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Biomedical subjects

M Scott

Publications and source records attributed to M Scott.

At least 235 records · Page 13Linked to original sources
PubMed1992

Hemodynamic effects of different temporary pacing modes for the management of bradycardias complicating acute myocardial infarction.

Twelve patients requiring temporary pacing following acute myocardial infarction (AMI) (10 heart block, 2 junctional bradycardia) had hemodynamic measurements taken with ventricular demand pacing at 80 ppm (VVI80), ventricular demand pacing at the atrial rate (VVIa), physiological pacing (DDD), and spontaneous (intrinsic) rhythm. VVI80 mode did not improve any hemodynamic parameter compared with spontaneous rhythm. VVIa mode improved diastolic and mean arterial pressures only. DDD mode improved most hemodynamic parameters compared with spontaneous rhythm (cardiac output by 29% [P less than 0.0001]; blood pressure: diastolic by 24% [P less than 0.01], systolic by 19% [P less than 0.01], mean by 21% [P less than 0.005]; pulmonary wedge pressure by 10% [P = 0.057] and right atrial pressure by 24% [P less than 0.005]) and also significantly improved some parameters compared with VVIa (cardiac output by 20% [P less than 0.001], systolic blood pressure by 11% [P less than 0.01] and right atrial pressure by 15% [P less than 0.01]). Physiological pacing is hemodynamically superior both to ventricular pacing and spontaneous rhythm for patients requiring temporary pacing following AMI. Ventricular pacing at 80 ppm has little hemodynamic advantage over spontaneous rhythm.

Adult↗
PubMed1992

Attempts to convert the cellular prion protein into the scrapie isoform in cell-free systems.

The scrapie prion protein (PrPSc) is derived from a cellular isoform (PrPC) that acquires protease resistance posttranslationally. We have used several different experimental approaches in attempts to reconstitute in vitro the processes leading to protease-resistant PrPSc molecules. In the first study, we performed mixing experiments by adding mouse PrP 27-30 (MoPrP27-30), the protease-resistant core of PrPSc, to PrPC and then incubating the mixture to investigate the possibility of heterodimer formation as a first step in prion replication. We used epitopically tagged PrP molecules, synthesized in murine neuroblastoma (N2a) cells transfected with the chimeric mouse/Syrian hamster MHM2 PrP construct, which are recognized by the Syrian hamster-specific monoclonal antibody 3F4. After as long as 24 h of incubation, the reaction mixture was assayed for heterodimeric intermediates of MHM2 PrPC and MoPrPSc and for protease-resistant 3F4-reactive PrP. We were unable to identify any aggregates of MHM2 PrPC and MoPrPSc on immunoblots; furthermore, we did not observe de novo formation of protease-resistant MHM2 PrP. In a second study, MoPrPC was metabolically radiolabeled in scrapie prion-infected N2a cultured cells, and then the cell extract was homogenized and incubated under various conditions to allow for the formation of protease-resistant MoPrPSc. We observed no radiolabeled MoPrPSc by immunoprecipitation after as long as 24 h of in vitro incubation. In a third approach, Syrian hamster PrP (SHaPrP) was synthesized in a cell-free translation system supplemented with microsomal membranes derived from either normal or scrapie prion-infected cultured cells. We found that all SHaPrP species translocated across microsomal membranes from scrapie prion-infected cells were protease sensitive in the presence of detergents and displayed the same topology as those generated by microsomes from normal cells or from dog pancreas. We also studied PrP molecules that encode the codon 102 mutation that causes the rare human prion disease Gerstmann-Sträussler-Scheinker (GSS) syndrome. On the basis of our data, GSSPrP appears to yield topological forms similar to those of the wild-type PrP when processed by either normal or scrapie prion-derived microsomes.

Animals↗
PubMed1992

Detection of subclinical autonomic neuropathy in constipated patients using a sweat test.

