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N Mehta

Publications and source records attributed to N Mehta.

At least 19 recordsLinked to original sources
PubMed2000

Pancreaticoduodenectomy for metastatic renal cell carcinoma: report of a case.

Metastasis to the pancreas from a distant primary cancer is uncommon, most cases being detected in the advanced stages of disease, often multiple in number, and diffusely displayed beyond surgical salvage. A solitary metastasis in the head of the pancreas is rarely encountered and although potentially amenable to surgical resection, surgeons are hesitant to perform pancreaticoduodenectomy for metastatic disease. Renal cell carcinoma is one malignancy with a propensity to metastasize to the pancreas. We report herein the case of a solitary pancreatic metastasis from renal cell carcinoma successfully treated by pancreaticoduodenectomy in a middle-aged man. A discussion on the indications and effectiveness of performing pancreaticoduodenectomy for metastatic renal cell carcinoma is also presented.

Carcinoma, Renal Cell↗
PubMed1999

alpha-Synuclein shares physical and functional homology with 14-3-3 proteins.

alpha-Synuclein has been implicated in the pathophysiology of many neurodegenerative diseases, including Parkinson's disease (PD) and Alzheimer's disease. Mutations in alpha-synuclein cause some cases of familial PD (Polymeropoulos et al., 1997; Kruger et al., 1998). In addition, many neurodegenerative diseases show accumulation of alpha-synuclein in dystrophic neurites and in Lewy bodies (Spillantini et al., 1998). Here, we show that alpha-synuclein shares physical and functional homology with 14-3-3 proteins, which are a family of ubiquitous cytoplasmic chaperones. Regions of alpha-synuclein and 14-3-3 proteins share over 40% homology. In addition, alpha-synuclein binds to 14-3-3 proteins, as well as some proteins known to associate with 14-3-3, including protein kinase C, BAD, and extracellular regulated kinase, but not Raf-1. We also show that overexpression of alpha-synuclein inhibits protein kinase C activity. The association of alpha-synuclein with BAD and inhibition of protein kinase C suggests that increased expression of alpha-synuclein could be harmful. Consistent with this hypothesis, we observed that overexpression of wild-type alpha-synuclein is toxic, and overexpression of alpha-synuclein containing the A53T or A30P mutations exhibits even greater toxicity. The activity and binding profile of alpha-synuclein suggests that it might act as a protein chaperone and that accumulation of alpha-synuclein could contribute to cell death in neurodegenerative diseases.

14-3-3 Proteins↗
PubMed1999

AsGM1+ NK cells prevent metastasis of invading LD-MCA-38 tumor cells in the nude mouse.

BACKGROUND: Although the liver is a potent tumor cell killing organ it is frequently the site of lethal metastases often signifying the endstage for patients with colorectal cancers. Enhancing hepatic-associated immunity remains elusive until the interactions among hepatic nonparenchymal cells (NPC) are deciphered. We sought to modulate the cellular components of the hepatic immune system of mice with anti-NK and anti-T-cell-neutralizing antibodies in order to determine the cell type most efficacious in preventing liver metastasis. MATERIALS AND METHODS: Liver-derived murine colon adenocarcinoma (LD-MCA-38) cells were injected into the ileocolic vein (ICV) of immunocompetent and immunodeficient C57BL/6 mice. Mice were pretreated 1 day prior to tumor cell injection with one of three antibodies: anti-AsGM1, Anti-NK1.1, or Anti-Thy1.2. On Day 21 laparotomy was performed to determine the extent of hepatic tumor foci. The number of hepatic tumor foci was recorded and compared by the Wilcoxon rank sum test. RESULTS: Mice pretreated with anti-AsGM1 or Anti-NK1.1 developed a massive increase in the number of hepatic tumor foci and decreased survival compared to the control treated mice. Pretreatment with anti-Thy1.2 antibody resulted in a significant decrease in the number of hepatic tumor foci. LD-MCA-38 tumor cells were unable to colonize the liver of C57BL/6 athymic nude mice; however, anti-AsGM1 antibody abolished this antimetastatic effect. There was no difference in the extent of hepatic metastasis and survival between immunodeficient C57BL/6 bg/bg and their conventional littermates bg/+. CONCLUSION: AsGM1+ NK cells exhibit a significant antitumor response in the absence of T-cells. The concept of stimulating NK cell activity and suppressing T-cell function may enhance liver-associated immunity and serve as a deterrent for blood-borne tumor cells metastasizing to the liver.

