High frequency of altered HLA class I phenotypes in invasive colorectal carcinomas

We examined the role of the cholecystokinin-A (CCK-A) receptor in acute inflammatory and regenerative stages of experimental pancreatitis using a rat model lacking the CCK-A receptor [Otsuka Long-Evans Tokushima Fatty (OLETF) rats]. OLETF and control [Long-Evans Tokushima Otsuka (LETO)] rats were prepared with an internal bile fistula and with obstruction of pancreatic flow and were sacrificed 1-14 days later. Histological examination was performed, and changes in pancreatic wet weight, protein concentration, CCK-A and -B receptor mRNA levels, tyrosine kinase activities, and plasma amylase and CCK levels were determined. The plasma amylase level showed a transient increase on day 1, the CCK level remained at high levels throughout, and tyrosine kinase activity was increased significantly on day 3 but declined thereafter. These parameters were comparable for both strains during the acute inflammatory stage. However, no regenerative findings were observed by histological examination and the protein concentration in the pancreas was significantly lower in OLETF rats on days 7-14, during which time regeneration was completed in LETO rats. These observations indicate that the absence of the CCK-A receptor did not modify the acute phase of pancreatitis but significantly retarded regeneration of the pancreatic tissue.     

Peripheral and central pharmacokinetics of apomorphine and its effect on dopamine metabolism in humans

Apomorphine is a dopamine receptor agonist increasingly used in the treatment of Parkinson's disease (PD). In the present study, we examined the plasma and ventricular cerebrospinal fluid (CSF) pharmacokinetics of apomorphine as well as its effects on dopamine metabolism in six patients (one woman and five men, mean age 79.5 years) without evidence of PD who underwent 48-h intracranial pressure monitoring for suspected normal pressure hydrocephalus. Maximal plasma apomorphine concentration (25.04 ng/ml) is found 20 min after subcutaneous injection (50 micrograms/kg), and the mean area under the curve is 1,439.37 ng/ml for 120 min. In contrast to plasma values, the maximal ventricular CSF apomorphine concentration (1.08 ng/ml) is found 30 min after injection and the mean area under that curve is 7% of that of plasma (96.69 ng/ml for 120 min). Apomorphine administration causes a significant reduction in ventricular CSF concentrations of dopamine and of its major metabolites sulfoconjugated dopamine, 3,4-dihydroxyphenylacetic acid (DOPAC), and homovanillic acid (HVA). This effect starts 10 min after the injection of apomorphine, is maximal after 30 min (free dopamine, -30%; sulfoconjugated dopamine, -28%; HVA, -21%; DOPAC, -31%) and is still present, although to a lesser extent (-5 to -10%), 120 min after the injection of apomorphine. This study shows that in humans a dose of apomorphine commonly used in PD causes significant inhibition of dopamine metabolism lasting > 120 min. In addition to their symptomatic effects, dopamine agonists such as apomorphine may play a role in preventing or slowing the neurodegeneration in PD by autoreceptor-mediated inhibition of dopamine metabolism.     

A possible increase in plasma norepinephrine by removal of the liver

BACKGROUND: It has recently been suggested that the human liver plays an important role in clearing plasma norepinephrine, especially in restricting most of the norepinephrine to reach the systemic circulation from the gut. METHODS: We examined the changes in plasma catecholamine levels in a patient undergoing extracorporeal hepatic resection and 4 patients undergoing living-related orthotopic liver transplantation. RESULTS: While the changes in plasma epinephrine levels were not necessarily consistent with the proposal that plasma catecholamine levels increase during the anhepatic period, plasma norepinephrine did show a transient increase in accordance with the anhepatic period in all cases. Although we could not rule out the increase in the inflow rate of norepinephrine into plasma, the interrupted hepatic elimination of norepinephrine, especially released from the gut, seemed to be partly responsible for the anhepatic period-associated increase in plasma norepinephrine. CONCLUSION: The present finding might have the potential to improve perioperative management of patients undergoing extracorporeal hepatic resection and orthotopic liver transplantation.     

