Unexplained hepatitis following halothane.

Full clinical and laboratory details of 203 patients with postoperative jaundice were submitted to a panel of hepatologists. All patients whose jaundice may have had an identifiable cause were excluded, which left 76 patients with unexplained hepatitis following halothane anaesthesia (UHFH). Hepatitis in 95% of these cases followed multiple exposure to halothane, with repeated exposure within four weeks in 55% of cases. Twenty-nine patients were obese, 52 were aged 41-70, and 53 were women. Thirteen patients died in acute hepatic failure. Rapid onset of jaundice after anaesthesia, male sex, and obesity in either sex were poor prognostic signs. Of the clinical stigmata of hypersensitivity, only eosinophilia was impressive. The UHFH group had a much greater incidence of liver kidney microsomal (LKM) and thyroid antibodies and autoimmune complement fixation than those patients whose jaundice related to identifiable factors. Thirteen of the 19 patients with LKM antibodies also had thyroid antibodies. In six patients retested two to three years later LKM antibodies had disappeared, although thyroid antibodies persisted. Rapidly repeated exposure to halothane may cause hepatitis, but such a complication is probably rare. Possibly obese women with a tendency to organ-specific autoimmunity may be more at risk. Nevertheless, the comparative risks of rapidly repeated halothane or non-halothane anaesthesia cannot be determined from the present data. If alternative satisfactory agents are available halothane should be avoided in patients with unexplained hepatitis after previous exposure, although in three to five patients with UHFH who were re-exposed to halothane jaundice did not recur.     

Recovery rate of the cardiovascular system in rabbits following short-term halothane anesthesia.

Mean arterial pressure, cardiac output and heart rate were determined in eight male New Zealand white rabbits while conscious and after being anesthetized with halothane plus nitrous oxide for 15 minutes. Delivery of the anesthetic agent was stopped and the measurement repeated at 15, 30, 60 and 210 minutes. In a separate experiment blood samples were obtained for plasma renin activity in six rabbits before anesthesia, after 15 minutes of halothane plus nitrous oxide administration, and again 210 minutes after cessation of the anesthesia. Later, this experiment was repeated with the same rabbits except that they were allowed to breathe room air instead of the anesthesia. The halothane anesthesia resulted in decreased mean arterial pressure and cardiac output, but these returned to the preanesthetic levels by 15 minutes after stopping the anesthesia. Heart rate increased during halothane administration, and although it tended to return toward control levels after cessation of the halothane, heart rate was still elevated 210 minutes later. Halothane plus nitrous oxide produced an increase in plasma renin activity, which then subsided to normal by 210 minutes following anesthesia; breathing room air did not result in increases in plasma renin activity. These studies revealed that although short-term anesthesia with halothane plus nitrous oxide resulted in cardiovascular changes in rabbits, after cessation of the anesthetic agent the cardiovascular system quickly returned to normal.     

Atrial Pacing to Control Heart Rate and Rhythm in Acute Cardiac Conditions

Increasing the heart rate by a bedside atrial pacing technique was successfully utilized to treat serious cardiac arrhythmia or failure in 13 patients. Nine of these had ventricular arrhythmia refractory to drugs. Seven had evidence of sinus node depression or disease since their sinus pacemaker was below 70 beats per minute under decompensated conditions. In five, coronary artery disease was associated with the bradycardia and in two, digitalis toxicity was related to depression of the intrinsic pacemaker rate. Two patients in the coronary group required implantation of a permanent demand ventricular pacemaker. Hemodynamic studies were performed in seven patients. Only one patient had no increase in cardiac output with pacing rates above his resting rate. The other six patients showed an increase in cardiac output from 22 to 81% at paced rates between 70 and 125/minute. The duration of pacing ranged from one hour to 14 days and averaged five days.     

