Obinutuzumab-induced acute thrombocytopenia: Report of two cases and review of literature.
Obinutuzumab (GA101) is a humanized anti-CD20 monoclonal antibody used in the treatment of B-cell malignancies. Under rare occasions, obinutuzumab may induce acute and severe thrombocytopenia. However, little is known about this side effect, referred to as "obinutuzumab-induced acute thrombocytopenia" (OIAT). Here, we report 2 cases of OIAT and review the literature to inform the management and outcome of this rare but life-threatening complication. The first case is a 74 year- old woman who was treated with obinutuzumab-Cyclophosphamide, Vincristine, Prednisone (CVP) for a previously untreated follicular lymphoma. This patient experienced an acute thrombocytopenia with a drop in her platelet count from 376 G/L to 3 G/L the day after treatment. The second case is a 44 year- old woman who was treated with obinutuzumab as a pre-treatment dose (day-8) before glofitamab infusion as a 4th line therapy for mantle cell lymphoma. This patient experienced an acute thrombocytopenia with a drop in her platelet count from 76 G/L (due to splenomegaly and bone marrow involvement) to 3 G/L the day after treatment. OIAT is a rare but life-threatening complication. Physicians should be aware of this adverse event to optimally detect and treat this complication.


Special considerations with regard to the dosage of tranexamic acid in patients with chronic renal diseases.
Tranexamic acid is a potent antifibrinolytic drug frequently used in the treatment of haematuria and a number of other haemorrhagic conditions. Since it is eliminated mainly in the urine, the drug accumulates in patients with uraemia. The excretion of tranexamic acid in patients with renal failure has been investigated and dosage recommendations are given for tranexamic acid therapy in cases of renal failure.


[Equipment for rapid and reliable perineal implantation of I-125 seeds in prostatic cancer with reduced radiation exposure].
The aim of an implantation of iodine seeds into the prostate controlled by ultrasound is reached by means of the equipment presented in this paper. The method, allowing to implant the seeds according to the therapy plan, has been developed above all in order to reduce the radiation exposure to the physicist, the radiotherapist and the surgeon.


Mammalian cadherins DCHS1-FAT4 affect functional cerebral architecture.
Cortical development is a complex process where a multitude of factors, including cadherins, plays an important role and where disruptions are known to have far reaching effects in neural development and cortical patterning. Cadherins play a central role in structural left-right differentiation during brain and body development, but their effect on a functional level remains elusive. We addressed this question by examining functional cerebral asymmetries in a patient with Van Maldergem Syndrome (VMS) (MIM#601390), which is caused by mutations in DCHS1-FAT4 cadherins, using a dichotic listening task. Using neurophysiological (EEG) data, we show that when key regulators during mammalian cerebral cortical development are disrupted due to DCHS1-FAT4 mutations, functional cerebral asymmetries are stronger. Basic perceptual processing of biaurally presented auditory stimuli was unaffected. This suggests that the strength and emergence of functional cerebral asymmetries is a direct function of proliferation and differentiation of neuronal stem cells. Moreover, these results support the recent assumption that the molecular mechanisms establishing early left-right differentiation are an important factor in the ontogenesis of functional lateralization.


Impact and adaptation of climate variability and change on small-holders and agriculture in Ethiopia: A review.
Ethiopia is highly vulnerable to climate variability and change due to depend on the rain-fed agricultural system. The paper provides comprehensive review of impact and adaptation of climate variability and change on small-holder farmers and agriculture in Ethiopia. The study used secondary data from journal articles, books and technical reports, and discussed and organized with desk review. The study explored that climate variability and change has significantly affected crop and livestock production, fisheries and aquaculture, and food security. The study found that over 38 million people seriously interrupted from their living condition associated to climate related crises since 2000s up to 2010s in Ethiopia. Locust upsurge with the pest spreads reduces 1,228,352, 1,026,132 and 843,241 quintals of cereal crop productions in Oromia, Somali and Tigray regions of Ethiopia, respectively in 2020 production year. Drought declined 26% of number of cattle herd sizes in Dire and Yabelo District, Borana zone, southern Ethiopia in 2010/2011year. Although Effect of climate variability and change has become a serious problem on crop cultivation, pastoralism, and agro-pastoralism in Ethiopia, pastoralism, and agro-pastoralism are more vulnerable comparatively. Small-holder farmers have practiced soil and water conservation, improved crop and livestock variety, tree planting, livestock mobility, crop diversification, planting date adjustment, irrigation, agronomic practices, livelihood diversification, integrating livestock with crop production to reduce adverse impact of climate variability and change in the country. Livestock ownership, farm size, extension service, credit service, distance to market, and access to climate information were major factor of adaptation strategies. It concluded that farmers have practiced different adaptation strategies to reduce impact of climate variability and change in different part of the country. The study suggest that scholars should conduct their studies in disaggregate way for impact and adaptation to climate related problem and the corresponding factors across agro-ecologies in Ethiopia.


Structural Changes in Large Intestinal Aggregated Lymphoid Follicles in Wistar Rats During Postnatal Ontogeny.
Quantitative evaluation of aggregated lymphoid follicles in various compartments of the large intestine was carried out in Wistar rats of different age: newborn (3-4 days), prepubertal (20-30 days), adult (2-3 months), and old (16-18 months). No aggregated lymphoid tissue was detected in the large intestinal mucosa of newborn animals. The cecum of prepubertal, adult, and old animals contained solitary patches with 7-9 follicles. Higher percentage of aggregated lymphoid tissue, associated with colonic mucosa, was explained by enlargement of the lymphoid patch area and of the number of solitary lymphoid follicles during the postnatal ontogenesis. The mean area of a patch in the distal part of the colon in prepubertal, adult, and old animals was 3.2, 2.5, and 2.2 times larger than in the medial part of the intestine, the number of follicles per patch was 2.8, 2.8, and 2.5 times higher, respectively. The differences were significant only for the two younger groups.


Defining Core Competencies for Generalist-Level Palliative Social Work.
Care provided to seriously ill patients by frontline social workers is a component of generalist-level palliative care. The core competencies for high-quality generalist-level palliative social work are necessary to promote training curricula and best practices but have not yet been defined in the U.S. The objective of this study was to develop consensus-derived core competencies for generalist-level palliative social work. Fifty-five proposed social work competencies were categorized by the eight domains of palliative care identified by the National Consensus Project for Quality Palliative Care. The competencies were rated by 41 regionally dispersed, Master's level social workers selected through purposive and snowball sampling using a Delphi method. Each was rated as essential for generalist-level palliative social work, acceptable with modifications, or rejected based on the judgment that it was not essential for generalist-level palliative social work or was outside the scope of practice. Consensus was defined as >70% agreement to accept or reject a competency. Three review rounds were needed to achieve consensus on all competencies. Two competencies were added to the original list. Of the 57 proposed competencies, 41 were accepted (19 after modification) and 16 were rejected. Competencies in the social, spiritual, cultural, and ethical/legal aspects of care domains were relatively more likely to be accepted compared with those in structure and processes of care, physical care, psychological care, and care of patient at the end of life. The 41 consensus-derived competencies for generalist-level palliative social work may inform the development of training curricula and standards for high-quality care.


Dextrin as excipient in pharmaceutical preparations.
The addition of commercial dextrins to aqueous solvents in thin layer chromatography on cellulose increases the Rf values of azodyes such as methyl orange. The increase is less than with cyclodextrins but shows that dextrins also form supramolecular complexes. This should be considered when dextrins are used as "inert" excipients in pharmacy.


Wound debridement: lessons learned of when and how to remove "wild" maggots.
Wounds, particularly chronic wounds, are a common presentation to the Emergency Department (ED), and in severe cases can contain maggots. Maggot debridement therapy is a popular technique for wound debridement, but is limited to the use of sterilized larvae due to concerns of contamination and invasion of "wild" maggots into healthy tissue. Wild maggots in chronic wounds, therefore, should be removed, yet there is no reported literature that describes a technique for their removal. This article presents a step-by-step approach for the safe removal of "wild" larvae in a wound using Yankauer suction. We present a case of a homeless man presenting to the ED with a foot wound found to have "wild" maggots that required removal. The technique described in this article is a simple, safe, and efficient way for the Emergency Physician to remove "wild" larvae from wounds.


Suitable combination of promoter and micellar catalyst for kilo fold rate acceleration on benzaldehyde to benzoic acid conversion in aqueous media at room temperature: a kinetic approach.
The kinetics of oxidation of benzaldehyde by chromic acid in aqueous and aqueous surfactant (sodium dodecyl sulfate, SDS, alkyl phenyl polyethylene glycol, Triton X-100 and N-cetylpyridinium chloride, CPC) media have been investigated in the presence of promoter at 303 K. The pseudo-first-order rate constants (kobs) were determined from a logarithmic plot of absorbance as a function time. The rate constants were found to increase with introduction of heteroaromatic nitrogen base promoters such as Picolinic acid (PA), 2,2'-bipyridine (bipy) and 1,10-phenanthroline (phen). The product benzoic acid has been characterized by conventional melting point experiment, NMR, HRMS and FTIR spectral analysis. The mechanism of both unpromoted and promoted reaction path has been proposed for the reaction. In presence of the anionic surfactant SDS, cationic surfactant CPC and neutral surfactant TX-100 the reaction can undergo simultaneously in both aqueous and micellar phase with an enhanced rate of oxidation in the micellar phase. Both SDS and TX-100 produce normal micellar effect whereas CPC produce reverse micellar effect in the presence of benzaldehyde. The observed net enhancement of rate effects has been explained by considering the hydrophobic and electrostatic interaction between the surfactants and reactants. SDS and bipy combination is the suitable one for benzaldehyde oxidation.


Radiotherapy of gastric cancer with a three field combination: feasibility, tolerance, and survival.
From 1980 to 1984, forty-five patients suffering gastric cancer were irradiated with curative intent. Twenty-three were considered at high risk of recurrence after complete surgical resection (invasion of the serosa, lymph nodes and/or surgical margins); eleven were treated after partial resection, and for eleven others, the local extension precluded surgery. Radiotherapy combined two lateral fields (usually with wedge filters) and an anterior field. The planned dose was 40 to 50 Gy, according to the amount of residual disease and doses delivered to the major part of the liver and the right and left kidneys did not exceed 30, 5, and 18 Gy, respectively. For patients aged less than 71 and whose general condition was acceptable, one cycle of chemotherapy (FAM for 20 patients and 5-FU for 10) preceded irradiation, followed if possible by 6 other cycles. Adverse effects, essentially anorexia, vomiting, and weight loss, led to definitively stopping irradiation in 8 cases, and were present in 21 other patients. Mean weight loss was 2.5 kg. Apart from one patient who developed a subphrenic abcess and died after reoperation, there was neither chronic complication, nor radiation hepatitis or nephritis. For 34 patients, the observation time was superior to 3 years: 23 died of their cancer, 1 of a subphrenic abcess, and 2 of an intercurrent disease. Eight were disease-free at 3 years (three of these were irradiated for macroscopic disease). For the overall series, the 4-year survival rate is 23%. There is a significant survival advantage for females versus males (p less than 0.01), a non-significant tendency in favor of microscopic residual disease versus macroscopic, and no advantage for the combination with FAM compared with no chemotherapy (non-randomized). This technique appears feasible with an acceptable tolerance and can control local tumor in a few cases. The planned dose of 40 Gy was probably too small and we are now testing 45 Gy delivered over the large initial volume, and boosts of 10-15 Gy to residual disease.