6-methylprednisolone ''mini-pulses'': a new modality of glucocorticoid treatment in systemic onset juvenile chronic arthritis

Fatty acid ethyl esters (FAEE), esterification products of ethanol and fatty acids, have been implicated as mediators of ethanol-induced organ damage. Because cytosolic enzymes such as aspartate aminotransferase, lipase, and amylase appear in the blood after liver or pancreatic damage, we hypothesized that FAEE synthase, which is both cytosolic and membrane bound, is also released into the blood of patients with liver or pancreatic disease. We used a method involving thin-layer chromatography coupled with gas chromatography-mass spectrometry to reliably identify and quantify FAEE. In this study, we demonstrated that patients with liver or pancreatic disease release FAEE synthase into their plasma in amounts proportional to the amount of aspartate aminotransferase (r = 0.78), amylase (r = 0.65), and lipase (r = 0.63). These data indicate that liver and pancreatic damage results in release of FAEE synthase into the blood. The presence of FAEE synthase in plasma permits nonoxidative ethanol metabolism in the plasma.     

Effects of isotretinoin therapy on lipoprotein (a) serum levels

BACKGROUND: Increases in plasma concentrations of lipids, triglycerides, and liver enzymes have been reported in patients on isotretinoin therapy. Lipoprotein (a). (Lp (a)), a cholesterol-rich plasma lipoprotein, influences the clotting system and is related to premature coronary heart disease and stroke. METHODS: Blood (7 mL) was obtained from 30 patients with cystic acne before and 30 days after the initiation of oral isotretinoin (0.5 mg/kg/day). RESULTS: An increase in liver enzymes and lipids, except high density lipoprotein, was found in our patients at the end of the study. The mean Lp (a) levels (initial value, 25.91 +/- 3.17 mg/dL) were statistically reduced (p < 0.0001) at the end of treatment (14.80 +/- 2.35 mg/dL). CONCLUSIONS: It is suggested that isotretinoin could be used as an Lp (a) lowering agent in the future.     

Adenovirus-mediated gene transfer is augmented in basilar and carotid arteries of heritable hyperlipidemic rabbits

OBJECTIVE: Regional presynaptic dopaminergic function and its regulation by dopamine agonists in different stages of PD can be measured by L-[11C]dopa and PET. In the current investigation, we studied the effects of therapeutic apomorphine on L-[11C]dopa uptake in patients with early and advanced PD. BACKGROUND: With disease progression and chronic dopamine agonist treatment, motor response complications supervene in a majority of PD patients. It is assumed that both presynaptic and postsynaptic changes in the dopaminergic system act to modify dopaminergic efficacy. METHODS: Patients with early and advanced stages of PD were included in the study. All patients were investigated twice with PET and L-[11C]dopa drug free and during a subsequent standardized therapeutic apomorphine infusion. RESULTS: Subregional analysis of the striatum showed differences in the effects of apomorphine infusion on the L-[11C]dopa influx rate in the two patient categories. In patients with early and uncomplicated PD, apomorphine infusion decreased the L-[11C]dopa influx rate. This decrease was most pronounced in the dorsal part of the putamen. In advanced PD patients, apomorphine did not affect the striatal L-[11C]dopa influx rate. CONCLUSIONS: We suggest that in mild and stable PD an upregulated presynaptic inhibitory feedback regulation, particularly in the dorsal putamen, acts to maintain congruity within the dopaminergic system in response to antiparkinsonian medication. However, this inhibitory feedback regulation is diminished with the progression of nigrostriatal degeneration and chronic dopamine agonist treatment.     

Marked increase in serum CA 19-9 level in patients with alcoholic cirrhosis: report of four cases

We report four cases of marked increase in serum carbohydrate antigen (CA 19-9) levels in patients with severe alcoholic cirrhosis without any evidence of gastric or pancreatic carcinoma. Brief reports were obtained from two hepatology units of four cirrhotic patients, three of them with alcoholic hepatitis. In the four cases, improvement of liver function and disappearance of jaundice were associated with a decrease to normal serum CA 19-9 levels. These observations show that a marked increase in serum CA 19-9 level in patients with severe hepatic dysfunction is not diagnostic of pancreatic or gastric carcinoma.     