Jaundice after Repeated Exposure to Halothane: An Analysis of Reports to the Committee on Safety of Medicines

Analysis of data derived from 130 reports of jaundice occurring after anaesthesia with halothane showed a significant relation between the number of exposures to this anaesthetic and the rapidity with which jaundice develops after exposure. This is considered to provide strong evidence of a cause-effect relationship between the use of halothane and jaundice. Out of 114 patients with complete anaesthetic histories 94 (82%) had been exposed more than once; of those so exposed 80% had been anaesthetized with halothane more than once within 28 days. Altogether 66 (51%) of the 130 patients died.     

Left Ventricular Wall Movement in Heart Failure

Of 34 patients admitted to hospital with left ventricular failure seven died before echocardiograms could be repeated after treatment and in three no echocardiograms could be obtained owing to chronic obstructive lung disease. In the remaining 24 patients echocardiograms were taken soon after admission and compared with echocardiograms taken later, after clinical improvement. The results show that in most patients both anterior and posterior motion of the posterior left ventricular wall increased. The rate of backward diastolic motion was appreciably less before and after treatment of heart failure compared with that in a small group of normal younger healthy men. This technique is a quick and apparently reliable way to assess ventricular function. The rate of diastolic motion is probably a reflection of left ventricular wall compliance.     

Immunocytochemical detection of the 72-kDa heat shock protein in halothane--induced hepatotoxicity in rats.

Liver sections removed from phenobarbital induced rats 24 to 48 hours after a 2 hour exposure to 1.0% halothane with 10% oxygen and subjected to immunocytochemical treatment showed evidence of centrilobular damage as well as evidence of the production of a protein which has immunoreactivity with anti HSP 72 antibodies. The cells showing evidence of immunoreactivity were within the area of the centrilobular lesion. The level of immunoreactive protein varied directly with the intensity of the lesion. Liver sections from animals treated with phenobarbital alone, phenobarbital plus 10% oxygen, or phenobarbital plus 20% oxygen and 1.0% halothane all were without lesions as well as the immunoreactive protein.     

Attenuation of diabetes-induced cardiac inflammation and pathological remodeling by low-dose radiation

In the present study, novel preventive effects of repeated low-dose radiation exposure on diabetes-induced cardiac inflammation and cardiac damage were investigated. C57BL/6J mice were given multiple low doses of streptozotocin (STZ, 60 mg/kg × 6) to generate type 1 diabetes. A week after the last STZ injection, hyperglycemic mice were diagnosed and treated with and without whole-body low-dose radiation exposure (25 mGy X rays) once every 2 days for 2, 4, 8, 12 and 16 weeks. Diabetes caused significant increases in cardiac inflammation, shown by time-dependent increases in mRNA and protein expressions of interleukin 18 (IL-18), tumor necrosis factor-alpha (TNF-α), intercellular adhesion molecule 1 (ICAM-1), plasminogen activator inhibitor 1 (PAI-1), and monocyte chemoattractant protein 1 (MCP-1). Repeated exposure of control mice to low-dose radiation caused mild increases in these inflammatory factors, except for ICAM-1. Repeated exposure of diabetic mice to low-dose radiation significantly reduced diabetes-increased cardiac expression of IL-18, TNF-α, MCP-1 and PAI-1 at both the mRNA and protein levels. Furthermore, cardiac histopathological abnormalities, oxidative damage and fibrosis were significant in diabetic mice but to a lesser extent in diabetic mice with repeated low-dose radiation exposure. These results suggest that although low-dose radiation contributes to mild cardiac inflammation in control mice, it can significantly reduce diabetes-induced cardiac inflammation and associated pathological changes. Therefore, low-dose radiation may potentially become a novel approach to the prevention of diabetic cardiovascular complications.     

