[Study on the effect of AIDS preventive cascade services provided by social organizations for men who have sex with men in China].

Objective: To analyze the effect and main gaps of each stage in the AIDS prevention cascade for men who have sex with men (MSM) provided in intervention projects supported by the China AIDS Fund for non-governmental organizations (CAFNGO) and provide suggestions to improve the quality of cascade services and project management. Methods: Data were collected through the CAFNGO management information system and field interviews to analyze the differences in the number of MSM receiving HIV testing and confirming tests, the newly reported patients, and the number of antiviral treatment (ART) referrals of newly established reported patients among different social organization service areas. A service chain chart was also drawn. Results: Between 2016 and 2020, 1 508 MSM intervention projects were funded by CAFNGO, including 1 183 234 MSM being mobilized to receive HIV testing. However, only 68.8% (1 183 234/1 719 139) of the testing capacity of social organizations was covered by these projects. As a result, 55 783 HIV-positive MSM were detected in preliminary screening, and only 86.6% (48 327/55 783) received confirming tests. The proportion of newly reported infections was 3.8% (45 347/1 183 234). The ratio of antiviral treatment (ART) referrals for newly reported patients between 2017 and 2020 was 89.8% (32 719/36 444). 75.8%(1 143/1 508) of total MSM intervention projects were implemented by community-based organizations (Non-registered civil affairs departments). In comparison, organizations registered in civil affairs departments took up 24.2% (365/1 508) of the total MSM intervention projects. No significant difference was noticed in the proportion of newly reported infected (3.8% and 3.8%) and the ratio of ART referrals (89.7% and 89.9%) between community-based organizations and registered organizations' projects. But these two proportions are significantly different between these two types of organizations in some areas in China. Conclusions: The AIDS prevention cascade established in CAFNGO has effectively promoted the early detection and treatment of infected MSM. However, CAFNGO needs more financial support to extend testing coverage for MSM. Meanwhile, confirmation testing for positives in preliminary screening and ART referrals needs to be improved for newly reported patients. In addition, various capacity building needs to be provided for different social organizations.

[Study on the demand of social organizations working for female sex workers regarding project management and capacity building of HIV prevention and treatment].

Objective: To understand the capacity building needs on social organizations providing HIV prevention and treatment services for female sex workers (FSW). Methods: Questionnaires and interview were conducted with the heads of social organizations participating in China AIDS Fund for Non-Governmental Organizations (CAFNGO) project 2017-2018. Data from the CAFNGO's information system were compiled and analyzed using Excel 2016 and SPSS 25.0 software. The distribution of social organizations, availability of funds, and social organizations' needs for capacity building were analyzed. Results: Nationwide, 184 social organizations were involved in project '2017-2018 CAFNGO's FSW field work'. Out of which, 156 answers were valid. Social organizations that participated in the implementation of fund projects were mainly concentrated in the western region, accounting for 44.0% (81/184), with Sichuan, Guangxi, and Yunnan being the majority. However, the eastern part received the most financial support. Social organizations expressed the highest demand for project data collection and analysis, accounting for 68.6% (107/156). Items on risk analysis, response, and quality control project ranked the second, accounting for 64.1% (100/156). Results showed that statistically significant differences were seen on capacity building needs among social organization leaders with different levels of training on management of planning and finance of the project (χ2=5.78,P=0.016;χ2=8.99,P=0.003). Conclusions: Currently, the number of social organizations and the related fund provision concerning HIV prevention and control among FSWs were not consistent in China. Thus, it is necessary to encourage, guide, and support the development of social organizations and satisfy social organizations' needs on capacity-building and planning.

The STING-IRF3 pathway is involved in lipotoxic injury of pancreatic ß cells in type 2 diabetes.

