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Biomedical subjects

P Mukherjee

Publications and source records attributed to P Mukherjee.

At least 19 recordsLinked to original sources
PubMed2004

Protective effects of IL-1Ra or vIL-10 gene transfer on a murine model of wear debris-induced osteolysis.

The current study evaluated the protective effects of anti-inflammatory cytokine gene transfer on osteolysis provoked by orthopedic biomaterial particles using a murine model of inflammatory bone loss. A section of bone was surgically implanted into an air pouch established on a syngeneic recipient mouse. Inflammation was provoked by introduction of ultra-high-molecular-weight polyethylene (UHMWPE) particles into the pouch, and retroviruses encoding for interleukin-1 receptor antagonist (hIL-1Ra), viral interleukin-10 (vIL-10), or LacZ genes were injected. Pouch fluid and tissue were harvested 7 days later for histological and molecular analyses. The results indicated that IL-1Ra or vIL-10 gene transfer significantly inhibited IL-1beta and tumor necrosis factor (TNF) expression at both mRNA and protein levels. There were significantly lower mRNA expressions of calcitonin receptor and cathepsin K in RNA isolated from hIL-1Ra- or vIL-10-transduced pouches than LacZ-transduced and virus-free controls. Both anti-inflammatory cytokine gene transfers significantly reduced the mRNA expression of M-CSF (70-90%) and RANK (>65%) in comparison with LacZ- and virus-free controls. Histological examination showed that hIL-1Ra or vIL-10 gene transfer dramatically abolished UHMWPE-induced inflammatory cellular infiltration and bone pit erosion compared to LacZ-transduced and virus-free controls. Histochemical staining revealed significantly fewer osteoclast-like cells in samples treated with IL-1Ra or vIL-10 gene transfer. In addition, bone collagen content was markedly preserved in the groups with anti-inflammatory cytokine gene transfers compared with the other two groups. Overall, retrovirus-mediated hIL-1Ra or vIL-10 gene transfer effectively protected against UHMWPE-particle-induced bone resorption, probably due to the inhibition of IL-1/TNF-induced M-CSF production and the consequent osteoclast recruitment and maturation.

Animals↗
PubMed2003

Role of glucose and ketone bodies in the metabolic control of experimental brain cancer.

Brain tumours lack metabolic versatility and are dependent largely on glucose for energy. This contrasts with normal brain tissue that can derive energy from both glucose and ketone bodies. We examined for the first time the potential efficacy of dietary therapies that reduce plasma glucose and elevate ketone bodies in the CT-2A syngeneic malignant mouse astrocytoma. C57BL/6J mice were fed either a standard diet unrestricted (SD-UR), a ketogenic diet unrestricted (KD-UR), the SD restricted to 40% (SD-R), or the KD restricted to 40% of the control standard diet (KD-R). Body weights, tumour weights, plasma glucose, beta-hydroxybutyrate (beta-OHB), and insulin-like growth factor 1 (IGF-1) were measured 13 days after tumour implantation. CT-2A growth was rapid in both the SD-UR and KD-UR groups, but was significantly reduced in both the SD-R and KD-R groups by about 80%. The results indicate that plasma glucose predicts CT-2A growth and that growth is dependent more on the amount than on the origin of dietary calories. Also, restriction of either diet significantly reduced the plasma levels of IGF-1, a biomarker for angiogenesis and tumour progression. Owing to a dependence on plasma glucose, IGF-1 was also predictive of CT-2A growth. Ketone bodies are proposed to reduce stromal inflammatory activities, while providing normal brain cells with a nonglycolytic high-energy substrate. Our results in a mouse astrocytoma suggest that malignant brain tumours are potentially manageable with dietary therapies that reduce glucose and elevate ketone bodies.

3-Hydroxybutyric Acid↗
PubMed2003

TNF receptor gene therapy results in suppression of IgG2a anticollagen antibody in collagen induced arthritis.