Associations of Adipokine Levels with Levels of Remnant Cholesterol: the Multi-Ethnic Study of Atherosclerosis (MESA).
The metabolic syndrome phenotype of individuals with obesity is characterized by elevated levels of triglyceride (TG)-rich lipoproteins and remnant particles, which have been shown to be significantly atherogenic. Understanding the association between adipokines, endogenous hormones produced by adipose tissue, and remnant cholesterol (RC) would give insight into the link between obesity and atherosclerotic cardiovascular disease. We studied 1,791 MESA participants of an ancillary study on body composition who had adipokine levels measured (leptin, adiponectin, resistin) at either visit 2 or 3. RC was calculated as non-high density lipoprotein cholesterol minus low-density lipoprotein cholesterol (LDL-C), measured at the same visit as the adipokines, as well as subsequent visits 4 through 6. Multivariable-adjusted linear mixed effects models were used to assess the cross-sectional and longitudinal associations between adipokines and levels of RC. Mean (SD) age was 64.5±9.6 years and for body mass index (BMI) was 29.9±5.0 kg/m2; 52.0% were women. In fully adjusted models that included BMI, LDL-C and lipid-lowering therapy, for each 1-unit increment in adiponectin, there was 14.4% (12.0, 16.8) lower RC. With each 1-unit increment in leptin and resistin, there was 4.5% (2.3, 6.6) and 5.1% (1.2, 9.2) higher RC, respectively. Lower adiponectin and higher leptin were also associated with longitudinal increases in RC levels over median follow-up of 5(4-8) years. Lower adiponectin and higher leptin levels were independently associated with higher levels of RC at baseline and longitudinal RC increase, even after accounting for BMI and LDL-C. What is new?: - Among individuals without history of cardiovascular disease, adiponectin is inversely associated with cross-sectional levels of remnant cholesterol, whereas leptin and resistin are directly associated.- Adiponectin had an inverse association with progression of remnant cholesterol levels over time.What are the clinical implications?: - Adiponectin levels were not associated with LDL-C levels but with levels of triglyceride-rich lipoproteins, particularly remnant cholesterol.-Incrementing adiponectin via lifestyle modification and/or pharmacological therapies (i.e. GLP-1 agonists) could be a mechanism to reduce remnant cholesterol levels and ultimately cardiovascular risk.


Disruption of the low affinity receptor-binding site in NGF allows neuronal survival and differentiation by binding to the trk gene product.
Nerve growth factor (NGF), like many other growth factors and hormones, binds to two different receptor molecules on responsive cells. The product of the proto-oncogene trk, p140trk, is a tyrosine kinase receptor that has been identified as a signal-transducing receptor for NGF, while the role of the low affinity NGF receptor, p75NGFR, in signal transduction is less clear. The crystal structure of NGF has recently been determined, although structures involved in receptor binding and biological activity are unknown. Here we show that Lys-32, Lys-34, and Lys-95 form a positively charged interface involved in binding to p75NGFR. Simultaneous modification of Lys-32 with either of the two other lysines resulted in loss of binding to p75NGFR. Despite the lack of binding to p75NGFR, these mutants retained binding to p140trk and biological activity, demonstrating a functional dissociation between the two NGF receptors.


Clinical results of islet transplantation.
Islet transplantation is considered an advanced therapy in the treatment of type-1 diabetes, with a progressive improvement of clinical results as seen in the Collaborative Islet Transplant Registry (CITR) report. It is an accepted method for the stabilization of frequent hypoglycemia, or severe glycemic lability, in patients with hypoglycemic unawareness, poor diabetic control, or a resistance to intensive insulin-based therapies. Worldwide data confirm a positive trend in this field, with the integrated management of pivotal factors: adequate islet mass, immunosuppressive protocols, additional anti-inflammatory therapy, and pre-transplant allo-immunity assessment. Insulin independence has been observed in several clinical trials with different rate, ranging 100-65% of patients; the maintenance of this condition during the follow-up progressively decreased, actually arranged on 44% 3 years after the last infusion, according to data reported from the CITR. Successful duration is progressively increasing, with ≥13 years being the longest reported insulin-free condition on record. The immediate results of functioning islet transplantation are an improvement in hypoglycemic awareness and a reduction in the glycated hemoglobin level. Furthermore, many studies have shown its influence on the chronic complications of diabetes, such as peripheral neuropathy, retinopathy, and macroangiopathy. Pre-transplant nephropathy remains an exclusion criterion as immunosuppressive therapy can exacerbate kidney-function deterioration. The problems linked to immunosuppression following islet transplantation for the treatment of type-1 diabetes need to be considered in order to achieve the correct risk/benefit ratio for each patient.


Association of the rat liver glucocorticoid receptor with Hsp90 and Hsp70 upon whole body hyperthermic stress.
The influence of whole body hyperthermic stress (41 degrees C, 15 min) on association of the glucocorticoid receptor (GR) with heat shock proteins Hsp90 and Hsp70 was followed in rat liver cytosol during a 24 h period after the stress. Total cytosolic concentration of the GR, Hsp90 and Hsp70 and the amounts of Hsp90 and Hsp70 co-immunopurified with the GR were determined by a quantitative Western blotting using appropriate monoclonal antibodies. A significant decrease in the cytosolic GR level in response to the stress was noticed. The ratio of the amount of the GR to Hsp90 recruited by the GR was found to be unaltered by hyperthermia, in spite of the stress-induced increase in the total Hsp90 concentration in the cytosol. Hsp70 was also found in association with the GR and its 2.5-fold induction by the stress was accompanied by about 3-fold increase in its relative amount that co-immunopurified with the GR. The results suggest that heat stress influences the interaction of the GR with Hsp70 through the mechanisms controlling the untransformed rat liver GR heterocomplexes assembly process.


Potential link between interleukin-6 and arachidonic acid metabolism in Alzheimer's disease.
Prostaglandins (PGs) and cytokines, such as interleukin-1 (IL-1) and interleukin-6 (IL-6), have been implicated in the etiopathology of various inflammatory and degenerative disorders, including Alzheimer's disease (AD). Previously, we detected the presence of IL-6 in cortices of AD patients. On the other hand, non-steroidal antiinflammatory drugs (NSAIDs), potent inhibitors of prostaglandin synthesis, have been shown to be beneficial in the treatment of AD. Until now, it remained unclear whether and how these two observations were functionally connected. Here, we show that PGs are able to induce IL-6 synthesis in a human astrocytoma cell line. PGE1 and PGE2, but not PGD2 and PGF2 alpha, led to a rapid and transient induction of astrocytic IL-6 mRNA, followed by IL-6 protein synthesis. Furthermore, PGE2 potentiated IL-1 beta-induced IL-6 mRNA synthesis. These results suggest a possible link between the release of PGs from activated microglia and the astrocytic synthesis of IL-6, which itself may affect neuronal cells, as hypothesized for Alzheimer's disease. Finally we demonstrate that microglia are a strong source of PGE2 synthesis indicating that these cells may act as the origin of the pathogenic cascade.


Efficacy and tolerability of peginterferon alpha plus ribavirin in the routine daily treatment of chronic hepatitis C patients in Korea: a multi-center, retrospective observational study.
We aimed to evaluate the efficacy and safety of peginterferon plus ribavirin for chronic hepatitis C (CHC) patients under real life setting in Korea. We retrospectively analyzed the medical records of 758 CHC patients treated with peginterferon plus ribavirin between 2000 and 2008 from 14 university hospitals in the Gyeonggi-Incheon area in Korea. Hepatitis C virus (HCV) genotype 1 was detected in 61.2% of patients, while genotype 2 was detected in 35.5%. Baseline HCV RNA level was ≥6×10(5) IU/mL in 51.6% of patients. The sustained virological response (SVR) rate was 59.6% regardless of genotype; 53.6% in genotype 1 and 71.4% in genotype 2/3. On multivariate analysis, male gender (p=0.011), early virological response (p<0.001), genotype 2/3 (p<0.001), HCV RNA <6×10(5) IU/mL (p=0.005) and adherence to the drug >80% of the planned dose (p<0.001) were associated with SVR. The rate of premature discontinuation was 35.7%. The main reason for withdrawal was intolerance to the drug due to common adverse events or cytopenia (48.2%). Our data suggest that the efficacy of peginterferon and ribavirin therapy in Koreans is better in Koreans than in Caucasians for the treatment of CHC, corroborating previous studies that have shown the superior therapeutic efficacy of this regimen in Asians.


Variation of the slope of the tentorium during childhood.
Neural structures in the posterior fossa grow at different rates during development. While there are computationally intensive approaches to analyze growth of the cerebellum and brainstem, there is a paucity of information about summary measures of normal posterior fossa development suitable for real-time clinical use. The present study investigates changes in the trajectory of the tentorium as measured by the occipital and tentorial angles at different stages of development. A retrospective study was conducted drawing from a Boston Children's Hospital database of over 1500 magnetic resonance imaging (MRI) studies. The imaging study population included fetuses older than 20 gestational weeks and children between the ages of 0 and 10 years. Two parameters were measured for all subjects: (1) the tentorial angle (the angle between the tentorium and a line from the internal occipital protuberance to the tuberculum sellae) and (2) the occipital angle (the angle between the tentorium and a line from the internal occipital protuberance to the opisthion). Descriptive statistics were used to analyze the study cohort. We reviewed 1510 brain MRI studies, and 367 studies met the inclusion criteria (125 fetal and 242 postnatal studies). During fetal development, the inclination of the tentorium showed an ascending course, while it plateaus after birth. During the second and third trimesters, the tentorial and occipital angles steadily increase reflecting the dynamic growth of the posterior fossa structures. Postnatally, the tentorial angle decreases and the tentorium slopes downward and plateaus, possibly due to stabilization of posterior fossa development and ongoing growth of the cerebrum. Together, these findings suggest that the tentorial angle can serve as an imaging biomarker of posterior fossa development during the second half of fetal life.


