Inflammatory parameters and color alterations of dental bleaching in patients wearing fixed orthodontic appliance: a randomized clinical trial.
Many orthodontic patients request dental bleaching during orthodontic treatment to achieve a faster aesthetic resolution, however, no attention has been paid to the inflammatory processes that can occur when both therapies are indicated together. So, this clinical trial evaluated the inflammatory parameters and color alterations associated with dental bleaching in patients wearing a fixed orthodontic appliance. Thirty individuals aged between 18 and 40 years were equally and randomly allocated into three groups: FOA (fixed orthodontic appliance), BLE (dental bleaching), and FOA + BLE (fixed orthodontic appliance + dental bleaching). The orthodontic appliances and the bleaching procedures were performed in the maxillary premolars and molars. For dental bleaching a 35% hydrogen peroxide was used. The gingival crevicular fluid (GCF) and nitric oxide (NO-) levels were evaluated at different time-points. Color evaluation was performed using an Easyshade spectrophotometer at baseline (FOA, FOA + BLE, BLE), one month after (FOA + BLE) and 21 days after appliance removing (FOA + BLE and FOA groups), in each tooth bleached. The ANOVA and Tukey's tests, with a significance level of 5%, were used for statistical analysis. The GCF volume in the FOA + BLE and FOA groups significantly increased at the time points evaluated (p < 0.001); however, this did not occur in the BLE group (p > 0.05). On the other hand, NO- levels significantly decreased during dental bleaching with or without fixed orthodontic appliances (FOA + BLE and BLE groups; p < 0.05), while no significant changes were observed in the FOA group (p > 0.05). Significant changes in color were observed in the FOA + BLE and BLE groups compared to in the FOA group (p < 0.01). However, the presence of fixed orthodontic appliance (FOA + BLE) negatively affected the bleaching efficacy compared to BLE group (p < 0.01). Dental bleaching did not increase the inflammatory parameters in patients wearing fixed orthodontic appliance. However, in the presence of orthodontic appliances, the bleaching efficacy was lower than that of bleaching teeth without orthodontic appliances. RBR-3sqsh8 (first trial registration: 09/07/2018).


Structure-activity studies on the corticotropin releasing factor antagonist astressin, leading to a minimal sequence necessary for antagonistic activity.
Corticotropin Releasing Factor (CRF) antagonists are considered promising for treatment of stress-related illnesses such as major depression and anxiety-related disorders. We report here the design, synthesis and biological evaluation of 91 truncated astressin analogues in order to deduce the pharmacophoric amino acid residues. Such truncated peptides may serve as valuable lead structures for the development of new small, non-peptide-based CRF antagonists. N-Terminal truncation of astressin led to active CRF antagonists that are substantially reduced in size and are selectively active at the human CRF receptor type 1 in vitro and in vivo. Subsequently, an alanine scan in combination with further truncated derivatives led to the proposal of a new pharmacophoric model of peptide-based CRF antagonists. It was found that the astressin(27-41)C sequence is the shortest active CRF antagonist. The first eight N-terminal amino acid residues were found to be an important structural determinant and were replaceable by alanine residues, thus enhancing the alpha-helical propensity. A covalent structural constraint is of utmost importance for the preorganization of the C-terminal amino acid residues. The C-terminal heptapeptide sequence, however, was found to be crucial for the antagonistic activity, since substitution or deletion of any residue led to inactive compounds.


The Role of Tissue Biopsy in the Management of Immune Checkpoint Inhibitor Toxicity.
Immune checkpoint inhibitors have revolutionized the treatment of cancer and are now omnipresent. However, immune-related adverse events can present with varying phenotypes and timing, which can pose diagnostic and therapeutic challenges for the treating oncologist as well as subspecialty consultants. Biopsies of affected organs may provide insight into biologic mechanisms as well as potentially guide management in certain circumstances.


Physical dependence on diazepam: precipitation of abstinence syndromes by peripheral and central benzodiazepine receptor antagonists.
This work was performed to compare withdrawal symptoms induced by the administration of the central vs. peripheral benzodiazepine antagonists in rats treated chronically with diazepam (15 mg/kg, SC) for 8 days. Withdrawal was expressed as motor, autonomic, and behavioral signs. Significant withdrawal occurred after the administration of both flumazenil (15 and 20 mg/kg, IP) and PK11195 (5 and 10 mg/kg, IP). With these doses, PK11195 induced diarrhea and decreased motor activity more than did flumazenil. These preliminary results suggest that peripheral benzodiazepine receptors are involved in the withdrawal syndrome in diazepam-dependent rats.


Electrode montage dependent effects of transcranial direct current stimulation on semantic fluency.
Transcranial direct current stimulation (tDCS) has proved to be valuable in improving many language processes. However, its influence on verbal fluency still needs to be fully proved. In the present study, we explored the effects of different electrode montages on a semantic fluency task, aimed at comparing their effectiveness in affecting language production. Ninety healthy, right-handed volunteers were randomly assigned to receive one of the following stimulation protocols: (1) anode over the left frontal cortex/cathode over the right supraorbital (rSO) area, (2) anode over the left fronto-temporal (lFT) cortex/cathode over the rSO area, (3) anode over the lFT cortex/cathode over the right FT cortex, (4) anode over the lFT cortex/big-size cathode over the rSO area, (5) sham. In the active stimulation conditions, 2 mA current was delivered for 20 min. Participants performed the semantic fluency task before the stimulation, immediately after it, and 15 min after the first post-stimulation task. Although none of the different protocols improved language production immediately after the stimulation, anodal stimulation over the left frontal cortex (standard-size cathode over the rSO area) improved fluency at the second post-stimulation task. This proved that small differences in either active electrode positioning, or reference positioning/size can impact tDCS behavioral effects also in the cognitive domain. These findings, which can be sometimes missed when tested immediately after the stimulation only, add new information on tDCS spatial and temporal features, thus providing new indications to increase the effectiveness of stimulation protocols.


Practice Expectations Compared to Reality for Women in Urology: A National Survey.
We determined the patient gender distribution for practicing male and female urologists in the U.S. compared to current resident expectations. Two mirrored surveys were distributed to AUA members practicing in the U.S. Questions were asked regarding years in training and practice, subspecialty, gender representation of patients and job satisfaction. Answer choices were based on a 5-point balanced Likert scale. Overall there were 894 respondents, including 704 practicing urologists and 190 urology residents, of whom women accounted for 14%. This figure reflects current AUA demographic data. Only 15.2% of female residents expected that once in practice more than 60% of their patients would be women compared to 45.5% of practicing female physicians who indicated that more than 60% of their patients are women. When stratified by fellowship training the 38.5% of female physicians who were trained in a specialty other than female pelvic medicine and reconstructive surgery and pediatrics still most commonly saw more than 60% female patients compared to 0.8% of male physicians. Overall satisfaction with the gender balance of patients was 76.0% for female physicians and 70.9% for male physicians. Female urologists report seeing greater numbers of female patients than their male counterparts and specialty training only modestly alters this gap. Current female residents may underestimate the number of women they will eventually see in practice based on current trends in our survey. However, overall satisfaction with the gender balance of patients seen is high.


Sleeve lobectomy by video-assisted thoracic surgery versus thoracotomy for non-small cell lung cancer.
Both video-assisted thoracic surgery (VATS) and thoracotomy are used for sleeve lobectomy for patients with non-small cell lung cancer (NSCLC). This retrospective study aimed to assess the safety and efficacy of VATS sleeve lobectomy for NSCLC patients. Between May 2009 and May 2013, 51 sleeve lobectomies (10 by VATS and 41 by thoracotomy) were performed for patients with NSCLC. Operative characteristics and postoperative course were compared between two groups. Patient demographics were similar between the two groups. Thoracotomy patients had larger tumors compared with VATS patients (p = 0.02). VATS patients had a longer operating time (p < 0.001) but a shorter length of postoperative hospital stay (p = 0.009). The two groups did not differ in pathologic stage, histologic results, blood loss, ICU stay, amount of chest drainage, duration of chest drainage, numbers and distributions of dissected lymph nodes and the occurrence of complications. There were no perioperative deaths in the VATS group, whereas there was one death (2.4 %) in the thoracotomy group. There were no conversions to thoracotomy in the VATS group. The overall median survival between the two groups was similar (3.2 years VATS versus 3.2 years thoracotomy, log-rank p = 0.58). VATS sleeve lobectomy for the treatment of NSCLC is technically feasible and safe and is associated with comparable complication rates and survival compared with thoracotomy approach, but it deserves further investigation in large series.


Physicochemical characterization and pharmacokinetics evaluation of β-caryophyllene/β-cyclodextrin inclusion complex.
β-Caryophyllene (BCP), a natural sesquiterpene existing in the essential oil of many plants, has exhibited a wide range of biological activities. However, its volatility and poor water-solubility limit its application in pharmaceutical field. β-Cyclodextrin (β-CD) has intrinsic ability to form specific inclusion complexes with different drugs to enhance their stability, solubility and bioavailability. The aim of this study is to investigate and compare the oral bioavailability and the pharmacokinetics of free BCP and BCP/β-CD inclusion complex after a single oral dose of 50mg/kg on rats. A simple, rapid, and sensitive gas chromatography-mass spectrometry method in selected ion monitoring (GC-MS/SIM) mode was developed on determination of BCP in rat plasma. The in vivo data showed that BCP/β-CD inclusion complex displayed earlier Tmax, higher Cmax and the AUC0-12h was approximately 2.6 times increase than those of free BCP. These results demonstrated that BCP/β-CD inclusion complex has significantly increased the oral bioavailability of the drug in rats than free BCP.


Insulinoma-associated protein 1 immunostaining for various types of neuroendocrine tumors on FNA smears.
Insulinoma-associated protein 1 (INSM1) has recently emerged as a reliable nuclear immunostaining marker for detecting neuroendocrine tumors (NETs) in paraffin-embedded surgical samples and cytologic cell blocks, but the reliability of INSM1 staining on cytologic smears is understudied. This study investigated the performance of INSM1 staining on cytologic smears for the detection of various NETs in comparison with chromogranin (CG) and synaptophysin (SYN). INSM1, CG, and SYN were stained on cytologic smears of 70 NETs, including 20 pancreatic NETs, 10 lung carcinoid tumors, 11 small cell lung carcinomas (SCLCs), 10 medullary thyroid carcinomas, 10 Merkel cell carcinomas, 4 thymic atypical carcinoid tumors, and 5 olfactory neuroblastomas. The detection rate, the percentage of positive cells, and the staining intensity were recorded. The overall detection rate of INSM1 (94%) was higher than the rates of CG (79%) and SYN (89%). The detection rate of INSM1 was higher than the rates of CG and SYN in SCLC, Merkel cell carcinoma, and olfactory neuroblastoma; higher than the rate of CG and equal to the rate of SYN in pancreatic NETs and medullary thyroid carcinoma; equal to the rate of CG and higher than the rate of SYN in thymic atypical carcinoid tumors; and equal to the rate of CG and lower than the rate of SYN in lung carcinoid tumors. INSM1 staining was easier to interpret than CG and SYN staining, especially in high-grade NETs. INSM1 can be reliably stained on cytologic smears and outperforms CG and SYN in the verification of clinically or radiologically suspected NETs.