BACKGROUND: Therapeutic strategies to block tumour necrosis factor alpha (TNFalpha) activity in experimental autoimmune arthritis models and rheumatoid arthritis (RA) have proved highly successful, and provide sustained beneficial effects. OBJECTIVE: To examine whether TNFalpha inhibition has immunological activity beyond the reduction of inflammation in collagen induced arthritis (CIA), an established experimental model of RA. METHODS: Arthritic DBA/1 mice received single periarticular injections of retroviral constructs encoding human TNF receptor (TNF-R) into the affected arthritic paw, at the onset of arthritis. Severity of arthritis, antibodies to collagen type II (CII), and extent of pathological joint damage of arthritic paws were compared between TNF-R and media treated (control) animals 3, 7, 14, 21, and 49 days after disease onset. RESULTS: Severity of CIA was significantly decreased in TNF-R treated animals compared with controls, 14-34 days after disease onset. Joint destruction was reduced in TNF-R injected joints and in the uninjected contralateral and ipsilateral paws of TNF-R treated animals. Seven days after disease onset, TNF-R treated mice had lower levels of inflammatory Th1 driven IgG2a antibodies to CII (p<0.05) than controls. This altered the anticollagen IgG2a:IgG1 ratio towards Th2 driven IgG1. CONCLUSIONS: Local TNF-R gene therapy in CIA appears to have systemic effects on the anti-CII antibodies. The overall influence of TNF-R gene therapy is that it inhibits the progression of CIA mainly by suppressing the inflammatory Th1 response rather than by stimulating a Th2 response. Therefore, periarticular TNF-R gene therapy may have excellent therapeutic potential in RA.

Animals↗
PubMed2003

Immunocytochemical detection of p21ras, Raf-1, ERK1/MAP kinase and PKC isoforms in a 20-methylcholanthrene-induced transformed murine embryonal fibroblast cells in culture.

An immunocytochemical study using antibodies against p21ras, Raf-1, MAP kinase/ERK1 and PKCalpha, beta, gamma, delta, epsilon, zeta, isoforms were performed on a 20-methylcholanthrene-induced transformed murine embryonal fibroblast cells in both in vitro and in vivo growth conditions. Altered expression of p21ras, Raf-1, MAP kinase in this particular cell line strongly supported the previous findings of the activation of one component of signal transduction under the influence of the other in the MAP kinase cascade of signal transduction during neoplastic transformation and which also seemed to be involved in CNCI-PM-20 cell line. The altered expression of PKCalpha, beta, and delta was thought to be an epigenetic event occurring under the indirect influence of other changes in these cells. Host physiology and metabolism did not have much impact on the expression of these gene products after biological incubation of these cells in syngenic host.

Animals↗
PubMed2002

Dietary restriction reduces angiogenesis and growth in an orthotopic mouse brain tumour model.

Diet and lifestyle produce major effects on tumour incidence, prevalence, and natural history. Moderate dietary restriction has long been recognised as a natural therapy that improves health, promotes longevity, and reduces both the incidence and growth of many tumour types. Dietary restriction differs from fasting or starvation by reducing total food and caloric intake without causing nutritional deficiencies. No prior studies have evaluated the responsiveness of malignant brain cancer to dietary restriction. We found that a moderate dietary restriction of 30-40% significantly inhibited the intracerebral growth of the CT-2A syngeneic malignant mouse astrocytoma by almost 80%. The total dietary intake for the ad libitum control group (n=9) and the dietary restriction experimental group (n=10) was about 20 and 13 Kcal x day(-1), respectively. Overall health and vitality was better in the dietary restriction-fed mice than in the ad libitum-fed mice. Tumour microvessel density (Factor VIII immunostaining) was two-fold less in the dietary restriction mice than in the ad libitum mice, whereas the tumour apoptotic index (TUNEL assay) was three-fold greater in the dietary restriction mice than in the ad libitum mice. CT-2A tumour cell-induced vascularity was also less in the dietary restriction mice than in the ad libitum mice in the in vivo Matrigel plug assay. These findings indicate that dietary restriction inhibited CT-2A growth by reducing angiogenesis and by enhancing apoptosis. Dietary restriction may shift the tumour microenvironment from a proangiogenic to an antiangiogenic state through multiple effects on the tumour cells and the tumour-associated host cells. Our data suggest that moderate dietary restriction may be an effective antiangiogenic therapy for recurrent malignant brain cancers.

