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Biomedical subjects

R J Cohen

Publications and source records attributed to R J Cohen.

At least 19 recordsLinked to original sources
PubMed2004

Role of individual predisposition in orthostatic intolerance before and after simulated microgravity.

Orthostatic intolerance (OI) is a major problem after spaceflight. Its etiology remains uncertain, but reports have pointed toward an individual susceptibility to OI. We hypothesized that individual predisposition plays an important role in post-bed rest OI. Twenty-four healthy male subjects were equilibrated on a constant diet, after which they underwent tilt-stand test (pre-TST). They then completed 14-16 days of head-down-tilt bed rest, and 14 of the subjects underwent repeat tilt-stand test (post-TST). During various phases, the following were performed: 24-h urine collections and hormonal measurements, plethysmography, and cardiovascular system identification (a noninvasive method to assess autonomic function and separately quantify parasympathetic and sympathetic responsiveness). Development of presyncope or syncope defined OI. During pre-TST, 11 subjects were intolerant and 13 were tolerant. At baseline, intolerant subjects had lower serum aldosterone (P < 0.01), higher excretion of potassium (P = 0.01), lower leg venous compliance (P = 0.03), higher supine parasympathetic responsiveness (P = 0.02), and lower standing sympathetic responsiveness (P = 0.048). Of the 14 subjects who completed post-TST, 9 were intolerant and 5 were tolerant. Intolerant subjects had lower baseline serum cortisol (P = 0.03) and a higher sodium level (P = 0.02) compared with tolerant subjects. Thus several physiological characteristics were associated with increased susceptibility to OI. We propose a new model for OI, whereby individuals with greater leg venous compliance recruit compensatory mechanisms (activation of the renin-angiotensin-aldosterone system and sympathetic nervous system, and withdrawal of the parasympathetic nervous system) in the face of daily postural challenges, which places them at an advantage to face orthostatic stress. With head-down-tilt bed rest, the stimulus to recruit compensatory mechanisms disappears, and differences between the two subgroups attenuate.

Adaptation, Physiological↗
PubMed2003

Androgen and oestrogen receptor status of the human appendix testis.

Since the human appendix testis is a Mullerian duct derivative it has been theorised that rising oestrogen levels in puberty result in enlargement of this organ and consequent predisposition to torsion. This study sought to establish the presence or absence of both androgen and oestrogen receptors in the human appendix testis. Bilateral appendix testis specimens surgically excised from ten patients undergoing scrotal exploration for acute scrotum were stained immunohistochemically for androgen and oestrogen receptors. These were examined by light microscopy. The human appendix testis was found to express both oestrogen and androgen receptors. Marked regional variation of androgen and oestrogen receptor positivity was demonstrated. The surface epithelium and some stromal cells were androgen receptor positive, whereas oestrogen receptors were confined to ductular invaginations, gland-like structures and some stromal cells. Rising levels of androgens and oestrogens in pubertal boys may account for enlargement and the predisposition of the human appendix testis for torsion since this structure contains receptors for both.

Adolescent↗
PubMed2003

T-wave alternans negative coronary patients with low ejection and benefit from defibrillator implantation.

In a trial of prophylactic implantation of a defibrillator, a mortality benefit was seen among patients with previous myocardial infarction and a left-ventricular ejection fraction of 0.30 or less. We identified 129 similar patients from two previously published clinical trials in which microvolt T-wave alternans testing was prospectively assessed. At 24 months of follow-up, no sudden cardiac death or cardiac arrest was seen among patients who tested T-wave alternans negative, compared with an event rate of 15.6% among the remaining patients. Testing of T-wave alternans seems to identify patients who are at low risk of ventricular tachyarrhythmic event and who may not benefit from defibrillator therapy.

Death, Sudden, Cardiac↗
PubMed2002

Effects of prolonged bed rest on the total peripheral resistance baroreflex.

Orthostatic intolerance following prolonged exposure to microgravity continues to be a primary concern of the human space program. Reduced autonomic tone has been demonstrated to contribute to this phenomenon, and the heart rate baroreflex, in particular, has been repeatedly shown to be impaired. However, only the works of Yelle et al. have attempted to address the role of the total peripheral resistance (TPR) baroreflex, a potentially more significant contributor to blood pressure regulation. We applied a previously developed method for estimating the static gains of both the arterial and cardiopulmonary TPR baroreflexes to data obtained before and after 16-day bed rest. Reductions in the estimated static gains of the arterial (statistically significant) and cardiopulmonary TPR baroreflexes were found after bed rest. This study supports the works of Yelle et al, which imply that the TPR baroreflex is reduced after spaceflight.