Differential regulation of low and high voltage-activated calcium channels in neonatal rat myocytes following chronic PKA modulation

The biophysical properties of voltage-dependent cardiac calcium channels (VDCC) can be modulated by protein kinases. In this study, we investigate whether long-term treatment with protein kinase A (PKA) modulators alters the VDCC activity in neonatal ventricular myocytes. Using whole-cell patch-clamp recordings, we found an increase in high-voltage activated (HVA) current density and a corresponding decrease in low-voltage activated (LVA) current density in neonatal rat ventricular myocytes up to 6 days in culture. Long-term exposure to 8Br-cAMP, a PKA stimulator, increased the HVA current density at 7 and 24 hours. In contrast, H89, a PKA inhibitor, caused a biphasic change in the HVA, an initial reduction at 7 hours exposure followed by an increase up to 4 days. In addition, H89 caused a sustained increase in LVA currents from 7 hours to 4 days. These findings suggest that chronic exposure to H89 changes LVA and HVA calcium current activities in cardiac myocytes. PKA is a key target of beta-adrenoceptor activiation, thus, our findings suggest long-term repeated use of beta-adrenergic drugs may induce unexpected functional alteration of VDCCs.     

Effects of Repeated Low-dose Soman Exposure on Monoamine Levels in Different Brain Structures in Mice

In order to better understand the effects of repeated low-dose exposure to organophosphorus (OPs) on physiological and behavioural functions, we analysed the levels of endogenous monoamines (serotonin and dopamine) in different brain areas after repeated exposure of mice to sublethal dose of soman. Animals were injected once a day for 3 days with 0.12 LD50 of soman (47 μg/kg, i.p.). They did not show either severe signs of cholinergic toxicity or pathological changes in brain tissue. 24 h after the last injection of soman, inhibition of cholinesterase was similar in plasma and brain (32% and 37% of inhibition respectively). Afterwards, recovery of cholinesterase activity was faster in the plasma than in the brain. Dopamine levels were not significantly modified. On the other hand, we observed a significant modification of the serotoninergic system. An increase of the 5-HIAA/5-HT ratio was maintained for 2 and 4 weeks after exposure in the hippocampus and the striatum respectively. This study provides the first evidence of a modification of the 5-HT turnover in the hippocampus and the striatum after repeated low-dose intoxication with a nerve agent. Further experiments are necessary to evaluate the relationship between these modifications and the unexpected neuropsychological disorders usually reported after chronic exposure of organophosphorus.     

Differential regulation of low and high voltage-activated calcium channels in neonatal rat myocytes following chronic PKA modulation

The biophysical properties of voltage-dependent cardiac calcium channels (VDCC) can be modulated by protein kinases. In this study, we investigate whether long-term treatment with protein kinase A (PKA) modulators alters the VDCC activity in neonatal ventricular myocytes. Using whole-cell patch-clamp recordings, we found an increase in high-voltage activated (HVA) current density and a corresponding decrease in low-voltage activated (LVA) current density in neonatal rat ventricular myocytes up to 6 days in culture. Long-term exposure to 8Br-cAMP, a PKA stimulator, increased the HVA current density at 7 and 24 hours. In contrast, H89, a PKA inhibitor, caused a biphasic change in the HVA, an initial reduction at 7 hours exposure followed by an increase up to 4 days. In addition, H89 caused a sustained increase in LVA currents from 7 hours to 4 days. These findings suggest that chronic exposure to H89 changes LVA and HVA calcium current activities in cardiac myocytes. PKA is a key target of β-adrenoceptor activiation, thus, our findings suggest long-term repeated use of β-adrenergic drugs may induce unexpected functional alteration of VDCCs.     

Experimental assessment of the role of acetaldehyde in alcoholic cardiomyopathy

Alcoholism is one of the major causes of non-ischemic heart damage. The myopathic state of the heart due to alcohol consumption, namely alcoholic cardiomyopathy, is manifested by cardiac hypertrophy, compromised ventricular contractility and cardiac output. Several mechanisms have been postulated for alcoholic cardiomyopathy including oxidative damage, accumulation of triglycerides, altered fatty acid extraction, decreased myofilament Ca²⁺ sensitivity, and impaired protein synthesis. Despite intensive efforts to unveil the mechanism and ultimate toxin responsible for alcohol-induced cardiac toxicity, neither has been clarified thus far. Primary candidates for the specific toxins are ethanol, its first and major metabolic product — acetaldehyde (ACA) and fatty acid ethyl esters. Evidence from our lab suggests that ACA directly impairs cardiac function and promotes lipid peroxidation resulting in oxidative damage. The ACA-induced cardiac contractile depression may be reconciled with inhibitors of Cytochrome P-450 oxidase, xanthine oxidase and lipid peroxidation Unfortunately, the common methods to investigate the toxicity of ACA have been hampered by the fact that direct intake of ACA is toxic and unsuitable for chronic study, which is unable to provide direct evidence of direct cardiac toxicity for ACA. In order to overcome this obstacle associated with the chemical properties of ACA, our laboratory has used the chronic ethanol feeding model in transgenic mice with cardiac over-expression of alcohol dehydrogenase (ADH) and anin vitro ventricular myocyte culture model. The combination of bothin vivo andin vitro approaches allows us to evaluate the role of ACA in ethanol-induced cardiac toxicity and certain cellular signaling pathways leading to alcoholic cardiomyopathy. Published: February 17, 2003     

