The late-presenting HIV-infected patient 30 years after the introduction of HIV testing: spectrum of opportunistic diseases and missed opportunities for early diagnosis.

OBJECTIVES: The aim of the study was to describe the characteristics of HIV-infected late presenters, opportunistic diseases at diagnosis and missed opportunities to diagnose HIV infection earlier. METHODS: In a retrospective cohort study, we reviewed the medical records of all adults with newly diagnosed HIV infection admitted to the Department of Infectious Diseases of the Vivantes Auguste-Viktoria Hospital, Berlin, Germany. RESULTS: In the 5-year period from 2009 to 2013, 270 late presenters were identified. The most common AIDS-defining conditions were oesophageal candidiasis (n = 136; 51%), wasting syndrome (n = 106; 40%) and pneumocystis pneumonia (n = 91; 34%). Fifty-five patients (21%) had presented with at least one HIV indicator condition on prior contact with health care services without being offered testing for HIV. Female patients and heterosexual men [not men who have sex with men ('non-MSM')] had a significantly higher chance of being among patients previously presenting with indicator conditions and not being tested [odds ratio (OR) 4.7; 95% confidence interval (CI) 2.2-10.0; P < 0.001; and OR 2.4; 95% CI 1.2-5.1; P < 0.01, respectively]. The most commonly missed indicator conditions were leucocytopenia (n = 13; 24%), thrombocytopenia (n = 12; 22%), oral candidiasis (n = 9; 16%), unexplained weight loss (n = 7; 13%), herpes zoster (n = 5; 9%) and cervical dysplasia/cancer (n = 4; 20% of women). The median time between presentation with an indicator condition and the diagnosis of HIV infection was 158.5 days [interquartile range (IQR) 40-572 days]. Patients with oral candidiasis and unexplained weight loss had the shortest time between the "missed opportunity" and the diagnosis of HIV infection. Fifty-five hospital admissions with a total cost of over EUR 500 000 and - most importantly - six in-hospital deaths might have been prevented if HIV testing had been performed in patients with documented indicator conditions. CONCLUSIONS: Indicator conditions are still missed by clinicians. Women and 'non-MSM' are at highest risk of presenting with an indicator condition but not being tested for HIV infection.

Effects of carnitine in ischemic and fatty acid supplemented swine hearts.

FREE FATTY ACIDS (FFA) IN EXCESS FFA: albumin molar ratios have been determined to additionally compromise mechanical performance in ischemic hearts. Carnitine, an intracellular carrier of FFA and an agent which is lost to the heart during ischemia, has been postulated to in part restore function with its replacement. To test whether its benefits are also operative in a setting of excess FFA, these studies were performed. In the main protocol, four groups of perfused swine hearts (n = 45) were compared during 50 min of control flow (179.7 ml/min) and 40 min of global ischemia (106.1 ml/min). Initial base-line serum FFA:albumin molar ratios and carnitine levels in all groups were 1.3:1 and 8.5 nmol/ml, respectively. In two of these groups FFA:albumin ratios were increased to 5.9:1 with constant infusions of Intralipid. In two alternate groups (one with and one without extra FFA supplements) dl-carnitine was supplied, sufficient to increase serum levels nearly 200-fold. Ischemia per se in 14 hearts significantly decreased several parameters of global and regional mechanical function including left ventricular (LV) and mean aortic pressures, LV isovolumetric pressure development (max dp/dt), LV epicardial motion, and LV work, together with concomitant decreases in myocardial oxygen consumption. Elevated FFA in 12 hearts rendered similarly ischemic further decreased mechanical function (LV pressure: -20.8%, P < 0.05; mean aortic pressure -26.9%, P < 0.05; LV max dp/dt: -39%, P < 0.05; regional LV shortening: -51.1%, P < 0.05; and LV work: -50.3%, P < 0.05) as compared with nonsupplemented hearts. dl-Carnitine treatments in nine hearts, not supplemented with extra FFA were without apparent effect in improving overall hemodynamic performance. However, dl-carnitine in 10 high FFA-ischemic hearts effected several improvements as compared with the untreated group: LV pressure was increased 25.6%, P < 0.025; mean aortic pressure: +43.5%, P < 0.05; LV max dp/dt: +41.5%, P < 0.05; regional LV shortening: +241.3%, P < 0.001; and LV work: +76.2%, P < 0.05 at comparable levels of myocardial oxygen consumption. In a separate protocol, the effects of stereospecificity were also studied by comparing l- with dl-carnitine in globally perfused, palmitate-supplemented hearts (five hearts in each treatment group). At similar conditions of flow and serum FFA, changes in mechanical function were comparable, except for a tendency to perform greater LV work at reduced flows in the l-carnitine-treated hearts. Thus, it was demonstrated that carnitine in ischemic hearts is capable of preserving mechanical function under conditions of excess FFA, presumably by modifying the toxic effects of FFA intermediates. The major therapeutic actions appeared to derive from the l-isomer of carnitine.

