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Biomedical subjects

J Robbins

Publications and source records attributed to J Robbins.

At least 109 records · Page 6Linked to original sources
PubMed1998

Chernobyl-related thyroid cancer in children of Belarus: a case-control study.

The accident at the Chernobyl nuclear power plant on April 26, 1986, released approximately 2 EBq of 131I and other radioiodine isotopes that heavily contaminated southern Belarus. An increase in thyroid cancer reported in 1992 and attributed to the Chernobyl accident was challenged as possibly the result of intensive screening. We began a case-control study to test the hypothesis that the Chernobyl accident caused the increase in thyroid cancer. Records of childhood thyroid cancer in the national therapy centers in Minsk in 1992 yielded 107 individuals with confirmed pathology diagnoses and available for interview. Pathways to diagnosis were (1) routine endocrinological screening in 63, (2) presentation with enlarged or nodular thyroid in 25 and (3) an incidental finding in 19. Two sets of controls were chosen, one matched on pathway to diagnosis, the other representing the area of heavy fallout, both matched on age, sex and rural/urban residence in 1986. The 131I dose to the thyroid was estimated from ground deposition of 137Cs, ground deposition of 131I, a data bank of 1986 thyroid radiation measurements, questionnaires and interviews. Highly significant differences were observed between cases and controls (both sets) with respect to dose. The differences persisted within pathway to diagnosis, gender, age and year of diagnosis, and level of iodine in the soil, and were most marked in the southern portion of the Gomel region. The case-control comparisons indicate a strong relationship between thyroid cancer and estimated radiation dose from the Chernobyl accident.

Adolescent↗
PubMed1997

Cardiac compartment-specific overexpression of a modified retinoic acid receptor produces dilated cardiomyopathy and congestive heart failure in transgenic mice.

Retinoids play a critical role in cardiac morphogenesis. To examine the effects of excessive retinoid signaling on myocardial development, transgenic mice that overexpress a constitutively active retinoic acid receptor (RAR) controlled by either the alpha- or beta-myosin heavy chain (MyHC) promoter were generated. Animals carrying the alpha-MyHC-RAR transgene expressed RARs in embryonic atria and in adult atria and ventricles, but developed no signs of either malformations or disease. In contrast, beta-MyHC-RAR animals, where expression was activated in fetal ventricles, developed a dilated cardiomyopathy that varied in severity with transgene copy number. Characteristic postmortem lesions included biventricular chamber dilation and left atrial thrombosis; the incidence and severity of these lesions increased with increasing copy number. Transcript analyses showed that molecular markers of hypertrophy, alpha-skeletal actin, atrial natriuretic factor and beta-MyHC, were upregulated. Cardiac performance of transgenic hearts was evaluated using the isolated perfused working heart model as well as in vivo, by transthoracic M-mode echocardiography. Both analyses showed moderate to severe impairment of left ventricular function and reduced cardiac contractility. Thus, expression of a constitutively active RAR in developing atria and/ or in postnatal ventricles is relatively benign, while ventricular expression during gestation can lead to significant cardiac dysfunction.

Animals↗
PubMed1997

Rescue of cardiac alpha-actin-deficient mice by enteric smooth muscle gamma-actin.

The muscle actins in higher vertebrates display highly conserved amino acid sequences, yet they show distinct expression patterns. Thus, cardiac alpha-actin, skeletal alpha-actin, vascular smooth muscle alpha-actin, and enteric smooth muscle gamma-actin comprise the major actins in their respective tissues. To assess the functional and developmental significance of cardiac alpha-actin, the murine (129/SvJ) cardiac alpha-actin gene was disrupted by homologous recombination. The majority ( approximately 56%) of the mice lacking cardiac alpha-actin do not survive to term, and the remainder generally die within 2 weeks of birth. Increased expression of vascular smooth muscle and skeletal alpha-actins is observed in the hearts of newborn homozygous mutants and also heterozygotes but apparently is insufficient to maintain myofibrillar integrity in the homozygous mutants. Mice lacking cardiac alpha-actin can be rescued to adulthood by the ectopic expression of enteric smooth muscle gamma-actin using the cardiac alpha-myosin heavy chain promoter. However, the hearts of such rescued cardiac alpha-actin-deficient mice are extremely hypodynamic, considerably enlarged, and hypertrophied. Furthermore, the transgenically expressed enteric smooth muscle gamma-actin reduces cardiac contractility in wild-type and heterozygous mice. These results demonstrate that alterations in actin composition in the fetal and adult heart are associated with severe structural and functional perturbations.

