Public interest in ∆8-Tetrahydrocannabinol (delta-8-THC) increased in US states that restricted ∆9-Tetrahydrocannabinol (delta-9-THC) use.
There is an expanding unregulated market for a psychotropic compound called ∆8-Tetrahydrocannabinol (delta-8-THC) that is being derived from hemp, but there are no empirical estimates of public interest in this compound. To measure public interest, we obtained yearly Google query fractions (QFs) that mentioned delta-8-THC (i.e., "delta 8," "delta-8," or "Δ8") for the past decade (from January 2011 through August 2021) for every country and territory in the world and every state in the United States (US) from Google Trends. We also obtained the same trends for the last complete month of data for all US states (July 2021) to compare across cannabis use policies. We summarized QFs across years, countries, US states and cannabis policies in US states using linear regression, means and ratios. We estimated raw search counts for the US using comscore.com. The global rate of delta-8-THC searches was stable between 2011 and 2019 before increasing by 257.0% from 2019 to 2020 and 705.0% from 2020 to 2021. In 2021, the rate of delta-8-THC searches in the US was at least 10 times higher than the rates in other countries or territories. In absolute terms, there were 22.3 million delta-8-THC searches in the US in the first 8 months of 2021 alone. Increases in delta-8-THC searches from 2020 to 2021 occurred in all 50 US states and the District of Columbia (Mean 854.2%; range = 256.4% - 2831.2%) but continued to vary substantially between states in 2021. In July 2021, the legal status of delta-9-THC use across US states explained 49.0% of the variance in delta-8-THC QFs between US states (R2 = 0.490; p < 0.001) and was inversely associated, where delta-8-THC QFs were higher in jurisdictions with stricter cannabis use policies. Public interest in delta-8-THC increased rapidly in 2020 and 2021 and was particularly high in US states that restricted delta-9-THC use. Jurisdictions should clarify whether delta-8-THC can be sold as a hemp product.


Exercise training during pulmonary rehabilitation in chronic obstructive pulmonary disease.
Exercise training is an essential part of a pulmonary rehabilitation program. Different forms of exercise training can be prescribed in COPD patients, depending on the mechanism of the exercise limitation in the individual patient.


(2,4,6-Trimethyl-phen-yl)boronic acid-triphenyl-phosphine oxide (1/1).
In the crystal structure of the title compound, C(9)H(13)BO(2)·C(18)H(15)OP, there are O-H⋯O hydrogen bonds between the O atom of triphenyl-phosphine oxide and one hy-droxy group of the boronic acid. Boronic acid mol-ecules form inversion-related hydrogen-bonded dimers in an R(2) (2)(8) motif. The structure is consolidated by inter-molecular C-H⋯O bonds and C-H⋯π inter-actions.


A biofuel cell harvesting energy from glucose-air and fruit juice-air.
The membraneless biofuel cell (BFC) is facile prepared based on glucose oxidase and laccase as anodic and cathodic catalyst, respectively, by using 1,1'-dicarboxyferrocene as the mediators of both anode and cathode. The BFC can work by taking glucose as fuel in air-saturated solution, in which air serves as the oxidizer of the cathode. More interestingly, the fruit juice containing glucose, e.g. grape, banana or orange juice as the fuels substituting for glucose can make the BFC work. The BFC shows several advantages which have not been reported to our knowledge: (1) it is membraneless BFC which can work with same mediator on both anode and cathode; (2) fruit juice can act as fuels of BFCs substituting for usually used glucose; (3) especially, the orange juice can greatly enhance the power output rather than that of glucose, grape or banana juice. Besides, the facile and simple preparation procedure and easy accessibility of fruit juice as well as air being whenever and everywhere imply that our system has promising potential for the development and practical application of BFCs.


HOTAIR functions as a competing endogenous RNA to regulate PTEN expression by inhibiting miR-19 in cardiac hypertrophy.
Sustained cardiac hypertrophy (CH) is related to a variety of physiological as well as pathological stimuli and eventually increases the risk of heart failure. HOTAIR has been identified as a competing endogenous RNA in multiple human biological processes. Whether lncRNA-HOTAIR is involved in the progress of CH and how it works still remain unknown. Herein, we found that HOTAIR was down-regulated, while miR-19 was up-regulated in both heart tissues from TAC-operated mice in vivo and cultural cardiomyocytes treated with Ang-II in vitro by real-time PCR. Meanwhile, HOTAIR expression was negatively correlated with miR-19 in TAC-operated mice. HOTAIR overexpression reduced cell surface area and the expression of hypertrophic markers ANP, BNP, and β-MHC in response to Ang-II stimulation as well as knockdown of miR-19. The further molecular mechanisms of HOTAIR action in CH demonstrated that HOTAIR may act as a competing endogenous RNA (ceRNA) for miR-19, thereby modulating the dis-inhibition of its endogenous target PTEN and playing an important role in inhibiting CH progress. These findings reveal a novel function of LncRNAs, which conduce to an extensive understanding of CH and provide novel research directions and therapeutic options for treating this disease.


Functional quorum sensing systems affect biofilm formation and protein expression in Yersinia pestis.
Gram-negative bacteria predominantly use two types of quorum sensing (QS) systems--LuxI-LuxR, responsible for synthesis of N-acylhomoserine lactones (AHL or AI-1 signal molecule), and LuxS, which makes furanones (AI-2 signal molecule). We showed that LuxS and two LuxI-LuxR (YtbIR and YpsIR) systems are functional in Y. pestis. Four different AHL molecules were detected in Y. pestis extracts using TLC bioassays. Our data suggest that YtbIR is responsible for the production of long chain AHLs. Confocal laser scanning microscopy showed that biofilm formation is decreased in an ytbIR ypsIR luxS mutant. Two-dimensional gel electrophoresis revealed altered levels of protein expression in a Y. pestis triple QS mutant at 26 degrees C and 37 degrees C.


A phantom study on usefulness of modifying image parameters to reduce radiation exposure and maintain image quality in chest HRCT.
To investigate the feasibility of reducing radiation dose by modifying tube voltage, window settings, and algorithm while maintaining image quality, based on the qualitative evaluation of its quality and the radiation dose, using raw data acquired in chest high-resolution computed tomography (HRCT). Radiation exposure was measured using a Fluke dosimeter while modifying the tube voltage to 80 and 100 from 120 kVp in a 64-slice multi-detector computed tomography for comparison and analysis. Changes in image quality as a result of the different tube voltage settings, 3 different window settings (-550, -600, and -700), and 2 algorithms (standard and edge) were analyzed using ImageJ. Relative to 120kVp, the dose decreased by approximately 67.8% and 36.9% at 80 and 100 kVp, respectively. Image quality assessment showed that changing the window setting to -700 (window level) after scanning with the tube voltage set at 100 kVp and applying the edge algorithm reduced the radiation dose while maintaining the image quality. The findings are significant with respect to the reduction of scan dose in that they demonstrate how radiation exposure can be reduced in a clinical scenario by altering the settings on an existing HRCT apparatus. Additional clinical trials and image assessments should be conducted on human participants to confirm the feasibility of altering HRCT settings for reducing scan doses.


Concentration and purification by magnetic separation of the erythrocytic stages of all human Plasmodium species.
Parasite concentration methods facilitate molecular, biochemical and immunological research on the erythrocytic stages of Plasmodium. In this paper, an adaptation of magnetic MACS(R) columns for the purification of human Plasmodium species is presented. This method was useful for the concentration/purification of either schizonts or gametocytes. The magnetic removal of non-parasitized red blood cells (in vivo and in vitro) using magnetic columns (MACS) was evaluated. This easy-to-use technique enriched schizonts and gametocytes from Plasmodium falciparum in vitro cultures with a very high degree of purity. In addition, all haemozoin-containing stages (schizonts and/or gametocytes) from the peripheral blood of infected patients could be concentrated using this method. This method is particularly useful for the concentration of non-falciparum species, which do not grow in culture and are otherwise difficult to obtain in large amounts.


Granulomatous and lymphocytic interstitial lung disease diagnosed by transbronchial lung cryobiopsy.
Granulomatous and lymphocytic interstitial lung disease is a pulmonary complication of common variable immune deficiency with significant morbidity and increased mortality. Diagnosis has historically been obtained by surgical lung biopsy as transbronchial biopsy typically yields insufficient tissue for definitive diagnosis from a disease process with a patchy distribution. However, the potential for significant morbidity and mortality with surgical lung biopsy exists, necessitating the development of alternative diagnostic approaches. We present a case of granulomatous and lymphocytic interstitial lung disease confirmed through minimally invasive transbronchial lung cryobiopsy and discuss the role of this modality in diagnosing interstitial lung disease.


Autoradiographic evidence that zona glomerulosa and capsular vessels of the human adrenal cortex are provided with different subtypes of adrenomedullin receptors.
Frozen sections of normal adrenal glands, obtained from patients undergoing unilateral nephrectomy for kidney cancer, were labeled in vitro with human [125I]ADM(1-52). Autoradiography and quantitative densitometry showed the presence of abundant ADM(1-52) binding sites in both zona glomerulosa (ZG) and capsular vessels, which were displaced with about the same efficiency by cold ADM(1-52) and rat ADM(1-50). The selective calcitonin gene-related peptide type 1 (CGRPI) ligand CGRP(8-37) eliminated, although less efficiently than ADMs, [125I]ADM(1-52) binding in the ZG, but not in the capsular vessels. These findings suggest the existence of different receptor subtypes for ADM in the human adrenal cortex. The CGRP(8-37)-sensitive receptors located in the ZG may mediate the well-known inhibitory effect of ADM on aldosterone secretion, while the CGRP(8-37)-insensitive receptors present in the capsular vessel may be involved in the ADM-induced rise in adrenal blood flow.


[The cilia of the lacrimal sac epithelium SEM studies (author's transl)].
On the basis of SEM studies it has been shown that the cilia are arranged into groups of 10 to 40 in the individual epithelial cells of the lacrimal sac. The cilia have a length of 15 to 20 micron.


Proteolysis of tropoelastin.
The presence of an enzyme associated with tropoelastin is described. The enzyme has a pH optimum between 7 and 9 and trypsin-like specificity. Upon incubation, tropoelastin (72,000 molecular weight) is cleaved into relatively high molecular weight fragments. In addition to the parent molecule, five discrete polypeptide bands are usually observed on SDS gels with molecular weights of approximately 57,000, 45,000, 36,000, 25,000 and 13-14,000.