Contrasting effects of dry-wet and freeze-thaw aging on the immobilization of As in As-contaminated soils amended by zero-valent iron-embedded biochar.
Zero-valent iron-embedded biochar (ZVI/BC) is considered as an effective material for arsenic (As) immobilization in soil, but the stability of As after remediation against aging remains unknown. Herein, the effects of dry-wet and freeze-thaw aging on the immobilization of As in two As-contaminated soils amended by ZVI/BC were evaluated. ZVI/BC showed high immobilization capacity for As-contaminated soils with an over 82% decrease of bioavailable As, mainly due to the As-Fe co-precipitation accompanied with ZVI oxidation. The aging of dry-wet and freeze-thaw had an opposite effect on the bioavailability of As. After 35 rounds of dry-wet aging, bioavailable As concentration increased from 1.25-9.50 to 1.83-21.75 mg/kg, because of the oxidation dissolution of ZVI and the formation of mobile reduced As(III). By contrast, the crystallization of amorphous iron with the structural incorporation of sorbed As and the oxidation of As(III) into stable As(V) occurred during the 35 rounds of freeze-thaw aging, leading to the decrease of bioavailable As concentration from 9.50-1.25 to 5.42-0.45 mg/kg. Our results revealed that the stability of soil As after remediation by ZVI/BC varied with the different aging process, which needs more consideration for the long-term soil As immobilization in the different whether areas.


Potential therapeutic effects of a traditional Chinese formulation, BJ-JN, on liver fibrosis induced by carbon tetrachloride in rats.
To evaluate the anti-fibrotic effects of BJ-JN (a traditional Chinese formulation) in CCl(4)-induced liver fibrosis in rats. BJ-JN (0.5, 1.0, 2.0 g/kg) was administrated via gavage once a day starting from the fifth weeks after the CCl(4) treatment for subsequent 9 weeks. Evaluated with liver and spleen index, serum levels of alanine aminotransferase (ALT), aspartate aminotransferase (AST), hyaluronic acid (HA), nitric oxide (NO), hepatic malondialdehyde (MDA) content and superoxide dismutase (SOD) activity, as well as with histopathologic changes of liver. The proliferation and collagen synthesis of primary hepatic stellate cells (HSCs) from normal, model and BJ-JN (2.0 g/kg) treatment rats were examined with (3)H-TdR and (3)H-Pro uptake assay, respectively. BJ-JN (0.5, 1.0, 2.0 g/kg) effectively reduced the elevated levels of liver and spleen index, serum ALT, AST, NO, HA, and hepatic MDA contents, enhance the reduced hepatic SOD activity in CCl(4)-treated rats. The histopathological analysis suggested that BJ-JN obviously alleviated the degree of liver fibrosis induced by CCl(4). The proliferation and collagen synthesis of HSC isolated from BJ-JN (2.0 g/kg) treatment rats were remarkably inhibited. Those results suggest BJ-JN has a protective and therapeutic effect on liver fibrosis induced by CCl(4), which might be associated with its anti-oxidative activity, inhibitory activity on HSC proliferation and collagen synthesis.


Perspective of dental medicine students learning in remote biochemistry laboratories during COVID-19.
Students at the Monastir Faculty of Dental Medicine were required to remain inside during the COVID-19 pandemic for their own safety and in accordance with official directives. It is evident that learners' perceptions are a recognized indicator of the efficiency of any teaching approach. Therefore, we focused on students' input on the validity of online biochemistry laboratories to assure their preferences with the finest teaching approaches. The study included 116 undergraduate dental students from the Faculty of Dental Medicine of Monastir. The survey has 40 questions. This investigation covered (i) information technology tool accessibility, (ii) course presentation, interactions in a virtual classroom, teachers' availability, and (iii) preferred learning styles. The percentages were then determined for each item and assessed. Our results showed that almost students were equipped with computers, smartphones and tablets but have encountered some connectivity issues. Moreover, participants find courses well presented, approved class interactions, and were satisfied with teachers' availability. Nevertheless, students were not already prepared for entirely online learning. Despite, the overall positive perception among students toward remote education during the COVID-19 outbreak; they preferred considering shared learning between face-to-face and online once the pandemic is over.


The effects of ulipristal on Bax/Bcl-2, cytochrome c, Ki-67 and cyclooxygenase-2 expression in a rat model with surgically induced endometriosis.
To evaluate the effect of ulipristal on Bax/Bcl-2, cytochrome C, Ki-67 and cyclooxygenase-2 expression in surgically induced endometriosis in a rat model. We conducted a prospective, randomized, controlled, experimental study at the Experimental Research Center of the Iuliu Hatieganu University of Medicine and Pharmacy in Cluj-Napoca, Romania. Endometriosis was induced in 40 female Wistar albino rats by transplanting two autologous fragments of uterine horn onto bowel mesentery. After a 4-week induction period, we formed two groups: the first group was treated with ulipristal (UPA+) for 8 weeks, while the second group was treated only with the vehicle used for ulipristal (UPA-). We measured the volumes and masses of the implants both before and after treatment. A pathologist examined the sections microscopically for histological hallmarks of endometriosis. Immunostaining for Bax/Bcl-2, cytochrome C, Ki-67 and cyclooxygenase-2 (COX-2) was assessed in both groups. Ulipristal reduced the average implant volume and mass, indicating that the drug is effective (P=0.01). The treatment induced a greater than 50% reduction in the volume and mass of endometrial implants, and the histological findings correspond to this result. The overall Bax positivity rate was higher in the group treated with ulipristal (42.37% vs. 21.05% for UPA+ and UPA-, respectively) (P=0.0062). The overall Bcl-2 positivity rate was smaller in the group treated with ulipristal (15% vs. 40% for UPA+ and UPA-, respectively) (P=0.0593). The cytochrome C global positivity rate was 5% in the UPA- group and increased to 50% in the UPA+ treatment group (P<0.0001). The COX-2 positivity rate decreased from 75% in the UPA- treatment group to 10% in the UPA+ treatment group (P<0.0001) and the Ki67 positivity rate also decreased from 55% in the UPA- group to 10% in the UPA+ treatment group (P<0.0002). Treatment with ulipristal contributed to the regression and atrophy of endometriotic lesions in rats. The immunohistochemical expression profiles of Bax/Bcl-2 and cytochrome C revealed a pro-apoptotic effect of ulipristal. We also observed a reduced cellular proliferation, indicated by a decrease in Ki-67 expression and an anti-inflammatory effect, shown by a decrease in COX-2 expression after treatment with ulipristal.


Identification of a population of blood circulating tumor cells from breast cancer patients that initiates metastasis in a xenograft assay.
It has been hypothesized that carcinoma metastasis is initiated by a subpopulation of circulating tumor cells (CTCs) found in the blood of patients. However, although the presence of CTCs is an indicator of poor prognosis in several carcinoma entities, the existence and phenotype of metastasis-initiating cells (MICs) among CTCs has not been experimentally demonstrated. Here we developed a xenograft assay and used it to show that primary human luminal breast cancer CTCs contain MICs that give rise to bone, lung and liver metastases in mice. These MIC-containing CTC populations expressed EPCAM, CD44, CD47 and MET. In a small cohort of patients with metastases, the number of EPCAM(+)CD44(+)CD47(+)MET(+) CTCs, but not of bulk EPCAM(+) CTCs, correlated with lower overall survival and increased number of metastasic sites. These data describe functional circulating MICs and associated markers, which may aid the design of better tools to diagnose and treat metastatic breast cancer.


Type I interferon in systemic lupus erythematosus.
Studies of the immunopathogenesis of systemic lupus erythematosus (SLE) have traditionally focused on the mechanisms of generation of the characteristic autoantibodies reactive with nucleic acid-containing intracellular particles and the contribution of autoantibody-autoantigen immune complexes to the inflammation and tissue damage that result in the clinical manifestations of lupus. The recent recognition of the central role of type I interferons (IFN) in this classic autoimmune disease has led to new understanding of the significant role of the innate immune system in the predisposition to and amplification of autoimmunity and tissue damage. Ongoing studies are defining the genetic factors, immune stimuli, and molecular pathways that contribute to production of IFN and induction of its downstream targets in SLE. Investigations of lupus patients and murine lupus models suggest a primary role for type I IFNs in systemic autoimmunity and support the case for therapeutic inhibition of the IFN pathway in lupus and possibly other systemic autoimmune diseases.


Effect of testosterone on diethylstilbestrol toxicity and comparison to a recovery study in the rat epididymis and vas deferens.
Effects of diethylstilbestrol (DES) treatment (30 daily i.m. injections) in reproductive function in the male rat were investigated. These functions were evaluated with sperm counts, motility, fertility, morphology, serum testosterone, and a number of biochemical tests in rat epididymis and vasa deferentia. DES treatment resulted in a 15% loss of body weight and a 60 to 90% loss of weight of testes, epididymis, and vas deferens. Sperm parameters and fertility were reduced to nil by DES treatment. Likewise, the majority of the biochemical measures were severely depressed by the DES treatment. In general, the measured parameters were less affected or recovered with either testosterone cotreatment or 60 days of recovery, showing the role of androgen in maintaining functional integrity and metabolism. However, sperm parameters and fertility did not recover with testosterone cotreatment, which differs from withdrawal of treatment.


Sunlight promoted self-fenton photodegradation and pathway of doxycycline: Interactive effects of nanomaterial on bean plant and its genotoxicity against Allium cepa.
Photocatalytic induction of electron/hole recombination, surface property and light response ability effectively enhance the photocatalytic activity of nanomaterial. In this work, the effective charge carrier separating Sn/Mn-ZnFe2O4-CdFe2O4-Ag3PO4 Quantum dots (M/SZFO-CFO-AP QDs) was fabricated for photocatalytic degradation of doxycycline (doxy) antibiotic. The result showed enhanced photocatalytic activity of doxy and the degradation efficiency of doxy was about 98.8% in short span of time. The calculated WH plot and urbach energy of prepared photocatalyst exhibited evidence for the prevalence of point defects and its contribution to efficient charge separation and transferability. The total organic carbon (TOC) removal was found to be 98.9%, which depicts the complete mineralization of doxy. The synergetic charge transfer of n-p-n heterojunction enables the effective removal of doxy under visible light irradiation. Further, the genotoxicity study was determined by interacting the SZFO-CFO-AP QDs with Allium Cepa. The results depict that SZFO-CFO-AP QDs show lower toxicity level and there were no trace of defective mitotic phases and micro nuclei. Further, the progression and development of bean plant was determined after treating with prepared nanomaterials and the result showed the enhanced growth in SZFO-CFO-AP QDs treated bean plant compared to the counterparts. Therefore, the prepared SZFO-CFO-AP QDs was can be used as an environmental friendly photocatalyst for effective treatment of antibiotic present in the water bodies.