Mechanical and metabolic functions in pig hearts after 4 days of chronic coronary stenosis.

OBJECTIVES: This study sought to evaluate the functional and metabolic consequences of imposing a chronic external coronary stenosis around the left anterior descending coronary artery for 4 days in an intact pig model. BACKGROUND: A clinical condition termed hibernating myocardium has been described wherein as a result of chronic sustained or intermittent coronary hypoperfusion, heart muscle minimizes energy demands by decreasing mechanical function and thus avoids cell death. The use of chronic animal models to stimulate this disorder may assist in establishing causative associations among determinants to explain this phenomenon. METHODS: A hydraulic cuff occluder was placed around the left anterior descending coronary artery in eight pigs. Coronary flow velocity was reduced by a mean (+/- SE) of 49 +/- 5% of prestenotic values, as estimated by a Doppler velocity probe. After 4 days the pigs were prepared with extracorporeal coronary circulation and evaluated at flow conditions dictated by the cuff occluder. Substrate utilizations were described using equilibrium labeling with [U-14C]palmitate and [5-3H]glucose. Results were compared with a combined group of 21 acute and chronic (4 day) sham animals. RESULTS: Four days of partial coronary stenosis significantly decreased regional systolic shortening by 54%. Myocardial oxygen consumption was maintained at aerobic levels, and rest coronary flows were normal. Fatty acid oxidation was decreased by 43% below composite sham values, and exogenous glucose utilization was increased severalfold. Alterations in myocardial metabolism were accompanied by a decline in tissue content of adenosine triphosphate. CONCLUSIONS: These data suggest that chronic coronary stenosis in the absence of macroscarring imparts an impairment in mechanical function, whereas coronary flow and myocardial oxygen consumption are preserved at rest. The increases in glycolytic flux of exogenous glucose are similar to observations on glucose uptake assessed by fluorine-18 2-deoxy-2-fluoro-D-glucose in patients with advanced coronary artery disease. We speculate that intermittent episodes of ischemia and reperfusion are the cause of this phenomenon.

Fatty acid kinetics in aerobic myocardium: characteristics of tracer carbon entry and washout and influence of metabolic demand.

These studies evaluated the kinetics of tracer uptake and washout after step-function labeling with 14C-palmitate. Washout and uptake function curve analysis for total radioactivity (TR) was derived according to the expressions: TR = Fx integral of 0 infinity C(t) x dt and TR = Fx integral of 0 infinity (Css - C(t)) x dt, respectively, with Vc = TR/Ca, where F = coronary flow; Css = steady-state concentration; C(t) = concentration with respect to time; Ca = arterial concentration; and Vc = distribution volumes within the fatty acid pathway. The only radioactive metabolites in venous effluent were fatty acids and 14CO2. The estimated Vc of fatty acids was small (1.2-1.7 ml/g dry wt or 0.4-0.5 mumol/g dry wt) and compatible with labeled substrate trapped in the blood volume. The Vc of 14CO2 was much larger (11.4-15.8 ml/g dry wt or 3.6-4.2 mumol/g dry wt) and correlated with counts contained in the aqueous soluble and fatty acid fractions in tissue. The counts in tissue were distributed between the aqueous soluble fraction (40%), which was rapidly depleted during washout, and a lipid fraction (60%) (triacylglycerols and phospholipids), which was resistant to washout. Distributions in tissue radioactivity between the aqueous soluble and lipid fractions support the notion of a dual pathway in fatty acid oxidation, one arm of which passes through the resident pool of triacylglycerols, which has a long time constant. The presence of this pool may impart an error in estimating fatty acid oxidation by external labeling techniques.

