Time-frequency transforms: a new approach to first heart sound frequency dynamics. This study employed a new analytical tool, the Binomial joint time-frequency transform, to test the hypothesis that first heart sound frequency rises during the isovolumic contraction period. Cardiac vibrations were recorded from eight open chest dogs using an ultralight accelerometer cemented directly to the epicardium of the anterior left ventricle. The frequency response of the recording system was flat +/- 3 dB from 0.1 to 400 Hz. Three characteristic time-frequency spectral patterns were evident in the animals investigated: 1) A frequency component that rose from approximately 40-140 Hz in a 30-50 ms interval immediately following the ECG R-wave. 2) A slowly varying or static frequency of 60-100 Hz beginning midway through the isovolumic contraction period. 3) Broad-band peaks occurring at the time of the Ia and Ib high frequency components. The presence of rapid frequency dynamics limits the usefulness of stationary analysis techniques for the first heart sound. The Binomial transform provided much better resolution than the spectrograph or spectrogram, the two most common non-stationary signal analysis techniques. By revealing the onset and dynamics of first heart sound frequencies, time-frequency transforms may allow mechanical assessment of individual cardiac structures.


Analysis of ECG from pole-zero models.

Analysis of ECG from pole-zero models. A complete solution to the fundamental problem of ECG analysis, viz., delineation of the signal into its component waves, is proposed from a system theoretic point of view. The discrete cosine transform of a bell shaped biphasic function is approximated mathematically by a system function with two poles and two zeros, i.e., of order (2, 2). Using this concept as the basis, a pole-zero model of suitable order is derived from the discrete cosine transform (DCT) of the given signal using Steiglitz-McBride method. This model is expanded into a unique set of partial fractions each of order (2, 2), and a biphasic function is recovered from each one of these fractions in the inverse process. Each of the P and T waves usually requires only one biphasic function, while the QRS complex needs two or at most three such fractions. A one-to-one relationship between the pole pattern in the z-plane and component wave pattern in the time signal is established. Results of analysis of continuous strips of ECG show that the delineated component waves are in excellent agreement with the original waves both qualitatively and quantitatively. The method is robust for the analysis of signals with artifacts of various kinds, independent of the sampling rate used, and is free from ad hoc back and forth search procedures.


Noninvasive optical polarimetric glucose sensing using a true phase measurement technique. The focus of this paper was to describe the development and testing of a noninvasive true phase optical polarimetry sensing system to monitor in vivo glucose concentrations. To demonstrate the applicability of this optical sensor for glucose measurement, we first calibrated the system and then tested it in vitro using both a glass test cell filled with glucose solution in the physiologic range, with a path length of 0.9 cm to approximate one centimeter path length present in the anterior chamber of the eye, and then on an excised human eye. Our technique used helium neon laser light which was coupled through a rotating linear polarizer along with two stationary linear polarizers and two detectors to produce reference and signal outputs whose amplitudes varied sinusoidally with a frequency of twice the angular velocity of the rotating polarizer, and whose phase was proportional to the rotation of the linear polarization vector passing through the glucose solution.


Measuring lung resistivity using electrical impedance tomography. We propose the use of electrical impedance tomography (EIT) imaging techniques in the measurement of lung resistivity for detection and monitoring of apnea and edema. In EIT, we inject currents into a subject using multiple electrodes and measure boundary voltages to reconstruct a cross-sectional image of internal resistivity distribution. We found that a simplified, therefore fast, version of the impedance imaging method can be used for detection and monitoring of apnea and edema. We have showed the feasibility of this method through computer simulations and human experiments. We speculate that the EIT imaging technique will be more reliable than the current impedance apnea monitoring method, since we are monitoring the change of internal lung resistivity. However, more study is required to verify that this method performs better in the presence of motion artifact than the conventional two-electrode impedance apnea monitoring method. Future work should include experiments which carefully simulate different kinds of motion artifacts.


Minimal repetition evoked potentials by modified adaptive line enhancement. A new method called modified adaptive line enhancement (MALE) to obtain evoked potentials with minimum stimulus repetitions is described. The theory of MALE is developed and the assumptions made are tested and shown to be adequate in the case of brain-stem auditory evoked potential. The signal distortion are characterized and methods to alleviate the problem are developed. Using the weighted exact least squares lattice algorithm, the MALE method is implemented and applied to real data. It is shown that brainstem auditory evoked potential can be obtained with less than 40 repetitions using MALE method compared to 2000 required if conventional ensemble averaging method is used.


Lewis K. Dahl Memorial Lecture. The renin system and four lines fo hypertension research. Nephron heterogeneity, the calcium connection, the prorenin vasodilator limb, and plasma renin and heart attack. As the major regulator of arterial blood pressure and sodium balance, the renin axis supports normotension or hypertension via angiotensin-mediated vasoconstriction and angiotensin plus aldosterone-induced renal sodium retention. In this endocrine servo control, renal renin is released by hypotension or salt depletion; conversely, with hypertension or volume excess, plasma renin activity falls to zero. Accordingly, any renal renin secretion is abnormal in the face of arterial hypertension. Human hypertensive disorders comprise a spectrum of abnormal vasoconstriction-volume products (renin-sodium profiles). Excess plasma renin activity for the sodium balance is created by nephron heterogeneity in which a subpopulation of ischemic nephrons hypersecretes renin and retains sodium. This excess renin impairs adaptive natriuresis of neighboring normal nephrons. Research defining the pivotal role of vascular cytosolic calcium for transducing sodium or renin-mediated vasoconstriction explains the selective value of calcium antagonists for correcting the sodium-volume-mediated, and beta-blockers or angiotensin converting enzyme inhibitors for correcting renin-mediated, arteriolar vasoconstriction. The renin precursor prorenin appears to be physiologically active, causing selective vasodilation that offsets renin-mediated vasoconstriction. Overactivity of prorenin may be involved in the hyperperfusion vascular injuries of diabetes mellitus and toxemias. Prorenin underactivity may facilitate renin-mediated ischemic vascular injury. In essential hypertension, undue plasma renin activity is powerfully and independently associated with heart attack risk. Conversely, patients with low renin activity are protected from heart attack despite higher blood pressures and greater age. Also, renin or angiotensin administration consistently causes vascular injury in the heart, brain, and kidneys of animals. These data suggest new potentials for the prevention of cardiovascular sequelae (heart attack and stroke) by using explicit strategies to curtail plasma renin activity.


Adrenal and circulating renin-angiotensin system in stroke-prone hypertensive rats. The plasma and adrenal renin-angiotensin system in stroke-prone spontaneously hypertensive rats (SHRSP) and Wistar-Kyoto (WKY) rats were examined in animals at 5, 11, 18, and 25 weeks of age. Plasma active renin was significantly increased in 18- and 25-week-old SHRSP with impaired renal function, whereas there was no difference in the plasma prorenin level or renal renin content between the two strains at all ages examined. Thus, the rate of activation of prorenin seems to be enhanced in the kidney of SHRSP with malignant hypertension. Adrenal renin contents were severalfold higher in SHRSP than WKY rats at all ages. However, adrenal angiotensin peptides were not increased in SHRSP aged 5 and 11 weeks. In 18-week-old SHRSP, adrenal angiotensin II (Ang II) and III (Ang III) levels were fourfold and 1.8-fold higher, respectively, than in WKY rats, accompanied by 1.5-fold higher plasma aldosterone. Increased adrenal angiotensin and plasma aldosterone were also found in 25-week-old SHRSP. Zonal distribution studies indicated that the elevated Ang II and III in SHRSP were derived mainly from the capsular tissue (the zona glomerulosa). To examine the contribution of circulating angiotensin to the adrenal angiotensin content, effects of bilateral nephrectomy on adrenal angiotensin and renin were examined in 18-week-old rats. At 24 hours after nephrectomy, plasma angiotensin, prorenin, and active renin were decreased to almost negligible concentrations. Conversely, in both adrenal capsular and decapsular tissues of SHRSP and WKY rats, neither angiotensin nor renin was significantly decreased after nephrectomy. These results suggest that the increase in adrenal capsular Ang II contents in SHRSP may be partly due to an enhanced local production of Ang II.


Endothelin-1 augments pressor response to angiotensin II infusion in rats. To assess possible roles of endothelin in the regulation of blood pressure, we studied effects of a subpressor dose of endothelin-1 (3 micrograms/kg/day) on chronic blood pressure responses to infusion of angiotensin II and norepinephrine in rats. Rats were infused with angiotensin II at a subpressor dose (400 micrograms/kg/day i.p.) or with norepinephrine at a subpressor dose (360 micrograms/kg/day i.p.) for 6 days. Systolic blood pressure was significantly elevated during combined infusion of endothelin-1 and angiotensin II, whereas endothelin-1 alone or angiotensin II alone failed to induce any significant changes in systolic blood pressure compared with vehicle alone. This effect was sustained for the whole experimental period and was not associated with any significant changes in body weight, fluid intake, urine volume, or urinary electrolyte excretion. In contrast, combined infusion of endothelin-1 and norepinephrine failed to elevate systolic blood pressure, and no significant difference in systolic blood pressure was observed for the whole experimental period among the four groups of rats with endothelin-1 in combination with norepinephrine, endothelin-1 alone, norepinephrine alone, and vehicle alone. The present results indicate that angiotensin II and endothelin-1, but not norepinephrine and endothelin-1, work synergistically to raise the blood pressure and also suggest the possibility that endothelin-1 may modulate blood pressure control.


