Showing papers by "University of Texas Health Science Center at Houston published in 1993"

Statistical tests of neutrality of mutations

Abstract: Mutations in the genealogy of the sequences in a random sample from a population can be classified as external and internal. External mutations are mutations that occurred in the external branches and internal mutations are mutations that occurred in the internal branches of the genealogy. Under the assumption of selective neutrality, the expected number of external mutations is equal to theta = 4Ne mu, where Ne is the effective population size and mu is the rate of mutation per gene per generation. Interestingly, this expectation is independent of the sample size. The number of external mutations is likely to deviate from its neutral expectation when there is selection while the number of internal mutations is less affected by the presence of selection. Statistical properties of the numbers of external mutations and of internal mutations are studied and their relationships to two commonly used estimates of theta are derived. From these properties, several new statistical tests based on a random sample of DNA sequences from the population are developed for testing the hypothesis that all mutations at a locus are neutral.

Incidence of Epilepsy and Unprovoked Seizures in Rochester, Minnesota: 1935–1984

Abstract: The incidence of epilepsy and of all unprovoked seizures was determined for residents of Rochester, Minnesota U.S.A. from 1935 through 1984. Age-adjusted incidence of epilepsy was 44 per 100,000 person-years. Incidence in males was significantly higher than in females and was high in the first year of life but highest in persons aged > or = 75 years. Sixty percent of new cases had epilepsy manifested by partial seizures, and two thirds had no clearly identified antecedent. Cerebrovascular disease was the most commonly identified antecedent, accounting for 11% of cases. Neurologic deficits from birth, mental retardation and/or cerebral palsy, observed in 8% of cases, was the next most frequently identified preexisting condition. The cumulative incidence of epilepsy through age 74 years was 3.1%. The age-adjusted incidence of all unprovoked seizures was 61 per 100,000 person-years. Age- and gender-specific incidence trends were similar to those of epilepsy, but a higher proportion of cases was of unknown etiology and was characterized by generalized onset seizures. The cumulative incidence of all unprovoked seizures was 4.1% through age 74 years. With time, the incidence of epilepsy and of unprovoked seizures decreased in children and increased in the elderly.

Muscle deficiency and neonatal death in mice with a targeted mutation in the myogenin gene

Abstract: Myogenin is a muscle-specific transcription factor that can induce myogenesis in a variety of cell types in tissue culture. To test myogenin's role in vivo, mice homozygous for a targeted mutation in the myogenin gene were generated. These mice survive fetal development but die immediately after birth and show a severe reduction of all skeletal muscle. Myogenin-mutant mice differ from mice carrying mutations in genes for the related myogenic factors Myf5 and MyoD, which have no muscle defects. Myogenin is therefore essential for the development of functional skeletal muscle.

Unbiased estimation of the rates of synonymous and nonsynonymous substitution

Abstract: The current convention in estimating the number of substitutions per synonymous site (K S ) and per nonsynonymous site (K A ) between two protein-coding genes is to count each twofold degenerate site as one-third synonymous and two-thirds nonsynonymous because one of the three possible changes at such a site is synonymous and the other two are nonsynonymous. This counting rule can considerably overestimate theK S value because transitional mutations tend to occur more often than transversional mutations and because most transitional mutations at twofold degenerate sites are synonymous. A new method that gives unbiased estimates is proposed. An application of the new and the old method to 14 pairs of mouse and rat genes shows that the new method gives aK S value very close to the number of substitutions per fourfold degenerate site whereas the old method gives a value 30% higher. Both methods give aK A value close to the number of substitutions per nondegenerate site.