Animals↗
PubMed2002

Are accident and emergency consultants as accurate as consultant radiologists in interpreting plain skeletal radiographs taken at a minor injury unit?

The objective of this study was to compare the accuracy of an accident and emergency (A&E) consultant in interpreting plain skeletal radiographs with that of a consultant radiologist (CR). It took the form of a retrospective study of 2133 radiographs taken in a Minor Injury Unit (MIU). A&E consultant reports on these films were compared with those of a CR and also with a gold standard. The A&E consultant diagnoses achieved an accuracy of 98.5% (CR 97.8%), sensitivity of 97.8% (CR 98.1%), specificity of 98.8% (CR 97.7%), positive predictive value of 97.3% (CR 95.1%) and negative predictive value of 98.97% (CR 99.07%) (gold standard of 100%). In conclusion, the A&E consultant reports of plain skeletal radiographs generated from an MIU were as accurate as those of a consultant radiologist. This could have significant implications for the wet reporting of A&E departmental radiographs.

Accidents↗
PubMed2002

Altered gene expression during nimesulide-mediated inhibition of apoptotic death in human chondrocytes.

We previously found that the cyclooxygenase (COX)-2 preferential inhibitor nimesulide protects rodents' chondrocytes against apoptotic death in vitro. In the present study, we found that nimesulide also reduces staurosporine-mediated apoptotic death in human chondrocytes in vitro. Using cDNA microarrays, we explored alterations in gene expression during human chondrocytic apoptosis, and the influence of nimesulide therapy on these changes. Based on their known biologic activities, candidate gene products with altered expression were assigned to clusters of biological functions and mechanisms, and analysed for specific sets of alterations. We found that the expression of genes involved in cell proliferation is differentially regulated during staurosporine-mediated apoptotic death in human chondrocytes. Treatment with nimesulide reversed the staurosporine-mediated effects on these gene products during protection against apoptosis. The study suggests that nimesulide, in addition to its analgesic effect, may confer chondroprotection through mechanisms beyond classical COX inhibition.

Adult↗
PubMed2001

Gene expression profiling of the tau mutant (P301L) transgenic mouse brain.

To provide a global analysis of the influence of Tau neuropathology at molecular level, we used cDNA arrays representing 8832 genes to determine the mRNA expression profile in transgenic mice expressing the most common frontotemporal dementia and parkinsonism linked to chromosome 17 (FTDP-17) Tau mutation (P301L) (Nat. Genet. (2000) 402). Genes whose expression is associated with development of neurofibrillary tangles and neuron loss in P301L mice with motor and behavioral deficits were identified. The data suggest that a major mechanism underlying P301LTau neurodegeneration primarily involved altered expression of genes contributing to inhibition of apoptosis and intracellular transport. We propose that the expression of mutated P301L may lead to select altered expression of genes which may cause neurodegeneration in FTDP-17.

Animals↗
PubMed2001

Efficient presentation of both cytosolic and endogenous transmembrane protein antigens on MHC class II is dependent on cytoplasmic proteolysis.