Chronic inhibition of nitric oxide synthesis. A new model of arterial hypertension. Recent studies have indicated that acute inhibition of nitric oxide biosynthesis in the rat promotes arterial hypertension and renal vasoconstriction. We evaluated the renal and systemic effects of 4-6 weeks of nitric oxide blockade in Munich-Wistar rats receiving the nitric oxide inhibitor nitro-L-arginine orally. Age-matched untreated rats were used as controls. In an additional seven rats, nitric oxide blockade was carried out in conjunction with oral administration of the novel angiotensin II antagonist losartan potassium. Tail-cuff pressure rose progressively in nitro-L-arginine-treated rats, reaching 164 +/- 6 mm Hg at 4-6 weeks, compared with 108 +/- 3 mm Hg in controls. In rats concomitantly receiving losartan, tail-cuff pressure reached 125 +/- 6 mm Hg, still elevated compared with rats receiving losartan alone (98 +/- 3 mm Hg). Nitro-L-arginine-treated rats presented marked renal vasoconstriction and hypoperfusion, as well as a 30% fall in glomerular filtration rate and a 39% increase in filtration fraction. Treatment with Losartan normalized glomerular filtration rate, but not filtration fraction or renal vascular resistance. Plasma renin activity was elevated after nitro-L-arginine treatment. Renal histological examination revealed widespread arteriolar narrowing, focal arteriolar obliteration, and segmental fibrinoid necrosis in the glomeruli. In a separate group of rats, nitro-L-arginine administered for 1 week induced hypertension that was partially reversed by acute L-arginine, but not D-arginine or L-glycine, infusions. We conclude that chronic nitric oxide blockade may constitute a new model of severe arterial hypertension.(ABSTRACT TRUNCATED AT 250 WORDS)


Enhanced release of endothelium-derived relaxing factor in mineralocorticoid hypertension. Ring segments of superior mesenteric arteries studied in vitro were used to determine the role of the vascular endothelium in regulating vascular contractile and relaxant sensitivity in deoxycorticosterone acetate (DOCA)-salt hypertension. Wistar rats were given DOCA (20 mg/kg s.c. twice per week) and 1% NaCl drinking water for 5 weeks. In ring segments containing endothelium, there was a decrease in contractile sensitivity to arginine vasopressin, no change in contractile sensitivity to norepinephrine and KCl, and no change in relaxant sensitivity to acetylcholine or isoproterenol in arteries from hypertensive rats compared with normotensive controls. Removal of the vascular endothelium by rubbing had no effect on the contractile response to arginine vasopressin and KCl or the relaxant response to isoproterenol in control arteries. In arteries without endothelium, DOCA-salt hypertension caused a threefold increase in contractile sensitivity for arginine vasopressin, norepinephrine, and KCl; a 50% reduction in maximal relaxation to isoproterenol; and a threefold decrease in relaxant sensitivity to sodium nitroprusside. Indomethacin (10 microM) had no effect on contraction or relaxation. However, N-monomethyl L-arginine unmasked altered contractile sensitivity to norepinephrine in arteries from DOCA-salt hypertensive rats. These data show that the endothelium compensates for increased contractile and reduced relaxant responses of vascular muscle in DOCA-salt hypertension by increasing the release of endothelium-derived relaxing factor. These data suggest that altered vascular responsiveness is masked by the endothelium, thus preventing these alterations from contributing to increased peripheral resistance during the development of DOCA-salt hypertension.


Effect of home blood pressure and gender on estimates of the familial aggregation of blood pressure. The Tecumseh Blood Pressure Study. Blood pressure (BP) readings from a single clinic visit are often used in population studies investigating the genetic basis of BP. We examined first-degree relatives in the Tecumseh Blood Pressure study to compare heritability estimates of BP readings obtained in the clinic-office setting (the average of two seated readings) with self-reported home BP readings (the average of 14 readings) taken over a 1-week period. The hypothesis tested was that repeated BP readings obtained in the home over the 1-week period would have fewer artifacts (i.e., environmentally induced variability in BP) and thus would better estimate the true "basal" BP that, in turn, would improve heritability estimates. We and others assume that the true basal BP level is heritable. We therefore expected that this "true" BP, by reducing BP variability of offspring, would show a stronger between-sibling correlation and that it would correlate better to parental BP as measured in a clinic setting. Correlation coefficients were calculated between siblings in the present Tecumseh study using self-reported home BP and clinic BP readings. Among 380 siblings (average age, 31.4 years), correlation coefficients for the home readings were of the same magnitude as for office readings (home, r = 0.23, p less than 0.01; office, r = 0.24, p less than 0.01). When offspring clinic BP readings were compared with archived BP data on parents, the correlation between offspring clinic and parental clinic BP readings was stronger (r = 0.24, p less than 0.05) than the correlation of offspring home BP readings to parental clinic BP readings (r = 0.17, p less than 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)


Hematocrit, blood pressure, and hypertension. The Gubbio Population Study. Baseline data from the Gubbio Population Study in north central Italy were used to investigate the relation of hematocrit to blood pressure and hypertension among 2,809 men and women aged 25-74 years. Independent of gender, age, and other confounders, the hypertensive group had a higher hematocrit than the nonhypertensive group (p less than 0.001). In comparison with the untreated hypertensive group, the hypertensive group being treated with diuretics or with other drugs only had similar mean hematocrit levels despite significantly lower blood pressures. Hematocrit was positively correlated with systolic pressure (r = 0.085, p less than 0.01 and r = 0.264, p less than 0.001 for men and women, respectively) and diastolic pressure (r = 0.214, p less than 0.001 and r = 0.266, p less than 0.001). In both sexes, whether or not the treated hypertensive group was included, age-adjusted prevalence of hypertension and average blood pressure were higher for persons in higher quintiles of hematocrit (p less than 0.001). The association of hematocrit with blood pressure and hypertension was significant and independent of several confounders. The regression coefficient of blood pressure on hematocrit ranged between 0.410 and 0.620 mm Hg per unit of hematocrit for systolic pressure and between 0.371 and 0.581 for diastolic pressure, depending on gender and whether the treated hypertensive group was included in multiple regression analysis. Based on exponentiation of the multiple logistic coefficient, prevalence of hypertension was at least two times greater for persons whose hematocrit levels were higher by 10 units.


Ethnicity, pressor reactivity, and children's blood pressure. Five years of observations. During the 5 years of this investigation, resting blood pressure and pressor reactivity were measured in 292 white children and 46 black children in 1987, 1988, 1989, and 1991. In 1987, all children were in the third grade; in 1991, the children were in the seventh grade. Reactivity was assessed with a standardized psychological stressor, a television video game. Children displayed significant stability of absolute blood pressure and heart rate reactivity between grades 3 and 7. At all examinations, black children demonstrated blood pressure reactivity that was significantly greater in magnitude (both absolute level and change from resting measurements) than that of white children. Black children exhibited significantly greater heart rate reactivity only when defined as change from the resting measurements; absolute levels of heart rate reactivity were comparable for blacks and whites. For black children, blood pressure reactivity in 1987 was the strongest predictor of resting blood pressure (both systolic and diastolic) in 1991. Among white children, resting blood pressure was the strongest predictor of future resting blood pressure. Further research is needed to determine if ethnic differences in children's pressor reactivity are associated with ethnic differences in the prevalence of hypertension.


Brain atrophy in hypertension. A volumetric magnetic resonance imaging study. To determine whether hypertension, the predominant risk factor for stroke and vascular dementia, is associated with brain atrophy, magnetic resonance imaging (MRI) scans were performed to quantify brain volumes and cerebrospinal fluid spaces. Eighteen otherwise healthy, cognitively normal older hypertensive men (mean +/- SD age, 69 +/- 8 years, duration of hypertension 10-35 years) and 17 age-matched healthy, normotensive male control subjects were studied in a cross-sectional design. Axial proton-density image slices were analyzed using region-of-interest and segmentation analyses. The hypertensive subjects had significantly larger mean volumes of the right and left lateral ventricles (p less than 0.05, both absolute volume and volume normalized to intracranial volume) and a significantly smaller normalized mean left hemisphere brain volume (p less than 0.05) with a trend toward significance for a smaller normalized mean right hemisphere volume (p less than 0.09). Four hypertensive subjects and one healthy control subject were found to have severe periventricular hyperintensities on T2-weighted MRI images. When data for these subjects were removed from the analyses, the normalized lateral ventricle volumes remained significantly larger in the hypertensive group. Lateral ventricle enlargement was not related to age or use of diuretics in the hypertensive group nor to duration of hypertension between 10 and 24 years. Our findings suggest that long-standing hypertension results in structural changes in the brain. Longitudinal studies will determine whether MRI-associated changes are progressive and if such changes identify hypertensive subjects at increased risk for clinically apparent brain dysfunction.


Resting and maximal forearm skin blood flows are reduced in hypertension. To find whether the vasodilator capacity of nonacral skin is reduced in hypertension, we measured forearm blood flow by venous occlusion plethysmography in 10 seated normotensive (mean +/- SD mean arterial pressure, 94 +/- 5 mm Hg) and 10 hypertensive (112 +/- 9 mm Hg) men at rest for 39 minutes while the forearm was heated with water at 42 degrees C, a maneuver known to selectively and maximally vasodilate skin. Blood pressure, measured every 5 minutes, did not change with heating. We found that in the normotensive group resting forearm blood flow was higher (3.64 +/- 1.12 versus 2.48 +/- 0.58 ml/100 ml tissue per minute, p less than 0.001; normotensive group versus hypertensive group) and resting forearm vascular resistance lower (30.17 +/- 10.99 versus 48.88 +/- 17.37 mm Hg.min.100 ml tissue per minute, p less than 0.05; normotensive group versus hypertensive group), and maximal forearm blood flow with local heating was higher (29.32 +/- 11.99 versus 18.19 +/- 4.50 ml/100 tissue per minute, p less than 0.018; normotensive group versus hypertensive group and vascular resistance lower (4.07 +/- 1.04 versus 6.54 +/- 1.17 mm Hg.min.100 ml tissue per minute, p less than 0.005; normotensive group versus hypertensive group). To find whether this degree and duration of local warming maximally vasodilated the skin in hypertensive subjects (as it does in normotensive subjects), we measured forearm skin blood flow before and during local heating plus 10 minutes of ischemia using a laser Doppler flowmeter.(ABSTRACT TRUNCATED AT 250 WORDS)


Detection of glycyrrhetinic acid-like factors (GALFs) in human urine. Patients with the syndrome of apparent mineralocorticoid excess and those who ingest licorice show markedly decreased 11 beta-hydroxysteroid dehydrogenase (11 beta-OHSD) and 5 beta-reductase activity; both are important for the deactivation of glucocorticoids and other steroid hormones. Glycyrrhetinic acid (GA), present as its glycoside in licorice, is a potent inhibitor of both 11 beta-OHSD and 5 beta-reductase and, as we have also shown, confers Na(+)-retaining properties on glucocorticoids and amplifies those of aldosterone and deoxycorticosterone. We report the results of our initial studies demonstrating the presence of naturally occurring substances, which inhibit both 5 beta-reductase and 11 beta-OHSD as does GA, in partially purified extracts of urine from normotensive men and nonpregnant and pregnant women. Since these substances exhibit GA-like activity, we have termed them GA-like factors (GALFs). This "inhibitory" material is heat stable and does not react with ninhydrin; the majority is not extractable with ethyl acetate and thus is not a "free" steroid. When further purified by high-performance liquid chromatography with a methanol/water gradient, the majority of these GALFs appeared in two regions of inhibitory activity. The chemical nature of this material is currently being investigated. These experiments indicate that normal human urine contains GALFs that may play a role in Na+ homeostasis and regulation of blood pressure.