Adenocarcinoma↗
PubMed1999

Widespread alterations of alpha-synuclein in multiple system atrophy.

Glial cytoplasmic inclusions (GCI) are the hallmark of multiple system atrophy (MSA), a rare movement disorder frequently associated with autonomic dysfunction. In this study of 21 cases of MSA, GCI were consistently immunoreactive for alpha-synuclein and double-immunostained for ubiquitin and oligodendroglial markers, but not glial fibrillary acidic protein. No statistically significant difference was found in the density of GCI in various brain regions in the two forms of MSA, striatonigral degeneration (SND) and olivopontocerebellar atrophy (OPCA). Postmortem brain samples from 9 cases of MSA were fractionated according to solubility in buffer, Triton-X 100, sodium dodecyl sulfate (SDS), and formic acid, and alpha-synuclein immunoreactivity was measured in Western blots. Total alpha-synuclein immunoreactivity was increased in MSA compared to controls, with no statistically significant difference between SND and OPCA. Most of the increase was due to alpha-synuclein in SDS fractions. In controls this fraction had little or no immunoreactivity. In 7 cases and 4 controls correlations were investigated between quantitative neuropathology and biochemical properties of alpha-synuclein. Surprisingly, the amount of SDS-soluble alpha-synuclein correlated poorly with the number of GCI in adjacent sections. Furthermore, areas with few or no GCI unexpectedly had abundant SDS-soluble alpha-synuclein. These findings provide evidence that modifications of alpha-synuclein in MSA may be more widespread than obvious histopathology. Moreover, these alterations may constitute a biochemical signature for the synucleinopathies.

Aged↗
PubMed1999

Antisense-induced reduction of presenilin 1 expression selectively increases the production of amyloid beta42 in transfected cells.

Autosomal dominant mutations in the presenilin 1 (PS1) gene are associated with familial, early-onset Alzheimer's disease. Although the pathogenic mechanism of these mutations is unclear, their common feature is that they lead to an increased concentration of amyloid beta-peptide (Abeta) 42 in the plasma of early-onset patients, in the conditioned media of transfected cells, and in the brains of transgenic mice that overexpress mutant PS1. To address the mechanism(s) by which the pathogenic PS1 mutations increase Abeta42, we constructed human cell lines expressing a doxycyclin (dox)-inducible antisense PS1 RNA and measured its effects on the levels of PS1, amyloid precursor protein (APP), and Abeta. In time course experiments, we observed a statistically significant (p = 0.0038) more than twofold elevation in secreted Abeta42 as early as 12 days after addition of dox. This correlated with an 80% decrease in the 46-kDa PS1 holoprotein and a 30% decrease in the 26-kDa N-terminal fragment (NTF). Furthermore, there was a significant fivefold (p = 0.002) increase in Abeta42 after 14-day dox treatment; this correlated with a >90% decrease in PS1 holoprotein and 60% decrease in NTF. At no time point did we observe significant changes in Abeta40, APP holoprotein, presenilin 2, or tubulin. Ten days after the removal of dox, we observed a return to constitutive levels for Abeta42, PS1 holoprotein, and NTF. These results suggest that in human cell lines, the reduction of normal PS1 activity results in the increased production of Abeta42. Furthermore, our results are consistent with a loss of function or dominant negative mechanism for the pathogenic PS1 mutations.

Alzheimer Disease↗
PubMed1999

Adjustments in energy expenditure and substrate utilization during late pregnancy and lactation.