Peptides from extracellular proteins presented on MHC class II are mostly generated and loaded in endolysosomal compartments, but the major pathways responsible for loading peptides from APC-endogenous sources on MHC class II are as yet unclear. In this study, we show that MHC class II molecules present peptides from proteins such as OVA or conalbumin introduced into the cytoplasm by hyperosmotic pinosome lysis, with efficiencies comparable to their presentation via extracellular fluid-phase endocytosis. This cytosolic presentation pathway is sensitive to proteasomal inhibitors, whereas the presentation of exogenous Ags taken up by endocytosis is not. Inhibitors of nonproteasomal cytosolic proteases can also inhibit MHC class II-restricted presentation of cytosolically delivered protein, without inhibiting MHC class I-restricted presentation from the same protein. Cytosolic processing of a soluble fusion protein containing the peptide epitope I-Ealpha(52-68) yields an epitope that is similar to the one generated during constitutive presentation of I-Ealpha as an endogenous transmembrane protein, but is subtly different from the one generated in the exogenous pathway. Constitutive MHC class II-mediated presentation of the endogenous transmembrane protein I-Ealpha is also specifically inhibited over time by inhibitors of cytosolic proteolysis. Thus, Ag processing in the cytoplasm appears to be essential for the efficient presentation of endogenous proteins, even transmembrane ones, on MHC class II, and the proteolytic pathways involved may differ from those used for MHC class I-mediated presentation.

Acetylcysteine↗
PubMed2001

N -butyldeoxynojirimycin reduces growth and ganglioside content of experimental mouse brain tumours.

Abnormalities in glycosphingolipid (GSL) biosynthesis have been implicated in the oncogenesis and malignancy of brain tumours. GSLs comprise the gangliosides and the neutral GSLs and are major components of the cell surface glycocalyx. N -butyldeoxynojirimycin (N B-DNJ) is an imino sugar that inhibits the glucosyltransferase catalysing the first step in GSL biosynthesis. The influence of N B-DNJ was studied on the growth and ganglioside composition of two 20-methylcholanthrene-induced experimental mouse brain tumours, EPEN and CT-2A, which were grown in vitro and in vivo. N B-DNJ (200 microM) inhibited the proliferation of the EPEN and CT-2A cells by 50%, but did not reduce cell viability. The drug, administered in the diet (2400 mg kg(-1)) to adult syngeneic C57BL/6 mice, reduced the growth and ganglioside content of subcutaneous and intracerebral EPEN and CT-2A tumours by at least 50% compared to the untreated controls. N B-DNJ treatment also shifted the relative distribution of tumour gangliosides in accordance with the depletion of metabolic substrates. Side effects of N B-DNJ treatment were generally mild and included reductions in body and spleen weights and intestinal distension. We conclude that N B-DNJ may inhibit tumour growth through an effect on ganglioside biosynthesis and may be useful as a new chemotherapy for brain tumours.

1-Deoxynojirimycin↗
PubMed2001

Carbon monoxide modeling from transportation sources.

Street canyon module and gaussian line source module of a regional-scale dispersion model Indic Airviro were used to simulate ambient carbon monoxide (CO) concentrations due to traffic flow at two roadside monitoring locations in Singapore. The fleet average emission factors for each vehicle category was estimated from US EPA MOBILE 5 A guidelines as a function of speed, vehicle deterioration rates and model years. 1-h CO concentrations and worst case 8-h levels have been simulated and compared with measured readings. This study used model-simulated rooftop concentration levels from non-localized sources as background levels at the two sites. The resulting CO concentrations correlate well with actual measured levels and provide a unique approach to predict the impact of CO from transportation.

Air Movements↗
PubMed2001

Spontaneous adenocarcinoma mouse models for immunotherapy.

Recent discoveries regarding the identification of tumor-associated antigens and antigen presentation have made successful immunotherapy strategies possible with little, if any, toxicity. Here, we describe transgenic mammary, pancreas, prostate, stomach and lung adenocarcinoma animal models that can be used to study various immunotherapeutic strategies. The challenge in developing a tumor vaccine is effective antigen presentation that elicits anti-tumor immune responses without precipitating autoimmunity. Clinical trials must be preceded by appropriate animal studies to demonstrate that the concepts can be translated into efficacious therapy for cancer. Although many xenograph or transplantable tumor models have been used, the most effective studies are in spontaneous tumor models. These models are clinically relevant, as tumors arise in an appropriate tissue background and in a host conditioned by the physiological events of neoplastic progression and tumorigenesis and in the context of a viable immune system.