Linking long-term toxicity of xeno-chemicals with short-term biological adaptation

Understanding the mechanisms of long-term toxicities of chemicals is challenging. The present review discusses evidence suggesting that the biological adaptation to acute xenobiotic exposure could lead in the long run to toxic side effects. Upon acute exposure, hydrophobic xenobiotics are sequestered in the adipose tissue, which consequently protects other organs. However, this could also lead to the persistence of these xenochemicals and to a chronic low level internal exposure. The intrinsic properties of the xenobiotic detection and metabolism systems could also account for long-term toxicity. Indeed, hydrophobic xenochemicals are metabolized into more hydrophilic compounds; the first step of this pathway consists in the “activation” of the parent compound into a more reactive intermediate by cytochromes P450 activity. Those intermediates can be extremely reactive with DNA and proteins and thus could lead to toxic side effects that may become significant over time. Furthermore, recent evidence suggests that xenobiotic receptors also display endogenous functions. It is likely that repeated exposure to xenobiotics disrupts those endogenous functions with possibly dire cellular consequences. Altogether, The hypothesis presented here proposes that one mechanism for long-term toxicity stems from cumulative side effects due to the repeated activity of adaptive pathways triggered by acute intoxication.     

三维斑点追踪技术对慢性肾功能不全患者左心室收缩功能和右心室功能的评估价值研究

摘要 目的：探讨慢性肾功能不全患者应用三维斑点追踪技术对其左心室收缩功能和右心室功能的评估价值。方法：选择我院收治的慢性肾功能不全患者82例,根据患者肾功能将其分为轻度慢性肾功能不全组[慢性肾脏病（CKD） 2期,47例],中-重度慢性肾功能不全组（CKD 3~5期,35例）,另选取同期医院体检的健康志愿者30例作为对照组,应用二维超声及三维斑点追踪技术检测各组心脏指标,比较三组二维超声指标、三维斑点追踪技术指标,应用受试者工作特征（ROC）曲线分析三维斑点追踪技术对患者左心室收缩功能和右心室功能的评估价值。结果：中-重度慢性肾功能不全组室间隔舒张末期厚度（IVSTd）、肺动脉收缩压（PASP）显著高于轻度慢性肾功能不全组、对照组,右心室面积变化分数（RVFAC）、组织运动三尖瓣环位移（TAPSE）、左心室射血分数（LVEF）显著低于轻度慢性肾功能不全组、对照组（P<0.05）。中-重度慢性肾功能不全组左室整体圆周收缩期峰值应变（LGCS）、左室整体纵向收缩期峰值应变（LGLS）、右室整体圆周收缩期峰值应变（RGCS）右室整体纵向收缩期峰值应变（RGLS）、显著高于轻度慢性肾功能不全组、对照组,左室整体径向收缩期峰值应变（LGRS）、三维左室射血分数（3D-LVEF）、右室整体径向收缩期峰值应变（RGRS）、三维右室射血分数（3D-RVEF）显著低于轻度慢性肾功能不全组、对照组（P<0.05）。ROC曲线分析显示,三维斑点追踪技术对慢性肾功能不全患者左心室收缩功能和右心室功能的评估价值较高。结论：三维斑点追踪技术可以准确检测心脏的纵向运动、圆周运动、径向运动,为临床早期发现慢性肾功能不全患者的心脏功能异常提供依据。     

