Aparajit B. Dey

Inhibiting the Programmed Death 1 Pathway Rescues Mycobacterium tuberculosis–Specific Interferon γ–Producing T Cells From Apoptosis in Patients With Pulmonary Tuberculosis

BACKGROUND Overexpression of programmed death 1 (PD-1) receptor is thought to inhibit the effector T-cell response in human tuberculosis. However, the precise mechanism of such inhibition remains unclear. The present study addresses the role of PD-1 in dampening host T-cell function among patients with pulmonary tuberculosis. METHODS Expression of PD-1 and its ligands (PD-L1/L2) on T cells, B cells, and monocytes was evaluated by flow cytometry (FACS). In vitro stimulation of peripheral blood mononuclear cells in the presence of Mycobacterium tuberculosis antigens was performed with and without blocking PD-1, and intracellular cytokine production was measured by FACS. RESULTS We showed higher frequencies of T cells, monocytes, and B cells expressing PD-1 and its ligand(s) among patients with pulmonary tuberculosis. Infections with live M. tuberculosis upregulated PD-L1 expression on monocytes. In vitro PD-1 blocking rescued M. tuberculosis-specific interferon γ (IFN-γ)-producing T cells from undergoing apoptosis. The number of PD-1-expressing T cells decreased significantly during therapy and inversely correlated with IFN-γ-dominant T-cell response against M. tuberculosis. CONCLUSIONS Manipulation of PD-1 signaling may restore the host T-cell response and thus may have therapeutic potential. PD-1 also may serve as a biomarker to monitor host immunity among patients with tuberculosis during therapy and vaccine studies.

Frailty is associated with longer hospital stay and increased mortality in hospitalized older patients

OBJECTIVES Frailty status is associated with altered glucose-insulin dynamics. Here, we sought to investigate whether alteration in the dynamics of other circulating energy metabolism hormones after oral glucose is associated with frailty status. DESIGN Substudy of older women in a prospective cohort. SETTING Baltimore, Maryland. PARTICIPANTS Seventy-three community-dwelling women aged 84-95 years without a diagnosis of diabetes who were enrolled in the Womens Health and Aging Study II. MEASUREMENTS We examined stimulus-response dynamics of free fatty acids (FFA), gut- (ghrelin,GLP-1) and adipocyte-derived hormones (leptin, adiponectin, resistin), growth hormone (GH), insulin-like growth factor 1 (IGF-1), and interleukin-6 (IL-6) at 0, 30, 60, 120, and 180-minutes after a 75-g glucose challenge according to frailty status (non-frail, pre-frail, or frail). RESULTS On average, frail women had higher fasting levels of glucose-raising hormones (FFA, resistin, GH, and IL-6) and lower fasting levels of glucose-lowering hormones (ghrelin, adiponectin, GLP-1 and IGF-1) versus non-frail women but these results were not statistically significant. Frail women also had higher fasting levels of leptin with relative adiposity compared to their counterparts, suggestive of leptin-resistance. Integrated area under the curve (AUC) values for each hormone followed similar trends by frailty status. After age and BMI adjustment, frail versus non-frail women were more likely to be in the lowest tertile of fasting ghrelin levels and 120-min ghrelin levels (both p<0.05) in logistic regression analyses. No large differences were found for other hormones in adjusted models. CONCLUSIONS Our findings suggest dysregulation of the orexigenic hormone ghrelin in the frailty syndrome. Further studies are needed to explore the role of ghrelin dysregulation in the clinical manifestation of frailty.IntroductionWith the onset of frailty, there is often a rapid, progressive, and self-perpetuating downward spiral towards death. Frailty has enormous impact on acute hospital care and has been shown to be a more effective predictor of mortality than conventional clinical measures.MethodsHospitalized older patients admitted in medical wards at a teaching public hospital were studied to determine the prevalence of frailty; its association with anemia, congestive heart failure, clinically active tuberculosis and cognitive impairment; as well as its impact upon short-term outcome.ResultsA total of 250 older hospitalized patients were included, and their frailty status was assessed using Fried’s criteria. Of these, 83 (33.2%) patients were frail, with frailty found to be significantly associated with increasing age. A lower mean level of haemoglobin (p, 0.002), higher chance of congestive heart failure (p, <0.001), lower mean MMSE score (p, <0.001), was found in frail older patients. Frail subjects had a higher median hospital stay. There were total of 5 deaths, all among the frail group.ConclusionOur study showed that almost a third of hospitalized older patients are frail, and have anemia, higher frequency of CHF, cognitive impairment, longer hospital stay and higher mortality.