Single-dose ciprofloxacin versus 12-dose erythromycin for childhood cholera: a randomised controlled trial.
Single-dose ciprofloxacin is effective for the treatment of severe cholera in adults. We assessed whether single-dose ciprofloxacin would be as effective as 3-day, 12-dose erythromycin in achieving clinical cure in children with severe cholera. We did a randomised, open label, controlled trial in children age 2-15 years with V cholerae O1 or O139 present in stool on dark-field microscopy. Children received either a single 20 mg/kg dose of ciprofloxacin (n=90) or 12.5 mg/kg of erythromycin (n=90) every 6 h for 3 days, and remained in hospital for 5 days. The primary outcome was clinical success of treatment, defined as cessation of watery stools within 48 h of start of drug treatment. Analysis was per protocol. This study is registered with the ClinicalTrials.gov Protocol Registration System at http://www.clinicaltrials.gov (registration number NCT 00142272) [corrected] Of 180 children randomised 162 completed the study. Treatment was clinically successful in 60% (47/78) of children treated with ciprofloxacin and in 55% (46/84) of those treated with erythromycin (difference 5% [95% CI -10 to 21]). Children receiving ciprofloxacin vomited less often (58%vs 74%; difference 16% [2 to 30]), had fewer stools (15 vs 21; 6 [0 to 9]), and less stool volume (152 vs 196 mL/kg; 43 mL/kg [13 to 87]) than those receiving erythromycin. Bacteriological failure was more common in ciprofloxacin-treated patients (58%vs 30%; 28% [13 to 43]) than erythromycin-treated patients. Single-dose ciprofloxacin achieves clinical outcomes similar to, or better than, those achieved with 12-dose erythromycin treatment in childhood cholera, but is less effective in eradicating V cholerae from stool.


Beneficial, safety, and antioxidant properties of lactic acid bacteria: A next step in their evaluation as potential probiotics.
The role of lactic acid bacteria (LAB) as probiotics as health promoting factors for human or veterinary practice has gained increasing interest during the last three decades. This is reflected in screening approaches of LAB strains in line with minimal requirements for a "probiotic" with regard to safety and functionality. The latter might also include natural antioxidant properties, thereby constituting an additional benefit in substituting synthetic antioxidants. The in vitro antioxidant assays conducted in this study included the scavenging of the 2,2-diphenyl-1-picrylhydrazil (DPPH) free radical, metal (Fe+2) ion chelation, determining the scavenging properties of the hydroxyl and superoxide radicals, and anti-lipid peroxidation. Analysis of DPPH free radical scavenging property for the microorganisms included in current study, showed Streptococcus salivarius ST59HK to exhibit the highest activity at a level of 85.24%. The greatest Fe+2 chelation activity with 98.2% was recorded for Str. salivarius ST62HK while the lowest was recorded for Str. salivarius ST48HK at 71.5%. The greatest and minimal hydroxyl radical scavenging levels were detected for Str. salivarius ST59HK (98.6%) and Lactiplantibacillus plantarum ST63HK (35.60%), respectively. Superoxide anion radical scavenging activity was highly exhibited by Str. salivarius ST61HK (54.62%) and the least exhibited by Enterococcus faecium ST651ea (18.7%). Lastly, the strains Lactobacillus gasseri ST16HK and E. faecium ST7319ea showed the highest and lowest anti-lipid peroxidation levels with 69.43% and 26.15%, respectively. Anti-oxidative properties appear to be strain specific and thus some of these strains could be potentially applied as natural antioxidants in fermented food products.


Selenium in placenta predicts birth weight in normal but not intrauterine growth restriction pregnancy.
Placental selenium, lead and cadmium concentrations were determined in a group of pregnancies with birth weight appropriate for gestational age and in a group of intrauterine growth restriction cases. Following adjustment for a number of confounding variables, selenium was found to be a significant predictor of newborn weight only in the group of pregnancies with birth weights appropriate for gestational age. Placental lead and cadmium levels were not associated with birth weight in either group.


Incomplete follow-up of hemoglobinopathy carriers identified by newborn screening despite reporting in electronic medical records.
Has the recent availability of newborn hemoglobinopathy screening results within patient electronic medical records (EMR) of birth hospitals facilitated follow-up by primary care pediatric providers? An online survey of all 137 primary care pediatric providers at a New York City academic medical center was conducted in 2008-2009 to assess practices for hemoglobin-apathy trait follow-up. Physicians were resurveyed 1 year later, following educational outreach and a letter of instruction underscoring the availability of screening results in the EMR. All 62 primary care pediatricians were surveyed at a nearby city hospital for comparison. Overall response rate for the initial survey at the teaching hospital was 58% for pediatricians (N = 57) and family physicians (N = 23), and 50% for pediatricians at the city hospital (N = 31). Despite high prevalence of hemoglobinopathies in the population served and screening results in EMRs, only 46.2% of providers surveyed at the academic center reported routinely checking results of their infant patients: 38.6% of pediatricians and 66.7% of family practitioners. Some respondents were unaware that results are available in the EMR. The proportion of providers checking screening results was not significantly affected by educational intervention (N = 40). Provision of recommended follow-up for a positive trait result was modestly improved, especially in referring families for genetic counseling (25% to 50%, p<.01). In contrast, most pediatricians (83%) at the city hospital routinely check and perform follow-up. Despite access to results in the EMR and targeted educational outreach, follow-up of hemoglobinopathy screening by primary care varies widely across clinical sites.


Factors associated with severity of COVID-19 disease in a multicenter cohort of people with HIV in the United States, March-December 2020.
Understanding the spectrum of SARS-CoV-2 infection and COVID-19 disease in people with HIV (PWH) is critical to provide clinical guidance and implement risk-reduction strategies. To characterize COVID-19 in PWH in the United States and identify predictors of disease severity. Observational cohort study. Geographically diverse clinical sites in the CFAR Network of Integrated Clinical Systems (CNICS). Adults receiving HIV care through December 31, 2020. COVID-19 cases and severity (hospitalization, intensive care, death). Of 16,056 PWH in care, 649 were diagnosed with COVID-19 between March-December 2020. Case fatality was 2%; 106 (16.3%) were hospitalized and 12 died. PWH with current CD4 count <350 cells/mm 3 (aRR 2.68; 95%CI 1.93-3.71; P<.001) or lowest recorded CD4 count <200 (aRR 1.67; 95%CI 1.18-2.36; P<.005) had greater risk of hospitalization. HIV viral load suppression and antiretroviral therapy (ART) status were not associated with hospitalization, although the majority of PWH were suppressed (86%). Black PWH were 51% more likely to be hospitalized with COVID-19 compared to other racial/ethnic groups (aRR 1.51; 95%CI 1.04-2.19, P=.03). Chronic kidney disease (CKD), chronic obstructive pulmonary disease, diabetes, hypertension, obesity, and increased cardiovascular and hepatic fibrosis risk scores were associated with higher risk of hospitalization. PWH who were older, not on ART, with current CD4 <350, diabetes, and CKD were overrepresented amongst PWH who required intubation or died. Unable to compare directly to persons without HIV; underestimate of total COVID-19 cases. PWH with CD4 <350 cells/mm 3 , low CD4/CD8 ratio, and history of CD4 <200, have a clear excess risk of severe COVID-19, after accounting for comorbidities also associated with severe outcomes. PWH with these risk factors should be prioritized for COVID-19 vaccination, early treatment, and monitored closely for worsening illness.


1-[5-(2H-1,3-Benzodioxol-5-yl)-3-(4-methyl-phen-yl)-2-pyrazolin-1-yl]ethanone.
In the title compound, C19H18N2O3, the pyrazoline ring is close to being planar (r.m.s. deviation = 0.035 Å) and subtends dihedral angles of 2.11 (8) and 82.63 (8)° with the p-tolyl and benzene rings, respectively. In the crystal, C-H⋯O and C-H⋯N hydrogen bonds link the mol-ecules, forming a three-dimensional network. A weak C-H⋯π inter-action involving the benzene ring is also observed.


Anion-Dependent Synthesis of Cu(II) Complexes with 2-(1H-Tetrazol-5-yl)-1H-indole: Synthesis, X-Ray Structures, and Radical Scavenging Activity.
Two mononuclear Cu(II) complexes, [Cu(phen)2(HL)]ClO4·H2O·2DMF (1) and [Cu(phen)2(HL)2]·EtOH (2), comprising 1,10-phentantroline (phen) and 2-(1H-tetrazol-5-yl)-1H-indole ligand (H2L) ligands are reported. Analysis and characterization of the samples were performed using standard physicochemical techniques, elemental analysis, nuclear magnetic resonance, Fourier transform infrared spectroscopy, and UV-vis spectroscopy. Single-crystal X-ray crystallography revealed the formation of a pentacoordinate complex in 1 and a hexacoordinate complex in 2, in which the anionic ligand HL- has undergone monodentate coordination through the tetrazole unit. Furthermore, the crystal structure of H2L·MeOH is also discussed. The potential application of compounds 1 and 2 in bioinorganic chemistry was addressed by investigating their radical scavenging activity with the 2,2-diphenyl-1-picrylhydrazyl radical (DPPH) and the results were supported also by theoretical calculations.


Selective lesion of medial septal cholinergic neurons followed by a mini-stroke impairs spatial learning in rats.
Reduced levels of hippocampal acetylcholine are a common finding in patients diagnosed with Alzheimer's disease, but it remains unclear what role this depletion plays in the development of dementia. It is possible that the reduced levels of acetylcholine increases the vulnerability of hippocampal neurons to future insults which could lead to neuronal death and cognitive impairment. One insult that is commonly observed in the demented elderly and often co-exists with Alzheimer's disease is stroke. In the current experiment, we used the immunotoxin 192 IgG-Saporin to specifically lesion the cholinergic neurons of the medial septum that project to the hippocampus. We then explored the effects of small, localised strokes in the hippocampus on spatial learning and memory. The combination of cholinergic depletion and stroke resulted in significant impairment on the spatial water maze compared to the performance of rats receiving either factor alone. Quantification of hippocampal damage revealed no difference in the overall lesion size of stroke-only or combined (cholinergic depletion and stroke) rats, suggesting that a more subtle mechanism is responsible for the observed impairment. We propose that healthy hippocampal neurons may normally be able to withstand, and compensate for a small ischemic insult. However, in the absence of cholinergic projections from the medial septum, these compensatory processes in the hippocampus may be compromised resulting in the spatial learning impairment reported here. This suggests an association between the cholinergic depletion observed during aging and the potential for functional recovery following stroke.