Actins↗
PubMed1997

Eating changes in mild-stage Alzheimer's disease: a pilot study.

Eating impairment is well documented in the late stage of Alzheimer's disease (AD) but when these eating changes actually begin in the disease process is not known. Eating was defined as consisting of two components, self-feeding and swallowing. Self-feeding and swallowing of healthy elderly were compared with a group of individuals with mild AD. AD subjects received significantly more partner-initiated cues or direct assistance than controls. In addition, subject-initiated cued behaviors occurred more frequently in the AD group. AD subjects demonstrated significantly prolonged swallow durations for the oral transit duration (cookie), pharyngeal response duration (liquid), and total swallow duration (liquid). This pilot study suggests that self-feeding and swallowing changes may occur early in the course of AD.

Aged↗
PubMed1997

The changing role of radioiodine in the management of differentiated thyroid cancer.

This article discusses several aspects of the evaluation and management of differentiated thyroid carcinoma that are changing or may change in the near future. Although conventional treatment of this disease is highly effective, some modification may improve the welfare of patients and the overall results. Because the symptoms of hypothyroidism are vexing, there has been great interest in using recombinant human thyroid-stimulating hormone (rhTSH) to prepare patients for iodine 131 imaging. rhTSH has been about as effective as thyroid hormone withdrawal for diagnostic imaging so that approval for this use is expected. Another topic of interest is the administration of 131I therapy to patients whose serum thyroglobulin levels are abnormal but whose diagnostic 131I scans are negative. Because the 131I scans after therapy are often abnormal in these patients and a reduction of serum thyroglobulin can occur, this approach seems effective. The long-term impact of this therapy on recurrence and survival, however, is unknown. A third issue that is currently under review is the amount of 131I that should be used for diagnostic scanning. Although past opinion favored larger doses, "stunning" of thyroid remnant and tumor can occur with diagnostic 131I imaging. Substituting iodine 123 is an alternative for postthyroidectomy scanning, but when administered as 300 uCi it is less accurate than 131I for recurrent disease or distant metastases. Related to these issues, two other topics are reviewed: the use of other radiopharmaceuticals for imaging patients with thyroid cancer, and 131I dosimetry.

Cell Differentiation↗
PubMed1997

Lessons from Chernobyl: the event, the aftermath fallout: radioactive, political, social.

The accident at the Chernobyl nuclear power station on April 26, 1986, released about 300 MCi of radioactive substances, including about 40 MCi of 131I and 100 MCi of short-lived radioiodines. In the immediate surroundings there were 143 cases of acute radiation syndrome, 34 deaths, and hundreds of thousands of people displaced from their homes, many permanently. The social and psychologic stresses that followed have been enormous and long-lasting. This article focuses on the rising incidence of thyroid cancer in exposed children. Radiation-induced thyroid cancer following external radiation is well documented but there is little evidence in humans of thyroid cancer from internal radiation and the risk coefficient for radioiodine exposure is known. To achieve this, thyroid dose reconstruction and prospective follow-up of about 50,000 persons who were children in 1986 will be required. Thyroid cancer in children of southern Belarus began to increase in 1990 and there now are about 1,000 cases in Belarus and northern Ukraine. These aggressively growing tumors, almost all variants of papillary thyroid cancer, are typical for thyroid cancer in children not exposed to radiation, and a low mortality rate is to be expected. It also is expected, however, that malignant as well as benign thyroid neoplasms will continue to arise in these exposed children well into their adult life.

Adult↗
PubMed1997

Measurement of intraventricular pressure and cardiac performance in the intact closed-chest anesthetized mouse.