Sirtuin1: A Promising Serum Protein Marker for Early Detection of Alzheimer’s Disease

Sirtuin (SIRT) pathway has a crucial role in Alzheimer’s disease (AD). The present study evaluated the alterations in serum sirtuin1 (SIRT1) concentration in healthy individuals (young and old) and patients with AD and mild cognitive impairment (MCI). Blood samples were collected from 40 AD and 9 MCI patients as cases and 22 young healthy adults and 22 healthy elderly individuals as controls. Serum SIRT1 was estimated by Surface Plasmon Resonance (SPR), Western Blot and Enzyme Linked Immunosorbent Assay (ELISA). A significant (p<0.0001) decline in SIRT1 concentration was observed in patients with AD (2.27±0.46 ng/µl) and MCI (3.64±0.15 ng/µl) compared to healthy elderly individuals (4.82±0.4 ng/µl). The serum SIRT1 concentration in healthy elderly was also significantly lower (p<0.0001) compared to young healthy controls (8.16±0.87 ng/µl). This study, first of its kind, has demonstrated, decline in serum concentration of SIRT1 in healthy individuals as they age. In patients with AD and MCI the decline was even more pronounced, which provides an opportunity to develop this protein as a predictive marker of AD in early stages with suitable cut off values.

Profiles of older patients in the emergency department: findings from the interRAI Multinational Emergency Department Study.

STUDY OBJECTIVE We examine functional profiles and presence of geriatric syndromes among older patients attending 13 emergency departments (EDs) in 7 nations. METHODS This was a prospective observational study of a convenience sample of patients, aged 75 years and older, recruited sequentially and mainly during normal working hours. Clinical observations were drawn from the interRAI Emergency Department Screener, with assessments performed by trained nurses. RESULTS A sample of 2,282 patients (range 98 to 549 patients across nations) was recruited. Before becoming unwell, 46% were dependent on others in one or more aspects of personal activities of daily living. This proportion increased to 67% at presentation to the ED. In the ED, 26% exhibited evidence of cognitive impairment, and 49% could not walk without supervision. Recent falls were common (37%). Overall, at least 48% had a geriatric syndrome before becoming unwell, increasing to 78% at presentation to the ED. This pattern was consistent across nations. CONCLUSION Functional problems and geriatric syndromes affect the majority of older patients attending the ED, which may have important implications for clinical protocols and design of EDs.

Apolipoprotein E Gene Polymorphism in Indian Patients with Alzheimer’s Disease and Vascular Dementia

The association of apolipoprotein E (ApoE) gene polymorphism with Alzheimer’s disease (AD) has been reported in several populations including one from a rural community in North India. However, the association of ApoE polymorphism with vascular dementia (VaD) is yet to be established in this population. In a case-control study involving 54 cases of dementia (29 AD and 25 VaD) and 76 age-matched healthy controls, the frequency of Ε4 allele was significantly higher among cases of AD and VaD compared with controls (p < 0.001). The Ε3Ε3 (p < 0.05) and Ε2Ε3 (p < 0.001) genotypes were found to be protective. The odds of developing AD or VaD were 4.4 and 3.7 times higher, respectively, in the presence of even a single Ε4 allele. Our results suggest that the increased risk of developing AD or VaD is similar among Asian Indians with ApoE Ε4 compared with the Caucasian population.

Identification of serum sirtuins as novel noninvasive protein markers for frailty.