Effect of berberine on catecholamine levels in rats with experimental cardiac hypertrophy

The aim of this study is to investigate the effect of berberine on catecholamine level (adrenaline and noradrenaline) in rats with experimental cardiac hypertrophy. Cardiac hypertrophy(CH) was induced by suprarenal abdominal aorta constriction, and the drugs were administered for 8 weeks starting from 4 weeks after surgery. The degree of cardiac hypertrophy was determined by heart and left ventricular weight. The level of adrenaline(AD) and noradrenaline(NA) was detected by HPLC. The data showed that in the CH model rats, the level of plasma and left ventricular tissue AD, and the level of NA in plasma were higher than that of the age-matched controls(indicating increased "total" sympathetic activity). The level of NA in left ventricular tissue of CH model rats was however lower than the age-matched controls. Berberine and captopril showed significant effect on inhibiting the development of cardiac hypertrophy. Berberine decreased plasma NA level and the AD level both in plasma and left ventricular tissue, but had no effect on improving the cardiac NA depletion. Captopril showed significant effect on increasing the depleted cardiac NA and in reducing the elevated plasma NA level. These findings show the efficacy of berberine on modulating the sympathetic nervous activity of rats with experimental cardiac hypertrophy, and reflect the therapeutic potentials of berberine in patients with cardiac hypertrophy and chronic heart failure.     

Clinical Effects of Cesium Intake

The knowledge about cesium metabolism and toxicity is sparse. Oral intake of cesium chloride has been widely promoted on the basis of the hypothesis referred to as “high pH cancer therapy”, a complimentary alternative medicine method for cancer treatment. However, no properly confirmed tumor regression was reported so far in all probability because of neither theoretical nor experimental grounds for this proposal. The aim of the present review was to resume and discuss the material currently available on cesium salts and their applications in medicine. The presence of cesium in the cell does not guarantee high pH of its content, and there is no clinical evidence to support the claims that cancer cells are vulnerable to cesium. Cesium is relatively safe; signs of its mild toxicity are gastrointestinal distress, hypotension, syncope, numbness, or tingling of the lips. Nevertheless, total cesium intakes of 6 g/day have been found to produce severe hypokalemia, hypomagnesemia, prolonged QTc interval, episodes of polymorphic ventricular tachycardia, with or without torsade de pointes, and even acute heart arrest. However, full information on its acute and chronic toxicity is not sufficiently known. Health care providers should be aware of the cardiac complications, as a result of careless cesium usage as alternative medicine.     

A new hepatoma cell line for toxicity testing at repeated doses

Many cell models that are used to assess basic cytotoxicity show a good correlation with acute toxicity. However, their correlation with the toxicity seen following chronic in vivo exposure is less evident. The new human hepatoma cell line HBG BC2 possesses the capacity of being reversibly differentiated in vitro and of maintaining a relatively higher metabolic rate when in the differentiated state (3 weeks) as compared to HepG2 cells, and thus may allow the conduct of repeated toxicity testing on cells in culture. In order to evaluate the genetic background of HBG BC2 cells, the expression of selected genes was analyzed in untreated cultures and, in addition, the behavior of HBG BC2 cultures under conditions of repeated treatment was studied with acetaminophen as a test substance and coupled with the use of standard staining techniques to demonstrate toxicity. Results showed that cultures of HBG BC2 cells retained a capacity to undergo apoptosis and proliferation, allowing probable replacement of damaged cells in the culture monolayer. MTT reduction was used to evaluate the toxicity of acetaminophen, acetylsalicylic acid, perhexiline, and propranolol, after both single and repeated (3 times/week for 2 weeks) administration. Under the conditions of repeated treatment, cytotoxicity was observed at lower doses as compared to single administration. In addition, the lowest nontoxic doses were in the same range as plasma concentrations measured in humans under therapeutic use. Our results suggest that the new human hepatoma HBG BC2 cell line is of interest for the evaluation of cell toxicity under conditions of repeated administration.     