Associations of complete blood count parameters with pancreatic beta-cell function and insulin resistance in prediabetes and type 2 diabetes mellitus.
Previous studies found controversial associations of CBC parameters with pancreatic beta-cell function (BCF) and insulin resistance (IR). The aim of this was to determine the independent associations of CBC parameters with BCF and IR in prediabetes and type 2 diabetes mellitus (T2DM). This study selected subjects who underwent health checkups at 16 health-promotion centers in 13 Korean cities during 2021. The subjects comprised 1470 patients with normoglycemia, 1124 with prediabetes, and 396 with T2DM. BCF and IR were assessed using the homeostasis model assessment (HOMA)-β and HOMA-IR, respectively. Correlation and multiple linear regression analyses were used to determine the correlation between CBC parameters and HOMA. While HOMA-IR gradually increased according to red blood cell count quartiles (1.22, 1.40, 1.47, and 1.91, in the first, second, third, and fourth quartiles, respectively; p < 0.001), there was no correlation after adjusting for waist circumference (WC) and HbA1c. The red blood cell distribution width (RDW) was associated with HOMA-β [coefficient (β) = 15.527, p = 0.002], but not with HOMA-IR. White blood cells (WBCs) were associated with HOMA-IR and HOMA-β, which was stronger in HOMA-β (β = 0.505 vs 15.171, p = 0.002) after adjusting for WC and HbA1c. The platelet count was correlated with HOMA-IR and HOMA-β, which only remained in HOMA-β (β = 15.581, p = 0.002) after adjusting for WC and HbA1c. RDW, WBC, and platelet counts were independently associated with only HOMA-β in prediabetes and T2DM. This suggests that these CBC parameters could represent BCF in prediabetes and T2DM.


Identification of cutaneous arteries of the perineal and caudal thigh region: A cadaveric study in 12 cats.
To describe the location of the dorsal perineal artery in cats and identify landmarks for axial pattern flaps based on this vessel. Anatomic study. Twelve feline cadavers. Nonselective barium sulfate angiography was performed via injection of the descending aorta. Skin excised from the perineum and thighs was evaluated via gross inspection and radiography to identify angiosomes. The dorsal perineal artery had a robust angiosome on the caudal thigh in 10 of 12 cadavers. The artery exited the ischiorectal fossa along the muscular furrow between the biceps femoris and semitendinosus muscles and passed sagittally toward the popliteal fossa in those 10 specimens. All cadavers had a consistent angiosome based on the ventral perineal artery, which was located on the caudomedial thigh. All cadavers also had a consistent angiosome from a cutaneous branch of the popliteal artery, which traveled in a distal to proximal direction starting at the popliteal fossa. The dorsal perineal artery had a large cutaneous angiosome on the caudal thigh, which was consistent in most cats. The ventral perineal artery and cutaneous branch of the popliteal artery had consistent but smaller cutaneous angiosomes. The axial pattern flaps of the cutaneous branches of the dorsal and ventral perineal arteries and the popliteal artery provide a robust arterial blood supply to the skin of the perineum and the caudal thigh. These three flaps may therefore have adequate vascular supply to consistently survive in most cats.


Sputum peroxidase activity correlates with the severity of lung disease in cystic fibrosis.
Patients with cystic fibrosis (CF) of the same age differ significantly in their degree of pulmonary disease. Based on preliminary observations, we postulated that the activity of myeloperoxidase would be significantly increased in patients with greater structural lung damage than in those with less lung damage. Acid extracts of weighed sputum samples were assayed for lactoferrin concentrations by ELISA. Activities of peroxidase, cathespsin G, and elastase (with and without proteinase 3) were determined by kinetic analysis using chromogenic substrates. The patients were divided into quartiles based on their Brasfield chest-radiograph score. Patients in the first quartile (least amount of structural lung abnormality) were compared to those in the fourth quartile. The concentration of lactoferrin, a specific (secondary) granule protein of neutrophils, did not differ between the two patient groups. However, the activities of the neutrophil primary granule proteins, peroxidase, elastase, and elastase plus proteinase 3, were significantly elevated in the group with the most structural lung abnormality. Sputum albumin concentration was used to estimate leakages of plasma proteins into the airways. Peroxidase activity, but not the activity of cathepsin G, of elastase, or of elastase plus proteinase 3, correlated significantly with albumin/g sputum in both quartile groups. To confirm the association of sputum peroxidase activity with differences in lung structure and to test its correlation with lung function, spirometry was performed in a second group of patients during the week prior to the time of sputum sampling. In this second group, increased sputum peroxidase activity was associated with worse Brasfield scores and with decreased percent-predicted forced expiratory volume in 1 sec.(ABSTRACT TRUNCATED AT 250 WORDS)


The E Sibling Project - exploratory randomised controlled trial of an online multi-component psychoeducational intervention for siblings of individuals with first episode psychosis.
Siblings of individuals with first episode psychosis are natural partners to promote service users' recovery and are themselves vulnerable to mental ill health due to the negative impact of psychosis within the family. This study aims to develop and undertake a preliminary evaluation of the efficacy of an online multi-component psychoeducational intervention for siblings of individuals with first episode psychosis. The impetus for the intervention arose from siblings' expressed needs for peer support and information on psychosis, coping and management strategies for common symptoms and ways to promote recovery. The project design draws on the Medical Research Council framework for the design and evaluation of complex interventions. Mixed methods comprising collection of qualitative focus group data, systematic review and expert advisory group consultation are used to develop the theoretical basis for and design of the intervention. This protocol focuses on the modelling and piloting phase which uses a randomised controlled trial with factorial design to test the efficacy of the intervention. Outcome data on participants' mental wellbeing, knowledge, perceived self-efficacy and experiences of caregiving will be assessed at baseline, at end of the intervention (10 weeks later) and at 10 week follow-up. In addition, a post-intervention semi-structured interview with 20% of the participants will explore their experiences and acceptability of the intervention. This multi-component online psychoeducational intervention aims to enhance siblings' knowledge about psychosis and their coping capacity, thus potentially improving their own mental wellbeing and promoting their contribution to service users' recovery. The factorial design randomised controlled trial with a supplementary process evaluation using semi-structured interviews and usage-monitoring will collect preliminary evidence of efficacy, feasibility and acceptability, as well as feedback about the barriers and strategies to using such an innovative resource. The RCT will provide data for estimating the likely effect size of the intervention on outcomes for siblings and inform the development of a definitive future trial. Trial registration: ISRCTN01416694.


A Modified Approach for Ultrasound-Guided Thoracic Paravertebral Block via Thoracic Intervertebral Foramen in an Adolescent Patient: A Case Report.
This case report describes a modified approach for a thoracic paravertebral block by performing a bilateral ultrasound-assisted injection of 12 mL of 0.5% levobupivacaine near the thoracic intervertebral foramen, combined with general anesthesia, in a patient who underwent emergent laparotomy for small intestinal volvulus. Two continuous catheter sets were used for a bilateral continuous block with levobupivacaine 0.25% at a rate of 5-8 mL/h. No complications during the execution of the block were recorded. No supplemental opioids were administered and the patient was hemodynamically stable, requiring no pharmacological cardiovascular support during surgery. At the end of the surgical procedure, the patient received a continuous flow of 0.2% levobupivacaine as postoperative analgesia, at a basal flow of 4 mL/h per each side, a bolus of 4 mL, and a lockout time of 60 min was used. The postoperative pain on the Numeric Rating Scale was 2 at rest and it was 4 in motion, without neurological or respiratory sequelae due to block in the first 72 h after surgery.


Amygdala hyperactivation during face emotion processing in unaffected youth at risk for bipolar disorder.
Youth at familial risk for bipolar disorder (BD) show deficits in face emotion processing, but the neural correlates of these deficits have not been examined. This preliminary study tests the hypothesis that, relative to healthy comparison (HC) subjects, both BD subjects and youth at risk for BD (i.e., those with a first-degree BD relative) will demonstrate amygdala hyperactivation when viewing fearful and happy faces. The at-risk youth were unaffected, in that they had no history of mood disorder. Amygdala activity was examined in 101 unrelated participants, 8 to 18 years old. Age, gender, and IQ-matched groups included BD (N = 32), unaffected at-risk (N = 13), and HC (N = 56). During functional magnetic resonance imaging, participants attended to emotional and nonemotional aspects of fearful and happy faces. While rating their fear of fearful faces, both BD and unaffected at-risk subjects exhibited amygdala hyperactivity versus HC. There were no between-group differences in amygdala activity in response to happy faces. Post-hoc comparisons revealed that, in at-risk youth, familial risk status (offspring versus sibling), presence of Axis I diagnosis (n = 1 attention-deficit/hyperactivity disorder [ADHD], n = 1 social phobia), and history of medication exposure (n = 1) did not influence imaging findings. We found amygdala hyperactivation in both unaffected at-risk and BD youth while rating their fear of fearful faces. These pilot data suggest that both face emotion labeling deficits and amygdala hyperactivity during face processing should receive further study as potential BD endophenotypes. Longitudinal studies should test whether amygdala hyperactivity to fearful faces predicts conversion to BD in at-risk youth.


miRNA regulated pathways in late stage murine lung development.
MicroRNAs play important roles in regulating biological processes, including organ morphogenesis and maturation. However, little is known about specific pathways regulated by miRNA during lung development. Between the canalicular and saccular stages of the developing lung several important cellular events occur, including the onset of surfactant synthesis, microvascular remodeling and structural preparation for subsequent alveolarization. The miRNAs that are actively regulated, and the identity of their targets during this important developmental interval in the lung remain elusive. Using TLDA low density real-time PCR arrays, the expression of 376 miRNAs in male and female fetal mouse lungs of gestational days E15 - E18 were profiled. Statistical analyses identified 25 and 37 miRNAs that changed significantly between sexes and with gestation, respectively. In silico analysis using Ingenuity Pathway Analysis (IPA) identified specific pathways and networks known to be targets of these miRNAs which are important to lung development. Pathways that are targeted by sex regulated miRNAs include retinoin, IGFR1, Tp53 and Akt. Pathways targeted by gestation-regulated miRNAs include VEGFA and mediators of glucose metabolism. MiRNAs are differentially regulated across time and between sexes during the canalicular and saccular stages of lung development. Sex-associated differential miRNA expression may regulate the differences in structural and functional male and female lung development, as shown by networks generated using in silico analysis. These data provide a valuable resource to further enhance the understanding of miRNA control of lung development and maturation.