Methacrylonitrile induced oxidative stress in rat liver

MeAN administration (40mg/kg body wt/day (i.e. 1/5 of LD50) resulted in increased levels of lipid peroxidation products, conjugated dienes and lipofuscin-like substances in rat liver. Significant decrease in GSH and a decreased activity of hepatic SOD, CAT and GPx were observed. There was also an increase in glutathione S-transferase and G6PD activities, decreased plasma ceruloplasmin and vitamin C implying oxidative stress caused by MeAN.     

Anti-HCV in patients without risk factors for hepatitis C. Prospective study in 200 patients

Using a second generation enzyme immunoassay (ELISA) for the detection of antibodies against Hepatitis C virus (HCV), we investigated the frequency of antibodies anti-HCV and the Alanine Aminotransferase (ALT) plasma levels of 200 patients without history of viral hepatitis, liver diseases, blood transfusions, intravenous drugs abuse, homosexuality, hemodialysis, infection by Human Immunodeficiency Virus (HIV), Hepatitis B virus (HBV), nor workers of health services. There plasma samples (1.5%), were positives for antibodies anti-HCV, all of these samples were confirmed by RIBA (Recombinant Immunoblot Assay). In these three patients, the ALT plasma level were more than two folds the normal upper limit, another six patients had high ALT levels but less than one fold the normal upper limit. None of the infected patients had any clues that suggested the possible way of infection in the clinic history. We concluded that the incidence of Hepatitis C in the studied patients is 1.5% and that the ALT levels could be used to identify Hepatitis C infection.     

Serum enzymatic changes modulated using trypsin: chymotrypsin preparation during burn wounds in humans

The levels of marker enzymes for liver function, namely transaminases (SGPT, SGOT), creatine phosphokinase (CPK), alkaline phosphatase (ALP) and lactate dehydrogenase (LDH) were estimated in the sera of burn patients by administering trypsin: chymotrypsin preparation and comparing with an untreated group. Neutrophil proteolytic activity was also measured by assaying the lysosomal enzymes, namely neutrophil elastase and cathepsin D. Our earlier studies have already proved the efficacy of the above enzyme preparation to burn patients on the enhancement of vascular responses during the acute phase of the burn injury. These beneficial responses were brought about by the modulation of acute phase proteins expressed in the liver. Hence, it is of interest to study the changes in the above mentioned liver enzymes and certain lysosomal enzymes in the serum during the first 10 days of burn injury. The levels of liver and lysosomal enzymes markedly decreased in the treated group when compared with the untreated group. The enzyme studies clearly indicated that the initial rise in the liver enzymes was minimized in the treated group when compared with the untreated group and this helped in reducing the stress to the liver in the treated cases. The increase in the activity of alpha 1-antitrypsin and alpha 2-macroglobulin and decreased levels of C-reactive protein are attributed to the reduction of proteolytic enzyme levels in the treated group and minimizing the degradative changes during wound repair.     

Tremor as a factor in prolonged reaction times of parkinsonian patients

Prolonged reaction times and tremor are symptoms of Parkinson's disease (PD). Recently, we showed the existence of a systematic phase relationship between tremor-at-rest and the onset of voluntary motor responses in PD patients. In the present study we investigated whether this phase relationship contributes to the prolongation of reaction time in PD. Eight PD patients with prominent tremor-at-rest and five age-matched controls performed rapid stimulus-evoked index finger abductions under isometric conditions. Force and surface electromyogram (EMG) signals from first dorsal interosseus muscle were recorded and analyzed off-line by means of automatic routines. Reaction times of PD patients exhibited a significant dependence of mean values and variability on the current tremor phase at the onset of the voluntary motor response. Responses with an onset of contraction during the beginning of an EMG tremor burst were substantially delayed (on average 50 ms) and showed more variability in comparison to responses initiated at later times in the tremor cycle. This effect can be modeled by a simple gating process splitting the tremor cycle into two different system states that supports and inhibits the initiation of voluntary motor responses, respectively. We conclude that attraction of voluntary motor initiation to the tremor oscillator clearly contributes to prolongation of reaction time in PD.     