Lipotoxic injury of pancreatic ß cells is an important pathological feature in type 2 diabetes mellitus (T2DM). Stimulator of interferon genes (STING) can recognize its own DNA leaked into the cytoplasm from damaged mitochondria or nuclei of the host cell, thus activating its downstream factor interferon regulatory factor 3 (IRF3), causing inflammation and apoptosis. The STING-IRF3 signaling pathway is closely related to glycolipid metabolism, but its relationship with the lipotoxicity of pancreatic ß cells has rarely been reported. Here, we investigated the role of the STING-IRF3 signaling pathway in lipotoxicity-induced inflammation, apoptosis, and dysfunction of pancreatic ß cells. We examined the activation of STING and IRF3 in islets of db/db mice and identified the role of the STING-IRF3 signaling pathway in palmitic acid (PA)-induced lipotoxic injury of INS-1, a rat insulinoma cell line. STING and phosphorylated IRF3 including downstream interferon-ß were upregulated in islets of db/db mice and PA-induced INS-1 cells. Gene silencing of STING or IRF3 ameliorated PA-induced INS-1 cell inflammation and apoptosis, and reversed impaired insulin synthesis. Additionally, PA induced downregulation of the phosphoinositide 3-kinase-AKT signaling pathway, and impaired high glucose-stimulated insulin secretion was reversed after knockdown of STING or IRF3. Our results suggest that activation of the STING-IRF3 pathway triggers inflammation and apoptosis of pancreatic ß cells, leading to ß-cell damage and dysfunction. Hence, inhibition of this signaling pathway may represent a novel approach for ß-cell protection in T2DM.

Correlation between the hemoporfin-mediated photodynamic treatment response and the dermoscopy vascular pattern in patients with a port-wine stain: a prospective study.

BACKGROUND: Vascular targeted photodynamic therapy (PDT) is a novel and promising therapy for the treatment of port-wine stains (PWS). There has been little prior exploration to our knowledge of how the dermatological vascular pattern may predict the response to PDT. OBJECTIVES: To analyse whether the vascular pattern classifications of PWS by dermoscopy can predict the efficacy of PDT. METHODS: This prospective cohort study included 163 patients with a clinical diagnosis of PWS who were treated twice with hemoporfin-mediated photodynamic therapy (HMME-PDT) at two-month intervals and followed up for 6 months. The vascular manifestations of dermoscopy with PWS were independently classified into 8 categories by 3 dermatologists. Images of the lesions were taken using VISIA, and the vascular patterns were imaged by dermoscopy by the same investigator. Images were captured before and after each treatment. The efficacy was evaluated with pre- and post-treatment VISIA images, and correlations between efficacy and vascular patterns were analysed by four dermatologists in a blinded and independent manner, between 10 January 2019 and 11 December 2019. RESULTS: In the dermoscopy images for the whole cohort, dotted and globular vessels (15.3%), short clubbed vessels (18.4%) and curved vessels (12.9%) were highly associated with cure and beneficial treatment effects. Pale halos surrounding brown dots (8.0%) and arborizing vessels (9.8%) were mainly correlated with skin lesion alleviation. Mixed vessels (12.9%), a grey-whitish veil (11.7%) and reticular patterns (11.0%) were mainly associated with no effect. The differences between each subgroup were statistically significant (P = 0.000). CONCLUSIONS: There is a clear correlation between the efficacy of PDT and the dermoscopy pattern in patients with PWS. Dermoscopy may therefore provide very useful clinical information prior to treatment in these cases. In addition, the vascular manifestations of PWS determined by dermoscopy help to predict response to PDT and manage patient expectations.

[Comparison of the intact and segmented dissection for surface preparation of the cochlea in mice].

Objective: To compare intact dissection and segmented dissection of cochlear surface preparation in adult mice. Methods: From February to March, 2019, Six adult C57BL/6 mice were randomly divided into 2 groups: one group (3 mice) for the intact dissection while the other group (3 mice) for the segmented dissection. Cochlear hair cells were labeled with phalloidin for evaluation of the integrity of the basilar membrane. Results: The basilar membranes can be completely dissected from the cochlea by two approaches. The average dissection time is (16.33±1.86)min with the intact dissection approach while (23.66±3.88) min with the segmented dissection(t=-4.173, P=0.002). Immunofluorescence analysis showed all cochlear hair cells werevisible and intact in two groups. Conclusion: Cochlear basilar membrane can be dissected intact in a short time through both approaches. The approaches selection is dependent on the purpose of experiment and operators' experience.

Concomitant targeting of BCL2 with venetoclax and MAPK signaling with cobimetinib in acute myeloid leukemia models.