Association of Hormone-Replacement Therapy with Various Cardiovascular Risk Factors in Postmenopausal Women

Abstract: Background Most epidemiologic studies of cardiovascular disease in postmenopausal women suggest that estrogen-replacement therapy has a protective effect. The effects of the use of estrogen combined with progestin are less well studied. Methods To examine the associations of hormone-replacement therapy with concentrations of plasma lipids and hemostatic factors, fasting serum concentrations of glucose and insulin, and blood pressure, we studied 4958 postmenopausal women participating in a population-based investigation. Using cross-sectional data, we classified the women into four groups according to their use of hormone-replacement therapy: current users of estrogen alone, current users of estrogen with progestin, nonusers who had formerly used these hormones, and nonusers who had never used them. Results Current users had higher mean levels of high-density lipoprotein cholesterol, its subfractions high-density lipoprotein2 and high-density lipoprotein3, and apolipoprotein A-I than nonusers, and lower me...

A Phase II Study of Moderate Hypothermia in Severe Brain Injury

Abstract: Forty-six patients with severe nonpenetrating brain injury [Glasgow Coma Scale (GCS) 4–7] were randomized to standard management at 37°C (n = 22) and to standard management with systemic hypothermia to 32 to 33°C (n = 24). The two groups were balanced in terms of age (Wilcoxon's rank sum test, p > 0.95), randomizing GCS (chi-square test, p = 0.54), and primary diagnosis. Cooling was begun within 6 h of injury by use of cooling blankets. Metocurine and morphine were given hourly during induction and maintenance of hypothermia. Rewarming was at a rate of 1°C per 4 h beginning 48 h after intravascular temperature had reached 33°C. Muscle relaxants and sedation were continued until core temperature reached 35°C. There were no cardiac or coagulopathy-related complications. Seizure incidence was lower in the hypothermia group (Fisher's exact text, p = 0.019). Sepsis was seen more commonly in the hypthermia group, but difference was not statistically significant (chi-square test). Mean Glasgow Outcome S...

Cerebellar cortex lesions disrupt learning-dependent timing of conditioned eyelid responses

Abstract: Among the many issues surrounding the involvement of the cerebellum in motor learning, the relative roles of the cerebellar cortex and cerebellar nuclei in Pavlovian conditioning have been particularly difficult to assess. While previous studies have investigated the effects of cerebellar cortex lesions on the acquisition and retention of conditioned movements, we have examined the effects of these lesions on the timing of Pavlovian eyelid responses. The rationale for this approach arises from previous studies indicating that this timing is a component of Pavlovian eyelid responses that is learned and that involves temporal discrimination. To permit within-animal comparisons, rabbits were trained to produce differently timed responses to high- and low-frequency auditory conditioned stimuli (CSs). Before the lesion the conditioned responses to both CSs were appropriately timed--each peaked near the time at which the unconditioned stimulus was presented for that CS. However, after the lesion both CSs could elicit similarly timed conditioned responses that peaked inappropriately at very short latencies. The changes in responses timing were sensitive to the size of the lesion, particularly its rostral-caudal extent. Similar results were obtained in animals trained with one CS, indicating that the disruption of response timing is not related to impaired auditory discrimination. Because response timing is learned and therefore requires synaptic plasticity, these data suggest that there are at least two sites of plasticity involved in the motor expression of Pavlovian eyelid responses. Plasticity at one site is necessary for the learned timing of conditioned responses, while plasticity at another site is revealed by the inappropriately timed responses observed following removal of the cerebellar cortex. This lesion-induced dissociation of the expression of motor responses and their learned timing supports a synthesis of competing views by suggesting that motor learning involves both the cerebellar cortex and cerebellar nuclei. We hypothesize that motor learning involves a decrease in strength of the granule cell-Purkinje cell synapses (e.g., Ito and Kano, 1982) in the cerebellar cortex and an increase in strength of the mossy fiber-cerebellar nuclei synapses (e.g., Racine et al., 1986). Finally, these data suggest that the cerebellar cortex may mediate the temporal discriminations that are necessary for the learned timing of conditioned responses.

Reversal of left-right asymmetry : a situs inversus mutation

Abstract: A recessive mutation was identified in a family of transgenic mice that resulted in a reversal of left-right polarity (situs inversus) in 100 percent of the homozygous transgenic mice tested. Sequences that flanked the transgenic integration site were cloned and mapped to mouse chromosome 4, between the Tsha and Hxb loci. During early embryonic development, the direction of postimplantation turning, one of the earliest manifestations of left-right asymmetry, was reversed in homozygous transgenic embryos. This insertional mutation identifies a gene that controls embryonic turning and visceral left-right polarity.