Cytogenetic effects of malathion insecticide on somatic and germ cells of mice.
Male mice dermally exposed to single or multiple treatment (5 days/2 weeks) showed that the ability of malathion to induce chromosome aberrations in somatic (bone marrow) and germ cells (primary spermatocytes) was related to the type of treatment and dose used. Statistically significant increases of chromosome aberrations in bone marrow cells occurred after single treatment (500 and 2000 mg/kg body wt) when chromatid gaps were included and after multiple treatment (250 and 500 mg/kg) when they were excluded. No dose-response relationships were observed for either treatment. In germ cells, malathion induced a significant increase of univalents in both types of treatment but structural chromosome aberrations were induced only by multiple treatment. Malathion induced a significant decrease of the mitotic indices in the bone marrow.


Parcellation of the frontal cortex of the New World monkey Callithrix jacchus by eight neurotransmitter-binding sites.
The most extensive development during primate brain evolution involves the cortex of the frontal lobe, especially its prefrontal region. The distribution of neurotransmitter receptors is unknown in this part of the cortex of New World monkeys. The respective distributions of eight different receptors for the transmitters L-glutamate (L-glu and NMDA), gamma-amino-butyric acid (GABAA), noradrenaline (alpha 1), acetylcholine (M1 and M2) and serotonin (5-HT1 and 5-HT2) were therefore studied in cortical areas of the frontal lobe of the lissencephalic New World monkey, Callithrix jacchus. The results are compared to earlier data on Old World monkeys in order to obtain insight into evolutionary trends at the level of chemical neuroanatomy. Our results indicate that the density and laminar pattern of some receptors change precisely at the cytoarchitectonic boundaries between different cortical areas, while some other receptors do not exhibit measurable changes. For example, the premotor area 6 can be distinguished from prefrontal areas by its high concentration of adrenergic alpha 1 receptors as labelled with [3H] prazosin, with only the cingulate area 24 showing higher values. In other cases, the receptor distribution changes within a cytoarchitectonically homogeneous area. Thus, area 8 can be subdivided into dorsal and ventral regions on the basis of the distribution of GABAA, muscarinic and serotonin receptors. Comparison of these results in a New World monkey with receptor distributions in other primate species reveals much larger interspecies differences in the areas of the frontal lobe than e.g. in the primary visual cortex.(ABSTRACT TRUNCATED AT 250 WORDS)


A new sinker-assisted endoscopic submucosal dissection for colorectal cancer.
Endoscopic submucosal dissection (ESD) is accepted as a minimally invasive treatment for early gastric cancer, but it is not widely used to treat the colorectum because of its degree of technical difficulty. Thus, a noninvasive tool that facilitates the direct visualization of the submucosal layer is needed. Traction-assisted dissection was performed on 4 superficial lesions. The system consisted of a metallic clip attached by a nylon line to a sinker 6 x 4 x 4 mm in size and weighing 1 g. After partially dissecting the submucosa, the clip was attached to the edge of the exfoliated mucosa and the weight of the sinker pulled down the partly resected lesion. In all 4 cases, the sinker allowed direct visualization of the cutting line, and en bloc resection was successfully accomplished. These preliminary results suggest that sinker-assisted ESD is effective for the complete removal of selected superficial early colorectal cancer.


Veterinary syndromic surveillance in practice: costs and benefits for governmental organizations.
We describe a veterinary syndromic surveillance system developed in Sweden based on laboratory test requests. The system is a desktop application built using free software. Development took 1 year. During the first year of operation, utility was demonstrated by the detection of statistically significant increases in the number of laboratory submissions. The number of false alarms was considered satisfactory in order to achieve the desired sensitivity. Besides the demonstrated benefit for disease surveillance, the system contributed to improving data quality and communication between the diagnostic departments and the epidemiology department.


Changes in mechanoreceptive field properties of trigeminal somatosensory brainstem neurons induced by stimulation of nucleus raphe magnus in cats.
Experiments were carried out on adult anesthetized cats in which the effects of nucleus raphe magnus (NRM) conditioning stimulation (20 ms) were tested on the responses evoked by orofacial stimuli in single brainstem neurons of trigeminal (V) subnucleus oralis. The NRM stimulation induced inhibition of the responses of 57 of 77 low-threshold mechanoreceptive (LTM) neurons and the one wide-dynamic range (WDR) neuron tested. The duration of the neuronal inhibition ranged from 300-600 ms and the mean threshold for inhibition ranged from 47.8 +/- 4.8 to 102.7 +/- 15 microA depending on the orofacial stimulation site (skin or tooth pulp) and form (mechanical or electrical) of cutaneous stimuli used to evoke neuronal responses. In 20 LTM neurons showing NRM-induced inhibition that were specifically examined for the effects of NRM stimulation on the mechanoreceptive field, one population (n = 11) showed shrinkage (mean 55 +/- 4.4% from control area) of the mechanoreceptive field while the remaining neurons (n = 9) showed no change in mechanoreceptive field size during NRM stimulation. The former group of neurons were also distinguished from the latter neurons by their significantly larger mechanoreceptive field and the activation of the majority of them by electrical stimuli applied outside their mechanoreceptive field. The responses of these neurons evoked by low-threshold inputs from the edge of the mechanoreceptive field were more sensitive to NRM conditioning stimulation than responses evoked from the mechanoreceptive field center, as judged by threshold, magnitude and duration of the NRM-induced inhibition. These findings underscore the sensitivity of LTM neurons to NRM influences. They also reveal a particular population of oralis neurons which have a differential sensitivity of low-threshold inputs evoked from the edge compared to the center of the mechanoreceptive field.


Comparative clinical characteristics among different age group of adult COVID-19 patients: A multicenter study.
Coronavirus disease (COVID-19) is a global infectious disease with a large burden of illness and high health care costs. This study aimed to compare clinical features among adult COVID-19 patients in different age groups. Laboratory-confirmed adult COVID-19 infection cases between December 31, 2019 to March 8, 2020 obtained from Neighboring Cities. Patients were divided into five age groups. Clinical characteristics were compared among different age groups. Of 299 cases, median age was 44 and 158 (53%) were male. A total of 53.3% of 30-40 years, 50% of 40-50 years, 36.6% of <30 years and 36.2% of 50-60 years were primary case, none of the elderly were primary case. Among all the observed symptoms, only symptom of dyspnea was significantly different between the elderly group and other groups (p < .001). Proportion of severe or critical type was 2.4%, 5.3%, 9.5%, 14.5%, and 35% in patients with age <30, 30-40, 40-50, 50-65, ≥65, respectively. A total of 285 patients (95.3%) were cured and discharged, 12 patients (4.0%) were still on medical treatment in hospital. There were 2 (0.7%) deaths which occurred among persons ≥65 years. Patients with a history of chronic heart disease had a more than a 56 times higher risk for severe or critical type of COVID-19 than those without a history of chronic heart disease (odds ratio [OR]: 56.038, 95% confidence interval [CI]: 2.764-1136.053, p = .009). Old age (OR: 1.055, 95% CI: 1.016-1.095, p = .006), high heart rate in admission (OR: 1.085, 95% CI: 1.03-1.144, p = .002), high respiratory rate in admission (OR: 1.635, 95% CI: 1.093-2.431, p = .017) were independently associated with severe or critical type in COVID-19. Proportion of severe or critical type increased with old age groups. Adults with old age and high heart rate, respiratory rate in admission and history of chronic heart disease were associated with severe or critical type in COVID-19.


Prey contaminated with neonicotinoids induces feeding deterrent behavior of a common farmland spider.
Neonicotinoids are thought to have negligible repellent or anti-feeding effects. Based on our preliminary observations, we hypothesized that the contamination of spider prey with commonly used neonicotinoids has repellent or feeding deterrent effects on spiders. We tested this hypothesis by providing prey treated or not with field-realistic concentrations of neonicotinoids to the spiders and determining the number of (a) killed only and (b) killed and eaten prey. We exposed adult freshly molted and starved Pardosa agrestis, a common agrobiont lycosid species, to flies treated with neonicotinoids (acetamiprid, imidacloprid, thiacloprid and thiamethoxam) at field-realistic concentrations or with distilled water as a control. There were no effects of the exposure of the prey to neonicotinoids on the number of flies captured. However, the spiders consumed less of the prey treated with neonicotinoids compared to the ratio of control prey consumed, which resulted in increased overkilling (i.e., killing without feeding). In female P. agrestis, the overkilling increased from only 2.6% of control flies to 25-45% of neonicotinoid-treated flies. As the spiders avoided consuming the already captured neonicotinoid-treated prey, the sublethal effects of neonicotinoids extend beyond the simple attractivity/deterrence of the prey itself. The present study demonstrated that prey overkilling serves as a physiological response of spiders to the contact with the prey contaminated with agrochemicals. We speculate that primary contact with neonicotinoids during prey capture may play a role in this unexpected behavior.


The role of miRNAs in laryngeal cancer pathogenesis and therapeutic resistance - A focus on signaling pathways interplay.
Laryngeal cancer (LC)is the malignancy of the larynx (voice box). The majority of LC are squamous cell carcinomas. Many risk factors were reported to be associated with LC as tobacco use, obesity, alcohol intake, human papillomavirus (HPV) infection, and asbestos exposure. Besides, epigenetics as non-coding nucleic acids also have a great role in LC. miRNAs are short nucleic acid molecules that can modulate multiple cellular processes by regulating the expression of their genes. Therefore, LC progression, apoptosis evasions, initiation, EMT, and angiogenesis are associated with dysregulated miRNA expressions. miRNAs also could have some vital signaling pathways such as mTOR/P-gp, Wnt/-catenin signaling, JAK/STAT, KRAS, and EGF. Besides, miRNAs also have a role in the modulation of LC response to different therapeutic modalities. In this review, we have provided a comprehensive and updated overview highlighting the microRNAs biogenesis, general biological functions, regulatory mechanisms, and signaling dysfunction in LC carcinogenesis, in addition to their clinical potential for LC diagnosis, prognosis, and chemotherapeutics response implications.


