Dexamethasone and lenalidomide have distinct functional effects on erythropoiesis

Corticosteroids and lenalidomide decrease red blood cell transfusion dependence in patients with Diamond-Blackfan anemia (DBA) and myelodysplastic syndrome (MDS), respectively. We explored the effects of dexamethasone and lenalidomide, individually and in combination, on the differentiation of primary human bone marrow progenitor cells in vitro. Both agents promote erythropoiesis, increasing the absolute number of erythroid cells produced from normal CD34(+) cells and from CD34(+) cells with the types of ribosome dysfunction found in DBA and del(5q) MDS. However, the drugs had distinct effects on the production of erythroid progenitor colonies; dexamethasone selectively increased the number of burst-forming units-erythroid (BFU-E), whereas lenalidomide specifically increased colony-forming unit-erythroid (CFU-E). Use of the drugs in combination demonstrated that their effects are not redundant. In addition, dexamethasone and lenalidomide induced distinct gene-expression profiles. In coculture experiments, we examined the role of the microenvironment in response to both drugs and found that the presence of macrophages, the central cells in erythroblastic islands, accentuated the effects of both agents. Our findings indicate that dexamethasone and lenalidomide promote different stages of erythropoiesis and support the potential clinical utility of combination therapy for patients with bone marrow failure.     

Hypertension, orthostatic hypotension, and the risk of falls in a community-dwelling elderly population: the maintenance of balance, independent living, intellect, and zest in the elderly of Boston study

OBJECTIVES: To investigate the relationships between uncontrolled and controlled hypertension, orthostatic hypotension (OH), and falls in participants of the Maintenance of Balance, Independent Living, Intellect, and Zest in the Elderly of Boston Study (N=722, mean age 78.1). DESIGN: Prospective population‐based study. SETTING: Community. PARTICIPANTS: Seven hundred twenty‐two adults aged 70 and older living within a 5‐mile radius of the study headquarters at Hebrew Rehabilitation Center in Boston. MEASUREMENTS: Blood pressure (BP) was measured at baseline in the supine position and after 1 and 3 minutes of standing. Systolic OH (SOH) and diastolic OH at 1 and 3 minutes were defined as a 20‐mmHg decline in systolic BP and a 10‐mmHg decline in diastolic BP upon standing. Hypertension was defined as BP of 140/90 mmHg or greater or receiving antihypertensive medications (controlled if BP<140/90 mmHg and uncontrolled if ≥140/90 mmHg). Falls data were prospectively collected using monthly calendars. Fallers were defined as those with at least two falls within 1 year of follow‐up. RESULTS: OH was highest in participants with uncontrolled hypertension; SOH at 1 minute was 19% in participants with uncontrolled hypertension, 5% in those with controlled hypertension, and 2% in those without hypertension (P≤.001)). Participants with SOH at 1 minute and uncontrolled hypertension were at greater risk of falls (hazard ratio=2.5, 95% confidence interval=1.3–5.0) than those with uncontrolled hypertension without OH. OH by itself was not associated with falls. CONCLUSION: Older adults with uncontrolled hypertension and SOH at 1 minute are at greater risk for falling within 1 year. Hypertension control, with or without OH, is not associated with greater risk of falls in older community‐dwelling adults.     

Subjective outcome and quality of life following external dacryocystorhinostomy

Purpose:To assess the patient reported outcome and quality of life in post external dacryocystorhinostomy operated patients.Methods:A prospective questionnaire based study was carried out on 112 patients diagnosed with chronic dacryocystitis who underwent external dacryocystorhinostomy in the department of Orbit and Oculoplasty at a tertiary eye hospital in South India.Results:We included 112 cases in our study. Mean (SD) of the age of patients was 48.03 (12.79) years and ranged from 7 to 72 years of age. 44 (39.3%) patients were males and 68 (60.7%) were females. All cases had subjective symptoms of tearing, pain and swelling at baseline which were relieved by post-operative 3 in all cases. The mean (SD) best corrected visual acuity was 0.28 (0.39) at baseline and 0.25 (0.37) at postoperative 3 (p < 0.001). All four parameters studied in the GBI questionnaire - total mean GBI (32.22 vs 48.86, P < 0.001), general subscale (31.21 vs 44.08, P < 0.001), social health (46.28 vs 61.01, P < 0.001), physical outcome (22.17 vs 55.80, P = 0.0001) scores showed significant improvement from 1 vs 3 months post DCR.Conclusion:The GBI questionnaire is an effective tool for assessing patients’ quality of life following DCR. External DCR can not only produce a successful anatomical outcome but also bring about a measurable improvement in subjective symptoms and quality of life among patients with symptomatic NLDO.     