Anti-inflammatory effect of an adhesive resin containing indomethacin-loaded nanocapsules.
To analyze the anti-inflammatory and analgesic effects of an adhesive resin containing indomethacin-loaded nanocapsules in rat model. Adhesive resin disks with or without indomethacin-loaded nanocapsules were subcutaneously implanted into right hind paw of rats. A week after surgical procedure, 2% formalin solution was intradermally injected into plantar surface of paw. Nociceptive and inflammatory responses were evaluated by formalin test. Paw edema by pletismometer and mechanical hyperalgesia by von Frey test were performed on day 2, day 4, day 6, day 8, day 10 and day 12 after surgery. IL-6, IL-10, and lactate dehydrogenase (LDH) serum levels were determined by ELISA-sandwich test. Group containing indomethacin-loaded nanocapsules (NC) presented lower edema in the right hind paw at 24h after formalin injection than those of the control group (CT) (P<0.01). NC group showed decrease in the nociceptive response in phase I (neurogenic pain) compared to CT group (NC - 66.86±22.83s X CT - 130.17±35.83s, P<0.001). NC group presented supporting higher intensity of stimulus on days 8 and 12 (24h and 72h after formalin injection) (P<0.01 and P<0.02 respectively). The IL-6 serum level was also significantly higher in the NC group than CT group (p<0.001). These results indicate that an adhesive resin containing indomethacin-loaded nanocapsules has anti-inflammatory and nociceptive activities in a chemical model of acute inflammation. The present investigation confirms an adhesive resin with drug-loaded nanocapsules may be useful for improving therapeutic effect for adhesives to be used in deep cavities.


In vitro atrial septal ablation using high-intensity focused ultrasound.
High-intensity focused ultrasound (HIFU) has been applied clinically as a noninvasive therapeutic tool. Atrial septostomy is a palliative treatment for pulmonary artery hypertension. The purpose of this study was to assess the feasibility of atrial septal ablation in vitro using HIFU. Fourteen sections of atrial septum from pig hearts were treated. Focused ultrasound energy was applied with an operating frequency of 5.25 MHz at the nominal focal point intensity of 4.0 kW/cm(2) for 0.4 sec in 1-sec intervals. Lesions were created with ultrasonic exposures ranging from 40 to 120 pulses. There were significant relationships between HIFU exposure time and lesion area on the exposed site (R(2) = 0.3389, P < .0001) and lesion volume (R(2) = 0.6161, P < .0001). HIFU has the potential to create focal perforations without direct tissue contact. This method may prove useful for noninvasive atrial septostomy.


Specificity and sensitivity of diluted aPTT and anticardiolipin antibodies towards thrombosis and miscarriages in patients with systemic lupus erythematosus.
In 36 patients suffering from systemic lupus erythematosus (SLE), lupus anticoagulant (LA), as assessed by aPTT and diluted aPTT, and anticardiolipin antibodies (aCL) were studied. 14 patients, had a clinical history complicated by thrombosis and/or miscarriages. Among patients with thrombosis LA was positive in 42% and in 100% of patients when assessed by aPTT and diluted aPTT respectively; aCL were positive in 85.7% of patients. Among patients without a clinical history of thrombosis, 1 had prolonged aPTT, 3 had prolonged diluted aPTT and 5 had aCL positivity. Diluted aPTT was more sensitive than aPTT and aCL (p less than 0.01) to thrombosis and miscarriages; specificity to thrombosis and miscarriages ranged from 77.3% for aCL and 86.4% for diluted aPTT to 95.5% for aPTT but not significant differences were found. The study suggests that LA, as assessed by a sensitive test like diluted aPTT, is strongly associated to thrombosis and should therefore be considered an important risk factor.


Gender-specific effects of thyroid hormones on cardiopulmonary function in SHHF rats.
Spontaneously hypertensive heart failure (SHHF) rats develop hypertension and heart failure. We hypothesized that induction of hyperthyroidism should accelerate development of heart failure in male SHHF rats. Male and female SHHF rats received diets containing desiccated thyroid glands (DTG) or a control diet for 8 wk. Male and female Wistar-Kyoto rats were used as normotensive controls. DTG treatment reduced body weight in male, but not female, SHHF rats but increased body temperature and heart weight-to-body weight ratio in both genders. In DTG-treated male SHHF rats, serum triiodothyronine levels doubled relative to SHHF controls, whereas O2 consumption increased in DTG-treated SHHF rats. Frequency of breathing in air increased in DTG-treated female rats, and ventilation increased in DTG-treated male rats. Ventilatory equivalents exhibited gender differences in SHHF rats, were decreased in both genders by DTG treatment, and reached levels similar to those of Wistar-Kyoto rats. DTG increased heart rate, right ventricular pressure, and contractility in both genders and increased left ventricular pressure in SHHF male rats. These results refute our hypothesis and suggest that cardiopulmonary function of SHHF male rats may be improved by DTG treatment.


Adult Burkitt's and Burkitt-like non-Hodgkin's lymphoma--outcome for patients treated with high-dose therapy and autologous stem-cell transplantation in first remission or at relapse: results from the European Group for Blood and Marrow Transplantation.
To investigate the results of treatment for adult patients with Burkitt's and Burkitt-like non-Hodgkin's lymphoma (NHL) undergoing high-dose therapy and autologous stem-cell transplantation (ASCT), and to determine prognostic factors for this group. A retrospective analysis of 117 adult patients reported to the lymphoma registry of the European Group for Blood and Marrow Transplantation (EBMT) between June 1984 and November 1994. Seventy of these patients received high-dose therapy and stem-cell transplantation in first complete remission (CR). Data on all patients were reviewed, and prognostic factors were determined by univariate and multivariate analysis. The actuarial overall survival (OS) rate for the entire group was 53% at 3 years. The major factor predicting for outcome after transplantation was disease status: the 3-year actuarial OS rate was 72% for patients transplanted in first CR, compared with 37% for patients in chemosensitive relapse, and 7% for chemoresistant patients. For patients transplanted in first CR, disease bulk at the time of ASCT was the only factor predictive of progression-free survival (PFS) and OS. The results of high-dose therapy and ASCT for patients with relapsed disease, particularly chemosensitive relapse, are superior to those reported for conventional-dose salvage regimens. The results for patients transplanted in first CR require comparison with modern dose-intensive regimens.


Female pelvic medicine and reconstructive surgery fellows' case logs remained stable during the COVID-19 pandemic.
During the COVID-19 pandemic and subsequent staffing shortages there was concern about the case volume, and thus competency, of graduating trainees due to reduced surgical volumes. Elective procedures were particularly affected, which includes Female Pelvic Medicine and Reconstructive Surgery (FPMRS) cases. To understand whether FPMRS fellows were affected, we assessed their case logs for changes during the pandemic. The nationally aggregated case logs of graduating FPMRS fellows, both urology and obstetrics and gynecology (OBGYN), were obtained from the Accreditation Council for Graduate Medical Education. The available academic years (AYs) included 2018-2019, 2019-2020, and 2020-2021. Standard deviation for each index category was derived from the average and 90th percentile data. One-way analysis of variance was used to compare differences in case volumes for tracked index categories between AYs. Graduating fellows logged an average of 517.4 (standard deviation [SD] 28.6) and 818.0 (SD 37.9) cases, for urology and OBGYN respectively, over their fellowship training during the examined period. No significant differences in total surgical procedures were found for either specialty between pre-COVID AY 2018-2019 and COVID-affected AYs 2019-2020 and 2020-2021. For urology fellows, gastrointestinal (GI) procedures was the only index case category with a significant difference, and it was a decrease between the two COVID-affected AYs: 2020-2021 compared to 2019-2020 (8.9 vs. 4.2, p = 0.04). For both urology and OBGYN fellows, there was a statistically significant decrease in graft/mesh augmentation procedures from COVID-affected AY 2019-2020 to AY 2020-2021. This may be attributed to the reclassification of mesh removal cases from graft/mesh augmentation procedures to genital procedures in 2020-2021. There was not a significant decrease in these procedures from pre-COVID AY 2018-2019 to the COVID-affected AYs. There were no other statistically significant differences between AYs for OBGYN fellows. Surgical case volumes for FPMRS urology and OBGYN fellows who trained during the COVID-19 pandemic were comparable to those of their pre-pandemic peers. No significant differences between pre-COVID and COVID-affected years were found for either total surgical procedures or index case categories. Despite disruptions in health care nationwide, FPMRS trainee case volumes were largely unaffected.


Exemplary Practices in Cardiovascular Care: Results on Clinical Quality Measures from the EvidenceNOW Southwest Cooperative.
Identifying characteristics of primary care practices that perform well on cardiovascular clinical quality measures (CQMs) may point to important practice improvement strategies. To identify practice characteristics associated with high performance on four cardiovascular disease CQMs. Longitudinal cohort study among 211 primary care practices in Colorado and New Mexico. Quarterly CQM reports were obtained from 178 (84.4%) practices. There was 100% response rate for baseline practice characteristics and implementation tracking surveys. Follow-up implementation tracking surveys were completed for 80.6% of practices. Adult patients, staff, and clinicians in family medicine, general internal medicine, and mixed-specialty practices. Practices received 9 months of practice facilitation and health information technology support, plus biannual collaborative learning sessions. This study identified practice characteristics associated with overall highest performance using area under the curve (AUC) analysis on aspirin therapy, blood pressure management, and smoking cessation CQMs. Among 178 practices, 39 were exemplars. Exemplars were more likely to be a Federally Qualified Health Center (69.2% vs 35.3%, p = 0.0006), have an underserved designation (69.2% vs 45.3%, p = 0.0083), and have higher percentage of patients with Medicaid (p < 0.0001). Exemplars reported greater use of cardiovascular disease registries (61.5% vs 29.5%,), standing orders (38.5 vs 22.3%) or electronic health record prompts (84.6% vs 49.6%) (all p < 0.05), were more likely to have medical home recognition (74.4% vs 43.2%, p = 0.0006), and reported greater implementation of building blocks of high-performing primary care: regular quality improvement team meetings (3.0 vs 2.2), patient experience survey (3.1 vs 2.2), and resources for patients to manage their health (3.0 vs 2.3). High improvers (n = 45) showed greater improvement implementing team-based care (32.8 vs 11.7, p = 0.0004) and population management (37.4 vs 20.5, p = 0.0057). Multiple strategies-registries, prompts and protocols, patient self-management support, and patient-team partnership activities-were associated with delivering high-quality cardiovascular care over time, measured by CQMs. ClinicalTrials.gov registration: NCT02515578.


