Activation of Functional Somatic Stem Cells Promotes Endogenous Tissue Regeneration.

Periodontal ligament derived stem cells (PDLSCs) are capable of differentiating into multiple cell types and inducing a promising immunomodulation for tissue regeneration and disease treatment. However, it is still challenging to develop a practical approach to activate endogenous stem cells for tissue self-healing and regeneration. In this study, transcriptome analysis reveals that resveratrol promotes PDLSC stemness through activation of stem cell, osteoprogenitor, and chondroprogenitor markers. Self-renewal and multipotent differentiation abilities are also improved in resveratrol-treated PDLSCs. In addition, immunomodulation of PDLSCs is dramatically increased after resveratrol treatment. Mechanistically, we show that resveratrol activates ERK/WNT crosstalk through elevation of olfactory and growth factor signaling pathways to upregulate the expression levels of RUNX2 and FASL for osteogenesis and immunomodulation, respectively. By using a periodontitis animal model, administration of resveratrol partially rescues bone loss through activation of endogenous somatic stem cells and inhibition of inflammatory T-cell infiltration. Taken together, our findings identify a novel pharmacological approach to achieve autotherapies for endogenous tissue regeneration.

Proof of concept for the clinical effects of oral rilzabrutinib, the first Bruton tyrosine kinase inhibitor for pemphigus vulgaris: the phase II BELIEVE study.

BACKGROUND: Bruton tyrosine kinase (BTK) inhibition targets B-cell and other non-T-cell immune cells implicated in the pathophysiology of pemphigus, an autoimmune disease driven by anti-desmoglein autoantibodies. Rilzabrutinib is a new reversible, covalent BTK inhibitor demonstrating preclinical efficacy as monotherapy in canine pemphigus foliaceus. OBJECTIVES: To evaluate the efficacy and safety of oral rilzabrutinib in patients with pemphigus vulgaris in a multicentre, proof-of-concept, phase II trial. METHODS: Patients with Pemphigus Disease Area Index severity scores 8-45 received 12 weeks of oral rilzabrutinib 400-600 mg twice daily and 12 weeks of follow-up. Patients initially received between 0 and ≤ 0·5 mg kg-1 prednisone-equivalent corticosteroid (CS; i.e. 'low dose'), tapered after control of disease activity (CDA; no new lesions, existing lesions healing). The primary endpoints were CDA within 4 weeks on zero-to-low-dose CS and safety. RESULTS: In total, 27 patients with pemphigus vulgaris were included: nine newly diagnosed (33%) and 18 relapsing (67%); 11 had moderate disease (41%) and 16 moderate to severe (59%). The primary endpoint, CDA, was achieved in 14 patients (52%, 95% confidence interval 32-71): 11 using low-dose CS and three using no CS. Over 12 weeks of treatment, mean CS doses reduced from 20·0 to 11·8 mg per day for newly diagnosed patients and from 10·3 to 7·8 mg per day for relapsing patients. Six patients (22%) achieved complete response by week 24, including four (15%) by week 12. Treatment-related adverse events were mostly mild (grade 1 or 2); one patient experienced grade 3 cellulitis. CONCLUSIONS: Rilzabrutinib alone, or with much lower CS doses than usual, was safe, with rapid clinical activity in pemphigus vulgaris. These data suggest that BTK inhibition may be a promising treatment strategy and support further investigation of rilzabrutinib for the treatment of pemphigus.

Global publication productivity in dermatology: a bibliometric description of the past and estimation of the future.

