Effect of vasodilator and immunosuppressive therapy on the endothelial dysfunction in patients with systemic sclerosis.

A comparative analysis of flow-mediated vasodilation (FMD), vasoactive angiogenic, and fibrogenic mediators between treatment-naive and treated systemic sclerosis (SSc) patients is an unmet need. (1)To assess the FMD and different pathogenic mediators in SSc patients about endothelial dysfunction. (2) To assess the proportion of circulating endothelial cells (CECs) in treatment-naïve patients. SSc patients were grouped into treatment-naïve (Group-I, n = 24) on vasodilator (Group-II, n = 10), on vasodilator + immunosuppressive (Group-III, n = 22)]. Age-sex matched healthy controls (n = 20) were included. Endothelial dysfunction (ED) was measured radiologically using FMD. Serum levels of NO, ET1, NO/ET1, sVCAM, sICAM, TGF, IL-6, and VEGF, as well as gene expressions of eNOS, iNOS, ET-1, and TGF, were measured to assess the status of ED in various study groups. CEC was measured in Group-I and HC. CEC was used as a marker to identify a key regulator of ED in SSc. FMD was significantly decreased in all SSc patients through receiving treatment. Upregulation of serum NO and ET concentrations was noted post-treatment with an unaltered NO/ET1 ratio. NO was positively correlated with FMD (r = 0.6) and negatively with TGFß (r = - 0.5). ET-1 showed a negative correlation with TGFß (r = - 0.5) but no significant correlation with FMD. Circulating endothelial cell (CEC) was significantly higher in Group-I (3.2%) than HC (0.8%) (p = 0.002), and it showed a good correlation with NO (r = - 0.7, p = 0.0001) and NO/ET1 (r = - 0.6, p = 0.007). Persistent ED was observed in all SSc patients irrespective of treatment. Dysbalance in NO/ET1 ratio might be the considering factor for the underlying progression of ED. Based on our findings, it may be hypothesized that reduced NO may be a contributing factor in the pathogenesis of endothelial dysfunction in SSc.

Validation of antioxidant, antiproliferative, and in vitro anti-rheumatoid arthritis activities of epigallo-catechin-rich bioactive fraction from Camellia sinensis var. assamica, Assam variety white tea, and its comparative evaluation with green tea fraction.

The epigallocatechin-rich polyphenolic fraction of Assam variety white tea, traditionally used for the management of diverse inflammatory ailments and health drink, was investigated through eco-friendly green aqueous extraction, TLC, and HPLC characterization, phytochemical screening, in vitro DPPH assay, anti-proteinase, MTT assay on synovial fibroblast and colon cancer cells, apoptotic FACS analysis, cytokine ELISA, p-STAT3 western blotting, and in silico docking analysis. HPLC-TLC standardized white tea fraction (WT-F) rendered higher extractive-yield (21%, w/w), than green tea fraction(GT-F) (12%, w/w). WT-F containing flavonoids and non-hydrolysable polyphenols showed better antioxidant activity, rather than equivalent GT-F. WT-F demonstrated remarkable anti-rheumatoid-arthritis activity via killing of synovial fibroblast cells (66.1%), downregulation of TNF-α (93.33%), IL-6 (87.97%), and p-STAT3 inhibition (77.75%). Furthermore, WT-F demonstrated better anti-proliferative activity against colon cancer cells (HCT-116). Collectively, our study revealed that the white tea fraction has boundless potential as anti-rheumatoid arthritis and anti-proliferative agent coupled with apoptotic, antioxidant anti-proteinase, and anti-inflammatory properties. PRACTICAL APPLICATIONS: Our eco-friendly extracted bioactive aqueous fraction of white tea, characterized by TLC-HPLC study and phytochemical screening have demonstrated remarkable anti-rheumatoid arthritis property and anti-proliferative action on colon cancer cells including potential anti-oxidant, anti-inflammatory, and anti-proteinase efficacy. The test WT-F sample has shown impressive safety on normal mammalian cells. WT-F has demonstrated better efficacy against rheumatoid arthritis and cancer model compared to equivalent green tea fraction. Traditionally, it is extensively used for boosting immunity, and energy, with cosmetic, and agricultural applications by the native inhabitants. So, the aqueous fraction of WT is suggested to be used as a prophylactic nutraceutical supplement and or therapeutic agent in commercial polyherbal formulation to attenuate and management of auto-inflammatory rheumatoid arthritis and carcinogenesis of colon. It is additionally suggested to establish in vivo rheumatoid arthritis animal and clinical study to validate their pharmacokinetic stability and dose optimization coupled with anti-inflammatory, cytotoxicity, and anti-oxidant property.