Adenocarcinoma↗
PubMed2001

Complement anaphylatoxin C5a neuroprotects through mitogen-activated protein kinase-dependent inhibition of caspase 3.

We previously reported that pretreatment of murine cortico-hippocampal neuronal cultures with the complement-derived anaphylatoxin C5a, protects against glutamate neurotoxicity. In this study we explored the potential mechanisms involved in C5a-mediated neuroprotection. We found that C5a neuroprotects in vitro through inhibition of apoptotic death because pretreatment with human recombinant (hr)C5a prevented nuclear DNA fragmentation coincidental to inhibition of the pro-apoptotic caspase 3 activity mediated by glutamate treatment. Also, hrC5a-mediated responses appeared to be receptor-mediated because pretreatment of cultures with the specific C5a receptor antagonist C177, prevented hrC5a-mediated neuroprotection. Based on this evidence, we further explored possible signaling pathways involved in hrC5a inhibition of caspase 3 activation and apoptotic neuronal death. We found that treatment of cultures with the mitogen-activated protein kinase (MAPK) pathway inhibitor PD98059 prevented hrC5a-mediated inhibition of caspase 3 and apoptotic neuron death. MAPK pathways, whose activation by hrC5a is inhibited by PD98059 and C177, include the extracellular signal-regulated kinase (ERK)2 and, to a lesser extent, ERK1. The study suggests that C5a may protect against glutamate-induced apoptosis in neurons through MAPK-mediated regulation of caspase cascades.

Animals↗
PubMed2001

T cells in mice expressing a transgenic human TCR beta chain get positively selected but cannot be activated in the periphery by signaling through TCR.

TCR-CD3 complex-mediated signaling is crucial for both developmental selection and antigenic activation of T cells. We report that mice expressing a recombined human TCRbeta chain (Tg), which have normal development of T cells, mounted very weak responses to immunization with protein antigens as well as the HA307-319 peptide recognized by the human T cell clone HA1.7 from which the transgene is derived. An anti-CD3epsilon mAb triggered equivalent proliferation from Tg and non-Tg T cells, but an anti-human TCRbeta mAb induced proliferation poorly in Tg T cells in contrast to human T cells or HA1.7. In Tg mice, T cells expressing endogenous TCR were CD44(high), whereas most transgene-expressing T cells remained CD44(low), suggesting that transgene-expressing cells are not activated in the periphery to participate in immune responses. However, anti-human TCRbeta could induce some activation markers on T cells and cross-linking of the Tg TCR by plate-coated anti-human TCRbeta efficiently induced T cell proliferation. Human TCRbeta-mediated Tg T cell activation could be rescued by exogenous IL-2, as well as by the calcium ionophore A23187, but not by phorbol esters. Thus, this human TCRbeta chain functions efficiently for positive selection of mouse T cells, but not for their peripheral activation, probably because of a lack of oligomerization leading to defects in signaling for calcium flux and IL-2 induction. The data thus suggest an early point of separation of signaling pathways between positive selection and peripheral activation of T cells.

Animals↗
PubMed2001

Normal brain maturation during childhood: developmental trends characterized with diffusion-tensor MR imaging.

PURPOSE: To characterize the maturational changes in water diffusion within central gray matter nuclei and central white matter pathways of the human brain by using diffusion-tensor magnetic resonance (MR) imaging. MATERIALS AND METHODS: Retrospective analysis of normal MR examination findings in 153 subjects (age range, 1 day to 11 years) referred for clinical neuroimaging was performed. All studies included diffusion tensor-encoded echo-planar MR imaging. Isotropic diffusion coefficient (D) and diffusion anisotropy (A(sigma)) were measured in the corpus callosum, internal capsule, caudate nucleus, lentiform nucleus, and thalamus. RESULTS: exhibited biexponential decay with age in gray and white matter regions, except for monoexponential decay in the genu of the corpus callosum. There was a steep nonlinear increase of A(sigma) in white matter tracts that paralleled the time course of the decline in D. In basal ganglia, only a small linear increase in A(sigma) was observed in patients. A(sigma) changes in the thalamus were intermediate between basal ganglia and white matter structures. CONCLUSION: Changes in magnitude and anisotropy of water diffusion follow stereotypical time courses during brain development that can be empirically described with multiexponential regression models, which suggests that quantitative scalar parameters derived from diffusion-tensor MR imaging may provide clinically useful developmental milestones for brain maturity.

