPs) and finally covered with magnetic nanoparticles. The synthesized nanocatalyst was characterized by Fourier transform infrared (FT-IR), proton nuclear magnetic resonance spectroscopy (1H NMR), X-ray powder diffraction (XRD), scanning electron microscopy (SEM), energy-dispersive X-ray spectroscopy (EDX), dynamic light scattering (DLS), thermogravimetric analysis (TGA) and atomic force microscopy (AFM). The carboxamido nitrogen in Ugi-ligand showed high affinity toward complexation with Cu NPs and has a profound effect on the reactivity of the copper center in this nanocatalyst. The catalytic activity of nanocatalyst was investigated in Ullmann cross-coupling reaction for practical and direct access to corresponding N-aryl amines in a deep eutectic solvent as a green and recyclable media. The results showed the capability of this designed catalytic system through N-arylation of N-heterocycles and aniline derivatives with high yields in short reaction times. In addition, both of the nanocatalyst and deep eutectic solvent were easily recovered and reused for five consecutive runs.


Disparities in cancer screening by occupational characteristics.
Cancer screening patterns according to occupation characteristics in the United States are not well known, but could be used to help inform cancer control efforts. We examined cervical (CC), breast (BC) and colorectal cancer (CRC) screening prevalence and prevalence ratios (PR) by occupational characteristics in 2010, 2013 and 2015 National Health Interview Surveys (NHIS) among eligible US workers (CC women 21-65years; n=20,997), (BC women ≥40years; n=14,258) and (CRC men and women ≥50years; n=17,333). Cervical, breast and colorectal cancer screening prevalence among US workers was 84.0%, 68.9%, and 56.8%, respectively. Unadjusted prevalence ratios for cervical (PR=0.92, 95%CI 0.90, 0.94), breast (PR=0.86, 95%CI 0.83, 0.90) and colorectal cancer screening (PR=0.83, 95%CI 0.80, 0.87) were lower among workers in small (<25 employees) compared to large organizations (≥500 employees). People in food service, construction, production, and sales occupations were 13-26%, 17-28% and 9-30% less likely to be up to date with cervical, breast, and colorectal cancer screening, respectively, compared to healthcare professionals. Adjustment for socioeconomic factors and insurance status eliminated most associations. Disparities in cancer screening by occupational characteristics were mostly attributed to lower socioeconomic status and lack of insurance. These findings underscore the need for innovative public health strategies to improve cancer screening in vulnerable populations.


Chronic lymphatic leukaemia: cellular effects of glucocorticoids in vitro.
Glucocorticoid receptor levels and steroid induced inhibition of nucleic acid precursors have been examined in lymphocytes from 27 patients at different stages of chronic lymphatic leukaemia. No correlation can be found between the level of glucocorticoid receptors and the stage of the disease. On the other hand, a significant difference (P less than 0.02) was found between stage O and stage III/IV patients, in terms of the in vitro effect of dexamethasone on [3H] uridine incorporation.


Mitotic Mysteries: The Case of HP1.
The role of Heterochromatin Protein-1 (HP1) during mitosis has been controversial. Two recent studies in Science and Developmental Cell, from Tanno et al. (2015) and Abe et al. (2016), suggest that the means of HP1 localization and its function at inner centromeres are altered in cancer cells with chromosomal instability.


Mycophenolate mofetil vs. sirolimus in kidney transplant recipients receiving tacrolimus-based immunosuppressive regimen.
Mycophenolate mofetil (MMF) and sirolimus (SRL) are effective immunosuppressive drugs with distinct safety profile. Kidney transplant recipients receiving tacrolimus (TAC)-based immunosuppressive regimen were randomized to receive fixed daily doses of MMF (2 g/d, n = 50) or SRL (one loading dose of 15 mg, 5 mg/d till day 7 and 2 mg/d thereafter, n = 50) without induction therapy. No differences were observed in the incidence of the composite (biopsy-confirmed acute rejection, graft loss or death) end-point (18% vs. 16%, p = 1.000), biopsy confirmed acute rejection (12% vs. 14%, p = 1.000), one-yr patient (94% vs. 98%, p = 0.308), graft (92% vs. 98%, p = 0.168), and death-censored graft survival (98% vs. 100%, p = 0.317) comparing patients receiving MMF or SRL respectively. Patients receiving SRL showed worse safety outcomes, higher mean creatinine (1.6 +/- 0.5 mg/dL vs. 1.4 +/- 0.3 mg/dL, p = 0.007), higher proportion of patients with proteinuria (52.0% vs. 10.7%, p = 0.041), higher mean urinary protein concentrations (0.3 +/- 0.5 g/L vs. 0.1 +/- 0.2 g/L, p = 0.012), higher mean cholesterol concentration (217 mg/dL vs. 190 mg/dL, p = 0.030), and higher proportion of patients prematurely discontinued from randomized therapy (26% vs. 8%, p = 0.031). In patients receiving TAC, MMF produced similar efficacy but superior safety profile compared with SRL.