High-avidity autoantibodies to cytokines

Chronic asymptomatic elevation of pancreatic enzymes is a well known entity although little has been reported. In most cases chronic asymptomatic elevation of amylase is due to a salival isoamylase increase or macroamylasemia. However, we have studied 10 cases with an increase in amylases due to pancreatic isoamylase and an increase in the remaining pancreatic enzymes which remained elevated during the follow up period ranging from 2 to 60 months. The amylase values ranged from 186 to 1,600; the lipase from 176 to 3,989, trypsin from 476 to 2,430 and pancreatic isoamylase from 122 to 1,263. In all patients CT and echography were carried out, which discarded structural damage. Nonetheless, an indirect test of pancreatic function presented unexplained pathologic values in 4 out of 10 patients. In conclusion, we suggest that chronic asymptomatic elevation of pancreatic enzymes is of unknown etiology with no associated structural pancreatic pathology demonstrable by the usual study methods.     

Ammonia-induced changes in pancreatic hormones and plasma amino acids in patients with liver cirrhosis

The contribution of hyperammonemia to plasma amino acid imbalance in patients with liver disease was assessed in 10 subjects with chronic hepatitis and in 17 advanced cirrhotics. Insulin, glucagon, and plasma amino acids were determined both in the basal state and 45 min after oral ammonium chloride, at doses used in the ammonia-tolerance test. In cirrhotics, ammonia increased to 3 times basal values, in association with a rise in insulin and, more marked, in glucagon. Aromatic amino acids and free tryptophan further increased, while a significant fall in branched-chain amino acids and glutamate was observed. The increase in ammonia levels strongly correlated with the increase in glucagon (r = 0.707). Two patients, with large esophageal varices, showed signs of disturbed consciousness, in association with a marked rise in ammonia and in the ration of free tryptophan to the sum of neutral amino acids. In patients with chronic hepatitis, whose ammonia levels rose slightly, minor variations in pancreatic glucoregulatory hormones and plasma amino acids were observed, as also happened in 10 healthy subjects following ammonium chloride ingestion. Our data fit with the hypothesis that the plasma amino acid imbalance of cirrhotics may be partly due to ammonia-induced changes in pancreatic hormones.     

Necrosis of myometrial choriocarcinoma with fulminating sepsis complicating chemotherapy for trophoblastic tumor

OBJECTIVE: In normal pregnancy and pregnancies complicated by preeclampsia it has been demonstrated that there is increased activation of platelets and the clotting and fibrinolytic system. We measured plasma levels of thrombopoietin, a major regulator of platelet production in these conditions. STUDY DESIGN: We compared the thrombopoietin plasma levels of healthy term pregnant patients (n = 21) with those of healthy nonpregnant controls (n = 17), as well as patients with severe preeclampsia (n = 8) and the hemolysis, elevated liver enzymes, low platelets syndrome (n = 6). RESULTS: Thrombopoietin levels in normal pregnant patients and pregnancies complicated by the hemolysis, elevated liver enzymes, low platelets syndrome were statistically significantly higher than thrombopoietin levels in nonpregnant controls. Data were analyzed with the Kruskal-Wallis one-way analysis of variance by ranks. CONCLUSIONS: This study is the first to report thrombopoietin levels in pregnancy. Thrombopoietin levels are significantly greater in pregnant patients and in pregnancies complicated by the hemolysis, elevated liver enzymes, low platelets syndrome compared with nonpregnant controls.     

