Biomedical subjects

Anirban Basu

Publications and source records attributed to Anirban Basu.

At least 19 recordsLinked to original sources

PubMed2007

Proinflammatory mediators released by activated microglia induces neuronal death in Japanese encephalitis.

While a number of studies have documented the importance of microglia in central nervous system (CNS) response to injury, infection and disease, little is known regarding its role in viral encephalitis. We therefore, exploited an experimental model of Japanese Encephalitis, to better understand the role played by microglia in Japanese Encephalitis Virus (JEV) infection. Lectin staining performed to assess microglial activation indicated a robust increase in reactive microglia following infection. A difference in the topographic distribution of activated, resting, and phagocytic microglia was also observed. The levels of various proinflammatory mediators, such as inducible nitric oxide synthase (iNOS), cyclooxygenase-2 (Cox-2), IL-6, IL-1beta, TNF-alpha, and MCP-1 that have been implicated in microglial response to an activational state was significantly elevated following infection. These cytokines exhibited region selective expression in the brains of infected animals, with the highest expression observed in the hippocampus. Moreover, the expression of neuronal specific nuclear protein NeuN was markedly downregulated during progressive infection indicating neuronal loss. In vitro studies further confirmed that microglial activation and subsequent release of various proinflammatory mediators induces neuronal death following JEV infection. Although initiation of immune responses by microglial cells is an important protective mechanism in the CNS, unrestrained inflammatory responses may result in irreparable brain damage. Our findings suggest that the increased microglial activation following JEV infection influences the outcome of viral pathogenesis. It is likely that the increased microglial activation triggers bystander damage, as the animals eventually succumb to infection.

Animals↗

PubMed2006

Estimating transitions between symptom severity states over time in schizophrenia: a Bayesian meta-analytic approach.

We obtain the posterior predictive distribution of transition probabilities between symptom severity states over time for patients with schizophrenia by (i) employing a Bayesian meta-analysis of published clinical trials and observational studies to estimate the posterior distribution of parameters that guide changes in Positive and Negative Syndrome Scale (PANSS) scores over time and under the influence of various drugs and (ii) by propagating the variability from the posterior distributions of the parameters through a micro-simulation model that is formulated based on schizophrenia progression. Results show detailed differences among haloperidol, risperidone and olanzapine in controlling various levels of severities of positive, negative and joint symptoms over time. For example, risperidone seems best in controlling severe positive symptoms while olanzapine is the worst in that during the first quarter of drug treatment; however, olanzapine seems to be best in controlling severe negative symptoms across all four quarters of treatment while haloperidol is the worst in this regard. These details may further serve to better estimate quality of life of patients and aid in resource utilization decisions in treating schizophrenic patients. In addition, consistent estimation of uncertainty in the time-profile parameters also has important implications for the practice of cost-effectiveness analysis and for future resource allocation policies in schizophrenia treatment.

Antipsychotic Agents↗

PubMed2006

Astrogliosis is delayed in type 1 interleukin-1 receptor-null mice following a penetrating brain injury.

The cytokines IL-1alpha and IL-1beta are induced rapidly after insults to the CNS, and their subsequent signaling through the type 1 IL-1 receptor (IL-1R1) has been regarded as essential for a normal astroglial and microglial/macrophage response. To determine whether abrogating signaling through the IL-1R1 will alter the cardinal astrocytic responses to injury, we analyzed molecules characteristic of activated astrocytes in response to a penetrating stab wound in wild type mice and mice with a targeted deletion of IL-1R1. Here we show that after a stab wound injury, glial fibrillary acidic protein (GFAP) induction on a per cell basis is delayed in the IL-1R1-null mice compared to wild type counterparts. However, the induction of chondroitin sulfate proteoglycans, tenascin, S-100B as well as glutamate transporter proteins, GLAST and GLT-1, and glutamine synthetase are independent of IL-1RI signaling. Cumulatively, our studies on gliosis in the IL-1R1-null mice indicate that abrogating IL-1R1 signaling delays some responses of astroglial activation; however, many of the important neuroprotective adaptations of astrocytes to brain trauma are preserved. These data recommend the continued development of therapeutics to abrogate IL-1R1 signaling to treat traumatic brain injuries. However, astroglial scar related proteins were induced irrespective of blocking IL-1R1 signaling and thus, other therapeutic strategies will be required to inhibit glial scarring.