BACKGROUND: Metabolic adjustments occur during pregnancy and lactation to support fetal growth and milk synthesis; however, the effect of body composition and hormonal milieu on these changes is poorly understood. OBJECTIVE: We hypothesized that energy metabolism changes during pregnancy and lactation to support fetal growth and milk synthesis, and that body composition and hormonal milieu influence these alterations. DESIGN: We measured energy expenditure, body composition, and hormone, metabolite, and catecholamine concentrations in 76 women (40 lactating, 36 nonlactating) at 37 wk gestation and 3 and 6 mo postpartum. Total energy expenditure (TEE), basal metabolic rate (BMR), sleeping metabolic rate (SMR), and minimal SMR (MSMR) were measured with room calorimetry. Fat-free mass (FFM) and fat mass were estimated with a 4-component model. RESULTS: TEE, BMR, SMR, and MSMR were 15-26% higher during pregnancy than postpartum after being adjusted for FFM, fat mass, and energy balance. TEE, SMR, and MSMR were higher in lactating than in nonlactating women. Fasting serum insulin, insulin-like growth factor I, fatty acids, and leptin, and 24-h urinary free norepinephrine, epinephrine, and dopamine correlated positively with TEE, BMR, SMR, and MSMR. In nonlactating women, the respiratory quotient decreased over time, carbohydrate oxidation decreased, and fat oxidation increased. Substrate utilization was not influenced by body composition, fasting serum hormones, or 24-h urinary catecholamines. CONCLUSIONS: These results indicate increased energy expenditure and preferential use of carbohydrates during pregnancy and lactation. Elevated respiratory quotient and carbohydrate utilization during pregnancy continue during lactation, consistent with preferential use of glucose by the fetus and mammary gland.

Adolescent↗
PubMed1999

Initiating a structural study of 2-keto-3-deoxy-6-phosphogluconate aldolase from Escherichia coli.

2-Keto-3-deoxy-6-phosphogluconate aldolase (KDPG aldolase, E.C. 4.1. 2.14) is a member of the pyruvate/phosphoenolpyruvate aldolase family. It is also a synthetically useful enzyme, capable of catalyzing the stereoselective aldol addition of pyruvate to a range of unnatural electrophilic substrates. The recombinant protein was purified by a two-step HPLC protocol involving anion-exchange and hydrophobic chromatography. Dynamic light-scattering experiments indicated the protein to be monodisperse. Crystals were obtained using the sitting-drop vapour-diffusion method, with PEG 6K as precipitant. Diffraction data were collected on a frozen crystal to a resolution of 2.26 A on station PX9.6 at the Daresbury synchrotron. The crystal belongs to space group P2(1)2(1)2(1), with unit-cell parameters a = 53.2, b = 77.9, c = 146.8 A.

Aldehyde-Lyases↗
PubMed1999

Combination of chemotherapy with interleukin-2 and interferon alfa for the treatment of metastatic melanoma.

PURPOSE: The primary objective of this clinical study was to assess the feasibility of administering recombinant interleukin-2 and recombinant interferon alfa-2a before and after combination cytotoxic chemotherapy. After encouraging initial responses, the study was expanded to further evaluate the therapeutic potential, clarify the toxicities of this regimen, and explore any associated immunologic changes. PATIENTS AND METHODS: Eighty-four patients with metastatic melanoma, including patients with brain metastases, were treated on this 6-week protocol. Patients received combination cisplatin (25 mg/m2/d) and dacarbazine (220 mg/m2/d) on days 1 through 3 and 22 through 24 plus carmustine (150 mg/m2) on day 1. Interleukin 2 (13.5 million IU/m2/d) and interferon alfa (6 MU/m2/d) were administered on days 4 through 8 and 17 through 21. RESULTS: Among 83 patients assessable for response, 12 complete and 34 partial responses were documented (55% response rate). The median time to disease progression was 7 months, the median survival from study entry was 12.2 months, and the median survival from diagnosis of metastatic disease was 15.5 months. Although patients were hospitalized to receive treatment, intensive care unit support generally was not needed. Dose-limiting toxicities were related to elevations in serum bilirubin and serum creatinine levels. No patient developed a grade 4 clinical toxicity. Treatment produced a skin depigmentation, which was associated with prolonged survival. CONCLUSION: A plateau in both the survival and time to progression curves beyond 2 years (15% of the patients) and a greater than 10% disease-free survival beyond 4 years indicate that there may be a long-term benefit for some patients. The limited toxicity of this regimen should permit its use in most oncology settings. A randomized trial of chemoimmunotherapy versus chemotherapy should be performed to establish the value of chemoimmunotherapy for melanoma.

Adult↗
PubMed1999

Characteristics and identification of sites of chagasic ventricular tachycardia by endocardial mapping.