Remediation of noxious wastewater using nanohybrid adsorbent for preventing water pollution.
Removal of toxic elements from wastewater effluent has got a lot of attention because of their severe negative effects on human and environmental health. In the past few years, rapid urbanization and industrial activities in developing countries have exacerbated the destruction of the environment. Most of the wastewater effluents are discharged untreated or inadequately treated, which has become a major concern due to its impact on sustainability and the environment. This is imperative to implement, innovative and resourceful wastewater treatment technologies requiring low investment. Among the various treatment technologies, cutting-edge processes in nano-material sciences have recently piqued the interest of scientists. Nanohybrid absorbents have the potential in improving wastewater treatment and increase water supply by utilizing unconventional water resources. Carbon nanotubes, titanium oxide, manganese oxide, activated carbon (AC), magnesium oxide, graphene, ferric oxides, and zinc oxide are examples of nano-adsorbents that are used to eliminate pollutants. This also demonstrated the effective removal of contaminants along with the harmful effects of chemicals, colorants, and metals found in wastewater. The present manuscript examines potential advances in nanotechnology in wastewater treatment for the prevention of water and soil pollution. This systematic review aims to highlight the importance of nanohybrid absorbents treatment technology for wastewater treatment and to explain how nanohybrid absorbents have the potential to revolutionize industrial pollution. There are also other published review articles on this topic but the present review covers an in-depth information on nano-adsorbents and their targeted contaminants.


Identification of the first multi-exonic WDR72 deletion in isolated amelogenesis imperfecta, and generation of a WDR72-specific copy number screening tool.
Amelogenesis imperfecta (AI) is a clinically and genetically heterogeneous disorder of tooth development which is due to aberrant deposition or composition of enamel. Both syndromic and isolated forms exist; they may be inherited in an X-linked, autosomal recessive, or autosomal dominant manner. WDR72 is one of ten currently known genes for recessive isolated AI; nine WDR72 mutations affecting single nucleotides have been described to date. Based on whole exome sequencing in a large consanguineous AI pedigree, we obtained evidence for presence of a multi-exonic WDR72 deletion. A home-made multiplex ligation-dependent probe amplification assay was used to confirm the aberration, to narrow its extent, and to identify heterozygous carriers. Our study extends the mutational spectrum for WDR72 to include large deletions, and supports a relevance of the previously proposed loss-of-function mechanism. It also introduces an easy-to-use and highly sensitive tool for detecting WDR72 copy number alterations.


Occurrence of deoxynivalenol (DON) and ochratoxin A (OTA) in dog foods.
The commercially available dog food samples (29 dry foods and 11 wet foods) were analysed for deoxynivalenol (DON) and ochratoxin A (OTA) using ELISA. All (100%) dry foods were contaminated with DON with various amount of the toxin (22-1837 μg/kg). In wet food 3 samples were found to be positive for DON in the range of 95-170 μg/kg. There were a few samples contaminated with OTA: 3 samples in dry foods (7-40 μg/kg) and 2 samples in wet foods (45 and 115 μg/kg).


The descriptions of new microanatomical structures of the male reproductive system and sperm of Myschocyttarus cassununga (Hymenoptera: Vespidae).
The male reproductive system of Mischocyttarus cassununga consists of two testes, each one with three follicles, as occurs in most Vespidae. The seminal vesicle is divided in two chambers, separated by a constriction, so that the anterior locus is a little larger. In the testicular follicles, the spermatozoa are organized in cysts, with approximately 128 per cyst, where the nuclei are oriented toward the follicle center. The spermatozoa of M. cassununga is about 97 μm in length, which makes them the shortest sperm described for Vespidae. Sperm ultrastructure of M. cassununga is very similar of the others Vespidae. But, despite these similarities, the bilobated mitochondrial derivative represents an autapomorphy for M. cassununga. The subdivision of the seminal vesicle has never been observed in any other Vespidae. Thus, this study supports the validity of insect sperm morphology as a tool for phylogenetic analysis within Hymenoptera.


