The role of stem cell factor and c‐KIT in keloid pathogenesis: do tyrosine kinase inhibitors have a potential therapeutic role?

Background Keloids are fibroproliferative disorders characterized by increased deposition of extracellular matrix components. Stem cell factor (SCF) and its receptor c‐KIT are expressed in a wide variety of cells and have also been demonstrated to be important modulators of the wound healing process. Objectives To examine the role of the SCF/c‐KIT system in keloid pathogenesis. Methods Immunohistochemical staining and Western blot analyses were used to examine localization and expression of SCF and c‐KIT in keloid and normal skin tissue. This was followed by the detection of SCF and c‐KIT expression in fibroblasts cultured in vitro and fibroblasts exposed to serum. To investigate the effect of epithelial–mesenchymal interactions, a two‐chamber system was employed in which keratinocytes on membrane inserts were cocultured with the fibroblasts. SCF and c‐KIT expression levels in all cell extracts and conditioned media were assayed by Western blotting. In another set of experiments, the effect of imatinib (Glivec^®, Gleevec^®; Novartis Pharma AG, Basel, Switzerland) on keloid fibroblasts was examined. Results SCF and c‐KIT were upregulated in keloid scar tissue and in cultured fibroblasts stimulated with serum, highlighting their importance in the initial phase of wound healing. We further demonstrated that epithelial–mesenchymal interactions, mimicked by coculture of keratinocytes and fibroblasts in vitro, not only stimulated secretion of the soluble form of SCF in keloid cocultures but also brought about shedding of the extracellular domain of c‐KIT perhaps by upregulation of tumour necrosis factor‐α converting enzyme which was also upregulated in keloid scars in vivo and keloid cocultures in vitro. In addition keloid cocultures expressed increased levels of phosphorylated c‐KIT highlighting an activation of the SCF/c‐KIT system. Finally, we demonstrated that imatinib, a tyrosine kinase inhibitor, may be a possible therapeutic agent for keloids. Conclusion These data indicate that the SCF/c‐KIT system plays an important role in scar pathogenesis, and underscore the role of imatinib as a key therapeutic agent in keloid scars.     

Feedback control of regulatory T cell homeostasis by dendritic cells in vivo

CD4⁺CD25⁺Foxp3⁺ natural regulatory T cells (T reg cells) maintain self-tolerance and suppress autoimmune diseases such as type 1 diabetes and inflammatory bowel disease (IBD). In addition to their effects on T cells, T reg cells are essential for maintaining normal numbers of dendritic cells (DCs): when T reg cells are depleted, there is a compensatory Flt3-dependent increase in DCs. However, little is known about how T reg cell homeostasis is maintained in vivo. We demonstrate the existence of a feedback regulatory loop between DCs and T reg cells. We find that loss of DCs leads to a loss of T reg cells, and that the remaining T reg cells exhibit decreased Foxp3 expression. The DC-dependent loss in T reg cells leads to an increase in the number of T cells producing inflammatory cytokines, such as interferon γ and interleukin 17. Conversely, increasing the number of DCs leads to increased T reg cell division and accumulation by a mechanism that requires major histocompatibility complex II expression on DCs. The increase in T reg cells induced by DC expansion is sufficient to prevent type 1 autoimmune diabetes and IBD, which suggests that interference with this feedback loop will create new opportunities for immune-based therapies.CD4⁺CD25⁺Foxp3⁺ natural regulatory T cells (T reg cells) are essential for maintaining self-tolerance (Kim et al., 2007; Sakaguchi et al., 2008). The loss of these cells leads to a fatal autoimmune syndrome affecting multiple organs (Sakaguchi et al., 1995; Kronenberg and Rudensky, 2005). In addition, these cells interfere with the development of organ-specific autoimmune diseases, such as type 1 diabetes (Salomon et al., 2000; Tarbell et al., 2004; You et al., 2008) and inflammatory bowel disease (IBD), by silencing self-reactive Th1 and Th17 cells (Powrie et al., 1993; Izcue et al., 2006; Korn et al., 2007).Several requirements for T reg cell homeostasis in vivo have been defined. For example, T reg cells are IL-2 dependent and maintained by constant homeostatic division in response to self-antigens (Fisson et al., 2003; von Boehmer, 2003; Setoguchi et al., 2005). In addition to self-antigen recognition, which is essential for their activation and function (Thornton and Shevach, 1998; Samy et al., 2005), T reg cell survival in the periphery also requires co-stimulation through the CD28 and B7 pathway (Salomon et al., 2000). Finally, actively dividing T reg cells appear to be more suppressive than those that are quiescent (Klein et al., 2003). However, it is not known whether antigen-presenting cells (and which ones, if any) are required for maintaining T reg cells in vivo in the steady state (Denning et al., 2007; Yamazaki et al., 2008).DCs are specialized antigen-presenting cells that capture, process, and present antigens to T cells (Banchereau and Steinman, 1998). The outcome of the encounter between these two cell types depends on the activation status of the DC. In the steady state, antigen presentation by DCs leads to tolerance by T cell deletion, induction of anergy, or expansion of antigen-specific T reg cells (Brocker et al., 1997; Hawiger et al., 2001; Steinman and Nussenzweig, 2002; Hawiger et al., 2004; Kretschmer et al., 2005; Luckashenak et al., 2008; Yamazaki et al., 2008). In contrast, antigen presentation by DCs that are activated or matured by Toll-like receptor ligands, CD40 ligation, Fc receptor signaling, or inflammatory cytokines leads to protective T cell immunity (Steinman and Nussenzweig, 2002). Given the importance of DCs for immune activation, it might be expected that the loss of these cells would lead to the absence of immune responses. However, congenital DC deficiency leads instead to a complex generalized lympho- and myeloproliferative syndrome with some features of autoimmune disease, including increased numbers of granulocytes, inflammatory mediators, and possibly T reg cells (Birnberg et al., 2008; Ohnmacht et al., 2009). Additional clues that DCs are involved in T reg cell homeostasis are given in the recent report that Flt3 ligand (FL) can expand T reg cells (Swee et al., 2009), and that loss of T reg cells increases DC division by a FL-dependent mechanism (Liu et al., 2009). Whether these effects on DCs result in direct or indirect feedback changes in T reg cell homeostasis in vivo is not known (Birnberg et al., 2008). In this report, we examined whether DCs are required to maintain T reg cells in vivo and uncovered the existence of a feedback regulatory loop required to maintain physiological numbers of the two cell types in the steady state.     