BACKGROUND: In the past two centuries, generations of dermatologists around the world have created an enormous number of publications. To our knowledge, no bibliometric analysis of these publications has been performed so far, nor have registered trials been analysed to anticipate future publication trends. OBJECTIVES: To determine the global distribution of national publication productivity, most published topics, institutions and funding sources contributing most to publications and to anticipate future trends based on registered clinical trials. METHODS: Following pre-assessment on PubMed, Embase, Web of Science and Scopus, the number of publications for 'dermatology' was determined for each of 195 countries, normalized per 1 Mio inhabitants and bibliometrically analysed. Dermatology-related trials registered at clinicaltrials.gov were specified by the top-10 diagnoses for the top-10 countries. RESULTS: The search yielded 1 071 518 publications between 1832 and 2019 with the top-5 diagnoses being melanoma, basal cell carcinoma, psoriasis, pruritus/itch and atopic dermatitis. The top-3 countries with highest absolute numbers of publications were the USA (30.6%), Germany (8.1%) and the UK (8.1%), whereas Switzerland, Denmark and Sweden had the highest publication rates when normalized by inhabitants. The most productive affiliation was the Harvard Medical School, the leading funding source the National Institutes of Health. Currently, maximum number of trials are registered in the USA (8111), France (1543) and Canada (1368). The highest percentage of all dermatology-related trials in a specific country were as follows: Melanoma in the Netherlands (24.8%), psoriasis in Germany (21.7%) and atopic dermatitis in Japan (15.9%). CONCLUSION: The top-10 countries including the USA, Canada, a few European and Asian countries contributed more than 3/4 of all publications. The USA hold the dominant leader position both in past publication productivity and currently registered trials. While most Western countries continue to focus their research on the top-10 topics, China and India appear to prioritize their scope towards other topics.

Assessment of health infrastructure in tackling COVID-19: A case study of European and American scenario.

The COVID-19 coronavirus pandemic is an unparalleled threat intoday's quickly developing climate, and we face it as a global community. Like climate change, it is challenging our resilience from environmental health, social security, and government, to knowledge exchange and economic policy in all sectors of the economy and all fields of growth. So much as climate change, everybody's coming together would require the initiative. Throughout Europe and America, several organizations have mobilized to ensure that the neediest are not left behind, encouraging emergencies and disruptions avoidance and preparedness. The coronavirus outbreak has highlighted the growing community's strengths and vulnerabilities that it has influenced, and has provided us with the ability to benefit from each other's accomplishments and shortcomings. The comparison graph has also been shown in this paper displaying European and American scenarios. The globe might feel smaller amid disaster states and global travel bans, but it is a period when teamwork and looking outward were never more relevant.

Flightless anchors IQGAP1 and R-ras to mediate cell extension formation and matrix remodeling.

Tractional remodeling of collagen fibrils by fibroblasts requires long cell extensions that mediate fibril alignment. The formation of these cell extensions involves flightless I (FliI), an actin-binding protein that contains a leucine-rich-repeat (LRR), which binds R-ras and may regulate cdc42. We considered that FliI interacts with small GTPases and their regulators to mediate assembly of cell extensions. Mass spectrometry analyses of FliI immunoprecipitates showed abundant Ras GTPase-activating-like protein (IQGAP1), which in immunostained samples colocalized with FliI at cell adhesions. Knockdown of IQGAP1 reduced the numbers of cell extensions and the alignment of collagen fibrils. In experiments using dominant negative mutants, cdc42 activity was required for the formation of short extensions while R-ras was required for the formation of long extensions. Immunoprecipitation of wild-type and mutant constructs showed that IQGAP1 associated with cdc42 and R-ras; this association required the GAP-related domain (1004-1237 aa) of IQGAP1. In cells transfected with FliI mutants, the LRR of FliI, but not its gelsolin-like domains, mediated association with cdc42, R-ras, and IQGAP1. We conclude that FliI interacts with IQGAP1 and co-ordinates with cdc42 and R-ras to control the formation of cell extensions that enable collagen tractional remodeling.

Antibacterial potential of Juglomycin A isolated from Streptomyces achromogenes, an endophyte of Crocus sativus Linn.

AIM: To evaluate the antimicrobial potential of Juglomycins isolated from Streptomyces achromogenes E91CS4, an endophyte of Crocus sativus Linn. METHODS AND RESULTS: The extract from E91CS4 displayed significant antimicrobial activity against several pathogens. The endophyte was identified as S. achromogenes on by 16S ribosomal gene analysis. Chemical investigation of the extract led to the isolation of two naphthoquinone antibiotics, Juglomycin A and B. Juglomycin A inhibited several pathogens, with an MIC value of 13·7µg ml-1 , whereas it was most potent against Escherichia coli, Bacillus thuringiensis and Xanthobacter flavus with MIC values of 6·8, 3·4 and 6·8 µg ml-1 respectively. It was found to reduce the biofilm formation in E. coli through inhibition of swimming and swarming motilities and downregulation of fimH gene. The α-haemolysin-related gene (hlyA) was also downregulated indicating that the compound is also reducing the virulence in E. coli. In vitro time kill kinetics showed efficient bactericidal activity of this compound. Furthermore, Juglomycin A inhibited bacterial transcription/translation in vitro, while also inducing postantibiotic effect in E. coli. CONCLUSIONS: Juglomycin A is a potential antimicrobial compound against several bacterial pathogens, particularly, E. coli. SIGNIFICANCE AND IMPACT OF THE STUDY: This study showed the promising potential of Juglomycin A as an antimicrobial agent. Efforts should be made to scale up the production of this compound and conduct further studies to explore its efficacy as an antibiotic, using in vivo models.