To fully utilize the potential of newly developed mouse models with specific genetic mutations, it is necessary to study the functional consequences of genetic manipulation in the fully intact animal. To this end, the purpose of the present study was to develop and validate a methodology for the study of myocardial performance in the fully intact, closed-chest mouse. Left ventricular function was evaluated in euthyroid, hypothyroid, and hyperthyroid mice, animals with well-documented alterations in myocardial function. The mice were anesthetized and instrumented with polyethylene catheters in the right femoral artery and vein and with a Millar MIKRO-TIP transducer in the left ventricle via the right carotid artery. Structural and functional evidence suggested that the instrumentation procedure did not cause myocardial damage, valvular insufficiency, or aortic obstruction. Isovolumic indexes of myocardial contractility derived from the left ventricular pressure pulse and its first derivative demonstrated a 40% increase in contractility in the hyperthyroid animals and a 40% decrease in contractility in the hypothyroid animals. Similar differences in the indexes of relaxation were observed. Furthermore, isoproterenol dose-response relationships of these contractile parameters were blunted in the hypothyroid animals and augmented in the hyperthyroid animals compared with euthyroid control animals. Given the small size of the mouse and the high frequency of the cardiac cycle, these data demonstrate the feasibilty of combining a high-fidelity, microtip manometer with a high-speed data-acquisition system to obtain faithful recordings of cardiac performance in the fully intact mouse.

Anesthesia, General↗
PubMed1997

A treadmill exercise regimen for identifying cardiovascular phenotypes in transgenic mice.

Cardiovascular stress in response to treadmill exercise is frequently used to detect cardiac abnormalities that are not readily apparent at rest. Herein we describe a treadmill exercise protocol for mice that allows for quantitation of the performance of an animal and the ability to gather metabolic information in a nonrestraining manner using telemetry implant devices. Transgenic (TG) mice overexpressing ventricular myosin regulatory light chain (MLC2v) were subjected to a 5-wk exercise regimen. The TG mice had significant decreases in their capacity for exercise at relatively high treadmill speeds compared with their nontransgenic (NTG) littermates. There was no indication of a hypertrophic response occurring in TG or NTG animals in response to the exercise protocol, and exercise had no effect on MLC2v phosphorylation. Ultrastructural examination of TG atria showed overtly normal myofibrillar organization but a proliferation of the transverse-axial tubular system. This exercise protocol should prove useful in detecting subtle phenotypes that occur in mice as a result of genetic manipulation of the cardiac compartment.

Animals↗
PubMed1997

Molecular remodeling of cardiac contractile function.

A number of techniques are now available that allow the contractile apparatus of the heart to be altered in a defined manner. This review focuses on those approaches that result in germ-line transmission of the remodeling event(s). Thus the desired modifications can be propagated stably throughout multiple generations and result in the creation of stable, new animal models. Necessarily, such stable changes need to be performed at the level of the genome, and two distinct but complementary approaches have been developed: transgenesis and gene targeting. Each results in the stable modification of the mammalian genome. Via gene targeting or gene ablation of sequences encoding various components of the sarcomere, the contractile apparatus of the heart can be altered dramatically. Ablating a gene may lead to a loss in function, which can help establish a function of the candidate sequence. Gene targeting can also be used to effect changes in the sequences encoding a functional domain of the contractile protein or at a single-amino acid residue, resulting in the establishment of precise structure-function relationships. With the use of transgenesis, the contractile apparatus of the heart can also be significantly remodeled. These approaches are rapidly creating a group of animals in which altered contractile protein complements will lead to a fundamental understanding of the structure-function relationships that underlie the function of the heart at the molecular, biochemical, whole organ, and whole animal levels.

Animals↗
PubMed1997

Transgenic remodeling of the regulatory myosin light chains in the mammalian heart.