Novel myokine: irisin may be an independent predictor for subclinic atherosclerosis in Behçet's disease.
Behçet's disease (BD) is a vasculitic and inflammatory disease causing endothelial dysfunction. Irisin is a metabolic hormone related to insulin resistance and endothelial functions. In this study, we investigated the relationship between irisin and carotid intima-media thickness (cIMT), which is a marker of atherosclerosis in patients with BD. 48 patients with BD and 50 healthy individuals were enrolled in the study. Disease severity was evaluated by BD current activity form. Irisin, glucose, insulin, C reactive protein, erythrocyte sedimentation rate and lipid panel were examined in all patients. Homeostasis Model Assessment of Insulin Resistance (HOMA-IR) was used to calculate insulin resistance. A simple and inexpensive cIMT test was used as indicator of atherosclerosis. cIMT was 0.62 (0.45-1.05) mm in the patients, while it was 0.38 (0.25-0.65) mm in the control group (p < 0.001). Irisin value was found to be 197.3 (24.8-834.2) ng/mL in the control group, while it was 85.4 (4.7-471.1) ng/mL in the patient group (p = 0.007). There was a negative correlation between irisin level and cIMT (r = -0.511, p < 0.001) and HOMA-IR (r = -0.371, p = 0.009). Decreased irisin levels (OR 0.996, 95% CI 0.992 to 1.000, p = 0.041), male gender (OR 7.634, 95% CI 1.415 to 41.191, p = 0.018), and HOMA-IR (OR 2.596, 95% CI 1.451 to 4.643, p = 0.001) are independent risk factors for cIMT in patients with BD. We detected a very strong relationship between cIMT, which is an indicator of subclinical atherosclerosis, and decreased irisin levels in patients with BD. BD is characterized by chronic inflammation, and low serum irisin levels in BD may be related to atherosclerosis.


Predicting autism at birth.
The amounts of at least three biochemical factors are more often abnormal in autistic people than neurologically normal ones. They include insulin-like growth factor, anti-myelin basic protein, and serotonin. This may explain why processes initiated in utero which hinder normal neurogenesis, especially myelination, continue after delivery. Quantitation of these parameters may make possible the calculation of an autism index, anticipating at birth which children will ultimately develop overt autism.


Regression of drug-resistant lung cancer by the combination of rosiglitazone and carboplatin.
Current therapy for lung cancer involves multimodality therapies. However, many patients are either refractory to therapy or develop drug resistance. KRAS and epidermal growth factor receptor (EGFR) mutations represent some of the most common mutations in lung cancer, and many studies have shown the importance of these mutations in both carcinogenesis and chemoresistance. Genetically engineered murine models of mutant EGFR and KRAS have been developed that more accurately recapitulate human lung cancer. Recently, using cell-based experiments, we showed that platinum-based drugs and the antidiabetic drug rosiglitazone (PPARgamma ligand) interact synergistically to reduce cancer cell and tumor growth. Here, we directly determined the efficacy of the PPARgamma/carboplatin combination in these more relevant models of drug resistant non-small cell lung cancer. Tumorigenesis was induced by activation of either mutant KRAS or EGFR. Mice then received either rosiglitazone or carboplatin monotherapy, or a combination of both drugs. Change in tumor burden, pathology, and evidence of apoptosis and cell growth were assessed. Tumor burden remained unchanged or increased in the mice after monotherapy with either rosiglitazone or carboplatin. In striking contrast, we observed significant tumor shrinkage in mice treated with these drugs in combination. Immunohistochemical analyses showed that this synergy was mediated via both increased apoptosis and decreased proliferation. Importantly, this synergy between carboplatin and rosiglitazone did not increase systemic toxicity. These data show that the PPARgamma ligand/carboplatin combination is a new therapy worthy of clinical investigation in lung cancers, including those cancers that show primary resistance to platinum therapy or acquired resistance to targeted therapy.


Bone morphogenetic proteins BMP-6 and BMP-7 have differential effects on survival and neurite outgrowth of cerebellar granule cell neurons.
The bone morphogenetic proteins (BMPs) play an inductive role in the generation of cerebellar granule cells embryonically. Therefore, we chose to look at their effects on cerebellar granule cell survival and differentiation postnatally. The cells express mRNA for both BMP-6 and BMP-7, as well as for the receptors BMPRIA and BMPRII, demonstrating that the postnatal cells have the ability to form the heterodimer receptors needed to respond to BMPs. BMP-7 promotes cell survival, with a maximal effect at 10 ng/ml, whereas tenfold more BMP-6 is needed: Both were active over the course of 8 days in culture. In addition, both BMPs were able to protect the neurons against death from induced apoptosis (exposure to serum-free, low-potassium medium) or exposure to glutamate. However, only BMP-6 could stimulate neurite outgrowth, measured with a neurofilament ELISA, an effect that was seen over the first 6 days in culture. These results, taken together with others in the literature, suggest that the BMPs have strong neurotrophic effects that are both neuron specific and BMP specific.


Rokitansky's syndrome in association with reno-ureteral abnormalities. Teratogenic period.
A case of Rokitansky's syndrome in association with complete duplication of the right upper urinary tract is presented. From a chronological point of view, the morphogenetic processes of the urinary and genital tract are analyzed. It is supposed that the congenital abnormality is produced between the 30th and 37th day of gestation, because reno-ureteral duplication appears at 30-32 days and involution of the Müllerian structures appears at 37 days.


Mucormycosis (black fungus) in COVID-19 patients-Will it be another matter of concern in the midst of the COVID-19 flare-up in Bangladesh?
Many countries of the world have been combating the new variant of severe acute respiratory syndrome coronavirus 2. Black fungus is an opportunistic foe that may cause fatal infection in immunocompromised and steroid-treated coronavirus disease 2019 (COVID-19) patients. The COVID-19 associated mucormycosis (CAM) is now a serious concern throughout the world, including many Asian countries. Therefore, along with early and accurate diagnostic facilities, special care, and prompt, but coordinated approach are recommended to combat the CAM in patients.


Electronic Structure Engineering of Single-Atom Ru Sites via Co-N4 Sites for Bifunctional pH-Universal Water Splitting.
The development of bifunctional water-splitting electrocatalysts that are efficient and stable over a wide range of pH is of great significance but challenging. Here, an atomically dispersed Ru/Co dual-sites catalyst is reported anchored on N-doped carbon (Ru/Co-N-C) for outstanding oxygen evolution reaction (OER) and hydrogen evolution reaction (HER) in both acidic and alkaline electrolytes. The Ru/Co-N-C catalyst requires the overpotential of only 13 and 23 mV for HER, 232 and 247 mV for OER to deliver a current density of 10 mA cmgeo -2 in 0.5 m H2 SO4 and 1 m KOH, respectively, outperforming benchmark catalysts Pt/C and RuO2 . Theoretical calculations reveal that the introduction of Co-N4 sites into Ru/Co-N-C efficiently modify the electronic structure of Ru by enlarging Ru-O covalency and increasing Ru electron density, which in turn optimize the bonding strength between oxygen/hydrogen intermediate species with Ru sites, thereby enhancing OER and HER performance. Furthermore, the incorporation of Co-N4 sites induces electron redistribution around Ru-N4, thus enhancing corrosion-resistance of Ru/Co-N-C during acid and alkaline electrolysis. The Ru/Co-N-C has been applied in a proton exchange membrane water electrolyzer and steady operation is demonstrated at a high current density of 450 mA cmgeo -2 for 330 h.


Exogenous artificial DNA forms chromatin structure with active transcription in yeast.
Yeast artificial chromosomes (YACs) are important tools for sequencing, gene cloning, and transferring large quantities of genetic information. However, the structure and activity of YAC chromatin, as well as the unintended impacts of introducing foreign DNA sequences on DNA-associated biochemical events, have not been widely explored. Here, we showed that abundant genetic elements like TATA box and transcription factor-binding motifs occurred unintentionally in a previously reported data-carrying chromosome (dChr). In addition, we used state-of-the-art sequencing technologies to comprehensively profile the genetic, epigenetic, transcriptional, and proteomic characteristics of the exogenous dChr. We found that the data-carrying DNA formed active chromatin with high chromatin accessibility and H3K4 tri-methylation levels. The dChr also displayed highly pervasive transcriptional ability and transcribed hundreds of noncoding RNAs. The results demonstrated that exogenous artificial chromosomes formed chromatin structures and did not remain as naked or loose plasmids. A better understanding of the YAC chromatin nature will improve our ability to design better data-storage chromosomes.


Assignment of the nonexchanging protons of the alpha-spectrin SH3 domain by two- and three-dimensional 1H-13C solid-state magic-angle spinning NMR and comparison of solution and solid-state proton chemical shifts.
The assignment of nonexchanging protons of a small microcrystalline protein, the alpha-spectrin SH3 domain (7.2 kDa, 62 residues), was achieved by means of three-dimensional (3D) heteronuclear (1H-13C-13C) magic-angle spinning (MAS) NMR dipolar correlation spectroscopy. With the favorable combination of a high B(0)-field, a moderately high spinning frequency, and frequency-switched Lee-Goldburg irradiation applied during 1H evolution, a proton linewidth < or =0.5 ppm at 17.6 Tesla was achieved for the particular protein preparation used. A comparison of the solid-state 1H chemical shifts with the shifts found in solution shows a remarkable similarity, which reflects the identical protein structures in solution and in the solid. Significant differences between the MAS solid- and liquid-state 1H chemical shifts are only observed for residues that are located at the surface of the protein and that exhibit contacts between different SH3 molecules. In two cases, aromatic residues of neighboring SH3 molecules induce pronounced upfield ring-current shifts for protons in the contact area.


Evolution and transcription of old world monkey globin genes.
Although apparently inactive in the whole animal, the delta globin genes from three species of Old World monkey (rhesus, baboon and green monkey) are all functional in an in vitro transcription assay. Their activities in vitro are similar to that of the functional human delta gene. A fourth monkey gene, from the colobus monkey, is transcribed approximately fivefold less efficiently than the others. This reduced in vitro activity results from a 20 base-pair deletion, which removes the normal site of mRNA initiation. When the deletion is repaired by site-directed mutagenesis, transcriptional activity increases to the level observed for the other delta genes. We also report the complete nucleotide sequences of the colobus beta, colobus delta, and rhesus delta genes. Sequence comparisons show that the delta and beta genes in the same species have not exchanged genetic information since the divergence of the human and monkey lineages. Phylogenetic analysis of these sequences affirms that the Old World monkey delta genes are evolving more rapidly than their functional counterparts. Moreover, the rate of replacement substitutions has risen to equal that of non-coding DNA, as expected for genes no longer under selective constraint.