Feasibility and acceptability of a proposed pharmacy-based harm reduction intervention to reduce opioid overdose, HIV and hepatitis C.

BACKGROUND: Evidence-based harm reduction intervention components which might benefit pharmacy patients have not been integrated and studied. OBJECTIVE: To investigate the feasibility and acceptability of a proposed pharmacy-based harm reduction intervention to reduce opioid overdose, HIV and hepatitis C called PharmNet. METHODS: Indiana managing pharmacists were surveyed in 2018 to assess the feasibility and acceptability of an intervention for opioid misuse screening, brief intervention, syringe and naloxone dispensing, and referrals provision. The Consolidated Framework for Implementation Research informed the survey development and analysis. RESULTS: The sample included 303 (30.8%) pharmacists; 215 (70.9%) provided detailed written comments. Intervention Characteristics: 83.3% believed PharmNet would benefit patients, and that staff could deliver the intervention with adequate training (70.0%). Inner Setting: While 77.2% believed their pharmacy culture supported practice change, 57.5% of chain pharmacists believed their pharmacies would not have time for PharmNet. Outer Setting: 73.3% believed additional addiction and overdose screening is needed in their community, and pharmacies should offer new services to help reduce opioid overdose and addiction among their patients (79.5%). A vast majority (97.7%) were asked by patients in the past 2 years about syringe related issues; 67.7% were asked about syringes for non-prescription injection drug use. Individuals Involved: While 62.4% believed PharmNet was within pharmacy scope of practice and 90.1% were comfortable consulting about syringe use, pharmacists reported that they had limited control over the implementation environment. PROCESS: 38.0% of pharmacists indicated interest in advising the development of PharmNet. CONCLUSIONS: An implementation trial of a modified version of PharmNet is likely feasible; yet will be challenged by structural pressures particularly in chain pharmacies. Successful implementation will involve the development of resources and policy components to manage outer and inner setting characteristics and align the intervention to the implementation environment.

Hand hygiene compliance of patients' family members in India: importance of educating the unofficial 'fourth category' of healthcare personnel.

INTRODUCTION: In India, due to manpower constraints, patients' family members are often actively involved in healthcare activities of their near and dear ones. They have significant contact with the patient at all World Health Organization (WHO) 'five moments for hand hygiene'. This study analysed the impact of decade-long awareness campaigns on the hand hygiene compliance (HHC) by our patients' carers. METHODS: Trained infection control nurses observed the HHC at each of the five moments for patients' attendants in different hospital settings from January 2014 to December 2018. Compliance was calculated as percentage of events divided by total opportunities. FINDINGS: A total of 7302 opportunities were observed with an overall compliance of 46.1% (35.5% in 2014 to 48.2% in 2018, P < 0.0001). Compliance at WHO moments 1, 2, 3, 4, and 5 was 51.0%, 47.4%, 67.6%, 48.8%, and 24.3% respectively. Among family members, mothers of newborns had a much higher HHC (77%) than others (44.5%) (P < 0.0001). Also, the compliance was higher in medical versus surgical wards and in paediatric wards versus adult wards (P < 0.0001 in both). CONCLUSION: This is the first study on family members' HHC in a hospital setting in a low- and middle-income country. The study shows that family members, once trained, exhibit fairly good HHC while caring for their patients, especially mothers of newborns. It is worthwhile empowering and educating patient attendants about the importance and process of hand hygiene as it is likely to result in immense benefit for patients.

Mass deworming for soil-transmitted helminths and schistosomiasis among pregnant women: A systematic review and individual participant data meta-analysis.