Increase in activity and level of pp60c-src in progressive stages of human colorectal cancer

Abstract: Activation of the tyrosine kinase of the c-src gene product, pp60c-src, has been shown to occur in nearly every primary colorectal carcinoma, and is found as early as in polyps of high malignant potential. However, no studies have addressed potential pp60c-src changes which occur during progression. To examine this question, we have studied kinase activity and protein levels in 7 colonic polyps, 19 primary lesions, and 19 liver metastases relative to normal colonic mucosa. Significant increases in tyrosine kinase activity were seen as early as in colonic polyps of high malignant potential. Further increases were observed in activity and level in primary tumors. However, the greatest increases in activity and protein levels were observed in liver metastases. Additionally, six metastatic lesions were obtained in which synchronous primary tumor was resected. In each of these liver metastases, pp60c-src activity and level were significantly increased relative to the corresponding primary tumor, as well as to normal colonic mucosa. Our results demonstrate that progression of colon primary tumors to liver metastases correlates with increased pp60c-src kinase activity and protein level.

Nosocomial outbreak due to Enterococcus faecium highly resistant to vancomycin, penicillin, and gentamicin.

Abstract: In October 1990, Enterococcus faecium that was highly resistant to glycopeptides, penicillins, and aminoglycosides was isolated from the peritoneal dialysis fluid from a patient in an intensive care unit. Over the following 6 months, multiresistant E. faecium organisms were isolated from cultures of blood, urine, or surgical wound specimens from eight additional patients. Surveillance cultures of groin and/or rectal swabs were positive for eight of 37 patients and four of 62 employees at risk. Restriction endonuclease digestion of chromosomal DNA from outbreak isolates was consistent with dissemination of a single strain throughout the intensive care unit. Strict infection control interventions contained the outbreak after several weeks. Review of patient charts suggested that renal insufficiency, length of hospital stay, duration of antibiotic treatment, and prior treatment with vancomycin were risks for infection due to multiresistant E. faecium. The emergence of multiple-drug-resistant enterococci presents serious infection control and therapeutic dilemmas.

Comparison of low-dose isotretinoin with beta carotene to prevent oral carcinogenesis

Abstract: Background High-dose isotretinoin therapy has been determined to be an effective treatment for leukoplakia. However, a high rate of relapses and toxic reactions led us to conduct a trial of a much lower dose of isotretinoin in the hope of maintaining a response and limiting toxicity. Methods In the first phase of the study, 70 patients with leukoplakia underwent induction therapy with a high dose of isotretinoin (1.5 mg per kilogram of body weight per day) for three months; in the second phase, patients with responses or stable lesions were randomly assigned to maintenance therapy with either beta carotene (30 mg per day) or a low dose of isotretinoin (0.5 mg per kilogram per day) for nine months. Results In the first phase, the rate of response to high-dose induction therapy in the 66 patients who could be evaluated was 55 percent (36 patients). The lesions of seven patients progressed, and therefore they did not participate in the second phase of the trial. Of the 59 patients included in the second phas...

Apoptosis and necrosis. Basic types and mechanisms of cell death.

Abstract: Apoptosis and necrosis are two fundamental types of cell death. Current knowledge indicates that the key mechanism of apoptosis is endonuclease activation leading to internucleosomal double-stranded chromatin (DNA) breaks, whereas the key mechanism of necrosis is cell membrane damage. The initial alterations of cellular metabolism and electrolyte homeostasis induced by an injurious agent may activate at least four major pathways leading to loss of membrane integrity: membrane phospholipid degradation, production of amphipathic lipids, damage to the cytoskeleton, and generation of toxic oxygen species and free radicals. These insights point the way for further research to establish definitive causes of specific types of cell injury and cell death, and they provide important clues for the design of improved diagnostic approaches and therapeutic interventions.