Downregulated expression of plasminogen activator inhibitor-1 augments myocardial neovascularization and reduces cardiomyocyte apoptosis after acute myocardial infarction.
The aim of this study was to examine whether selective plasminogen activator inhibitor type 1 (PAI-1) downregulation in the acutely ischemic heart increases the myocardial microvasculature and improves cardiomyocyte (CM) survival. Endogenous myocardial neovascularization is an important process enabling cardiac functional recovery after acute myocardial infarction. Expression of PAI-1, a potent inhibitor of angiogenesis, is induced in ischemic heart tissue. A sequence-specific catalytic deoxyribonucleic acid (DNA) enzyme was used to reduce PAI-1 levels in cultured endothelial cells and in ischemic myocardium. At the time of coronary artery ligation, rats were randomized into three groups, each receiving an intramyocardial injection (IMI) of a single dose at three different sites of the peri-infarct region consisting, respectively, of DNA enzyme E2 targeting rat PAI-1 (E2), scrambled control DNA enzyme (E0), or saline. Cardiomyocyte apoptosis, capillary density, and echocardiography were studied two weeks following infarction. The E2 DNA enzyme, which efficiently inhibited rat PAI-1 expression in vitro, induced prolonged suppression (>2 weeks) of PAI-1 messenger ribonucleic acid and protein in rat heart tissues after a single IMI. At two weeks, hearts from experimental rats had over five-fold greater capillary density, 70% reduction in apoptotic CMs, and four-fold greater functional recovery compared with controls. These results imply a causal relationship between elevated PAI-1 levels in ischemic hearts and adverse outcomes, and they suggest that strategies to reduce cardiac PAI-1 activity may augment neovascularization and improve functional recovery.


Developmental regulation of the A-type potassium-channel current in hippocampal neurons: role of the Kvbeta 1.1 subunit.
The rapidly inactivating A-type K+ current (IA) is prominent in hippocampal neurons; and the speed of its inactivation may regulate electrical excitability. The auxiliary K+ channel subunit Kvbeta 1.1 confers fast inactivation to Shaker-related channels and is postulated to affect IA. Whole-cell patch clamp recordings of rat hippocampal pyramidal neurons in primary culture showed a developmental decrease in the time constant of inactivation (tau(in)) of voltage-gated K+ currents: 17.9+/-1.5 ms in young neurons (5-7 days in vitro; n=53, mean+/-S.E.M.); 9.9+/-1.0 ms in mature neurons (12-15 days in vitro; n=72, mean+/-S.E.M., P<0.01). During the same developmental time, the level of Kvbeta 1.1 transcript increased more than two-fold in vitro and in vivo, determined by semi-quantitative reverse transcriptase-polymerase chain reaction for hippocampus. The hypothesis that up-regulation of Kvbeta 1.1 led to the changes in tau(in) was tested in vitro, using antisense knockdown. Kvbeta 1.1-specific antisense DNA was introduced with a modified herpes virus co-expressing enhanced green fluorescent protein and knockdown of Kvbeta 1.1 was verified by immunocytochemistry. Following transduction with the antisense virus, mature neurons reverted to tau(in) values characteristic of young neurons: 18.3+/-2.4 ms (n=20). The effect of antisense knockdown on electrical excitability was tested using current-clamp protocols to induce repetitive firing. Treatment with the antisense virus increased the interspike interval over a range of membrane depolarization (baseline membrane potential=-40 to +20 mV). This effect was most pronounced at -40 mV, where the ISI of the first pair of action potentials was nearly doubled. These data indicate that Kvbeta 1.1 contributes to the developmental control of IA in hippocampal neurons and that the magnitude of effect is sufficient to regulate electrical excitability. Viral-mediated antisense knockdown of Kvbeta 1.1 is capable of decreasing the electrical excitability of post-mitotic hippocampal neurons, suggesting this approach has applicability to gene therapy of neurological diseases associated with hyperexcitability.


Nrf2-mediated redox signalling in vascular health and disease.
Cells have evolved endogenous defence mechanisms to counteract oxidative stress, and the redox sensitive transcription factor nuclear factor erythroid 2-related factor 2 (Nrf2) plays a key role in the defence against oxidative stress via the induction of phase II and antioxidant enzymes.1-3 Under low oxidative or nitrosative stress, Nrf2 is sequestered by its cytosolic binding protein Kelch-like ECH Associated Protein 1 (Keap1) and targeted for proteasomal degradation.4 GSK-3β phosphorylation may also lead to Nrf2 degradation via an adaptor protein β-TrCP independent of Keap1.5 Modification of Keap1 cysteine residues leads to nuclear accumulation of Nrf2 via de novo synthesis, and in the nucleus Nrf2 binds to a Maf recognition/antioxidant response element in the promoter of phase II and antioxidant genes, such as NQO1, HO-1, and glutamate cysteine ligase and cystine transporter xCT involved in glutathione synthesis. Our studies in wild type and Nrf2-/- murine macrophages identified Nrf2 as an important transcription factor involved in the induction of CD36 and antioxidant stress genes in atherosclerosis.2 Notably, Nrf2 regulated redox signalling and antioxidant defences in response to hydroxynonenal are impaired in fetal umbilical vein endothelial and artery smooth muscle cells isolated from gestational diabetic and pre-eclamptic pregnancies.6,7 More recently, we have shown that pretreatment of rodents with the Nrf2 inducer sulforaphane increases Nrf2 mediated HO-1 expression in neurovascular unit after a stroke, maintaining blood-brain barrier (BBB) integrity and neurological function.8 Targeting the Nrf2 defence pathway using pharmacological and/or dietary inducers may provide a therapeutic approach to prevent oxidative stress induced damage in the peripheral vasculature or the BBB in stroke.Supported by British Heart Foundation, Heart Research UK, Henry Smith Charity.


Simulation of cross-correlograms resulting from synaptic connections between neurons.
A cross-correlation simulation program is presented. It is intended for use as a rapid initial screening test, to discriminate between possible connection configurations that may underlie observed cross-correlations. It can also serve to introduce students to the event cross-correlation technique. The simulation employs a simple model of two neurons with noisy membranes that may excite or inhibit one another or receive a common input from a third neuron. The model differs from its predecessors in that the user specifies the neurons and their interconnections by the resulting membrane potential trajectories, rather than discharge statistics. Illustrations of some simple performance characteristics are given, as well as examples of cross-correlograms resulting from more complex interactions between neurons. The latter demonstrate the usefulness of the simulation in the interpretation of cross-correlograms obtained from experimental data. The simulation is a LabVIEW (National Instruments) program executable under the Windows operating system (Microsoft) and is available for downloading from website www.utoronto.ca/respgrp/sim.htm.


Airway peptidoglycan and immunostimulatory DNA exposures have divergent effects on the development of airway allergen hypersensitivities.
Environmental exposures to toll-like receptor (TLR) ligands have been suggested to provide immunologic protection against allergic diseases. However, some TLRs use unique intracellular signaling pathways, suggesting that ambient TLR ligand exposures might induce a range of host responses. These investigations compared peptidoglycan (PGN; TLR2)-induced and immunostimulatory sequence DNA oligodeoxynucleotide (ISS-ODN; TLR9)-induced innate responses and determined how airway exposures to these TLR ligands affect adaptive immunity and the asthmatic phenotype. In in vitro and in vivo studies innate responses to PGN and ISS-ODN were compared. Alternatively, mice were intranasally immunized with ovalbumin (OVA) alone or OVA plus PGN or ISS-ODN, and adaptive immune profiles and responses to airway OVA challenge were assessed. PGN and ISS-ODN induced divergent innate responses predictive of their having TH2- and TH1-biasing adjuvant potential, respectively. Consistent with these findings, mice intranasally immunized with OVA alone had relatively weak adaptive responses, whereas intranasal OVA/PGN- and OVA/ISS-ODN-coimmunized mice had much stronger humoral and cellular responses that were TH2 and TH1 biased, respectively. Finally, on airway allergen challenge, mice intranasally immunized with OVA alone had modest TH2-biased airway hypersensitivity responses, whereas airway responses were greatly exaggerated for intranasal OVA/PGN-immunized mice. In contrast, intranasal OVA/ISS-ODN-immunized mice had little evidence of airway hypersensitivity after airway allergen challenge. Considered in a larger context, these results suggest that inspired air is likely to contain TLR ligands capable of both preventing and precipitating the asthmatic phenotype.


Private theatre utilisation in South Africa: a case study.
A large private operating theatre complex was investigated to address the lack of published South African benchmarks for utilisation. All major theatres were staffed during normal working hours (07h00 - 19h00), emergency cases being provided for on an ad hoc basis through spare capacity. An extensive billing database, amounting to 28 991 records of procedures performed during normal working hours and spanning the period October 2007 - February 2010, was data-mined using Visual Basic for Applications (VBA) scripts. Theatre utilisation was analysed per day, per theatre. The results showed an average utilisation of 43% with significant variation in day-to-day operations. If the very underutilised minor theatre was excluded from the analysis, overall utilisation rose to 48%. Individual theatre utilisation ranged from 14% to 61%. An analysis of change in utilisation with time during a day showed that peak utilisation of 71% was achieved at 09h30 (90 minutes after lists start). Utilisation dropped to 25% at the end of the working day and was sustained for some time after hours. The 48% utilisation observed was significantly lower than the global benchmark of between 70% and 80%.


Emotional and psychological impact of delayed craniosynostosis repair.
Among children with craniosynostosis, there exists an interesting dynamic involving parents' preconceptions of craniosynostosis and its repair, influenced in large part by differing cultural perspectives. In a time in which we are understanding how critical a child's early formative years are in influencing his/her emotional and psychological development, the authors describe one medical aspect involved in that dynamic process. The authors reviewed their cumulative experience at the Children's Hospital San Diego between January 2000 and June 2004 and identified nine children with significant craniofacial deformities and, for one reason or another, had delayed surgical repair. The authors have found that by age 6, parents will often bring their children back to their physician and insist on surgical correction. The significant motivating factor in most of these cases stems from teasing by classmates with respect to head shape. In this manuscript, we report and discuss some of the emotional and psychological issues associated with delayed craniosynostosis repair. Often times, these issues are overlooked or underemphasized in the overall surgical care of such patients.


Hydroethanolic extract of Smallanthus sonchifolius leaves improves hyperglycemia of streptozotocin induced neonatal diabetic rats.
To evaluate the effect of hydroethanolic extract of yacon on the hyperglycemia induced by streptozotocin (STZ) in neonatal rats. Wistar rats aged two days old received an intraperitoneal injection of STZ (160 mg/kg); after seven weeks, glycosuria was determined and animals with glucose levels above 250 mg/dL were included in the study. Groups of diabetic and non-diabetic rats were treated orally with yacon extract at a dose of 400 mg/kg/d for 14 d. Tests were made for phytochemical characterization, glucose tolerance and toxicity. The results showed that treatment with the extract reduced the glucose levels of fed diabetic rats and did not change the glucose levels of fasting diabetic and normal rats. Additionally, also it was observed that treatment with the extract reduced blood glucose levels of diabetic rats during the oral and intravenous glucose tolerance tests. There was no change in body weight, liver enzymes or mortality with yacon extract treatment. The phytochemical screening revealed the presence of caffeic acid, chlorogenic acid, ferulic acid and gallic acid. The data suggest that yacon extract reduces hyperglycemia, possibly by improving insulin sensibility through its phytochemicals constituents (phenolic compounds).