Prescribing patterns and predictors of high-level polypharmacy in the elderly population: A prospective surveillance study from two teaching hospitals in India

Background: Polypharmacy has been reported to increase the risks for inappropriate prescribing, adverse drug reactions, geriatric syndromes, and morbidity and mortality in elderly populations in the United States and Europe. Data on prescribing patterns and polypharmacy in the elderly population in India are limited.Objectives: The aims of this study were to assess prescribing patterns and to determine the predictors of high-level polypharmacy in the elderly population in 2 tertiary care hospitals in India.Methods: This prospective surveillance study used medical records from patients aged 60 to 95 years admitted to the medicine wards of the 2 tertiary care hospitals between January 2008 and June 2009. Data on medication prescribing from admission through discharge were reviewed. Diseases were coded using the World Health Organization (WHO) International Classification of Diseases, 10th Revision, and medications were coded using the WHO Anatomical, Therapeutic, and Chemical classification. Concordance of prescribing with the indications in the product labeling as listed in the American Hospital Formulary Services Drug Information 2007 was determined. The prevalences of polypharmacy (5–9 medications) and high-level polypharmacy (≥10 medications) were determined. Bivariate analysis and multivariate logistic regression analysis were used to determine the influential predictors of high-level polypharmacy during hospital stays.Results: Data from 814 patients were included (493 [60.6%] men, 321 [39.4%] women; median age, 66 years [range, 60–95 years]). Systemic antibacterials were the most commonly prescribed therapeutic class of medications (574 [70.5%]), and pantoprazole was the most commonly prescribed medication (498 [61.2%]). The majority (7/10 [70.0%]) of the most commonly prescribed medications were prescribed as indicated. Medications prescribed “off-label” included pantoprazole (432/498 [86.7%]), ceftriaxone (212/259 [81.9%]), and atorvastatin (109/237 [46.0%]). Polypharmacy and high-level polypharmacy were prescribed in 366 (45.0%) and 370 (45.5%) patients, respectively. On multivariate logistic regression analysis, multiple (≥3) diagnoses (odds ratio [OR] = 1.55; 95% CI, 1.16–2.08; P = 0.003), angina pectoris (OR = 2.58; 95% CI, 1.50–4.37; P < 0.001), and a length of stay ≥10 days (10–<15 days, OR = 3.14; 95% CI, 2.09–4.71; P < 0.001; and ≥15 days, OR = 5.74; 95% CI, 2.43–13.51; P < 0.001) were found to be predictors of high-level polypharmacy during hospital stays.Conclusions: The campaign for rational drug use in hospitalized elderly patients in India should promote pantoprazole, ceftriaxone, and atorvastatin prescribing in concordance with their indications. Interventions to reduce the high-level polypharmacy in the elderly during their stays in tertiary care hospitals in India should focus on patients with ≥3 diagnoses, angina pectoris, and/or ≥10 days of hospital stay.     

