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Biomedical subjects

V Mittal

Publications and source records attributed to V Mittal.

At least 19 recordsLinked to original sources
PubMed2005

Induction of complete regressions of oncogene-induced breast tumors in mice.

Over the past decade, mouse models of cancer have come to resemble human disease much more closely than simple subcutaneous or orthotopic systems. Intervention strategies that work on these new model systems are more likely to have an impact clinically. We have shown recently that antiangiogenic stress imposed by loss of Id protein in endothelial progenitor cells results in dramatic central necrosis in breast tumors initiated in mice by overexpression of the her2/neu oncogene. Tumor cells remain viable at the periphery, perhaps via the hypoxic response pathway which allows the lesions to expand. Inhibition of this pathway by the inactivation of the Hif-1alpha chaperone Hsp90 in combination with antiangiogenic stress leads to the first reported complete regression of these aggressive breast tumors.

Angiogenesis Inhibitors↗
PubMed2005

Postprandial lipid abnormalities in type 2 diabetes mellitus.

AIM AND OBJECTIVES: To study the postprandial lipid abnormalities in patients with type 2 diabetes mellitus. MATERIAL AND METHODS: Postprandial lipids were studied in 20 male type 2 diabetic subjects (age 49.75 +/- 4.82 years) and 20 age and sex matched healthy controls (age 49.55 +/- 4.82 years) after an oral fat challenge which consisted of a meal providing 729 keal/m2 body surface area with 68 gm fat. RESULTS: Average duration of diabetes among diabetic was 2.32 +/- 3.03 years. The body mass index (cases 25.84 +/- 4.52; controls 25.74 +/- 5.0; p > 0.05) and waist-hip ratio (cases 1.06 +/- 0.13; controls 1.14 +/- 0.2; p > 0.05) were similar in both groups. While fasting serum lipids were not significantly different between the two groups, a number of serum lipid abnormalities were noted in type 2 diabetic subjects in the postprandial state. These included a higher triglyceride-area under curve (AUC) (cases 1298.08 +/- 485.2 vs. controls 922.15 +/- 390.47 mg/dl/8h; p=0.01), a higher triglyceride-area under incremental curve (AUIC) (cases 549.68 +/- 382.24; control 294.75 +/- 172.6 mg/dl/8h; p=0.01), a higher peak triglyceride level (cases 425.2 +/- 204.47 mg%, controls 283.9 +/- 11.6.94 mg%, p=0.01), a lower HDL-AUC (cases 130.35 +/- 33.55 vs. controls 168.48 +/- 56.01 mg/dl/8h, p=0.013) and a lower HDL nadir (Cases 28.05 +/- 10.94 mg%, controls 37.13 +/- 13.52 mg%, p < 0.02). Triglyceride AUC correlated significantly with fasting serum triglyceride (r=0.62) and BMI (r=0.7), but not with waist hip ratio or fasting serum insulin levels. Postprandial lipaemia did not correlate with age, duration of diabetes, fasting blood glucose or glycosylated hemoglobin. CONCLUSION: In conclusion, make type 2 diabetics demonstrate significant postprandial lipid abnormalities, particularly of triglycerides, which appear to be independent of glycaemic control.

Adult↗
PubMed2004

Traumatic handlebar hernia: a rare abdominal wall hernia.

Traumatic abdominal wall herniation (TAWH) caused by direct trauma from bicycle handlebars are rare. There are only 21 reported cases of handlebar hernias. An 11-year-old boy presented to the emergency room soon after falling from his bicycle and hitting his right lower quadrant on the handlebars. The patient's vital signs and initial laboratory studies were normal. Physical exam showed a soft tissue bulge in the right lower quadrant with superficial ecchymosis and tenderness to palpation. Computed tomography showed intestinal loops protruding through a defect in the abdominal wall into the subcutaneous space. Surgical exploration found a defect throughout his entire abdominal wall including the fascia, muscular layers, and peritoneum, with bowel protruding into the subcutaneous space. The defect was repaired in layers, and the child's postoperative course was unevenful. The authors recommend a high level of clinical suspicion for TAWH in all patients with traumatic abdominal wall injuries. Definitive treatment includes surgical exploration with primary repair of all tissue layers of the abdominal wall.