Pre-pandemic Predictors of Loneliness in Adult Men During COVID-19.
Loneliness is a major public health issue, with its prevalence rising during COVID-19 pandemic lockdowns and mandated "social distancing" practices. A 2020 global study (n = 46,054) found that, in comparison to women, men experienced the greatest levels of loneliness. Although research on predictors of loneliness during COVID-19 is increasing, little is known about the characteristics of men who may be particularly vulnerable. Studies using prospective data are needed to inform preventative measures to support men at risk of loneliness. The current study draws on rare longitudinal data from an Australian cohort of men in young to mid-adulthood (n = 283; aged M = 34.6, SD = 1.38 years) to examine 25 pre-pandemic psychosocial predictors of loneliness during COVID-19 social restrictions (March-September 2020). Adjusted linear regressions identified 22 pre-pandemic predictors of loneliness across a range of trait-based, relational, career/home and mental health variables. Given the extensive set of predictors, we then conducted penalized regression models (LASSO), a machine learning approach, allowing us to identify the best fitting multivariable set of predictors of loneliness during the pandemic. In these models, men's sense of pre-pandemic environmental mastery emerged as the strongest predictor of loneliness. Depression, neuroticism and social support also remained key predictors of pandemic loneliness (R 2 = 26, including covariates). Our findings suggest that men's loneliness can be detected prospectively and under varying levels of social restriction, presenting possible targets for prevention efforts for those most vulnerable.


Including 'learned sexuality' in the organization of sexual behavior.
Learning plays numerous important roles in sexual development. Yet, the possible impacts on sexuality, of learning from experience, are rarely included in discussions of the organization of behavioral sex differences and the differentiation of psychosexual function. This article reviews the empirical evidence for 'learned sexuality' with a goal of reintroducing the topic of nurture into discussions of the ontogenetic processes that lead to sexual reproduction in nature. Evolutionarily relevant examples of sexual learning are broadly represented in the animal kingdom, and can occur relatively early in development, leading to lasting changes in behaviors that might otherwise appear to be instinctive, or in other cases, maladaptive. The lasting effects of social and sexual experiences across the lifespan provide an essential link between steroid-mediated events occurring during development, behavioral plasticity, and changes in motivational states in adulthood.


Effect of anterior capsular polishing on the rate of posterior capsule opacification: A retrospective analytical study.
To determine whether anterior capsule polishing during cataract surgery done by phacoemulsification has any effect on the rate of posterior capsule opacification. We conducted a 3 year retrospective analytical study at our hospital. The medical records of patients who underwent cataract extraction by phacoemulsification with foldable square edge hydrophilic PCIOL between April 2007 and March 2010 were reviewed. The study included 1009 eyes of 950 patients who underwent phacoemulsification with foldable square edge hydrophilic IOL in the bag implantation with anterior capsular polishing. The control group included 981 eyes of 957 patients in whom anterior capsular polishing was not done. Patients in the age group of 45-65 years with well dilating pupils were included in the study. They were evaluated at 1 week, 1 month and 1 year post-operatively. Exclusion criteria included glaucoma, shallow anterior chamber, uveitis, high myopia, pseudoexfoliation, diabetes mellitus, traumatic cataracts, posterior polar cataract, subluxated cataracts, previous ocular surgeries, patients allergic to dilating drops, and steroid intake. Intraoperatively, the exclusion criteria were not achieving the total anterior capsule cover on the IOL optic, sulcus fixated IOL, and any intraoperative complications like posterior capsule rupture. After bimanual irrigation/aspiration, all enrolled patients were randomly assigned to receive either 360 degree anterior capsular polishing or No anterior capsular polishing and results were studied. The rate of posterior capsule opacification in the study group and in the control group was not statistically significant. Though it was thought that anterior capsular polishing will lead to reduced rate of PCO formation, our study showed that there was no significant difference in PCO formation between the two groups. However, it was seen that the rate of anterior capsule opacification and capsular phimosis showed a significant reduction in cases in which anterior capsular polishing was done.