Journal Article↗

PubMed2006

Differential trends in prevalence of diabetes and unrelated general medical illness for schizophrenia patients before and after the atypical antipsychotic era.

OBJECTIVE: To estimate the net growth in the risk of type 2 diabetes mellitus (DM) in the population of patients with schizophrenia that may be attributable to the increased use of the class of atypical antipsychotics (A-APDs), adjusting for community trends in DM risk. METHODS: Using data from the National Hospital Discharge Survey, we perform trend analyses for prevalence of DM and general illness unrelated to insulin resistance in patients with schizophrenia, as well as in individuals without known mental illness, during three time periods: 1) prior to any A-APDs introduction (1979-1989); 2) short-term after their introduction (1990-1995), and long-term following their introduction (1996-2001). RESULTS: Trends in DM and general illness risks were comparable among inpatients with schizophrenia and those without mental illness during the pre-A-APD era and the short-term post-A-APDs era. During 1996-2001, the net difference in DM prevalence grew at an increasing rate (0.7% per year, p<0.001). By 2001, over a base DM prevalence of 10% in patients with schizophrenia, 3.1 percentage points (p=0.016) could be attributed to the use of A-APDs. There was no significant net growth in the prevalence of general illness during this period for these patients. This growth was most pronounced among African-American females and middle aged (35-49 years old) patients. This increased risk of DM translates into additional direct medical costs of $800 million per year. CONCLUSIONS: The introduction of A-APDs, after a lag period, is associated with increased risk of DM. This needs to be considered in light of the advantages of these drugs in efficacy and tolerability. Long-term studies are necessary to identify the effect of individual A-APDs on DM risk.

Adolescent↗

PubMed2006

Scale of interest versus scale of estimation: comparing alternative estimators for the incremental costs of a comorbidity.

We investigate how the scale of estimation in risk-adjustment models for health-care costs affects the covariate effect, where the scale of interest for the covariate effect may be different from the scale of estimation. As an illustrative example, we use claims data to estimate the incremental costs associated with heart failure within one year subsequent to myocardial infarction. Here, the scale of interest for the effect of heart failure on costs is additive. However, traditional methods for modeling costs use predetermined scale of estimation - for example, ordinary least squares (OLS) regression assumes an additive scale while log-transformed OLS and generalized linear models with log-link assume a multiplicative scale of estimation. We compare these models with a new flexible model that lets the data determine the appropriate scale of estimation. We use a variety of goodness-of-fit measures along with a modified Copas test to assess robustness, lack of fit, and over-fitting properties of the alternative estimators. Biases up to 19% in the scale of interest are observed due to the misrepresentation of the scale of estimation. The new flexible model is found to appropriately represent the scale of estimation and less susceptible to over-fitting despite estimating additional parameters in the link and the variance functions.

Bias↗

PubMed2006

Health literacy as a predictor of follow-up after an abnormal Pap smear: a prospective study.