Multi-modal antidepressant-like action of 6- and 7-chloro-2-aminodihydroquinazolines in the mouse tail suspension test.
2-Amino-6-chloro-3,4-dihydroquinazoline (e.g., A6CDQ) represents a novel putative antidepressant originally thought to act through a 5-HT3 serotonin receptor antagonist mechanism. Here, we investigated this further by examining a positional isomer of A6CDQ (i.e., A7CDQ). 5-HT3 receptor and transporter activity (uptake-1 and uptake-2) were investigated using a variety of in vitro assays and the in vivo mouse tail suspension test (TST). Although A7CDQ binds at 5-HT3 receptors with low affinity (Ki = 1975 nM) compared to A6CDQ (Ki = 80 nM), it retained 5-HT3 receptor antagonist action (IC50 = 5.77 and 0.26 μM, respectively). In the mouse TST A7CDQ produced antidepressant-like actions (ED50 = 0.09 mg/kg) comparable to that of A6CDQ. In addition, A6CDQ was found to be a 5-HT releasing agent (Km = 2.8 μM) at hSERT and a reuptake inhibitor (IC50 = 1.8 μM) at hNET, whereas A7CDQ was a weak reuptake inhibitor (Km = 43.6 μM) at SERT but a releasing agent (EC50 = 3.3 μM) at hNET. Moreover, A6CDQ and A7CDQ were potent inhibitors of uptake-2 (e.g.; OCT3 IC50 = 3.9 and 5.9 μM, respectively). A simple shift of a substituent in a common quinazoline scaffold from one position to another (i.e., a chloro group from the 6- to the 7-position) resulted in a common action in the TST but via a somewhat different mechanism. A6CDQ and A7CDQ might represent the first members of a new class of potential antidepressants with a unique multi-modal mechanism of action.


Energy demand and emissions of a passenger vehicle fueled with CNG, gasohol, hydrous ethanol and wet ethanol based on the key points of the WLTC.
A compact sedan vehicle powered by a 1.4 dm3 spark ignition engine fueled with compressed natural gas (CNG), Brazilian gasoline, hydrous ethanol 95% v/v and wet ethanol 88% v/v was evaluated throughout the Worldwide harmonized Light vehicles Test Cycle (WLTC) key points. The vehicle operating points with longest residence time on the WLTC were selected to fuel consumption and emissions evaluation at steady state conditions. The top five key operating points reported in this work accounted for 22% of the total time spent in the entire cycle. The results indicated a significant reduction on greenhouse gases (GHG) emissions and energy demand for operation with CNG. The ethanol-water blends provided reduced emissions of nitrogen oxides (NOx), but increased specific fuel consumption, carbon monoxide (CO) and GHG emissions in comparison to CNG and gasoline. The operation with gasoline resulted in the minimum CO emissions for all fuels tested, as well as the best fuel consumption between liquid fuels, despite the highest values of carbon dioxide (CO2), and increased NOx. Even though ethanol produced little total unburned hydrocarbons (THC), the emissions of alcohols and aldehydes raised an alert for this renewable fuel, whereas CNG emitted the least amount of such pollutants.


[The value of serum endothelin for differential diagnosis of the decreased cerebral blood flow perfusion foci of epilepsy patients].
To observe the level of serum endothelin (ET) of interictal epilepsy patients with regional cerebral blood flow (rCBF) decreased foci in SPECT brain perfusion imaging and to investigate its value for diagnosis and differential diagnosis of epilepsy. Seventy-six interictal epilepsy patients were enrolled and SPECT brain perfusion imaging, EEG, X-CT or MRI were performed, with 25 healthy volunteers as controls whose serum ET levels were measured by radioimmunoassay. The serum ET levels of 49 idiopathic epilepsy patients were significantly higher (P < 0.01) than that of healthy controls. The ET levels of 21 symptomatic epilepsy patients were not significantly different from that of the healthy controls (P > 0.05). The ET levels of 6 non-epilepsy patients were significantly higher than that of the healthy controls (P < 0.05). The level of serum ET is of value to the differential diagnosis for interictal epilepsy cases, and can contribute to the qualitative diagnosis of idiopathic epilepsy.


Differential expression of glyceraldehyde-3-phosphate dehydrogenase (GAPDH), beta actin and hypoxanthine phosphoribosyltransferase (HPRT) in postnatal rabbit sclera.
GAPDH, beta-actin, HPRT and 18S rRNA are constitutively expressed in all mammalian cells. In accordance with the nature of invariant control, these genes have been used to standardize genes of interest in expression studies. Recent studies have suggested that GAPDH, beta-actin and HPRT in special situations may come under temporary regulatory control, but that 18S rRNA may be more likely to remain constitutive. However, little is known about the quantitative expression of these genes in fibroblasts and in particular during early postnatal development, a time of rapid changes in cell metabolism. In this study we have examined the differential expression of these genes in association with scleral development from an early postnatal age up to young adult status. GAPDH, beta-actin, HPRT, and 18S rRNA gene expression were analyzed in the rabbit sclera from 1 day to 8 weeks postnatally by real-time, comparative PCR. Real-time PCR analysis showed that the expression levels of GAPDH, beta-actin, and HPRT were higher in the first postnatal week and then declined. However, from 2 to 8 weeks, the mRNA levels of these three genes underwent significant variations (P < 0.01) in their levels of expression. In contrast, the expression level of 18S rRNA showed no significant variation (P >or= 0.5) over this time period. Conclusions. The present study shows that GAPDH, beta actin and HPRT gene were differentially expressed in early postnatal scleral development. It also suggests that these gene products could be implicated in the developmental process and have a crucial role in the early postnatal period. This study demonstrates that 18S rRNA may be preferable to normalize genes of interest in studies of early development.


Phenotyping Occupational Asthma Caused by Acrylates in a Multicenter Cohort Study.
While acrylates are well-known skin sensitizers, they are not classified as respiratory sensitizers although several cases of acrylate-induced occupational asthma (OA) have been reported. To evaluate the characteristics of acrylate-induced OA in a large series of cases and compare those with OA induced by other low-molecular-weight (LMW) agents. Jobs and exposures, clinical and functional characteristics, and markers of airway inflammation were analyzed in an international, multicenter, retrospective cohort of subjects with OA ascertained by a positive inhalation challenge to acrylates (n = 55) or other LMW agents (n = 418) including isocyanates (n = 125). Acrylate-containing glues were the most prevalent products, and industrial manufacturing, dental work, and beauty care were typical occupations causing OA. Work-related rhinitis was more common in acrylate-than in isocyanate-induced asthma (P < .001). The increase in postchallenge fractional exhaled nitric oxide was significantly greater in acrylate-induced OA (26.0; 8.2 to 38.0 parts per billion [ppb]) than in OA induced by other LMW agents (3.0; -1.0 to 10.0 ppb; P < .001) or isocyanates (5.0; 2.0 to 16.0 ppb; P = .010). Multivariable models confirmed that OA induced by acrylates was significantly and independently associated with a postchallenge increase in fractional exhaled nitric oxide (≥17.5 ppb). Acrylate-induced OA shows specific characteristics, concomitant work-related rhinitis, and exposure-related increases in fractional exhaled nitric oxide, suggesting that acrylates may induce asthma through different immunologic mechanisms compared with mechanisms through which other LMW agents may induce asthma. Our findings reinforce the need for a reevaluation of the hazard classification of acrylates, and further investigation of the pathophysiological mechanisms underlying their respiratory sensitizing potential.


Boosting magnetic resonance imaging signal-to-noise ratio using magnetic metamaterials.
Magnetic resonance imaging (MRI) represents a mainstay among the diagnostic imaging tools in modern healthcare. Signal-to-noise ratio (SNR) represents a fundamental performance metric of MRI, the improvement of which may be translated into increased image resolution or decreased scan time. Recently, efforts towards the application of metamaterials in MRI have reported improvements in SNR through their capacity to interact with electromagnetic radiation. While promising, the reported applications of metamaterials to MRI remain impractical and fail to realize the full potential of these unique materials. Here, we report the development of a magnetic metamaterial enabling a marked boost in radio frequency field strength, ultimately yielding a dramatic increase in the SNR (~ 4.2X) of MRI. The application of the reported magnetic metamaterials in MRI has the potential for rapid clinical translation, offering marked enhancements in SNR, image resolution, and scan efficiency, thereby leading to an evolution of this diagnostic tool.


The influence of diazepam and thiouracil upon the carcinogenic effect of diethylnitrosamine in gerbils.
N-diethylnitrosamine (DEN) was simultaneously administered with diazepam (DZP) or thiouracil (TU) once weekly for life to gerbils (Meriones unguiculatus). Additional DZP or TU treatment increased significantly average survival time and inhibited the development of cholangiocarcinomas, although cholangiomas were still observed in these groups. Tumor type and incidence in the nasal cavities were not influenced by DZP or TU. However, in comparison to DEN alone tumor latencies were prolonged.


THEMIS increases TCR signaling in CD4+CD8+ thymocytes by inhibiting the activity of the tyrosine phosphatase SHP1.
The T cell lineage-restricted protein THEMIS plays a critical role in T cell development at the positive selection stage. In the SHP1 activation model, THEMIS is proposed to enhance the activity of the tyrosine phosphatase SHP1 (encoded by Ptpn6), thereby dampening T cell antigen receptor (TCR) signaling and preventing the inappropriate negative selection of CD4+CD8+ thymocytes by positively selecting ligands. In contrast, in the SHP1 inhibition model, THEMIS is proposed to suppress SHP1 activity, rendering CD4+CD8+ thymocytes more sensitive to TCR signaling initiated by low-affinity ligands to promote positive selection. We sought to resolve the controversy regarding the molecular function of THEMIS. We found that the defect in positive selection in Themis-/- thymocytes was ameliorated by pharmacologic inhibition of SHP1 or by deletion of Ptpn6 and was exacerbated by SHP1 overexpression. Moreover, overexpression of SHP1 phenocopied the Themis-/- developmental defect, whereas deletion of Ptpn6, Ptpn11 (encoding SHP2), or both did not result in a phenotype resembling that of Themis deficiency. Last, we found that thymocyte negative selection was not enhanced but was instead impaired in the absence of THEMIS. Together, these results provide evidence favoring the SHP1 inhibition model, supporting a mechanism whereby THEMIS functions to enhance the sensitivity of CD4+CD8+ thymocytes to TCR signaling, enabling positive selection by low-affinity, self-ligand-TCR interactions.


Mother's perceptions and concerns over sharing sexual and reproductive health information with their adolescent daughters- A qualitative study among mothers of adolescent girls aged 14-19 years in the developing world, Sri Lanka.
Studies across the world have shown that parent-adolescent SRH communication can prevent unhealthy sexual and reproductive health (SRH) practices among adolescents and promote their sexual and reproductive health. Parents have the ability to provide individualized sex education to suit the needs of their children, their families, and societal values. The fact that children have more opportunities in the family, makes parent-based sexuality education of children a better approach to Sri Lankan context. To explore mother's perceptions and concerns over sharing SRH information with their daughters among Sinhalese mothers of adolescent girls aged 14-19 years in Sri Lanka. Six Focus group discussions (FGD) were carried out among mothers of adolescent girls aged 14-19 years. Each focus group discussion included 10-12 participants who were recruited using the purposive sampling method. A focus group discussion guide developed after an extensive literature search and expert opinion was used to retrieve information from mothers. Data management and analysis mainly followed an inductive approach to thematic analysis principles. The findings were presented in narrative form using respondents' quotes in their own words and were developed into codes and themes. The mean age of the participants was 43.5 years while 62.4% (n = 40) were educated above the Ordinary level. Analysis of data identified eight main themes from the FGDs. Many mothers thought that sexual and reproductive information is important to adolescent girls. They tried to keep their girl adolescents informed about Adolescent sexual and reproductive health (ASRH) issues. They preferred abstinence-only education over abstinence-plus education. Lack of skills and lack of knowledge on adolescent SRH issues was a major challenge identified by the mothers to communicate SRH matters with their children. Although mothers perceived their role as primary sex educators to their children, they were not confident about their knowledge and skills in discussing SRH matters with children. Implementation of interventions to improve mothers' attitudes and skills in communicating SRH matters with children is recommended.