Interleukin-17 as a predictor of subclinical synovitis in the remission state of rheumatoid arthritis.

OBJECTIVES: To compare the level of pro and anti-inflammatory cytokines, and angiogenic mediators between Rheumatoid arthritis (RA) patients with and without subclinical synovitis (SS) in remission state, to find the correlation of these mediators with Greyscale synovitis (GSS) and power Doppler (PD) scores, and to find the probable predictor/s of SS. METHODS: 52 RA patients in remission state were recruited and subdivided into with and without SS group by Ultrasonography (USG) of 14 joints. Total GSS and PD scoring was done. The serum levels of the pro/anti-inflammatory cytokines and angiogenic mediators were compared between groups, and correlation and regression analysis were done with GSS and PD scores. RESULT: 63.46% patients had USG evidence of SS. Patients with SS had significantly higher levels of pro-inflammatory and angiogenic mediators [matrix-metalloproteinase -3 (p = 0.0001), Tumour necrosis factor-α (p = 0.0001), Interleukin (IL)-6 (p = 0.001), IL-1b (p = 0.0001), IL-17 (p = 0.0005), IL-33 (p = 0.0003), Tie-2 (p = 0.0001), vascular endothelial growth factor (VEGF (p = 0.03)], and lower anti-inflammatory cytokines [IL-27 (p = 0.0003), IL-10(p = 0.0001)]. A strong positive correlation of GSS score was noted with IL-17(r = 0.7), IL-6 (r = 0.7), IL-1b (r = 0.7), and IL-33 (r = 0.6). Multiple linear regression model identified IL-17 and IL-6 as predictors of GSS score, and TNF-α and VEGF as predictors of PD score. IL-17 level > 249 picogram/millilitre (pg/ml) could predict the SS with high specificity (89.5%). CONCLUSION: Patients with SS in the remission state of RA showed altered expression of some of the pro/anti-inflammatory/angiogenic markers compared to those not having SS. IL-17, IL-6, VEGF, and TNF-α could be the predictors of USG synovial scores.

A combination of circulating microRNA-375-3p and chemokines CCL11, CXCL12, and G-CSF differentiate Crohn's disease and intestinal tuberculosis.

Differentiation of Crohn's disease (CD) from intestinal tuberculosis (ITB) is a big challenge to gastroenterologists because of their indistinguishable features and insensitive diagnostic tools. A non-invasive biomarker is urgently required to distinguish ITB/CD patients particularly in India, a TB endemic region, where CD frequency is increasing rapidly due to urbanization. Among the three differentially expressed miRNAs obtained from small RNA transcriptomic profiling of ileocaecal/terminal ileal tissue of ITB/CD patients (n = 3), only two down-regulated miRNAs, miR-31-5p, and miR-215-5p showed comparable data in qRT-PCR. Out of which, only miR-215-5p was detectable in the patient's plasma, but there was no significant difference in expression between ITB/CD. On the other hand, miR-375-3p, the pulmonary TB specific marker was found in higher amount in the plasma of ITB patients than CD while reverse expression was observed in the ileocaecal/terminal ileal tissues of the same patients. Next, using Bioplex pro-human cytokine 48-plex screening panel, only three chemokines, Eotaxin-1/CCL11, SDF-1α/CXCL12, and G-CSF have noted significantly different levels in the serum of ITB/CD patients. ROC analysis has revealed that compared to a single molecule, a combination of miR-375-3p + Eotaxin-1/CCL11 + SDF-1α /CXCL12 + G-CSF showed a better AUC of 0.83, 95% CI (0.69-0.96) with 100% specificity and positive predictive value while sensitivity, negative predictive value, and accuracy were 56%, 69%, and 78% respectively in distinguishing ITB from CD. This study suggests that a combination of plasma markers shows better potential in differentiating ITB from CD than a single marker and this panel of markers may be used for clinical management of ITB/CD patients.

