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Biomedical subjects

M Patel

Publications and source records attributed to M Patel.

At least 73 records · Page 4Linked to original sources
PubMed2001

Neuroprotection from delayed postischemic administration of a metalloporphyrin catalytic antioxidant.

Reactive oxygen species contribute to ischemic brain injury. This study examined whether the porphyrin catalytic antioxidant manganese (III) meso-tetrakis (N-ethylpyridinium-2-yl)porphyrin (MnTE-2-PyP(5+)) reduces oxidative stress and improves outcome from experimental cerebral ischemia. Rats that were subjected to 90 min focal ischemia and 7 d recovery were given MnTE-2-PyP(5+) (or vehicle) intracerebroventricularly 60 min before ischemia, or 5 or 90 min or 6 or 12 hr after reperfusion. Biomarkers of brain oxidative stress were measured at 4 hr after postischemic treatment (5 min or 6 hr). MnTE-2-PyP(5+), given 60 min before ischemia, improved neurologic scores and reduced total infarct size by 70%. MnTE-2-PyP(5+), given 5 or 90 min after reperfusion, reduced infarct size by 70-77% and had no effect on temperature. MnTE-2-PyP(5+) treatment 6 hr after ischemia reduced total infarct volume by 54% (vehicle, 131 +/- 60 mm(3); MnTE-2-PyP(5+), 300 ng, 60 +/- 68 mm(3)). Protection was observed in both cortex and caudoputamen, and neurologic scores were improved. No MnTE-2-PyP(5+) effect was observed if it was given 12 hr after ischemia. MnTE-2-PyP(5+) prevented mitochondrial aconitase inactivation and reduced 8-hydroxy-2'-deoxyguanosine formation when it was given 5 min or 6 hr after ischemia. In mice, MnTE-2-PyP(5+) reduced infarct size and improved neurologic scores when it was given intravenously 5 min after ischemia. There was no effect of 150 or 300 ng of MnTE-2-PyP(5+) pretreatment on selective neuronal necrosis resulting from 10 min forebrain ischemia and 5 d recovery in rats. Administration of a metalloporphyrin catalytic antioxidant had marked neuroprotective effects against focal ischemic insults when it was given up to 6 hr after ischemia. This was associated with decreased postischemic superoxide-mediated oxidative stress.

Aconitate Hydratase↗
PubMed2001

NY-ESO-1 and CTp11 expression may correlate with stage of progression in melanoma.

BACKGROUND: As tumor cells spread beyond their primary site they undergo changes in their gene expression that may be detectable and useful for microstaging. The cancer/testis (CT) antigens are a family of proteins that include MAGE 1-3, NY-ESO-1, SSX 1-5, and others that are potential markers for microstaging melanoma. CT antigens are produced by many tumor types but few normal tissues other than testis. One CT antigen, CTp11, was shown to be expressed by metastasizing melanoma cell lines but not by nonmetastasizing variants. We tested this finding by studying the expression of CTp11 and NY-ESO-1 by melanoma samples from different stages of progression. MATERIALS AND METHODS: We collected 20 primary, 22 locoregional, and 10 distant metastatic melanoma samples. We extracted total RNA, and reverse transcription yielded cDNA, which was PCR-amplified using primers to detect beta-actin, tyrosinase, MART-1, NY-ESO-1, and CTp11. The PCR products were separated on ethidium bromide-stained agarose gels and visualized by UV transillumination. RESULTS: All samples were positive for beta-actin and MART-1 and all but two were positive for tyrosinase, confirming RNA integrity and the presence of melanoma. Twenty-seven samples were positive for NY-ESO-1, CTp11, or both. CTp11 tended to be expressed by primary melanomas and NY-ESO-1 by metastatic samples (P < 0.02). CONCLUSIONS: There is a statistically significant difference in the distribution of the expression of CTp11 and NY-ESO-1 in melanoma from different stages of progression. NY-ESO-1 may be a marker of more advanced disease and CTp11 of less advanced disease.