Brain↗
PubMed2001

Reversible posterior leukoencephalopathy syndrome: evaluation with diffusion-tensor MR imaging.

PURPOSE: To characterize the changes in brain water diffusion caused by reversible posterior leukoencephalopathy syndrome (RPLS). MATERIALS AND METHODS: Twelve patients with the clinical features and conventional magnetic resonance (MR) imaging findings of RPLS underwent diffusion-tensor echo-planar MR imaging. The isotropic diffusion coefficient (D) and diffusion anisotropy (A(sigma)) were measured in posterior regions of diffusion abnormality and in anterior areas of normal-appearing brain. RESULTS: Across all 12 subjects, the mean D of (1.09 +/- 0.13 [SD]) x 10(-3) mm(2)/sec in affected posterior regions was 26% greater than its value of (0.87 +/- 0.07) x 10(-3) mm(2)/sec in normal-appearing anterior regions. The mean A(sigma) of 0.15 +/- 0.03 in posterior regions was 35% less than its value of 0.23 +/- 0.02 in anterior regions (t(11) = 9.58; P <.001). There was a significant inverse correlation between D and A(sigma) in posterior regions (r = -0.67; P <.018) but not in anterior regions (r = -0.12; P =.719). A follow-up study performed in one patient after resolution of symptoms documented reversal of elevated isotropic diffusion and at least partial recovery of anisotropy loss. CONCLUSION: The increased magnitude of brain water diffusion characteristic of RPLS is accompanied by reduced A(sigma). The magnitudes of these two effects are correlated and may be reversible. These observations support the proposal that vasogenic edema due to cerebrovascular autoregulatory dysfunction is the underlying pathophysiologic mechanism in uncomplicated RPLS.

Adult↗
PubMed2001

Evaluating pediatric brain tumor cellularity with diffusion-tensor imaging.

OBJECTIVE: MR imaging of central nervous system (CNS) malignancies falls short of a definitive evaluation. Tissue diagnosis remains the gold standard. Diffusion-tensor MR imaging measures the apparent diffusion coefficient and diffusion anisotropy of water in tissue. The purpose of this study was to test the hypothesis that the apparent diffusion coefficient may improve the MR imaging evaluation of newly diagnosed CNS neoplasms. We examined the relationship between the apparent diffusion coefficient, anisotropy, and tumor cellularity in 12 pediatric patients. MATERIALS AND METHODS: On the basis of histopathologic evaluation, tumors in this case series were segregated into three types: low-grade gliomas, embryonal tumors, and nonembryonal high-grade tumors. Mean apparent diffusion coefficient and anisotropy values obtained from the solid components of each tumor were compared with cellularity, total cellular area, and total nuclear area derived from biopsy material. RESULTS: The apparent diffusion coefficient ratio (tumor to normal brain) correlated well with tumor classification (p = 0.001). Anisotropy was decreased similarly in all tumor classifications. The absolute apparent diffusion coefficient correlated well with cellularity (p = 0.014) and total nuclear area (p = 0.005) per high-power field. The correlation between apparent diffusion coefficient and total cellular area per high-power field was not statistically significant. CONCLUSION: The apparent diffusion coefficient may be predictive of tumor classification and may be a useful tool in characterizing tumor cellularity and total nuclear area. These parameters are not available in standard MR imaging. Therefore, diffusion-tensor imaging may enhance the diagnostic process in pediatric CNS malignancies.

Adolescent↗