The regulatory myosin light chain (MLC) regulates contraction in smooth muscle. However, its function in striated muscle remains obscure, and the different functional activities of the various isoforms that are expressed in the mammalian heart (ventricle- and atrium-specific MLC2) remain undefined. To begin to explore these issues, we used transgenesis to determine the feasibility of effecting a complete or partial replacement of the cardiac regulatory light chains with the isoform that is normally expressed in fast skeletal muscle fibers (fast muscle-specific MLC2). Multiple lines of transgenic mice were generated that expressed the transgene at varying levels in the heart in a copy number-dependent fashion. There is a major discordance in the manner in which the different cardiac compartments respond to high levels of overexpression of the transgene. In atria, isoform replacement with the skeletal protein was quite efficient, even at low copy number. The ventricle is much more refractory to replacement, and despite high levels of transgenic transcript, protein replacement was incomplete. Replacement could be further increased by breeding the transgenic lines with one another. Despite very high levels of transgenic transcript in these mice, the overall level of the regulatory light chain in both compartments remained essentially constant; only the protein isoform ratios were altered. The partial replacement of the ventricular with the skeletal isoform reduced both left ventricular contractility and relaxation, although the unloaded shortening velocity of isolated ventricular cardiomyocytes was not significantly different.

Animals↗
PubMed1997

Silent brain infarction on magnetic resonance imaging and neurological abnormalities in community-dwelling older adults. The Cardiovascular Health Study. CHS Collaborative Research Group.

BACKGROUND AND PURPOSE: Infarctlike lesions are frequently detected in symptomatic and asymptomatic older persons undergoing cerebral MRI, but their significance in older adults has not been examined. We determined the prevalence of MRI infarcts in a population-based sample of men and women aged > or = 65 years and related these findings to demographic, cognitive, and neurological status. METHODS: MRI scanning was performed in 3660 Cardiovascular Health Study (CHS) participants after brief neurological examinations and tests of cognitive function. MRIs were read centrally for the presence of an infarct > or = 3 mm in diameter or smaller infarctlike lesions. RESULTS: MRI infarcts were detected in 1131 of 3647 participants with readable infarct information (31%) and in 961 of the subgroup of 3397 participants (28%) without known prior stroke ("silent" MRI infarcts). Smaller infarctlike lesions were found in 196 of 2516 participants who had no MRI infarcts > or = 3 mm. MRI infarcts were more common in participants who were older, had prior stroke, impaired cognition, visual field deficits, slowed repetitive finger tapping (all P < .0001), weakness on toe and heel walking, and history of memory loss, coma, or migraine headaches. Multivariate analysis in those without prior stroke showed strong associations of silent MRI infarcts with older age, history of migraines, lower digit symbol scores, and more abnormalities on neurological examination. CONCLUSIONS: MRI evidence of brain infarction is common in older men and women without a clinical history of stroke. Their strong associations with impaired cognition and neurological deficits suggest that they are neither silent nor innocuous.

Aged↗
PubMed1997

Muscle isoactin expression during in vitro differentiation of murine embryonic stem cells.

Embryonic stem (ES) cells are pluripotent cells derived from mouse blastocysts. ES cells can differentiate into complex embryoid bodies (EBs) which exhibit many of the characteristics of 4-10-d embryos, including areas which rhythmically contract. The expression of the four muscle isoactins was examined in EBs by using transcript-specific probes for each of the muscle actin mRNAs and selectively reactive MAbs to muscle actins. Northern blot analyses from undifferentiated ES cells and EBs after 5, 10, 15, and 20 d in suspension culture demonstrated that no muscle actin transcripts could be detected in the undifferentiated cells, whereas during differentiation, the vascular and enteric smooth muscle isoactin mRNAs were easily detected. To further define the pattern of expression polymerase chain reaction analyses were carried out on RNA isolated from individual EBs. The data indicated that all four muscle-specific actin genes are transcribed. We also demonstrated the presence of muscle actins in at least two distinct cell populations within the EBs using selectively reactive MAbs. Fibroblast-like cells exhibit significant levels of the two smooth muscle actins (vascular and enteric) localized to stress fibers. In addition, one or both of the striated muscle actins (cardiac and skeletal) are expressed in cardiomyocyte-like cells. As is the case in embryonic heart, alpha-smooth muscle actin and the striated muscle actin(s) are incorporated into well organized sarcomeres in these cardiomyocyte-like cells. Thus, differentiating EBs provide an in vitro system to study both striated and smooth muscle cell gene expression.