Antigens, Neoplasm↗
PubMed2001

Acid dissociation constant, a potential physicochemical factor in the inhibition of the enzyme estrone sulfatase (ES).

We report the initial results of the synthesis and biochemical evaluation of a series of aminosulfonate based compounds of phenol and the determination of the pKa of the parent phenol in an attempt to investigate the role of this physicochemical factor in the irreversible inhibition of the enzyme estrone sulfatase (ES). The results of the study show that there is a strong correlation between the observed pKa and inhibitory activity. We postulate that the stability of the phenoxide ion, as indicated by the acid dissociation constant, is an important factor in the irreversible inhibition of this enzyme.

Estrogens↗
PubMed2001

Novel inhibitors of the enzyme estrone sulfatase (ES).

We report the initial results of our study into a series of simple 4-sulfamated phenyl alkyl ketones as potential inhibitors of the enzyme estrone sulfatase. The results of the study show that these compounds are potent inhibitors, possessing greater inhibitory activity than COUMATE, but weaker activity than EMATE. Furthermore, the compounds are observed to be irreversible inhibitors.

Alkanes↗
PubMed2001

Efficient gene transfection by bisguanylated diacetylene lipid formulations.

We have previously shown that cationic cholesterol derivatives bearing guanidinium groups were efficient vectors for gene transfer. To further evaluate the potentiality of this novel class of cationic lipids, we undertook to study the transfection efficiency of guanidinium-based lipids with other hydrophobic moieties. Specifically, we synthesized a reagent where two guanidinium groups are linked to a diacetylene lipid which may provide the lipoplexes with favorable structural features. We report here that the cationic lipid bisguanidinium-diacetylene (BGDA) is highly efficient for in vitro gene transfection when formulated with dioleoylphosphatidyl ethanolamine (DOPE). We also show that liposomes composed of BGDA, DOPE, and a neutral diacetylene colipid, hydroxyethylenediacetylene (HEDA), are efficient for transfection. Thus, diacetylene-based lipids provide a novel scaffold for gene transfection and will be particularly useful for gaining new insights into the structure-activity relationships of the lipid/DNA complexes as they offer a means to study the effects of polymerizable domains.

Acetylene↗
PubMed2001

Functional correction of fanconi anemia group C hematopoietic cells by the use of a novel lentiviral vector.

Lentiviral vectors transduce nondividing hematopoietic cells more efficiently than other currently available vector systems. Here we report the results of human hematopoietic cell gene transfer using lentiviral vectors based upon human immunodeficiency virus (HIV-1) and equine infectious anemia virus (EIAV). EIAV is a nonprimate lentivirus and is severely restricted in its host range to horses and closely related equines. We employed the EIAV vector system to test for gene transfer to human Fanconi anemia (FA) hematopoietic cells by comparison with HIV-1- and Moloney murine leukemia virus-based systems. Fanconi anemia is characterized by bone marrow failure secondary to stem cell dysfunction. Fanconi anemia group C EBV-transformed lymphoblasts were transduced with all three viral vectors. Phenotypic correction of FA cells, as measured by mitomycin C drug resistance, was observed with a similar efficiency in all vector systems. This is the first description of lentiviral correction of FA cells and suggests that lentiviral vectors may be useful for FA gene transfer.

Cell Cycle↗
PubMed2001

Target cell induced activation of NK cells in vitro: cytokine production and enhancement of cytotoxic function.