The objective of the review is to use individual participant data (IPD) meta-analysis to explore the effect of mass deworming during pregnancy. We developed a search strategy and searched the databases till March 2018. We included individually randomised controlled trials; cluster randomised controlled trials and quasi randomised studies providing preventive or therapeutic deworming drugs for soil transmitted helminthiases and schistosomiasis during pregnancy. All IPD were assessed for completeness, compared to published reports and entered into a common data spreadsheet. Out of the seven trials elgible for IPD, we received data from three trials; out of 8,515 potential IPD participants; data were captured for 5,957 participants. Findings from this IPD suggest that mass deworming during pregnancy reduces maternal anaemia by 23% (Risk ratio [RR]: 0.77, 95% confidence intreval [CI]: 0.73-0.81; three trials; 5,216 participants; moderate quality evidence). We did not find any evidence of an effect of mass deworming during pregnancy on any of the other outcomes. There was no evidence of effect modification; however these findings should be interpreted with caution due to small sample sizes. The quality of evidence was rated as moderate for our findings. Our analyses suggest that mass deworming during pregnancy is associated with reducing anaemia with no evidence of impact on any other maternal or pregnancy outcomes. Our analyses were limited by the availability of data for the impact by subgroups and effect modification. There is also a need to support and promote open data for future IPDs.

The leucine-rich region of Flightless I interacts with R-ras to regulate cell extension formation.

Flightless I (FliI) is a calcium-dependent, actin severing and capping protein that localizes to cell matrix adhesions, contributes to the generation of cell extensions, and colocalizes with Ras. Currently, the mechanism by which FliI interacts with Ras to enable assembly of actin-based cell protrusions is not defined. R-Ras, but not K-ras, H-ras, or N-ras, associated with the leucine-rich region (LRR) of FliI. Mutations of the proline-rich region of R-ras (P202A, P203A) prevented this association. Knockdown of Ras GTPase-activating SH3 domain-binding protein (G3BP1) or Rasgap120 by small interfering RNA inhibited the formation of cell extensions and prevented interaction of R-ras and G3BP1 in FliI wild-type (WT) cells. Pull-down assays using G3BP1 fusion proteins showed a strong association of R-ras with the C-terminus of G3BP1 (amino acids 236-466), which also required the LRR of FliI. In cells that expressed the truncated N-terminus or C-terminus of G3BP1, the formation of cell extensions was blocked. Endogenous Rasgap120 interacted with the N-terminus of G3BP1 (amino acids 1-230). We conclude that in cells plated on collagen FliI-LRR interacts with R-ras to promote cell extension formation and that FliI is required for the interaction of Rasgap120 with G3BP1 to regulate R-ras activity and growth of cell extensions.

Tele-evidence: A videoconferencing tool as a viable alternative to physical appearance of doctors for the judicial summons.

Introduction: The role of physicians often extends beyond provision of direct patient care and includes appearance in courts as professional or expert witnesses to give their testimony in various legal cases. This often consumes precious time and resources of the doctors and the hospitals. This study was taken up to evaluate the present system of the physical appearance of the doctors to various courts and compare it with the videoconferencing mode of giving testimony (tele-evidence). Materials and Methods: Available records of summons and vehicles used were analyzed to calculate the cost involved and man-hours consumed in honoring the court summons. Telemedicine facility, available in our institute, was used for conducting tele-evidence with selected courts of the two states as a pilot, which was later expanded. A survey was also done to assess the experience of the physicians with physical appearance and videoconferencing using structured questionnaire after approval from the Institute's Ethics Committee. Likert scale of 0-10 points was used to measure satisfaction. Results: There was 43% drop in the monthly mileage of vehicles, 49% reduction in the fuel cost per month, and 28% savings in terms of time consumed for court duties. Satisfaction score for parameters of time consumed, physical strain, mental strain, communication with Honorable Judges, and overall experience was 87% through tele-evidence as compared to 31% with physical appearance. Conclusion: Tele-evidence is an acceptable and implementable mode of testifying and has led to tremendous resource savings in our tertiary care setting. The model needs to be replicated for deliverance of justice and is in consonance with Government's push toward Digital India.

Galectin-3: an emerging biomarker in stroke and cerebrovascular diseases.

