Doxycycline host-directed therapy in human pulmonary tuberculosis

BACKGROUNDMatrix metalloproteinases (MMPs) are key regulators of tissue destruction in tuberculosis (TB) and may be targets for host-directed therapy. We conducted a phase II double-blind, randomized, controlled trial investigating doxycycline, a licensed broad-spectrum MMP inhibitor, in patients with pulmonary TB.METHODSThirty patients with pulmonary TB were enrolled within 7 days of initiating anti-TB treatment and randomly assigned to receive either 100 mg doxycycline or placebo twice a day for 14 days, in addition to standard care.RESULTSWhole blood RNA-sequencing demonstrated that doxycycline accelerated restoration of dysregulated gene expression in TB towards normality, rapidly down-regulating type I and II interferon and innate immune response genes, and up-regulating B-cell modules relative to placebo. The effects persisted for 6 weeks after doxycycline discontinuation, concurrent with suppressed plasma MMP-1. Doxycycline significantly reduced sputum MMP-1, -8, -9, -12 and -13, suppressed type I collagen and elastin destruction, reduced pulmonary cavity volume without altering sputum mycobacterial loads, and was safe.CONCLUSIONAdjunctive doxycycline with standard anti-TB treatment suppressed pathological MMPs in PTB patients. Larger studies on adjunctive doxycycline to limit TB immunopathology are merited.TRIAL REGISTRATIONClinicalTrials.gov {"type":"clinical-trial","attrs":{"text":"NCT02774993","term_id":"NCT02774993"}}NCT02774993.FUNDINGSingapore National Medical Research Council (NMRC/CNIG/1120/2014, NMRC/Seedfunding/0010/2014, NMRC/CISSP/2015/009a); the Singapore Infectious Diseases Initiative (SIDI/2013/013); National University Health System (PFFR-28 January 14, NUHSRO/2014/039/BSL3-SeedFunding/Jul/01); the Singapore Immunology Network Immunomonitoring platform (BMRC/IAF/311006, H16/99/b0/011, NRF2017_SISFP09); an ExxonMobil Research Fellowship, NUHS Clinician Scientist Program (NMRC/TA/0042/2015, CSAINV17nov014); the UK Medical Research Council (MR/P023754/1, MR/N006631/1); a NUS Postdoctoral Fellowship (NUHSRO/2017/073/PDF/03); The Royal Society Challenge Grant (CHG\R1\170084); the Sir Henry Dale Fellowship, Wellcome Trust (109377/Z/15/Z); and A*STAR.     

Racial/Ethnic Differences in Cardiovascular Symptoms in Four Major Racial/Ethnic Groups of Midlife Women: A Secondary Analysis

Ethnic minority midlife women frequently do not recognize cardiovascular symptoms that they experience during the menopausal transition. Racial/ethnic differences in cardiovascular symptoms are postulated as a plausible reason for their lack of knowledge and recognition of the symptoms. The purpose of this study was to explore racial/ethnic differences in midlife women’s cardiovascular symptoms and to determine the factors related to these symptoms in each racial/ethnic group. This was a secondary analysis of the data from a larger study among 466 participants, collected from 2006 to 2011. The instruments included questions on background characteristics, health and menopausal status, and the Cardiovascular Symptom Index for Midlife Women. The data were analyzed using inferential statistics, including Poisson regression and logistic regression analyses. Significant racial/ethnic differences were observed in the total numbers and total severity scores of cardiovascular symptoms (p < .01). Non-Hispanic Asians had significantly lower total numbers and total severity scores compared to other racial/ethnic groups (p < .05). The demographic and health factors associated with cardiovascular symptoms were somewhat different in each racial/ethnic group. Further studies are needed about possible reasons for the racial/ethnic differences and the factors associated with cardiovascular symptoms in each racial/ethnic group.     

Prevalence and correlates of obesity and overweight among asian immigrant women in Korea

This study examines the prevalence of obesity and overweight as well as associations between obesity and overweight and demographic, sociocultural, and lifestyle factors among Asian immigrant women in Korea. Data were collected from physical measurements and standardized questionnaires from 287 adult women from China, Vietnam, the Philippines, and other Asian countries. The mean BMI (body mass index) was 22.0 kg/m(2); 15.0% of the sample were obese (BMI ≥ 25.0), and 17.1% were overweight (23.0 ≤ BMI < 25.0). The highest obesity proportion was found in Filipino (22.0%) and the lowest in Vietnamese women (7.8%). Adjusted for demographic, sociocultural, and lifestyle variables, individuals with greater length of residence (5+ years; odds ratio = 3.22, P = .010) were more likely to be obese or overweight. For prevention of excess body weight, public health efforts need to be targeted to immigrants starting at arrival in Korea.     