Chronic idiopathic constipation may be the result of an autonomic neuropathy. This hypothesis was tested in 23 constipated patients and 17 age matched controls, using the acetylcholine sweat spot test devised to test autonomic integrity in diabetes. Acetylcholine (0.01%) was injected in the dorsum of the foot painted with a mixture of starch and iodine. Active sweat glands appeared on the surface of the skin as small black dots which were photographed and counted, using a grid with 60 subareas. Two measurements were made: the number of dots per unit subarea (sweat spot test score) and the % number of abnormal subareas (with less than six spots). These two parameters were correlated. The median sweat spot test score was 9.53 in patients and 13.92 in controls (p = 0.0001), the receiver operating characteristic curve showing that a score of 12 delimited normal and abnormal subjects. Increasing age was correlated with a low score in patients, probably because of prolonged symptoms. Seventy per cent of patients and one control had a borderline or abnormal number of subareas. These results suggest that idiopathic constipation is associated with a degree of autonomic denervation. The sweat spot test is an easy, inexpensive method to test this hypothesis and deserves a place in the clinical assessment of slow transit constipated patients.

Acetylcholine↗
PubMed1992

In vivo measurements of lead in bone at four anatomical sites: long term occupational and consequent endogenous exposure.

Measurements of bone lead concentrations in the tibia, wrist, sternum, and calcaneus were performed in vivo by x ray fluorescence on active and retired lead workers from two acid battery factories, office personnel in the two factories under study, and control subjects. Altogether 171 persons were included. Lead concentrations in the tibia and ulna (representative of cortical bone) appeared to behave similarly with respect to time but the ulnar measurement was much less precise. In an analogous fashion, lead in the calcaneus and sternum (representative of trabecular bone) behaved in the same way, but sternal measurement was less precise. Groups occupationally exposed to lead were well separated from the office workers and the controls on the basis of calculated skeletal lead burdens, whereas the differences in blood lead concentrations were not as great, suggesting that the use of concentrations of lead in blood might seriously underestimate lead body burden. The exposures encountered in the study were modest, however. The mean blood lead value among active lead workers was 1.45 mumol l-1 and the mean tibial lead concentration 21.1 micrograms (g bone mineral)-1. The kinetics of lead in the tibia appeared to be noticeably different from that in the calcaneus. Tibial lead concentration increased consistently both as a function of intensity of exposure and of duration of exposure. Calcaneal lead concentration, by contrast, was strongly dependent on the intensity rather than duration of exposure. This indicated that the biological half life of lead in calcaneus was less than the seven to eight year periods into which the duration of exposure was split. Findings for retired workers clearly showed that endogenous exposure to lead arising from skeletal burdens accumulated over a working lifetime can easily produce the dominant contribution to systemic lead concentrations once occupational exposure has ceased.

Adult↗
PubMed1992

Fractionation of urine to allow desmosine analysis by radioimmunoassay.

The present study was designed to re-evaluate the radioimmunoassay for desmosine in urine, which is currently used as a measure of elastin metabolism. Using ion exchange chromatography, gel filtration and affinity chromatography it was shown that at least five other compounds in hydrolysates of human urine competed for desmosine in the RIA. Fractionating the urine prior to hydrolysis with acetone removed one of the major contaminants. The other contaminants could subsequently be removed by extracting the urine hydrolysate with a mixture of chloroform/ethanol (60:40). Samples from nine normal adult urines showed that an average of 45% of the RIA competing material in unfractionated urine was not desmosine. The final extracted residue retained all of the desmosine and only 16% of the original solids. The average adult urine contains approximately 50 pmol desmosine/mg creatinine, reflecting a daily turnover of between 3 and 4 mg of elastin per day.

Chemical Fractionation↗
PubMed1991

Epitope mapping of the Syrian hamster prion protein utilizing chimeric and mutant genes in a vaccinia virus expression system.