Frailty has emerged as a major health issue among older patients. A consensus on definition and diagnosis is yet to be achieved. Various biochemical abnormalities have been reported in frailty. Activation of sirtuins, a conserved family of NAD‐dependent proteins, is one of the many mimics of calorie restriction which improves lifespan and health in experimental animals. In this cross‐sectional study, we assessed the circulating sirtuin levels in 119 (59.5%) nonfrail and 81 (40.5%) frail individuals, diagnosed by Frieds criteria. Serum SIRT1, SIRT2, and SIRT3 were estimated by surface plasmon resonance (SPR) and Western blot. Serum sirtuins level in mean+SD; SIRT1 (nonfrail –4.67 ± 0.48 ng/μL; frail – 3.72 ± 0.48 ng/μL; P < 0.0001), SIRT2 (nonfrail – 15.18 ± 2.94 ng/μL; frail – 14.19 ± 2.66 ng/μL; P = 0.016), and SIRT3 (nonfrail‐7.72 ± 1.84 ng/μL; frail – 6.12 ± 0.97 ng/μL; P < 0.0001) levels were significantly lower among frail patients compared with the nonfrail. In multivariable regression analysis, lower sirtuins level were significantly associated with frailty after adjusting age, gender, diabetes mellitus, hypertension, cognitive status (Mini Mental State Examination scores) and number of comorbidities. For detecting the optimum diagnostic cutoff value a ROC analysis was carried out. The area under curve for SIRT1 was 0.9037 (cutoff – 4.29 ng/μL; sensitivity – 81.48%; specificity – 79.83%) and SIRT3 was 0.7988 (cutoff – 6.61 ng/μL; sensitivity – 70.37%; specificity – 70.59%). This study shows that lower circulating SIRT1 and SIRT3 levels can be distinctive marker of frailty.

Geriatric syndromes predict postdischarge outcomes among older emergency department patients: findings from the interRAI Multinational Emergency Department Study.

OBJECTIVES Identifying older emergency department (ED) patients with clinical features associated with adverse postdischarge outcomes may lead to improved clinical reasoning and better targeting for preventative interventions. Previous studies have used single-country samples to identify limited sets of determinants for a limited number of proxy outcomes. The objective of this study was to identify and compare geriatric syndromes that influence the probability of postdischarge outcomes among older ED patients from a multinational context. METHODS A multinational prospective cohort study of ED patients aged 75 years or older was conducted. A total of 13 ED sites from Australia, Belgium, Canada, Germany, Iceland, India, and Sweden participated. Patients who were expected to die within 24 hours or did not speak the native language were excluded. Of the 2,475 patients approached for inclusion, 2,282 (92.2%) were enrolled. Patients were assessed at ED admission with the interRAI ED Contact Assessment, a geriatric ED assessment. Outcomes were examined for patients admitted to a hospital ward (62.9%, n=1,436) or discharged to a community setting (34.0%, n=775) after an ED visit. Overall, 3% of patients were lost to follow-up. Hospital length of stay (LOS) and discharge to higher level of care was recorded for patients admitted to a hospital ward. Any ED or hospital use within 28 days of discharge was recorded for patients discharged to a community setting. Unadjusted and adjusted odds ratios (ORs) were used to describe determinants using standard and multilevel logistic regression. RESULTS A multi-country model including living alone (OR=1.78, p≤0.01), informal caregiver distress (OR=1.69, p=0.02), deficits in ambulation (OR=1.94, p≤0.01), poor self-report (OR = 1.84, p≤0.01), and traumatic injury (OR=2.18, p≤0.01) best described older patients at risk of longer hospital lengths of stay. A model including recent ED visits (OR=2.10, p≤0.01), baseline functional impairment (OR=1.68, p≤0.01), and anhedonia (OR=1.73, p≤0.01) best described older patients at risk of proximate repeat hospital use. A sufficiently accurate and generalizable model to describe the risk of discharge to higher levels of care among admitted patients was not achieved. CONCLUSIONS Despite markedly different health care systems, the probability of long hospital lengths of stay and repeat hospital use among older ED patients is detectable at the multinational level with moderate accuracy. This study demonstrates the potential utility of incorporating common geriatric clinical features in routine clinical examination and disposition planning for older patients in EDs.