Adult↗
PubMed2002

A computational model-based validation of Guyton's analysis of cardiac output and venous return curves.

Guyton developed a popular approach for understanding the factors responsible for cardiac output (CO) regulation in which 1) the heart-lung unit and systemic circulation are independently characterized via CO and venous return (VR) curves, and 2) average CO and right atrial pressure (RAP) of the intact circulation are predicted by graphically intersecting the curves. However, this approach is virtually impossible to verify experimentally. We theoretically evaluated the approach with respect to a nonlinear, computational model of the pulsatile heart and circulation. We developed two sets of open circulation models to generate CO and VR curves, differing by the manner in which average RAP was varied. One set applied constant RAPs, while the other set applied pulsatile RAPs. Accurate prediction of intact, average CO and RAP was achieved only by intersecting the CO and VR curves generated with pulsatile RAPs because of the pulsatility and nonlinearity (e.g., systemic venous collapse) of the intact model. The CO and VR curves generated with pulsatile RAPs were also practically independent. This theoretical study therefore supports the validity of Guyton's graphical analysis.

Atrial Function, Right↗
PubMed2001

Polyamines in prostatic epithelial cells and adenocarcinoma; the effects of androgen blockade.

BACKGROUND: Recent identification of eosinophilic prostatic secretory granules (PSG) as the major secretory mechanism of the prostate gland and their loss in neoplasia has prompted scrutiny of their chemical constituents. Polyamines, in particular spermine and spermidine (sp/spd) are the major cations found within prostatic secretions, yet their secretory mechanism in normal and neoplastic tissues has not been investigated. METHODS: Normal prostatic tissues and adenocarcinoma from intact and chemically castrated men were preserved in a glutaraldehyde-based fixative (Solufix((R))). Immunostains for sp/spd were performed before and after harsh acid hydrolysis whereby all protein was removed from tissue sections. RESULTS: Sp/spd immunoreactivity correlated with PSG as recognized in routine stains in tissues from intact patients before and after acid digestion. Decrease in sp/spd in untreated carcinomas was directly related to loss of PSG. After chemical castration, normal glands were mostly devoid of sp/spd while surviving malignant cells stained positively, despite a significant reduction or absence of PSG. Similarly, cancers progressing after castration were intensely decorated with anti-spermine, despite an almost complete loss of PSG. Cytoplasmic sp/spd staining of these androgen resistant clones was in contrast to normal glands no longer acid resistant. CONCLUSIONS: The intense eosinophilia of PSG is attributable to polyamines. Androgen blockade arrests sp/spd production in normal tissue. In contrast, sp/spd production continues in androgen resistant tumor clones, thereby uncoupling polyamines from their normal androgen dependent environment.

Adenocarcinoma↗
PubMed2001

Respiratory sinus arrhythmia: opposite effects on systolic and mean arterial pressure in supine humans.

1. Are arterial blood pressure fluctuations buffered or reinforced by respiratory sinus arrhythmia (RSA)? There is still considerable debate about this simple question. Different results have been obtained, triggering a discussion as to whether or not the baroreflexes are responsible for RSA. We suspected that the measurements of different aspects of arterial pressure (mean arterial pressure (MAP) and systolic pressure (SP)) can explain the conflicting results. 2. Simultaneous recordings of beat-to-beat MAP, SP, left cardiac stroke volume (SV, pulsed ultrasound Doppler), heart rate (HR) and respiration (RE) were obtained in 10 healthy young adults during spontaneous respiration. In order to eliminate HR variations at respiratory frequency we used propranolol and atropine administration in the supine and tilted positions. Respiration-synchronous variation in the recorded variables was quantified by spectral analysis of the recordings of each of these variables, and the phase relations between them were determined by cross-spectral analysis. 3. MAP fluctuations increased after removing heart rate variations in both supine and tilted position, whereas SP fluctuations decreased in the supine position and increased in the head-up tilted position. 4. RSA buffers respiration-synchronous fluctuations in MAP in both positions. However, fluctuations in SP were reinforced by RSA in the supine and buffered in the tilted position.