This study examines the effect of fixed AK-5 tumour cells on rat NK cells. Co-culture of NK cells with fixed tumour cells augmented the cytotoxicity of NK cells against NK-sensitive targets, YAC-1 and AK-5, and induced the secretion of IFN-gamma by NK cells. Antibody against IFN-gamma suppressed the anti-tumour activity of NK cells, whereas the addition of T cells during co-culture enhanced this activity. However, macrophages and B cells had no significant effect when present during co-culture with NK cells. All the inducible cytotoxicity was contained within the NK (CD161+) and NKT (CD3+, CD161+) subsets of lymphocytes. However, in the presence of T cells, the cytolytic potential of NKT cells was higher than that of NK cells alone. The augmentation of cytotoxic activity of NK cells by AK-5 cells in presence of T cells was dependent on IL-2 and IFN-gamma secretion. NK cell activation was blocked by specific antibodies to IL-2 and IFN-gamma in the presence of T cells. Interaction between fixed AK-5 cells with NK and T cell populations induced the expression of Fas-L and perforin in NK cells. These data demonstrate that fixed AK-5 cells initiated cytokine synthesis by NK cells, and the enhanced cytotoxic activity in the presence of T cells was induced as a consequence of the products secreted by activated T lymphocytes. The present observations reflect the possible interactions taking place in vivo after the transplantation of AK-5 tumour in animals. They also suggest direct activation of NK cells after their interaction with the tumour cells.

Animals↗
PubMed2001

Involvement of endometrial membrane sulphydryl groups in blastocyst implantation: sulphydryl groups as a potential target for contraceptive research.

The role of membrane sulphydryl groups in blastocyst implantation was studied by masking the membrane sulphydryl groups in the endometrium of Swiss albino mice, Mus musculus, using 10(-5) M cobalt chloride and 0.05 mM as well as 0.005 mM n-ethylmaleimide. Here we show that the blocking of sulphydryl groups with cobalt resulted in a decrease in superoxide radical surge and an increase in superoxide dismutase levels at the time of implantation. We hypothesize that it may be due to either a decrease in membrane fluidity or the unavailability of sulphydryl groups of endometrial membrane, thus preventing blastocyst implantation. These sulphydryl groups can be targeted for future contraceptive research.

Animals↗
PubMed2001

Cost implications of routine tirofiban use in the management of acute coronary syndromes.

BACKGROUND: Several studies have shown that glycoprotein IIb/IIIa receptor inhibitors confer benefit for patients admitted with acute coronary syndromes. However, these drugs are widely regarded as expensive. We therefore decided to assess the theoretical cost implications of introducing glycoprotein IIb/IIIa receptor inhibitors on our coronary care unit (CCU). METHODS: We audited 304 admissions (188 male, mean age 68 years) with unstable angina or a non-q-wave myocardial infarction to the CCU of a large district general hospital between January and December 1998. The main outcome measure was eligibility for treatment with tirofiban in accordance with the entry and exclusion criteria of the PRISM-PLUS trial. RESULTS: Of the 304 admissions, only 77 (25.3%) would have been eligible for randomisation in the PRISM-PLUS trial. The annual cost of selectively treating this subgroup with tirofiban would be 11,090 pounds sterling (Euro 18,520) per 100 admissions overall. Using tirofiban to treat all admissions with unstable angina and non-q-wave myocardial infarction would treat almost four times as many patients at a cost of 43,833 pounds sterling (Euro 73,201) per 100 admissions, with unproven benefits for the majority. CONCLUSIONS: We have found significant differences between patients treated in 'real life' and those enrolled into a randomised controlled trial, and demonstrated the importance of maintaining a patient registry in such trials. Deciding whether to treat only those patients for whom there is trial-based evidence of benefit, or all patients regardless of their similarity to trial populations, is an important factor which needs to be taken into account in preparing treatment protocols and in planning for drug expenditure.

Acute Disease↗
PubMed2001

Management of sexual assault.

The incidence of sexual assault continues to escalate, and it is under-reported. Victim care requires special attention in the emergency department because the history and physical examination are unique and frequently time consuming. The victim should receive counseling and treatment for potential STDs, HIV, and hepatitis exposure, while stressing the importance of follow-up care. The emergency department physician must fulfill obligations not only to the patient but also to law enforcement. To be done well, documentation of findings and the completion of the evidentiary portion of the exam require a familiarity with the process.

Clinical Laboratory Techniques↗
PubMed2001

Relation between sodium-lithium countertransport and hypertriglyceridemia in type V hyperlipidemia.