BACKGROUND: Low literacy influences cervical cancer screening knowledge, and is a possible contributor to racial disparities in cervical cancer. OBJECTIVE: To examine the hypothesis that literacy predicts patient adherence to follow-up recommendations after an abnormal Pap smear. DESIGN: A prospective, continuity clinic-based study. PARTICIPANTS: From a sample of 538 women undergoing literacy testing at the time of Pap smear screening, we studied 68 women with abnormal Pap smear diagnoses. MEASUREMENTS: Literacy was assessed using the Rapid Evaluation of Adult Literacy in Medicine (REALM). We also measured other proxies for literacy, including educational attainment and physician estimates of patients' literacy level. Outcome measures included on-time and 1-year follow-up and duration of time to follow-up after an abnormal Pap smear. RESULTS: Only one-third of the cohort adhered to follow-up recommendations. At 1 year, 25% of the women had not returned at all. Patients with inadequate literacy (as assessed by the REALM) were less likely to follow up within 1 year, although this result was not statistically significant (adjusted odds ratio [OR]=3.8, 95% confidence interval [CI]: 0.8 to 17.4). Patients subjectively assessed by their physician to have low literacy skills were significantly less likely to follow up within 1 year (adjusted OR=14, 95% CI: 3 to 65). Less than high school education (hazard ratio (HR)= 2.3; 95% CI: 1.2, 4.6) and low physician-estimated literacy level (HR=3.4, 95% CI: 1.4, 8.2), but not objective literacy level, were significant predictors of duration of time to follow-up, adjusting for recommended days to follow-up and other factors. CONCLUSIONS: Among women with an abnormal Pap smear, those perceived by their physician to have low literacy were significantly more likely to fail to present for follow-up.

Adolescent↗

PubMed2005

Neuroinflammation and both cytotoxic and vasogenic edema are reduced in interleukin-1 type 1 receptor-deficient mice conferring neuroprotection.

BACKGROUND AND PURPOSE: Interleukin-1 (IL-1) is a proinflammatory cytokine implicated in multiple neurodegenerative diseases, including stroke. However, to date, there is no consensus regarding which receptor(s) mediates the detrimental effects of IL-1. We hypothesized that abrogating IL-1 type 1 receptor (IL-1R1) signaling would reduce edema, chemokine expression, and leukocyte infiltration; lower levels of iNOS; and, consequently, decrease free radical damage after mild hypoxia/ischemia (H/I), thus preserving brain cells. METHODS: IL-1R1 null mice and wild-type mice were subjected to a mild H/I insult. MRI was used to measure the area affected at 30 minutes and 48 hours after H/I. An RNAse protection assay was used to evaluate changes in chemokine mRNA expression. RT-PCR was used to assess inducible nitric oxide synthase (iNOS) and endothelial nitric oxide synthase mRNA levels. Immunohistochemistry was used to assess leukocyte infiltration. Western blots were used to assess iNOS and glutamate aspartate transporter protein levels. RESULTS: IL-1R1 null mice had reduced cytotoxic and vasogenic edema. The volume of hyperintense signal on T2-weighted images was reduced on average by 90% at 48 hours after H/I. The induction of multiple chemokine mRNAs was significantly reduced in IL-1R1 null mice compared with wild-type mice at 18 and 72 hours after H/I, which correlated with fewer infiltrating CD3+ leukocytes. Levels of iNOS protein and mRNA (but not glutamate aspartate transporter) were significantly reduced in the IL-1R1 mouse brain. CONCLUSIONS: These findings indicate that abrogating IL-1R1 signaling could protect brain cells subsequent to a mild stroke by reducing edema and immune cell recruitment, as well as by limiting iNOS-mediated free radical damage.

Amino Acid Transport System X-AG↗

PubMed2005

Implications of spillover effects within the family for medical cost-effectiveness analysis.

Medical cost-effectiveness analyses traditionally treat patients as isolated individuals and neglect the effects of improvement in patients' health on the welfare of their family members. We use a model based on a family utility function with altruistic linkages to show that there can be direct and indirect effects on the welfare of all family members. We focus specially on a model of how the spillover effects to the spouse in a two-person family might affect choice of treatments for prostate cancer. We then test the predictions of this model by analyzing treatment choices of prostate cancer patients using the linked SEER-Medicare database. We find that our results are consistent with the model's predictions. We conclude that cost-effectiveness analyses may better reflect the full costs and benefits of medical interventions if they incorporate these family effects. However, concerns about equity present a dilemma for the practice of CEA from the societal perspective.

Aged↗

PubMed2005

Generalized modeling approaches to risk adjustment of skewed outcomes data.