The pathogenesis of acute myeloid leukemia (AML) involves serial acquisition of mutations controlling several cellular processes, requiring combination therapies affecting key downstream survival nodes in order to treat the disease effectively. The BCL2 selective inhibitor venetoclax has potent anti-leukemia efficacy; however, resistance can occur due to its inability to inhibit MCL1, which is stabilized by the MAPK pathway. In this study, we aimed to determine the anti-leukemia efficacy of concomitant targeting of the BCL2 and MAPK pathways by venetoclax and the MEK1/2 inhibitor cobimetinib, respectively. The combination demonstrated synergy in seven of 11 AML cell lines, including those resistant to single agents, and showed growth-inhibitory activity in over 60% of primary samples from patients with diverse genetic alterations. The combination markedly impaired leukemia progenitor functions, while maintaining normal progenitors. Mass cytometry data revealed that BCL2 protein is enriched in leukemia stem/progenitor cells, primarily in venetoclax-sensitive samples, and that cobimetinib suppressed cytokine-induced pERK and pS6 signaling pathways. Through proteomic profiling studies, we identified several pathways inhibited downstream of MAPK that contribute to the synergy of the combination. In OCI-AML3 cells, the combination downregulated MCL1 protein levels and disrupted both BCL2:BIM and MCL1:BIM complexes, releasing BIM to induce cell death. RNA sequencing identified several enriched pathways, including MYC, mTORC1, and p53 in cells sensitive to the drug combination. In vivo, the venetoclax-cobimetinib combination reduced leukemia burden in xenograft models using genetically engineered OCI-AML3 and MOLM13 cells. Our data thus provide a rationale for combinatorial blockade of MEK and BCL2 pathways in AML.

CD56 expression in benign and malignant thyroid lesions.

INTRODUCTION: Thyroid cancer is the most common endocrine malignancy with more than 95% originating from follicular epithelial cells. Diagnostic dilemma may arise in occasional cases such as when an encapsulated nodule with a follicular growth pattern exhibits clear nuclei with grooves making it difficult to distinguish a follicular adenoma from encapsulated follicular variant papillary thyroid carcinoma. This study aimed to evaluate the diagnostic utility of an immunohistochemical marker, CD56, to distinguish between benign and malignant thyroid lesions. MATERIALS AND METHODS: We retrospectively studied CD56 expression in 54 benign and 54 malignant thyroid lesions using archival formalin fixed paraffin-embedded tissue blocks for the study period from January 2010 to December 2015, diagnosed in a tertiary hospital. RESULTS: CD56 was expressed in 52/54 (96.3%) of benign specimens and only 24/54 (44.4%) of malignant ones. The malignant specimens comprised 31 (57.4%) papillary thyroid carcinomas (PTC), 11 (20.3%) follicular carcinomas (FC), seven (13%) medullary thyroid carcinomas (MC), one (1.9%) poorly differentiated carcinoma (PC) and four (7.4%) anaplastic carcinomas (AC). CD56 was not expressed in 28/31 (90.3%) of the PTCs, 1/11 (9.1%) FCs, 1/4 (25%) of ACs while all MCs and the PD were positive. The benign group comprised nodular hyperplasias (29/54), lymphocytic thyroiditis (10/54), follicular adenomas (FA) (14/54) and one hyalinising trabecular tumour. CD56 was expressed in all the benign cases except one FA and one nodular hyperplasia. Thirteen of the 14 FAs were CD56 positive. The difference in expression between benign and malignant tumours was statistically significant as the p value was <0.01. CONCLUSION: CD56 is a potentially good immunohistochemical marker for differentiating papillary thyroid carcinoma from other benign follicular lesions of the thyroid especially in differentiating follicular variant PTC from FA in equivocal cases.

Bilateral Proximal Femur Fractures in a Patient with Renal Tubular Acidosis: A Case Report.

The diagnosis of pathological fractures is on the rise. The morbidity involved does not only burden the patient and their families but it has a great toll on the healthcare system as well. Early identification of the patient at risk is an invaluable tool to cut cost and improve the patient's quality of life. Multiple renal pathologies have been highlighted in relation to the risk of pathological fractures; however, complications in renal tubular acidosis have been rarely documented. Nevertheless, prompt action with adequate and relevant patient education ultimately can reduce the associated morbidity. We present a case of poor control of the disease and its debilitating pathological fracture complications.

[Comparison of the pulmonary function between adolescent patients with Chiari malformation associated scoliosis and idiopathic scoliosis].