Development of the rat thalamus: V. The posterior lobule of the thalamic neuroepithelium and the time and site of origin and settling pattern of neurons of the medial geniculate body.
Long-survival, sequential, and short-survival thymidine radiograms of rat embryos, fetuses, and young pups were analyzed in order to examine the time of origin, site of origin, migratory route, and settling pattern of neurons of the medial geniculate body (MG). Quantitative evaluation of long-survival radiograms established that the bulk of MG neurons are generated between embryonic (E) days E13 and E15, with a pronounced peak on day E14. There is an overall lateral-to-medial and caudal-to-rostral chronological gradient in MG neurogenesis. On the basis of significant regional differences in the birth dates of neurons, the MG was divided into several chronoarchitectonic areas. The earliest-generated neurons (with close to 20% of the cells produced on day E13 and a negligible proportion on day E15) form the dorsal and ventral clusters far laterally. Next in sequential order are the neurons of the lateral shell, intermediate shell, and medial shell of the MG. The medial shell with it latest-generated neurons (with over 30% produced rostrally on day E15) corresponds to the medial (magnocellular) subnucleus of the MG. There were no neurogenetic differences between the traditional dorsal and ventral divisions of the MG. Examination of sequential radiograms in rats labeled with 3H-thymidine on day E14 or E15 and killed on successive days brought supportive evidence for our earlier identification, in short-survival radiograms, of a posteroventral thalamic neuroepithelial evagination as the putative source, or committed cell line, of MG neurons. Wave fronts of apparently migrating unlabeled and labeled cells could be traced from this sublobule in a posterolateral direction to the future site of the MG.


Hyperthermia: an effective strategy to induce apoptosis in cancer cells.
Heat has been used as a medicinal and healing modality throughout human history. The combination of hyperthermia (HT) with radiation and anticancer agents has been used clinically and has shown positive results to a certain extent. However, the clinical results of HT treatment alone have been only partially satisfactory. Cell death following HT treatment is a function of both temperature and treatment duration. HT induces cancer cell death through apoptosis; the degree of apoptosis and the apoptotic pathway vary in different cancer cell types. HT-induced reactive oxygen species production are responsible for apoptosis in various cell types. However, the underlying mechanism of signal transduction and the genes related to this process still need to be elucidated. In this review, we summarize the molecular mechanism of apoptosis induced by HT, enhancement of heat-induced apoptosis, and the genetic network involved in HT-induced apoptosis.


Assessment of behavioral determinants influencing success of supervised exercise therapy in patients with intermittent claudication: A cross sectional survey.
Supervised exercise therapy is the first step in treatment of intermittent claudication. However, adherence to supervised exercise therapy is low. Limited access and reimbursement issues are known reasons, though lack of motivation is often leading. Behavioral determinants influencing motivation and thus adherence to supervised exercise therapy remain to be investigated. In this study we sought to determine which behavioral determinants would be of influence on the long-term adherence of supervised exercise therapy. 200 patients, newly diagnosed with peripheral arterial disease Rutherford classification II-III, were sent a questionnaire to assess motivation and behavior with regard to supervised exercise therapy. The questionnaire was constructed using the I-CHANGE model for explaining motivational and behavioral change. Baseline characteristics were acquired from medical records. Alpha Cronbach's was calculated to test reliability of the questionnaire. 108 (54%) patients returned their questionnaire. A total of 79% patients followed supervised exercise therapy. Patients who increased their walking distance after supervised exercise therapy have significantly greater knowledge (p = 0.05), positive attitude (p = 0.03) and lower negative attitude (p = 0.01). Patients with a higher self-efficacy remained significantly more active after participating in supervised exercise therapy (p = 0.05). Increasing the determinants knowledge, attitude and self-efficacy will improve adherence to supervised exercise therapy and result in delayed claudication onset time.


The relationship between chronic musculoskeletal pain, anxiety and mindfulness: Adjustments to the Fear-Avoidance Model of Chronic Pain.
The Fear-Avoidance Model of Chronic Pain proposed by Vlaeyen and Linton states individuals enter a cycle of chronic pain due to predisposing psychological factors, such as negative affectivity, negative appraisal or anxiety sensitivity. They do not, however, address the closely related concept of anxious rumination. Although Vlaeyen and Linton suggest cognitive-behavioral treatment methods for chronic pain patients who exhibit pain-related fear, they do not consider mindfulness treatments. This cross-sectional study investigated the relationship between chronic musculoskeletal pain (CMP), ruminative anxiety and mindfulness to determine if (1) ruminative anxiety is a risk factor for developing chronic pain and (2) mindfulness is a potential treatment for breaking the cycle of chronic pain. Middle-aged adults ages 35-50 years (N=201) with self-reported CMP were recruited online. Participants completed standardized questionnaires assessing elements of chronic pain, anxiety, and mindfulness. Ruminative anxiety was positively correlated with pain catastrophizing, pain-related fear and avoidance, pain interference, and pain severity but negatively correlated with mindfulness. High ruminative anxiety level predicted significantly higher elements of chronic pain and significantly lower level of mindfulness. Mindfulness significantly predicted variance (R2) in chronic pain and anxiety outcomes. Pain severity, ruminative anxiety, pain catastrophizing, pain-related fear and avoidance, and mindfulness significantly predicted 70.0% of the variance in pain interference, with pain severity, ruminative anxiety and mindfulness being unique predictors. The present study provides insight into the strength and direction of the relationships between ruminative anxiety, mindfulness and chronic pain in a CMP population, demonstrating the unique associations between specific mindfulness factors and chronic pain elements. It is possible that ruminative anxiety and mindfulness should be added into the Fear-Avoidance Model of Chronic Pain, with ruminative anxiety as a psychological vulnerability and mindfulness as an effective treatment strategy that breaks the cycle of chronic pain. This updated Fear-Avoidance Model should be explored further to determine the specific mechanism of mindfulness on chronic pain and anxiety and which of the five facets of mindfulness are most important to clinical improvements. This could help clinicians develop individualized mindfulness treatment plans for chronic pain patients.


Three-dimensional analysis of per-rotational nystagmus.
Head rotation produces a vestibulo-ocular reflex (VOR). In horizontal rotation, not only lateral semicircular canals but also posterior semicircular canals are stimulated, because posterior canals cupulae are not horizontal in the sitting position. Therefore, theoretical nystagmus is horizontal and torsional. Convection of endolymph does not occur, because the centre of head rotation is a dens of the second cervical vertebra, not the center of lateral canal. Although per-rotational nystagmus is a result of VOR, whether it could be explained by the movement of cupula remains undetermined. To answer this question, we analysed per-rotational nystagmus using three-dimensional video-oculography. To clarify whether per-rotational nystagmus is the same as the physical movement of cupula (theoretical nystagmus). Five healthy human were evaluated. The participant's head was rotated (sinusoidal yaw rotation) manually (frequency, 0.33 Hz; amplitude, 60°). The experiment was performed in a dark, with the participant's eyes open. Nystagmus was recorded and converted into digital data. In all participants, the direction of nystagmus was rightward on rightward rotation and leftward on leftward rotation. In all participants, nystagmus was purely horizontal. Practical per-rotational nystagmus differs completely from the theoretical nystagmus. Therefore, VOR is strongly influenced by the central nervous system.


Application of an equivalent circuit to signal-to-noise calculations in MRI.
Transfer functions determined from the component values of an equivalent circuit are used to calculate the relative signal-to-noise ratio of rf coils for magnetic resonance imaging. Experimental verification of the method is obtained by directly measuring signals from three solenoidal coils and by measuring the signal-to-noise ratio of these solenoids. The transfer functions separate the total noise voltage into contributions from the coil resistance and contributions from magnetic and electric field interactions with the sample. The use of this technique in understanding and improving coil design is discussed.


Funding Victoria's public hospitals: the casemix policy of 2000-2001.
On 1 July 1993 Victoria became the first Australian state to use casemix information to set budgets for its public hospitals commencing with casemix funding for inpatient services. Victoria's casemix funding approach now embraces inpatient, outpatient and rehabilitation services.


Studies on the effects of an ornithine decarboxylase inhibitor on lupus nephritis reveal a post-transcriptional modification of the enzyme.
Upregulation of ornithine decarboxylase (ODC) activity and polyamine levels is found in the kidney of MRL-lpr/lpr (lpr) mouse, an animal model of lupus. To understand the molecular genetics of ODC regulation in lpr mouse, we analyzed ODC mRNA and activity in the kidney of lpr and normal BALB/c and MRL(-)+/+ mice. Although ODC activity was significantly higher in lpr kidney, its mRNA level was lower compared to normal strains, as measured by Northern blot hybridization. Treatment of lpr mouse with difluoromethylornithine (DFMO) reduced ODC activity in lpr kidney to the level of normal strains. In contrast, ODC mRNA level increased 12-fold by DFMO treatment. These results suggest that post-transcriptional modification of ODC in lpr genetic background might be responsible for increased ODC activity and polyamines. The beneficial effect of DFMO on murine lupus suggests a pathogenic role for altered ODC regulation in lpr mouse.