There are two broad classes of models used to address the econometric problems caused by skewness in data commonly encountered in health care applications: (1) transformation to deal with skewness (e.g., ordinary least square (OLS) on ln(y)); and (2) alternative weighting approaches based on exponential conditional models (ECM) and generalized linear model (GLM) approaches. In this paper, we encompass these two classes of models using the three parameter generalized Gamma (GGM) distribution, which includes several of the standard alternatives as special cases-OLS with a normal error, OLS for the log-normal, the standard Gamma and exponential with a log link, and the Weibull. Using simulation methods, we find the tests of identifying distributions to be robust. The GGM also provides a potentially more robust alternative estimator to the standard alternatives. An example using inpatient expenditures is also analyzed.

Models, Statistical↗

PubMed2005

Interleukin-1 and the interleukin-1 type 1 receptor are essential for the progressive neurodegeneration that ensues subsequent to a mild hypoxic/ischemic injury.

Excessive inflammation has been implicated in the progressive neurodegeneration that occurs in multiple neurological diseases, including cerebral ischemia, and elevated levels of the proinflammatory cytokine interleukin-1 (IL-1) have been shown to exacerbate brain damage, whereas diminishing IL-1 levels limits the extent of injury. However, to date there is no consensus regarding which receptor(s) mediates the detrimental effects of IL-1. Because we have previously demonstrated that signaling through the IL-1 type 1 receptor (IL-1R1) is necessary for microglial activation and because results from other studies have implicated microglia as effectors of neurodegeneration, we hypothesized that inactivating the IL-1R1 would decrease the extent of damage caused by a hypoxic-ischemic (H/I) insult. It is shown that a mild insult initiates progressive neurodegeneration that leads to cystic infarcts, which can be prevented by inactivating the IL-1R1. The IL-1R1 null mice also show preserved sensorimotor function at 1 month's recovery. The mild insult induces multiple proinflammatory cytokines and activates microglia, and these responses are dramatically curtailed in mice lacking the IL-1R1. Importantly, the neuroinflammation precedes the progressive enlargement of the infarct, suggesting that the inflammation is causal rather than a consequence of the brain damage. These findings show that abrogating the inflammation consequent to a mild H/I insult will prevent brain damage and preserve neurological function. Additionally, these data incriminate the IL-1R1 as a master proinflammatory cytokine receptor.

Animals↗

PubMed2005

Estimating marginal and incremental effects on health outcomes using flexible link and variance function models.

We propose an extension to the estimating equations in generalized linear models to estimate parameters in the link function and variance structure simultaneously with regression coefficients. Rather than focusing on the regression coefficients, the purpose of these models is inference about the mean of the outcome as a function of a set of covariates, and various functionals of the mean function used to measure the effects of the covariates. A commonly used functional in econometrics, referred to as the marginal effect, is the partial derivative of the mean function with respect to any covariate, averaged over the empirical distribution of covariates in the model. We define an analogous parameter for discrete covariates. The proposed estimation method not only helps to identify an appropriate link function and to suggest an underlying distribution for a specific application but also serves as a robust estimator when no specific distribution for the outcome measure can be identified. Using Monte Carlo simulations, we show that the resulting parameter estimators are consistent. The method is illustrated with an analysis of inpatient expenditure data from a study of hospitalists.

Adult↗

PubMed2005

Minocycline reduces proinflammatory cytokine expression, microglial activation, and caspase-3 activation in a rodent model of diabetic retinopathy.