Suppression of dyskinesias in advanced Parkinson's disease. I. Continuous intravenous levodopa shifts dose response for production of dyskinesias but not for relief of parkinsonism in patients with advanced Parkinson's disease

We characterized the clinical dose-response curves for relief of parkinsonism and production of dyskinesias as a function of plasma levodopa and 3-O-methyldopa levels in six patients with advanced Parkinson's disease (PD) and fluctuating responses to oral levodopa/carbidopa. Dose response to ramped intravenous levodopa infusion was measured after overnight drug withdrawal on two occasions: first after chronic, intermittent oral levodopa/carbidopa, and second after 3 to 5 days of continuous intravenous levodopa. Continuous intravenous levodopa shifted the dyskinesia dose-response curve to the right, reduced maximum dyskinesia activity, but did not significantly alter dose response for relief of parkinsonism. Improvement in dyskinesia was apparent by the second day of continuous levodopa, during which ratios of plasma dopa/3-O-methyldopa remained constant. Our results support the hypothesis that relief of parkinsonism and production of dyskinesia by levodopa occur by separate mechanisms.     

Clinical pathways in home nutrition support

Ten liver transplant patients were studied in basal conditions and after ingestion of a standard mixed test meal. Control groups included 10 normal subjects, 10 patients with nonalcoholic liver cirrhosis, and seven kidney transplant patients. Plasma somatostatin, blood glucose, and plasma insulin, C-peptide, and glucagon were determined before and 15, 30, 45, 60, 90, 120, and 180 minutes after the start of the meal. In liver transplant patients, basal somatostatin and insulin levels were significantly lower than in cirrhotics and were comparable to those recorded in controls and in kidney transplant patients. The time course of the somatostatin secretory response after the meal was similar in any group, but the increase, evaluated as the incremental area above baseline, was significantly higher in liver transplant patients than in controls and cirrhotics and comparable to that recorded in kidney transplant patients. Insulin incremental areas were also lower than in cirrhotics and comparable to those recorded in controls and kidney transplant patients. The data suggest that in liver transplant patients an increased somatostatin response to a meal may be related to a relative beta-cell secretory defect, which in turn seems consequent to immunosuppressive treatment.     

Complement activation as a cause of transient hypotension during plasmapheresis

Hypotension is one of the most common adverse effect of plasmapheresis (PP) and often is attributed to hypovolemia due to extracorporeal circulation and the vasovagal reflex. Complements are activated during PP, and the activated complements are strong anaphylatoxins and potent vasodilators. Therefore, we studied the relationship between the transient hypotension and the plasma levels of activated complements during and after PP in 8 sessions of 7 patients using the Plasmafro OP-08 as a plasma separator. Five of the patients underwent immunoadsorption PP using the IM-TR 350 or IM-PH 350 as the adsorption column. The other underwent double filtration PP using the Evaflux 4A as a second filter. In 4 of 8 sessions, patients experienced transient hypotension with significantly elevated plasma levels of activated complements C3a and C5a. In contrast, patients without hypotension showed no increases in C3a and C5a values during PP. In this report, we emphasize the critical role of activated complements for hypotension during PP.     

Glucose response to abrupt initiation and discontinuation of total parenteral nutrition

Plasma glucose was studied during the initiation of total parenteral nutrition (TPN) and the discontinuation of TPN without a tapering schedule. Blood was sampled every 5 minutes for 2 hours after the start of TPN and 1 week later as TPN was discontinued. A total of 14 initiations and 14 discontinuations were studied in 18 patients. Severity of illness in patients ranged from stable condition postoperatively to multiple-system failure; six patients had diabetes mellitus. The TPN solution was a 3:1 admixture that provided a caloric intake equal to 1.2 times the resting energy expenditure, with 40% fat and 60% carbohydrate calories. An average of 1963 kcal was provided per day (340 g of glucose, 79 g of fat). During the initiation phase, the mean increase in plasma glucose was 60 mg/dL. The increase for diabetic patients was 79 +/- 14 mg/dL compared with 52 +/- 23 mg/dL for the nondiabetics. During the discontinuation phase, the mean plasma glucose decreased 40 +/- 20 mg/dL; two patients with high concentrations of regular insulin (50 and 100 units) showed an increase in plasma glucose when the TPN was stopped. Plasma glucose returned to the preinfusion baseline after discontinuation. During both initiation and discontinuation, plasma glucose showed little change after the first 60 minutes. No clinical symptoms of hypoglycemia were observed. In conclusion, TPN as a 3:1 admixture can be safely started as full nutrition support and stopped abruptly without a tapering schedule. Plasma glucose response is rapid, predictable, and mostly complete within 60 minutes.     