Comparison of fatty acid tracers FTHA and BMIPP during myocardial ischemia and hypoxia.

UNLABELLED: To study the sensitivity of two fatty acid tracers to changes in beta-oxidation, the myocardial retention kinetics of 125I-iodine-15-(p-iodophenyl)-3(R,S)-methylpentadecanoic acid (BMIPP) and 14-18F-fluoro-6-thia-heptadecanoic acid (FTHA) were compared in states of oxygen deprivation due to ischemia and hypoxia. METHODS: Nineteen swine were studied by extracorporeal perfusion of the three coronary arteries. Fatty acid beta-oxidation rates were determined by infusion of tritiated palmitate into the left anterior descending artery (LAD) and by measurement of labeled water production in the LAD perfusion bed. After a baseline period of 30 min, animals were divided into three groups and subjected to a 50-min intervention period. For the control group, there was no change in perfusion; for the ischemia group, there was a 60% decrease in LAD perfusion; and for the hypoxia group, the perfusion rate was unchanged, but venous blood was used as the LAD perfusate. Continuous infusion of FTHA and BMIPP into the LAD started 10 min into the intervention period and continued until the end of the intervention period. Retention rates of the two tracers were compared between the LAD and circumflex perfusion beds. RESULTS: No difference in beta-oxidation rate occurred from the baseline to the intervention period in the control group. A 50% reduction in beta-oxidation occurred in the ischemia group, and an 80% reduction occurred in the hypoxia group. No difference in retention of BMIPP or FTHA occurred in the control group. In the ischemia group, reduction in retention of both tracers occurred. However, in the hypoxia group, FTHA uptake was unchanged, whereas BMIPP retention increased compared to the circumflex arterial bed. CONCLUSION: Decreased retention of both BMIPP and FTHA occurred with ischemia, despite the known differences in metabolism of the two tracers. This difference in metabolism was further highlighted in the setting of hypoxia with increased BMIPP uptake. Thus, these results suggest that uptake of both FTHA and BMIPP tracks reduction of fatty acid utilization in myocardial ischemia but fails in tracking reduction of fatty acid oxidation during hypoxia.

Myocardial uptake of the fatty acid analog 14-fluorine-18-fluoro-6-thia-heptadecanoic acid in comparison to beta-oxidation rates by tritiated palmitate.