Targeting of heparanase-modified syndecan-1 by prosecretory mitogen lacritin requires conserved core GAGAL plus heparan and chondroitin sulfate as a novel hybrid binding site that enhances selectivity.
Cell surface heparan sulfate (HS) proteoglycans shape organogenesis and homeostasis by capture and release of morphogens through mechanisms largely thought to exclude the core protein domain. Nevertheless, heparanase deglycanation of the N-terminal HS-rich domain of syndecan-1 (SDC1), but not SDC2 or -4, is a prerequisite for binding of the prosecretory mitogen lacritin (Ma, P., Beck, S. L., Raab, R. W., McKown, R. L., Coffman, G. L., Utani, A., Chirico, W. J., Rapraeger, A. C., and Laurie, G. W. (2006) Heparanase deglycanation of syndecan-1 is required for binding of the epithelial-restricted prosecretory mitogen lacritin. J. Cell Biol. 174, 1097-1106). We now report that the conserved and hydrophobic GAGAL domain in SDC1, adjacent to predicted HS substitution sites, is necessary to ligate and substantially enhance the α-helicity of the amphipathic C terminus of lacritin. Swapping out GAGAL for GADED in SDC2 or for GDLDD in SDC4 (both less hydrophobic) abrogated binding. HS and chondroitin sulfate are also essential. Both are detected in the N terminus, and when incubated with antibodies HS4C3 (anti-HS) or IO3H10 (anti-chondroitin sulfate), binding was absent, as occurred when all three N-terminal glycosaminoglycan substitution sites were mutated to alanine or when cells were treated with 4-methylumbelliferyl-β-d-xylopyranoside or chlorate to suppress glycosaminoglycan substitution or sulfation, respectively. SDC1 interacts with the hydrophobic face of lacritin via Leu-108/Leu-109/Phe-112 as well as with Glu-103/Lys-107 and Lys-111 of the largely cationic face. Carving a hybrid hydrophobic/electrostatic docking site out of SDC1 in a manner dependent on endogenous heparanase is a dynamic process appropriate for subtle or broad epithelial regulation in morphogenesis, health, and disease.


Multiscale single-cell analysis reveals unique phenotypes of raphe 5-HT neurons projecting to the forebrain.
Serotonergic neurons of the raphe nuclei exhibit anatomical, neurochemical and elecrophysiological heterogeneity that likely underpins their specific role in multiple behaviors. However, the precise organization of serotonin (5-HT) neurons to orchestrate 5-HT release patterns throughout the brain is not well understood. We compared the electrophysiological and neurochemical properties of dorsal and median raphe 5-HT neurons projecting to the medial prefrontal cortex (mPFC), amygdala (BLA) and dorsal hippocampus (dHP), combining retrograde tract tracing with brain slice electrophysiology and single-cell RT-PCR in Pet1-EGFP mice. Our results show that 5-HT neurons projecting to the dHP and the mPFC and the BLA form largely non-overlapping populations and that BLA-projecting neurons have characteristic excitability and membrane properties. In addition, using an unbiased clustering method that correlates anatomical, molecular and electrophysiological phenotypes, we find that 5-HT neurons with projections to the mPFC and the dHP segregate from those projecting to the BLA. Single-cell gene profiling showed a restricted expression of the peptide galanin in the population of 5-HT neurons projecting to the mPFC. Finally, cluster analysis allowed identifying an atypical subtype of 5-HT neuron with low excitability, long firing delays and preferential expression of the vesicular glutamate transporter type 3. Overall, these findings allow to define correlated anatomical and physiological identities of serotonin raphe neurons that help understanding how discrete raphe cells subpopulations account for the heterogeneous activities of the midbrain serotonergic system.


Differential repression of Otx2 underlies the capacity of NANOG and ESRRB to induce germline entry.
Primordial germ cells (PGCs) arise from cells of the post-implantation epiblast in response to cytokine signaling. PGC development can be recapitulated in vitro by differentiating epiblast-like cells (EpiLCs) into PGC-like cells (PGCLCs) through cytokine exposure. Interestingly, the cytokine requirement for PGCLC induction can be bypassed by enforced expression of the transcription factor (TF) NANOG. However, the underlying mechanisms are not fully elucidated. Here, we show that NANOG mediates Otx2 downregulation in the absence of cytokines and that this is essential for PGCLC induction by NANOG. Moreover, the direct NANOG target gene Esrrb, which can substitute for several NANOG functions, does not downregulate Otx2 when overexpressed in EpiLCs and cannot promote PGCLC specification. However, expression of ESRRB in Otx2+/- EpiLCs rescues emergence of PGCLCs. This study illuminates the interplay of TFs occurring at the earliest stages of PGC specification.


Effectiveness of interventions to reduce ordering of thyroid function tests: a systematic review.
To evaluate the effectiveness of behaviour changing interventions targeting ordering of thyroid function tests. Systematic review. MEDLINE, EMBASE and the Cochrane Database up to May 2015. We included studies evaluating the effectiveness of behaviour change interventions aiming to reduce ordering of thyroid function tests. Randomised controlled trials (RCTs), non-randomised controlled studies and before and after studies were included. There were no language restrictions. 2 reviewers independently screened all records identified by the electronic searches and reviewed the full text of any deemed potentially relevant. Study details were extracted from the included papers and their methodological quality assessed independently using a validated tool. Disagreements were resolved through discussion and arbitration by a third reviewer. Meta-analysis was not used. 27 studies (28 papers) were included. They evaluated a range of interventions including guidelines/protocols, changes to funding policy, education, decision aids, reminders and audit/feedback; often intervention types were combined. The most common outcome measured was the rate of test ordering, but the effect on appropriateness, test ordering patterns and cost were also measured. 4 studies were RCTs. The majority of the studies were of poor or moderate methodological quality. The interventions were variable and poorly reported. Only 4 studies reported unsuccessful interventions but there was no clear pattern to link effect and intervention type or other characteristics. The results suggest that behaviour change interventions are effective particularly in reducing the volume of thyroid function tests. However, due to the poor methodological quality and reporting of the studies, the likely presence of publication bias and the questionable relevance of some interventions to current day practice, we are unable to draw strong conclusions or recommend the implementation of specific intervention types. Further research is thus justified. CRD42014006192.


Time perception: modality and duration effects in attention-deficit/hyperactivity disorder (ADHD).
Time perception performance was systematically investigated in adolescents with and without attention-deficit/hyperactivity disorder (ADHD). Specifically, the effects of manipulating modality (auditory and visual) and length of duration (200 and 1000 ms) were examined. Forty-six adolescents with ADHD and 44 controls were administered four duration discrimination tasks and two control tasks, and a set of standardized measures. Participants with ADHD had higher thresholds than controls on all of the duration discrimination tasks, with the largest effect size obtained on the visual 1000 ms duration discrimination task. No group differences were observed on the control tasks. Visual-spatial memory was found to be a significant predictor of visual and auditory duration discrimination at longer intervals (1000 ms) in the ADHD sample, whereas auditory verbal working memory predicted auditory discrimination at longer intervals (1000 ms) in the control sample. These group differences suggest impairments in basic timing mechanisms in ADHD.


Bioethanol production from sorghum grain with Zymomonas mobilis: increasing the yield and quality of raw distillates.
The present study aimed to demonstrate the superiority of bioethanol yield and its quality from sorghum using the granular starch degrading enzyme Stargen™ 002 over simultaneous saccharification and fermentation, and separate hydrolysis and fermentation using Zymomonas mobilis CCM 3881 and Ethanol Red® yeast. Bacteria were found to produce ethanol at higher yield than the yeast in all fermentations. The highest ethanol yield was obtained with Z. mobilis during 48 h of simultaneous saccharification and fermentation (83.85% theoretical yield) and fermentation with Stargen™ 002 (81.27% theoretical yield). Pre-liquefaction in fermentation with Stargen™ 002 did not improve ethanol yields for both Z. mobilis and Saccharomyces cerevisiae. Chromatographic analysis showed twice less total volatile compounds in distillates obtained after bacterial (3.29-5.54 g L-1 ) than after yeast (7.84-9.75 g L-1 ) fermentations. Distillates obtained after bacterial fermentation were characterized by high level of aldehydes (up to 65% of total volatiles) and distillates obtained after yeast fermentation of higher alcohols (up to 95% of total volatiles). The process of fermentation using granular starch hydrolyzing enzyme cocktail Stargen™ 002 resulted in low amounts of all volatile compounds in distillates obtained after bacterial fermentation, but the highest amounts in distillates obtained after yeast fermentation. The present study emphasizes the great potential of bioethanol production from sorghum with Z. mobilis using granular starch hydrolyzing enzyme Stargen™ 002, which leads to reduced water and energy consumption, especially when energy sources are strongly related to global climate change. © 2023 Society of Chemical Industry.


Reactive oxygen species and regulation of gene expression.
In eucaryotic cells reactive oxygen species (ROS) are produced in the reactions catalyzed by NAD(P)H oxidase and by some other specialized oxidases and also as an inevitable by-product of many redox reactions. Intracellular ROS synthesis is regulated by various hormones, cytokines, and growth factors. An increase in the ROS levels above a certain threshold (so-called oxidative stress) is accompanied by processes that are harmful for cell survival, such as lipid peroxidation and oxidative modification of proteins and nucleic acids. However, at low concentrations ROS act as secondary messengers responsible for a signal transduction from extracellular signaling molecules and their membrane receptors to the intracellular regulatory systems which control gene expression. Cellular transcriptional response to ROS is mediated mainly by activation of MAP protein kinases and submitted transcription factors AP-1, ATF, and NF-kappaB. A number of specific genes is also induced under hypoxia, i.e., under conditions opposite to oxidative stress. Cellular transcriptional response on hypoxia is mediated by activation of transcription factors HIF-1 and AP-1. Together with ROS, nitric oxide fulfills the role of a mobile and highly reactive redox-sensitive signaling molecule. Chemical reactions of NO with the superoxide anion and with other free radicals leads to production of highly reactive intermediates. Depending on the ratio of their intracellular concentrations, NO and ROS can either enhance or attenuate their reciprocal effects on cells.