Sodium-lithium countertransport (SLC) kinetics were measured in 30 patients with type V hyperlipidemia, 30 patients with type IIB hyperlipidemia on similar treatment, and 30 age- and sex-matched healthy controls. Clinical and laboratory data including basic anthropometry and blood pressure were obtained and blood was taken for detailed lipid biochemistry, glucose, insulin, and leptin measurements. Patients with type V hyperlipidemia were normotensive but more obese than controls, had elevated triglycerides, very low-density lipoprotein, glucose, and insulin; and reduced HDL cholesterol compared with type IIb controls. The median SLC activity (0.23 v 0.21 mmol Li+/L RBC/h) and median maximal velocity (0.33 v 0.31 mmol Li+/L RBC/h) were increased, but not significantly, compared to controls. In patients with type V hyperlipidemia SLC maximal velocity correlated with log triglycerides (r2 = 0.853; P < .001) and log very low-density lipoprotein (VLDL) triglycerides (r2 = 0.947; P < .001). Sodium-lithium countertransport maximal velocity correlated weakly with the homeostasis model assessment index of insulin resistance (r2 = 0.224; P = .06). The sodium affinity of the transporter did not differ between the groups and was independent of any of clinical or biochemical parameter studied. We conclude that VLDL triglyceride is strongly correlated with SLC maximal velocity and activity in patients with type V hyperlipidemia.

Adult↗
PubMed2001

Hospital separations indicate increasing need for prevention of diabetic foot complications in central Australia.

The aim of this study was to guide service provision for prevention of diabetic foot complications through the analysis of hospital separation data for those with diabetes in central Australia. We reviewed the hospital separation data for central Australia from 1992 to 1997 for adults known to be diabetic and those with diabetic foot complications. Foot complications were identified from International Classification of Diseases-9th Revision (ICD-9) codes. Additionally, we assessed the proportion of cases with diabetic foot, identified by ICD-9 coding and confirmed by record review, that were identified by Australian National-Diagnostic Related Group-Version 3 (AN-DRG-3) coding. Separations with diabetes doubled from 352 in 1992 to 796 in 1997. This represents an increase from 1232 to 2521 separations per 100,000 people over 15 years of age. Separations with foot complications increased threefold from 28 in 1992 to 90 in 1997, a rate increase from 98 to 285 per 100,000 people over 15 years of age. The proportion of diabetes separations that had foot complications remained around 10% during the 6 year period. Aboriginal people made up 89% of the individuals with foot complications and 91% of separations for diabetic foot. Foot complications were predominantly of the more acute type (90%), amenable to early intervention. The AN-DRG-3 code for diabetic foot identified only 59% (37/63 in 1997) of the separations identified by the ICD-9 codes, and admitted primarily for foot complications in Alice Springs Hospital. The known burden of hospital care for diabetes and diabetic foot complications has increased markedly in recent years. A combination of changes in prevalence, primary care utilisation, detection, hospital access or re-admission rates may underlie the observed increases. As it is very unlikely that diabetes or diabetic foot complications are being over diagnosed, or that the hospitals are over utilised, this analysis shows there is an increasingly apparent need for improved prevention of diabetic foot complications. Therefore primary health care systems should ensure that they implement evidence-based care for preventing foot complications among people with diabetes.

Adolescent↗
PubMed2001

Dependence of excitotoxic neurodegeneration on mitochondrial aconitase inactivation.