The cellular prion protein (PrPc) is a host-encoded sialoglycoprotein bound to the external surface of the cell membrane by a glycosyl phosphatidylinositol anchor. A posttranslationally modified PrP isoform (PrPSc) is a component of the infectious particle causing scrapie and the other prion diseases. mAb have been raised against the protease-resistant core of Syrian hamster (SHa) PrPSc designated PrP 27-30. To map the epitopes within PrP reacting to these antibodies, we have expressed wild-type, chimeric mouse (Mo)/SHa and mutant MoPrP genes using recombinant vaccinia virus systems. The fidelity of the expression of recombinant PrPC was examined using vaccinia viruses expressing SHa-PrPC. It is full length, possesses Asn-linked carbohydrates and is attached to the external surface of the cell membrane by a glycosyl phosphatidylinositol anchor that is sensitive to cleavage by phosphatidylinositol-specific phospholipase C. We have tested 18 mAb for their ability to bind to chimeric prion proteins on immunoblots. Three distinct epitopes were identified that mapped to amino acid differences between SHa and MoPrP sequences. The first epitope, recognized by three of the antibodies tested, was defined by methionines at amino acids 108 and 111 in the mouse protein. The second epitope was dependent upon the presence of asparagines at positions 154 and 174 in MoPrP and was recognized by four of the antibodies tested. The third epitope mapped to a single amino acid substitution at residue 138 in MoPrP. mAb raised against SHaPrP 27-30 specific for this epitope are able to bind MoPrPC which has a single amino acid change (Ile to Met) at position 138. Eleven of the 18 antibodies tested mapped to this immunodominant epitope. It is located within a postulated amphipathic helix, a structure associated with immunodominant Ag. Inasmuch as PrPC, in its native form on the cell surface, is detected by the mAb 13A5 (a prototypic antibody of the immunodominant third epitope class), it is likely that this epitope is accessible in the native conformation of this protein.

Animals↗
PubMed1991

Comparison of effects of thrombolytic therapy on left ventricular function in patients over with those under 60 years of age.

This study examined the effect of age on left ventricular (LV) function, assessed by contrast ventriculography 3 weeks after a first acute myocardial infarction in 312 patients who received thrombolytic therapy within 4 hours of the onset of infarction and in 83 patients who received placebo. Streptokinase was given to 188 patients and recombinant tissue-type plasminogen activator (rt-PA) to 124. Patients were divided into 2 age groups: less than 60 years (n = 244) and greater than or equal to 60 years (n = 151). Thrombolytic therapy improved ejection fraction in both age groups: from 54 +/- 13 to 59 +/- 11% (p = 0.021) in the younger group and from 50 +/- 14 to 57 +/- 13% (p = 0.004) in the older group. Ejection fraction was identical in streptokinase- and rt-PA-treated patients. Multifactor analysis of variance revealed that younger age and thrombolytic therapy were independently associated with improved ejection fraction. Thrombolytic therapy also reduced end-systolic volume (p = 0.001) by 14 ml in the elderly and 9 ml in the younger group. Minor bleeding complications were more frequent in the elderly and 3 serious hemorrhages occurred in patients greater than or equal to 60 years. These findings reveal that thrombolysis improves LV function in all age groups studied. Because increasing age is independently associated with a lower ejection fraction after acute myocardial infarction, thrombolytic therapy may confer greater benefits in older patients.

Age Factors↗
PubMed1991

A comparison of Zoladex and DES in the treatment of advanced prostate cancer: results of a randomized, multicenter trial.

This open, prospective study was conducted to compare ZOLADEX (goserelin acetate implant) and diethylstilbestrol (DES) in the treatment of stage D2 prostate cancer. Sixty-seven patients were allocated to receive 3.6 mg of ZOLADEX every 28 days by subcutaneous injection (n = 48) or 3 mg of DES daily by oral administration (n = 19). Median serum levels of testosterone were reduced to castrate levels (less than 50 ng/dl) within one month of therapy in each group and remained so for up to 120 weeks. According to modified criteria of the National Prostatic Cancer Project, 88% of patients in the ZOLADEX group and 84% in the DES group were objective responders. Time to treatment failure and survival were not significantly different between groups, yet the confidence limits for the hazard ratios were wide. ZOLADEX was better tolerated than DES. We conclude that ZOLADEX is an alternative to DES in patients with stage D2 prostate cancer.

Aged↗
PubMed1991

Sample size and dimensionality in multivariate classification: implications for body surface potential mapping.