Hearing Loss-a Camouflaged Manifestation of COVID 19 Infection

The symptomatology of novel Severe Acute Respiratory Syndrome Corona virus type 2 infection runs the entire gamut of mild to moderate and serious illness among the affected individuals. As listed in recent literature, respiratory, cardiovascular, gastrointestinal, olfactory and gustatory systems are commonly involved. With the growing knowledge about the disease, varied manifestations have been identified and lately, otorhinolaryngology dysfunctions in COVID 19 have been described. Hearing loss in COVID era is one of the emerging areas of concern and calls for further research in the field for the better understanding and treatment of this entity. This study was designed to assess the audiological profile among 100 mild to moderately affected COVID-19 individuals, so as to make a contribution to the emerging literature on otologic manifestations in COVID 19. In our case series, high frequency hearing loss and referred OAE was noted among significant number of COVID 19 positive patients. This was even observed in patients without any otologic symptoms. Hence, early identification and intervention if required helps to give a better quality of life to the patient.     

Plants in our combating strategies against Mycobacterium tuberculosis: progress made and obstacles met

Context: Traditionally used plants for treating chest-related problems/tuberculosis (TB) have not been evaluated in detail and hence a thorough study is needed in this regard. This knowledge may find application in developing new anti-TB drugs.

Objective: This article elaborates on studying the activity of medicinal plants against different forms of Mycobacterium tuberculosis (Mtb) using different model strains, in vitro and ex vivo assays for studying the tuberculocidal activity and discusses the results from different studies on the activity against different forms of Mtb and human immunodeficiency virus-tuberculosis (HIV-TB) co-infection.

Methods: Scientific databases such as PubMed, Elsevier, Scopus, Google scholar, were used to retrieve the information from 86 research articles (published from 1994 to 2016) related to the topic of this review.

Results: Twenty-three plant species have been reported to possess active molecules against multi-drug resistant (MDR) isolates of Mtb. Seven plants were found to be active against intracellular Mtb and six against dormant bacilli. Seven plants were synergistically effective when combined with anti-TB drugs. Six studies suggest that the beneficial effects of plant extracts are due to their wide array of immuno-modulatory effects manifested by the higher expression of cytokines. Some studies have also shown the dual activity (anti-HIV and anti-TB) of plants.

Conclusion: We emphasize on identifying plants based on traditional uses and testing their extracts/phytomolecules against MDR strains, intracellular Mtb as well as against dormant Mtb. This will help in future to shorten the current therapeutic regimens for TB and also for treating HIV-TB co-infection.     

Electrochemical and surface studies on chemically modified glucose derivatives as environmentally benign corrosion inhibitors

Three glucose derivatives, namely Ethylenediamine-modified glucose, Tetramethylenediamine-modified glucose, and Hexamethylenediamine-modified glucose with three different carbon chain lengths were synthesized using environmentally benign and low-cost reactants at ambient temperature. The synthesized derivatives were evaluated as inhibitors for mild steel corrosion in 1 M HCl using electrochemical, surface analysis (XPS, AFM and contact angle), as well as computational (DFT) techniques. The obtained results suggest that the synthesized glucose derivatives significantly mitigate the corrosion of mild steel and show a rise in the inhibition efficiency with increasing inhibitor dosage. The inhibitor adsorption obeyed the Langmuir isotherm. The XPS analyses provided an elucidation on the interaction of the inhibitors with the steel substrate. The DFT studies showed that the protonated forms of the inhibitors act more prominently compared to the neutral form. The inhibitor HMG having the alkyl chain with six carbon atoms exhibited the highest inhibition performance of >95% at 22.71 × 10^?5 mol L^?1.     

Detection of Oxacillin-Susceptible mecA-Positive Staphylococcus aureus Isolates by Use of Chromogenic Medium MRSA ID

Reports of oxacillin-susceptible mecA-positive Staphylococcus aureus strains are on the rise. Because of their susceptibility to oxacillin and cefoxitin, it is very difficult to detect them by using routine phenotypic methods. We describe two such isolates that were detected by chromogenic medium and confirmed by characterization of the mecA gene element.