Abdominal Injuries↗
PubMed2001

Design of a retroviral-mediated ecdysone-inducible system and its application to the expression profiling of the PTEN tumor suppressor.

We have engineered the ecdysone-inducible mammalian expression system for general retroviral delivery to cultured mammalian cells. We inducibly expressed PTEN in the glioblastoma cell line, U87MG, lacking this gene. Because nearly all cells are recruited on induction, we find both up- and down-regulated genes by cDNA microarray analysis. The changes we see are similar to those observed after treatment with LY294002, an inhibitor of phosphatidylinositol 3-OH kinase, fully consistent with the model that PTEN antagonizes phosphatidylinositol 3-OH kinase. Both treatments result in suppressed expression of the transforming growth factor (TGF)-beta gene and the genes of the cholesterol biosynthesis pathway. Our results illustrate the power of using a fully inducible expression system in conjunction with cDNA microarray analysis for exploring gene function.

Ecdysone↗
PubMed2001

Aminopeptidase A: a nephritogenic target antigen of nephrotoxic serum.

BACKGROUND: We investigated potential targets of antibody-mediated glomerular injury induced with a noncomplement binding fraction of sheep anti-rat nephrotoxic serum (NTS). This model is characterized by severe complement- and leukocyte-independent proteinuria within 24 hours of NTS injection into rats. METHODS: NTS-reactive glomerular cell and matrix proteins were identified by immunoprecipitation, Western blot analysis, protein sequencing, cDNA library screening, and enzyme-linked immunosorbent assay. Proteinuria was measured in rats injected with NTS from which reactivity against type IV collagen had been removed by immunoadsorption, and antibodies were eluted from the glomeruli of proteinuric rats that had been injected with unabsorbed NTS. Having identified aminopeptidase A (APA) as a major target of NTS, we studied the effect of NTS and anti-APA on mouse glomerular epithelial cells in culture. RESULTS: NTS identified several podocyte and matrix proteins; however, APA was the only cell surface protein reactive with antibodies eluted from the glomeruli of rats injected with NTS. Although the eluate also contained reactivity to the noncollagenous domains of alpha1 and alpha3 chains of type IV collagen, immunodepletion of these antibodies did not diminish the ability of NTS to cause proteinuria. We also documented the surface expression of APA on mouse glomerular epithelial cells in culture, and found that NTS and specific anti-APA antibodies induce a time- and temperature-dependent redistribution of the antigen. CONCLUSIONS: APA, a type II integral membrane metallopeptidase, is a major target of NTS in vivo and is known to be present on the surface of podocytes. NTS-induced proteinuria is independent of reactivity to known nephritogenic matrix proteins. These findings, in combination with previous studies showing that monoclonal anti-APA antibodies induce severe proteinuria in mice, suggest that anti-APA antibodies are responsible for complement-independent proteinuria in this model.

Aminopeptidases↗
PubMed2001

Detection of antibodies to Taenia solium in sera of patient with epilepsy using ELISA.

Enzyme linked immunosorbent assay (ELISA) was used for detection of antibodies to cysticerci of Taenia solium in patients suffering from suspected neurocysticercosis. Serum antibodies to cysticercosis were detected in 10.4% of the patients. Antibodies were absent in healthy controls. No cross-reactivity was observed in sera from patients with other parasitic diseases viz. toxoplasmosis, filariasis and kala-azar. However sera from patients with hydatid disease showed cross reactions in 20%. Age group distribution showed gradual non-significant increase in seropositivity rates with advancing age. No significant gender difference, was observed. Analysis of dietary habits of patients showed statistically significant difference in seropositivity rates in non-vegetarians (15.4%) as compared to vegetarians (6.9%) (P value < .001).