Diabetes leads to vascular leakage, glial dysfunction, and neuronal apoptosis within the retina. The goal of the studies reported here was to determine the role that retinal microglial cells play in diabetic retinopathy and assess whether minocycline can decrease microglial activation and alleviate retinal complications. Immunohistochemical analyses showed that retinal microglia are activated early in diabetes. Furthermore, mRNAs for interleukin-1beta and tumor necrosis factor-alpha, proinflammatory mediators known to be released from microglia, are also increased in the retina early in the course of diabetes. Using an in vitro bioassay, we demonstrated that cytokine-activated microglia release cytotoxins that kill retinal neurons. Furthermore, we showed that neuronal apoptosis is increased in the diabetic retina, as measured by caspase-3 activity. Minocycline represses diabetes-induced inflammatory cytokine production, reduces the release of cytotoxins from activated microglia, and significantly reduces measurable caspase-3 activity within the retina. These results indicate that inhibiting microglial activity may be an important strategy in the treatment of diabetic retinopathy and that drugs such as minocycline hold promise in delaying or preventing the loss of vision associated with this disease.

Animals↗

PubMed2004

A curious truncation of N=4 supersymmetric Yang-Mills theory.

The coupling constant dependence of correlation functions of Bogomol'nyi-Prasad-Sommerfield operators in the N=4 supersymmetric Yang-Mills theory can be expressed in terms of integrated correlation functions. We approximate these integrated correlators by using a truncated operator product expansion. This leads to differential equations for the coupling dependence. When applied to a particular 16 point correlator, the coupling dependence we find agrees with the corresponding amplitude computed via the gauge theory/string theory correspondence. We conjecture that this truncation becomes exact in the large N and large 't Hooft coupling limit.

Journal Article↗

PubMed2004

Cost-effectiveness analysis of pharmacological treatments in schizophrenia: critical review of results and methodological issues.

OBJECTIVE: To comprehensively review and critically appraise the results and the methodological issues in the cost-effectiveness literature on pharmacological treatments in schizophrenia. METHODS: Relevant literature published in peer-reviewed journals was identified through a computer search in Medline from 1975 to 2002. Further studies were identified using reference lists and published review articles. Articles included in the review were required to evaluate both costs and clinical outcomes in the same study. RESULTS: Seventeen articles met all inclusion criteria. Cost-effectiveness analysis (CEA) in schizophrenia spans three types of studies-randomized trial-based studies (six), retrospective cohort-based studies (six) and decision model-based studies (five). Comparing results from CEA across all types of studies in schizophrenia reveals a large ambiguity in the incremental evaluation of newer atypicals. For treatment-resistant patients, clozapine seems to produce cost saving and better outcomes compared to standard neuroleptics. However, there is tremendous uncertainty in the estimates of cost savings and clinical benefits that may prevent decision makers from making optimal policy decisions about insurance coverage and formulary design based on these results. For chronic schizophrenic patients, the results are even more ambiguous. For example, the studies based on trial settings find risperidone to cost more than haloperidol, while studies based on cohort design and decision models find risperidone to be either equivalent or lower in costs than haloperidol. CONCLUSIONS: Further studies of cost-effectiveness need to be carried out with careful consideration of the limitations of published analyses. There are a variety of theoretical and methodological issues that are important to consider during the development of new decision models in this field.

Antipsychotic Agents↗

PubMed2004

Interleukin-1: a master regulator of neuroinflammation.

Interleukins 1alpha and 1beta (IL-1) are very potent signaling molecules that are expressed normally at low levels, but are induced rapidly in response to local or peripheral insults. IL-1 coordinates systemic host defense responses to pathogens and to injury and not surprisingly it has similar effects within the central nervous system (CNS). Numerous reports have correlated the presence of IL-1 in the injured or diseased brain, and its effects on neurons and nonneuronal cells in the CNS, but it is only recently that the importance of IL-1 signaling has been recognized. This article reviews studies that demonstrate that IL-1 is at or near the top of the hierarchical cytokine signaling cascade in the CNS that results in the activation of endogenous microglia and vascular endothelial cells to recruit peripheral leukocytes (i.e., neuroinflammation). The IL-1 system thus provides an attractive target for therapeutic intervention to ameliorate the destructive consequences of neuroinflammation.

Animals↗

PubMed2004

Comparing alternative models: log vs Cox proportional hazard?