Fludarabine potentiates metabolism of cytarabine in patients with acute myelogenous leukemia during therapy.

Abstract: Purpose A protocol was designed to test the hypothesis that fludarabine infusion before arabinosylcytosine (cytarabine [ara-C]) would increase the accumulation of the active metabolite ara-C triphosphate (ara-CTP) in acute myelogenous leukemia (AML) blasts during therapy. Patients and methods Patients (n = 5) received 1 g/m2 of ara-C infused intravenously (IV) for 2 hours, followed at 20 hours by 30 mg/m2 of fludarabine for 30 minutes. At 24 hours, another identical dose of ara-C was infused. To determine the optimal duration of ara-C infusion following fludarabine, five additional patients were treated on an amended protocol in which the ara-C infusion was extended to 3 g/m2 infused over 6 hours. Results Comparison of ara-CTP pharmacokinetics in circulating AML cells demonstrated that the area under the curve (AUC) of ara-CTP increased significantly (median, 1.8-fold; range, 1.6 to 2.4; P = .004) after fludarabine infusion. Neither the median plasma ara-C concentrations, the levels of its deamination product arabinosyluracil, nor the rate of ara-CTP elimination from circulating blasts was affected by fludarabine infusion. However, the rate of ara-CTP accumulation by AML cells was increased by a median of 2.0-fold (range, 1.8 to 2.2; P = .001) after fludarabine; the peak occurred within 1 hour of the end of the infusion. In vitro incubation of these cells with arabinosyl-2-fluoroadenine (F-ara-A) before ara-C also produced a median 1.7-fold increase in the ara-CTP accumulation rate. Pharmacology studies in patients receiving 6-hour infusions of ara-C demonstrated that the rate of ara-CTP accumulation was potentiated beyond 2 hours, but not for 6 hours. Conclusion Infusion of fludarabine before ara-C augments the rate of ara-CTP synthesis in circulating AML blasts during therapy. Evaluation of 6-hour ara-C infusions demonstrated that potentiation of ara-CTP synthesis is maximal up to 4 hours in most patients; this pharmacologically optimized regimen should be considered for combination with other antileukemia drugs.

VNTR allele frequency distributions under the stepwise mutation model: a computer simulation approach.

Abstract: Variable numbers of tandem repeats (VNTRs) are a class of highly informative and widely dispersed genetic markers. Despite their wide application in biological science, little is known about their mutational mechanisms or population dynamics. The objective of this work was to investigate four summary measures of VNTR allele frequency distributions: number of alleles, number of modes, range in allele size and heterozygosity, using computer simulations of the one-step stepwise mutation model (SMM). We estimated these measures and their probability distributions for a wide range of mutation rates and compared the simulation results with predictions from analytical formulations of the one-step SMM. The average heterozygosity from the simulations agreed with the analytical expectation under the SMM. The average number of alleles, however, was larger in the simulations than the analytical expectation of the SMM. We then compared our simulation expectations with actual data reported in the literature. We used the sample size and observed heterozygosity to determine the expected value, 5th and 95th percentiles for the other three summary measures, allelic size range, number of modes and number of alleles. The loci analyzed were classified into three groups based on the size of the repeat unit: microsatellites (1-2 base pair (bp) repeat unit), short tandem repeats [(STR) 3-5 bp repeat unit], and minisatellites (15-70 bp repeat unit). In general, STR loci were most similar to the simulation results under the SMM for the three summary measures (number of alleles, number of modes and range in allele size), followed by the microsatellite loci and then by the minisatellite loci, which showed deviations in the direction of the infinite allele model (IAM). Based on these differences, we hypothesize that these three classes of loci are subject to different mutational forces.