Minimum ten-year follow-up of a randomized trial comparing acetabular component fixation of two porous in-growth surfaces using radiosteriometric analysis.
To compare the in vivo long-term fixation achieved by two acetabular components with different porous ingrowth surfaces using radiostereometric analysis (RSA). This was a minimum ten-year follow-up of a prospective randomized trial of 62 hips with two different porous ingrowth acetabular components. RSA exams had previously been acquired through two years of follow-up. Patients returned for RSA examination at a minimum of ten years. In addition, radiological appearance of these acetabular components was analyzed, and patient-reported outcome measures (PROMs) obtained. In all, 15 hips were available at ten years. There was no statistically significant difference in PROMS between the two groups; PROMs were improved at ten years compared to preoperative scores. Conventional radiological assessment revealed well-fixed components. There was minimal movement for both porous surfaces in translation (X, Y, Z, 3D translation in mm (median and interquartile range (IQR)), StikTite (Smith and Nephew, Memphis, Tennessee, USA): 0.03 (1.08), 0.12 (0.7), 0.003 (2.3), 0.37 (0.30), and Roughcoat (Smith and Nephew): -0.6 (0.59),-0.1 (0.49), 0.1 (1.12), 0.48 (0.38)), and rotation (X, Y, Z rotation in degrees (median and IQR), (Stiktite: -0.4 (3), 0.28 (2), -0.2 (1), and Roughcoat: - 0.4 (1),-0.1 (1), 0.2 (2)). There was no statistically significant difference between the two cohorts (p-value for X, Y, Z, 3D translation - 0.54, 0.46, 0.87, 0.55 and for X, Y, Z rotation - 0.41, 0.23, 0.23 respectively) at ten years. There was significant correlation between two years and ten years 3D translation for all components (r = 0.81(p =< 0.001)). Both porous ingrowth surfaces demonstrated excellent fixation on plain radiographs and with RSA at ten years. Short-term RSA data are good predictors for long-term migration data.


Cefoperazone versus combination antibiotic therapy of hospital-acquired pneumonia.
Cefoperazone monotherapy was compared with combination antibiotic therapy in a randomized prospective evaluation of patients with hospital-acquired pneumonia. Cefoperazone was as effective as either clindamycin/gentamicin or cefazolin/gentamicin (cure rate: 45 of 52 cefoperazone-treated patients [87 percent], versus 44 of 61 combination-therapy patients [72 percent], p = 0.069). With the exception of hypoprothrombinemia in those patients who did not receive prophylactic vitamin K, there was no difference in the incidence of side effects. In addition, no difference was noted in the incidence of superinfections or secondary pneumonias. When antibiotic costs, administration costs, and laboratory costs were considered, cefoperazone monotherapy was the least expensive antibiotic regimen. Cefoperazone is a suitable alternative to combination antibiotic therapy for the treatment of hospital-acquired pneumonia.


Macrophages show up in style when Th2 lymphocytes organize their homecoming.
Monocytes can differentiate into tissue-resident pleural macrophages, but the mechanisms underlying this process are not yet fully understood. In this issue of Immunity, Finlay et al.1 show that Th2 cytokines promote this differentiation in resistant mice infected with Litomosoides sigmodontis.


Pharmacological characterisation of anti-inflammatory compounds in acute and chronic mouse models of cigarette smoke-induced inflammation.
Candidate compounds being developed to treat chronic obstructive pulmonary disease are typically assessed using either acute or chronic mouse smoking models; however, in both systems compounds have almost always been administered prophylactically. Our aim was to determine whether the prophylactic effects of reference anti-inflammatory compounds in acute mouse smoking models reflected their therapeutic effects in (more clinically relevant) chronic systems. To do this, we started by examining the type of inflammatory cell infiltrate which occurred after acute (3 days) or chronic (12 weeks) cigarette smoke exposure (CSE) using female, C57BL/6 mice (n = 7-10). To compare the effects of anti-inflammatory compounds in these models, mice were exposed to either 3 days of CSE concomitant with compound dosing or 14 weeks of CSE with dosing beginning after week 12. Budesonide (1 mg kg-1; i.n., q.d.), roflumilast (3 mg kg-1; p.o., q.d.) and fluvastatin (2 mg kg-1; p.o., b.i.d.) were dosed 1 h before (and 5 h after for fluvastatin) CSE. These dose levels were selected because they have previously been shown to be efficacious in mouse models of lung inflammation. Bronchoalveolar lavage fluid (BALF) leukocyte number was the primary endpoint in both models as this is also a primary endpoint in early clinical studies. To start, we confirmed that the inflammatory phenotypes were different after acute (3 days) versus chronic (12 weeks) CSE. The inflammation in the acute systems was predominantly neutrophilic, while in the more chronic CSE systems BALF neutrophils (PMNs), macrophage and lymphocyte numbers were all increased (p < 0.05). In the acute model, both roflumilast and fluvastatin reduced BALF PMNs (p < 0.01) after 3 days of CSE, while budesonide had no effect on BALF PMNs. In the chronic model, therapeutically administered fluvastatin reduced the numbers of PMNs and macrophages in the BALF (p ≤ 0.05), while budesonide had no effect on PMN or macrophage numbers, but did reduce BALF lymphocytes (p < 0.01). Roflumilast's inhibitory effects on inflammatory cell infiltrate were not statistically significant. These results demonstrate that the acute, prophylactic systems can be used to identify compounds with therapeutic potential, but may not predict a compound's efficacy in chronic smoke exposure models.


Decrease of the electroacupuncture-induced analgesic effects in nuclear factor-kappa B1 knockout mice.
To investigate the involvement of nuclear factor kappa B1 (NF-kappaB1; p50/p105) in electroacupuncture (EA)-induced analgesia, 2 and 100 Hz EA stimulations were applied at acupoint ST36 (Zusanli) in NF-kappaB1 knockout mice. EA was performed for 30 min and tail-flick latencies (TFLs) were evaluated every 15 min for 1 h. Wild-type mice displayed a 63.3% increase in TFLs compared to baseline after 2 Hz EA, whereas NF-kappaB1+/- mice exhibited a 41.8% increase and NF-kappaB1-/- mice showed only a 3.9% increase of TFLs. The TFLs of 100 Hz EA showed similar trends: a 72.6% increase of TFLs in wild-type, a 38.6% increase in NF-kappaB1+/- and a 9.3% increase in NF-kappaB1-/- mice. The present findings suggest that NF-kappaB1 may play a crucial role in both low and high frequency EA-induced analgesic effects.


A dietary pattern that is associated with C-peptide and risk of colorectal cancer in women.
Higher serum C-peptide concentrations have shown to be associated with an increased risk of colorectal cancer (CRC). Therefore, we used diet information to identify food groups that correlated with fasting serum concentrations of C-peptide and assess the association of this dietary pattern and CRC risk. Major food contributors to fasting C-peptide concentrations were identified with stepwise linear regression in a subsample (n = 833) of women from a large cohort. We then summed the consumption frequency of the major food contributors to form a C-peptide dietary pattern for the entire cohort (n = 66,714). Risk for CRC was computed using Cox proportional hazard model with the C-peptide dietary pattern score as the predictor. In up to 20 years of follow-up, we ascertained 985 cases of CRC and 758 colon cancer. After adjusting for confounders, the C-peptide dietary pattern, characterized by higher meat, fish, and sweetened beverage intake, but lower coffee, high fat dairy, and whole grains intake, showed direct association with CRC risk (RR comparing extreme quintiles = 1.29, 95 % CI = 1.05-1.58, p trend = 0.048). The same comparison was slightly stronger for colon cancer (RR = 1.35, 95 % CI = 1.07-1.70, p trend = 0.009). In stratified analysis, there was no association between the C-peptide dietary pattern and colon cancer among lean and active women. However, for overweight or sedentary women, RR for the same comparison was 1.58 (95 % CI = 1.20-2.07, p trend = 0.002) (p for interaction = 0.007). We derived a dietary pattern that correlated with C-peptide concentrations. This pattern was associated with an increase in colon cancer, especially among women who were overweight or sedentary.


Anatomy of the Scapula Applied to the Posterior Surgical Approach: Safety Parameters during Access to the Lateral Angle.
Objective The objective of this paper was to identify safety parameters in the posterior surgical approach of the scapula through a cross-sectional cadaver study. Methods Thirteen cadaver shoulders with no history of surgery or prior musculoskeletal dysfunction, with mean age, weight, and height of 70.1 years, 61.5 kg, and 1.64 m, respectively, were dissected. The anatomic landmark of the studied pathway (infraglenoid tubercle) and its distance to the axillary and suprascapular nerves were measured. Results The mean distance between the infraglenoid tubercle (IT) and the axillary nerve (AN) was 23.8 mm, and the mean distance from the IT to the suprascapular nerve (SN) was 33.2 mm. Conclusion The posterior approach may be considered safe through the interval between the infraspinatus and teres minor. However, caution should be taken during muscle spacing because of the short distance between the fracture site and the location of the SN and AN. These precautions help to avoid major postoperative complications.


Ropinirole metabolite mimics a new psychoactive substance (4-HO-MET) in LC-MS/MS.
Liquid chromatography tandem mass spectrometry (LC-MS/MS) is often regarded as a highly reliable methodology for confirmatory testing in analytical toxicology, especially for detection of new psychoactive substances (NPS) by clinical and forensic laboratories. However, false positives still do occur and erroneous reporting can have substantial legal implications. In this study, we investigated into the mechanism behind a clinically implausible, but apparently analytically sound, finding of a NPS (4-hydroxy-N-methyl-N-ethyltryptamine; 4-HO-MET) in a urine specimen for toxicology screening by LC-MS/MS. We discovered that a ropinirole metabolite (N-despropyl-ropinirole) was the culprit of interference as it shares high structural similarities with 4-HO-MET. The chemical similarities eluded various rigorous regulatory guidelines for compound identification utilizing computer-aided spectral library matching. After careful scrutiny of the mass spectra and comparison with a reference specimen, the compound was correctly identified. Our findings emphasize the important synergy between scientists and pathologists in considering the clinical context, especially drug history, in clinical and forensic toxicology analysis on biological specimens. Mass spectra should be reviewed for relative ion ratios in case of doubt. Understanding drug metabolism is essential for troubleshooting and result interpretation.


Nuclear medicine training and practice in Portugal.
Nuclear medicine in Portugal has been an autonomous speciality since 1984. In order to obtain the title of Nuclear Medicine Specialist, 5 years of training are necessary. The curriculum is very similar to the one approved under the auspices of the European Union of Medical Specialists, namely concerning the minimum recommended number of diagnostic and therapeutic procedures. There is a final assessment, and during the training the resident is in an approved continuing education programme. Departments are accredited by the Medical College in order to verify their capacity to host nuclear medicine residencies.


Concomitant back pain as a predictor of outcome after single level lumbar micro-decompressive surgery - A study of 995 patients.
To determine if preoperative leg pain and low back pain severity affected postoperative outcome. Prospectively collected Spine-Tango data was analysed for 995 consecutive patients who underwent a primary, single level, lumbar micro-decompression/microdiscectomy at a single tertiary spinal centre. At 3 months, 72% of patients were satisfied with the outcome of surgery. Pre-operative low back pain was a significant predictor of poor outcome (P < 0.01). Our study has shown that patients with a low back pain VAS of 6 or more have a significantly greater chance of a poor outcome following primary lumbar microdecompressive/microdiscectomy surgery.