UNLABELLED: The fatty acid tracer 14-18F-fluoro-6-thia-heptadecanoic acid (FTHA) is a metabolically trapped tracer of exogenous fatty acid utilization. The objectives of this study were to determine the relationship of FTHA uptake to changes in perfusion and fatty acid oxidation and to confirm the retention of FTHA in the mammalian heart. METHODS: Six pigs with extracorporeal perfusion of the left anterior descending artery (LAD) and cannulation of the LAD vein were studied. The extraction fraction (EF) of FTHA, measured from LAD arterial and venous blood samples, was compared to beta-oxidation rates, determined by water production from tritiated palmitate. After a baseline period, changes in FTHA EF were measured in 15-min periods of hyperemia, control (baseline flow rate) and lactate infusion. After the lactate infusion, FTHA infusion was terminated, and a 15-min washout period was observed. RESULTS: Beta-oxidation rate was unchanged from the baseline period during the hyperemic and control periods. With lactate infusion, the expected myocardial preference for lactate was noted, with a decline in exogenous fatty acid oxidation. Fluorine-18-FTHA EF paralleled the changes in beta-oxidation, with a decrease in EF during lactate infusion. Increase in perfusion was associated with a decrease in FTHA EF, compared to control, such that the product of flow and extraction was maintained. A linear relationship of FTHA EF to fractional tritiated water production was found. Washout analysis confirmed minimal washout of tracer at 15 min after termination of infusion. Organic solvent extraction of tissue samples suggested that the majority of tissue radioactivity was protein-bound. CONCLUSION: In the extracorporeally perfused mammalian heart, FTHA EF declined during suppression of beta-oxidation with lactate infusion and alteration in perfusion without change in fatty acid oxidation rate. The linear relationship of FTHA EF with fractional water production from tritiated palmitate further confirms a correlation of the uptake of FTHA with fatty acid beta-oxidation rate and supports the utility of FTHA in the noninvasive determination of fatty acid oxidation rate. Furthermore, the trapped nature of the tracer may allow the use of graphical analysis for the quantification of beta-oxidation rates.

Effects of alcohol on cardiovascular performance after experimental nonpenetrating chest trauma.

Electrocardiographic and hemodynamic correlates were recorded before and after a standardized nonpenetrating blow to the chest in 9 anesthetized control dogs (Group I), 5 dogs, pretreated with alcohol, 0.4 g/kg intravenously (Group II), and 12 dogs undergoing chest trauma after alcohol infusions (Group III). In animals in Group I, transient major arrhythmias, including complete heart block and ventricular tachycardia, occurred immediately after impact. One animal died with ventricular fibrillation. In the eight survivors these disturbances were accompanied by acute reductions in aortic pressure and cardiac index; values for both variables gradually increased after restoration of sinus mechanism. Alcohol alone (Group II) produced no significant alterations in either hemodynamic performance or electrical activity, but when combined with nonpenetrating chest injury (Group III) it caused a mortality rate of 92 percent, the majority of animals dying with electromechanical dissociation. Mean survival time in Group III was 23.1 plus and minus 6.5 (standard error of the mean) minutes compared with 80.3 plus and minus 9.6 minutes in Group I. At autopsy, minor cardiac lesions of either the pericardium or myocardium were observed in all animals in Groups I and III, but none were considered lethal. It is concluded that administration of alcohol, even in small doses, can effect catastrophic reductions in mechanical performance in the presence of otherwise nonfatal cardiac injury secondary to nonpenetrating chest trauma. The clinical implications of this association are discussed.

Effects of excess glucose and insulin on glycolytic metabolism during experimental myocardial ischemia.

The selective metabolic effects of glucose and insulin were tested in an intact working swine heart preparation. Supplements of glucose (26.6 millimolar [mM] and insulin (0.025 units/ml) were provided to 18 hearts, 9 control hearts (coronary flow 151 ml/min) and 9 hearts rendered globally ischemic (coronary flow reduced from 167 to 85 ml/min). These hearts were compared with 14 additional hearts (6 control and 8 ischemic) given no supplements (glucose 8.6 mM, no excess insulin). In hearts without supplements, ischemic significantly decreased mechanical performance, myocardial oxygen consumption, fatty acid oxidation and tissue high energy phosphate stores. Glucose consumption was reduced from 133 micromoles (mumol)/hr per g (before ischemia) to 58 mumol/hr per g (P less than 0.05), presumably from inhibition at glyceraldehyde-3-phosphate dehydrogenase. Data for control hearts with excess glucose and insulin were similar to data in control hearts without supplements except that glucose consumption and glycolytic flux were increased. Ischemia in treated hearts, as compared with untreated ischemic hearts, effected similar significant decreases in myocardial oxygen consumption, fatty acid oxidation and high energy phosphate stores and resulted in greater reductions in mechanical performance and in 10 minutes' less average survival time. Glucose consumption was reduced from 483 (before ischemia) to 242 mumol/hr per g (P less than 0.005) and inhibition at glyceraldehyde-3-phosphate dehydrogenase was again noted. Thus, excess carbohydrate and insulin hormone, when infused directly into the ischemic myocardium, did not provide an efficacious increase in either glycolytic flux or energy production. These findings suggest that an alternative explanation for the reported efficacy of glucose-insulin-potassium infusions must be sought.