Adolescent↗
PubMed1999

SNAP(c): a core promoter factor with a built-in DNA-binding damper that is deactivated by the Oct-1 POU domain.

snRNA gene transcription is activated in part by recruitment of SNAP(c) to the core promoter through protein-protein contacts with the POU domain of the enhancer-binding factor Oct-1. We show that a mini-SNAP(c) consisting of a subset of SNAP(c) subunits is capable of directing both RNA polymerase II (Pol II) and Pol III snRNA gene transcription. Mini-SNAP(c) cannot be recruited by Oct-1, but binds as efficiently to the promoter as SNAP(c) together with Oct-1 and directs activated RNA Pol III transcription. Thus, SNAP(c) represses its own binding to DNA, and repression is relieved by interactions with the Oct-1 POU domain that promote cooperative binding. We have shown previously that TBP also represses its own binding, and in that case repression is relieved by cooperative interactions with SNAP(c). This may represent a general mechanism to ensure that core promoter-binding factors, which have strikingly slow off-rates, are recruited specifically to promoter sequences rather than to cryptic-binding sites in the genome.

DNA-Binding Proteins↗
PubMed1999

Improved continuity of care in a community teaching hospital model.

HYPOTHESIS: We created an ambulatory resident clinic in a community teaching hospital to improve the continuity of care in a surgery residency program. DESIGN: A retrospective chart review analysis. SETTING: A community hospital, general surgery residency training program, and its ambulatory practice. INTERVENTIONS: Providence Hospital, Southfield, Mich, has established a new model, the Surgical Associates of Michigan, which is an association comprising private practice physicians serving as full-time faculty in the Department of Surgery. In addition to clarification of teaching requirements and reimbursement for educational activities, the most dramatic feature is the relocation of private practice offices and the staff surgical office to one central location within the hospital. The proximity of the staff and private surgical offices facilitates closer interaction of attending physicians, residents, and patients. MAIN OUTCOME MEASURES: Compliance rates of continuity of patient care provided by the same resident, as presented by the Surgery Residency Review Committee, including confirmation of diagnosis, provision of preoperative care, discussion with attending physician, selection and provision of intervention, direction of postoperative care, and postdischarge follow-up. RESULTS: Since the inception of this arrangement at our institution, surgical residents have seen 229 staff patients and 465 private patients in the offices under supervision. Compliance rate of continuity of care was defined as patient follow-up with the same senior surgical resident who performed an operation or evaluated the patient on initial presentation to the emergency department or offices. We achieved a compliance rate of 92.8% (169/182) in the staff surgical clinics. A compliance rate of 63.5% (205/323) for private general surgical patients and 70.4% (100/142) for vascular surgical patients was obtained. With the establishment of the teaching faculty group and the relocation of offices, we were able to achieve a dramatic improvement in continuity of care. CONCLUSIONS: In addition to fulfilling the Surgery Residency Review Committee requirements, we believe our model facilitates broader education of surgical residents and improves risk management. We recommend further similar studies, greater involvement of primary care specialties in recruiting staff surgical referrals, and implementation of a specialized computer program to continue to improve continuity of care in surgery residency programs.

Continuity of Patient Care↗
PubMed1999

Correlation of acetylator phenotype with peripheral, autonomic and central neuropathy in Northern Indian non-insulin-dependent diabetes mellitus patients.