OBJECTIVE: To study electrophysiological characteristics that enable the identification and ablation of sites of chagasic tachycardia. METHODS: Thirty-one patients with chronic Chagas' heart disease and sustained ventricular tachycardia (SVT) underwent electrophysiological study to map and ablate that arrhythmia. Fifteen patients had hemodynamically stable SVT reproducible by programmed ventricular stimulation, 9 men and 6 women with ages ranging from 37 to 67 years and ejection fraction varying from 0.17 to 0.64. Endocardial mapping was performed during SVT in all patients. Radiofrequency (RF) current was applied to sites of presystolic activity of at least 30 ms. Entrainment was used to identify reentrant circuits. In both successful and unsuccessful sites of RF current application, electrogram and entrainment were analyzed. RESULTS: Entrainment was obtained during all mapped SVT. In 70.5% of the sites we observed concealed entrainment and ventricular tachycardia termination in the first 15 seconds of RF current application. In the unsuccessful sites, significantly earlier electrical activity was seen than in the successful ones. Concealed entrainment was significantly associated with ventricular tachycardia termination. Bystander areas were not observed. CONCLUSION: The reentrant mechanism was responsible for the genesis of all tachycardias. In 70.5% of the studied sites, the endocardial participation of the slow conducting zone of reentrant circuits was shown. Concealed entrainment was the main electrophysiological parameter associated with successful RF current application. There was no electrophysiological evidence of bystander regions in the mapped circuits of SVT.

Adult↗
PubMed1999

Searching the Internet for medical information: practical tips.

The Internet can be useful for physicians, but beginning users are apt to encounter two problems: too much irrelevant information, and difficulty finding the desired information. This paper offers some practical tips that can prevent frustration and wasted time when searching for medical information on the Internet.

Education, Medical↗
PubMed1999

Changes in adult zebra finch song require a forebrain nucleus that is not necessary for song production.

Male zebra finches normally crystallize song at approximately 90 days and do not show vocal plasticity as adults. However, changes to adult song do occur after unilateral tracheosyringeal (ts) nerve injury, which denervates one side of the vocal organ. We examined the effect of placing bilateral lesions in LMAN (a nucleus required for song development but not for song maintenance in adults) upon the song plasticity that is induced by ts nerve injury in adults. The songs of birds that received bilateral lesions within LMAN followed by right ts nerve injury silenced, on average, 0.25 syllables, and added 0.125 syllables (for an average turnover of 0.375 syllables), and changed neither the frequency with which individual syllables occurred within songs nor the motif types they used most often. In contrast, the songs of birds that received sham lesions followed by ts nerve injury lost, on average, 1.625 syllables, silenced 0.125 syllables, and added 0.75 syllables, turning over an average of 2.5 syllables. They also significantly changed both the frequency with which individual syllables were included in songs and the motif variants used. Thus, song plasticity induced in adult zebra finches with crystallized songs requires the presence of LMAN, a nucleus which had been thought to play a role in vocal production only during song learning. Although the changes to adult songs induced by nerve transection are more limited than those that arise during song development, the same circuitry appears to underlie both types of plasticity.

Aging↗
PubMed1998

Truncated presenilin 2 derived from differentially spliced mRNA does not affect the ratio of amyloid beta-peptide 1-42/1-40.

Numerous mutations in the presenilin (PS) genes cause early onset familial Alzheimer's disease (FAD). Here we characterize the expression of two naturally occurring alternative PS2 transcripts which lack either exons 3 and 4 (PS2 deltaexon3,4) or exons 3, 4, and 8 (PS2 deltaexon3,4,8). These transcripts do not contain the natural initiation codon within exon 3. The transcripts are efficiently translated as N-terminal truncated proteins. These deleted proteins are still able to regulate formation of endogenous PS fragments, indicating that the C-terminal half of the PS2 protein is sufficient for this phenomenon. Although approximately 50% of the PS1 and both PS2 mutations occur within the N-terminal region lacking in the PS2 deltaexon3,4 and PS2 deltaexon3,4,8 proteins, expression of these truncated proteins does not affect pathological generation of amyloid beta-peptide (Abeta). This suggests that point mutations causing AD are gain of function mutations.

Alzheimer Disease↗
PubMed1998

Successful nonsurgical removal of a knotted and entrapped pulmonary artery catheter.

Knotting of a balloon-tipped, flow-directed catheter leading to difficulty in its removal is a rare but serious complication. Several methods have been used to remove such catheters with nonsurgical techniques. A case of knotted catheter that was also entrapped in a surgical suture in a patient undergoing emergency mitral valve replacement is presented and a method for its nonsurgical removal is described.

Adult↗
PubMed1998

Cloning and characterization of the presenilin-2 gene promoter.