Triterpenoid saponins from Neonauclea sessilifolia Merr.
Two new triterpenoid saponins, quinovic acid 3-O-6-deoxy-beta-D-glucopyranoside, 28-beta-D-glucopyranosyl ester and quinovic acid 3-O-alpha-L-rhamnopyranosyl-(4 --> 1)-beta-D-glucopyranoside, along with three known saponins, have been isolated from the EtOAc extracts of the dried stems of N. sessilifolia Merr. Structure elucidation of 1-3 was based on NMR, MS, IR and chemical analysis.


Dithiocarbazate complexes with the [M(PPh3)]2+ (M = Pd or Pt) moiety: synthesis, characterization and anti-Trypanosoma cruzi activity.
New neutral Pd(II) and Pt(II) complexes of the type [M(L)(PPh(3))] (M = Pd or Pt) were prepared in crystalline form in high-yield synthesis with the S-benzyldithiocarbazates and S-4-nitrobenzyldithiocarbazates derivatives from 2-hydroxyacetophenone, H(2)L(1a) and H(2)L(1b), and benzoylacetone, H(2)L(2a) and H(2)L(2b). The new complexes [Pt(L(1a))(PPh(3))] (1), [Pd(L(1a))(PPh(3))] (2), [Pt(L(1b))(PPh(3))] (3), [Pd(L(1b))(PPh(3))] (4), [Pt(L(2a))(PPh(3))] (5), [Pd(L(2a))(PPh(3))] (6), [Pt(L(2b))(PPh(3))] (7) and [Pd(L(2b))(PPh(3))] (8) were characterized on the basis of elemental analysis, conductivity measurements, UV-visible, IR, electrospray ionization mass spectrometry (ESI-MS), NMR ((1)H and (31)P) and by X-ray diffraction studies. The studies showed that differently from what was observed for the H(2)L(1a) and H(2)L(1b) ligands, H(2)L(2a) and H(2)L(2b) assume cyclic forms as 5-hydroxypyrazolinic. Upon coordination, H(2)L(2a) and H(2)L(2b) suffer ring-opening reaction, coordinating in the same manner as H(2)L(1a) and H(2)L(1b), deprotonated and in O,N,S-tridentate mode to the (MPPh(3))(2+) moiety. All complexes show a quite similar planar fourfold environment around the M(II) center. Furthermore, these complexes exhibited biological activity on extra and intracellular forms of Trypanosoma cruzi in a time- and concentration-dependent manner with IC(50) values ranging from 7.8 to 18.7 μM, while the ligand H(2)L(2a) presented a trypanocidal activity on trypomastigote form better than the standard drug benznidazole.


Borrelia burgdorferi DNA is undetectable by polymerase chain reaction in skin lesions of morphea, scleroderma, or lichen sclerosus et atrophicus of patients from North America.
Borrelia burgdorferi has been linked to the pathogenesis of morphea and lichen sclerosus et atrophicus (LSA). However, considerable controversy still exists as to the actual role, if any, that this spirochete plays in the development of these diseases. Antibody titer determinations have been inconclusive and polymerase chain reaction (PCR) studies have yielded conflicting results. We sought to show whether PCR analysis detected B. burgdorferi in archival tissue specimens from the involved skin of 20 North American patients with morphea, 10 patients with LSA, and four patients with scleroderma. We used two different sets of PCR primers for the B. burgdorferi flagellin gene, one specific for European strains of B. burgdorferi, and another common to both European and American strains. A subset of these samples were further amplified with nested PCR primers. None of the samples showed PCR products with either primer sets, whereas purified B. burgdorferi DNA and lesional erythema chronicum migrans tissues, which were used as positive controls, yielded easily detectable products with all primer sets. These data suggest that B. burgdorferi infection plays no role in the development of morphea, LSA, or scleroderma in North American patients; these findings further support the recent observations that B. burgdorferi strain variability is associated with differential spectra of disease in North America compared with that found in various parts of Europe.