This paper presents empirically determined guidelines for specifying the number of features appropriate for multivariate classification studies for given sample sizes. Sample size was considered adequate if the mean distance between two sample sets, taken from the same continuous multivariate distribution and projected onto the best separating direction, remained below a prescribed level. To quantitate the sample size requirement, homogeneity of sample set pairs of equal size. N, taken from the same continuous multivariate distribution was studied as a function of dimensionality. M. Homogeneity was characterized by the maximum absolute distances (Dmax) between the corresponding pairs of empirical cumulative probability distributions on the best separating projection. Computer generated data sets were used to estimate the cumulative probability distribution, P(D)M.N, for sample sizes, N, ranging from 5 to 100 and the dimensionality, M, ranging from 1 to 4. An empirical relationship between the estimated step-polygons and the Kolmogorov type one dimensional limiting distribution L(z) has been established. Based on the sample size data of 34 key papers on clinical body surface potential mapping (BSPM) it is noted that in 30% of the cases only one, and in 6% of the cases only two parameters could be used for statistical group representation to ensure a reasonable reliability (Dmax less than 0.2). In 56% of the published cases the sample sizes could not guarantee this reliability even for one feature or parameter.

Computer Simulation↗
PubMed1991

Zoladex versus orchiectomy in treatment of advanced prostate cancer: a randomized trial. Zoladex Prostate Study Group.

We report preliminary results for the first 164 patients enrolled in a multicenter study comparing the endocrine effects, efficacy, and safety of 3.6 mg of goserelin acetate (Zoladex) and orchiectomy in patients with Stage D2 prostate cancer. Eighty-one patients were randomly allocated to receive Zoladex and 83 to orchiectomy. The median follow-up time for all patients was two hundred ten days. Median serum levels of testosterone were reduced to castrate levels (less than 50 ng/dL) within four weeks in both groups and remained suppressed for up to sixty weeks. An objective response according to modified criteria of the National Prostatic Cancer Project was observed in 81 percent and 78 percent of patients in the Zoladex and orchiectomy groups, respectively. There were no statistically significant differences between treatment groups in the distributions of time to treatment failure or time to disease progression. The most commonly reported adverse events in both treatment groups were hot flashes, cancer-related pain, unspecified pain, and urinary symptoms. These results suggest that Zoladex may offer an alternative to orchiectomy in the treatment of advanced prostate cancer.

Acid Phosphatase↗
PubMed1991

Paradoxical shortening of scrapie incubation times by expression of prion protein transgenes derived from long incubation period mice.

Prolonged incubation times for experimental scrapie in I/LnJ mice are dictated by a dominant gene linked to the prion protein gene (Prn-p). Transgenic mice were analyzed to discriminate between an effect of the I/LnJ Prn-pb allele and a distinct incubation time locus designated Prn-i. Paradoxically, 4 independent Prn-pb transgenic mouse lines had scrapie incubation times shorter than nontransgenic controls, instead of the anticipated prolonged incubation periods. Aberrant or overexpression of the Prn-pb transgenes may dictate abbreviated incubation times, masking genuine Prn-p/Prn-i congruence; alternatively, a discrete Prn-i gene lies adjacent to Prn-p.

Animals↗
PubMed1991

Biofilm and scleral buckle-associated infections. A mechanism for persistence.

Scleral buckle infections tend to be persistent as well as resistant to antimicrobial treatment. Often, scleral buckle infections require removal of the buckling elements for resolution. To determine if bacteria are able to persist on scleral buckles by elaborating a glycocalyx matrix or biofilm that offers protection against host defenses and antimicrobial treatment, the authors cultured 28 scleral buckle elements removed for infection and extrusion. Bacteria were isolated from 18 elements (64%). The most frequently isolated bacteria were Staphylococcus epidermidis and other coagulase-negative staphylococci (8), Staphylococcus aureus (3), corynebacteria (3), Mycobacterium chelonei (3), and Proteus mirabilis (3). Eleven (65%) of 17 buckles evaluated with scanning electron microscopy demonstrated the presence of bacteria encased in biofilm. Biofilm was demonstrated on the surfaces and ends of solid silicon elements. In the silicon sponges, biofilm also extended into the matrix of the sponges. The authors believe that bacterial production of biofilm offers an explanation for the persistence of scleral buckle infections and their ability to withstand antimicrobial treatment.