Objective: To compare the pulmonary function between adolescent patients with Chiari malformation associated scoliosis (CMS) and adolescent idiopathic scoliosis (AIS). Methods: A retrospective analysis was performed on 52 patients with CMS, and 52 patients with AIS were selected as the control group to match the CMS patients by age, sex, and Cobb angle. Preoperative pulmonary function tests were completed by all the patients, including vital capacity (VC), forced vital capacity (FVC), forced expiratory volume in one second (FEV(1)), maximal mid-expiratory flow (MMEF), and ratio of FEV(1) to FVC. The difference of pulmonary function parameters was analyzed between the two groups; Correlation between pulmonary function and radiographic parameters was analyzed in patients with CMS. Results: There were no significant differences in terms of sex, age, and the main coronal Cobb angle between the two groups. There were 42(80.7%) and 44(84.6%) of patients with restrictive ventilatory dysfunction (the percentage of predicted FVC<80%) in CMS and AIS group respectively. 18(42.8%) and 10 (22.7%) out of these patients were also with obstructive ventilation dysfunction (FEV(1)/FVC<92%) in CMS and AIS group respectively. Types of ventilation dysfunction distributed between the two groups had no significant difference (P>0.05). No significant difference was noted between the two groups in the percentage of predicted VC, FVC, FEV(1) and FEV(1)/FVC (P>0.05). The percentage of predicted MMEF in patients with CMS was lower compared to those with AIS[(57.9±13.3)% vs (67.2±23.3)%, P=0.053]. In patients with CMS, the percentage of predicted VC, FVC, FEV(1) and MMEF had significantly negative correlation with the number of vertebrae involved (P<0.01). Main coronal Cobb angle had negative correlation with the percentage of predicted VC, FVC and FEV(1) (P<0.05). The percentage of predicted VC, FVC and FEV(1) had positive correlation with thoracic kyphosis (P<0.05). Conclusions: There are no significant differences in characteristics of the pulmonary dysfunction between patients with AIS and CMS without obviously neural deficit. Both groups mainly present with restrictive ventilation dysfunction.

Bilateral Proximal Femur Fractures in a Patient with Renal Tubular Acidosis: A Case Report

@#The diagnosis of pathological fractures is on the rise. Themorbidity involved does not only burden the patient and theirfamilies but it has a great toll on the healthcare system aswell. Early identification of the patient at risk is aninvaluable tool to cut cost and improve the patient’s qualityof life. Multiple renal pathologies have been highlighted inrelation to the risk of pathological fractures; however,complications in renal tubular acidosis have been rarelydocumented. Nevertheless, prompt action with adequate andrelevant patient education ultimately can reduce theassociated morbidity. We present a case of poor control ofthe disease and its debilitating pathological fracturecomplications.

Is accredited social health activists' basic oral health knowledge appropriate in educating rural Indian population?

INTRODUCTION: Accredited social health activists (ASHAs) are the grassroot level health activists in the community who are involved in health education and community mobilization toward utilizing the health services. MATERIALS AND METHODS: A descriptive cross-sectional study was carried out to assess the oral health knowledge among ASHAs working in Guntur district of Andhra Pradesh, India. Five Primary Health Centers were randomly selected, and the total sample was 275. Categorical data were analyzed using Chi-square test. P ≤ 0.05 was considered to be statistically significant. RESULTS: The mean age was 32 ± 5.11 years and mean education was 9 ± 1.329 years of schooling. ASHAs were categorized into two groups based on their education levels, i.e., Group I whose education qualification is <10th class and Group II whose education qualification is above 10th class to observe any difference in knowledge based on their education. Overall knowledge among ASHAs was poor and also it was observed that both the groups were having poor knowledge regarding dental caries, calculus, dental plaque, oral cancer, and change of tooth brush. About 69.5% of the ASHAs were approached by public with dental problems, but only a few, i.e., 15.8% have referred the patients to the nearby dentist. CONCLUSION: As we know that most of the dental diseases are preventable, there is a dire need that ASHAs should be thoroughly educated in the aspects of oral health and diseases during their training period. This not only helps in creating awareness among them but also serves the ultimate purpose of improving the oral health of rural population.

[Genetic analysis of posterior cranial fossa morphology in families of Chiari malformation type â ].