OBJECTIVES: Genetic susceptibility to diabetic neuropathy has been suspected and tentatively explored; however, diabetic autonomic and central neuropathies are poorly investigated areas. Previous trials correlating types of diabetes and diabetic neuropathy with acetylator dimorphisms have not been conclusive. The present study was designed to test peripheral neuropathy, autonomic neuropathy and integrity of central conduction pathways in patients of non-insulin-dependent diabetes mellitus (NIDDM), and to correlate the findings with the acetylator phenotype. METHODS: Twenty-six patients of NIDDM with stable glycaemic control and 11 age- and sex-matched control subjects were recruited, clinically examined and investigated with glycaemic and lipid profile, renal function tests, nerve conduction studies (sensory and motor), auditory brain stem evoked responses (ABERs) and somatosensory evoked potentials (SEPs). Acetylator status of the subjects was determined by sulphadimidine test. RESULTS: Out of 26 NIDDM patients, eight (30.7%; group 1A) were slow acetylators and 18 (69.3%; group 1B) were fast acetylators. The distribution of slow and rapid acetylators in both the groups was similar. Glycaemic and lipid profiles and 24-h urinary albumin excretion in groups 1A and 1B were also similar. Motor nerve conduction velocity, latency of F wave, sensory nerve conduction and amplitudes of sensory nerve action potentials were not different between fast and slow acetylator NIDDM patients. On testing for ABERs, there were no statistically significant differences in peak latencies of waves I, III and V; interpeak latencies (IPLs) I-III, III-V and I-V; amplitude of waves I, III and V on both sides between NIDDM patients and controls. However, peak latencies of wave III (P < 0.01), wave V (P < 0.005), IPLs I-III and I-V (P < 0.005), IPLs III-V (P < 0.05), and amplitudes of wave I (P < 0.05) and wave V (P < 0.05) on the left side were significantly different in slow acetylator NIDDM patients. Increase on the right side for the same group was statistically significant for IPLs I-III and I-V (P < 0.05). SEPs showed no statistically significant difference between NIDDM patients and controls, and slow and fast acetylator NIDDM patients. CONCLUSIONS: No significant association of acetylator status with peripheral neuropathy in NIDDM subjects was observed in the present study. However, central neural conduction, primarily tested by ABERs, was significantly delayed in slow acetylators compared with fast acetylator NIDDM patients. Hence, there may be a predisposition to neuropathy in this group of patients, and such a predisposition may be better detected by studying central rather than peripheral nervous conduction pathways in NIDDM patients.

Adult↗
PubMed1999

Penetrating cardiac injuries.

Our objective was to determine the influence of several clinical factors on the survival of patients with penetrating wounds to the heart. A retrospective review of 80 consecutive penetrating cardiac injuries treated in a Level II urban trauma center from 1980 through 1994 were examined. Thirty-six patients (45%) had gunshot wounds (including 1 shotgun wound), and 44 (55%) had stab wounds. Intervention consisted of emergency room (ER) or operating room thoracotomy. We measured the effect of several clinical factors on morbidity and patient survival. Survival rate was 17 of 36 (47%) in gunshot injuries and 35 of 44 (80%) in stab injuries, with an overall survival rate of 52 of 80 patients (65%). The average age was 24 years (range, 9-53), and there were 3 female patients. Twelve patients (15%) had multiple cardiac injuries, and 63 (79%) had other associated injuries. Fourteen patients (17%) presented with no blood pressure, and 55 (69%) were hypotensive on admission. ER thoracotomy was performed on 7 of 52 survivors (13%) and 24 of 28 nonsurvivors (86%). Survival after ER thoracotomy was 7 of 31 patients (22%). A selective approach is recommended, because ER thoracotomy has a limited role in penetrating cardiac injury. A high index of suspicion, prompt resuscitation, and immediate definitive surgical management resulted in a high survival rate for these frequently lethal injuries.

Adolescent↗
PubMed1998

SNAP19 mediates the assembly of a functional core promoter complex (SNAPc) shared by RNA polymerases II and III.