Effects of coronary perfusion during myocardial hypoxia. Comparison of metabolic and hemodynamic events with global ischemia and hypoxemia.

The effects of metabolic accumulation on myocardial metabolism during global heart oxygen deprivation were evaluated in a working in situ swine heart preparation with controlled total coronary blood flow. Myocardial oxygen consumption was depressed to a similar extent by either reducing total coronary flow 60 per cent (ischemia, low coronary perfusion) in 10 swine or by decreasing coronary perfusate PO2 to 30 mm. Hg at normal flows (hypoxemia, high coronary perfusion) in 13 swine. Compared with findings in 13 control hearts, ischemia significantly (p less than 0.05) decreased myocardial oxygen consumption (640 to 390 mumole per hour per gram), glucose uptake (185 to 16 mumole per hour per gram), and free fatty acid consumption (32 to 17 mumole per hour per gram). ttissue levels of glycogen, creatine phosphate, and adenosine triphosphate (tatp) were significantly reduced (p less than 0.005), and tissue lactate, adenosine diphosphate (ADP), and adenosine monophosphate (AMP) were increased (p less than 0.001). During hypoxemia, glucose uptake was increased (240 mumole per hour per gram) and free fatty acid consumption was somewhat less depressed (19 mumole per hour per gram). Creatine phosphate and ATP were higher than with ischemia (p less than 0.01), and lactate, ADP, and AMP accumulations were less (p less than 0.01). Thus, in the period immediately following myocardial oxygen deprivation, inadequate coronary perfusion caused greater metabolic buildup which inhibited myocardial substrate utilization and energy production. High coronary perfusion, even though the perfusate was unoxygenated, was associated with greater preservation of substrate utilization, higher levels of high-energy phosphates, less accumulation of metabolic products, and a longer survival. These data suggest a critical role of coronary perfusion in protecting myocardial metabolism in the immediate period following global heart hypoxia.

Functional reductions in left ventricular volume. Minimum chamber size consonant with effective hemodynamic performance.

A heart model in dogs was developed to evaluate quantitatively the extent to which left ventricular chamber size could be reduced and yet retain residual mechanical function to perform adequately as a pump. In 9 animals placed on right heart bypass perfusion to control systemic flows; left ventricular performance was estimated from high-fidelity left ventricular pressure and aortic flowmeter recordings and from lateral plane left ventricular angiograms. Studies were made during unrestricted left ventricular filling at varying cardiac outputs and with inflation of a balloon in the left ventricular cavity at a physiological cardiac output. As compared with control data (cardiac output 1.4 L. per minute), balloon inflation to 18.7 ml. caused an increase in total left ventricular end-diastolic volume (from 35.4 to 44.3 ml., p less than 0.001) and left atrial pressure (from 7.8 to 21.2 mm. Hg; p less than 0.001); it also caused a reduction in left ventricular stroke work (from 12.5 to 8.1 Gm.-M., P LESS THAN 0.005) ANd max. dp/dt (from 2,487 to 1,320 mm. Hg per second, p less than 0.05). Importantly, left ventricular stroke volume was unchanged. When compared with preload augmentation (with the balloon deflated), the magnitude of depression of cardiac performance caused by balloon inflation was more fully appreciated (left ventricular stroke work, max. dp/dt, and ejection fraction reduced 69, 61, and 45 per cent, respectively). Even so, with appropriate compensations, principally by the Frank-Starling mechanism, up to 42 per cent of the left ventricular cavity volume could be functionally eliminated with retention of adequate mechanical performance. Such data may have implications regarding the extent of resections possible in patients undergoing surgery for left ventricular aneurysm.