Dietary sodium chloride increases blood pressure in obese Zucker rats. In the rat, elevated arterial pressure is not consistently associated with obesity. The purpose of this study was to compare measurements of blood pressure, cardiac output, and total peripheral resistance in obese and lean Zucker rats on different NaCl intakes. Obese and lean rats drank either water or isotonic NaCl for 18 days. Tail systolic blood pressures of saline-drinking obese rats were higher than all other groups (p less than 0.05). NaCl intake did not affect blood pressure in lean rats, and blood pressures of water-drinking obese rats did not differ from those of lean controls. In a subsequent experiment, direct arterial pressures and cardiac outputs (thermodilution) were measured in separate groups of conscious rats that had been maintained on a 1% or 4% NaCl intake for 12 weeks. Arterial pressure was higher (p less than 0.01) in obese rats fed 4% NaCl (130 +/- 4 mm Hg) than in obese rats fed 1% NaCl (118 +/- 2 mm Hg) or than in lean rats fed either NaCl intake (118 +/- 3 mm Hg and 116 +/- 3 mm Hg, respectively). Cardiac output of obese rats was higher than that of lean rats (p less than 0.01); however, the NaCl-induced increase of blood pressure was accounted for by an increase of peripheral resistance (p less than 0.01). Thus, in contrast to the lean Zucker rat, arterial pressure of the obese Zucker rat is increased by a high dietary intake of NaCl.


Drug metabolism by cytochromes P450 in the liver and small bowel. Most drugs used clinically are metabolized by cytochromes P450. These enzymes have been best characterized in the liver, where it appears the major drug-metabolizing P450s belong to three gene families. There appear to be remarkable differences among patients in the catalytic activity of each of the P450s within these three families, and it is increasingly evident that this heterogeneity accounts, at least in part, for differences among patients in response to many medications. In addition, it is clear that many important drug interactions result from induction or inhibition, or both, of the catalytic activity of P450s. Many interactions involving P450s can be reproduced in liver microsomes or in cultured hepatocytes, and it is likely that such studies will, in the future, alert physicians to potential drug interactions before they are reported. Finally, mounting evidence shows that many of the clinically relevant aspects of P450s that have been ascribed to the liver may in fact be occurring at the level of the intestinal mucosa. This finding has been demonstrated most clearly with CsA and P450IIIA, in which enterocyte metabolism appears largely to account for drug interactions and differences among patients in dosing requirements. It remains to be determined whether other enterocyte P450s are also clinically important.


Prokinetic agents.

Prokinetic agents. Prokinetic agents are medications that promote gastrointestinal motility. This article reflects the current state of our understanding of their mechanisms of action and their clinical utility in treating disorders of gastrointestinal motility, including gastroesophageal reflux, gastroparesis, small-intestinal dysmotility, and constipation.


The role of newer antibiotics in gastroenterology. The past decade has seen the introduction of a number of new potent antimicrobial agents, including broad-spectrum beta-lactam compounds such as the ureidopenicillins, third-generation cephalosporins, carbapenems, and monobactams; combinations of penicillins with inhibitors of beta-lactamase; and the quinolones. Most of these agents have excellent activity against enteric gram-negative rods and some are active against anaerobic organisms, the two bacterial groups most likely to be encountered in gastrointestinal infections. Despite the potency and wide spectrum of many of these new agents, there are currently relatively few clinical situations in which any of the newer antimicrobials are the first-line agents for therapy or prophylaxis of gastrointestinal diseases. Reluctance to use these agents as first-line therapy is based on concerns about the selection and spread of resistant organisms, superinfection syndromes, and the high cost of many of the newer agents. Specific clinical settings in which these agents may be given preference are as follows: 1. use of a third-generation cephalosporin (cefotaxime or ceftriaxone) in the treatment of spontaneous bacterial peritonitis. 2. use of broad-spectrum beta-lactam compounds to provide gram-negative coverage in patients who should not receive aminoglycosides 3. use of a third-generation cephalosporin (ceftriaxone) in the treatment of central nervous system relapses of Whipple's disease 4. use of quinolones for the empiric treatment of suspected bacterial diarrhea in patients sufficiently ill to require empiric initiation of antibiotics. 5. use of quinolones for the treatment of chronic carriers of Salmonella typhi 6. use of norfloxacin for prophylaxis against SBP. As further experience with these new antimicrobial agents is obtained and as more bacteria develop resistance to current first-line agents, there can be little doubt that these new antibiotics will play an increasing role in the prevention and treatment of gastrointestinal disease.


Prostaglandins, NSAIDs, and cytoprotection. Although the effects of prostaglandins on gastrointestinal secretion, blood flow, and motility are quite well characterized, the mechanism underlying the cytoprotective actions of this group of lipid mediators has yet to be clearly established. It seems likely that the ability of NSAIDs to inhibit gastric prostaglandin synthesis is an important contributing factor to the pathogenesis of this disorder; however, it is still not clear why depletion of gastric prostaglandins predisposes the mucosa to injury. The study of prostaglandin receptors in the gastrointestinal tract is still in its infancy. As we learn more about the distribution of these receptors and develop specific agonists, it may become possible to develop prostaglandin analogues that are highly selective in enhancing mucosal defense but without the untoward effects frequently associated with analogues currently used clinically in the treatment of NSAID-induced gastropathy.


Immunosuppressants.

Immunosuppressants. The role and pharmacology of a variety of immunosuppressant agents in the gastrointestinal tract and liver are reviewed in this article. Immunosuppressants covered include cyclosporine, corticosteroids, OKT3, antithymocyte globulin, azathioprine, methotrexate, and FK506. Guidelines for the use and complications of immunosuppressants in liver, pancreas, and small bowel transplantations are presented. Controlled and uncontrolled data for use of immunosuppressants in the management of gastrointestinal and hepatic disorders are also described.


Chemotherapy in the management of malignant gastrointestinal disease. Malignancies arising from the gastrointestinal tract represent a diversity of histologies and natural history. The role of chemotherapy in the multidisciplinary approach to these malignancies is reviewed in this article.


Gallstone-dissolving agents.

Gallstone-dissolving agents. It can be anticipated that most new therapies will generate considerable excitement and optimism when introduced. This is usually tempered with time as additional clinical experience is gained and therapeutic limitations and adverse effects are realized. All areas in the nonsurgical management of gallstones have experienced this course--some, such as ESWL, rather meteorically. Perspective, however, is important and may allow the appropriate use of each of these modalities in the correct clinical setting. For example, ursodiol when given in sufficient dose to nonobese patients with small radiolucent stones, could be expected to effect partial or complete dissolution in as many as 75% of patients, with minimal or no adverse effects and in a cost-effective manner. Contact dissolution using MTBE has been shown to be safe and generally effective but requires diligent characterization of stones to avoid those that are pigmented or heavily calcified. Similarly, ESWL combined with oral bile acids may be consistently effective if treatment is restricted to patients with acceptable cholesterol stone burdens and if treatment can be safely continued until fragments are substantially reduced. Continued experience with each of these treatment options, along with advances in research providing new solvents and technologies or in preventing recurrence, is likely to establish this field in an appropriately optimistic light.


Respiratory gas monitoring in the pediatric patient. Parents of soon-to-be-anesthetized children frequently express concern about their child's safety because they have heard that "anesthesia is the most dangerous part of the operation." Although I don't believe that statement was ever true, it is even less true today. With the development of reliable capnography and volatile agent measurement in infants and children, we have significantly reduced the risks associated with anesthesia. I think we can, and should, confidently reassure parents that the "anesthesia part of the operation" has been made much safer and that the child's breathing (as well as heart beat, temperature, oxygenation, etc.) will be vigilantly monitored by the anesthesiologist using both human senses and the latest in monitoring equipment.


Temperature monitoring in pediatric anesthesia. Thermoregulatory responses in infants and children are now fairly well understood. The phenomenon of heat loss in children during surgery is widely acknowledged. Hypothermia is most likely to occur during long surgical procedures in an air-conditioned operating room, particularly when respiration is controlled. Its consequences have prompted clinicians to take extra care in maintaining normothermia, especially in the very young. It is well known that anesthetized infants and children are capable of active thermoregulation and that their vasoconstrictive threshold differs little from that in adults [31]. Body temperatures can be measured using a variety of thermometers. Most clinically used thermometers are reasonably accurate. Perioperative hypothermia results from decreased metabolic heat production, increased environmental heat loss, redistribution of heat within the body, and anesthesia-induced inhibition of thermoregulation. Radiation and convection from the skin surface combine with evaporation from tissues inside surgical incisions to decrease mean body temperature. Perioperative hypothermia can be limited by prewarming the skin surface before induction of anesthesia, warming the operating room, humidifying the airway, and warming intravenous fluids.


Noninvasive monitoring in the pediatric patient. Substantial technological improvements have been made in the field of noninvasive monitoring. Additionally, our understanding of what these monitors will and will not do has changed the practice of pediatric anesthesia. In the 1990s it has become apparent that many cardiorespiratory parameters can be easily and safely monitored noninvasively. It is also apparent that no single monitor is capable of providing all the information necessary to provide safe anesthetic care. Those of us who provide anesthesia for children on a regular basis have come to appreciate these monitors not as an annoyance required for medicolegal protection but as tools that help improve the quality and safety of the anesthesia care our children receive. Use of these monitors represents the leading edge of an effort to reduce anesthesia morbidity and mortality to zero.