Primary structure of porcine Cu,Zn superoxide dismutase.
The complete amino acid sequence of Cu,Zn superoxide dismutase from porcine erythrocytes has been determined. Comparison of the sequence with that of the bovine enzyme shows an overall high degree of homology with conservation of the crucial residues and the presence of two regions prone to variation. In one of these hypervariable regions the insertion of one residue with respect to the bovine enzyme and evidence of structural microheterogeneity has been observed. On the basis of the three-dimensional structure of the bovine enzyme no obvious relationship is apparent between a specific amino acid replacement and the unique pH-dependence pattern of the activity of the porcine enzyme.


Molecular adsorption of H2 on small cationic nickel clusters.
An H2 molecule can bind molecularly on Ni4+ but it binds exclusively dissociatively on Ni5+ and Ni6+ and the adsorption behavior correlates with the relative reactivity of the metal clusters towards H2.


Cytoskeletal reorganization by soluble Wnt-3a protein signalling.
Wnt-3a is an intercellular signalling molecule that is involved in a variety of morphogenetic events. However, the molecular mechanisms underlying Wnt-3a signalling are poorly understood. We have sought to establish in vitro systems to assay the activity of this protein and investigate its biological roles. We prepared mouse L cells transfected with Wnt-3a cDNA, and found that their beta-catenin protein level was up-regulated. When conditioned medium (CM) was collected from cultures of the transfectants and added to nontransfected L cells, the beta-catenin level of the latter was also increased. Approximately 50% of the Wnt-3a proteins synthesized by the transfectants were secreted into the CM in a soluble form. These secreted Wnt-3a proteins formed an activity gradient in the environment surrounding the transfectants. Then, we studied whether Wnt-3a had any effect on cellular behaviour in vitro. When the CM containing Wnt-3a (W3a-CM) was added to cultures of C57MG mammary epithelial cells, their morphology was altered to exhibit closer intercellular contacts. Immunostaining for various adhesion and cytoskeletal proteins showed that the actin-microfilamental system was re-organized by the W3a-CM treatment. It induced a directional alignment of actin stress fibres and other actin-associated proteins. Moreover, villin, localized only at the perinuclear regions in untreated C57MG cells, was re-distributed to the leading edges of the cells, co-localizing with F-actin, in the presence of Wnt-3a. Our findings suggest that Wnt-3a protein, in the soluble form, can act to re-organize cytoskeletal structures.


Paediatric sutureless circumcision and modified circumcision: video demonstration.
Circumcision is undertaken using a variety of surgical methods. Modified circumcision for the hooded prepuce or mild glanular hypospadias mandates an excellent cosmetic result. Tissue glue is an alternative to sutures for circumcision in children and has significant advantages in terms of cosmesis and postoperative pain. We present two detailed videos demonstrating our technique for sutureless circumcision and modified circumcision. The incisions were marked on the outer and inner preputial skin. Incisions were made with a scalpel. Complete haemostasis was ensured. Tissue adhesive was placed onto the wound using a 32-gauge needle to allow controlled application. It is important to ensure that the coronal sulcus is free of glue at the end of the procedure. Once the circumcision is complete the penis can be cleaned and temporarily dressed. Between November 2008 and September 2011, we have used this technique for 57 circumcisions and 30 modified circumcisions. No complications occurred. All were followed up for a minimum of 3-6 months. The technique allows reproducible excellent cosmetic results, can be easily taught to junior surgical staff and should be considered as an alternative to a standard sutured circumcision.


Study of deformation and shape recovery of NiTi nanowires under torsion.
The nanomechanical properties, deformation, and shape recovery mechanism of NiTi nanowires (NWs) under torsion are studied using molecular dynamics simulations. The effects of loading rate, aspect ratio of NWs, and NW shape are evaluated in terms of atomic trajectories, potential energy, torque required for deformation, stress, shear modulus, centro-symmetry parameter, and radial distribution function. Simulation results show that dislocation nucleation starts from the surface and then extends to the interior along the {110} close-packed plane. For a high loading rate, the occurrence of torsional buckling of a NW is faster, and the buckling gradually develops near the location of the applied external loading. The critical torsional angle and critical buckling angle increase with aspect ratio of the NWs. Square NWs have better mechanical strength than that of circular NWs due to the effect of shape. Shape recovery naturally occurs before buckling.


Association between polymorphisms in the type 1 sigma receptor gene and schizophrenia.
Several antipsychotic agents such as haloperidol and rimcazole are known to bind to sigma receptors with high affinity, and evidence for a potential link between sigma receptors and the etiology of schizophrenia has been reported. The present study was conducted to systematically search for nucleotide variants of the type 1 sigma receptor gene in 48 schizophrenics. Two polymorphisms were found: GC-241-240TT in the 5' flanking region and Gln2Pro. These two polymorphisms were in nearly complete linkage disequilibrium with each other. The Pro2 variant of the Gln2Pro polymorphism changes the endoplasmic reticulum retention signal motif. These polymorphisms were examined in an extended sample of schizophrenics (n = 308) and controls (n = 433) and a significant association between the presence of the TT/Pro2 haplotype and schizophrenia was observed (odds ratio = 1.27, P = 0.04).


Fabrication of triple-crosslinked gelatin/alginate hydrogels for controlled release applications.
Hydrogels have been demonstrated as smart drug carriers to recognize the tumor microenvironment for cancer treatment, where the dynamic crosslinks in the hydrogel network contribute to the stimuli-responsive features but also result in poor stability and weak mechanical property of the hydrogels. Here, phenylboronic acid-grafted polyethyleneimine (PBA-PEI)-modified gelatin (PPG) was synthesized to crosslink alginate dialdehyde (ADA) through imine bonds and boronate ester bonds, and then calcium ions (Ca2+) were added to introduce the third calcium-carboxylate crosslinking in the network to form the triple-crosslinked PPG/ADA-Ca2+ hydrogels. Given the three types of dynamic bonds in the network, PPG/ADA-Ca2+ hydrogels possessed a self-healing manner, stimuli-responsiveness, and better mechanical properties compared to single- or double-crosslinked hydrogels. The controlled release capability of PPG/ADA-Ca2+ hydrogels was also demonstrated, showing the encapsulated molecules can be rapidly released from the hydrogel network in the presence of hydrogen peroxide while the release rate can be slowed down at acidic pH. Furthermore, PPG/ADA-Ca2+ hydrogels presented selected cytotoxicity and drug delivery to cancer cells due to the regulated degradation by the cellular microenvironment. Taken together, PPG/ADA-Ca2+ hydrogels have been demonstrated as promising biomaterials with multiple desirable properties and dynamic features to perform controlled molecule release for biomedical applications.


Diagnosis and prognostic value of restrictive ventilatory disorders in the elderly: a systematic review of the literature.
Although less extensively studied compared to pulmonary obstructive diseases, restrictive lung disease (RLD) is highly prevalent and frequently disabling in the adult and, more, the elderly population. The underlying conditions may be either primarily pulmonary diseases, such as idiopathic pulmonary fibrosis, or non respiratory conditions secondarily affecting the lung, e. g. congestive heart failure, or else conditions affecting the lung expansion, e. g. obesity or rib cage deformity. The diagnosis is frequently based on the measurement of surrogate indexes such as the forced vital capacity (FVC) used as a proxy for total lung capacity (TLC). As a consequence, diagnosis of RLD is often characterized by poor specificity. In the elderly, worsening in the quality of life and poor prognosis are variably, but significantly, associated to RLD, being the underlying condition an important source of variability. Several causes of RLD are preventable and treatable conditions. A prompt identification of these conditions may allow to slow the decline of respiratory reserve and, thus, to preserve both personal independence and resistance to acute respiratory infections. This review gives an update on the latest evidence available on the prevalence and the prognosis of RLD in the elderly. Studies were identified through systematic searches of the electronic database MEDLINE. Reference list of eligible papers were also manually searched.


Left kidney mobilization technique during radical antegrade modular pancreatosplenectomy (RAMPS).
Radical antegrade modular pancreatosplenectomy (RAMPS) has been accepted as a standard operation for distal pancreatic cancer. While enbloc retroperitoneal dissection in the "medial to lateral" direction is one of the most important steps in this oncologic procedure, it is technically challenging due to the depth of organs under the left costal margin, and poor exposure of the resecting organs in this area will increase the risk of incomplete oncologic dissection. To improve exposure of the left upper quadrant organs, left kidney was completely mobilized during RAMPS, and all the left upper quadrant organs were elevated and medialized by lap sponges packed in the retro-renal space. The operative and oncologic outcomes for patients who underwent our modified RAMPS with left kidney mobilization were evaluated. One hundred and forty-four patients with distal pancreatic cancer underwent this procedure from 2005 through 2016. The median operation time was 310 min (range, 132-899), and blood loss was 440 ml (25-2430). There was no complication associated to left kidney mobilization. The median number of harvested lymph nodes was 27 (3-87). While 77% of the tumors had microscopic retroperitoneal invasion, 96% of patients achieved negative retroperitoneal margin. Left kidney mobilization is useful for safe and oncologically sound lateral retroperitoneal dissection during RAMPS for distal pancreatic cancer.


MRI method for labeling and imaging decellularized extracellular matrix scaffolds for tissue engineering.
To develop a facile method for labeling and imaging decellularized extracellular matrix (dECM) scaffolds intended for regenerating 3D tissues. A small molecule manganese porphyrin, MnPNH2 , was synthesized and used to label dECM scaffolds made from porcine bladder and trachea and murine whole lungs. The labeling protocol was optimized on bladder dECM, and imaging on a 3T clinical scanner was performed to assess reductions in T1 and T2 relaxation times. In vivo MRI was performed on dECM injected in the rat dorsum to verify sensitivity of detection. Toxicity assays for cell viability, metabolism, and proliferation were performed on human umbilical vein endothelial cells. The incorporation of MnPNH2 and its long-term retention in dECM were assessed on transmission electron microscopy and ultraviolet absorbance of eluted MnPNH2 over time. All tissues, including thick whole 3D organs, were uniformly labeled and demonstrated high signal-to-noise on MRI. A nearly 10-fold reduction in T1 was consistently obtained at a labeling dose of 0.4 mM, and even 0.2 mM provided sufficient contrast in vivo and ex vivo. No toxicity was observed up to 0.4 mM, the maximum tested. Binding studies suggested nonspecific association, and retention studies in the labeled whole decellularized lungs revealed less than 20% MnPNH2 loss over 30 days, the majority occurring in the first 3 days after labeling. The proposed labeling method is the first report for visualizing dECM on MRI and has the potential for long-term monitoring and optimization of dECM-based organ tissue engineering.