Validation of 24-hour recalls assisted by food records in third-grade children

Abstract: Objective The objective of the study was to validate the use of 24-hour recalls assisted by food records as a dietary assessment tool for use with third-grade children. Design Trained staff observed children during mealtime at school, and parents observed and recorded what children ate in their presence. The following day children participated in a 24-hour recall interview. Children's ability to recall what they consumed during a 24-hour period was compared with observational data collected during the same period. Setting All data were collected in elementary school settings at four sites involved in the Child and Adolescent Trial for Cardiovascular Health. Subjects The sample of 49 children was self-selected, based on parents' willingness to observe and record their child's food intake. Main outcome measures Recalled and observed data for energy and nutrient levels were compared using mean energy and nutrient analysis and quartile classification. In addition, recalled and observed foods were compared by meal type and estimation of portion size. Statistical analysis performed Paired t tests, Pearson and Spearman correlations, and classification analysis were used to compare recalled and observed data. Results Comparison of observed and recalled food intakes showed no significant differences in percentage of energy from total fat, saturated fat, monounsaturated fat, and polyunsaturated fat or in the amount of sodium consumed, although there were differences in energy intakes. Spearman rank order correlations between recalled and observed nutrients ranged from .45 to .79. A 77.9% agreement was found across all meals in the food items children recalled having consumed compared with those adults actually observed them consuming. Conclusions We conclude that the 24-hour recall assisted by food records is a valid method for assessing the dietary intake of children as young as 8 years old for the purpose of group comparison.

A Comparison of Management Patterns after Acute Myocardial Infarction in Canada and the United States

Abstract: Background There are major differences in the organization of the health care systems in Canada and the United States. We hypothesized that these differences may be accompanied by differences in patient care. Methods To test our hypothesis, we compared the treatment patterns for patients with acute myocardial infarction in 19 Canadian and 93 United States hospitals participating in the Survival and Ventricular Enlargement (SAVE) study, which tested the effectiveness of captopril in this population of patients after a myocardial infarction. Results In Canada, 51 percent of the patients admitted to a participating coronary care unit had acute myocardial infarctions, as compared with only 35 percent in the United States (P<0.001). Despite the similar clinical characteristics of the 1573 U.S. patients and 658 Canadian patients participating in the study, coronary arteriography was more commonly performed in the United States than in Canada (in 68 percent vs. 35 percent, P<0.001), as were revascularization pro...

Selective lymphadenectomy: Emerging role for lymphatic mapping and sentinel node biopsy in the management of early stage melanoma

Abstract: The percentage of melanoma patients diagnosed at an early stage is increasing. Many of these patients, particularly those with primary tumors thicker than 1.5 mm, harbor occult metastases in regional nodes and are eligible for regional lymphadenectomy as part of their primary management. Until the results of recently completed prospective randomized trials are available the role for elective lymphadenectomy in terms of survival benefit remains a controversial issue. A new technique, intraoperative lymphatic mapping and sentinel node biopsy, has emerged as a simple way to determine whether or not metastatic disease is present. An intradermal injection of a vital blue dye at the site of the primary tumor allows identification of a "sentinel" node in the regional basin. A study of 237 patients was recently reported by Morton et al. (Arch Surg 127:392-399, 1992; Surg Oncol Clin North Am 1:247-259, 1992) demonstrating that the sentinel node can be readily identified > 80% of the time and that histologic examination of the node results in at least a 95% accuracy rate in staging the nodal basin for metastases. Our present series substantiates the results of the original study. An international multicenter trial has been proposed to further confirm the accuracy and universal feasibility of this technique. Acceptance of this technique will lead to a selective approach to regional lymphadenectomy, as only patients with proven micrometastases will undergo lymph node dissections. This approach should satisfy both the advocates and the opponents of elective regional lymphadenectomy.