The basal transcription factor SNAPc binds to the PSE, a core element in the RNA polymerase II and III human snRNA promoters. SNAPc contains at least four subunits, but it has not been possible to assemble a fully defined recombinant SNAPc. Here we reconstitute SNAPc from five recombinant subunits, SNAP43, SNAP45, SNAP50, SNAP190, and a newly identified subunit, SNAP19. This recombinant complex binds specifically to the PSE and directs both RNA polymerase II and III snRNA gene transcription. Thus, the same core SNAPc nucleates the assembly of two classes of initiation complexes.

Amino Acid Sequence↗
PubMed1998

The Impact of Positive and Negative Affect and Issue Framing on Issue Interpretation and Risk Taking.

Two studies examined the influence of transient affective states and issue framing on issue interpretation and risk taking within the context of strategic decision making. In Study 1, participants in whom transient positive or negative affective states were induced by reading a short story showed systematic differences in issue interpretation and risk taking in a strategic decision making context. Compared to negative mood participants, those in a positive mood were more likely to interpret the strategic issue as an opportunity and displayed lower levels of risk taking. Study 2 replicated and extended these results by crossing affective states with threat and opportunity frames. Results showed that framing an issue (as a threat or an opportunity) had a stronger impact on issue interpretation among negative affect participants than among positive affect participants. Affective states also moderated the impact of issue framing on risk taking: the effect of framing on risk-taking was stronger under negative rather than positive affect. These results are interpreted via information-processing and motivational effects of affect on a decision maker. Copyright 1998 Academic Press.

Journal Article↗
PubMed1998

Amyloid formation by mutant huntingtin: threshold, progressivity and recruitment of normal polyglutamine proteins.

Huntington's disease (HD) is caused by an expanded CAG trinucleotide repeat encoding a tract of consecutive glutamines near the amino terminus of huntingtin, a large protein of unknown function. It has been proposed that the expanded polyglutamine stretch confers a new property on huntingtin and thereby causes cell and region-specific neurodegeneration. Genotype-phenotype correlations predict that this novel property appears above a threshold length (approximately 38 glutamines), becomes progressively more evident with increasing polyglutamine length, is completely dominant over normal huntingtin and is not appreciably worsened by a double genetic dose in HD homozygotes. Recently, an amino terminal fragment of mutant huntingtin has been found to form self-initiated fibrillar aggregates in vitro. We have tested the capacity for aggregation to assess whether this property matches the criteria expected for a fundamental role in HD pathogenesis. We find that that in vitro aggregation displays a threshold and progressivity for polyglutamine length remarkably similar to the HD disease process. Moreover, the mutant huntingtin amino terminus is capable of recruiting into aggregates normal glutamine tract proteins, such as the amino terminal segments of both normal huntingtin and of TATA-binding protein (TBP). Our examination of in vivo aggregates from HD post-mortem brains indicates that they contain an amino terminal segment of huntingtin of between 179 and 595 residues. They also contain non-huntingtin protein, as evidenced by immunostaining for TBP. Interestingly, like the in vitro aggregates, aggregates from HD brain display Congo red staining with green birefringence characteristic of amyloid. Our data support the view that the expanded polyglutamine segment confers on huntingtin a new property that plays a determining role in HD pathogenesis and could be a target for treatment. Moreover, the new property might have its toxic consequences by interaction with one or more normal polyglutamine-containing proteins essential for the survival of target neurons.

Adult↗
PubMed1997

Role for the amino-terminal region of human TBP in U6 snRNA transcription.

Basal transcription from the human RNA polymerase III U6 promoter depends on a TATA box that recruits the TATA box-binding protein (TBP) and a proximal sequence element that recruits the small nuclear RNA (snRNA)-activating protein complex (SNAPc). TBP consists of a conserved carboxyl-terminal domain that performs all known functions of the protein and a nonconserved amino-terminal region of unknown function. Here, the amino-terminal region is shown to down-regulate binding of TBP to the U6 TATA box, mediate cooperative binding with SNAPc to the U6 promoter, and enhance U6 transcription.