Synthesis, properties and application research of atrazine Fe₃O₄@SiO₂ magnetic molecularly imprinted polymer.
Magnetic Fe3O4 nanoparticles were prepared by coprecipitation and then were coated with SiO2 on the surface. Fe3O4@SiO2 composite microspheres were modified by KH570. Using molecular imprinting technology, atrazine magnetic molecularly imprinted polymer was prepared by using atrazine as template molecule, methacrylic acid as functional monomer and ethylene glycol dimethacrylate as cross-linkers. The morphology, composition and magnetic properties of magnetic nanoparticles were characterized. The recognition selectivity of polymer was studied for template molecule and simulation by UV spectrophotometry. The adsorption properties and selectivity ability were analyzed by Scatchard analysis. Scatchard linear regression analysis indicated that there are two binding sites of the target molecules. The magnetic molecularly imprinted polymer has been applied to the analysis of atrazine in real samples. The results show that: the recovery rates and the relative standard deviation were 94.0∼98.7% and 2.1∼4.0% in corn, the recovery rates and the relative standard deviation were 88.7∼93.5% and 2.8∼7.2% in water.


Improving the quality of maternity services in Nepal through accelerated implementation of essential interventions by healthcare professional associations.
To assess whether the implementation of a package of activities through the joint action of three international healthcare professional associations (HCPAs) increased the use of essential interventions (EIs) for delivery and neonatal care. A noncontrolled pre-intervention versus post-intervention study was conducted from June 13 to December 13, 2016, among women older than 18 years of age, who had delivered at one of two urban tertiary hospitals in Nepal. The study included 9252 women. Minimal change was found after the implementation of EIs that were used frequently at baseline (e.g. social support during delivery in the emergency room, and promotion and support for early initiation of breastfeeding). By contrast, an increase was recorded for some EIs that had not been used regularly at baseline. For example, the rate of timely administration of prophylactic antibiotics before cesarean delivery increased from 0.0% (0/496) to 94.0% (409/435) at one hospital. Nonetheless, some EIs with low use at baseline did not show improvement after implementation (e.g. kangaroo mother care). The present study strengthened previous findings regarding the uptake of EIs following joint promotion by HCPAs in low-income settings.


Argon laser peripheral iridoplasty versus systemic intraocular pressure-lowering medications as immediate management for acute phacomorphic angle closure.
The purpose of this study was to compare the efficacy and safety of argon laser peripheral iridoplasty (ALPI) and systemic intraocular pressure (IOP)-lowering medications in the immediate management of acute phacomorphic angle closure. Consecutive cases of acute phacomorphic angle closure were randomized to receive ALPI and an intravenous or oral carbonic anhydrase inhibitor as initial treatment. Intravenous mannitol was administered for presenting IOP > 60 mmHg or IOP > 40 mmHg 2 hours posttreatment in both arms. Of 10 consecutive cases, six received medical therapy and four received ALPI. Fifty percent in the medical group and none in the ALPI group required intravenous mannitol. The ALPI group took less time to achieve IOP < 25 mmHg (18.8 ± 7.5 minutes versus 115.0 ± 97.0 minutes, P = 0.001, F test); had a greater IOP reduction within 30 minutes (69.8% ± 7.7% versus 40.9 ± 23.9%, P = 0.03, t-test); and had a consistently smaller post-attack cup to disc ratio (0.50 ± 0.02 versus 0.60 ± 0.20, P = 0.002, F test). ALPI offers greater safety, consistency, and efficacy than systemic IOP-lowering medications as initial treatment for phacomorphic angle closure.


Increased psychopathology and maladaptive personality traits, but normal cognitive functioning, in patients after long-term cure of acromegaly.
Active acromegaly is associated with psychopathology, personality changes, and cognitive dysfunction. It is unknown whether, and to what extent, these effects are present after long-term cure of acromegaly. The aim of the study was to assess psychopathology, personality traits, and cognitive function in patients after long-term cure of acromegaly. This was a cross-sectional study. We studied 68 patients after long-term cure (13±1 yr) of acromegaly and 68 matched controls. We compared these data with 60 patients treated for nonfunctioning pituitary macroadenomas (NFMAs) and 60 matched controls. Psychopathology was assessed using the Apathy Scale, Irritability Scale, Hospital Anxiety and Depression Scale, and Mood and Anxiety Symptoms Questionnaire short-form, and personality was assessed by the Dimensional Assessment of Personality Pathology short-form (DAPPs). Cognitive function was assessed by 11 tests. Compared with matched controls, patients cured from acromegaly scored significantly worse on virtually all psychopathology questionnaires and on several subscales of the DAPPs. Compared with NFMA patients, patients cured from acromegaly scored worse on negative affect (P=0.050) and somatic arousal (P=0.009) and seven of 18 subscales of the DAPPs (P<0.05). Cognitive function in patients cured from acromegaly did not differ from matched controls or patients treated for NFMA. Patients with long-term cure of acromegaly show a higher prevalence of psychopathology and maladaptive personality traits but not cognitive dysfunction, compared with matched controls and patients treated for NFMA. These results suggest irreversible effects of previous GH excess, rather than effects of pituitary adenomas per se and/or their treatment, on the central nervous system.


The human insulin-like growth factor II gene contains two development-specific promoters.
The insulin-like growth factors (IGF) play an important role in fetal and postnatal development. Recently, the nucleotide sequences of the cDNAs encoding IGF-I and IGF-II and part of the human IGF genes were reported. In this communication we describe two distinct IGF-II cDNAs isolated from a human adult liver and a human hepatoma cDNA library, respectively. Using these two cDNAs, we have established that the human IGF-II gene contains at least 7 exons. Two different IGF-II promoters have been identified, 19 kilobases (kb) apart, which are active in a development-specific manner. The promoter, active in the adult stage, is located only 1.4 kb downstream from the insulin gene.


Allele-specific gene expression and epigenetic modifications and their application to understanding inheritance and cancer.
Epigenetic information is characterized by its plasticity during development and differentiation as well as its stable transmission during mitotic cell divisions in somatic tissues. This duality contrasts to genetic information, which is essentially static and identical in every cell in an organism with only a few exceptions such as immunoglobulin genes in lymphocytes. Epigenetics is traditionally perceived as a means to regulate gene expression without a change in DNA sequence. This, however, does not exclude a potential role for genetic variations in providing differential backgrounds on which epigenetic modulations and their regulatory consequences are achieved. An effective approach to investigating the interplay between genetic variations and epigenetic variations is through allele-specific analysis of epigenetics and gene expression. Such studies have generated many new insights into functions of genetic variations, mechanisms of gene expression regulation, and the role of mutations and epigenetic alterations in human cancer. This article is part of a Special Issue entitled: Chromatin in time and space.


A Randomized, Multicenter, Evaluator-blind Study to Evaluate the Safety and Effectiveness of VYC-12L Treatment for Skin Quality Improvements.
Skin quality may be assessed by degrees of skin smoothness, fine lines, and hydration. VYC-12L is a recently developed hyaluronic acid filler to improve skin quality. This was a randomized, evaluator-blind study assessing safety and effectiveness of intradermal VYC-12L treatment for improving cheek skin smoothness, fine lines, and hydration. Participants (≥22 years) with moderate-to-severe investigator-assessed Allergan Cheek Smoothness Scale (ACSS) scores were randomized in 2:1 ratio to receive VYC-12L or control (no treatment with optional treatment). Effectiveness was assessed 1 month after last injection (initial or touch-up) by a responder rate (≥1-grade improvement from baseline on both cheeks) using investigator-rated ACSS and Allergan Fine Lines Scale (AFLS), and tissue dielectric constant probe-measured skin hydration. Safety was evaluated throughout. Participants (VYC-12L, n = 131; control, n = 71) were 86.1% female with a median age of 58.0 years. At month 1, ACSS and AFLS responder rates were statistically significantly higher in the VYC-12L group (57.9%, 58.3%, respectively) than in the untreated controls (4.5%, 5.4%, respectively; p < .001). VYC-12L ACSS and AFLS responder rates remained consistent throughout the 6-month follow-up. Six participants reported treatment-related adverse events; none led to study discontinuation. VYC-12L is an effective, well-tolerated treatment for lasting improvement of cheek skin smoothness, fine lines, and hydration.


Glucagonomas/diabetico-dermatogenic syndrome (DDS): a statistical evaluation of 407 reported cases.
Of the rare pancreatic endocrinomas, glu-cagonomas, either with or without diabetico-dermatogenic syndrome (DDS), are probably third in frequency after insulinomas and gastrinomas. This study was carried out to evaluate the present status of glucagonoma/DDS in a statistically reliable number of cases and to provide precise information to investigators actively working in this particular field of research. A total of 407 cases of glucagonoma were collected from the international literature and evaluated according to characteristic clinicopathologic features. Findings were: (1) The incidence of DDS was 57.2% (233/407). (2) The tail of the pancreas was predominantly involved, in 53.7% (213/397). (3) One-third of the tumors (80 of 276 for whom size was recorded; 29.0%) measured 20 mm or less. (4) Metastases occurred in 51.4% (209/407) and malignant tumors in 60.7% (247/407). (5) Multiplicity occurred in 11.8% (48/407), and associated multiple endocrine neoplasia type 1 in 13. 0% (53/407). (6) In the patients with DDS, the rates of hyperglucagonemia, necrolytic migratory erythema, diabetes mellitus, loss of weight, hypo-aminoacidemia, or anemia, as representative constituents of DDS, were all higher than rates in the overall series (P < 0.01). (7) The 10-year survival rate in the 233 patients with DDS was 51.6% in those with metastases and 64.3% in those without metastases (P < 0.001).


The Spanish Flu of 1918: A Historical Reflection and Lessons from Masonic Lodges.
A catastrophic Spanish flu pandemic spread throughout the world during 1918-1919. In the spring of 1918, an army training center at the Fort Riley Kansas reported the first cases of Spanish flu in the United States. The first reported cases of the Spanish Flu of the virus in Kansas were quite moderate. The Spanish flu took an ominous turn in the fall of 1918 when injured soldiers who contracted the Spanish flu returned to the United States, spreading the illness across urban and rural communities. During this period of the Spanish flu, the freemason lodges served as accessory hospitals to help manage the growing Spanish flu cases across the United States. In this paper, we explore the experiences, challenges, and lessons from Freemason lodges during the Spanish flu to provide context and historical insights into the overlaps between the Spanish Flu and the current COVID-19 pandemic.