Effect of different culture techniques used to induce capacitation on the chromatin stability of human sperm. To validate an in-vitro bioassay for assessing chromatin stability of human sperm, 38 semen samples from infertile men were studied using sodium dodecyl sulphate, an anionic detergent which disorganizes only the cytoplasmic membrane. Assay sensitivity was 50 sperm, whilst the within- and between-assay variation, and the between-observer variation were found to be within the accepted range for this type of bioassay. The influence of different in-vitro treatments currently used in some clinical assisted fertilization programmes was evaluated: a destabilizing effect occurred in Grade I (stable) and Grade III (swollen) sperm. In the former, all treatments reduced stable sperm; in the latter, a significant (P less than 0.001) increase in swollen sperm was shown with two methods that used Ham's F-10 as culture medium. Different chromatin patterns found in the treated sperm suggest the possibility that the recovered samples could be modified compared to their status at the time of isolation.


A double-blind trial of clomiphene citrate for the treatment of idiopathic male infertility. World Health Organization. A multicentre, randomized double-blind study was performed to assess the effect on male fertility of treatment with low dose clomiphene citrate. One hundred and ninety couples were included in whom the male diagnosis was idiopathic impairment of semen quality, and the female partner had no demonstrable abnormality or was under successful treatment for a minor endocrine problem. A total of 1308 couple-months were studied. Men received either 25 mg clomiphene citrate daily or placebo for 6 months. The cumulative life-table pregnancy rates at 8 months were 11.7% and 8.1% in the placebo and clomiphene groups respectively. There were no significant differences between the changes in semen quality during intake of either clomiphene or placebo. This study provides no evidence for the efficacy of clomiphene citrate for the treatment of idiopathic male infertility.


Deficiency in major high molecular-weight seminal proteins in men producing poorly coagulating and alkaline liquid ejaculates. Using SDS-PAGE three major high molecular-weight coagulum proteins (57, 75 and 79 kD) were identified in unliquefied human ejaculates. Washed coagulum was prepared at pH 4.5 and demonstrated negligible proteolysis as determined by a highly sensitive fluorescamine-based method. Laser densitometric scanning of these high molecular-weight proteins in unliquefied ejaculates in relation to their coagulational failure revealed that the total content of 57, 75 and 79 kD proteins in whole semen represented approximately 44% of levels in the normally coagulated, approximately 24% in poorly coagulated (P less than 0.005) and approximately 3% in the non-coagulated (alkaline liquid, P less than 0.001) samples. The findings imply that these predominant high molecular-weight proteins play a major role in human seminal coagulum formation.


Therapy with human chorionic gonadotrophin alone induces spermatogenesis in men with isolated hypogonadotrophic hypogonadism--long-term follow-up. The effects of long-term (14-120 months) hCG-treatment of 17 male patients affected by isolated hypogonadotrophic hypogonadism (IHH) on testicular volume, plasma testosterone levels, and sperm concentration were assessed. Mean testicular volume increased from 3.8 +/- 0.2 (Mean +/- SEM) ml to a maximal of 14.9 +/- 1.1 ml after 22.2 +/- 2.3 months of hCG treatment. Maximal testicular volume correlated positively with the volume recorded before the patients had undergone any previous treatment. Testicular growth was also analysed by sorting the patients into two sub-groups according to whether their initial testicular volume was less than 4 ml (small testis subset, STS) or greater than or equal to 4 ml (large testis subset, LTS), supposedly indicating complete or partial gonadotrophin deficiency, respectively. Testicular volumes in the LTS group were always greater than those of the STS. Plasma testosterone levels reached adulthood values during hCG treatment and no statistically significant difference was detected between LTS and STS patients with IHH. Thirteen patients (70%) became sperm-positive during treatment with hCG alone; five out of eight (60%) were STS patients and eight out of nine (90%) were LTS. In addition, LTS patients always had a greater sperm output than did STS patients. Sperm concentration correlated positively with maximal testicular volume, but not with patient age, length of treatment, or initial testicular volume. The administration of hMG to eight of these patients caused an increase in testicular volume in two patients but the mean volume was not statistically different from that recorded at the end of treatment with hCG alone. Similarly, sperm concentration improved in three patients but again it did not differ significantly from that achieved in the course of hCG treatment. It is noteworthy that one patient became sperm-positive after the addition of hMG to his therapeutic regimen. Among sperm-positive patients attempting conception, seven out of 10 succeeded, two of whom were from the STS group. In summary, this study indicates that hCG alone is an effective treatment to induce complete spermiogenesis in IHH patients regardless of their initial testicular volume. However, a number of IHH patients may benefit from the addition of hMG in terms of testicular volume, sperm output, and pregnancy outcome.


Sperm nuclear instability and staining with aniline blue: abnormal persistence of histones in spermatozoa in infertile men. During mammalian spermiogenesis, replacement of the somatic histones by basic proteins, the protamines, allows normal sperm nuclear condensation. In this study we have evaluated the degree of chromatin compaction in spermatozoa from 191 infertile subjects, affected by different testicular disorders, compare with that in 50 fertile sperm donors (controls). In infertile men, there was a higher percentage of unstable spermatozoa after incubation with sodium dodecyl sulphate (SDS) and of stained spermatozoa after staining with aniline blue (P less than 0.001 vs. controls). Furthermore, a positive linear correlation was found between SDS-unstable spermatozoa and stained spermatozoa (P less than 0.001), suggesting that sperm instability was related to a defect in histone-replacement by sperm-specific nucleoproteins, protamines. When the patients were considered according to pathology, high sperm nuclear instability and a high percentage of stained spermatozoa were detected in groups affected by varicocele, idiopathic infertility and in patients with a history of unilateral cryptorchidism. In the latter group the same alterations were observed even when the cryptorchid testis had been removed during surgery. In the group with a past history of mumps orchitis these parameters did not show any difference when compared with controls.


Efficacy of varicocele embolization versus ligation of the left internal spermatic vein for improvement of sperm quality. Efficacy of surgical varicocelectomy versus embolization of the spermatic vein was studied in 137 men diagnosed as suffering from left varicocele. The men were divided randomly into three groups according to the methods of treatment: A--embolization of the internal spermatic vein (51 men); B--Ivanissevich technique of high ligation of the spermatic veins (43 men); and C--Bernardi technique of high ligation (43 men). The groups were similar in terms of age, duration of infertility and possessed semen characterized as oligoteratoasthenozoospermia. The fertility of the female partners was evaluated carefully and they were found to be potentially fertile. Varicocele was diagnosed by at least two of the following methods: physical palpation during valsalva manoeuvre, venography, or scrotal scanning using the technetium pertechnetate radioactive method. Semen quality was assessed before treatment and at 3, 6 and 9 months post-treatment. Fecundity was followed-up for 18 months. The major results were: (i) Shrinkage of the varicocele was found in all three groups studied. The same rate of recurrence was recorded in the three groups (24%, 37% and 35% in groups A, B and C, respectively). (ii) Improvement of sperm quality was significant in groups A and B, with better results in group B. (iii) The pregnancy rate was significantly higher in group B, compared with A (38.2% vs. 20.6%; P less than 0.05). Thus, high ligation of the internal spermatic vein yields better results than low ligation or embolization as far as semen quality and pregnancy is concerned.


Temporal changes in the serum levels of gonadotrophins and testosterone in male rats bearing subcutaneous implants of 5 alpha-dihydrotestosterone. This study has assessed the effect of s.c. implants of 5 alpha-dihydrotestosterone (DHT) on the blood levels of testosterone and gonadotrophins in intact and castrated adult male rats. The rats were bled via cardiac puncture at 1, 3, 7, 14, 21, 28, 35, 42, 49, 56, 63 and 70 days after DHT implantation. On days 28 and 49 post-implantation, rats were injected with LHRH (25 ng) and bled 15 min later. In intact rats bearing DHT implants, the serum levels of LH and testosterone were suppressed significantly with no significant changes in FSH levels. Ventral prostate, seminal vesicles and the pituitary were reduced significantly in weight when compared with controls with empty implants. DHT significantly inhibited LHRH-induced release of FSH in intact rats. In castrated rats, DHT implants inhibited the secretion of both LH and FSH, with a rise in serum DHT levels. DHT stimulated the LHRH-induced release of LH but inhibited FSH. DHT implants increased the weight of the seminal vesicles and ventral prostate but inhibited the weight of the pituitary when compared to castrated rats bearing empty implants. This study demonstrates specific inhibition of serum LH and testosterone by DHT implants in intact adult rats.


Does follicle-stimulating hormone or pregnant mare serum gonadotrophin influence testicular blood flow in rats? Treatment of adult rats with 25 iu follicle-stimulating hormone (FSH) did not influence testicular blood flow, serum testosterone, vasomotion or intravascular leucocyte concentration at 6, 12 and 24 h after treatment. Treatment of adult rats with 50 iu pregnant mare serum gonadotrophin (PMSG) resulted in a two-fold increase in testicular blood flow at 24 h, and an increase in interstitial fluid volume at 36 h after treatment. This PMSG-induced increase in blood flow did not occur in Leydig cell-depleted animals, suggesting that the effect on blood flow is mediated via the Leydig cells. PMSG injection stimulated testosterone secretion but it did not influence vasomotion, and it only marginally increased the secretion of leucotactic factors in the testis. The present study suggests that FSH has no apparent effects on testicular blood flow and that the effects of PMSG (a hormone with both FSH and LH-like activity) is mediated via stimulation of the Leydig cells.


Hypoglycemia in diabetics on dialysis with poor glycemic control: hemodialysis versus continuous ambulatory peritoneal dialysis. Eight diabetic men with poor glycemic control, probably worsened by severe congestive heart failure and gastroparesis, were sequentially dialyzed by CAPD and hemodialysis. Mean blood glucose concentration, blood glycosylated hemoglobin, and insulin dose were higher during CAPD than during hemodialysis. Among blood glucose determinations, however, the frequency of hypoglycemia (glucose less than 3.3 mmol/L) was higher during hemodialysis (13.2 +/- 8.9%) than during CAPD (2.8 +/- 2.1% p = 0.012), whereas the frequencies of hyperglycemia (glucose greater than 11.1 mmol/L) and euglycemia (glucose between 3.5 and 11.1 mmol/l) did not differ between the two dialysis modalities. Furthermore, hypoglycemia was severe during hemodialysis and was associated with two deaths. There were no deaths linked to abnormalities in blood glucose concentration during CAPD. When hypoglycemia is frequent in diabetics with poor glycemic control, CAPD is preferable to hemodialysis.