Health economists often use log models (based on OLS or generalized linear models) to deal with skewed outcomes such as those found in health expenditures and inpatient length of stay. Some recent studies have employed Cox proportional hazard regression as a less parametric alternative to OLS and GLM models, even when there was no need to correct for censoring. This study examines how well the alternative estimators behave econometrically in terms of bias when the data are skewed to the right. Specifically we provide evidence on the performance of the Cox model under a variety of data generating mechanisms and compare it to the estimators studied recently in Manning and Mullahy (2001). No single alternative is best under all of the conditions examined here. However, the gamma regression model with a log link seems to be more robust to alternative data generating mechanisms than either OLS on ln(y) or Cox proportional hazards regression. We find that the proportional hazard assumption is an essential requirement to obtain consistent estimate of the E(y|x) using the Cox model.

Health Services Research↗

PubMed2003

Sentinel lymph node versus axillary lymph node dissection for early-stage breast carcinoma: a comparison using a utility-adjusted number needed to treat analysis.

BACKGROUND: The current study was performed to compare the value of sentinel lymph node dissection (SND) and axillary lymph node dissection (AND) in improving the utility-adjusted survival for early-stage breast carcinoma patients. METHODS: A number needed to treat (NNT) analysis was used to compare SND with AND. In the NNT equation, 1/(S(SND) - S(AND)), S is the 5-year utility-adjusted survival. A literature review was performed to estimate 1) the prevalence of axillary lymph node disease for early-stage breast carcinoma, 2) the sensitivity and specificity of SND and AND, 3) the 5-year overall survival as a function of axillary lymph node involvement, 4) the risk of arm lymphedema as a function of the intervention performed, and 5) the utility correction (Uc; impairment of quality of life) for arm lymphedema. RESULTS: The NNT method of analysis favored SND over nearly the entire range of parameters with a sign change to a negative value occurring only as Uc becomes very close to unity. This suggests the superiority of the SND approach. Only when there is minimal loss of utility does AND become favored and then only minimally. CONCLUSIONS: Compared with AND, SND improves the utility-adjusted survival in patients with early-stage breast carcinoma. This finding is quite robust and was found to remain constant over a range of values for utility and lymph node prevalence.

Breast Neoplasms↗

PubMed2003

Astrocytic ceruloplasmin expression, which is induced by IL-1beta and by traumatic brain injury, increases in the absence of the IL-1 type 1 receptor.

IL-1alpha and IL-1beta are induced immediately after insults to the brain, and signaling through the type 1 IL-1 receptor is essential for a normal microglial and astroglial response to injury. To better understand which genes are induced in astrocytes by IL-1beta, we used the unbiased technique of differential display to analyze mouse astroglial gene expression after IL-1beta treatment. Two novel genes were induced, as well as the gene for ceruloplasmin, a ferroxidase with antioxidant properties. Ceruloplasmin was analyzed further by Northern and Western blot. RNA and protein levels of ceruloplasmin were increased when astrocytes were treated with IL-1beta. To determine whether the IL-1 type 1 receptor (IL-1R1) is essential for the injury-induced expression of ceruloplasmin, a Western blot analysis was performed after a traumatic brain injury on mice that were IL-1R1-deficient. Ceruloplasmin increased significantly above controls after injury; however, injury-induced levels of ceruloplasmin were lower in IL-1R1-deficient (2.7-fold increase) than in the wild-type animals (3.5-fold increase). These data indicate that while IL-1R1 deletion has a slight effect on ceruloplasmin expression, it is not essential for either the basal or the induced expression of ceruloplasmin in vivo. Since ceruloplasmin buffers free copper, oxidizes ferrous iron, and catalyzes the dismutation of free radicals, increased levels of ceruloplasmin likely protect neurons and glia from sustaining damage after injury. Furthermore, as the IL-1R1 has been proposed to be a target for achieving neuroprotection after injury, these data suggest that the protection afforded by ceruloplasmin will be retained even when the IL-1R1 is antagonized.

Animals↗