Strong semantic segmentation for Covid-19 detection: Evaluating the use of deep learning models as a performant tool in radiography.
With the increasing number of Covid-19 cases as well as care costs, chest diseases have gained increasing interest in several communities, particularly in medical and computer vision. Clinical and analytical exams are widely recognized techniques for diagnosing and handling Covid-19 cases. However, strong detection tools can help avoid damage to chest tissues. The proposed method provides an important way to enhance the semantic segmentation process using combined potential deep learning (DL) modules to increase consistency. Based on Covid-19 CT images, this work hypothesized that a novel model for semantic segmentation might be able to extract definite graphical features of Covid-19 and afford an accurate clinical diagnosis while optimizing the classical test and saving time. CT images were collected considering different cases (normal chest CT, pneumonia, typical viral causes, and Covid-19 cases). The study presents an advanced DL method to deal with chest semantic segmentation issues. The approach employs a modified version of the U-net to enable and support Covid-19 detection from the studied images. The validation tests demonstrated competitive results with important performance rates: Precision (90.96% ± 2.5) with an F-score of (91.08% ± 3.2), an accuracy of (93.37% ± 1.2), a sensitivity of (96.88% ± 2.8) and a specificity of (96.91% ± 2.3). In addition, the visual segmentation results are very close to the Ground truth. The findings of this study reveal the proof-of-principle for using cooperative components to strengthen the semantic segmentation modules for effective and truthful Covid-19 diagnosis. This paper has highlighted that DL based approach, with several modules, may be contributing to provide strong support for radiographers and physicians, and that further use of DL is required to design and implement performant automated vision systems to detect chest diseases.


Cyclophosphamide and sequential cisplatin for advanced seminoma: long-term followup in 52 patients.
Fifty-two patients with advanced seminoma were treated with primary chemotherapy: 44 received cyclophosphamide and weekly cisplatin, and 8 received sequential weekly cisplatin alone. Of the patients treated with chemotherapy alone only 44 achieved a complete remission and 4 were salvaged with further therapy (1 chemotherapy and 3 radiation therapy). These 48 patients (92 per cent) remained free of disease at a followup of 30 to 471 weeks. Six prognostic factors were tested by univariate analysis (chi-square) and only the use of previous chemotherapy predicted for a lower complete remission rate (p equals 0.02). Renal toxicity (greater than 0.4 mg. per dl. increase in serum creatinine) occurred in 2 patients (4 per cent). Neurotoxicity occurred in 16 patients (31 per cent). No fatal toxicity occurred. Cyclophosphamide and weekly cisplatin were well tolerated in patients previously treated with radiation therapy and is the treatment of choice for patients with disseminated seminoma.


Dner inhibits neural progenitor proliferation and induces neuronal and glial differentiation in zebrafish.
Delta/notch-like epidermal growth factor (EGF)-related receptor (DNER) is a single-pass transmembrane protein found to be a novel ligand in the Notch signaling pathway. Its function was previously characterized in the developing cerebellum and inner ear hair cells. In this study, we isolated a zebrafish homolog of DNER and showed that this gene is expressed in the developing nervous system. Overexpression of dner or the intracellular domain of dner was sufficient to inhibit the proliferation of neural progenitors and induce neuronal and glial differentiation. In contrast, the knockdown of endogenous Dner expression using antisense morpholino oligonucleotides increased the proliferation of neural progenitors and maintained neural cells in a progenitor status through inhibition of neuronal and glial differentiation. Through analysis of the antagonistic effect on the Delta ligand and the role of the potential downstream mediator Deltex1, we showed that Dner acts in Notch-dependent and Notch-independent manner. This is the first study to demonstrate a role for Dner in neural progenitors and neuronal differentiation and provides new insights into mediation of neuronal development and differentiation by the Notch signaling pathway.


Anti-Asian American Hate Crimes Spike During the Early Stages of the COVID-19 Pandemic.
The recent high-profile cases of hate crimes in the U.S., especially those targeting Asian Americans, have raised concerns about their risk of victimization. Following the onset of the COVID-19 pandemic, intimations-and even accusations-that the novel coronavirus is an "Asian" or "Chinese" virus have been linked to anti-Asian American hate crime, potentially leaving members of this group not only fearful of being victimized but also at risk for victimization. According to the Stop AAPI Hate Center, nearly 1900 hate crimes against Asian Americans were reported by victims, and around 69% of cases were related to verbal harassment, including being called the "Chinese Coronavirus." Yet, most of the evidence martialed on spikes in anti-Asian American hate crime during the COVID-19 pandemic has been descriptive. Using data from four U.S. cities that have large Asian American populations (New York, San Francisco, Seattle, and Washington D.C.), this study finds that hate crime against Asian Americans increased considerably in 2020 compared with that of 2019. Specifically, hate crime against Asian Americans temporarily surged after March 16, 2020, when the blaming labels including "Kung flu" or "Chinese Virus" were used publicly. However, the significant spike after March 16, 2020, in anti-Asian American hate crime was not sustained over the follow-up time period available for analysis.


Functional outcomes of transurethral thulium laser enucleation versus bipolar transurethral resection for benign prostatic hyperplasia over a period of 12 months: A prospective randomized study.
To evaluate functional outcomes over a year for benign prostatic hyperplasia treated with thulium laser enucleation of the prostate or bipolar transurethral resection of the prostate. In this study, we prospectively included 140 patients who were treated for benign prostatic hyperplasia from April 2017 to February 2019. A randomization list was used for non-blind assignment to treatment groups (thulium laser enucleation of the prostate or bipolar transurethral resection of the prostate). The International Prostate Symptom Score, International Prostate Symptom Score quality of life, Overactive Bladder Symptom Score, uroflowmetry and International Index of Erectile Function-5 were used for the assessment of outcomes. Scores were taken before treatment, and at 1, 3, 6, 9 and 12 months after treatment. Preoperatively, characteristics of patients in the thulium laser enucleation of the prostate group (n = 70) and the bipolar transurethral resection of the prostate group (n = 70) did not significantly differ. The thulium laser enucleation of the prostate group had a lower median decrease in hemoglobin (0.10 g/dL vs 0.69 g/dL, P < 0.0001) and shorter median catheterization (2 days vs 3 days, P < 0.0001) than the bipolar transurethral resection of the prostate group. Both groups had significantly improved International Prostate Symptom Score, International Prostate Symptom Score quality of life, Overactive Bladder Symptom Score, maximum flow rate and residual urine compared with preoperative values. In the thulium laser enucleation of the prostate group, erectile function was significantly impaired at 1 month post-treatment compared with pretreatment, but improved to baseline at 3 months; however, the transurethral resection of the prostate group did not recover. However, total energy (P = 0.001) and laser irradiation time (P = 0.025) were significantly different between the patients who had preserved erectile function and those who did not after the treatment in the thulium laser enucleation of the prostate group. Thulium laser enucleation of the prostate is superior to bipolar transurethral resection of the prostate in resection efficacy, hemostasis, catheterization time and preservation of erectile function. However, excessive laser irradiation time in thulium laser enucleation of the prostate has the possibility to delay improvement of overactive bladder symptoms and decrease sexual function.


Comparison of the effectiveness of moxalactam and cefazolin in the prevention of infection in patients undergoing abdominal operations.
Patients undergoing elective intraabdominal operations received a three-dose prophylactic regimen of either moxalactam (83 patients) or cefazolin (98 patients) in a blinded, randomized fashion. There was a 9% overall infection rate with 6% for those in the cefazolin group (6/98), and 12% for those treated with moxalactam (10/83) (p = 0.26). Infection rates stratified by types of surgery were similar for both regimens. The drugs were well tolerated, with minimal side effects. Patients at highest risk of infection were those with obstruction of upper gastrointestinal tract and those with pancreatitis. We concluded that moxalactam was no more effective than cefazolin in preventing postoperative infections in this study population.


Involvement of GABA and cholinergic receptors in the nucleus accumbens on feedback control of somatodendritic dopamine release in the ventral tegmental area.
The objectives of the present study were to examine the involvement of GABA and cholinergic receptors within the nucleus accumbens (ACB) on feedback regulation of somatodendritic dopamine (DA) release in the ventral tegmental area (VTA). Adult male Wistar rats were implanted with ipsilateral dual guide cannulae for in vivo microdialysis studies. Activation of the feedback system was accomplished by perfusion of the ACB with the DA uptake inhibitor GBR 12909 (GBR; 100 microm). To assess the involvement of GABA and cholinergic receptors in regulating this feedback system, antagonists (100 microm) for GABAA (bicuculline, BIC), GABAB (phaclofen, PHAC), muscarinic (scopolamine, SCOP), and nicotinic (mecamylamine, MEC) receptors were perfused through the probe in the ACB while measuring extracellular DA levels in the ACB and VTA. Local perfusion of the ACB with GBR significantly increased (500% of baseline) the extracellular levels of DA in the ACB and produced a concomitant decrease (50% of baseline) in the extracellular DA levels in the VTA. Perfusion of the ACB with BIC or PHAC alone produced a 200-400% increase in the extracellular levels of DA in the ACB but neither antagonist altered the levels of DA in the VTA. Co-perfusion of either GABA receptor antagonist with GBR further increased the extracellular levels of DA in the ACB to 700-800% of baseline. However, coperfusion with BIC completely prevented the reduction in the extracellular levels of DA in the VTA produced by GBR alone, whereas PHAC partially prevented the reduction. Local perfusion of the ACB with either MEC or SCOP alone had little effect on the extracellular levels of DA in the ACB or VTA. Co-perfusion of either cholinergic receptor antagonist with GBR markedly reduced the extracellular levels of DA in the ACB and prevented the effects of GBR on reducing DA levels in the VTA. Overall, the results of this study suggest that terminal DA release in the ACB is under tonic GABA inhibition mediated by GABAA (and possibly GABAB) receptors, and tonic cholinergic excitation mediated by both muscarinic and nicotinic receptors. Activation of GABAA (and possibly GABAB) receptors within the ACB may be involved in the feedback inhibition of VTA DA neurons. Cholinergic interneurons may influence the negative feedback system by regulating terminal DA release within the ACB.