Malignant mesothelioma of the tunica vaginalis of the testis without exposure to asbestos

IntroductionMesotheliomas are rare tumours that usually are seen in the pleura after asbestos exposure. Mesotheliomas have been reported around the testicular region but are even rarer following trauma, herniorrhaphy and long term hydrocoele.Case presentationAn elderly male farmer presented to us with an insidious onset of painless swelling in his left lower limb which gradually progressive. At the time of presentation it had involved his entire limb. A hard palpable mass of size 5 * 4 cms was detected in the left iliac fossa and a testicular enlargement was noted on the left side. The ultrasound of the testes showed that the left testis was enlarged 3.9*3*3.2 cms showing diffusely heterogenous echo-texture and irregular nodular surface with irregular hypoechoic thickening of the scrotal wall with left sided hydrocele. A separate hypoechoic *1.2 cms lesion was visualized in the anterior scrotal wall. FNAC from the scrotal mass showed tumour cells of simialr morphology present singly in monolayered sheets and in three dimensional fragments. The overall immunomorphological features suggested a malignant mesothelioma likely to have arisen from the tunica vaginalis.ConclusionIn conclusion, though a rare tumor, malignant mesothelioma of the tunica vaginalis of the testis should be considered whenever a paratesticular mass lesion is seen even without a history of trauma or asbestos exposure as is highlighted in this case. Ultrasound findings are helpful and fine needle aspiration of the tumor may assist in arrival at a diagnosis. Surgical orchidectomy remains the modality of treatment.

A study of empyema thoracis and role of intrapleural streptokinase in its management

BackgroundClinical spectrum, microbiology and outcome of empyema thoracis are changing. Intrapleural instillation of fibrinolytic agents is being increasingly used for management of empyema thoracis. The present study was carried out to describe the clinical profile and outcome of patients with empyema thoracis including those with chronic empyema and to study the efficacy and safety of intrapleural streptokinase in its management.MethodsClinical profile, etiological agents, hospital course and outcome of 31 patients (mean age 40 ± 16 years, M: F 25: 6) with empyema thoracis treated from 1998 to 2003 was analyzed. All patients were diagnosed on the basis of aspiration of frank pus from pleural cavity. Clinical profile, response to therapy and outcome were compared between the patients who received intrapleural streptokinase (n = 12) and those who did not (n = 19).ResultsEtiology was tubercular in 42% of the patients (n = 13) whereas the rest were bacterial. Amongst the patients in which organisms could be isolated (n = 13, 42%) Staphylococcus aureus was the commonest (n = 5). Intrapleural streptokinase was instilled in 12 patients. This procedure resulted in increase of drainage of pleural fluid in all patients. Mean daily pleural fluid drainage after streptokinase instillation was significantly higher for patients who received intrapleural streptokinase than those who did not (213 ml vs 57 ml, p = 0.006). Only one patient who was instilled streptokinase eventually required decortication, which had to be done in five patients (16.1%). Mean hospital stay was 30.2 ± 17.6 days whereas two patients died.ConclusionsTubercular empyema is common in Indian patients. Intrapleural streptokinase appears to be a useful strategy to preserve lung function and reduce need for surgery in patients with late stage of empyema thoracis.

Rapid diagnosis of typhoid fever by an in-house flagellin PCR

Enteric fever is an important public-health problem in developing countries. Effective control of the disease requires early detection of cases, definitive treatment and elimination of the source of infection, as well as improvement of the public-health system. Symptoms and signs of the disease are non-specific and laboratory testing is essential for diagnosis. Accurate diagnosis of cases is often not possible as empirical antibiotic therapy decreases the sensitivity of isolation procedures and serological tests lack specificity in endemic areas. Enteric fever is a common cause of morbidity in the Indian subcontinent and Salmonella Typhi accounts for approximately 90 % of infections. Salmonella Paratyphi A is less common but has shown a trend of rising incidence over the past few years, whereas S. Paratyphi B is exceedingly rare. Typhoid fever is an acute systemic infection caused by the bacterium S. Typhi. Worldwide an estimated 21.5 million people develop typhoid fever annually. The diagnosis of typhoid fever still relies on conventional serology and blood culture identification systems. The isolation procedures are very time consuming and expensive. PCR assays facilitate prompt and appropriate treatment of confirmed cases and also help in the detection of carriers thereby limiting spread.