Blood pressure after three different forms of correction of anemia in hemodialysis. It is not known whether recombinant human erythropoietin has a direct, clinically apparent pressor effect in hemodialysis patients or whether hypertension developing or aggravated in these patients merely reflects increased hematocrit. We compared blood pressure after three different methods of partial correction of anemia in hemodialysis patients with similar baseline hematocrits (erythropoietin n = 12, intravenous iron alone n = 10, androgens n = 9). Shortly after the start of treatment and with a minimally increased hematocrit, the need for antihypertensive medication increased in the erythropoietin group. No such pressor effect was observed with iron or androgens. These data suggest a direct hypertensive effect of erythropoietin in some patients on hemodialysis.


Can teledialysis help in the clinical management of patients on remote hemodialysis? This study investigated whether transmission of the parameters monitored from a remote center to the main center could improve the control of a dialysis session. The parameters of the computer connection module Monitral SC in remote and main centers, were transmitted by means of the Hospal data collection software (Demoplus) by modem, to the host computer. Each remote center can be temporarily disconnected, if necessary, from the telephone line and linked directly to a local computer. We checked 101 hemodialyses. The dialysis was monitored from filter washing to disconnection of the patients and the following parameters were selected: backfiltration during washing and hemodialysis: ultrafiltration, conductivity and temperature. From the sessions recorded (93%) we observed that backfiltration during the filter preparation phase was high (30%) in 28 sessions. Backfiltration during the preparatory phase is the major problem for correct management of dialysis sessions. The high percentage in which ultrafiltration had to be stopped shows that control of this parameter is still not ideal. Finally, the collection of monitor parameters and the comparative analysis of clinical data is useful for improving dialytic management.


Beta 2-microglobulin synthesis of mononuclear cells in chronic dialysis patients. Beta 2 microglobulin (B2M) has been identified as a major component of amyloid deposits. This study was designed to determine whether changes occur in the synthesis of B2M in dialysis patients. Mononuclear cells (MNC) were isolated in peripheral blood from healthy volunteers, patients on hemodialysis (HD) and on continuous ambulatory peritoneal dialysis (CAPD). MNC were cultured in a medium of RPMI 1640 with or without interleukins IL-1, IL-2 or interferon INF-r. B2M in the cultured cells and supernatant was measured by enzyme immunoassay. IL-2 or INF-r stimulated B2M synthesis was significantly lower (25%) in patients on HD than in normal controls regardless of the type of dialysis membranes used, with no change in basal B2M synthesis. No differences were detected between healthy volunteers and CAPD patients. Preincubation of MNC with complement--activating or non-complement--activating membrane had no influence on B2M synthesis. The basal B2M synthesis of MNC significantly increased after a 4-hour HD regardless of the membranes used, and IL-2 and IFN-r stimulated synthesis were both essentially the same before and after HD. It was thus concluded that maximum capacity for B2M synthesis of MNC decreases in hemodialysis patients. This low responsiveness of MNC may be partially the cause for the reduction in cell-mediated immune response in HD patients.


In vivo clearance and elimination of nine marker substances during hemofiltration with different membranes. The handling of low, middle and high molecular weight markers was examined in seven stable dialysis patients during hemofiltration with different membranes. Four membranes were examined in a randomized, crossover order (polysulfone, polyamide, AN69 polyacrylonitrile, Asahi polyacrylonitrile) by measuring plasma and dialysate concentrations of phosphate, creatinine, vitamin B12, beta 2-microglobulin, furanic acid, hippuric acid, retinol-binding protein, alpha-1-antitrypsin, and albumin. Sieving coefficients and plasma clearances of beta 2-microglobulin or retinol-binding protein were markedly or slightly lower during hemofiltration with the Asahi polyacrylonitrile membrane than with the other membranes (highest removal with polysulfone/AN69 polyacrylonitrile membranes). No differences of obvious clinical relevance could be seen between the four membranes. A high beta 2-microglobulin removal rate might be important to prevent dialysis-associated amyloidosis.


Acute renal failure in hepatitis A.

Acute renal failure in hepatitis A. A 21-year-old man developed acute renal failure early in the course of hepatitis A infection and recovered after 17 days. There was no evidence of pre-renal azotemia, the hepato-renal syndrome, ischemic acute tubular necrosis, rhabdomyolysis, or thrombotic microangiopathy. There was, however, transient proteinuria and hypocomplementemia. It would appear that the renal failure resulted from viral-induced injury, either direct or mediated by immune complexes.


A modular mock circulation for hydromechanical studies on valves, stenoses, vascular grafts and cardiac assist devices. P6vices for hydrodynamic simulation are required in a variety of studies such as device evaluation, cardiovascular modeling and for student training. Most studies today use different, incompatible circuits, which must be redesigned for every new application. To obtain a universal apparatus, a unitized system with standard connectors was developed. Three types of connectors were selected: 1" flange connectors, 1/2" tubing connectors and Luer-connectors with a 2 mm lumen. The complete system consists of reservoirs, throttles, valve holders, adapters for Doppler ultrasound probes, and converters to link these basic diameters. The apparatus can be driven by membrane, centrifugal and geared pumps. The system has successfully been used in echocardiographic studies of stenosis and valvular insufficiency, for pulse propagation in vascular grafts, and to test the hydraulic performance of cardiac assist devices. Flow rates between 0.1 and 30 l/min and pressure gradients up to 250 mmHg were achieved. In practical use, the system can be adapted to suit various investigations, with minimal expense. Standardization of the parts and connectors results in simple documentation and good reproducibility.


Lung involvement in systemic sclerosis sine scleroderma treated by plasma exchange. Systemic sclerosis sine scleroderma can present in some patients as pulmonary interstitial fibrosis. Until now ten cases with this particular clinical variant, all men, have been reported in the literature. The knowledge of systemic sclerosis sine scleroderma presenting as lung interstitial involvement is important in clinical practice for an early diagnosis and correct therapeutic strategy. This work reports the clinico-serological features of two further cases, one a woman, of systemic sclerosis sine scleroderma with prevalent lung involvement, and describes the effects of therapeutic plasma exchange.


Spontaneous dialytic ultrafiltration with intraperitoneal reinfusion of the concentrate versus large paracentesis in cirrhotic patients with intractable ascites: a randomized study. Dialytic ultrafiltration of ascites through a hemofilter associated with peritoneal reinfusion (DUF) of the concentrate has been proposed for the treatment of refractory ascites. In five cirrhotic patients, 18 ascites evacuation procedures were randomized either to DUF (n = 8) or to large paracenteses (LP) (n = 10). The effects of these two methods on hemodynamic and renal function were assessed. After DUF, the protein concentration in ascites increased transiently from 28 +/- 7 g/l to 64.8 +/- 8 g/l (p less than 0.04); urinary output increased from day 1 to day 4 (1000 +/- 100) VS 1430 +/- 140 ml/24h; p less than 0.02). After LP, ascitic protein concentration and urinary output were unchanged. No side effects were observed with the two methods. The mean amount of albumin infused was 20 +/- 15 g after DUF and 15 +/- 5 after LP (ns).


Stapedius reflex in patients with an inner ear prosthesis. The stapedius reflex elicited by electrical stimulation was investigated in 21 deaf individuals supplied with an inner ear prosthesis. All patients were implanted with the Vienna cochlear implant using intra or extracochlear electrodes. Analog stimulation with sinus bursts of various durations (25, 50, 100, 300, 500 ms) and frequencies (125, 500, 1000, 2000 Hz) was used. The time course of the contralateral acoustic reflex was monitored using a fast-response impedance meter. The stapedius reflex was observed in about half of the cases. Reflex threshold was observed at a stimulation level close to uncomfortable loudness. The time course in case of electrical stimulation differs in some aspects (rise time, onset) from acoustic stimulation in hearing individuals. Temporal integration of the stapedius reflex was observed also in case of electrostimulation through the cochlear implant.


Maximum likelihood estimation of signal detection model parameters for the assessment of two-stage diagnostic strategies. The methodology of Receiver Operating Characteristic curves based on the signal detection model is extended to evaluate the accuracy of two-stage diagnostic strategies. A computer program is developed for the maximum likelihood estimation of parameters that characterize the sensitivity and specificity of two-stage classifiers according to this extended methodology. Its use is briefly illustrated with data collected in a two-stage screening for auditory defects.


Mathematical modeling of the human fetal arterial blood circulation. A mathematical model of the human fetal arterial circulation based on mass and momentum conservation for one-dimensional flow is presented. We simplified the fetal arterial vascular system from the heart to the placenta, defined 16 anatomical segments and studied the characteristics of the vascular system in relation to changes in morphology and hemodynamics. The two-step Lax-Wendroff finite difference scheme was used to solve the system of equations, after introducing the rheological constants, the diameter and length of the segments measured by two-dimensional imaging and the mean arterial velocity at the inlet segments obtained by pulsed Doppler. The model was validated by comparing the numerical results to our non-invasive ultrasound direct measurements and to previous published data.


GALE: a graphics assisted learning environment for computer-based interactive videodisc education. GALE, a Graphics Assisted Learning Environment, is a computer-based interactive videodisc authoring tool. GALE was created as the authoring package for AI/LEARN/Rheumatology, an independent study system for teaching rheumatology to medical trainees. GALE has potential widespread application beyond rheumatology. Interactive videodisc technology is a prime feature of GALE. Other highlights are: WordPerfect macros which simplify programming, graphics-based large text characters, tracking of user responses, hypertext-like definition capabilities, color coded screens to distinguish between hypertext branches and the mainstream of the course content and ability to overlay text on the video image. GALE runs on a PC-compatible computer with selected Pioneer LaserDisc players. GALE uses WordPerfect 5.1 for text editing and has been designed for use by non-programmers.


Simulation modelling for HIV infection and AIDS. In this paper we describe a computer model developed jointly by mathematicians and medical consultants. The aim of the model is to provide practical help to people involved with caring for HIV-infected patients. The program is easy to use and can provide a wide variety of output, ranging from resource requirements and costs to detailed clinical information. The model uses the technique of computer simulation to study the progression of HIV-related diseases in a set of patients. The model can help planners concerned with the broad issues of health care provision, as well as clinical users whose main interest is the management and treatment of individual patients. The model is currently being tested in the Department of Genito-Urinary Medicine in the Royal Victoria Hospital, Bournemouth. The potential capability of the model is illustrated by some results from program runs using data from a set of Bournemouth patients. We argue that the power and flexibility of computer simulation as a technique for dealing with uncertainty and variability is especially appropriate in the case of HIV and AIDS.