Risks of Depression and Suicide After Diagnosis With Heart Failure: A National Cohort Study.
Heart failure (HF) has been associated with psychosocial distress, but other long-term mental health sequelae are unclear. In this study, the authors sought to determine risks of major depression and suicide, susceptible time periods, and sex-specific differences after HF diagnosis in a large population-based cohort. A national cohort study was conducted of all 154,572 persons diagnosed with HF at ages 18-75 years during 2002-2017 in Sweden and 1,545,720 age- and sex-matched population-based control subjects who were followed up for major depression and suicide ascertained from nationwide inpatient, outpatient, and death records through 2018. Poisson regression was used to compute incidence rate ratios (IRRs) while adjusting for sociodemographic factors and comorbidities. HF was associated with increased risks of major depression and death by suicide in both men and women, with highest risks in the first 3 months, then declining to modest risks at ≥12 months after HF diagnosis. Within 3 months after HF diagnosis, adjusted IRRs for new-onset major depression were 3.34 (95% CI: 3.04-3.68) in men and 2.78 (95% CI: 2.51-3.09) in women, and for suicide death were 4.47 (95% CI: 2.62-7.62) in men and 2.82 (95% CI: 1.11-7.12) in women. These risks were elevated regardless of age at HF diagnosis. HF was associated with significantly more depression cases in women (P < 0.001). In this large national cohort, HF was associated with substantially increased risks of depression and suicide in men and women, with highest risks occurring within 3 months after HF diagnosis. Men and women with HF need timely detection and treatment of depression and suicidality.


Use of PD-1 inhibitor tislelizumab in the treatment of advanced pulmonary sarcomatoid carcinoma: A case report.
Pulmonary sarcomatoid carcinoma (PSC), characterized by poor differentiation, aggressive progression, and early metastasis, is a rare type of non-small cell lung carcinoma (NSCLC), which shows a low response rate to conventional antitumor therapies and has a poor prognosis. With the achievements in gene sequencing, targeted therapy, and immunotherapy, several new approaches have recently been explored in PSC treatment. A small case series of PSC patients were found to have programmed death-ligand 1 (PD-L1) overexpression, a prerequisite for PD-1 inhibiting therapy, which made immunotherapy possible. However, anti-PD-1 treatment for PSCs was still at a preliminary stage. Here, we report the successful outcome of tislelizumab monotherapy in a patient with advanced PSC with pleural invasion, thus providing a novel promising approach for PSC patients with PD-L1 overexpression.


Short tube decompressive jejunostomy.
Experience with short tube decompressive jejunostomy in twenty-nine patients with small bowel obstruction is presented. Many advantages are gained by operative decompression of obstructed, dilated small bowel. The favorable results with its use make short tube decompressive jejunostomy a safe, acceptable method of decompressing dilated small bowel.


Porous silicon pillar structures/photosynthetic reaction centre protein hybrid for bioelectronic applications.
Photosynthetic biomaterials have attracted considerable attention at different levels of the biological organisation, from molecules to the biosphere, due to a variety of artificial application possibilities. During photosynthesis, the first steps of the conversion of light energy into chemical energy take place in a pigment-protein complex, called reaction centre (RC). In our experiments photosynthetic reaction centre protein, purified from Rhodobacter sphaeroides R-26 purple bacteria, was bound to porous silicon pillars (PSiP) after the electropolymerisation of aniline onto the surface. This new type of biohybrid material showed remarkable photoactivity in terms of measured photocurrent under light excitation in an electrochemical cell. The photocurrent was found to increase considerably after the addition of ubiquinone (UQ-0), an e--acceptor mediator of the RC. The photoactivity of the complex was found to decrease by the addition of terbutryn, the chemical which inhibits the e--transport on the acceptor side of the RC. In addition to the generation of sizeable light-induced photocurrents, using the PSiP/RC photoactive hybrid nanocomposite material, the system was found to be sensitive towards RC inhibitors and herbicides. This highly ordered patterned 3D structure opens new solution for designing low-power (bio-)optoelectronic, biophotonic and biosensing devices.


Learning Rat-Like Behavioral Interaction Using a Small-Scale Robotic Rat.
In this paper, we propose a novel method for emulating rat-like behavioral interactions in robots using reinforcement learning. Specifically, we develop a state decision method to optimize the interaction process among 6 known behavior types that have been identified in previous research on rat interactions. The novelty of our method lies in using the temporal difference (TD) algorithm to optimize the state decision process, which enables the robots to make informed decisions about their behavior choices. To assess the similarity between robot and rat behavior, we use Pearson correlation. We then use TD-λ to update the state value function and make state decisions based on probability. The robots execute these decisions using our dynamics-based controller. Our results demonstrate that our method can generate rat-like behaviors on both short- and long-term timescales, with interaction information entropy comparable to that between real rats. Overall, our approach shows promise for controlling robots in robot-rat interactions and highlights the potential of using reinforcement learning to develop more sophisticated robotic systems.