An experimental model for studying myocardial ischemia. Correlation of hemodynamic performance and metabolism in the working swine heart.

An intact, working swine heart preparation with controlled coronary perfusion is described. In this model, hemodynamic and metabolic functions were correlated in control and ischemic myocardium. A closed-loop, extracorporeal coronary perfusion circuit in series with a perfusion pump and oxygenator was designed to return reoxygenated coronary venous blood at controlled flow rates to the left and right coronary arteries. In 9 swine at normal flows (232 plus or minus 17 ml. per minute), the preparation maintained stable hemodynamic performance and oxygen consumption for a 1 hour period, after which ischemia was induced by reducing coronary flow by 50 per cent. As a result, left ventricular end-diastolic pressure (LVEDP) rose by 227 per cent, whereas heart rate (-17 per cent), aortic pressure (-9 per cent), pressure time/minute (PTM) (-28 per cent), left ventricular work (-47 per cent), and oxygen consumption (-39 per cent) all decreased. The ischemic myocardium shifted from lactate extraction to production. With this model, we can define, over a period of time, several mechanical and metabolic collations as a function of total coronary blood flow in an intact, large animal. We can also test interventions during the acute phases of ischemia in an effort to reduce myocardial damage.

Ischemic injury to the conducting system of the heart. Involvement of myocardial lysosomes.

The conducting system was studied in an in situ perfused swine heart preparation with reduced coronary flow (ischemia) using perfusate containing high and low levels of glucose (26.6 versus 8.6mM) with and without insulin. Coronary flow was maintained at normal levels for 60 minutes in control hearts. In ischemic hearts flow was reduced to about 50 percent of control levels for 30 minutes. Ultrastructural studies documented only subtle modifications of Purkinje fibers in ischemic hearts. Glycogen depletion and disruption of cell junctions were observed in some fibers. One consistent finding was the activation of the lysosomal system. The outer membranes of primary lysosomes appeared herniated and in some cases disrupted, and small vesicles containing hydrolytic enzymes were seen in association with the Golgi apparatus and larger primary lysosomes. Specimens prepared for the demonstration of acid phosphatase indicated a redistribution of hydrolytic enzymes in Purkinje fibers with a depostion of acid hydrolases in smaller lysosomal vesicles, the transverse and side-to-side junctions between cells, and occasionally in the sarcoplasmic reticulum. Enriched perfusate containing high levels of glucose with insulin appeared to have no therapeutic effects in terms of the structure of the Purkinje fibers. The results suggest that alterations in the lysosomal system may be one of the earliest structural changes which occur in oxygen-deficient hearts.

Determinants of cardiac performance in severe aortic stenosis.

Left ventricular (LV) myocardial function and the influence on LV pump performance of associated coronary arterial disease, of outflow obstruction and its consequences, and of altered ventricular pressure-volume characteristics were examined in a representative group of 28 adult patients with symptomatic severe aortic stenosis (valvular orifice area less than 0.50 sq cm/sq m). Eighteen patients (64%) exhibited depressed LV pump performance with levels of ejection fraction less than 0.50. In seven patients, coronary arterial disease documented by either arteriographic studies or postmortem analyses was associated with a segmental (i.e., nonhomogeneous) LV contractile disorder consistent with previous myocardial infarction. In the remaining 11 patients a homogeneous LV contractile disorder was the result of chronic outflow obstruction and its consequences. The possibility that reduced ventricular performance might be accounted for by increased afterload could not be supported by significant correlation between LV contractile characteristics (estimated from the ejection fraction and the mean circumferential fiber shortening rate) and indices of afterload (including LV systolic pressure, aortic valvular orifice area, and mean systolic wall tension). This observation suggested that myocardial hypertrophy and other consequences of longstanding obstruction to outflow played a primary role in depression of LV performance in these patients. Left ventricular end-diastolic volume was abnormal in all but three patients with depressed LV function; this increase was accompanied by a disproportionately greater increment in end-diastolic pressure, suggesting that reduced distensibility limited the ability of the ventricle to compensate for reduced contractile performance by means of the Starling mechanism.