Objective: To explore genetic characteristic of posterior cranial fossa morphology in families of Chiari malformation type Ⅰ (CMI). Methods: From April 2010 to May 2016, a total of 47 cases of CMI families (CMI group) and their 94 parents (CMI-P group)collected were retrospectively reviewed in Department of Spinal Surgery, Drum Tower Hospital, School of Medicine, Nanjing University.Another cohort of 50 asymptomatic adults was enrolled to serve as the control group.Patients with skull fracture or other diseases which can lead to secondary CMI were excluded.On mid-sagittal T2-weighted magnetic resonance (MR) imaging, four measurements were evaluated and compared between these three groups, including the length of cerebellar tonsillar descent, the area of posterior cranial fossa(PCF area), the area of the brain tissue in posterior cranial fossa (PCF tissue area), and the PCF crowdedness indexes (PCF tissue area/ PCF area×100%). Results: Totally 47 CMI patients (21 males and 26 females; mean age, 16.4 years), 94 parents (47 males and 47 females; mean age, 39.2 years) and 50 controls (23 males and 27 females; mean age, 22.3 years) were recruited in this study.Significant differences in all four indexes were found between CMI group and the control group.The length of cerebellar tonsillar descent were much bigger in CMI-P group than in the control group (1.5±2.2 mm vs -0.9±1.1 mm), with 7 cases reach the diagnostic criteria of Chiari malformation(≥5 mm) and one with syingomyelia.Compared to the control group, CMI-P group had smaller PCF area, and its PCF crowdedness indexes averaged 90.0% as between the control group (85.3%) and the CMI group (93.6%). Conclusions: In CMI families, parents have similar posterior cranial fossa abnormalities with their CMI children, presenting obviously narrow and crowded.Their PCF crowdedness indexes are between normal subjects and CMI patients, and their cerebellar tonsils are lower, even some parents are also CMI patients, suggesting genetic mechanisms involved in the development of CMI.

[Analysis on funds application of community based organizations involved in HIV/AIDS response and government financial investment in China, 2014].

Objective: To understand the government financial investments to community based organizations (CBO) involved in HIV/AIDS Control and Prevention of China and its influencing factors. Methods: Questionnaire of the situation of CBO involved in HIV/AIDS control and prevention were designed, and filled by the staff of Provincial Health Administrative Departments of 31 provinces (autonomous regions and municipalities). The research focused on the fields of CBO involved in HIV/AIDS response in 31 provinces (autonomous regions and municipalities), including intervention on HIV/AIDS high risk population (female sex worker (FSW), man who sex with man (MSM), drug user (DU) and case management and care for people living with HIV/AIDS (PLWH)). 29 valid questionnaires were collecting, with Shanxi Province and Inner Mongolia Autonomous Regions not filled. Questionnaire included financial supports from local governments, transfer payment from central government for CBO involved in HIV/AIDS response in 2014, and unit cost for CBO involved in HIV/AIDS control and prevention. Multivariate analysis was conducted on the project application and financial investment of community based organizations involved in HIV/AIDS control and prevention in 2014. Results: The total amount of CBO to apply for participation in AIDS prevention and control was 64 482 828 Yuan in 2014. The actual total amount of investment was 50 616 367 Yuan, The investment came from the central government funding, the provincial level government funding, the prefecture and county level government funding investment and other sources of funding. 22 of 28 provinces (autonomous regions and municipalities) received the funds from the central government finance, and median of investment funds 500 000 Yuan. 15 provinces (autonomous regions and municipalities) gained the funds from the provincial government finance, and median of investment funds 350 000 Yuan. 12 provinces (autonomous regions and municipalities) got the funds from the prefecture and county level government finance, and median of investment funds 408 750 Yuan. 12 provinces (autonomous regions and municipalities) acquired the funds from other sources, and median of investment funds 228 400 Yuan. The median (P(25), P(75)) unit costs of intervention for FSW from 16 provinces (autonomous regions and municipalities) was 70 (23, 280) Yuan per year; DU from 14 provinces (autonomous regions and municipalities) was 83 (44, 200 ) Yuan per year; MSM from 16 provinces (autonomous regions and municipalities) was 100 (35, 280) Yuan per year; the follow-up and care for PLWH from 17 provinces (autonomous regions and municipalities) was 200 (45, 500) Yuan per year. Multivariate linear regression analysis results showed that the amount of PLWH in 2014 influenced on the total number of application funds of CBO involved in HIV/AIDS response (b=178.11, 95% CI: 51.86-305.36) and the amount of PLWH (b=77.72, 95% CI: 16.28-139.16), and Gross Domestic Product (GDP) per capita of the province (b=36.20, 95% CI: 4.60-67.80) impacted financial investment to CBO involved in HIV/AIDS response, respectively. Conclusion: Funds application and financial investment of CBO involved in HIV/AIDS control and prevention were huge. Financial investment from government was main resources for CBO in 2014. The amount of financial investment funds from governments was influenced by the HIV/AIDS epidemic situation and the development level of local economic.

BUILD EXITO: a multi-level intervention to support diversity in health-focused research.