MiR-142-3p inhibits adipogenic differentiation and autophagy in obesity through targeting KLF9.
MiR-142-3p has been shown to be suppressed in obese patients, while the underlying regulatory mechanism is unclear. Body shape indexes as well as peripheral blood for biochemical parameter analysis were obtained from obese and healthy subjects. When 3T3-L1 cells were induced to differentiate, miR-142-3p expression was detected by quantitative real-time polymerase chain reaction (qRT-PCR). The effects of miR-142-3p on triglyceride (TG) and adipogenic differentiation-related genes during the adipogenic differentiation of 3T3-L1 cells were detected by transfection, Oil Red O staining, and Western blot. The targeting relationship between miR-142-3p and Krueppel-like transcription factor 9 (KLF9) was verified by TargetScan and dual-luciferase experiment. The specific regulatory effects of miR-142-3p on cell adipogenic differentiation and autophagy were analyzed by rescue experiments. In vivo experiments further validated the results of in vitro experiments through obese mouse models. Obesity-marked biochemical indicators increased whereas high density lipoprotein and miR-142-3p decreased in obese patients. The content of miR-142-3p gradually decreased with cell lipid differentiation. Overexpression of miR-142-3p reduced TG deposition in cells by down-regulating lipid formation and fatty acid synthesis genes and up-regulating fatty acid oxidation genes. KLF9 targeting miR-142-3p was suppressed by miR-142-3p. KLF9 overexpression partially reversed the inhibitory effect of miR-142-3p mimic on adipogenic differentiation and the expressions of autophagy related-genes in 3T3-L1 cells. MiR-142-3p overexpression also inhibited fat cell differentiation and autophagy in obese mice. Overexpressed miR-142-3p inhibited adipogenic differentiation and autophagy through targeting KLF9.


Genetic aspects of control of anaemia development in trypanotolerant N'Dama cattle.
148 one-year-old N'Dama cattle, progeny of 29 sires, were exposed for 92 days to a medium natural tsetse-trypanosome challenge in Gabon, Central Africa. Matching health and performance data were recorded on 11 occasions. Average packed red cell volume percent (PCV) and lowest PCV reached during the period were evaluated as measures of ability to control the development of anaemia. Attempts were made to systematically control other possible causes of anaemia. In animals detected as parasitaemic, those with above average average PCV values or above average lowest PCV reached had 34% and 35% respectively higher daily weight gains than those with below average. Even when not detected as parasitaemic, those with above average average PCV values or above average lowest PCV reached had 14% and 12% respectively higher gain indicating that a proportion of these animals actually were parasitaemic. When all environmental and parasitaemia information was taken into account, the heritability of growth, average PCV and lowest PCV reached was 0.39 +/- 0.31, 0.64 +/- 0.33 and 0.50 +/- 0.32 respectively. The genetic correlation between average PCV and growth was 0.70 +/- 0.42 and between lowest PCV reached and growth was 0.28 +/- 0.55. While the standard errors are large, the higher heritabilities of PCV measures compared to animal growth and the positive genetic correlations between PCV and growth do indicate an opportunity for selection on PCV when animals can be detected as parasitaemic. All heritabilities and genetic correlations increased in size when parasitaemia information was utilized in the analysis.(ABSTRACT TRUNCATED AT 250 WORDS)


Characterization of the annular lipid shell of the Sec translocon.
The bacterial Sec translocase in its minimal form consists of a membrane-embedded protein-conducting pore SecYEG that interacts with the motor protein SecA to mediate the translocation of secretory proteins. In addition, the SecYEG translocon interacts with the accessory SecDFyajC membrane complex and the membrane protein insertase YidC. To examine the composition of the native lipid environment in the vicinity of the SecYEG complex and its impact on translocation activity, styrene-maleic acid lipid particles (SMALPs) were used to extract SecYEG with its lipid environment directly from native Escherichia coli membranes without the use of detergents. This allowed the co-extraction of SecYEG in complex with SecA, but not with SecDFyajC or YidC. Lipid analysis of the SecYEG-SMALPs revealed an enrichment of negatively charged lipids in the vicinity of SecYEG, which in detergent assisted reconstitution of the Sec translocase are crucial for the translocation activity. Such lipid enrichment was not found with separately extracted SecDFyajC or YidC, which demonstrates a specific interaction between SecYEG and negatively charged lipids.


The Alzheimer's disease-associated protective Plcγ2-P522R variant promotes immune functions.
Microglia-specific genetic variants are enriched in several neurodegenerative diseases, including Alzheimer's disease (AD), implicating a central role for alterations of the innate immune system in the disease etiology. A rare coding variant in the PLCG2 gene (rs72824905, p.P522R) expressed in myeloid lineage cells was recently identified and shown to reduce the risk for AD. To assess the role of the protective variant in the context of immune cell functions, we generated a Plcγ2-P522R knock-in (KI) mouse model using CRISPR/Cas9 gene editing. Functional analyses of macrophages derived from homozygous KI mice and wild type (WT) littermates revealed that the P522R variant potentiates the primary function of Plcγ2 as a Pip2-metabolizing enzyme. This was associated with improved survival and increased acute inflammatory response of the KI macrophages. Enhanced phagocytosis was observed in mouse BV2 microglia-like cells overexpressing human PLCγ2-P522R, but not in PLCγ2-WT expressing cells. Immunohistochemical analyses did not reveal changes in the number or morphology of microglia in the cortex of Plcγ2-P522R KI mice. However, the brain mRNA signature together with microglia-related PET imaging suggested enhanced microglial functions in Plcγ2-P522R KI mice. The AD-associated protective Plcγ2-P522R variant promotes protective functions associated with TREM2 signaling. Our findings provide further support for the idea that pharmacological modulation of microglia via TREM2-PLCγ2 pathway-dependent stimulation may be a novel therapeutic option for the treatment of AD.


Emerging advances in biosecurity to underpin human, animal, plant, and ecosystem health.
One Biosecurity is an interdisciplinary approach to policy and research that builds on the interconnections between human, animal, plant, and ecosystem health to effectively prevent and mitigate the impacts of invasive alien species. To support this approach requires that key cross-sectoral research innovations be identified and prioritized. Following an interdisciplinary horizon scan for emerging research that underpins One Biosecurity, four major interlinked advances were identified: implementation of new surveillance technologies adopting state-of-the-art sensors connected to the Internet of Things, deployable handheld molecular and genomic tracing tools, the incorporation of wellbeing and diverse human values into biosecurity decision-making, and sophisticated socio-environmental models and data capture. The relevance and applicability of these innovations to address threats from pathogens, pests, and weeds in both terrestrial and aquatic ecosystems emphasize the opportunity to build critical mass around interdisciplinary teams at a global scale that can rapidly advance science solutions targeting biosecurity threats.


Pathological fear of death, panic attacks, and hypochondriasis.
The article has presented a concept of the pathological fear of death as a categorically defined phenomenon and outlined its distinguishing features. In an attempt to account for the origin of the pathological fear of death, most weight has been given to developmental and structural abnormalities in the regulation and control of the primary and disruptive forms of anxiety. The additional contributing factors have also been taken into consideration: a defect in the defensive and symbolic representation of death, and a general collapse of defensive functioning, with regression to a state of infantile helplessness and revival of the infantile death cognitions. A role of the cognitive abnormalities in the genesis of the pathological fear of death has been examined in the panic attacks and hypochondriasis, while a developmentally determined, pervasive mistrust in the bodily functioning and bodily worth has been stressed as a factor that crucially predisposes to the pathological fear of death in hypochondriasis, and to the respective type of hypochondriasis as well. A relationship between panic disorder and hypochondriasis has been examined in the light of the pathological fear of death that they often share. Finally, the article has briefly dealt with the relevance of the pathological fear of death for diagnostic assessment and psychotherapy of patients with panic disorder and hypochondriasis. The concept of the pathological fear of death requires further study and refinement in the area of its descriptive demarcation, psychogenesis, and clinical application.


Translational regulation as a novel mechanism for the development of cellular drug resistance.
Cellular drug resistance is one of the principal obstacles to the clinical efficacy of cancer chemotherapy. In this review, we describe the potential role for translational regulation as a novel mechanism for modulating chemosensitivity. The evidence for the translational control of thymidylate synthase, dihydrofolate reductase, and p53 will be presented, as will experimental data showing how disruptions in this important regulatory process can lead to the rapid emergence of cellular drug resistance.


The surgical approach can be determined from the pathological specimen obtained after open or robot-assisted laparoscopic radical prostatectomy.
To assess the surgical approach using the pathological specimen obtained after open radical prostatectomy (ORP) or robot-assisted radical prostatectomy (RALRP). A prospective study has been performed in patients who underwent either ORP or RALRP for localized prostate cancer. Two dedicated uro-pathologists, blinded to the surgeons and the operating rooms' schedules, analyzed the pathological specimens according to the Stanford protocol. Both pathologists also determined the surgical approach used based on several criteria pertaining to the pathological specimen. Overall, 117 patients with a median age of 63 years were included. The main characteristics (i.e., Gleason score, pTNM stage, preoperative PSA and margin) were comparable in both groups (p > 0.05). Pathologists 1 and 2 were able to significantly assess the surgical procedure from the pathological specimen provided (in 76.1 and 69.2 % of cases, respectively). Pathologist 1 had a better performance than pathologist 2 (AUC 0.75, IC 95 % [0.67-0.83] vs. AUC = 0.68 IC 95 % [0.59-0.77]) (p = 0.017). The κ index of the inter-observer agreement was satisfactory (0.76). In a univariate analysis, the criteria linked to the pathologist's assessment were as follows: macroscopic integrity of the specimen (p = 0.04), presence of periprostatic fat (p = 0.04), width of periprostatic tissue (p < 0.001) and nerve-sparing status (p < 0.001). It was possible to determine the surgical procedure from the analysis of the specimen obtained after a radical prostatectomy. In view of these data and from this perspective, one could infer that there are indeed oncological differences between the robotic and open approaches to radical prostatectomy.


A Modified Arthroscopic Outside-in Shoulder Release Approach for Severe Shoulder Stiffness.
Arthroscopic release is effective for patients with shoulder stiffness, but the traditional inside-out procedure cannot effectively alleviate the mobility of some severe stiff shoulder and even cause itrogenic injuries sometimes. The aim of this study is to evaluate the clinical efficacy and advantages of a modified outside-in shoulder release approach for severe shoulder stiffness. Included in this retrospective study were 15 patients (five male and 10 female) with severe shoulder stiffness who underwent modified outside-in shoulder release surgery at our hospital between June 2019 and March 2021. Of them, 10 patients had a primary frozen shoulder and five had secondary shoulder stiffness, involving the right shoulder in six cases and the left shoulder in nine cases. The mean age of the 15 patients was 56.7 (34-69) years. The patients were instructed to exercise passively from second-day post-operation and enhance the rehabilitation exercise gradually. All patients received a range of motion (ROM) examination before and after surgery. The American Shoulder and Elbow Surgeon's Score (ASES), Constant Score (CS), and Visual Analog Scale (VAS) score for pain were recorded. All data were tested by normal distribution first and then by paired T test, otherwise by Wilcoxon rank sum test. The mean follow-up period was 18.2 (12-33) months. Compared with the preoperative value, the mean ASES score at the final follow-up improved from 38.4 ± 7.37 to 88.13 ± 6.33 points; the mean CS score from 43.27 ± 6.71 to 78.74 ± 6.93 points; the mean VAS score from 5.07 ± 1.03 to 0.81 ± 0.83 points; forward flexion from 81.93° ± 11.45° to 156.73° ± 9.12°; abduction from 65.93° ± 16.82° to 144.80° ± 8.83°; neutral external rotation from 13.53° ± 10.38° to 51.20° ± 4.77°; internal rotation from the buttock to waist (L3), all showing a significant difference (P < 0.0001). No serious complication was observed in any patient during the postoperative follow-up periods. The present study has demonstrated that the modified arthroscopic outside-in shoulder release approach can improve ROM of patients and alleviate pain effectively, proving it to be an appropriate surgical option for the treatment of severe shoulder stiffness.