Actins↗
PubMed1997

Depression in primary care: patient factors that influence recognition.

BACKGROUND: Recognition of depression in primary care is both important and difficult. To study recognition of depression, we monitored care delivered to new adult patients randomly assigned to primary care providers. METHODS: At study entry, 508 patients completed the Beck Depression Inventory (BDI) and the Medical Outcomes Study Short-form Health Survey-36 (SF-36), a measure of health status. Chart notes were reviewed at the end of 1 year. RESULTS: Only 36 of 130 patients with elevated BDI scores > or = 9 (moderate-to-severe depression) were noted as depressed on the chart. Patient characteristics predicting chart notation of depression included BDI scores, health status, gender, and education. When controlling for these factors, neither age nor race were statistically significant in the prediction of the recognition of depression. Female patients were more likely to be diagnosed as depressed than men with comparable BDI and SF-36 scores. Greater patient education was associated with enhanced likelihood of diagnosis of depression. Both BDI scores and health status were important predictors of diagnosis of depression. All SF-36 subscales correlated highly with BDI scores, suggesting that these measures may lack adequate discriminant validity. CONCLUSIONS: Identifying diagnostic tendencies may help primary care providers improve detection of depression, a critical first step toward effective management.

Adult↗
PubMed1997

Glycophorin A as a biological dosimeter for radiation dose to the bone marrow from iodine-131.

The frequency of peripheral blood erythrocyte variants exhibiting allelic loss of glycophorin A (N/M antigen) has been used previously as a biological dosimeter to assess somatic mutations in bone marrow cells from external whole-body irradiation. The aim of the present study was to determine whether this marker could be used as a measure of bone marrow genotoxicity induced by 131I in the treatment of thyroid cancer. Flow cytometry of immunolabeled erythrocytes was performed to enumerate glycophorin A variants before and after eight therapy doses of 131I administered to five patients with differentiated thyroid carcinoma. Bone marrow radiation exposure from each dose was calculated from the integrated retention of 131I in the whole body and in the blood. In addition, the accumulated dose to the bone marrow received from earlier 131I therapy was calculated for each patient. Regression analysis was performed on the frequency of two glycophorin A variant cell types (N/O and N/N) as a function of accumulated dose to the bone marrow. Frequency of N/O variant cells showed a significant dose-related increase with a slope of 10.9 x 10(-6) per sievert. This dose effect is about one-half that previously observed after whole-body external irradiation at high dose rate. This decreased response could be explained by the low dose rate of the radiation to the bone marrow from 131I.

Bone Marrow↗
PubMed1997

The Sleep Heart Health Study: design, rationale, and methods.

The Sleep Heart Health Study (SHHS) is a prospective cohort study designed to investigate obstructive sleep apnea (OSA) and other sleep-disordered breathing (SDB) as risk factors for the development of cardiovascular disease. The study is designed to enroll 6,600 adult participants aged 40 years and older who will undergo a home polysomnogram to assess the presence of OSA and other SDB. Participants in SHHS have been recruited from cohort studies in progress. Therefore, SHHS adds the assessment of OSA to the protocols of these studies and will use already collected data on the principal risk factors for cardiovascular disease as well as follow-up and outcome information pertaining to cardiovascular disease. Parent cohort studies and recruitment targets for these cohorts are the following: Atherosclerosis Risk in Communities Study (1,750 participants), Cardiovascular Health Study (1,350 participants), Framingham Heart Study (1,000 participants), Strong Heart Study (600 participants), New York Hypertension Cohorts (1,000 participants), and Tucson Epidemiologic Study of Airways Obstructive Diseases and the Health and Environment Study (900 participants). As part of the parent study follow-up procedures, participants will be surveyed at periodic intervals for the incidence and recurrence of cardiovascular disease events. The study provides sufficient statistical power for assessing OSA and other SDB as risk factors for major cardiovascular events, including myocardial infarction and stroke.

Adult↗