Clinical assessment of the surgical patient with heart disease.

This article is a review of available data describing those identifying features that should prospectively alert surgeons, anesthesiologists, and their medical consultants to a subpopulation of cardiac patients most likely to tolerate noncardiac surgery poorly. Appropriate management decisions are discussed also.

Determination of individual long-chain fatty acyl-CoA esters in heart and skeletal muscle.

A method has been developed for determination of individual long-chain fatty acyl-CoA esters from heart and skeletal muscle using high performance liquid chromatography (HPLC). The esters were extracted from freeze-clamped tissue of pig and rat hearts and rat skeletal muscle for analysis on a radially compressed C18 5mu reverse-phase column. Nine peaks in the extract with carbon chain lengths from C12 to C20 that subsequently disappeared on alkaline hydrolysis were identified. The major acyl-CoA peaks were 14:1, 18:2, 16:0 and 18:1 and additionally in rat heart 18:0. Total long-chain acyl-CoA esters obtained by summation of the individual molecular species was 11.34 +/- 1.48 nmol/g wet wt. pig heart; 14.51 +/- 2.11 nmol/g wet wt. in rat heart, and 4.35 +/- 0.71 nmol/g wet wt. in rat skeletal muscle. These values were approximately 132% of those obtained using a separate procedure that measured total CoA by HPLC after alkaline hydrolysis of the esters. The described method demonstrates the quantitation of individual acyl-CoA species in muscle tissue. Therefore, it has a number of advantages in that it permits information to be obtained on the individual molecular species under various nutritional and metabolic conditions.

Cardiomyopathy. 2. Hypertrophic and restrictive/obliterative types.

The functional classification of the three types of cardiomyopathy has been helpful in organizing practitioners' thinking. The past three decades have witnessed tremendous advances in understanding of the pathophysiology, clinical and laboratory diagnosis, and treatment of these disorders. New doors of exploration are opening to answer such nagging questions as whether medical therapy alters long-term survival rates in dilated (congestive) cardiomyopathy, whether immunologic therapy will alter the course of dilated or restrictive/obliterative cardiomyopathy, and whether genetic manipulation or in utero therapy will prevent hypertrophic cardiomyopathy. The goals of effective treatment in all these disorders remain the same: amelioration of symptoms, prevention of sudden death, and constraint or resolution of the basic disease process. Achieving these goals requires a multidisciplinary approach, involving cardiologists, surgeons, immunologists, geneticists, cell biologists, virologists, and pathologists. Prospects are that one day treatment will no longer be an imprecise, palliative art but a definitive, curative science.

Effects of clofibric acid alone and in combination with 17ß-estradiol on mRNA abundance in primary hepatocytes isolated from rainbow trout.

Clofibric acid (CA) is the active substance of lipid lowering drugs. It is resistant to degradation, polar in nature, and has been found ubiquitously in the aquatic environment. Though CA is classified as a peroxisomal proliferator in rodents and is considered as a potential endocrine disruptor, little information exists on the effects of CA in aquatic organisms, such as fish. In the present study, we examined the mRNA levels of peroxisome proliferator- and estrogen-sensitive genes on the exposure of primary rainbow trout (Oncorhynchus mykiss) hepatocytes to CA alone and in combination with the natural female sex hormone, 17ß-estradiol (E2). Our results demonstrate that rainbow trout hepatocytes are relatively refractory to the effects of CA on the PPAR signaling pathway and lipid metabolism. Moreover, CA did not show recognizable estrogenic activity, but after the induction of vitellogenesis by E2, CA significantly reduced vitellogenin (VTG) mRNA abundance. Apparently, the indirect repression of VTG transcription, independent of estrogen receptors, occurred. The mechanism is not yet clearly understood but may involve disruption of the stabilization of VTG mRNA known to be induced by E2.