BACKGROUND AND PURPOSE: As part of the NIH BUILD initiative to diversify the scientific workforce, the EXITO project is a large multi-institutional effort to provide comprehensive support and training for undergraduates from traditionally underrepresented student populations who aspire to health-related research careers. Portland State University, a major public urban university that prioritizes student access and opportunity, and Oregon Health & Science University, a research-intensive academic health center, lead the EXITO network comprised of eleven 2-year and 4-year institutions of higher education spanning Oregon, Washington, Alaska, Hawaii, Guam, American Samoa, and the Northern Mariana Islands. The EXITO project aims for impact in biomedical research by training diverse scholars from indigenous and underserved communities affected by adverse health disparities. PROJECT APPROACH: Guided by socio-ecological theory, the EXITO project is a multi-level intervention offering a three-year research training pathway for scholars in the biomedical, behavioral, health, and social sciences. Fundamental components of the model include student outreach and engagement, integrated curricular enhancements, intensive research experiences, multi-faceted developmental mentoring, supportive community and services, and rigorous evaluation and quality improvement. EXITO also advances faculty and institutional development in these domains by holding curriculum development conferences, creating research learning communities, awarding pilot project research funding, providing mentor training and ongoing support, collaborating with other research equity programs, and developing campus infrastructure and services to support scholars with diverse backgrounds and needs. HIGHLIGHTS: The large and geographically broad network of EXITO institutions engages a range of diverse students, including indigenous populations and students beginning post-secondary education at community colleges. The EXITO model specifically accommodates many students transferring from 2-year partner institutions and facilitates seamless transfer to the 4-year institution. EXITO features several approaches to research training, including supported summer entry into research placements, the incorporation of responsible conduct of research content into general education curriculum, and the intentional matching of scholars with three types of mentors (e.g., peer, career, research). IMPLICATIONS: EXITO provides an example of a comprehensive research training initiative for traditionally underrepresented students that can be implemented across a diverse range of 2-year and 4-year institutions.

Down-regulation of N-acetylglucosamine-1-phosphate transferase (WecA) enhanced the sensitivity of Mycobacterium smegmatis against rifampin.

AIMS: To construct a conditional N-acetylglucosamine-1-phosphate transferase (WecA) knockdown strain of Mycobacterium smegmatis and to investigate the biological effect of WecA on mycobacterial growth, morphology and susceptibilities against anti-tuberculosis drugs. METHODS AND RESULTS: Mycobacterium smegmatis wecA knockdown strain was constructed by using a tetracycline-inducible expression vector pMind and the expression of WecA was regulated by antisense RNA. The results of growth curves and the colony formation unit curves showed that the growth rate of WecA down-regulation strain was decreased and the amount of live bacterial cells dropped. In addition, the wecA knockdown strain exhibited dramatically morphological alterations through scanning electron microscopy observation. The susceptibility of WecA low-expression strain to anti-tuberculosis drugs was detected by using a rapid resazurin microtitre assay as well as a traditional agar dilution method. Notably, the wecA knockdown strain was more sensitive to rifampin, compared with the wecA normal-expression strain. In addition, the sensitivity of wild type Myco. smegmatis mc(2) 155 strain against rifampin was also enhanced in the presence of a low concentration of tunicamycin, a natural WecA inhibitor. CONCLUSIONS: Down-regulation of WecA enhanced the sensitivity of Myco. smegmatis against rifampin. SIGNIFICANCE AND IMPACT OF THE STUDY: These results provided a possibility of combined application of rifampin together with tunicamycin or other WecA inhibitors, which could be a new approach for the treatment of tuberculosis.

Effect of canagliflozin on liver function tests in patients with type 2 diabetes.

AIMS: To report changes in liver function tests observed with canagliflozin, a sodium glucose co-transporter 2 inhibitor, across phase 3 studies in patients with type 2 diabetes, and to examine the relationship between changes in liver function tests and the weight loss and glycaemic improvements observed with canagliflozin. METHODS: Data were pooled from four 26-week, placebo-controlled studies of canagliflozin 100 and 300mg (n=2313) and two 52-week, active-controlled studies of canagliflozin 300mg versus sitagliptin 100mg (n=1488). Analysis of covariance was performed to determine the contribution of changes in body weight and HbA1c to the changes in liver function tests. RESULTS: Reductions in alanine aminotransferase, aspartate aminotransferase, alkaline phosphatase and gamma-glutamyl transferase, and increases in bilirubin were seen with canagliflozin 100 and 300mg versus placebo (nominal P<0.001 for alanine aminotransferase, aspartate aminotransferase and gamma-glutamyl transferase [both doses]; P<0.001 for alkaline phosphatase and P=0.015 for bilirubin [canagliflozin 300mg only]) at week 26 and with canagliflozin 300mg versus sitagliptin 100mg (nominal P<0.001 for alanine aminotransferase, aspartate aminotransferase, gamma-glutamyl transferase and bilirubin, and P<0.01 for alkaline phosphatase) at week 52. Few patients met predefined limits of change criteria for liver function tests, and none met Hy's law criteria. In both populations, alanine aminotransferase, aspartate aminotransferase and gamma-glutamyl transferase reductions were fully explained by HbA1c and body weight reductions. CONCLUSIONS: Canagliflozin provided improvements in liver function tests versus either placebo or sitagliptin treatments that were fully explained by the combined effects of HbA1c and body weight reductions with canagliflozin.