A Retroviral Wild-type p53 Expression Vector Penetrates Human Lung Cancer Spheroids and Inhibits Growth by Inducing Apoptosis

Abstract: Multicellular tumor spheroids approximate the three-dimensional configuration of primary and metastatic tumors. The effects of retrovirus-mediated transduction of wild-type p53 (wt-p53) were studied on multicellular tumor spheroids of human non-small cell lung cancer cell lines H322a, the p53 gene of which is homozygously mutated at codon 248, and WT226b, which has endogenous wt-p53. The growth of WT226b spheroids was not affected by exogenous wt-p53 transduction; the growth of H322a spheroids, however, was significantly inhibited by the addition of wt-p53 virus stocks. Transduction of cells by the wt-p53 retroviral vector and penetration of multiple cell layers in H322a spheroids was demonstrated by in situ polymerase chain reaction/hybridization with the neomycin-resistant neo probe. Apoptotic changes indicating programmed cell death were observed in H322a spheroids treated with the wt-p53 virus. These results suggest that retroviral vectors can penetrate into multiple cell layers of three-dimensional tumor masses and induce potentially therapeutic effects.

A unified approach to study hypervariable polymorphisms: Statistical considerations of determining relatedness and population distances

Abstract: Relatedness between individuals as well as evolutionary relationships between populations can be studied by comparing genotypic similarities between individuals When hypervariable loci are used to describe genotypes, it is shown that both of these problems can be approached with a unified theory based on allele sharing between individuals The distributions of the number of shared alleles between individuals indicate their kin relationships Extending this, we obtain statistics for genetic distances between populations based on average number of alleles shared between individuals within and between two different populations

Cellular origin of cancer: dedifferentiation or stem cell maturation arrest?

Abstract: Given the fundamental principle that cancer must arise from a cell that has the potential to divide, two major nonexclusive hypotheses of the cellular origin of cancer are that malignancy arises a) from stem cells due to maturation arrest or b) from dedifferentiation of mature cells that retain the ability to proliferate. The role of stem cells in carcinogenesis is clearly demonstrated in teratocarcinomas. The malignant stem cells of teratocarcinomas are derived from normal multipotent stem cells and have the potential to differentiate into normal benign mature tissue. A widely studied model supporting dedifferentiation has been the putative origin of hepatocarcinomas from "premalignant" foci and nodules induced in the rat liver by chemicals. However, the dedifferentiation concept for hepatocarcinogenesis is challenged by more recent interpretations indicating that hepatocellular carcinoma arises from maturation arrest caused by aberrant differentiation of determined stem cells. Either hypothesis is supported by the cellular changes that occur in the rodent liver after different hepatocarcinogenic regimens. The formation of foci and nodules from altered hepatocytes supports dedifferentiation; the proliferation of small oval cells with the potential to differentiate into either biliary ducts or hepatocytes supports arrested maturation of determined stem cells. It is now postulated that foci and nodular change reflect adaptive changes to the toxic effects of carcinogens and not "preneoplastic" stages to cancer. The stem cell model predicts that genotoxic chemicals induce mutations in the determined stem cell which may be expressed in its progeny. Proliferation of initiated cells is induced by promoting events which also allow additional mutations to occur.

Male-driven evolution of DNA sequences.

Abstract: It is commonly believed that the mutation rate is much higher in the human male germ line than in the female germ line because the number of germ-cell divisions per generation is much larger in males than in females. But direct estimation of mutation rates is difficult, relying mainly on sex-linked genetic diseases, so the ratio (alpha m) of male to female mutation rates is not clear. It has been noted that if alpha m is very large, then the rate of synonymous substitution in X-linked genes should be only 2/3 of that in autosomal genes, and comparison of human and rodent genes supported this prediction. As the number of X-linked genes used in the study was small and the X-linked and autosomal sequences were non-homologous, and given that the synonymous rate varies among genes, we sequenced the last intron (approximately 1 kb) of the Y-linked and X-linked zinc-finger-protein genes (ZFY and ZFX) in humans, orang-utans, baboons and squirrel monkeys. The ratio Y/X of the substitution rate in the Y-linked intron to that in the X-linked intron is approximately 2.3, which is close to that estimated from synonymous rates in the ZFY and ZFX genes and implies alpha m approximately 6. This estimate of alpha m supports the view that the evolution of DNA sequences in higher primates is male-driven. It is, however, much lower than the previous estimate and therefore raises a number of issues.