Adult↗
PubMed2001

Applicability of the single equivalent point dipole model to represent a spatially distributed bio-electrical source.

Although the single equivalent point dipole model has been used to represent well-localised bio-electrical sources, in realistic situations the source is distributed. Consequently, position estimates of point dipoles determined by inverse algorithms suffer from systematic error due to the non-exact applicability of the inverse model. In realistic situations, this systematic error cannot be avoided, a limitation that is independent of the complexity of the torso model used. This study quantitatively investigates the intrinsic limitations in the assignment of a location to the equivalent dipole due to distributed electrical source. To simulate arrhythmic activity in the heart, a model of a wave of depolarisation spreading from a focal source over the surface of a spherical shell is used. The activity is represented by a sequence of concentric belt sources (obtained by slicing the shell with a sequence of parallel plane pairs), with constant dipole moment per unit length (circumferentially) directed parallel to the propagation direction. The distributed source is represented by N dipoles at equal arc lengths along the belt. The sum of the dipole potentials is calculated at predefined electrode locations. The inverse problem involves finding a single equivalent point dipole that best reproduces the electrode potentials due to the distributed source. The inverse problem is implemented by minimising the chi2 per degree of freedom. It is found that the trajectory traced by the equivalent dipole is sensitive to the location of the spherical shell relative to the fixed electrodes. It is shown that this trajectory does not coincide with the sequence of geometrical centres of the consecutive belt sources. For distributed sources within a bounded spherical medium, displaced from the sphere's centre by 40% of the sphere's radius, it is found that the error in the equivalent dipole location varies from 3 to 20% for sources with size between 5 and 50% of the sphere's radius. Finally, a method is devised to obtain the size of the distributed source during the cardiac cycle.

Computer Simulation↗
PubMed2001

T wave alternans threshold in normal children.

INTRODUCTION: Sustained microvolt-level T wave alternans (TWA) during exercise is a predictor of ventricular arrhythmia propensity in adult populations. TWA occurs in normal adults, but it is rare at < 70% of predicted maximum heart rate. An onset heart rate < or = 110 is believed to be significant. The aim of this study was to examine the feasibility of performing the test in children and to determine the normal heart rate threshold for sustained TWA in children. METHODS AND RESULTS: Alternans was evaluated during bicycle exercise in 100 normal volunteers aged 8 to 17 years. Adequate resting data were obtained in 76 of 100 children and was negative in all. Exercise data from 16 of 100 was excluded due to excessive noise. Median maximum heart rate was 192 (range 140 to 214). Sustained alternans was absent in 75 (89%) of 84. In the nine children with sustained alternans, median onset heart rate was 138 (range 120 to 158), and 7 of 9 had an onset heart rate > or = 135. Median heart rate threshold as a percentage of predicted maximum heart rate (220 - age) was 67% (range 58% to 76%). Only 1 subject (1.2%) had an onset heart rate < 60% of predicted maximum. There was no significant difference between age, gender, endurance, maximum heart rate, QRS duration, QT interval, or QTc in those with and those without sustained TWA. CONCLUSION: Noninvasive assessment of TWA is feasible at > or = 8 years of age. Sustained TWA was present in 11% of normal children, but was absent at heart rates below 120 and rare (1.2%) below 60% of predicted maximum heart rate.

Adolescent↗
PubMed2001

Role of cytologic criteria in the histologic diagnosis of Gleason grade 1 prostatic adenocarcinoma.