Basophil degranulation control.

Basophil degranulation control. We first present a global simulation model describing inhibition of human basophil degranulation by means of high dilutions. Then we study an optimal control problem associated to a non-linear compartmental model. This control is associated to an antigen concentration. For solving this control problem we used a dynamic programming method.


Relationship among age, serum cholesterol level and population percentile in adults. The data of the National Health and Nutrition Examination Survey comprehensively have shown that distributions of serum cholesterol levels in the US adult population are age and sex dependent. General formulas were constructed and published by the author on the basis of the data of the National Health and Nutrition Examination Survey to predict the population percentile for serum cholesterol levels by age. A mathematical model and a computer program previously published by the author were employed in the study. Analysis of the computer-assisted predicted and the National Health and Nutrition Examination Survey-reported percentiles indicated that the designed program for calculating the formulas was accurate and reliable. The formula could determine the relationship among adult age, serum cholesterol level and population percentile. A comprehensive table and nomograms that show the relationship among age, serum cholesterol level and population percentile in men and women for each year group between 20 and 79 years of age are obtained in this study, using the previously published formulas. The population percentiles predicted by the formula may reflect the relative degrees of risk for coronary heart disease. The population percentile, simultaneously expressed as 'risk percentile', may be used as a parameter of risk assessment for coronary heart disease for all adult ages and sexes. Seventy-five population percentile of serum cholesterol level is suggested as a cutoff point of high 'risk percentile' for coronary heart disease. This information on the percentile may have a preventive diagnostic value for detection, evaluation and treatment of patients with high cholesterol levels. The comprehensive table and nomograms showing the relationship among age, serum cholesterol level and population percentile may be hopefully available to clinicians and useful in their medical practice and may also be helpful in future clinical investigation.


A four-parameter generalization of the Gompertz curve suitable for somatic growth. A four-parameter generalization of the Gompertz curve is proposed which passes through the origin with respect to total age and is often more suitable for somatic growth than the three-parameter Gompertz curve. Applied to published cross-sectional data on 44 male white rats, the new curve differs from another four-parameter curve proposed earlier by Jolicoeur and Pirlot (1988) in that it does not involve initial growth delays and it avoids an arbitrary assumption concerning the initial curvature, but it nevertheless yields approximately similar descriptions of chronological growth and complex allometry. The new four-parameter version of the Gompertz curve may be useful in cases where other growth curves do not provide a satisfactory fit.


Growth and utilization of nutrients in newly-hatched chick with or without removal of residual yolk. Two experiments were conducted to characterize the growth and utilization of nutrients in newly-hatched chicks, and to determine nutritional roles of residual yolk by comparing chicks with or without deutectomy (removal of residual yolk sac). Rapid growth during 14 days after hatch was shown in the fed chicks. Daily feed intake increased linearly for 15 days posthatch, resulting in a high efficiency (80%) of feed utilization. Residual yolk in the abdomen averaged 6.4 g at hatch and rapidly disappeared during the first 3 days. Posthatch starvation resulted in a decrease in carcass lipid content but did not modify the disappearance rate of yolk in the abdomen. Weight of the digestive tract per unit body weight increased markedly up to 3-7 days of age followed by a gradual decrease in the fed chicks. Metabolizability of dietary energy and absorption of dietary lipid were the highest at hatch, then declined to the lowest at day 5 or 6, and thereafter gradually increased. The deutectomy did not influence the metabolizability of dietary energy and lipid, and the carcass composition, but delayed the growth by 2 days behind the control chicks. These results indicate that the metabolism and nutrition of newly-hatched chicks markedly fluctuate and that the residual yolk has crucial roles in complementing the nutrients absorbed to assure their rapid growth posthatch.


Morphometrical analysis of the short-term effects of hypophysectomy and food restriction on skeletal muscle fibers in relation to growth and aging changes in the rat. Muscle fiber growth is impaired by lack of hormonal influence. In the case of the gastrocnemius muscle of the male Wistar rat, ablation of the pituitary at age 60 days results in cessation of the growth of type 1 muscle fibers, and a reduction in the size of type 2 muscle fibers at 120 days of age, 60 days after hypophysectomy. The effects of food restriction, which are known to reduce pituitary hormone secretion, are not as great as hypophysectomy in inhibiting muscle fiber growth. Food restriction slowed the growth of type 1 muscle fibers (hypophysectomy abolished growth) and caused cessation of growth of type 2 muscle fibers (hypophysectomy caused atrophy).


NMR study on solution structure of the site-specific mutant Leu48----Ala transforming growth factor alpha. The NMR spectra of the Leu48----Ala mutant of human transforming growth factor alpha were compared to that of the wild-type. All chemical shift changes are less than or equal to 0.02 ppm with the exception of resonances associated with residues 47, 48 and 50 (all less than or equal to 0.07 ppm). Minimal changes were observed for NOEs associated with residues Val1 to His45. The weakening of some NOEs associated with the region Ala46-Ala50 may suggest a slightly increased flexibility for this region. Refinement of the previously calculated wild-type structures using distance constraints derived from the L48A mutant had little overall effect. Leu48-Ala50 is ill-defined for both wild-type and mutant proteins. These results suggest that Leu48 has no structural role and thus must be an important factor in the protein-receptor interface.


1H-NMR conformational study of a synthetic peptide derived from the consensus sequence of annexins. The solution conformation of a synthetic 18 amino acid peptide derived from a consensus sequence of Annexins has been investigated by 1H NMR. Full sequential assignment has been achieved. Conformational properties of the peptide were deduced from the analysis of J(NH-CH alpha) coupling constants, amide proton exchange, 2D NOESY connectivities and computer modeling.


Cyclo(L-prolyl-L-N-methylphenylalanyl). Conformation in solution and in the crystal. Detailed analysis of the proton and carbon-13 NMR spectra of cyclo(L-prolyl-L-N-methylphenylalanyl) in chloroform and methanol in relation to its nonmethylated analog provided information on the conformation of the title compound in solution as well as on the effect of N-methylation and solvation. The X-ray structure of the title compound in the crystalline state showed the same conformational features as the solution structure. The phenyl group folds over the diketopiperazine ring which resembles a flattened half-chair. Both amide bonds are considerably nonplanar. The pyrrolidine ring of proline shows a strong pucker at the ring junction with the largest chi 5 value hitherto observed.


Search for peptide immunogens of the beta-subunit of human chorionic gonadotropin (hCG) capable of eliciting hormone specific and neutralizing antisera. Identification of an undecapeptide eliciting hCG-specific antisera. The work reported herein describes our attempts to identify peptide immunogens of the beta-subunit of the pregnancy-specific placental hormone, human chorionic gonadotropin (hCG), capable of eliciting hormone specific and neutralizing antisera. Hydrophilicity profiles of the beta-subunits of hCG and the homologous pituitary hormone, human luteinizing hormone (hLH) were compared and two sequences which are hydrophilic but unique to hCG-beta were identified. They are 6-12 and 109-119 of hCG-beta. Results of the studies with the undecapeptide 109-119 of hCG-beta are reported in this paper. The undecapeptide amide was synthesized using the p-(acyloxy) benzhydrylamine resin and antisera to the peptide were elicited in rabbits using the peptide-diphtheria toxoid conjugate. The peptide is highly immunogenic as both the rabbits responded with high titers of antibodies to the peptide. The antipeptide antibodies bound to hCG but not to hLH showing thereby that the region 109-119 of hCG-beta is a unique determinant of hCG. However, the antibodies were found not to neutralize the biological activity of hCG.


14-membered cyclic opioids related to dermorphin and their partially retro-inverso modified analogues. I. Synthesis and biological activity. As a continuation of our program to study structure-activity relationships of opiate peptides, we report the syntheses and biological activities of a series of 14-membered cyclic dermorphin analogues closely related to enkephalin analogue Tyr-c[D-A2bu-Gly-Phe-Leu] incorporating a phenylalanine at the third position in place of glycine. In addition to two parent dermorphin analogues Tyr-c[D-A2bu-Phe-Phe-(L and D)-Leu], four stereoisomeric retro-inverso modified analogues Tyr-c[D-A2bu-Phe-gPhe-(S and R)-mLeu] with a reversed amide bond between residues four and five, and Tyr-c[D-Glu-Phe-gPhe-(L and D)-rLeu] with two reversed amide bonds between residues four and five, and between residue five and the side chain of residue two have been synthesized. The results from the guinea pig ileum (GPI) and mouse vas deferens (MVD) assays show that all analogues are superactive at either one or both opiate receptors and in general display higher activities as compared to the corresponding enkephalin analogues with a glycine at the third position. Results from the in vitro biological assays and conformational analysis using 1H-NMR spectroscopy (adjoining paper) will provide useful information to understand the role of the Phe3 aromatic side chain in dermorphin, and that of the Phe4 aromatic side chain in enkephalin, on opiate activity since these cyclic dermorphin analogues contain two Phe residues at both the third and fourth positions.


14-membered cyclic opioids related to dermorphin and their partially retro-inverso modified analogues. II. Preferred conformations in solution as studied by 1H-NMR spectroscopy. The 1H-NMR studies were extensively carried out to elucidate preferred conformations of a series of 14-membered cyclic dermorphin analogues containing two phenylalanines at both the third and fourth positions, e.g., Tyr-c[D-A2bu-Phe-Phe-(L and D)-Leu], Tyr-c[D-A2bu-Phe-gPhe-(S and R)-mLeu], and Tyr-c[D-Glu-Phe-gPhe-(L and D)-rLeu]. The temperature coefficients of the amide proton chemical shifts, vicinal 1H-1H coupling constants for the NH-CH groupings, and nuclear Overhauser effects provided information regarding the preferred conformations of the backbones. The conformational preferences and flexibility of the side chains were also estimated from the vicinal 1H-1H coupling constants around the C-C beta and C beta-C bonds in the articulated side chains. A comparison of the results obtained was made with the results previously obtained for the corresponding enkephalin analogues containing a glycine at the third position. It was found that the replacement of the glycine with the phenylalanine at the third position increases the conformational flexibility of the molecules with an L-, or S-, residue at the fifth position but reduces the flexibility of the molecules with D-, or R-, residue at the same position. The rotating frame nuclear Overhauser experiments gave direct evidence for compact conformations, with the Tyr side chain folding back over the 14-membered ring in Tyr-c[D-Glu-Phe-gPhe-rLeu], which displays relatively high selectivity for the delta-receptor over the mu-receptor. This observation is in agreement with our model proposed for the cyclic enkephalin analogues: folded forms with close aromatic ring placement are required for the activity at the delta-receptor.