Protective effect of Etlingera elatior (torch ginger) extract on lead acetate--induced hepatotoxicity in rats

Lead is known to disrupt the biological systems by altering the molecular interactions, cell signaling, and cellular function. Exposure to even low levels of lead may have potential hazardous effects on brain, liver, kidneys and testes. The efficacy of Etlingera elatior (torch ginger) to protect hepatotoxicity induced by lead acetate was evaluated experimentally in male Sprague - Dawley rats. Rats were exposed to lead acetate in drinking water (500 ppm) for 21 days and the effects of concurrent treatment with extract of E. elatior on hepatic lipid hydroperoxides (LPO), protein carbonyl content (PCC), total antioxidants (TA), superoxide dismutase (SOD), glutathione peroxidase (GPX) and glutathione S- Transferase (GST) levels and histopathological changes in liver were evaluated. There was a significant decrease in TA and other antioxidant enzymes (p < 0.05) and increase in LPO and PCC (p < 0.05) with lead acetate ingestion. Concurrent treatment with E. elatior extract significantly reduced the LPO and PCC (p < 0.05) in serum and increased the antioxidant enzyme levels (p < 0.05) in the liver. Significant histopathological changes were seen in hepatic tissue with chronic lead ingestion. Treatment with E. elatior significantly reduced these lead-induced changes in hepatic architecture. E. elatior has also reduced the blood lead levels (BLL). Thus, there has been extensive biochemical and structural alterations indicative of liver toxicity with exposure to lead and E. elatior treatment significantly reduced these oxidative damage. Our results suggest that E. elatior has a powerful antioxidant effect against lead-induced hepatotoxicity.     

Lifestyle drugs: concept and impact on society

Lifestyle has changed from being an indicator of the overall well being of an individual to a cause of disease and now "lifestyle" has itself become an object of medical attention. Alcohol has been used enormously as one of the oldest 'lifestyle' drugs, and currently sildenafil citrate (Viagra), the drug of choice for erectile dysfunction, exemplifies a turning point in the era of modern lifestyle drugs. This drug has transformed the lifestyles of millions and greatly increased the revenue of many pharmaceutical companies. With the Indian economy growing rapidly at an annual rate of 8-9%, a new era of drug discovery and development coupled with an enormous increase in the marketing of new drugs is being seen. This has certainly made the Indian public vulnerable to issues related to lifestyle drugs. There is a need to study this concept deeply and the impact of these drugs on Indian society, particularly since this topic has already been the centre of many discussions in other developed nations.     

Concordance of adherence measurement using self-reported adherence questionnaires and medication monitoring devices

The primary objective of this review was to identify and examine the literature on the association between medication adherence self-reported questionnaires (SRQs) and medication monitoring devices. The primary literature search was performed for 1980-2009 using PubMed, PubMed In Process and Non-Indexed, Ovid MEDLINE, Ovid MEDLINE In-Process, PsycINFO (EBSCO), CINAHL (EBSCO), Ovid HealthStar, EMBASE (Elsevier) and Cochrane Databases and using the following search terms: 'patient compliance', 'medication adherence', 'treatment compliance', 'drug monitoring', 'drug therapy', 'electronic', 'digital', 'computer', 'monitor', 'monitoring', 'drug', 'drugs', 'pharmaceutical preparations', 'compliance' and 'medications'. We identified studies that included SRQs and electronic monitoring devices to measure adherence and focused on the SRQs that were found to be moderately to highly correlated with the monitoring devices. Of the 1679 citations found via the primary search, 41 full-text articles were reviewed for correlation between monitoring devices and SRQs. A majority (68%) of articles reported high (27%), moderate (29%) or significant (12%) correlation between monitoring devices (37 using Medication Event Monitoring System [MEMS?] and four using other devices) and SRQs (11 identified and numerous other unnamed SRQs). The most commonly used SRQs were the Adult/Pediatric AIDS Clinical Trial Group (AACTG/PACTG; 24.4%, 10/41) followed by the 4-item Morisky (9.8%, 4/41), Brief Medication Questionnaire (9.8%, 4/41) and visual analogue scale (VAS; 7.3%, 3/41). Although study designs differed across the articles, SRQs appeared to report a higher rate of medication adherence (+14.9%) than monitoring devices. In conclusion, several medication adherence SRQs were validated using electronic monitoring devices. A majority of them showed high or moderate correlation with medication adherence measured using monitoring devices, and could be considered for measuring patient-reported adherence prospectively.     

Foxp3 induces IL-4 gene silencing by affecting nuclear translocation of NFkappaB and chromatin structure

The forkhead family protein Foxp3 is a unique marker of regulatory T cells and plays a crucial role in the development and function of those cells. Ectopic expression of Foxp3 abolishes the expression of many cytokines in uncommitted cells but there is little information about whether it causes gene silencing in differentiated cells. In this study, we showed that ectopic expression of Foxp3 in primary T helper 2 cells abolished IL-4 gene expression. Foxp3 inhibited nuclear translocation of NFkappaB by increasing the stability of the NFkappaB inhibitor IkappaBalpha, which in turn reduced in vivo binding of NFkappaB to the IL-4 promoter region. Moreover, Foxp3 over-expression induced inactive chromatin structure by decreasing in vivo binding levels of acetylated histone 3 while increasing methylated histone 3 at lysine 9 in the IL-4 genomic locus. Our results suggest that Foxp3 could induce gene silencing by inhibiting NFkappaB activity and by causing its target loci to adopt an inactive chromatin configuration.     

Immune suppression leading to hepatitis C virus re-emergence after sustained virological response

Sustained virological response SVR is defined as undetectable HCV RNA in plasma 6 months after therapy has been discontinued. Relapse or re-emergence of viremia after SVR is rare. We report two patients that relapsed when immune suppressive therapy was given within a few weeks of achieving SVR. Patient 1 received prednisone for bronchitis and patient 2 relapsed soon after immune suppression was started post renal transplantation. These data suggest that the early phase of SVR might be associated with incomplete protective immunity. They suggest that sterilizing immunity with complete elimination of virus is unlikely. The cases also caution against the use of immune suppressive therapy in the immediate aftermath of SVR.