Methotrexate and theaflavin-3, 3'-digallate synergistically restore the balance between apoptosis and autophagy in synovial fibroblast of RA: an ex vivo approach with cultured human RA FLS.

BACKGROUND: Imbalance between apoptosis and autophagy in fibroblast-like synoviocytes (FLS) is one of the pathogenic mechanisms responsible for their abnormal proliferation in rheumatoid arthritis (RA). Methotrexate (MTX) demonstrated limited efficacy in amending this imbalance in fluid-derived (fd)-FLS. The active compound of black tea Theaflavin 3,3'-digallate (TF3) may be effective in restoring apoptosis-autophagy imbalance in (fd)-FLS. The combined effect of MTX + TF3 upon the same is yet to be elucidated. OBJECTIVE: To evaluate the effect of MTX + TF3 on fd-FLS to induce apoptosis and inhibit autophagy through Endoplasmic Reticulum (ER) stress-mediated pathways. METHODS: FLS from synovial fluid of 11 RA and 10 osteoarthritis patients were cultured after treatment with MTX/TF3 or a combination of MTX (125 nM) and TF3(10 µM) and the following parameters were evaluated. C-reactive protein, cytokines (TNF-α, IL-6), angiogenic markers were quantified by ELISA. fd-FLS viability was determined by MTT assay and apoptosis by flow cytometry. ER stress markers were estimated by RT-PCR (IRE1A, spliced-XBP-1) and immunoblotting (Grp78, Hsp70, CHOP, HIF-1α). Immunoblot studies were done to evaluate apoptotic (Bcl-2, Bax, Caspases) and autophagic (Beclin1, LC3b, p62) proteins. RESULTS: MTX (IC25) and TF3 (IC50) both in single doses could down-regulate the levels of pro-inflammatory and angiogenic markers. Combinatorial treatment modulated autophagosomal proteins in fd-FLS and induced apoptosis by regulating ER stress response. CONCLUSION: Disruption in homeostasis between apoptosis and autophagy in fd-FLS might be an underlying phenomenon in the progression of pathophysiology in RA. Co-administration of MTX + TF3 successfully restored the homeostasis by inducing apoptosis.

Early-onset bipolar disorder, stress, and coping responses of mothers: A comparative study.

BACKGROUND: Providing care and nurturance to a child with bipolar disorder (BPAD) is a challenging task for parents, especially mothers. In Indian contexts, mothers are the primary caregivers of ailing children and they have to keep intrafamily situation stable, which makes their role more stressful. OBJECTIVES: The objective of the study was to assess maternal stress and coping in mothers of adolescents with BPAD. MATERIALS AND METHODS: This study was a comparative one and carried out on sixty mothers of adolescents; of which thirty were adolescents with BPAD, and the remaining thirty were the mothers of normal adolescents. The participants were selected purposively as per the mothers' age and education level, and the socioeconomic status of the families they belong to. Sociodemographic and clinical data sheet, Parenting Stress Index/Short Form (PSI/SF), and Brief COPE were applied on the mothers for data collection. RESULTS: Mothers' of the BPAD adolescents reported higher scores in the both PSI/SF and Brief COPE. CONCLUSION: Mothers of the adolescents with BPAD tend to perceive high level of stress and they also use maladaptive coping more in dealing with stressful situations.

Phenotypic characterization of circulating endothelial cells induced by inflammation and oxidative stress in ankylosing spondylitis.