Deacidification of Microalgal Oil with Alkaline Microcrystalline Cellulose.
Microalgal oil is considered a promising candidate for edible oils. However, investigation of the refining processes of microalgal oil has been limited, especially deacidification. In this work, microcrystalline cellulose (MCC) was pretreated using different methods and utilized for the first time in the deacidification of microalgal oil. Detection results from FTIR and XRD indicated alkali pretreatment had a significant effect on the structure of MCC. Some inter- and intramolecular hydrogen bonds in AMCC (alkali-pretreated MCC) were destroyed, and crystallinity index of cellulose decreased, which increased its adsorption capacity and the reaction of OH groups with free fatty acids. Some NaOH was adsorbed into AMCC through cellulose swelling, which also contributed to deacidification. The interaction with oil was also improved with many cracks and voids on the surface of AMCC. AMCC could reduce the acid value to about 2 mg KOH/g. Comparatively, original MCC and MCC pretreated with microwave or ultrasound did not exhibit the ability to deacidify. Furthermore, the conditions of alkali treatment were optimized. Treatment with 20% NaOH for 20 min was optimal. Compared with other adsorbents, such as sodium silicate and chitosan treated with alkali and resin, only AMCC could effectively reduce acid value while maintaining high lipid recovery. Therefore, AMCC was considered a better adsorbent for the deacidification of microalgal oil.


Curing experimental Bryophyllum tubiflorum poisoning of cattle with activated carbon, electrolyte replacement solution and antiarrhythmic drugs.
A slurry of activated carbon (activated charcoal) in electrolyte replacement solution given by stomach tube and antiarrhythmic drugs given parenterally cured 9 of 11 calves dosed 7 to 24 h previously with a lethal amount (20g/kg) of Bryophyllum tubiflorum flower heads. Two of another 4 calves treated 26 to 36 h after dosing with flowers survived. B. tubiflorum toxins are bufadienolides (cardiac glycosides). Activated carbon was effective at a single dose of 5 g/kg. Calves were rehydrated with oral electrolyte replacement solution at 150 ml/kg in divided doses over 24 h. Tachycardia was treated with intravenous lignocaine (200 mg doses) or propranolol (5 mg doses) and atrioventricular block with atropine (0.5 mg/kg).


Evaluating metabolic stress and plasmid stability in plasmid DNA production by Escherichia coli.
In the context of recombinant DNA technology, the development of feasible and high-yielding plasmid DNA production processes has regained attention as more evidence for its efficacy as vectors for gene therapy and DNA vaccination arise. When producing plasmid DNA in Escherichia coli, a number of biological restraints, triggered by plasmid maintenance and replication as well as culture conditions are responsible for limiting final biomass and product yields. This termed "metabolic burden" can also cause detrimental effects on plasmid stability and quality, since the cell machinery is no longer capable of maintaining an active metabolism towards plasmid synthesis and the stress responses elicited by plasmid maintenance can also cause increased plasmid instability. The optimization of plasmid DNA production bioprocesses is still hindered by the lack of information on the host metabolic responses as well as information on plasmid instability. Therefore, systematic and on-line approaches are required not only to characterise this "metabolic burden" and plasmid stability but also for the design of appropriate metabolic engineering and culture strategies. The monitoring tools described to date rapidly evolve from laborious, off-line and at-line monitoring to online monitoring, at a time-scale that enables researchers to solve these bioprocessing problems as they occur. This review highlights major E. coli biological alterations caused by plasmid maintenance and replication, possible causes for plasmid instability and discusses the ability of currently employed bioprocess monitoring techniques to provide information in order to circumvent metabolic burden and plasmid instability, pointing out the possible evolution of these methods towards online bioprocess monitoring.


Cost of renal transplant in Belgium.
The objective of this study was to analyze 1-year direct medical costs of kidney transplantation in Belgium. The analysis included the last 150 patients who received a kidney transplant, were treated with cyclosporine, and had 1 year follow-up data. All patient were adults (>18 years) at the time of transplantation. Patient files were retrospectively analyzed. Key clinical events, such as primary hospitalization for transplantation; immunosuppressive drug use; patient survival; graft survival; acute rejection; CMV infection; adverse events and serious complications; treatment of adverse events; treatment of complications; repeat hospitalization; and follow-up hospital consultations were recorded. Total length of stay in the hospital was also recorded. For each patient, information up to 1 year following renal transplantation (or until death if death occurred before 1 year posttransplantation) was collected. Cost information was obtained from anonymous hospital bills that provided amounts paid by the health care payer and patient. Two perspectives are considered in this study: health care payer (INAMI/RIZIV) perspective and patient perspective. For the whole population (n = 143), 7 patients with graft failure were excluded. The mean direct medical costs from the health care payer's perspective, and patient's perspective were 37,792 Euro, and 2,034 Euro, respectively. During this 1-year period, patients were hospitalized for an average of 29 days. One-year direct medical costs of kidney transplantation are substantial. In Belgium, most of the direct medical costs are borne by the health care payer.


Metabolome modulatory effects of Kigelia africana (Lam.) Benth. fruit extracts on oxidative stress, hyperlipidaemic biomarkers in STZ-induced diabetic rats and antidiabetic effects in 3T3 L1 adipocytes.
The management of diabetes is considered a global problem, and a cure is yet to be discovered. This study investigated the modulatory effect of Kigelia africana fruit on oxidative stress and hyperlipidaemic biomarkers in STZ-induced diabetic rats, profiled phytoconstituents using GC-TOF-MS and evaluated antidiabetic effects on 3T3 L1 adipocytes. Thirty male Wistar rats (120-150 g) were divided into six groups (n = 5). Diabetes was induced by a single intraperitoneal injection of STZ (60 mg/kg) and treated with 100, 200 and 400 of hexane fraction of KA for 28 days. Immunohistochemical evaluation was carried out using avidin-biotin immunoperoxidase (ABI) method. Catalase and SOD activities as well as the levels of total protein, albumin, bilirubin, triglyceride, cholesterol, and high-density lipoprotein were measured. The expressions of oxidative stress and hyperlipidaemic biomarkers alongside fasting blood glucose concentrations were remarkedly decreased in KA-treated diabetic rats. Moreover, there was a significant increase in endocrine cell distribution, area covered with increase in β-cell mass, composition and morphology of KA-treated animals. Additionally, there was constant up-regulation in 3T3 L1 adipocytes due to the presence of phytoconstituents. Kigelia africana fruit can act as a modulatory agent due to its ameliorative effects against oxidative stress.


Consequences and causes of geographic variation in the body size of a keystone predator,Notophthalmus viridescens.
Two subspecies of the predatory aquatic salamanderNotophthalmus, N. viridescens viridescens andN. v. dorsalis, differ in adult body size and geographic distribution. We tested whether experimental populations of the two predator subspecies differed in their effects on prey populations ofB. americanus, and whether observed differences in predator body size were genetic and/or environmentally induced. We compared the effects of predation by bothNotophthalmus subspecies on larvalBufo americanus by experimentally manipulating the densities (0, 2, or 4 newts/m3) and subspecies ofNotophthalmus (N. v. viridescens orN. v. dorsalis) added to artificial ponds. BothNotophthalmus subspecies significantly reducedB. americanus survival, but differed significantly in this effect. FewerBufo survived with the larger subspecies,N. v. viridescens, than with the smallerNotophthalmus subspecies,N. v. dorsalis. TheNotophthalmus subspecies differed in their patterns of adult and larval growth. Adults of the smaller subspecies,N. v. dorsalis, had a significantly higher growth rate than the larger subspecies,N. v. viridescens, under common environmental conditions, suggesting that differences in predator size were partly genetic, rather than entirely environmentally induced. LarvalN. v. dorsalis metamorphosed significantly later in the season than larvae ofN. v. viridescens, suggesting that larvalN. v. dorsalis had a lower growth rate than larvalN. v. viridescens. Differences in adult and larval growth, together with differences in the minimum adult size observed in natural populations, suggest that differences in the rate or duration of pre-adult growth may contribute substantially to observed differences in size.


Interleukin-18 Antagonism Improved Histopathological Conditions of Malaria Infection in Mice.
Interleukin 18 (IL-18) exerts pleiotropic roles in many inflammatory-related diseases including parasitic infection. Previous studies have demonstrated the promising therapeutic potential of modulating IL-18 bioactivity in various pathological conditions. However, its involvement during malaria infection has yet to be established. In this study, we demonstrated the effect of modulating IL-18 on the histopathological conditions of malaria infected mice. Plasmodium berghei ANKA infection in male ICR mice was used as a model for malaria infection. Modulation of IL-18 release was carried out by treatment of malarial mice with recombinant mouse IL-18 (rmIL-18) and recombinant mouse IL-18 Fc chimera (rmIL-18Fc) intravenously. Histopathological study and analysis were performed on major organs including brain, liver, spleen, lungs and kidney. Treatment with rmIL-18Fc resulted in significant improvements on the histopathological conditions of the organs in malaria-infected mice. IL-18 is an important mediator of malaria pathogenesis and targeting IL-18 could prove beneficial in malaria-infected host.


Changes in self-reported family history of breast cancer with change in case-control status.
In order to study recall bias in self-reported family history of breast cancer, we selected a sample of cases and controls from a case-control study nested in a cohort, and compared family history reported in a questionnaire at enrollment, and after the development of the disease. We assessed whether changes occurred in self-reported familial breast cancer due to a change in health status in women who developed breast cancer. The kappa of agreement for maternal history of breast cancer was 0.92 in cases, and 1.00 in controls; the kappa for history of breast cancer in sisters was 0.65 in cases, 0.88 in controls. By comparing two questionnaires collected before the diagnosis of the cases (index date), and one questionnaire administered after the index date, we were able to assess that the changes in answer observed among the cases were recorded in the second questionnaire before the index date, and therefore were independent from the diagnosis of cancer. The study seems to suggest that change in recall is of limited importance when collecting family history of first degree relatives, and that women recall the health history of their mother better than the health history of their sisters.


Organophosphate ester flame retardants and plasticizers in human placenta in Eastern China.
Organophosphate esters (OPEs) have been widely used in various products as alternatives to brominated flame retardants. Although widespread OPE exposure is expected in humans, the accumulation of OPEs has seldom been studied in the human body. In this study, 12 OPE analogs were analyzed in 50 human placentas collected in Eastern China. The concentrations of the 9 most frequently detected OPEs (Σ9OPEs) ranged from 34.4 to 862ng/g lipid weight (lw), with a median of 301ng/g lw. Tri(2-chloroethyl) phosphate (TCEP) was identified as the most abundant analog, with a median concentration of 142ng/g lw, followed by tributoxyethyl phosphate (TBEP) and triphenyl phosphate (TPhP). Statistical analysis showed no analog of OPEs or Σ9OPEs was positively correlated with the lipid content of the placentas. There were no correlations observed between the OPE concentrations and maternal characteristics. Food consumption habits exhibited weak effects on OPE levels in the placentas. Further investigation is required to determine the effects of OPEs on fetuses due to the expected increase in maternal exposure to these esters.