Single i.v. ketamine augmentation of newly initiated escitalopram for major depression: results from a randomized, placebo-controlled 4-week study.

BACKGROUND: While oral antidepressants reach efficacy after weeks, single-dose intravenous (i.v.) ketamine has rapid, yet time-limited antidepressant effects. We aimed to determine the efficacy and safety of single-dose i.v. ketamine augmentation of escitalopram in major depressive disorder (MDD). METHOD: Thirty outpatients with severe MDD (17-item Hamilton Rating Scale for Depression total score ⩾ 24) were randomized to 4 weeks double-blind treatment with escitalopram 10 mg/day+single-dose i.v. ketamine (0.5 mg/kg over 40 min) or escitalopram 10 mg/day + placebo (0.9% i.v. saline). Depressive symptoms were measured using the Montgomery-Asberg Depression Rating Scale (MADRS) and the Quick Inventory of Depressive Symptomatology - Self-Report (QIDS-SR). Suicidal ideation was evaluated with the QIDS-SR item 12. Adverse psychopathological effects were measured with the Brief Psychiatric Rating Scale (BPRS)-positive symptoms, Young Mania Rating Scale (YMRS) and Clinician Administered Dissociative States Scale (CADSS). Patients were assessed at baseline, 1, 2, 4, 24 and 72 h and 7, 14, 21 and 28 days. Time to response (⩾ 50% MADRS score reduction) was the primary outcome. RESULTS: By 4 weeks, more escitalopram + ketamine-treated than escitalopram + placebo-treated patients responded (92.3% v. 57.1%, p = 0.04) and remitted (76.9% v. 14.3%, p = 0.001), with significantly shorter time to response [hazard ratio (HR) 0.04, 95% confidence interval (CI) 0.01-0.22, p < 0.001] and remission (HR 0.11, 95% CI 0.02-0.63, p = 0.01). Compared to escitalopram + placebo, escitalopram + ketamine was associated with significantly lower MADRS scores from 2 h to 2 weeks [(peak = 3 days-2 weeks; effect size (ES) = 1.08-1.18)], QIDS-SR scores from 2 h to 2 weeks (maximum ES = 1.27), and QIDS-SR suicidality from 2 to 72 h (maximum ES = 2.24). Only YMRS scores increased significantly with ketamine augmentation (1 and 2 h), without significant BPRS or CADSS elevation. CONCLUSIONS: Single-dose i.v. ketamine augmentation of escitalopram was safe and effective in severe MDD, holding promise for speeding up early oral antidepressant efficacy.

Sigma-1 receptor deficiency reduces MPTP-induced parkinsonism and death of dopaminergic neurons.

Sigma-1 receptor (σ1R) has been reported to be decreased in nigrostriatal motor system of Parkinson's disease patients. Using heterozygous and homozygous σ1R knockout (σ1R+/- and σ1R-/-) mice, we investigated the influence of σ1R deficiency on 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-impaired nigrostriatal motor system. The injection of MPTP for 5 weeks in wild-type mice (MPTP-WT mice), but not in σ1R+/- or σ1R-/- mice (MPTP-σ1R+/- or MPTP-σ1R-/- mice), caused motor deficits and ~40% death of dopaminergic neurons in substantia nigra pars compacta with an elevation of N-methyl-d-aspartate receptor (NMDAr) NR2B phosphorylation. The σ1R antagonist NE100 or the NR2B inhibitor Ro25-6981 could alleviate the motor deficits and the death of dopaminergic neurons in MPTP-WT mice. By contrast, MPTP-σ1R+/- mice treated with the σ1R agonist PRE084 or MPTP-σ1R-/- mice treated with the NMDAr agonist NMDA appeared to have similar motor deficits and loss of dopaminergic neurons as MPTP-WT mice. The pharmacological or genetic inactivation of σ1R suppressed the expression of dopamine transporter (DAT) in substantia nigra, which was corrected by NMDA. The activation of σ1R by PRE084 enhanced the DAT expression in WT mice or σ1R+/- mice. By contrast, the level of vesicular monoamine transporter 2 (VMAT2) in σ1R+/- mice or σ1R-/- mice had no difference from WT mice. Interestingly, MPTP-WT mice showed the reduction in the levels of DAT and VMAT2, but MPTP-σ1R-/- mice did not. The inactivation of σ1R by NE100 could prevent the reduction of VMAT2 in MPTP-WT mice. In addition, the activation of microglia cells in substantia nigra was equally enhanced in MPTP-WT mice and MPTP-σ1R-/- mice. The number of activated astrocytes in MPTP-σ1R-/- mice was less than that in MPTP-WT mice. The findings indicate that the σ1R deficiency through suppressing NMDAr function and DAT expression can reduce MPTP-induced death of dopaminergic neurons and parkinsonism.