Mechanistic insights into chemopreventive effects of phenethyl isothiocyanate in N-nitrosobis(2-oxopropyl)amine-treated hamsters

The influence of phenethyl isothiocyanate (PEITC) on cell kinetics in the target organs of N-nitrosobis(2-oxopropyl)amine (BOP) tumorigenicity and on xenobiotic-metabolizing enzymes was investigated in hamsters. Female 5-week-old Syrian hamsters were given a single s.c. dose of 0, 20 or 50 mg/kg of BOP 2 h after receiving PEITC by gavage at a dose of 0, 100 or 250 mumol/animal (0, 16.3 or 40.8 mg/animal). Six and 22 h after the BOP administration, hamsters were killed and tissues were sampled. Proliferating cell nuclear antigen immunohistochemistry demonstrated significant reduction (P < 0.05-0.001) by PEITC of the labeling indices in the pancreatic acini and ducts, bronchioles, and renal tubules of the BOP-treated animals in a dose-dependent manner. In the lungs, the PEITC pretreatment significantly (P < 0.001) reduced the O6-methyldeoxyguanosine levels as compared to the BOP-alone value. Immunoblot analysis of liver cytochrome P450 isoenzymes showed CYP 2B1 to be mainly involved in the metabolic activation of BOP. PEITC significantly (P < 0.05) inhibited the induction of several isoenzymes, including CYP 2B1, while lowering the hepatic glutathione S-transferase activity as well as glutathione levels, regardless of BOP administration. Our results thus suggest that PEITC exerts its chemopreventive activity against BOP initiation of carcinogenesis in hamsters by decreasing cell turnover and DNA methylation in the target organs, and by influencing hepatic xenobiotic-metabolizing phase I enzymes, although the relationship, if any, of the latter with the former events remains to be investigated.     

Expansion of the liver-associated macrophage system in systemic lupus erythematosus-prone NZB/W mice

The relation between propafenone dose, serum level, electrocardiographic parameters, antiarrhythmic drug efficacy and adverse effects was studied in 47 children with symptomatic supraventricular arrhythmias aged 1 day to 10.3 years (median 2.2 months) with a mean follow-up of 14.3 months. Propafenone trough serum levels were measured using gas chromatography. Oral propafenone (mean dose 353 mg/m2/day) was effective in 41 of the 47 patients (87.2%). Serum levels did not differ between patients responding and not responding to propafenone (0.45 +/- 0.40 vs 0.36 +/- 0.41 mg/liter). PR interval and QRS complex duration increased more significantly with propafenone dose increments (p < 0.001), than with propafenone serum levels (p < 0.05). At successful treatment PR interval and QRS complex were prolonged by a mean of 19.2 and 20.5% compared with pretreatment status. Five patients exhibited unexpected marked QRS complex prolongation (50 to 200%) despite low propafenone dosage (< 300 mg/m2/day) and level ranging from 0.05 to 1.33 mg/liter. Three patients (6.1%) were suspected of being "poor" metabolizers of propafenone. Mild chronic elevation of serum liver enzymes was observed in 5 patients treated with a larger dose (mean 448 mg/m2/day, p < 0.001). No proarrhythmia was noted on serial Holter monitors. One patient with Wolff-Parkinson-White syndrome and a normal heart had cardiac arrest after aspiration. Serial monitoring of PR interval and QRS complex duration was more useful for proper dosage adjustment than propafenone serum levels. Serum liver enzymes should be closely monitored when using higher propafenone doses. Malignant proarrhythmia could not be excluded in the 1 patient with cardiac arrest.