Ankylosing spondylitis (AS) is a chronic auto-immune disease, affecting the spine, sacroiliac, and sometimes peripheral joints. It is also involved with cardio-vascular risk factors due to accelerated atherosclerosis. Oxidative burst, systemic inflammation coupled with endothelial dysfunction (ED), resulting in reduced bioavailability of the vasodilator nitric oxide (NO) and an increased number of circulating endothelial cells (CECs) may correlate with disease activity and its sustenance. Hence, the study was aimed to detect and quantify CECs and assess the oxidative stress and inflammatory status in AS patients vis-à-vis healthy controls, as well as relate these parameters with AS disease activity and atherosclerotic markers in patients. Our study showed an increased frequency of endothelial cells in peripheral blood of AS patients in pro-inflammatory conditions. In AS patient population, they showed significant reduction of flow-mediated dilatation (%FMD) (p < 0.05), and increased soluble adhesion molecules such as sICAM-1 (p < 0.01) and sVCAM-1 (p < 0.05) compared to healthy controls. A marked increase in pro-inflammatory markers such as TNF-α (p < 0.01) and IL-1ß (p < 0.001) and reactive free radicals (p < 0.05) along with reduced serum nitrite in AS, provided a strong pro-inflammatory milieu which positively correlated with Bath ankylosing spondylitis disease activity and functional indices (BASDAI and BASFI). The observed significant upregulation in CECs (CD45-/CD31+/CD105+/CD144+) in patients compared to healthy controls positively correlated with disease activity and duration as well as with markers of oxidative stress. Thus, chronic inflammation and oxidative burst induce loss of NO bioavailability, leading to ED. This may cause the derangement of CECs that may be considered as a prognostic biomarker for ED.

Expressed Emotions and Coping among Relapsed Persons with Alcohol Dependence Syndrome: A Comparative Study.

BACKGROUND: Alcohol dependence is a global public health issue; it is a chronic and relapsing illness. Relapse is multifaceted by both neurobiological and psychosocial processes. AIM: To examine the expressed emotions and coping among persons with alcohol dependence. METHODS: The study was descriptive and hospital-based. A purposive sampling technique was used. This study was conducted at the Centre for Addiction Psychiatry, CIP, Ranchi. The total sample size was 50. Twenty-five persons with alcohol dependence who relapsed within six months following treatment formed a study group. Another 25 persons with alcohol dependence who were abstinent for a minimum period of six months after treatment formed a comparative group. Ways of coping questionnaire and the level of expressed emotions scale were used, and informed consent was taken from the participants. Chi-square and independent sample 't' test, Pearson's correlation was used to analyse the data. RESULTS: Mean age of relapsed patients was 35.3 years (S.D±7.6), and abstinent patients were 35.4 yrs (S.D±6.8), years of education of relapsed patients score was 12 yrs ±2.63 and 11.6 yrs ±3.26 in abstinent patients. A majority (60% )of relapsed patients were from rural background, 92% in the abstinent group were employed. 60% of abstinent patients had a family history of alcohol dependence. Abstinent patients had scored significantly high in all the domains of ways of coping. Relapse patients had higher scores in perceived lack of emotional support, perceived irritability, perceived intrusiveness, and perceived criticism compared to abstinent patients. CONCLUSION: The study provided further evidence that coping and perceived expressed emotions significantly influenced relapse among persons with alcohol dependence.

Pre-Basal Insulin Analog Era: Paving the Way for Modern Day Basal Insulins.

Prior to the discovery of insulins, diabetes was managed predominantly by dietary interventions. Discovery of insulin and its first human trial highlighted the need for higher purity insulin thereby steering the subsequent journey of insulin development. Considering the limitations of the early preparations like short duration of action and need for several injections per day, attempts at protracting the duration of insulin action were made. This led to the development of intermediate-acting Neutral Protamine Hagedorn (NPH) and the Lente family of insulins. This review provides insights into the discovery of insulins and the shortcomings of early protracted release preparations, which in turn, gave impetus to the search for a 'true' basal insulin, which could mimic the endogenous human basal insulin secretion.

Progressive Non-familial Adult onset Cerebellar Degeneration: An Unusual Occurrence with Hashimoto's Thyroiditis.