The influence of vision and support base on balance during quiet standing in patients with adolescent idiopathic scoliosis before and after posterior spinal fusion.
Scoliosis is the most common postural alteration in adolescence and is characterized by deviations of the spine in three planes. Surgical treatment based on arthrodesis has been developed, but the effects of such restructuring on the systems involved in postural control need to be better understood. To assess the influence of vision and the support base on balance in the quiet standing position in adolescents awaiting surgical treatment for idiopathic scoliosis. Longitudinal study/Ribeirão Preto Clinics Hospital (HC-FMRP-USP) and Laboratory of Assessment and Rehabilitation of Equilibrium at the FMRP-USP. Adolescent idiopathic scoliosis patients and controls. Center of pressure (CoP) sway area of the 95% confidence ellipse. Thirty female adolescents were divided into two groups according to their spinal alignment: control (n=15) and scoliosis groups (SGs) (n=15). The subjects with scoliosis were evaluated before and 7, 30, 60, and 90 days after surgery; the controls were evaluated once. The area of CoP oscillation was measured with the eyes open and closed and with two different support bases (feet apart or together). The force platform was purchased with funding support (US $8,375.00) provided by the Research Foundation of São Paulo (FAPESP). The study sponsors had no involvement in the study. Data were collected from the force platform and then statistically assessed through a linear model analysis of mixed effects. Data reveal that subjects in the SG oscillated more than controls, and postsurgery subjects had more oscillation than presurgery subjects. The results also indicated that both groups (control and scoliosis) showed more oscillation among those subjects with feet apart and eyes closed, but subjects with scoliosis were more affected by vision deprivation than by a reduced support base. Our results indicate that adolescents with idiopathic scoliosis are more dependent on visual information and that surgical correction does not change this relationship.


Impact of a modified progressive Copenhagen adduction exercise programme on hip adduction strength and postexercise muscle soreness in professional footballers.
Reduced hip adduction strength has been identified as a key predisposing factor in developing hip and groin injuries. The Copenhagen adduction programme has been shown to increase hip adduction strength in semiprofessional footballers but can cause muscle soreness. Therefore, a modified progressive Copenhagen adduction (MPCA) programme has been designed to increase hip adduction strength while limiting muscle soreness. To investigate the effect of an 8-week MPCA exercise on eccentric hip adduction and abduction strength in senior professional footballers. 25 senior professional footballers completed an 8-week MPCA strengthening programme. Eccentric hip adduction (EHAD) and eccentric hip abduction (EHAB) strengths were measured. Changes in preintervention and postintervention strengths and EHAD:EHAB ratios were calculated. The statistical significance between strength changes was assessed with dependent t-tests and Wilcoxon signed-rank tests due to the distribution of the data (p<0.05). Delayed onset of muscle soreness (DOMS) and rate of perceived exertion were measured throughout the programme. There were statistically significant increases in EHAD strength (24% and 25%, left and right), EHAB strength (10% and 13%, left and right) and the EHAD:EHAB ratio (12% and 10%, left and right) (p<0.01).Professional footballers were able to complete the MPCA exercise with low levels of DOMS. An 8-week MPCA exercise elicited significant EHAD and EHAB strength increases with reduced levels of muscle soreness in senior professional footballers.


N-ras oncogene expression changes the growth characteristics of human melanoma in two independent SCID-hu mouse models.
Fifteen percent of all human melanomas carry mutations in ras genes, the majority of which are located in codon 61 of the N-ras gene. However, the biological significance of these mutations is as yet unknown. In this study, we investigated the influence of N-ras oncogene products mutated in codon 61 on the growth characteristics of human melanoma in vivo by establishing 2 SCID-hu mouse xenotransplantation models. Tumors grown in SCID mice injected with human melanoma carrying activated N-ras genes were significantly larger (p < 0.004) than tumors grown in animals injected with the appropriate control transfectants. Additionally, tumors with N-ras point mutations clearly showed a more pleomorphic phenotype than the control groups. Our results, obtained in 2 independent SCID-hu xenotransplantation models, suggest that mutated N-ras oncogene expression may be an important factor influencing growth characteristics of human melanoma without altering metastatic potential. These novel in vivo model systems provide a tool for further study of the biology of mutated ras in melanoma and should also prove useful for testing new and improved treatment strategies for human melanoma carrying mutated ras genes.


Reporter Scaffolds for Clinically Relevant Cell Transplantation Studies.
There are a number of cell therapies that are either in clinical trials or moving toward clinical trials, particularly for diseases of the retina. One of the challenges with cell therapies is tracking the status of cells over time. Genetic manipulation can facilitate this, but it can limit the clinical application of the cells. There are a host of fluorophores that have been developed to assess the status of cells, but these molecules tend to be cleared rapidly from cells. There are preclinical strategies that use degradable scaffolds, and we hypothesized that these scaffolds could be used to track the state of cells during preclinical studies. In this work, we explored whether fluorophores could be delivered from simple scaffolds fabricated under extremely harsh conditions, be active upon release, and report on the cells growing on the scaffolds over time. We encapsulated CellROX® Green Reagent, and pHrodo™ Red AM in poly(lactic-co-glycolic acid) (PLGA) scaffolds, showed that they could be delivered over weeks and were still active upon release and taken up by cells. These experiments provide the foundation for using scaffolds to deliver molecules to report on cells.


Effect of dose adjustments on the efficacy and safety of tofacitinib in patients with rheumatoid arthritis: a post hoc analysis of an open-label, long-term extension study (ORAL Sequel).
We assess the impact of switching versus staying on the same tofacitinib dose on efficacy and safety in patients with rheumatoid arthritis (RA). ORAL Sequel was an open-label, long-term extension study of patients with RA receiving tofacitinib 5 or 10 mg BID for up to 9.5 years. Tofacitinib doses could be switched during the study at investigator discretion. In this post hoc analysis, data from ORAL Sequel were stratified into four groups: 5 → 10 mg BID (Dose-up); 5 mg BID (Stay-on 5); 10 → 5 mg BID (Dose-down); and 10 mg BID (Stay-on 10). Efficacy assessments over 12 months included: change from baseline in 4-component Disease Activity Score in 28 joints, erythrocyte sedimentation rate (DAS28), and DAS28 minimum clinically important difference, remission, and low disease activity (LDA) rates. Safety was assessed for the study duration. Generally, DAS28 improvements and minimum clinically important difference rates were significantly greater (p < 0.05) in Dose-up versus Stay-on 5 up to month 12. DAS28 remission rates were significantly greater in Dose-up versus Stay-on 5 at month 12. Change from baseline in DAS28 was similar in Dose-down and Stay-on 10. No significant differences in DAS28 LDA rates were observed between groups. Safety data were similar overall across the four groups. In patients with RA receiving open-label tofacitinib, this analysis found that some benefited from increasing dose from 5 to 10 mg BID and did not find that reducing dose from 10 to 5 mg BID affected efficacy or that dose switching in either direction affected safety. ClinicalTrials.gov number NCT00413699. Registered December 20, 2006. https://clinicaltrials.gov/ct2/show/NCT00413699 Key Points • This post hoc analysis of data from the long-term extension study, ORAL Sequel, assessed the impact of dose switching between tofacitinib 5 and 10 mg twice daily (BID), at the investigator's discretion, on efficacy and safety in patients with rheumatoid arthritis (RA). • Dosing up from tofacitinib 5 to 10 mg BID was associated with improved efficacy up to 12 months versus staying on 5 mg BID, and dosing down from 10 to 5 mg BID was not generally associated with a significant loss of efficacy. • Safety outcomes were generally consistent across dose groups and did not change markedly after switching dose in either direction. • These findings can help to inform physicians on what may be expected in terms of efficacy and safety when adjusting tofacitinib dose according to clinical need. The recommended tofacitinib dosage for the treatment of RA in most jurisdictions is 5 mg BID.


Feasibility and efficacy of an intervention to reduce secondhand smoke exposure among infants discharged from a neonatal intensive care unit.
To examine the feasibility and efficacy of a hospital-based, motivational intervention to reduce secondhand smoke exposure (SHSe) with mothers of infants in a neonatal intensive care unit (NICU). One-hundred and forty-four mothers with infants ( ≤ 1500 g at birth or ≥ 12 h ventilation) in a NICU who reported a smoker in the household were randomized to two sessions of motivational interviewing (MI) conducted in the hospital, usual care (UC) or usual care-reduced measurement (UC-RM); follow-up occurred at 1- and 6-months post discharge. For households that did not have a total smoking ban at baseline, 63.6% of those in the MI group instituted a ban by 1-month post discharge compared with 20% of the UC group, P<0.02. Six months post discharge, fewer smoking bans were noted in the UC-RM group relative to MI and UC, P<0.01. A need for SHSe interventions among NICU parents exists and initial evidence suggests MI can impact SHSe after discharge.


Bronchoscopic visualization of the inner cavity caused by Pasteurella multocida infection.
We report a 69-year-old man who presented to our hospital with cough and sputum production. He had been in close contact with six domestic cats. He had a smoking history of 40 pack-years and had been in close contact with six domestic cats. A chest computed tomography scan revealed multiple consolidations with cavities in both lung fields. Pasteurella multocida was cultured from his sputum. On bronchoscopic evaluation, the flexible bronchoscope was navigated through the right middle lobe bronchus, which opened inside the cavity, allowing visualization of a spider-web-appearing architecture consisting of many cord-like lung tissues loosely adherent to the cavity lumen. Using these findings, a diagnosis of cavity formation was made secondary to Pasteurella multocida infection. Pasteurella infection should be considered as a cause of a lung cavity in patients with chronic lung disease. History taking regarding animal exposure is important for its diagnosis.


Malignancies of human thyroid tumors and dynamic magnetic resonance imaging (MRI).
Time intensity curves for gadolinium-diethylene triaminepentacetic acid (Gd-DTPA) enhanced magnetic resonance imaging (MRI), namely dynamic MRI, were determined for thyroid diseases and compared with findings of histopathologic examination. Time intensity curves for solid lesions were determined, excluding cases with secondary changes such as calcification, hemorrhage, necrosis and fibrosis. Three different patterns of time intensity curves were observed: rapid washout, delayed washout and no change. In our previous study, malignant grades of thyroid tumors were estimated immunohistochemically by epidermal growth factor receptor (EGFR) antibody. In most of malignant diseases and a few benign diseases that had marked cell proliferative activity with staining EGFR strongly, the time intensity curve displayed a delayed washout pattern, in which intensity was above 1/2-maximal value within 10 min after injection Gd-DTPA. Almost all benign diseases and a few well differentiated carcinomas displayed a rapid washout pastern, in which intensity was decreased to lower than 1/2 of peak grade within 10 min following injection and showed staining EGFR weakly. Benign diseases showing no change of time intensity curve, did not almost show aEGFR positive cell. These findings suggested that the time intensity curve obtained from dynamic MRI might indicate differentiated grades and cell proliferating activity of thyroid tumors.


Structural and functional changes in gill mitochondrial membranes from the Mediterranean mussel Mytilus galloprovincialis exposed to tri-n-butyltin.
The use of tributyltin (TBT) as a biocide in antifouling paints leads to a ruinous input of this contaminant in the aquatic environment. Human exposure to TBT mainly occurs through ingestion of contaminated seafood such as filter-feeding mollusks. Tributyltin is known to act as a membrane-active toxicant on several targets, but especially on the mitochondria, and by several mechanisms. The effects of tributyltin on fatty acid composition, on Mg-adenosine triphosphatase (ATPase) activities, and on the membrane physical state were investigated in gill mitochondrial membranes from cultivated mussels Mytilus galloprovincialis exposed to 0.5 µg/L and 1.0 µg/L TBT and unexposed for 120 h. The higher TBT exposure dose induced a decrease in the total and n-3 polyunsaturated fatty acids (PUFAs), especially 22:6 n-3, and an activation of the oligomycin-sensitive Mg-ATPase. Both TBT concentrations decreased mitochondrial membrane polarity detected by Laurdan steady-state fluorescence spectroscopy. These findings may help cast light on the multiple modes of action of this toxicant.