Pharmacodynamic differences between canagliflozin and dapagliflozin: results of a randomized, double-blind, crossover study.

AIMS: To compare the pharmacodynamic effects of the highest approved doses of the sodium glucose co-transporter 2 (SGLT2) inhibitors canagliflozin and dapagliflozin on urinary glucose excretion (UGE), renal threshold for glucose excretion (RTG ) and postprandial plasma glucose (PPG) excursion in healthy participants in a randomized, double-blind, two-period crossover study. METHODS: In each treatment period, participants (n = 54) received canagliflozin 300 mg or dapagliflozin 10 mg for 4 days (20 min before breakfast). A mixed-meal tolerance test (600 kcal; 75 g glucose) was performed at baseline and on day 4 of each treatment period to assess changes in incremental PPG (PPGΔAUC0-2 h ). We measured 24-h UGE and plasma glucose on day 4 to determine 24-h mean RTG . RESULTS: Canagliflozin 300 mg and dapagliflozin 10 mg had similar effects on UGE and RTG for 4 h after dosing, but canagliflozin was associated with higher UGE and greater RTG reductions for the remainder of the day. Mean 24-h UGE was ∼25% higher with canagliflozin than with dapagliflozin (51.4 vs. 40.8 g), and 24-h mean RTG was ∼0.4 mmol/l (7 mg/dl) lower with canagliflozin than with dapagliflozin (3.79 vs. 4.17 mmol/l; p < 0.0001). Dapagliflozin had no effect on PPG excursion; canagliflozin delayed and reduced PPG excursion (between-treatment difference in PPGΔAUC0-2 h from baseline expressed as a percentage of baseline mean, -10.2%; p = 0.0122). Canagliflozin and dapagliflozin were generally well tolerated. CONCLUSIONS: In healthy participants, canagliflozin 300 mg provided greater 24-h UGE, a lower RTG and smaller PPG excursions than dapagliflozin 10 mg.

Effect of the sodium glucose co-transporter 2 inhibitor canagliflozin on plasma volume in patients with type 2 diabetes mellitus.

AIM: To evaluate the effects of canagliflozin on plasma volume, urinary glucose excretion (UGE), fasting plasma glucose (FPG), glycated haemoglobin (HbA1c) and additional measures of fluid/electrolyte balance in patients with type 2 diabetes on background therapy with metformin and angiotensin-converting enzyme inhibitors or angiotensin receptor blockers. METHODS: Patients (N = 36) were randomized (1:1) to receive canagliflozin 300 mg or placebo for 12 weeks. Pharmacodynamic parameters were assessed at baseline and at weeks 1 and 12. RESULTS: Increased 24-h UGE was seen in the canagliflozin group compared with a reduction in the placebo group at both week 1 (91.8 vs. -2.4 g) and week 12 (82.6 vs. -0.4 g). Canagliflozin also reduced both FPG and HbA1c. Reductions in body weight and blood pressure were observed at weeks 1 and 12. Canagliflozin decreased plasma volume compared with an increase with placebo at week 1 (-5.4 vs. 4.3%; p = 0.02), but this was largely attenuated at week 12 (4.6 vs. 5.8%; p = 0.76). A modest numerical increase in urine volume was observed with canagliflozin at week 1 that was attenuated at week 12; other measures of volume status (i.e. blood urea nitrogen, serum creatinine and haematocrit) remained modestly increased with canagliflozin at week 12. CONCLUSION: Canagliflozin provided sustained effects on UGE and FPG over 12 weeks and a transient reduction in plasma volume that was largely attenuated by week 12.