Implantable cardioverter defibrillator: an update

Automatic implantable cardioverter defibrillator is now a well established therapy to prevent sudden cardiac death. In secondary prevention (patients with a previous cardiac arrest) defibrillator can be considered as a class I indication, if there is no transient or reversible cause. The level of proof is A. in primary prevention the defibrillator is indicated in coronary artery disease patients with or without symptoms of mild to moderate heart failure (NYHA II or III), an ejection fraction lower than 30 %, measured at least one month after a myocardial infarction and 3 months after a revascularisation, surgery or angioplasty (level of proof B). It is also indicated in symptomatic spontaneous sustained ventricular tachycardias with underlying heart disease (level of proof B), in patients with spontaneous sustained ventricular tachycardia, poorly tolerated, without underlying heart disease for which pharmacological treatment or ablation can not be performed or failed (level of proof B). Finally it is also indicated in patients with syncope of unknown cause with sustained ventricular tachycardia or inducible ventricular fibrillation, with an underlying heart disease (level of proof B). The guidelines proposed by the different societies have also proposed class IIa recommendations which are the following: coronary artery disease patients with left ventricular dysfunction (ejection fraction between 31 or 35 %) measured at least one month after a myocardial infarction and 3 months after a revascularisation with an inducible ventricular arrhythmia. It can be also indicated in idiopathic dilated cardiomyopathies with an ejection fraction lower than 30% and NYHA class II or III. It can be also indicated in familial or inherited conditions with a high risk of sudden cardiac death by ventricular fibrillation without any other efficient known treatment and finally in heart failure patients remaining symptomatic, in class III or IV NYHA, with an optimal medical therapy, an ejection fraction lower than 35 % and a QRS complex duration higher than 120 ms: in this case it is an indication of cardiac resynchronization therapy device associated to the defibrillator. All these class IIa indications have a level of proof B.     

The effect of psychoemotional state on Lewis lung carcinoma metastasis

The effect of a depression-like status formed by chronic stress on development of Lewis lung carcinoma metastases in C57Bl/6J mice was investigated. Two types of acute stress (restraint and social stress) were used for comparison. The depression-like status was induced by eight-week exposure to repeated but unpredictable stressors (chronic mild stress model) and was assessed in the forced swim test. Tumor cells were inoculated an hour after the onset of social stressor or immediately after physical or chronic stressor impacts. The number of metastases was counted 17 days after the inoculation. The results indicate that chronic mild stress provokes the development of a depression-like state in mice and causes a twofold increase in the number of metastases in the lungs, while both types of acute stress have no such effects. Thus, a depression-like psychoemotional status of animals enhances the metastasis of Lewis lung carcinoma.     

Cocaine-induced ventricular fibrillation: protection afforded by the calcium antagonist verapamil

There is increasing evidence that the use of cocaine can trigger lethal cardiac events, including ventricular fibrillation. The mechanism responsible for these lethal cardiac arrhythmias remains to be determined. Therefore, 13 mongrel dogs were instrumented so that heart rate, left ventricular pressure (LVP), and d(LVP)/dt could be measured. After a 3- to 4-wk recovery period, the left circumflex coronary artery was occluded for 2 min, beginning with the last minute of an exercise stress test and continuing for 1 min after the cessation of exercise. None of the dogs developed cardiac arrhythmias during the control exercise plus ischemia test. On a subsequent day, the test was repeated after the injection of cocaine HCl (1.0 mg/kg). Cocaine significantly (P less than 0.01) elevated heart rate, systolic LVP, and d(LVP)/dt, and it elicited cardiac arrhythmias in 12 of the 13 animals during the exercise plus test. In fact, 11 animals developed ventricular fibrillation. Verapamil, a calcium channel antagonist (250 micrograms/kg), attenuated the hemodynamic effects of cocaine and prevented the development of ventricular arrhythmias. These data suggest that cocaine can induce ventricular fibrillation during myocardial ischemia and that these lethal arrhythmias may be prevented by a calcium channel antagonist.