Gleason grade 1 prostatic adenocarcinoma is defined by its gland architecture, which resembles that of benign prostate more than any other grade. It is characterized by closely spaced glands and expansile tumor border. Cytoplasm is clear to pale, superficially identical to benign nodular hyperplasia (BPH). However, there is recent evidence that prostatic "clear-cell carcinoma," including grade 1, has cytoplasm whose composition is distinctively different from BPH, being filled with lipid rather than with the protein-rich granules that characterize benign secretory cells or the nongranular protein matrix of other prostate cancers. We reasoned that grade 1 cancer might also have additional distinctive cellular features; we tested this hypothesis by observations on 17 grade 1 carcinoma foci found as components of transition zone clear-cell cancers. Unlike BPH secretory cells, cells of grade 1 cancer were uniformly large with even, straight borders laterally and luminally. Nuclei appeared sometimes benign but were fixed in a basal row dissimilar to the uneven distribution in BPH. Nuclear pyknotic foci, blue-tinged cytoplasm, and abundant dense luminal secretion were distinctively common. Immunostain for glutathione-S transferase was negative in grade 1 cancer but lightly positive in BPH secretory cells. These cytologic findings were proposed to be useful as diagnostic clues, especially in small-needle biopsy samples, in which architecture may be difficult to interpret. HUM PATHOL 32:441-446.

Adenocarcinoma↗
PubMed2001

Iron supplementation of breast-fed Honduran and Swedish infants from 4 to 9 months of age.

OBJECTIVE: The objective was to study the effects of iron supplementation on hemoglobin and iron status in 2 different populations. STUDY DESIGN: In a randomized, placebo-controlled, masked clinical trial, we assigned term Swedish (n = 101) and Honduran (n = 131) infants to 3 groups at 4 months of age: (1) iron supplements, 1 mg/kg/d, from 4 to 9 months, (2) placebo, 4 to 6 months and iron, 6 to 9 months, and (3) placebo, 4 to 9 months. All infants were breast-fed exclusively to 6 months and partially to 9 months. RESULTS: From 4 to 6 months, the effect of iron (group 1 vs 2 + 3) was significant and similar in both populations for hemoglobin, ferritin, and zinc protoporphyrin. From 6 to 9 months, the effect (group 2 vs group 3) was significant and similar at both sites for all iron status variables except hemoglobin, for which there was a significant effect only in Honduras. In Honduras, the prevalence of iron deficiency anemia at 9 months was 29% in the placebo group and 9% in the supplemented groups. In Sweden, iron supplements caused no reduction in the already low prevalence of iron deficiency anemia at 9 months (<3%). CONCLUSION: Iron supplementation from 4 to 9 months or 6 to 9 months significantly reduced iron deficiency anemia in Honduran breast-fed infants. The unexpected hemoglobin response at 4 to 6 months in both populations suggests that regulation of hemoglobin synthesis is immature at this age.

Age Factors↗
PubMed2001

Effects of exclusive breastfeeding for four versus six months on maternal nutritional status and infant motor development: results of two randomized trials in Honduras.

To examine whether the duration of exclusive breastfeeding affects maternal nutrition or infant motor development, we examined data from two studies in Honduras: the first with 141 infants of low-income primiparous women and the second with 119 term, low birth weight infants. In both studies, infants were exclusively breastfed for 4 mo and then randomly assigned to continue exclusive breastfeeding (EBF) until 6 mo or to receive high-quality, hygienic solid foods (SF) in addition to breast milk between 4 and 6 mo. Maternal weight loss between 4 and 6 mo was significantly greater in the exclusive breastfeeding group (EBF) group than in the group(s) given solid foods (SF) in study 1 (-0.7 +/- 1.5 versus -0.1 +/- 1.7 kg, P < 0.05) but not in study 2. The estimated average additional nutritional burden of continuing to exclusively breastfeed until 6 mo was small, representing only 0.1-6.0% of the recommended dietary allowance for energy, vitamin A, calcium and iron. Women in the EBF group were more likely to be amenorrheic at 6 mo than women in the SF group, which conserves nutrients such as iron. In both studies, few women (10-11%) were thin (body mass index <19 kg/m(2)), so the additional weight loss in the EBF group in study 1 was unlikely to have been detrimental. Infants in the EBF group crawled sooner (both studies) and were more likely to be walking by 12 mo (study 1) than infants in the SF group. Taken together with our previous findings, these results indicate that the advantages of exclusive breastfeeding during this interval appear to outweigh any potential disadvantages in this setting.

Amenorrhea↗
PubMed2001

Children's expectations and memories of acute distress: short- and long-term efficacy of pain management interventions.