Circular dichroism of reduced and oxidized recombinant human epidermal growth factor. To further elucidate the role of the disulfide bonds in determining the protein folding of recombinant human epidermal growth factor (r-HuEGF) we studied the structure of reduced and oxidized r-HuEGF using circular dichroism (CD). The far UV CD spectrum of reduced r-HuEGF in 10 mM sodium phosphate pH 3.0 is very different from that of the oxidized molecule. The spectrum of the reduced molecule consists of a plateau from 225 to 200 nm, consistent with the presence of alpha-helix, beta-sheet, and unordered structure. The addition of the alpha-helix inducer trifluoroethanol to the reduced molecule resulted in an enhancement of alpha-helix, at the apparent expense of beta-sheet, while the oxidized molecule was unaffected by the presence of this reagent. Secondary structure predictions based on the amino acid sequence of EGF correlate most closely with the structure of the reduced molecule. From these results, it appears that the r-HuEGF has a more regular secondary structure in the absence of the disulfide bonds than in their presence. This suggests that the folding of EGF occurs by destroying the regular secondary structure that was present in the reduced state, and that the structure of the native molecule is dictated largely by disulfide bonding.


Hydrogen bond connectivity patterns and hydrophobic interactions in crystal structures of small, acyclic peptides. Crystal structures of all available unblocked linear peptides with two to five residues were retrieved from the Cambridge Structural Database and their intermolecular contacts and packing modes studied using molecular graphics. This survey reveals that interactions between hydrophobic portions of the molecules are critically important in determining the overall features of their crystal packing patterns. Distinct hydrophobic columns or layers are observed in almost all crystal structures. Analyses of the relationships between these interactions and crystal growth properties of small peptides are given. It is suggested that needle growth is promoted by hydrophobic packing, usually along a short crystallographic axis (4.6-6.0 angstroms). Also contributing to these morphologic characteristics are entropic factors associated with hydrophobic aggregation as well as tightly bound water molecules on hydrophobic faces. The paper also provides a comprehensive overview of hydrogen bond patterns in acyclic peptide crystals. It is demonstrated that one of their primary roles is to provide a scaffolding within which hydrophobic groups can aggregate. Even though there is a high density of hydrogen bonds in the crystals, often with complex patterns and networks, certain motifs are found to recur in a number of structures indicating specific hydrogen bond preferences. Water, for example, is an integral part of the hydrogen bond networks in these crystals, usually acting as the primary donor for main-chain carboxylate groups in peptide hydrates.


Psychosocial and psychopathologic influences on management and control of insulin-dependent diabetes. The objective of this research was to explore the relationship of psychosocial variables to management and control of insulin-dependent diabetes, as measured by a scale of reported behavioral adherence and by glycosylated hemoglobin, respectively. The method includes a relatively large sample (127 subjects) drawn from a clinic, a broad range of psychosocial variables (depression, anxiety, family process, health locus of control), and documented reliability and validity of psychosocial measurement (alpha coefficients ranging from .63 to .95). The results show that both anxiety and depression have weak positive correlations with blood sugar. Family process variables also are weakly correlated with blood sugar. The measure of behavioral adherence is moderately correlated with blood sugar. The life stage of the diabetic appears to affect these relationships markedly. The conclusion is that there is no broad strong association of psychosocial variables with blood sugar but that there may be subgroups of diabetics, especially adolescents with recent onset, for whom the relationships may be more powerful.


High "need for control" as a psychological risk in women suffering from ischemic stroke: a controlled retrospective exploratory study. The assumption is tested that women scoring high on dimensions of coping pattern termed "need for control," which underlies several of the components of Type A behavior, are at increased risk of ischemic cerebrovascular disease. Consecutively admitted patients to medical wards, nineteen with ischemic cerebrovascular disease, were compared with nineteen patients with non-arteriovascular disease and nineteen healthy females doing volunteer hospital work. "Need for control" was assessed by a psychometric test based on forty-five dichotomous items defining six unidimensional scales. The Bortner Type A behavior was filled out by the subjects and by their next of kin for an impression of the subject. In ANOVA the dimensions "work commitment, hard driving" (F = 6.87, p less than .002), "perfectionism, need for making plans" (F = 6.26, p less than .003), and "inability to withdraw from work obligations" (F = 3.89, p less than .02) differentiated the three groups in the expected direction. Duncan multiple range test resulted in very similar, significant findings, as did Bortner measures, filled out by a next of kin (F = 4.63, p less than .01). In all analyses, effects of age, current smoking, and coronary artery disease (CAD) were controlled. Our results suggest that high "need for control" defines a psychological risk in women suffering from ischemic stroke. Prospective studies should be undertaken. If they confirm our results, interventions aimed at modifying the "need for control" should be planned.


Provocation of pseudoseizures by psychiatric interview during EEG and video monitoring. This paper discusses a new technique for diagnosing pseudoseizures. The technique consists of an intensive psychiatric interview designed to provoke a pseudoseizure during EEG and video monitoring. We wished to determine the overall efficacy of the technique and learn how our patients felt about having undergone the procedure. We were also interested in whether their seizures persisted approximately three years later. We reviewed medical records and conducted telephone interviews with thirty of thirty-two patients who had previously undergone the procedure as part of an evaluation for unusual or intractable seizures. All evaluations had been performed on a university hospital neurology service. The patients were consecutive referrals to the consultative psychiatry service for suspicion of pseudoseizures. Nineteen of the thirty-two patients interviewed had a pseudoseizure under EEG and video monitoring. Of the thirty reached by telephone for follow-up, twenty-two recalled the procedure as helpful or benign. None regarded the overall psychiatric consultation negatively. Among the patients who had exhibited pseudoseizures there was a variety of psychiatric diagnoses with a preponderance of personality disorders. Two thirds of those patients without coexisting epilepsy stopped having seizures or rarely had seizures following their evaluations. The diagnostic technique described here is useful in patients with possible pseudoseizures. It does not appear to be harmful when employed as part of a comprehensive psychiatric consultation. How it may compare with other methods of pseudoseizure diagnosis will have to be determined by further study.


Psychological profile of somatizing patients attending the integrative clinic. A clinic to evaluate and treat referred somatizing patients was established in the medicine clinic of a university medical center. Fifty-four patients were evaluated and compared to an age- and sex-matched non-somatizing patient group. Somatizing patients had increased rates of psychiatric and alcohol and substance abuse histories. Somatizing patients scored high on all subscales of the SCL-90 and were most frequently found in the Anxious/Moody Cluster of the MBHI. These patients also endorsed highly beliefs in medical problems as a focus of their lives. These patients' psychological beliefs set the stage for conflict in the medical setting. The implications of these results are discussed in relation to liaison clinics, early identification, and treatment approaches.


A prospective study of the effectiveness of brief professionally-led support groups for infertility patients. This study prospectively evaluates the effectiveness and patient acceptability of professionally-led support groups in alleviating psychologic distress in infertility patients. Sixty-four consecutive patients in a university hospital infertility program were administered a battery of psychologic tests before and after attendance at an 8 weekly session support group. The comparison group consisted of 35 consecutive infertility referrals to the same unit who were not initially offered the support group and were similarly tested over an 8 week period. Support group patients had significantly greater (p less than or equal to 0.01) entry than exit scores on several measures of psychologic distress and depression (the Beck Depression Inventory, the Hamilton Rating Scale for Depression, and the Global Severity Index, Anxiety, Depression, Hostility and Obsessive Compulsive Subscales of the Brief Symptom Inventory). The Avoidance Coping Style on the Moos Coping Responses Inventory was correlated with a higher Global Severity Index (p less than or equal to 0.01). Comparison group patients had similar psychometric scores to the support group patients at entry but showed no change over 8 weeks. Attenders expressed a high rate of satisfaction with the support group. Professionally-led support groups are a highly acceptable and effective intervention in self-referred patients in alleviating psychological distress related to infertility.


A brief depression scale for use in the medically ill. Using items from two existing depression scales, we have sought to develop a brief self-rated instrument for detecting major depressive disorder (M.D.D.) in medically ill, hospitalized patients. Forty-two items from the Geriatric Depression Scale (G.D.S.) and Carroll Depression Scale were administered to 559 men under age 40 or over age 70 consecutively admitted to the hospital. Eighty-two M.D.D.'s were diagnosed in this group by structured psychiatric interview. After eliminating 12 items confounded by medical illness, 11 items were selected using regression analysis, correlation with the total score, and factor analysis. The 11-item scale includes an assessment of the five DSM-III-R criteria for M.D.D. which are least confounded by medical illness (mood, suicidal intent, guilt or worthlessness, concentration, and psychomotor agitation). The scale was then tested in 78 medical inpatients who were later assessed for M.D.D. using a structured psychiatric interview. Ten out of twelve M.D.D.'s were identified (83% sensitivity) and depression excluded in 51 of 66 non-depressed subjects (77% specificity) (compared with 82% sensitivity and 76% specificity for the 30-item G.D.S.). Scores on the 11-item scale were also correlated with the G.D.S. (.92), the Zung Depression Scale (.58), and the C.E.S.-D (.67). The 11-item scale is a practical tool for clinicians who screen patients for depression and for investigators who need a brief measure of depression in studies involving medical inpatients.


Nursing evaluation: purposes, achievements and opportunities. Evaluation has become a powerful, specialized discipline in recent decades, with its own sophisticated conceptual and technical apparatus. Evaluation of nursing has benefited strongly from these developments, as examples of cogent, recent evaluations demonstrate. Evaluation is already proving an indispensable practical tool for raising the quality of health care, and for advancing professional nursing standards. Nonetheless, there is room for further improvement. Neglected areas of nursing should be brought under the spotlight of evaluation, conceptual and methodological rigour should be strengthened, and training in research skills should be extended.