Yeast Pif1 helicase exhibits a one-base-pair stepping mechanism for unwinding duplex DNA.
Kinetic analysis of the DNA unwinding and translocation activities of helicases is necessary for characterization of the biochemical mechanism(s) for this class of enzymes. Saccharomyces cerevisiae Pif1 helicase was characterized using presteady state kinetics to determine rates of DNA unwinding, displacement of streptavidin from biotinylated DNA, translocation on single-stranded DNA (ssDNA), and ATP hydrolysis activities. Unwinding of substrates containing varying duplex lengths was fit globally to a model for stepwise unwinding and resulted in an unwinding rate of ∼75 bp/s and a kinetic step size of 1 base pair. Pif1 is capable of displacing streptavidin from biotinylated oligonucleotides with a linear increase in the rates as the length of the oligonucleotides increased. The rate of translocation on ssDNA was determined by measuring dissociation from varying lengths of ssDNA and is essentially the same as the rate of unwinding of dsDNA, making Pif1 an active helicase. The ATPase activity of Pif1 on ssDNA was determined using fluorescently labeled phosphate-binding protein to measure the rate of phosphate release. The quantity of phosphate released corresponds to a chemical efficiency of 0.84 ATP/nucleotides translocated. Hence, when all of the kinetic data are considered, Pif1 appears to move along DNA in single nucleotide or base pair steps, powered by hydrolysis of 1 molecule of ATP.


Risks of Topical Carbonic Anhydrase Inhibitors in Glaucoma Patients With Chronic Kidney Disease: A Nationwide Population-Based Study.
To investigate the risks of metabolic acidosis and renal outcomes after topical carbonic anhydrase inhibitor (CAI) use in patients with both primary open-angle glaucoma (POAG) and advanced chronic kidney disease (CKD). Nationwide, population-based cohort study. This study was conducted with population data from Taiwan's National Health Insurance (NHI) Research Database between January 2000 and June 2009. Patients with advanced CKD who were diagnosed with glaucoma (International Classification of Diseases, Ninth Revision [ICD-9] code 365) and had been receiving eye drops for glaucoma (including carbonic anhydrase inhibitors selected by NHI drug code) were enrolled. Using Kaplan-Meier methods, we compared the cumulative incidence of mortality, long-term dialysis, and cumulative incidence of metabolic acidosis over time between CAI users and CAI non-users. Primary outcomes comprised mortality, renal outcome (progression to hemodialysis), and metabolic acidosis. In this cohort, topical CAI users had a higher incidence of long-term dialysis than non-users (incidence = 1,216.85 vs 764.17 events per 100 patient-years; adjusted hazard ratio = 1.17, 95% CI = 1.01-1.37). Hospital admissions due to metabolic acidosis were higher in CAI users compared with non-users (incidence = 21.54 vs 11.87 events per 100 patient-years; adjusted hazard ratio = 1.89, 95% CI = 1.07-3.36). Topical CAIs may be associated with higher risks of long-term dialysis and metabolic acidosis in patients with POAG and pre-dialysis advanced CKD. Therefore, topical CAIs should be used with caution in advanced CKD patients.


MiR-135a-5p and Mst1 regulate MPP + -1 induced apoptosis and autophagy in Parkinson's disease model in vitro.
The mammalian Ste20-like kinases 1 (Mst1) is essential for regulating cell proliferation, differentiation, apoptosis, and autophagy. However, the molecular mechanisms of Mst1 in neuronal cell death remains incompletely understood. Here, we showed that Mst1 is up-regulated in Parkinson's disease (PD) model induced by MPP+. Knockdown of Mst1 resulted in a reduction in MPP+-induced apoptosis and autophagy in SH-SY5Y and CHP 212 cells. Mechanistically, Mst1 silencing suppressed autophagy by activating mTOR/ULK1/S6K1 pathway. We also showed that miR-135a-5p was lower while Mst1 was inversely higher in MPP+-treated cells. Furthermore, miR-135a-5p has a protective role on MPP+-induced neuronal cell death via targeting Mst1. On the whole, the miR-135a-5p/Mst1 axis might serve as a potential therapeutic target in PD treatment.


Enhancement in mechanical and antimicrobial properties of epoxidized natural rubber via reactive blending with chlorhexidine gluconate.
An epoxidized natural rubber (ENR) blend with chlorhexidine gluconate (CHG) was prepared using a two-roll mill at 130 °C. CHG was added at concentrations of 0.2, 0.5, 1, 2, 5, and 10% (w/w) as an antimicrobial additive. The ENR blend with 10% (w/w) CHG showed the best tensile strength, elastic recovery, and Shore A hardness. The ENR/CHG blend exhibited a smooth fracture surface. The appearance of a new peak in the Fourier transform infrared spectrum confirmed that the amino groups of CHG reacted with the epoxy groups of ENR. The ENR with 10% CHG exhibited an inhibition zone against Staphylococcus aureus. The proposed blending improved the mechanical properties, elasticity, morphology, and antimicrobial properties of the ENR.


Airway pathology in severe asthma is related to airflow obstruction but not symptom control.
Patients with asthma present structural and inflammatory alterations that are believed to play a role in disease severity. However, airway remodeling and inflammation have not been extensively investigated in relation to both symptom control and airflow obstruction in severe asthmatics. We aimed to investigate several inflammatory and structural pathological features in bronchial biopsies of severe asthmatics that could be related to symptom control and airflow obstruction after standardized treatment. Fifty severe asthmatics received prednisone 40 mg/d for 2 weeks and maintenance therapy with budesonide/formoterol 400/12 μg twice daily + budesonide/formoterol 200/6 μg as needed for 12 weeks. Endobronchial biopsies were performed at the end of 12 weeks. We performed extensive immunopathological analyses of airway tissue inflammation and remodeling features in patients stratified by asthma symptom control and by airflow obstruction. Airway tissue inflammation and remodeling were not associated with symptom control. Asthmatics with persistent airflow obstruction had greater airway smooth muscle (Asm) area with decreased periostin and transforming growth factor beta-positive cells within Asm bundles, in addition to lower numbers of chymase-positive mast cells in the submucosa compared to patients with nonpersistent obstruction. Symptom control in severe asthmatics was not associated with airway tissue inflammation and remodeling, although persistent airflow obstruction in these patients was associated with bronchial inflammation and airway structural changes.


Effects of leukotrienes on isolated guinea-pig pulmonary arteries.
Leukotrienes C4 (LTC) and D4 (LTD) produced contractions of the isolated guinea-pig pulmonary arteries, but were much less potent in these segments than in the isolated trachea and parenchymal strip from the same species. Among the arterial segments, the leukotrienes were more effective in contracting the distal end of the main pulmonary artery than the arterial branches. FPL55712 was an effective competitive antagonist of LTC, but not LTD, in the arterial segments. The data suggest that the pulmonary arteries may possess leukotriene receptors which differ from those of airway smooth muscle.


Metalloenzymes: Cutting out the middleman.
In vivo, hydrogenases require maturases for active site incorporation. However, in vitro, an active site model with limited catalytic activity could be incorporated into the apo form of [FeFe]-hydrogenase without the aid of maturases, generating enzyme with native activity.


Full face laser resurfacing: therapy and prophylaxis for actinic keratoses and non-melanoma skin cancer.
Although there are many effective treatment modalities for individual actinic keratoses (AKs), widespread lesions on the photoaged face pose a challenge due to inefficient and ineffective therapy resulting in high rates of recurrence after local destruction. Full face laser resurfacing offers an effective and efficient treatment option that successfully reduces the number of AK's on diffusely damaged skin and may show a prophylactic benefit for preventing non-melanoma skin cancers. To assess the efficacy of full face laser resurfacing in reducing the number of facial AK's by comparing preoperative and postoperative numbers of lesions present and to observe the incidence of non-melanoma skin cancer after full face laser resurfacing. A retrospective chart review of 24 patients with widespread facial AK's (greater than 30) treated with full face UPCO(2) and/or Er:Yag laser resurfacing was performed. All patients were a minimum of 1 year post-operative following facial laser resurfacing. The recurrence of AK's and the occurrence of facial non-melanoma skin cancers in these patients was assessed through chart analysis. Widespread AK's were effectively eliminated in all patients. Twenty-one patients (87%) remained lesion free for at least 1 year. Fourteen of the 24 patients (58.3%) showed no new lesions during a 2-year follow-up. There was an overall 94% reduction in total number of AK's. Adverse effects included transient perioral scarring in one patient, S. aureus infection in two patients, and dyschromia in two patients. Full face laser resurfacing provides long-term effective prophylaxis against AKs and may reduce the incidence of AK related squamous cell carcinoma.


Renal extravasation of urine due to bladder outflow obstruction.
Spontaneous extravasation of urine from the kidney is uncommon. The majority of cases in adults are associated with ureteral calculi, while in children the condition is associated with urethral valves of ureteropelvic junction obstruction.


Metalloproteinases and their natural inhibitors in inflammation and immunity.
Over the past 50 years, steady growth in the field of metalloproteinase biology has shown that the degradation of extracellular matrix components represents only a fraction of the functions performed by these enzymes and has highlighted their fundamental roles in immunity. Metalloproteinases regulate aspects of immune cell development, effector function, migration and ligand-receptor interactions. They carry out ectodomain shedding of cytokines and their cognate receptors. Together with their endogenous inhibitors TIMPs (tissue inhibitor of metalloproteinases), these enzymes regulate signalling downstream of the tumour necrosis factor receptor and the interleukin-6 receptor, as well as that downstream of the epidermal growth factor receptor and Notch, which are all pertinent for inflammatory responses. This Review discusses the metalloproteinase family as a crucial component in immune cell development and function.


Child Health Advocacy: The Journey to Antiracism.
The last several years have seen accelerated activity and discourse directed at antiracism. Specifically following the 2020 murder of George Floyd, institutions across the country engaged in a range of introspective exercises and transparent reckonings examining their practices, policies, and history insofar as equity and racism is concerned. The authors of this article, both active protagonists in this domain, have been, and continue to be, part of ongoing national efforts and have learned much about the strategies and tactics necessary to initiate, engage, and sustain traction on the path to antiracism.