Disturbances of rhythm formation in patients with Parkinson's disease: part II. a forced oscillation model.
The origin of the characteristic disturbances of rhythm formation in patients with Parkinson's disease (the hastening phenomenon) was discussed, using a second-order system of the periodic response. The input signal was regarded as a pulse series of a Dirac function. The output process of the system had maximal errors of response at input frequencies of f = omega0/n (n = 1, 2, . . .), where omega0 was the intrinsic frequency of the system. Damping coefficient epsilon represented a function of an inhibitor against these maximal errors and the errors diverged to infinity when epsilon = 0. The solution of this forced oscillation system indicated that the intrinsic oscillation of the system has a possibility to be excited at these critical frequencies f = omega/n. Inferred from data on the tapping test, the frequency of an intrinsic oscillation was 5 Hz in the central nervous system, then the critical frequencies were predicted 5/n = 5, 2.5, . . . Hz. On the tapping test the errors of response become maximum around 2.5 and 5 Hz (taps per second), and their peak heights increased from the minimum in well trained normal subjects to the maximum in patients. An inhibitory mechanism against the maximal error would function well, i.e. epsilon greater than 0, in normal subjects but so insufficiently (epsilon leads to 0) in patients that the excited intrinsic oscillation would control their response directly. Thus some patients could no longer maintain a synchronous tapping response at 2.5 Hz or 5 Hz and showed a hastened tapping of 5 6 Hz independent of the signal frequency.


Pressure sensitivity of active tension in glycerinated rabbit psoas muscle fibres: effects of ADP and phosphate.
The effect of changes in hydrostatic pressure (up to 10 MPa) on the maximally calcium-activated tension in glycerinated rabbit psoas fibres has been examined. The steady active tension was depressed by 0.8% per MPa pressure rise. This pressure sensitivity was enhanced by the pressure of millimolar phosphate and depressed by millimolar ADP. These results support the conclusions that increased pressure is perturbing a crossbridge event. The results are discussed in terms of a three state crossbridge model and are shown to be compatible with a pressure effect on the transition from an attached crossbridge state to a tension bearing state. This is compatible with the effects of pressure on the isolated proteins in solution.


Evaluation of the in vitro synergy of polymyxin B-based combinations against polymyxin B -resistant gram-negative bacilli.
This study aimed to evaluate the in vitro synergy of polymyxin B (PMB) combined with 11 other antibiotics against PMB-resistant gram-negative bacilli (GNBs). Thirty-six clinical isolates of PMB-resistant GNBs were used. The MICs of all the antimicrobials tested were determined by the broth microdilution method and the checkerboard assay method. Carbapenemase genes were detected by PCR. In vitro synergy results were interpreted using the fractional inhibitory concentration index (FICI). Four combinations that showed positive interactions were subsequently evaluated in a time-kill study. Among the 36 strains, 15 harboured the carbapenemase gene, and blaKPC was the predominant carbapenemase. The resistance rates of the 36 strains to tigecycline, meropenem, ceftazidime, and cefepime were 100% (36/36), 97% (35/36), 94% (34/36), and 97% (35/36), respectively. For Enterobacteriaceae and Pseudomonas aeruginosa, the resistance rates to aztreonam and ceftazidime-avibactam (avibactam at a fixed concentration of 4 mg/L) were 95% (19/20) and 25% (5/20), respectively. The PMB-based combinations exhibited synergism to a certain degree. The most synergistic combinations were PMB plus meropenem-avibactam (avibactam at a fixed concentration of 4 mg/L) and PMB plus tigecycline, with the synergy rates of 83.3% and 80.6%, respectively. Compared to tazobactam- and sulbactam-based β-lactam-β-lactamase inhibitor combinations (BL-BLIs), PMB with avibactam-based BL-BLIs exhibited a better synergistic effect. For Acinetobacter baumannii, PMB plus sulbactam exhibited a strong synergism with a 2∼7-fold MIC reduction of PMB. In time-kill studies, the highest degree of synergism was observed for PMB with cefepime-avibactam on all the tested isolates. For isolates with low-level resistance to PMB, PMB combined with other partner antimicrobials also showed a certain degree of synergism. PMB in combination with tigecycline and avibactam-based BL-BLIs could be a potential clinical option for clinical treatment of infections caused by PMB -resistant GNBs.


