Search PubMed⌕ Search

Biomedical subjects

R J Cohen

Publications and source records attributed to R J Cohen.

At least 19 recordsLinked to original sources
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↗
PubMed2000

Distinction between intraductal carcinoma of the prostate (IDC-P), high-grade dysplasia (PIN), and invasive prostatic adenocarcinoma, using molecular markers of cancer progression.

BACKGROUND: Prostate ducts and acini whose lumens are filled with malignant cells represent a well-recognized histological pattern recently termed intraductal carcinoma of the prostate (IDC-P). These tumors are often associated with rapid disease progression, and most recur after radical surgery. Controversy exists as to whether IDC-P should be recognized as a separate entity, an extension of high-grade dysplasia (PIN) or invasive carcinoma as described by the Gleason grading system. This study investigates the use of molecular markers in defining the position of IDC-P in the evolutionary hierarchy of prostate cancer progression. METHODS: IDC-P, high-grade dysplasia, and invasive cancers from a cohort of 20 selected radical prostatectomy specimens were screened for loss of heterozygosity (LOH), using 12 polymorphic microsatellite markers frequently lost in prostate cancer. RESULTS: LOH was absent in Gleason grade 3 cancer, infrequent in high-grade dysplasia (9%) and Gleason grade 4 cancer (29%), but common in IDC-P (60%). In IDC-P, and to a lesser extent Gleason grade 4 cancers, multiple sites of allelic loss in individual cases were usual. CONCLUSIONS: Allelic instability provides further evidence that IDC-P is not a simple extension of dysplasia, nor does it represent invasion of Gleason grade 3 cancers into the ductal/acinar system. IDC-P and Gleason grade 4 cancer represent late but possibly separate events in prostate cancer evolution.

Adenocarcinoma↗
PubMed2000

Predictive value of T-wave alternans for arrhythmic events in patients with congestive heart failure.

Measurement of microvolt level T-wave alternans in the surface electrocardiogram is a novel way to assess the risk of ventricular arrhythmias. Seven tests of arrhythmic risk, including T-wave alternans, were undertaken in 107 consecutive patients with congestive heart failure and no history of sustained ventricular arrhythmias; the patients were followed up for arrhythmic events during the next 18 months. Of the patients with events, 11 had positive and two indeterminate T-wave alternans results; there were no arrhythmic events among patients with negative T-wave alternans results. Of the seven tests, only T-wave alternans was a significant (p=0.0036) and independent predictor of arrhythmic events.

Arrhythmias, Cardiac↗
PubMed2000

Identification of the glycosaminoglycan keratan sulfate in the prostatic secretory cell.

BACKGROUND: Prostate secretory granules (PSG) represent the basic secretory unit of the prostate gland, containing many of its exocrine proteases. Recent analysis of intraluminal corpora amylacea, a proposed by-product of PSG secretion, detected sulfated glycosaminoglycans (GAG) possibly keratan sulfate (KS), indicating a secretory mechanism for GAG in the human prostate surface epithelial cell. METHODS: Immunostains using anti-KS and anti-prostate-specific antigen (PSA) were evaluated on 10 sequential radical prostatectomy specimens, three of which had received neoadjuvant antiandrogen therapy. Extracts of normal secretory tissue as well as a sample composed almost entirely of prostatic stroma were subjected to Western blot analysis, using the same antibody panel. RESULTS: Keratan sulfate secretion from the normal prostate epithelial cell has been confirmed and correlates, as does PSA, with the presence of cytoplasmic PSG. No such correlation exists in most adenocarcinomas or in benign epithelium after androgen ablation. Western blot analyses confirmed tissue immunostains and demonstrated a secretory proteoglycan of 70-95 kDa. CONCLUSIONS: Recognition of PSG heralds a novel secretory mechanism within the human prostate gland that is linked to the secretion of KS. The role of KS in normal prostate secretion remains unknown, although it appears downregulated in neoplastic and androgen-ablated cells.

Aged↗