Amino Acid Sequence↗
PubMed1996

The Oct-1 POU-specific domain can stimulate small nuclear RNA gene transcription by stabilizing the basal transcription complex SNAPc.

The RNA polymerase II and III human small nuclear RNA promoters have a common basal element, the proximal sequence element, which binds the TATA box-binding protein-containing complex SNAPc. They also contain an enhancer characterized by a highly conserved octamer sequence, which constitutes a binding site for the broadly expressed POU domain transcription factor Oct-1. The POU domain is a bipartite DNA-binding domain consisting of a POU-homeo (POUH) domain and a POU-specific (POUs) domain joined by a flexible linker. Here, we show that the Oct-1 POU domain but not the related Pit-1 POU domain can facilitate the binding of SNAPc to the proximal sequence element, and activate transcription. The effect is probably mediated by protein-protein contacts, and 1 of 30 amino acid differences between the Oct-1 and Pit-1 POUs domains is the key determinant for the differential interaction with SNAPc and the ability to activate transcription. These results show that a function that is the hallmark of activation domains, namely, recruitment of a basal transcription complex resulting in activation of transcription, can be performed by a DNA-binding domain. In this case, subtle changes between activator DNA-binding domains, as subtle as a single amino acid difference, can profoundly affect interaction with the basal transcription machinery.

Amino Acid Sequence↗
PubMed1996

Replication initiates at multiple dispersed sites in the ribosomal DNA plasmid of the protozoan parasite Entamoeba histolytica.

In the protozoan parasite Entamoeba histolytica (which causes amoebiasis in humans), the rRNA genes (rDNA) in the nucleus are carried on an extrachromosomal circular plasmid. For strain HM-1:IMSS, the size of the rDNA plasmid is 24.5 kb, and 200 copies per genome are present. Each circle contains two rRNA transcription units as inverted repeats separated by upstream and downstream spacers. We have studied the replication of this molecule by neutral/neutral two-dimensional gel electrophoresis and by electron microscopy. All restriction fragments analyzed by two-dimensional gel electrophoresis gave signals corresponding to simple Y's and bubbles. This showed that replication initiated in this plasmid at multiple, dispersed locations spread throughout the plasmid. On the basis of the intensity of the bubble arcs, initiations from the rRNA transcription units seemed to occur more frequently than those from intergenic spacers. Multiple, dispersed initiation sites were also seen in the rDNA plasmid of strain HK-9 when it was analyzed by two-dimensional gel electrophoresis. Electron microscopic visualization of replicating plasmid molecules in strain HM-1:IMISS showed multiple replication bubbles in the same molecule. The location of bubbles on the rDNA circle was mapped by digesting with PvuI or BsaHI, which linearize the molecule, and with SacII, which cuts the circle twice. The distance of the bubbles from one end of the molecule was measured by electron microscopy. The data corroborated those from two-dimensional gels and showed that replication bubbles were distributed throughout the molecule and that they appeared more frequently in rRNA transcription units. The same interpretation was drawn from electron microscopic analysis of the HK-9 plasmid. Direct demonstration of more than one bubble in the same molecule is clear evidence that replication of this plasmid initiates at multiple sites. Potential replication origins are distributed throughout the plasmid. Such a mechanism is not known to operate in any naturally occurring prokaryotic or eukaryotic plasmid.

Amebiasis↗
PubMed1996

Eliminate the negative. Managers should optimize rather than maximize performance to enhance patient satisfaction.

Performance on a particular attribute has an asymmetric impact on patient satisfaction. Gaining insight into this asymmetric effect can help refine management tools such as impact analysis. For overall satisfaction, negative performance on an attribute will have a much larger impact than positive performance. Therefore, managers should optimize, rather than maximize attribute-level performance to maximize patient satisfaction. Because of this asymmetry, the benefit from eliminating negative performance may be larger than the benefit gained from increasing positive performance on an attribute. So you can increase overall satisfaction faster by eliminating the negatives.

Administrative Personnel↗