The carbohydrate-binding molecule galectin-3 has garnered significant attention recently as a biomarker for various conditions ranging from cardiac disease to obesity. Although there have been several recent studies investigating its role in stroke and other cerebrovascular diseases, awareness of this emerging biomarker in the wider neurology community is limited. We performed a systematic search in PubMed, Embase, Scopus, CINAHL, Clinicaltrials.gov and the Cochrane library in November and December 2016 for articles related to galectin-3 and cerebrovascular disease. We included both human and pre-clinical studies in order to provide a comprehensive view of the state of the literature on this topic. The majority of the relevant literature focuses on stroke, cerebral ischemia and atherosclerosis, but some recent attention has also been devoted to intracranial and subarachnoid hemorrhage. Higher blood levels of galectin-3 correlate with worse outcomes in atherosclerotic disease as well as in intracranial and subarachnoid hemorrhage in human studies. However, experimental evidence supporting the role of galectin-3 in these phenotypes is not as robust. It is likely that the role of galectin-3 in the inflammatory cascade within the central nervous system following injury is responsible for many of its effects, but its varied physiological functions and multiple sites of expression mean that it may have different effects depending on the nature of the disease condition and the time since injury. In summary, experimental and human research raises the possibility that galectin-3, which is closely linked to the inflammatory cascade, could be of value as a prognostic marker and therapeutic target in cerebrovascular disease.

Cytokinesis requires localized ß-actin filament production by an actin isoform specific nucleator.

Cytokinesis is initiated by the localized assembly of the contractile ring, a dynamic actomyosin structure that generates a membrane furrow between the segregating chromosomal masses to divide a cell into two. Here we show that the stabilization and organization of the cytokinetic furrow is specifically dependent on localized ß-actin filament assembly at the site of cytokinesis. ß-actin filaments are assembled directly at the furrow by an anillin-dependent pathway that enhances RhoA-dependent activation of the formin DIAPH3, an actin nucleator. DIAPH3 specifically generates homopolymeric filaments of ß-actin in vitro. By employing enhancers and activators, cells can achieve acute spatio-temporal control over isoform-specific actin arrays that are required for distinct cellular functions.

Effect of Microbial inoculation in combating the aluminium toxicity effect on growth of Zea mays.

The present study is aimed at improving the aluminium tolerance in maize crop employing the potential of microbial inoculants in conferring resistance to these toxicities via production of certain chelating compounds like siderophores, exopolysachharides and organic acids. Acid soils have now-a-days become one of the key factors for limiting growth of many agriculturally important crops. Aluminium  is one of the major elements present in acid soils and is mainly responsible for toxicity in the soil. This aluminium is rapidly soluble in soil water and hence absorbed by plant roots under conditions where soil pH is below 5. This toxicity leads to severe root growth inhibition, thereby limiting the production of maize crops. It was observed that use of microbial inoculums can be helpful in elimination of these toxic compounds and prevent the inhibition of root growth . It was found that the soils contaminated with aluminium toxicity decreased the root length of maize plant significantly by 65% but Bacillus and Burkholderia inoculation increased this root length significantly by 1.4- folds and 2- folds respectively thereby combating the effect of aluminium toxicity. Aluminium concentration was found maximum in roots of plants which were grown under aluminium stress condition. But this aluminium accumulation decreased Ì´ 2-folds when Burkholderia was used as seed inoculants under aluminium stress conditions. Also, at 60mM aluminium accumulation, phosphorus solubilisation in roots was found to be increased upto 30% on Burkholderia inoculation. However, Bacillus inoculation didn't show any significant difference in either of the case. Thus, the inoculation of seeds with Burkholderia isolates could prove to be a boon in sequestering aluminium toxicity in Zea mays.

Galectin-3 and risk of ischaemic stroke: Reasons for Geographic and Racial Differences in Stroke cohort.