Progressive non-familial adult onset cerebellar degeneration has been rarely associated with hypothyroidism and is known to be reversible after therapy. We report a case of cerebellar atrophy in a 31 year old female whose detailed evaluation had revealed sub-clinical hypothyroidism secondary to autoimmune thyroiditis with a very high anti-TPO (anti-thyroid peroxidase) antibody levels. MRI (Magnetic Resonanace Imaging) of brain showed diffuse bilateral cerebellar atrophy. She was treated with thyroid hormone supplementation and after one year of follow up, cerebellar signs had disappeared completely with significant reduction in anti-TPO antibody levels. Imaging of the brain post one year of follow-up revealed normal cerebellum. Hence, we opine that thyroid dysfunction should always be kept in mind while evaluating patients presenting with acute onset cerebellar ataxia as it can be easily reversed with thyroid hormone replacement therapy.

Risk of GERD with Diabetes Mellitus, Hypertension and Bronchial Asthma - A Hospital based Retrospective Cohort Study.

INTRODUCTION: The rise in Gastro-Esophageal Reflux Disease (GERD) prevalence appears to have coincided with a simultaneous increase in the prevalence of diabetes mellitus, hypertension and bronchial asthma amongst the Indian population. Despite being evaluated extensively for their role as a risk factor for GERD, till date this relationship has remained a debatable one. Moreover, literature available on such studies conducted within Indian population remains scarce. AIM: The aim of the present study was to examine the risk of developing GERD in patients suffering from diabetes mellitus, hypertension and asthma in a Southern Indian population. The present retrospective, triple cohort and hospital based study was conducted by accessing the patient records from the medical records department of a tertiary care hospital in Southern India. MATERIALS AND METHODS: The patient's records were accessed from the year 2011 onwards. Relative Risk (RR) was calculated to determine the risk of development of GERD with every disease. Chi-square test was used to determine the statistical significance of the relationship between each disease and the development of GERD. A p-value of <0.05 was considered statistically significant. RESULTS: In view of the time constraints as well as the limitations of the inclusion and exclusion criteria, data pertaining to only 40, 71 and 53 patients in Cohort 1 (diabetics), 2 (hypertensives) and 3 (bronchial asthmatics) respectively could be analyzed in the present study. The relative risk of GERD development was greater than 1 for patients belonging to Cohort 2 and 3, suggesting that the risk of GERD development is higher amongst hypertensives and asthmatics. Surprisingly, the diabetics (Cohort 1) were not associated with a high risk of GERD development. However, the relationship between any of the disease and GERD development was not statistically significant. CONCLUSION: The present study found an increased risk of GERD development amongst patients suffering from hypertension and bronchial asthma, but not with diabetes mellitus.

Escitalopram Induced SIADH in an Elderly Female: A Case Study.

Hyponatraemia is a well-established and potentially, a life-threatening adverse effect of selective serotonin receptor uptake inhibitors (SSRI). However, its occurrence secondary to syndrome of inappropriate antidiuretic hormone secretion (SIADH) with escitalopram, has been reported extremely sporadically. The reporting of such rare, but life-threatening adverse effects of escitalopram assumes immense significance in light of the fact that SSRIs presently form the mainstay of treatment of depressive disorders. Here, we report a case where a 58 year old diabetic lady, when initiated on escitalopram for dysthymia developed severe hyponatraemia within 2 weeks. Further, we discuss other relevant cases that have been reported in the past with an eye on the management of SIADH and hyponatraemia.

Extrapyramidal Symptoms Probably Related to Risperidone Treatment: A Case Series.