Adult↗
PubMed1991

Spontaneous neurodegeneration in transgenic mice with prion protein codon 101 proline----leucine substitution.

Gerstmann-Sträussler-Scheinker syndrome (GSS) is an autosomal, dominantly inherited, human neurodegenerative disease that can sometimes be transmitted to non-human primates and rodents through intracerebral inoculation of brain homogenates from patients. Recent studies of GSS demonstrated significant genetic linkage between GSS and a leucine substitution at codon 102 of the human prion protein (PrP) gene. Transgenic mice were created to test the biologic activity of this mutation. Spontaneous neurologic disease with spongiform degeneration developed in one of three lines of transgenic mice containing murine PrP genes with a leucine substitution at codon 101 (homologous to codon 102 in humans). Transmission studies of brain homogenates from affected mice are in progress. These results indicate that some of the clinical and pathologic features of GSS can be reproduced in a transgenic mouse paradigm; this represents the first time a dominantly inherited, neurodegenerative process similar to a human disease has been genetically modeled in an experimental animal (Hsiao and Prusiner 1990).

Amino Acid Sequence↗
PubMed1991

Use of in vitro clonogenic assays to differentiate acquired from genetic causes of insulin resistance.

Insulin resistance may be due directly to genetically programmed disorders of insulin action or acquired defects in which environmental factors influence insulin action. To address the issue of this distinction, we studied the ability of insulin to stimulate colony formation in primary cultures of erythroid progenitors (assumed to retain environmental influences) and immortalized T lymphocytes (presumed to reflect only genetic influences). Four patients with hyperinsulinemia and disturbed glucose metabolism were studied (2 patients with acanthosis nigricans, 1 of whom had circulating anti-insulin-receptor antibodies, 1 with partial lipodystrophy, and 1 with Cushing's syndrome). The mean colony-forming ability of their erythroid progenitor cells in response to insulin stimulation (less than or equal to 1.6 pM) was significantly blunted compared with control cells (P less than 0.05). The mean responsiveness of their immortalized T-lymphoblast cell lines to similar insulin concentrations was no different than that of control T-lymphocyte lines, consistent with an acquired cause for the observed insulin resistance in each case. A T-lymphocyte line from a patient with leprechaunism, however, showed no stimulation in response to physiological concentrations of insulin. With these same in vitro methodologies, there was normal T-lymphocyte line responsiveness to insulinlike growth factor I (IGF-I) or insulin concentrations greater than 8.6 pM; both of these responses could be completely blocked by preincubation with an antibody to the IGF-I receptor. These findings suggest that, despite resistance to physiological levels of insulin, the high circulating insulin concentrations present in the serum of these patients could mediate unwanted tissue-specific growth through an intact IGF-I receptor-effector mechanism.

Acanthosis Nigricans↗
PubMed1991

The effects of increase testicular temperature on spermatogenesis in the stallion.

Stallions can experience an increase in testicular temperature from bouts of fever or from injury to the testes. In species other than the horse, increased temperature models have been used to study testicular degeneration. This study was undertaken to examine the effects of increased testicular temperature on spermatogenesis in the stallion as measured by semen evaluation. The results of this investigation demonstrate that increased testicular temperature is associated with significant transitory alterations in the routine semen evaluation of the stallion. The duration of increased testicular temperature affected the degree of change observed. The temporal nature and degree of the change in the semen evaluation is described. Predictive formulae for expected changes in the semen evaluation have been derived.

Animals↗
PubMed1991

Determination of product shelf life and activation energy for five drugs of abuse.

Estimating the shelf life of reagents and controls is a critical step in evaluating new formulations. We describe several stability assessment techniques, giving particular attention to experimental design. Activation energy was experimentally determined for five major drugs of abuse and metabolites: morphine, 11-nor-delta-9-tetrahydrocannabinol-9-carboxylic acid, amphetamine, phencyclidine, and benzoylecgonine. The use of activation energy in establishing shelf life is illustrated for SENTRY (Hycor Biomedical Inc.) Drugs of Abuse Screen Control, a liquid urine-based product.

Drug Stability↗