Mutations in the presenilin-2 (PS-2) have been shown to cause early onset Alzheimer's disease (AD) in a series of families known as the Volga Germans and in an unrelated Italian kindred. Expression of the PS-2 gene is regulated during AD, aging, development and brain injury. Although expressed primarily in neurons, enhanced levels of PS-2 have been reported in astrocytes activated by neuronal damage. Understanding the regulation of the PS-2 gene may thus provide an insight into its role in AD. We have isolated a 3635 bp DNA fragment that contains 2934 bp of DNA sequence upstream from the PS-2 gene. Primer extension analysis was used to map three major transcriptional start sites within the PS-2 gene. The promoter sequence, upstream of each transcriptional start site, does not contain TATA or CAAT boxes but does contain several GC rich sites (Sp-1 and AP-2). A reporter gene construct containing the PS-2 promoter (PS2P, -2934 to +702) transfected into M17 cells drives basal transcription to 20% of the levels of the SV-40 viral promoter. Addition of NGF to PC-12 cells was found to upregulate the PS2P promoter and an NGF-responsive element was localized by deletional analysis between -403 and +13 within the promoter. Since the PS-2 gene has multiple start sites and the upstream sequence is GC rich with no TATA box, the PS-2 promoter is consistent with the GC class of 'housekeeping' genes.

5' Untranslated Regions↗
PubMed1998

Low density lipoproteins and Lovastatin modulate the organ-specific transendothelial migration of primary and metastatic human colon adenocarcinoma cell lines in vitro.

Tumor cell arrest and tumor migration are two of the critical steps in the metastatic cascade. We hypothesized that these steps may be facilitated by the low density lipoprotein (LDL)-induced activation of microvessel endothelial cells (MVEC). The purpose of our study was to investigate the biological effects of an LDL-enriched milieu and the effects of the anticholesterol drug Lovastatin on metastatic behavior. The SW480 and SW620 are primary and metastatic human colonic adenocarcinoma cell lines derived from the same patient. We investigated the effect of LDL on adhesion and migration of the two tumor cell lines across human brain, lung, liver and dermal endothelial monolayers. Adhesion and migration assays were done before and after pretreatment of the MVEC or tumor cells with LDL (100 microg/ml) for 24 h. Although metastatic SW620 cells were more adherent to MVEC compared with primary SW480 cells, LDL pretreatment of SW480 and SW620 cells did not affect tumor cell adhesion to MVEC. In contrast, tumor cell migration was significantly increased across endothelial monolayers when MVEC were pretreated with LDL. Transendothelial cell migration was not significantly affected by pretreatment of the tumor cells with LDL. Lovastatin is an inhibitor of HMG-CoA reductase, the rate-limiting enzyme in cholesterol biosynthesis. It has been shown to have anti-tumor activity in vitro. We investigated the effect of Lovastatin on tumor cell kinetics and tumor cell migration across MVEC. Growth curves and migration assays were done before and after pretreatment of the tumor cells with Lovastatin (30 microg/ml). Migration assays were also done after treatment of unstimulated or LDL-stimulated MVEC (100 microg/ml) for 24 h with Lovastatin. Lovastatin inhibited the in vitro growth of the metastatic SW620 cell line to a greater extent than the invasive SW480E cell line. On the other hand, pretreatment of tumor cells with Lovastatin (30 microg/ml) did not suppress transendothelial tumor cell migration of tumor cells. Finally, Lovastatin given to mice effectively suppressed the number of MCA-26 tumor colonies in the liver of Balb/c mice compared with untreated mice.

Adenocarcinoma↗
PubMed1998

A variant of Alzheimer's disease with spastic paraparesis and unusual plaques due to deletion of exon 9 of presenilin 1.

We describe a novel variant of Alzheimer's disease (AD) in a Finnish pedigree with 17 affected individuals of both sexes in three generations. The disease is characterized by progressive dementia which is, in most cases, preceded by spastic paraparesis. Neuropathological investigations revealed numerous, distinct, large, round and eosinophilic plaques as well as neurofibrillary tangles and amyloid angiopathy throughout the cerebral cortex. The predominant plaques resembled cotton wool balls and were immunoreactive for Abeta but lacked a congophilic dense core or marked plaque-related neuritic pathology. Molecular genetic analysis revealed that the disease was caused by a deletion of exon 9 (delta9) of the presenilin 1 (PS1) gene from the mRNA: unlike previous examples of the delta9 variant, the deletion was not caused by a splice acceptor site mutation.

Age of Onset↗