BACKGROUND AND PURPOSE: Galectin-3 is a biomarker of atherosclerotic and cardiovascular disease, and may be a useful marker for ischaemic stroke risk. METHODS: The Reasons for Geographic and Racial Differences in Stroke (REGARDS) cohort enrolled and examined 30 239 US participants between 2003 and 2007 (41% black, 59% white and 55% in the southeastern stroke belt). Baseline galectin-3 was measured in 526 subjects with incident ischaemic stroke over 5.4 years and in a cohort random sample (CRS) of 947 participants. Cox proportional hazards models were used to calculate hazard ratios (HRs) of ischaemic stroke by quartiles of galectin-3. RESULTS: In the CRS, galectin-3 was significantly higher with older age, black race, female sex, body mass index, hypertension, diabetes mellitus and kidney disease, and also in those who developed incident stroke. Participants with galectin-3 levels in the fourth versus first quartile had a 2.3-fold increased stroke risk [95% confidence interval (CI) 1.6, 3.4] in an unadjusted model. An interaction with age was found (P = 0.06), and therefore age-stratified analyses were performed. Amongst those younger than age 64, baseline galectin-3 in the second-fourth quartiles was associated with increased stroke risk (HR 3.0, 95% CI 1.6, 5.5) compared to the first quartile in an age-, race- and sex-adjusted model. The HR was 2.0 (95% CI 1.0, 4.0) with multivariable adjustment. There was no association amongst older participants. CONCLUSIONS: Galectin-3 was associated with incident ischaemic stroke in younger but not older individuals. Confirmation of this finding, and elucidation of its implications for stroke pathophysiology and prevention, is needed.

Innate and humoral recognition of the products of cell death: differential antigenicity and immunogenicity in lupus.

While apoptotic debris is believed to constitute the original antigenic insult in lupus (which is characterized by a time-dependent diversification of autoreactivity), whether such debris and autoantibodies specifically recognizing its constituents mediate differential effects on innate and humoral responses in lupus-prone mice is currently unknown. Apoptotic blebs (as opposed to cellular lysate) enhanced preferentially the maturation of dendritic cells (DCs) from bone marrow precursors drawn from lupus-prone mice. Murine, somatically mutated, apoptotic cell-reactive immunoglobulin (Ig)G monoclonal antibodies demonstrated enhanced recognition of DCs and also displayed a prominent lupus strain-specific bias in mediating DC maturation. Further, immunization of such antibodies specifically in lupus-prone mice resulted in widespread humoral autoreactivity; hypergammaglobulinaemia (a hallmark of systemic autoimmunity) was observed, accompanied by enhanced antibody titres to cellular moieties. Induced antibodies recognized antigens distinct from those recognized by the antibodies employed for immunization; in particular, nephritis-associated anti-double stranded (ds) DNA antibodies and neonatal lupus-associated anti-Ro60 antibodies were elicited by a non-dsDNA, non-Ro60 reactive antibody, and Sm was a favoured target. Further, only in lupus-prone mice did such immunization enhance the kinetics of humoral anti-self responses, resulting in the advanced onset of glomerulosclerosis. These studies reveal that preferential innate and humoral recognition of the products of cell death in a lupus milieu influence the indices associated with autoimmune pathology.

Effect of narrow band ultraviolet B phototherapy on T helper 17 cell specific cytokines (interleukins-17, 22 and 23) in psoriasis vulgaris.

BACKGROUND: Psoriasis is mediated by a T helper 17 (Th17) cell inflammatory process. This study describes the changes in serum levels of IL-17, 22 and 23 in patients of psoriasis vulgaris treated with narrow band ultraviolet B (NBUVB). METHODS: The serum levels of IL-17, 22 and 23 were compared with a control group (n = 30) before and after NBUVB. In addition, post-NBUVB levels were compared with healthy controls. Psoriasis Area Severity Score (PASI) and Body Surface Area scoring were used to evaluate severity of disease. RESULTS: When compared with the non-psoriasis control group, IL-17, 22 and 23 were higher in psoriasis patients (p < 0.05, p < 0.001, p < 0.001, respectively). The serum levels of all three interleukins strongly correlated with severity of disease. Although IL-17, 22 and 23 decreased after NBUVB, decline in IL-17 was not significant after phototherapy as compared to controls (p = 0.634). IL-22 and 23 continued to remain elevated post-phototherapy when compared with control group (p < 0.05, p < 0.0001, respectively). CONCLUSIONS: The serum levels of IL-17, 22 and 23 decrease after phototherapy in psoriasis. Post-phototherapy only the IL-17 levels decrease to that of non-psoriasis controls. Our study supports the role of T helper 17 cell specific cytokines in psoriasis and a possible mechanism of action of NBUVB via inhibition of these cytokines.