The Effect of Melasma on the Quality of Life in a Sample of Women Living in Singapore

Introduction: Melasma is a common disorder of acquired hyperpigmentation characterized by irregular brown macules and patches that occur primarily on sun-exposed areas. Methods: This was a prospective cross-sectional study that recruited 49 women clinically diagnosed with melasma from a tertiary dermatology referral center in Singapore. Trained investigators assessed the melasma severity objectively using the chromameter and mexameter and subjectively using the Melasma Area and Severity Index. The effect of melasma on the quality of life on the patients was assessed using the melasma quality of life scale and dermatology life quality index questionnaires. Results: The mean ± SD Melasma Area and Severity Index score was 12.1±6.5 (median 10.8). The mean ± SD melasma quality of life scale score was 25.6±15.3 (median 24.0). Melasma quality of life scale scores are significantly correlated (Spearman’s coefficient = 0.597, p-value <0.001) with the dermatology life quality index scores. There was no correlation between Melasma Area and Severity Index with melasma quality of life scale or dermatology life quality index scores. There is no difference in the melasma quality of life scale scores with different demographic variables including age, duration of disease, levels of education, and employment. Conclusion: This study contributes to building evidence regarding the validity of melasma quality of life scale in accurately evaluating the effect of melasma on a patient’s quality of life and the burden of disease in Singaporean women.Melasma is a common disorder of acquired hyperpigmentation characterized by irregular brown macules and patches that occur primarily on sun-exposed areas on the face and neck. Although the exact pathogenesis of melasma has not been fully elucidated, risk factors identified include exposure to ultraviolet radiation, genetic influences, hormonal therapy, phototoxic drugs, and anticonvulsant medications. This disfiguring cutaneous disorder can cause significant impact on the psychosocial well-being of patients.1     

Moderate traumatic brain injury is linked to acute behaviour deficits and long term mitochondrial alterations

Traumatic brain injury (TBI) remains one of the leading causes of death and disability worldwide. Mild TBI may lead to neuropsychiatric sequelae, including memory loss and motor impairment. Mitochondrial dysfunction and oxidative stress have a contributory role in several neurological disorders; however, their association with mitophagy in mild TBI is unclear. TBI was induced in female Sprague Dawley (SD) rats using a New York University Impactor (10 g, impactor head 2.5 mm diameter, weight drop 50 mm) and compared to sham surgery controls. The novel object recognition and error ladder tests were performed at 24 hours and for 6 weeks post injury, and the brains were examined histologically to confirm the extent of injury. Mitochondria manganese superoxide dismutase (MnSOD) and the oxidative phosphorylation (OXPHOS) complexes I‐V (CI‐CV), as well as mitophagy markers, dynamin related protein 1 (DRP‐1), LC3A/B and PTEN‐induced putative kinase 1 (PINK‐1), were measured in the penumbra by western blot. At 24 hours sham rats performed as expected on a novel object recognition test while TBI rats showed cognitive deficits at the early time points. TBI rats also showed more early motor deficits on a horizontal ladder, compared with the sham rats. MnSOD, OXPHOS CI, CIII and CV protein levels were significantly lower in the TBI group at 24 hours. DRP‐1, LC3A/B I and II, and PINK‐1 were increased at 6 weeks suggesting abnormal mitophagy. Moderate TBI caused immediate cognitive and mild motor functional deficits in the rats that did not persist. Reduced antioxidative capacity and possibly compromised mitochondrial function may affect the long term functional recovery.     

Surface characteristics of acrylic modified polysulfone membranes improves renal proximal tubule cell adhesion and spreading

Current polyvinylpyrrolidone-modified polysulfone (PVP-PSU) membranes in haemodialysers do not facilitate the attachment and proliferation of renal proximal tubule cells (RPTCs). For bioartificial kidney (BAK) development expensive extracellular matrices are employed to ensure the PVP-PSU membranes can serve as a substrate for RPTCs. In this study we modified PSU using an acrylic monomer (am-PSU) and polymerization using ultraviolet irradiation. We demonstrated that on adjusting the PSU or acrylic content of the membranes the wettability and surface chemistry were altered, and this affected the amount of fibronectin (Fn) that was adsorbed onto the membranes. Using an integrin blocking assay we ascertained that Fn is an important extracellular matrix component that mediates RPTC attachment. The amount of Fn adsorbed also led to different bioresponses of RPTCs, which were evaluated using attachment and proliferation assays and qualitative quantification of vinculin, focal adhesion kinase, zonula occludens and Na(+)/K(+) ATPase. Our optimized membrane, am-PSU1 (21.4% C-O groups, 19.1% PVP-PSU; contact angle 71.5-80.80, PVP-PSU: 52.4-67.50), supports a confluent monolayer of RPTCs and prevents creatinine and inulin diffusion from the apical to the basal side, meeting the requirements for application in BAKs. However, further in vivo evaluation to assess the full functionality of RPTCs on am-PSU1 is required.