BACKGROUND: Atypical antipsychotics, like risperidone purportedly, score over their typical counterparts in terms of their lower propensity toward producing extrapyramidal symptoms (EPS). However, recent studies have furnished evidence to the contrary. Hereby, we present a case series implicating risperidone as the causative agent for EPS. METHODS: As a part of the pharmacovigilance programme of India, the authors have assessed 10 physician-reported cases of EPS among the 1,830 patients who were prescribed risperidone within the time period of January 2012-December 2014 in a tertiary care hospital in South India. Causality, severity, and preventability assessments of adverse reaction were done as per Naranjo's, Hartwig's, and Thornton'scale respectively. RESULTS: Of the 10 cases, a dose-dependent occurrence of EPS was noted in all and the time duration for development of EPS ranged from 1 week to 2 years. Four patients developed EPS at a dose of 6-8 mg, 4 developed at a dose of 4-6 mg, and the remaining 2 developed at 2 and 1 mg. CONCLUSION: A strong temporal correlation between risperidone and EPS was noted in all cases. High doses produced EPS early, whereas moderate to low doses produced EPS at a later date. Thus, cautious use and close monitoring are warranted in the chronic use of risperidone.

The Evolutionary Tale and Future Directions of Aromatase Inhibitors in Breast Carcinoma.

Aromatase inhibitors have often been likened to that of 'medical scalpels' for the treatment of breast carcinoma. By inhibiting the singular step of aromatisation, they have proven to be extremely effective allies in the treatment of breast cancer among postmenopausal women. However, their relevance soon may not be limited to the post-menopausal age group alone. Recent studies have hinted at their utility amongst the premenopausal women; combined with ovarian ablation techniques, aromatase inhibitors may prove to be equally effective and more, as compared to tamoxifen in this age-group. Additionally, explorations aimed at ascertaining their potential utility as an effective preventive strategy against breast carcinoma have yielded encouraging results. However, for aromatase inhibitors to be able to attain their full potential, further strategic fine-tuning aimed at maximising their efficacy and minimising their potentially far-reaching adverse effects, is the need of the hour. Despite the recent diversification, the issue of resistance to aromatase inhibitors in breast cancer threatens to derail the advances so gained till date. Fortunately, a few novel ploys have come to the fore, for instance combining aromatase inhibitors with HER-2 antibodies that could potentially help circumvent the menace of resistance in the near future. Till date, the utility of aromatase inhibitors can at best be described as onedimensional. However, with the unearthing of potential new avenues for its application, this assortment of molecules today stands on the precipice of ushering in a new revolution in the treatment of breast carcinoma.

Wernicke's Encephalopathy - 'Pushing the Envelope' of Patient's Profile: A Case Report.

Wernicke's encephalopathy (WE), an acute neuropsychiatric condition, is caused by thiamine deficiency. Traditionally, it has been associated with patients with a background of alcoholism. However, in the past few decades, with increasing trends in the incidence of WE among patients without a history of alcohol consumption, a pressing need was felt to examine the existing guidelines for the management of WE and its sequelae. The need for a revision was felt as the guidelines for the management of WE were developed around the premise that this affliction is observed mainly among alcoholics. In light of the opportunity presented to us by one of our patients who did not 'fit the bill' of a traditional case of WE, we decided to compare and contrast the management of WE among patients with and without a background of alcoholism. After analyzing the available data on WE among alcoholics and non-alcoholics, we concluded that a high degree of suspicion should be kept in mind if any of the classical features are observed, with a special emphasis on eliciting the underlying causes through a detailed history. Furthermore, thiamine supplementation at a lower dose of 100-200 mg should be initiated first, followed by laboratory and radiological investigations.

Epigenetics: The New Frontier in the Landscape of Asthma.

Over the years, on a global scale, asthma has continued to remain one of the leading causes of morbidity, irrespective of age, sex, or social bearings. This is despite the prevalence of varied therapeutic options to counter the pathogenesis of asthma. Asthma, as a disease per se, is a very complex one. Scientists all over the world have been trying to obtain a lucid understanding of the machinations behind asthma. This has led to many theories and conjectures. However, none of the scientific disciplines have been able to provide the missing links in the chain of asthma pathogenesis. This was until epigenetics stepped into the picture. Though epigenetic research in asthma is in its nascent stages, it has led to very exciting results, especially with regard to explaining the massive influence of environment on development of asthma and its varied phenotypes. However, there remains a lot of work to be done, especially with regard to understanding how the interactions between immune system, epigenome, and environment lead to asthma. But introduction of epigenetics has infused a fresh lease of life in research into asthma and the mood among the scientific community is that of cautious optimism.