Using the inactivation of mitochondrial and cytosolic aconitases as markers of compartment-specific superoxide (O2(-)) production, we show that oxygen-glucose deprivation (OGD) or excitotoxin exposure produce a time-dependent inactivation of mitochondrial, but not cytosolic, aconitase in cortical cultures. To determine if mitochondrial O2(-) production was an important determinant in neuronal death resulting from OGD, metalloporphyrins with varying superoxide dismutase (SOD) activity were tested for their ability to protect against mitochondrial aconitase inactivation and cell death. OGD-induced mitochondrial aconitase inactivation and cell death was inhibited by manganese tetrakis (4-benzoic acid) porphyrin (MnTBAP), manganese tetrakis (N-ethylpyridinium-2-yl) porphyrin (MnTE-2-PyP) and NMDA receptor antagonists. By contrast, NMDA- or kainate (KA)-induced mitochondrial aconitase inactivation and cell death was inhibited by MnTBAP, but not MnTE-2-PyP. Moreover, both MnTBAP and MnTE-2-PyP penetrated mitochondrial fractions of cortical cells. These data suggest that mitochondrial aconitase inactivation closely correlates with subsequent neuronal death following excitotoxicity produced by OGD or NMDA/KA exposure. Assessment of biological rather biochemical antioxidant activities better predicted neuroprotection by metalloporphyrins. Moreover, antioxidants that protect oxidant-sensitive mitochondrial targets such as aconitase may be useful as therapies for disease states involving excitotoxicity.

Aconitate Hydratase↗
PubMed2001

Enhanced hippocampal F2-isoprostane formation following kainate-induced seizures.

We attempted to obtain evidence for the occurrence of oxidant injury following seizure activity by measuring hippocampal F2-isoprostanes (F2-IsoPs), a reliable marker of free radical-induced lipid peroxidation. Formation of F2-IsoPs esterified in hippocampal phospholipids was correlated with hippocampal neuronal loss and mitochondrial aconitase inactivation, a marker of superoxide production in the kainate model. F2-IsoPs were measured in microdissected hippocampal CA1, CA3 and dentate gyrus (DG) regions at various times following kainate administration. Kainate produced a large increase in F2-IsoP levels in the highly vulnerable CA3 region 16 h post injection. The CA1 region showed small, but statistically insignificant increases in F2-IsoP levels. Interestingly, the DG, a region resistant to kainate-induced neuronal death also showed marked (2.5-5-fold) increases in F2-IsoP levels 8, 16, and 24 h post injection. The increases in F2-Isop levels in CA3 and DG were accompanied by inactivation of mitochondrial aconitase in these regions. This marked subregion-specific increase in F2-Isop following kainate administration suggests that oxidative lipid damage results from seizure activity and may play an important role in seizure-induced death of vulnerable neurons.

Aconitate Hydratase↗
PubMed2001

A controlled study of MRI signal hyperintensities in older depressed patients with and without hypertension.

OBJECTIVES: To compare the frequency/severity of signal hyperintensities--likely markers of cerebrovascular disease--in the subcortical gray and deep white matter on magnetic resonance imaging (MRI) scans of brains of hypertensive and normotensive older depressed and nondepressed comparison subjects. DESIGN: Between-groups comparison of cross-sectional MRI data employing analyses of covariance controlling for the effects of age, gender, and height. SETTING: A comprehensive inpatient-outpatient geriatric psychiatry service in a university hospital. PARTICIPANTS: Nondemented older depressed (n = 81) and nondepressed comparison (n = 70) subjects divided into four groups (hypertensive depressed (n = 40), hypertensive normals (n = 21), normotensive depressed (n = 41), normotensive normals (n = 49)). MEASUREMENTS: Signal hyperintensities were rated on T-2 weighted MRI scans blind to patient diagnoses employing two standardized hyperintensity rating systems (Fazekas, Boyko). RESULTS: Hypertensive depressives had significantly more- severe hyperintensity ratings in both subcortical gray and deep white matter than did normotensive depressives and controls (P < .05) and significantly more-severe hyperintensity ratings only in subcortical gray matter (P < .05) than did hypertensive controls. Hypertensive controls had significantly more-severe ratings in deep white matter than either normotensive group (P < .05). CONCLUSIONS: Findings suggest a relationship between deep white matter hyperintensities and hypertension (regardless of depressive state), and a particular role of subcortical gray matter hyperintensities (possibly interacting with more-severe deep white matter lesions) in older depressed hypertensives, as compared with older depressed normotensives of similar ages and severity of depression. These data support possible heterogeneous pathogenic contributions in late-life depression subgroups, one of which appears to be influenced by cerebrovascular disease.