HIB/SPOP inhibits Ci/Gli-mediated tumorigenesis by modulating the RNA Polymerase II components stabilities.
Hedgehog (Hh) signaling mediated by transcription factor Ci/Gli plays a vital role in embryonic development and adult tissue homeostasis in invertebrates and vertebrates, whose dysregulation leads to many human disorders, including cancer. However, till now, cofactors of Ci/Gli which can affect tumorigenesis are not well known. Here, through genetic screen, we find overexpression of active Ci alone is not sufficient to generate tumor-like eye phenotype in Drosophila, however, its overexpression combined with knockdown of hib causes a striking tumor-like big eye phenotype. Mechanistically, HIB/SPOP inhibits Ci/Gli-mediated tumorigenesis by modulating the RNA polymerase II (RNAPII) components Rpb3/Rpb7 stabilities in E3 ligase dependent manner. In addition, Ci/Gli can promote HIB/SPOP-mediated Rpb7/Rpb3 degradation. Taken together, our results indicate Ci/Gli needs to hook up with suitable RNAPII together to achieve the tumor-like eye phenotype and HIB/SPOP plays dual roles through controlling Ci/Gli and Rpb3/Rpb7 protein stabilities to temper Ci/Gli/RNAPII-mediated tumorigenesis.


High-Quality Draft Genome Sequence of a Rickettsiales Bacterium Found in Acropora tenuis Coral from Okinawa, Japan.
Rickettsiales-like organisms are important for the survival and functioning of corals, prompting an investigation of their complete genomes. Earlier reports of the genomes of these organisms remain incomplete. Here, we report a novel draft genome of Rickettsiales bacterial strain SESOKO1, found in Acropora tenuis coral, using single-cell genome technology.


GABA potentiates potassium-stimulated 3H-dopamine release from slices of rat substantia nigra and corpus striatum.
GABA (10-5--10-3 M) had no effect on the spontaneous outflow of previously accumulated 3H-DA or 3H-5HT from rat nigral or striatal slices. However, GABA markedly potentiated the potassium-stimulated release of 3H-DA in both brain regions, while the depolarization-induced output of 3H-5HT was only slightly increased. This action of GABA was blocked by pictotoxin but not by bicuculline. Amphetamine likewise evoked a dose-related efflux of 3H-DA and 3H-5HT from nigra and striatum, but these releases were unchanged by GABA. The data suggest that GABA acts presynaptically in these areas to regulate dopaminergic cell function.


Risks of perimenopausal fractures--a prospective population-based study.
To examine the associations between potential risk factors and fractures in perimenopausal women. A total of 3,140 women (mean age 53.4 +/- 2.8 (s.d.) years) were followed-up for 2.4 years after axial bone densitometry (lumbar spine and femoral neck) with regard to the occurrence of fractures. In all, 5.6% of the women sustained a fracture. There were 169 low energy fractures (falling on a level surface) in 157 women after the exclusion of 18 fractures caused by a high energy trauma. The wrist was the most frequent site of fracture (n = 46). Lumbar bone mineral density was 5.8% lower and femoral bone mineral density 4.6% lower among fracture cases compared with non-fracture cases (p < 0.0001). History of a fracture during 1980-1989 elevated the risk of all fractures 2.83-fold (95% confidence interval (CI) 1.95-4.10) and the risk of a first wrist fracture 2.25-fold (95% CI 1.10-4.62). The amount of weekly alcohol intake was higher among fracture cases than among non-fracture cases yielding an age-adjusted odds ratio (OR) of 1.45 (95% CI 1.05-2.02). Past or present use of hormone replacement therapy was protective against fractures (age-adjusted OR 0.70, 95% CI 0.50-0.96). If bilateral oophorectomy had been carried out under the age of 45 years, the risk of fracture was 3.64-fold (95% CI 1.01-13.04) compared with women operated upon after the age of 45 years. Age at menarche, parity, lactation and smoking history did not differ between the fracture and non-fracture groups. A former history of fractures, low baseline bone mineral density (BMD) and use of alcohol are predisposing factors associated with perimenopausal fractures, while hormone replacement therapy is protective in this respect.