Evaluating computer assisted learning for renal patients. Healthcare professionals have become increasingly concerned with evaluating the impact of their interventions. Consumerism, quality initiatives and financial constraints have contributed in large measure to this concern. Consequently, the focus of many studies which involve the introduction of new and untried techniques is often on demonstrating their relative usefulness. This study sought to evaluate the usefulness and acceptability of computer assisted learning (CAL) for use in the education of renal patients on continuous ambulatory peritoneal dialysis. However, several problems were encountered which limited or impaired the evaluation process. We describe these problems and use them to illustrate the difficulties inherent in evaluative research.


Health visiting: action research in a controlled environment. The nature of health visiting is discussed. It operates in a radically different way from any of the curative services. Research into the effectiveness of health visiting must therefore take into account the many differences in context, in professional goals and in the nature of the interaction between health visitors and their "clients", compared with the work of the curative professions within their more controlled and controlling environments. The evaluation of one large scale health visitor intervention study is used here to highlight these differences. Health visiting research needs to free itself from the attempts by some to apply the laboratory model of evaluation, if it is to develop a corpus of "action research" thinking which reflects its more human and developmental characteristics.


Issues in the evaluation of small-scale adult day care programs. Evaluation of health care programs is a complex process which presents many challenges. A case study of a small-scale adult day care program evaluation is presented to illustrate these issues. The rationale for developing the program and the findings from the evaluation study are discussed. Several evaluation issues including the use of multiple methods, levels of analysis, characteristics of the sponsoring agency, political influences, methodological issues and influences on utilization of findings are addressed.


Piloting an evaluation of triage.

Piloting an evaluation of triage. This paper takes a broad view of the work involved in pilot studies of evaluation research. Drawing on their experience of preparation for a field experiment in a British Accident and Emergency department, which was to evaluate the effectiveness of a nurse triage system, the authors stress the importance of careful observation of the system to be studied, in the environment in which it is to be studied. In addition, the usual evaluations of research instruments which comprise formal pilot studies are included.


Evaluation in mental health services: some quality assurance models. This paper examines the context in which a concern for evaluation in mental health services has emerged. Quality assurance activities are seen as the main method of evaluating such services at the present time. A distinction is made between internal and external approaches to quality assurance and an example of each method is examined for its strengths and weaknesses. Successful quality assurance programmes are seen as being dependent on an amalgamation of these two approaches and two generic systems which adopt this method, "QUARTZ" and "Psychiatric Monitor" are considered for their strengths and weaknesses. It is suggested that evaluation strategies should be assessed for their capacity to promote organizational change. The increasing influence of the User movement is discussed.


Survey of nursing quality assurance programs in selected hospitals in Alberta, Canada. This study represents a survey of the nursing quality assurance programs in 12 hospitals in Alberta. The objectives of the study were: to identify the nature, content and costs of the programs, to determine the extent of nurse involvement in the design and operation of the programs, and the value and importance nurses place on their programs. The major findings of the study tend to support the view that the principles of organizational change theory have not been adequately addressed in terms of nursing quality assurance programs. Generally, nurses reported that they were insufficiently informed concerning their programs. Among the study recommendations is a call for improvements in the audit tools used, with greater emphasis being placed on the patient and the nurse providing the care and more decentralization of programs to the unit level to improve staff involvement and program relevancy.


Evaluation of nursing education programmes--theory and practice. In this paper, the history of educational evaluation is considered through a review of the literature, in order to try and understand how current evaluation methods have developed. It is important that a historical perspective is gained, as there has been a big shift in thinking from a strongly behaviourist code of practice to a more investigative and less prescriptive approach, during the relatively short time span that evaluation has had to develop as a subject in its own right. The application of the theory to practice is also considered in terms of a working evaluation model developed through work on continuing education courses in Scotland.


Serum levels of vitamin A and retinol binding protein in chronic renal patients treated by continuous ambulatorial peritoneal dialysis. The possible causes and consequences of hypervitaminosis A and retinol binding protein (RBP) levels were investigated in patients with chronic renal disease submitted or not to dialysis treatment. The study was conducted on 20 patients divided into two groups: 10 patients with chronic renal failure (CRF) treated by continuous ambulatorial peritoneal dialysis (CAPD), and 10 CRF patients with no dialysis treatment. Ten normal subjects formed the control group. Retinol levels were determined by HPLC, and RBP levels by immunoassay in plasma and in post-dialysis fluid at different periods of time. Laboratory tests were carried out on all subjects, and dietary history was taken. Patients on dialysis had higher retinol levels than untreated patients. Retinol levels were found to be correlated with RBP levels. Serum retinol and RBP levels did not vary with diet, age or time of disease, dialysis group or time of dialysis, nor were they correlated with the levels measured in the dialysis fluid (CAPD). There was no significant correlation in retinol levels between chronic patients and controls. It is suggested that vitamin A and RBP clearances during dialysis do not accompany urea or creatinine clearance. Hypervitaminosis A did not show any toxic effect.


Effects of dietary retinol on hepatic retinol storage and on plasma and tissue alpha-tocopherol in pigs. A feeding experiment was carried out with pigs to investigate the effects of graded dietary retinol supplements on hepatic and plasma retinol and on alpha-tocopherol in plasma and selected tissues. Four groups of twelve weanling pigs each with a mean body weight of 7 kg were fed a complete ration containing 54 IU vitamin E/kg and supplemented with 5, 10, 20 or 40 x 10(3) IU retinol/kg for Treatments 1 to 4, respectively. The feed was fed in restricted amounts for 150 days when the pigs were slaughtered at 105 kg body weight. Overall daily body weight gain and feed conversion ratio were 660 g and 2.49, respectively, without treatment differences (p less than 0.01). Hepatic retinol concentration (y, IU/g fresh weight) was linearly related to dietary retinol concentration (x, IU/kg feed) as expressed by y = -88.9 + 0.077 x [r2 = 0.94]. Total hepatic retinol (y, IU) and total retinol intake (x, IU) were linearly related as expressed by y = -194.9 x 10(3) + 0.4585 x [r2 = 0.98]. Hepatic retinol retention relative to intake ranged from 30.0% to 44.9%. Plasma retinol concentration was not affected by dietary retinol (p less than 0.01). Plasma alpha-tocopherol levels remained on a plateau for 42 days in all treatments. After 150 days plasma levels exceeded those at 42 days in Treatments 1 to 3, but not in Treatment 4. The effect of retinol on tissue alpha-tocopherol varied with tissues. While there was no effect on M. Longissimus and backfat, alpha-tocopherol levels in heart and liver showed an inverse relationship with dietary retinol.(ABSTRACT TRUNCATED AT 250 WORDS)


Tolerance of growing pigs for dietary vitamin A, with special reference to bone integrity. Weanling crossbred pigs (144) of 8 kg initial weight were fed to 90 kg on diets containing graded levels of vitamin A representing 0, 1, 5, 10, 50 and 100 times the NRC (1988) estimated requirement. No clinical signs of deficiency or toxicity were recorded although plasma and liver retinol levels were affected by treatment. Histopathological examination indicated a high incidence of lesions in the cartilage of the distal femur and ulna, but they were not related to treatment. There was some evidence that excessive vitamin A levels in the diet significantly reduced the uronic acid concentration in joint cartilage, indicating a reduced concentration of proteoglycans. However no relationship was established between dietary vitamin A level and the incidence of clinical osteochondrosis. The results suggest that the allowable range of vitamin A set out in the Canadian feeds regulations is appropriate for practical pig production.


Morphological changes in the tracheal epithelium of guinea pigs in conditions of "marginal" vitamin A deficiency. A light, scanning- and transmission-electron microscopic study under special breeding conditions appropriate to early vitamin A deficiency. The aim of the study was to find out the influence of marginal vitamin A deficiency on morphological structures in the tracheobronchial epithelium in guinea pigs. The tracheobronchial epithelium of animals with vitamin A deficiency (n = 15) and control animals (n = 7), kept under optimal laboratory conditions, was evaluated by light and electron microscopy. The cellular ultrastructure was morphometrically analyzed. The height of the respiratory epithelium was slightly increased. The basal cells were arranged in a loose cell band of three to four layers. The quantity of cytofilaments in their cytoplasm was enhanced. Goblet cells were significantly reduced in vitamin A deficiency. There was also a significant decrease in their secretory granules. The number of ciliated cells was almost unchanged. They showed a significant reduction in mitochondria. The kinocilia often contained an atypical structure of the microtubules. Our findings confirm multiple ultrastructural dysplasias in early vitamin A deficiency which may lead to a disturbance of mucociliary clearance.


Retinoid glucuronides do not interact with retinoid binding proteins. Retinoid glucuronides have recently been described as water soluble, biologically active retinoids. In mouse mammary gland organ cultures retinoyl glucuronide, a retinoic acid counterpart, inhibited hormone induced differentiation. In this report we examined whether the effects of retinoyl and retinyl glucuronides are mediated by specific retinoid binding protein in mammary glands in organ culture. Results indicated that neither retinoyl nor retinyl glucuronide competed for cytosolic retinoic acid or retinol binding proteins respectively. These results indicate that either the effects of retinoid glucuronides are independent of retinoid binding proteins or they have to be metabolized to an active component which may in turn bind to retinoid binding protein for the glucuronide action.


Zinc deficiency reduces hepatic cellular retinol-binding protein in rats. Hepatic cellular retinol-binding protein (cRBP) levels were measured from the livers of four groups of Sprague-Dawley rats after three weeks of dietary treatment. The experimental group (n = 8) received a zinc-deficient (2.3 mg/kg dry powder) liquid diet ad libitum. A pair-fed control group (n = 8) received the same amount of liquid diet with supplemental zinc (60 mg/kg dry powder). Another control group (n = 8) received liquid diet ad libitum with supplemental zinc (60 mg/kg powder). A third control group (n = 7) received a pellet diet which also contained the same amount of zinc as the other control groups (60 mg/kg). Hepatic cRBP was reduced by more than 50% in the experimental group as compared to each of three control groups. It appears that zinc may be an essential element for the intra-cellular transport of vitamin A, in addition to its well-established role in the intercellular transport of vitamin A.