Developing and Evaluating the Psychometric Properties of the Nurses' Exercise Beliefs Scale.
No instrument exists that measures oncology nurses' exercise beliefs for women with breast cancer experiencing cancer-related fatigue. This article reports on the psychometric evaluation of the Nurses' Exercise Beliefs scale. There were 20 items generated for the scale from a review of the literature. An expert panel review achieved content validity of the scale. The scale was administered to 387 registered nurses and the data were analyzed. The scale content validity index (S-CVI) was .85. A 2-factor solution explained 50.4% of the variance in exercise beliefs, supporting construct validity. The factors were exercise benefits beliefs (8 items, α = .94) and exercise barriers beliefs (12 items, α = .81). The findings support the subscales as valid and reliable tools.


Sonographic appearances of the normal ulnar nerve in the cubital tunnel.
To investigate the sonographic characteristics of the normal ulnar nerve in the cubital tunnel, as well as any differences related to age, sex, and dominant arm. Two hundred twelve elbows in healthy volunteers were evaluated sonographically. The cross-sectional area (CSA) of the ulnar nerve within the cubital tunnel was measured with the elbow in extension and in flexion. The presence and number of fascicles was determined. The displacement of the ulnar nerve out of the cubital tunnel in full elbow flexion was also investigated. The mean +/- SD CSA of the ulnar nerve was 6.6 +/- 1.7 mm(2) (6.7 +/- 1.8 mm(2) in men and 6.5 +/- 1.7 mm(2) in women). The mean CSA of the ulnar nerve was highest for subjects aged 50-59 years, and lowest for subjects aged 30-39 years. Forty-two of 212 (19.8%) ulnar nerves had 2 fascicles, and 5 (2.4%) had 3 fascicles. The remaining 165 (77.8%) nerves had 1 fascicle. During elbow flexion, 49 of 212 (23.1%) ulnar nerves showed subluxation, and 18 (8.5%) were dislocated. There were differences in the CSA of the ulnar nerve between some age groups, but there was no variation with sex or handedness. Sonography can evaluate the morphologic changes of the nerve during flexion of the elbow.


The use of the levonorgestrel-releasing intrauterine system in the management of menorrhagia in women with hemostatic disorders.
The study was undertaken to evaluate the levonorgestrel-releasing intrauterine system (LNG-IUS) in managing menorrhagia associated with hemostatic disorders. Retrospective notes review. Nineteen of 28 (68%) patients experienced improvement with the LNG-IUS. There was nonacceptance by 9 of 28 (32%) who refused the LNG-IUS or had it definitively removed. The LNG-IUS should be considered when managing menorrhagia because surgery carries additional risks in this subset of patients.


"Design and implementation challenges of massive open online course on research methods for Indian medical postgraduates and teachers -descriptive analysis of inaugural cycle".
In view of the growing popularity, reach and access for Massive Open Online Courses (MOOCs), India's apex body for medical education, the National Medical Commission (NMC) mandated uniform foundational course on research methods for the medical post graduates (PGs) and faculty members of the medical institutions under NMC as MOOC. This course is a pioneering effort in the field of India's PG medical education. NMC entrusted Indian Council of Medical Research (ICMR)-National Institute of Epidemiology (NIE) to design and offer the MOOC, named as Basic Course in Biomedical Research (BCBR). We describe the experience of designing and that of implementation challenges in the inaugural cycle of the course. The course objective was to inculcate the fundamental concepts in research methods covering epidemiology and biostatistics in the form of video lectures, resource materials, discussion forum, assignments, feedback and a final proctored examination. The course was delivered over 16 weeks through MOOCs platform under the Indian Ministry of Education. We reviewed records, documents and faculty notes and described the course conceptualization, development, design and implementation process. We abstracted information from course portal on enrolment profile of the participants, self-reported course feedback (structured and open-ended on format, lectures and quality of contents), examination registration form, scores obtained in the assignments/examination and that of the participant queries. We described quantitative data using descriptive statistics. We presented the thematic analysis of qualitative data from open-ended questions in the feedback system and that of email interactions. The inaugural cycle (September-December 2019) was taken by 24,385 participants. Majority, 15,879 (65%) were from medical background. 13,242 (54%) were medical postgraduates and 2637 (11%) were medical teachers. Among the enrolled, 14,720 (60%) cleared the assignments. A total of 11,392 (47%), 8,205 (62%) medical PGs and 896 (34%) faculty members successfully completed the course. Feedback from 1305 (5%) participants had mean score of 4.5/5 (±0.7) for quality of teaching. We faced challenges in customizing the course for medical participants, unawareness among target group, digital illiteracy and the ongoing pandemic. During the inaugural cycle of the online Basic Course in Biomedical Research course, nearly half of the enrolled participants successfully completed and received the certificate. India's MOOC for enhancing research capabilities of future medical researchers encountered successes and challenges. Lessons learnt from the inaugural cycle will guide future directions and to address larger issues in terms of sustainability and replication by stakeholders in medical education in India or elsewhere.


Oral tacrolimus as maintenance therapy for refractory ulcerative colitis--an analysis of outcomes in two London tertiary centres.
The medical management of refractory ulcerative colitis (UC) remains a significant challenge. Two randomised controlled studies have demonstrated tacrolimus therapy is effective for the induction of remission of moderate to severe UC. However, the long term outcomes of UC patients treated with tacrolimus as maintenance therapy are not certain. This study aims to assess the efficacy of tacrolimus maintenance therapy for refractory UC. A retrospective review of patients with UC treated with tacrolimus at two London tertiary centres was performed. Clinical outcomes were assessed at six months, at the end of tacrolimus treatment, or at the last follow-up for patients continuing tacrolimus treatment. Modified Truelove-Witts score (mTW) and Mayo endoscopy subscores were calculated. 25 patients with UC, treated with oral tacrolimus between 2005 and 2011, were identified. The median duration of tacrolimus treatment was 9 months (IQR 3.7-18.2 months). The median duration of follow-up was 27 months (range 3-66 months). At six months thirteen (52%) patients had achieved and maintained clinical response and eleven (44%) were in clinical remission. The mean mTW score decreased from 10+/-0.5 before therapy, to 5.8+/-0.8 (p≤0.001 95% CI 2.7-5.8) at cessation of treatment or last follow-up. Mayo endoscopy subscore decreased from 2.6+/-0.1 to 1.2+/-0.2 (p≤0.001 mean reduction 1.4, 95% CI 0.8-1.9). Eight patients (32%) subsequently underwent a colectomy within a mean time of 17 months (range 2-45 months). Tacrolimus is effective for the maintenance of refractory UC and can deliver sustained improvement in mucosal inflammation.


The use of cyclooxygenase-2 inhibitors for improvement of efficacy of radiotherapy in cancers.
Cyclooxygenase-2 (COX-2) is overexpressed in cancer cells and is associated with carcinogenesis and maintenance of progressive tumour growth as well as resistance of cancer cells to ionising radiation (IR). COX-2 inhibitors can attenuate tumour growth and expression of markers of cell proliferation as well as induce apoptosis in tumour cells. These agents can have a synergistic effect with IR in the killing of cancer cells. In this review, we discuss the rational basis and molecular mechanisms regarding the usefulness of COX-2 inhibitors in cancer therapy, and also their potential role in increasing the therapeutic index of chemoradiation by protecting normal cells and sensitising tumour cells to radiotherapy.


Synergistic premalignant effects of chronic ethanol exposure and insulin receptor substrate-1 overexpression in liver.
Insulin receptor substrate, type 1 (IRS-1) transmits growth and survival signals, and is overexpressed in more than 90% of hepatocellular carcinomas (HCCs). However, experimental overexpression of IRS-1 in the liver was found not to be sufficient to cause HCC. Since chronic alcohol abuse is a risk factor for HCC, we evaluated potential interactions between IRS-1 overexpression and chronic ethanol exposure by assessing premalignant alterations in gene expression. Wild-type (wt) or IRS-1 transgenic (Tg) mice, constitutively overexpressing the human (h) transgene in the liver, were pair-fed isocaloric liquid diets containing 0% or 24% ethanol for 8 weeks. The livers were used for histopathologic study and gene expression analysis, focusing on insulin, insulin-like growth factor (IGF) and wingless (WNT)-Frizzled (FZD) pathways, given their known roles in HCC. In wt mice, chronic ethanol exposure caused hepatocellular microsteatosis with focal chronic inflammation, reduced expression of proliferating cell nuclear antigen (PCNA) and increased expression of IGF-I and IGF-I receptor. In hIRS-1 Tg mice, chronic ethanol exposure caused hepatic micro- and macrosteatosis, focal chronic inflammation, apoptosis and disordered lobular architecture. These effects of ethanol in hIRS-1 Tg mice were associated with significantly increased expression of IGF-II, insulin, IRS-4, aspartyl-asparaginyl beta hydroxylase (AAH), WNT-1 and FZD 7, as occurs in HCC. In otherwise normal liver, chronic ethanol exposure mainly causes liver injury and inflammation with impaired DNA synthesis. In contrast, in the context of hIRS-1 overexpression, chronic ethanol exposure may serve as a cofactor in the pathogenesis of HCC by promoting expression of growth factors, receptors and signaling molecules known to be associated with hepatocellular transformation.


Induction, purification and characterization of alpha-N-acetylgalactosaminidase from Aspergillus Niger.
A set of filamentous fungi (42 strains) was screened for alpha-N-acetylgalactosaminidase activity, and a series of inducers and different cultivation conditions were tested. Enzyme production by the best producer Aspergillus niger CCIM K2 was optimized and scaled up. alpha-N-Acetylgalactosaminidase was purified to apparent homogeneity by cation exchange chromatography, gel filtration, and chromatofocusing, and basic biochemical data of the enzyme were determined: The native molecular weight was estimated by gel filtration to be approximately 440 kDa, the molecular weight of the subunit was determined to be 76 kDa and the pI = 4.8. The K (M) was 0.73 mmol/l for o-nitrophenyl 2-acetamido-2-deoxy-alpha-D-galactopyranoside (o-NP-alpha-GalNAc), and optimum enzyme activity was achieved at pH 1.8 and 55 degrees C. This alpha-N-acetylgalactosaminidase is a retaining-type glycosidase, and it was N-deglycosylated without any loss of activity.