Does the addition of cone-beam CT to panoral imaging reduce inferior dental nerve injuries resulting from third molar surgery? A systematic review.
This systematic review aims to examine whether cone-beam CT (CBCT) assessment influences the incidence of nerve injury following high-risk mandibular third molar (MTM) surgery. Randomised controlled trials comparing two and three-dimensional imaging for assessing high-risk MTMs were included. MEDLINE, EMBASE, CENTRAL and the Dentistry and Oral Science Source (DOSS) were systematically searched along with extensive grey literature searches, hand searching of web sites, and detailed citation searching up to 3 September 2022. Risk of bias was assessed against the Cochrane Risk of Bias Tool (RoB 2.0). Certainty of the evidence was assessed using GRADE. Two authors independently screened 402 abstracts prior to full text screening of 27 articles, which culminated in seven RCTs for inclusion. Two studies were assessed as high risk of bias overall. The other five raised some concerns largely due to unblinded patients and lack of prior trial registration. Just one study reported significantly less nerve injuries following CBCT. The remaining six articles found no significant difference. The seven RCTs included in this systematic review offered moderate quality evidence that CBCT does not routinely translate to reduced incidence of nerve injury in MTM removal. A single study provided low quality evidence for a consequent change in the surgical approach. Low quality evidence from 3 studies suggested CBCT does not influence the duration of third molar surgery.


Evaluating the Role of Hepatobiliary Phase of Gadoxetic Acid-Enhanced Magnetic Resonance Imaging in Predicting Treatment Impact of Lenvatinib and Atezolizumab plus Bevacizumab on Unresectable Hepatocellular Carcinoma.
Atezolizumab plus bevacizumab therapy has high response rates in patients with unresectable hepatocellular carcinoma (HCC). The hepatobiliary phase of gadoxetic acid-enhanced magnetic resonance imaging (EOB-MRI) has been reported to be useful as an imaging biomarker for detecting β-catenin mutations. We evaluated whether the pretreatment of the hepatobiliary phase of EOB-MRI could predict the therapeutic effect of lenvatinib and atezolizumab plus bevacizumab. This study included 68 patients (lenvatinib group (n = 33) and atezolizumab plus bevacizumab group (n = 35)). The visual assessment and relative enhancement ratio (RER) of the largest HCC lesions were evaluated using the hepatobiliary phase of EOB-MRI. The hyperintensity type (RER ≥ 0.9) was 18.2% in the lenvatinib group and 20.0% in the atezolizumab plus bevacizumab group. In the lenvatinib group, progression-free survival (PFS) was not different between the heterogeneous and homogenous types (p = 0.688) or between the hyperintensity and hypointensity types (p = 0.757). In the atezolizumab plus bevacizumab group, the heterogeneous type had significantly shorter PFS than the homogenous type (p = 0.007), and the hyperintensity type had significantly shorter PFS than the hypointensity type (p = 0.012). The hepatobiliary phase of EOB-MRI was useful for predicting the therapeutic effect of atezolizumab plus bevacizumab therapy on unresectable HCC.


Discriminative stimulus properties of levo-alpha-acetylmethadol and its metabolites.
The discriminative stimulus properties of l-alpha-acetylmethadol (LAAM), its metabolities 1-alpha-acetyl-N-normethadol (NorLaam) and l-alpha-acetyl-N,N-dinormethadol (DiNorLAAM), and methadone were evaluated in rats trained to discriminate between saline and morphine in a two-choice discrete-trial avoidance paradigm. All four compounds produced dose-related increases in the number of trials completed on the morphine-appropriate choice lever after either SC or oral administration indicating that the discriminative stimulus properties of the four compounds and morphine are qualitatively similar. LAAM and DiNorLAAM had a slow onset and long duration of action, and an oral: parenteral potency ratio of 1:3. NorLaam had a more rapid onset and shorter duration of action and was more potent following SC administration than either LAAM or DiNorLAAM; its oral: parenteral potency ratio was 1:10. These results are consistent with evidence from other studies that the pharmacologic activity of LAAM is dependent upon the conversion of LAAM to an active metabolite, probably NorLAAM. The similarities between DiNorLAAM and LAAM suggest that the discriminative stimulus effects of the former compound are also attributable to a metabolite.