Should hypertension be treated after acute stroke? A randomized controlled trial using single photon emission computed tomography

Abstract: • Objective. —To determine if previously hypertensive patients with acute ischemic stroke should be treated with antihypertensive medication in the immediate poststroke period. Design. —Randomized double-blind, placebo-controlled trial. Setting. —Acute-care teaching hospital. Patients. —Sixteen consecutive hypertensive patients (four men and 12 women; mean age, 66 years [age range, 46 to 83 years]) with middle cerebral artery infarction within 72 hours of onset and blood pressure between 170 and 220 mm Hg (systolic) and 95 and 120 mm Hg (diastolic). Intervention. —Placebo (n=6), nicardipine hydrochloride (20 mg [n=5]), captopril (12.5 mg [n=3]), or clonidine hydrochloride (0.1 mg [n=2]) given every 8 hours for 3 days. Main Outcome Measures. —Decline in blood pressure, change in cerebral blood flow as measured by single photon emission computed tomography, and clinical change as determined by the National Institutes of Health Stroke Scale. Results. —Blood pressure fell significantly in both the drug-treated group as a whole and in those patients receiving placebo ( P Conclusions. —Hypertensive ischemic stroke patients with a moderate elevation of blood pressure in the first few days may not require antihypertensive therapy. Nicardipine and possibly other calcium channel blockers may cause an excessive fall in blood pressure and impair cerebral blood flow in these patients and should therefore be used with caution.

Magnetic resonance imaging in the staging of solitary plasmacytoma of bone.

Abstract: PURPOSETo assess prospectively the role of magnetic resonance (MR) imaging in the staging of patients with a solitary bone plasmacytoma (SBP).PATIENTS AND METHODSTwelve consecutive patients with an apparent SBP underwent MR imaging of both the primary tumor and the thoracic and lumbosacral spine to seek additional foci of marrow involvement that might have been undetected by standard skeletal survey. All patients received megavoltage irradiation (total dose, 40 Gy) to the primary lesion.RESULTSMR imaging of the thoracic and lumbosacral spine showed additional foci of marrow replacement in four of 12 patients, with signal characteristics identical to those of the primary tumor. In all four patients, the abnormal protein persisted at greater than 50% of the pretreatment value following radiation treatment. In contrast, the myeloma protein disappeared or was reduced by greater than 50% in five of the six patients with secretory disease and without additional marrow abnormalities. One of four patients progres...

Rapid‐onset dystonia‐parkinsonism

Abstract: We studied a large family with a previously undescribed, autosomal dominant dystonia-parkinsonism syndrome. We chose to call the disorder "rapid-onset dystonia-parkinsonism" (RDP) based on the unusually rapid evolution of signs and symptoms. Affected individuals developed dystonia and parkinsonism between 14 and 45 years of age. The onset was acute in six individuals with the abrupt onset of symptoms over the course of several hours, and subacute in four others who had evolution over several days or weeks. Thereafter, progression of symptoms was usually very slow. Two had intermittent focal dystonia without parkinsonism, and one obligate gene carrier was asymptomatic at 68 years. CSF levels of homovanillic acid were decreased in the two individuals tested, but dopaminergic therapy provided only slight benefit. The DYT1 gene responsible for early-onset, generalized idiopathic torsion dystonia in Jewish and some non-Jewish families has been mapped to chromosome 9q34. Linkage analysis with three markers near the DYT1 gene showed several obligate recombinations, excluding DYT1 as a candidate gene for RDP. We believe RDP is unique and should be classified separately from other forms of hereditary dystonia-parkinsonism.

Thrombolysis in Acute Myocardial Infarction

Abstract: Acute myocardial infarction is the most common cause of death in the United States and in almost all Western industrialized countries. Although unadjusted rates of mortality due to myocardial infarction in the United States have been falling in recent years, rates of mortality from all other causes have also been falling, so that the proportion of mortality caused by acute myocardial infarction has not changed. Mortality due to heart disease (mostly infarctions) accounted for 37 percent of all deaths for which a cause could be identified in 1950, for 39 percent in 1960, 1970, and 1980, and for 36 percent . . .