Analysis of Variance↗
PubMed2001

Recovery from poststroke urinary incontinence: associated factors and impact on outcome.

OBJECTIVES: To determine factors associated with recovery from poststroke urinary incontinence and to estimate the impact of this recovery on stroke outcome at 3 months. DESIGN: Prospective, observational study. SETTING: Population-based stroke register. PARTICIPANTS: Three hundred twenty-four incident cases of stroke with incontinence 1 week poststroke were identified from the register between January 1, 1995, and December 31, 1998. MEASUREMENTS: At 3 months, 105 patients were dead and 12 were lost to follow-up. The remaining patients were classified by continence status; those who had regained continence (n = 127) were compared with those who remained incontinent (n = 80) in terms of demographic details, stroke risk factors, premorbid disability, neurological impairments, and Oxfordshire Community Stroke Project stroke subtypes. Data at 3 months included disability using the modified Barthel Index (BI) (without its urinary continence component) and the Frenchay Activity Index (FAI), and institutionalization. RESULTS: Multivariate analysis showed being age 75 and older (odds ratio (OR) = 0.38; 95% confidence interval (CI) = 0.17-0.83) was associated with poor recovery from incontinence. Compared with subjects with total anterior circulatory infarctions, those with lacunar infarctions were more likely to regain continence (OR = 3.66; 95% CI =1.10-12.2), and compared with subjects with a BI between 0 and 14, those with a BI between 15 and 18 were also more likely to regain continence (OR = 21.8; 95% CI = 5.95-79.7). At 3 months, the incontinent group had greater institutionalization rates (27 (34%) vs 9 (7%), P <.001) and worse disability, measured with BI and FAI (BI: P <.001, FAI: P =.002). CONCLUSIONS: Age 75 and older is independently associated with poor recovery from poststroke urinary incontinence. Further clinical trials are required to explore underlying mechanisms and efficacy of possible interventions for this group of stroke survivors. Recovery from poststroke urinary incontinence should be a major goal of stroke professionals because it is associated with lower institutionalization rates and less disability at 3 months.

Aged↗
PubMed2001

Myocardial protection during ventricular fibrillation by reduction of proton-driven sarcolemmal sodium influx.

Although the inhibition of proton-driven sarcolemmal sodium influx ameliorates ischemic injury in the quiescent myocardium, the effects when ventricular fibrillation is present are largely unknown. We used an isolated rat heart model to investigate whether inhibition of the sodium-hydrogen exchanger isoform-1 (with the benzoylguanidine derivatives HOE-694 and cariporide) with or without concomitant inhibition of the sodium-bicarbonate co-transporter (with perfusate buffered with N-2-hydroxyethylpiperazine-N-2-ethanesulfonic acid [HEPES]) during ischemia and ventricular fibrillation could ameliorate functional myocardial abnormalities presumed to limit cardiac resuscitability. Ischemic contracture, which typically develops during ventricular fibrillation, was ameliorated by HOE-694 when either a bicarbonate-buffered (20 +/- 7 mm Hg vs 15 +/- 5 mm Hg, P <.05) or a HEPES-buffered (14 +/- 5 mm Hg vs 10 +/- 3 mm Hg, P <.04) perfusate was used. Maximal amelioration occurred when cariporide and HEPES-buffered perfusate were used simultaneously (25 +/- 14 mm Hg vs 11 +/- 3 mm Hg, P <.01), and this was accompanied by lesser leftward shifts of the end-diastolic pressure-volume curves after defibrillation. Intramyocardial sodium increases of 76% during ischemia and ventricular fibrillation (P <.05) were ameliorated by the sodium-influx-limiting interventions. Thus interventions limiting sarcolemmal sodium influx during ischemia and ventricular fibrillation may facilitate successful resuscitation from ventricular fibrillation.

Animals↗