A novel p-terphenyl derivative inducing cell-cycle arrest and apoptosis in MDA-MB-435 cells through topoisomerase inhibition.
A novel series of p-terphenyl derivatives (1-4, 1a-4a) was successfully synthesized and their in vitro anticancer activities were evaluated. Compound 1, showing the best antiproliferative activity with IC50<1 μM against MDA-MB-435 cells, was further investigated. Compound 1 brought about a remarkable accumulation of MDA-MB-435 cells in G2/M phase prior to the induction of apoptosis. Further antitumor mechanism study indicated that compound 1, which inhibited the enzyme activity of Topo I and Topo IIα by interfering predominantly with the enzyme, could be topoisomerase suppressors instead of poisons. We conclude that compound 1 represents a novel class of Topo catalytic suppressors for developing new chemotherapeutic agents.


Interactions between inflammatory mediators in expression of antitumor cytostatic activity of macrophages.
Antitumor properties and participation in inflammatory events are important characteristics of activated macrophages. We show here that both antitumor cytostatic function of macrophages and participation of these cells at inflammatory sites are controlled by two main groups of mediators: cytokines (IL-1, TNF alpha) and eicosanoids (prostanoids and leukotrienes). These two groups of mediators represent a complex system of mutual interactions in regulation of their production and activities. Multiple sets of experiments with murine macrophages are discussed in favor of the views that PGE2 and lipoxygenase products oppose each other's actions, and that the regulating role of PGE2 in the secretions of cytokines are of pivotal importance in antitumor cytostasis of macrophages in vitro. Such observations can be extended to a situation ex vivo, showing that human macrophages harvested from inflammatory sites have markedly augmented cytostatic expression. It thus appears that the antitumor cytostatic function of macrophages is related to the production of inflammatory mediators by these cells. Accordingly, it might be that occurrence of inflammation in tumor-bearing individuals plays a role in the promotion of antitumor activity of macrophages.


Novel 3-aroylpyrazolo[5,1-c][1,2,4]benzotriazine 5-oxides 8-substituted, ligands at GABAA/benzodiazepine receptor complex: synthesis, pharmacological and molecular modeling studies.
The synthesis and binding studies of a series of 3-acylpyrazolo[5,1-c][1,2,4]benzotriazine 5-oxides 8-substituted are reported. High-affinity ligands at benzodiazepine site on GABA(A) receptor complex (GABA(A)/BzR complex) were obtained when the 3-aroyl substituent is represented by a five-member heteroaroyl ring (furoyl-, thenoyl-, and pyrroyl-). Moreover the type of heteroaroyl ring at position 3 influences the feature of the substituent at position 8 to obtain high-affinity ligands: a 'hydrogen-bond acceptor ring' at position 3 is synergic with an electron donor substituent at position 8, while a 'hydrogen-bond donor ring' is synergic with a withdrawing substituent. Compounds 8a, 9b, and 11 were deeply studied in vivo for their pharmacological effects considering six potential benzodiazepine actions: motor coordination, anticonvulsant action, spontaneous motor activity and explorative activity, anxiolytic-like effects, mouse learning and memory modulation, and ethanol-potentiating action. To rationalize and qualitatively interpret the GABA(A)/Bz binding affinities of compounds 8a and 11, a dynamic molecular modeling study has been performed, with the aim of assessing the preferred geometry of protein-ligand complex.


The cytotoxic activity of hematoheme: evidence for two different mechanisms.
Hematoheme displays a potent cytolytic activity toward erythrocytes either in the presence of hydrogen peroxide and a halide ion (system I) or in the presence of oxygen and a reducing agent (system II). In system I it resembles the cytotoxic activity of various peroxidases, whereas in system II it resembles the destructive activity of bleomycin and a variety of metal complexes. Both types of reactions presumably involve the generation of active oxygen species, which are responsible for the damaging effects. In a first attempt to compare the chemical mechanisms of the two types of reactions we used various traps and scavengers of active oxygen species. Tryptophan as well as tyrosine and uric acid were found to be potent inhibitors of the hematoheme-H2O2-halide reaction but do not significantly inhibit the hematoheme-O2-ascorbate reaction. Pyridine, on the other hand, inhibits the oxygen-mediated reaction, but does not affect the peroxide-halide-mediated activity. The cytolytic activity of photoactivated hematoporphyrin, which involves the generation of singlet oxygen, is activated by pyridine and is strongly inhibited by diphenylisobenzofuran. The latter compound is a weak activator of both hematoheme reactions. We conclude that the two hematoheme reactions proceed by two different mechanisms and probably generate different toxic intermediates. The results further suggest that the toxic intermediate generated by photoactivated hematoporphyrin (singlet oxygen) does not play a dominant role in either of the two hematoheme reactions.


Anatomical acromioclavicular joint stabilization with chemically sterilized tendon allografts: A retrospective study.
The purpose of this retrospective study was to analyze whether chemically sterilized tendon allografts perform as well as other non-sterilized allografts and autografts as described in the literature for anatomical acromioclavicular joint stabilization for the treatment of Rockwood III-V. Allografts are still described as a factor for higher re-rupture rates. Retrospective data were collected from 21 acromioclavicular joint stabilizations performed by a single surgeon and performed between 2011 and 2014 using sterilized semitendinosus allografts. The primary endpoints were re-rupture and complication rates. Secondary endpoints were AC-joint stability, pain level, return to work and sport and the range of motion. No re-ruptures occurred during the mean follow-up time of 33 months. Zero complications occurred directly after surgery, but three complications later than three weeks after surgery. All cases resolved without further surgery. After surgery, stability significantly improved for all patients. Post-surgery, 19 patients had stable acromioclavicular joints and only two patients showed minor instabilities. Range of motion returned to the range of the healthy shoulders for all patients. Chemically sterilized semitendinosus allograft use for anatomic AC-joint stabilization is equivalent to the use of other allografts or autografts and required no hardware removal. No donor age or graft size dependence was observed, due to zero re-ruptures.


From Structure-Activity Relationships on Thiazole Derivatives to the In Vivo Evaluation of a New Radiotracer for Cannabinoid Subtype 2 PET Imaging.
Upregulation of the cannabinoid type 2 receptors (CB2R) unveils inflammation processes of pathological disorders, such as cancer, pain, or neurodegenerative diseases. Among others, CB2R agonist A-836339 has been labeled with carbon-11 for PET imaging of the CB2R and displayed promising results in a mouse model of Alzheimer's disease. The aim of the present work was to develop fluorinated analogs of A-836339 for labeling with fluorine-18 to design a new PET tracer for CB2R imaging. Seven fluorinated analogs of A-836339 were synthesized in two to three steps and their binding affinities and selectivities for both the human and the mouse CB2R were measured as well as their early ADME profiles. Among them, compound 2f (KihCB2R = 0.1 nM, KihCB1R/KihCB2R = 300) displayed high affinity and selectivity for CB2R but also promising lipophilicity, kinetic solubility, and membrane permeation properties and was further selected for in vitro metabolism studies. Incubation of 2f with human or rat liver microsomes followed by LC/MS analysis revealed the presence of six different metabolites mainly resulting from oxidation reactions. A tosylated precursor of 2f was synthesized in two steps and radiolabeled with fluorine-18 to afford [18F]2f in 15 ± 5% radiochemical yield and a molar activity of 110 ± 30 GBq/μmol. Autoradiographies of rat spleen and biodistribution studies in healthy rats including pretreatments with either CB2R or CB1R-specific compounds suggested that [18F]2f is a specific tracer for the CB2R in vivo. We have therefore demonstrated here that [18F]2f is a promising novel tracer for imaging CB2R in vivo using PET. Further investigation in animal models of inflammation will follow.


Differences in allele frequencies of autosomal dominant hypercholesterolemia SNPs in the Malaysian population.
Hypercholesterolemia is caused by different interactions of lifestyle and genetic determinants. At the genetic level, it can be attributed to the interactions of multiple polymorphisms, or as in the example of familial hypercholesterolemia (FH), it can be the result of a single mutation. A large number of genetic markers, mostly single nucleotide polymorphisms (SNP) or mutations in three genes, implicated in autosomal dominant hypercholesterolemia (ADH), viz APOB (apolipoprotein B), LDLR (low density lipoprotein receptor) and PCSK9 (proprotein convertase subtilisin/kexin type-9), have been identified and characterized. However, such studies have been insufficiently undertaken specifically in Malaysia and Southeast Asia in general. The main objective of this study was to identify ADH variants, specifically ADH-causing mutations and hypercholesterolemia-associated polymorphisms in multiethnic Malaysian population. We aimed to evaluate published SNPs in ADH causing genes, in this population and to report any unusual trends. We examined a large number of selected SNPs from previous studies of APOB, LDLR, PCSK9 and other genes, in clinically diagnosed ADH patients (n=141) and healthy control subjects (n=111). Selection of SNPs was initiated by searching within genes reported to be associated with ADH from known databases. The important finding was 137 mono-allelic markers (44.1%) and 173 polymorphic markers (55.8%) in both subject groups. By comparing to publicly available data, out of the 137 mono-allelic markers, 23 markers showed significant differences in allele frequency among Malaysians, European Whites, Han Chinese, Yoruba and Gujarati Indians. Our data can serve as reference for others in related fields of study during the planning of their experiments.


Rat astrocytes express interferon-gamma immunoreactivity in normal optic nerve and after nerve transection.
Astrocytes are pivotal components of immune reactions in the CNS. We further support this notion by the localization of the lymphokine interferon-gamma (IFN-gamma), which plays an important role during immune responses, to astrocytes in rat optic nerve (ON). Astrocytes identified by glial fibrillary acidic protein immunoreactivity were IFN-gamma positive in normal and transected ON while oligodendrocytes did not express IFN-gamma immunoreactivity. These findings indicate that astrocytes can generate important signals which orchestrate immunoinflammatory responses in the brain.


The lysosome as an imperative regulator of autophagy and cell death.
Lysosomes are single membrane-bound organelles containing acid hydrolases responsible for the degradation of cellular cargo and maintenance of cellular homeostasis. Lysosomes could originate from pre-existing endolysosomes or autolysosomes, acting as a critical juncture between autophagy and endocytosis. Stress that triggers lysosomal membrane permeabilization can be altered by ESCRT complexes; however, irreparable damage to the membrane results in the induction of a selective lysosomal degradation pathway, specifically lysophagy. Lysosomes play an indispensable role in different types of autophagy, including microautophagy, macroautophagy, and chaperone-mediated autophagy, and various cell death pathways such as lysosomal cell death, apoptotic cell death, and autophagic cell death. In this review, we discuss lysosomal reformation, maintenance, and degradation pathways following the involvement of the lysosome in autophagy and cell death, which are related to several pathophysiological conditions observed in humans.