OBJECTIVE: To examine the effect of psychologic and pharmacologic interventions on children's expectations and 6-month recollections of painful procedures. METHODS: A repeated measures design allowed examination of 22 fourth graders' expectations, experiences, and memories of distress across three conditions (typical care, distraction, topical anesthetic) for a three-injection vaccination series. All participants were African American and from urban, low-income families. RESULTS: Across conditions, children's expectations of distress were significantly higher than their experience of distress. Distress ratings did not differ among conditions prior to or immediately following the injections; however, children later recalled that the treatment conditions were superior to control for distress relief. Analyses of recall accuracy suggest that the interventions buffered the children from forming negative recollections that occurred with typical care. CONCLUSIONS: Children have negative expectations prior to a procedure despite knowing that a distress management intervention will be employed. However, interventions may thwart the development of negative memories of distress.

Adaptation, Psychological↗
PubMed2001

A forward model-based validation of cardiovascular system identification.

We present a theoretical evaluation of a cardiovascular system identification method that we previously developed for the analysis of beat-to-beat fluctuations in noninvasively measured heart rate, arterial blood pressure, and instantaneous lung volume. The method provides a dynamical characterization of the important autonomic and mechanical mechanisms responsible for coupling the fluctuations (inverse modeling). To carry out the evaluation, we developed a computational model of the cardiovascular system capable of generating realistic beat-to-beat variability (forward modeling). We applied the method to data generated from the forward model and compared the resulting estimated dynamics with the actual dynamics of the forward model, which were either precisely known or easily determined. We found that the estimated dynamics corresponded to the actual dynamics and that this correspondence was robust to forward model uncertainty. We also demonstrated the sensitivity of the method in detecting small changes in parameters characterizing autonomic function in the forward model. These results provide confidence in the performance of the cardiovascular system identification method when applied to experimental data.

Autonomic Nervous System↗
PubMed2001

Midodrine prevents orthostatic intolerance associated with simulated spaceflight.

Many astronauts after being weightless in space become hypotensive and presyncopal when they assume an upright position. This phenomenon, known as orthostatic intolerance, may interfere with astronaut function during reentry and after spaceflight and may limit the ability of an astronaut to exit a landed spacecraft unaided during an emergency. Orthostatic intolerance is more pronounced after long-term spaceflight and is a major concern with respect to the extended flights expected aboard the International Space Station and for interplanetary exploration class missions, such as a human mission to Mars. Fully effective countermeasures to this problem have not yet been developed. To test the hypothesis that alpha-adrenergic stimulation might provide an effective countermeasure, we conducted a 16-day head-down-tilt bed-rest study (an analog of weightlessness) using normal human volunteers and administered the alpha(1)-agonist drug midodrine at the end of the bed-rest period. Midodrine was found to significantly ameliorate excessive decreases in blood pressure and presyncope during a provocative tilt test. We conclude that midodrine may be an effective countermeasure for the prevention of orthostatic intolerance following spaceflight.

Adrenergic alpha-Agonists↗
PubMed2001

Regulation of functional nuclear pore size in fibroblasts.

Protein-NLS-coated gold particles up to approximately 250 A in diameter are transported through the nuclear pores in normal, proliferating BALB/c 3T3 cells. This size can increase or decrease, depending on cellular activity. It has been suggested that increases in functional pore size are related to a reduction in the amount of available p53. To further test this hypothesis, we investigated the effects of cycloheximide and pifithrin-alpha, which inhibits p53-dependent transcriptional activation, on nuclear transport. After 3 hours in cycloheximide, there was a significant increase in the size of the gold particles that entered the nucleoplasm. When the incubation period was extended to 6 hours or longer, transport capacity returned to the control level. By using proteasome inhibitors, it was shown that the cycloheximide-dependent increase in functional pore size was due to the inhibition of protein synthesis, consistent with the fact that p53 is a short-lived protein, and requires the activity of at least two different factors. Although cycloheximide increases the functional diameter of the channel available for signal-mediated transport by approximately 60 A, it had no significant effect on either the import rate of small NLS-containing substrates (FITC-BSA-NLS), or passive diffusion of fluorescent-labeled proteins across the envelope. This suggests that changes in transport capacity were not caused by an increase in overall pore diameter but instead are due to a transient increase in pore size that accompanies signal-mediated transport. Pifithrin-alpha also caused an increase in functional pore diameter without altering the import rate of FITC-BSA-NLS, providing further support for the view that p53 can initiate changes in nuclear transport capacity.

3T3 Cells↗