The impact of strength level on adaptations to combined weightlifting, plyometric, and ballistic training.

The purpose of this investigation was to determine whether the magnitude of adaptation to integrated ballistic training is influenced by initial strength level. Such information is needed to inform resistance training guidelines for both higher- and lower-level athlete populations. To this end, two groups of distinctly different strength levels (stronger: one-repetition-maximum (1RM) squat = 2.01 ± 0.15 kg·BM-1 ; weaker: 1.20 ± 0.20 kg·BM-1 ) completed 10 weeks of resistance training incorporating weightlifting derivatives, plyometric actions, and ballistic exercises. Testing occurred at pre-, mid-, and post-training. Measures included variables derived from the incremental-load jump squat and the 1RM squat, alongside muscle activity (electromyography), and jump mechanics (force-time comparisons throughout the entire movement). The primary outcome variable was peak velocity derived from the unloaded jump squat. It was revealed that the stronger group displayed a greater (P = .05) change in peak velocity at mid-test (baseline: 2.65 ± 0.10 m/s, mid-test: 2.80 ± 0.17 m/s) but not post-test (2.85 ± 0.18 m/s) when compared to the weaker participants (baseline 2.43 ± 0.09, mid-test. 2.47 ± 0.11, post-test: 2.61 ± 0.10 m/s). Different changes occurred between groups in the force-velocity relationship (P = .001-.04) and jump mechanics (P ≤ .05), while only the stronger group displayed increases in muscle activation (P = .05). In conclusion, the magnitude of improvement in peak velocity was significantly influenced by pre-existing strength level in the early stage of training. Changes in the mechanisms underpinning performance were less distinct.

Accuracy of primary systematic template guided transperineal biopsy of the prostate for locating prostate cancer: a comparison with radical prostatectomy specimens.

PURPOSE: We determined whether systematic template guided transperineal biopsies can accurately locate and sensitively detect prostate cancer. In addition, we reported discrepancies between diagnostic and pathological Gleason scores, and investigated whether prostate size had an effect on the cancer detection rate. MATERIALS AND METHODS: This retrospective diagnostic accuracy study compares the results of primary transperineal biopsies with the radical prostatectomy pathology of 414 consecutive patients treated at a single institution between November 2002 and August 2010. RESULTS: The average sensitivity and specificity for the detection of cancer in all prostates across all biopsy zones was 48% (95% CI 42.6-53.4) and 84.1% (95% CI 80-88.2), respectively. There was a statistically significant decrease in the sensitivity of transperineal biopsy in larger prostates (t11=4.687, p=0.001). The overall Kappa value was 0.255 (95% CI 0.212-0.298). Grading concordance between biopsy and pathology specimens was achieved in 65.7% of patients. Upgrading of Gleason scores occurred in 25.6% of patients and downgrading occurred in 8.8%. CONCLUSIONS: Our current transperineal biopsy method has only demonstrated fair agreement with the histopathology findings of the corresponding radical prostatectomy specimens. This finding is most likely due to the small, multifocal nature of prostate cancer in the patient series. The cancer detection rate was lower in larger prostates. Thus, clinicians may consider increasing the number of cores in larger prostates as a strategy to improve cancer detection.

Impaired Driving Associated with the Synthetic Cannabinoid 5f-Adb.

Synthetic marijuana compounds are more potent than Δ9-tetrahydrocannabinol (∆9-THC) and are known to produce a wide variety of clinical symptoms including cardiac toxicity, seizures, and death. Erratic driving by a 45 y/o male was witnessed in the fall of 2017 and roadside evaluation of the driver by the responding law enforcement officer concluded that the driver was intoxicated. Comprehensive analysis of the cigarettes by gas chromatography-mass spectrometry detected the synthetic cannabinoid 5-fluoro-ADB (5F-ADB or 5F-MDMB-PINACA). Validated forensic liquid chromatography-tandem mass spectrometry (LC-MS/MS) methods were used to detect the 5-fluoro ADB metabolite 7 (26.37 ng/mL) in the driver's blood sample. No other drugs were detected. This case report is one of the first to conclusively show that designer synthetic cannabinoids, commonly referred to as "K2" and "Spice", can significantly impair driving at relatively low concentrations.

Ontogeny of dextromethorphan O- and N-demethylation in the first year of life.

The exponential increase in the number of drugs used to treat infant and childhood illnesses necessitates an understanding of the ontogeny of drug biotransformation for the development of safe and effective therapies. Healthy infants received an oral dose (0.3 mg/kg) of dextromethorphan (DM) at 0.5, 1, 2, 4, 6, and 12 months of age. DM and its major metabolites were measured in urine. CYP2D6 genotype was determined by polymerase chain reaction-restriction fragment length polymorphism. Genotyping data indicated a strong correlation between CYP2D6 genotype and DM O-demethylation (beta=-0.638; 95% CI: -0.745, -0.532; P<0.001). CYP2D6 activity was detectable and concordant with genotype by 2 weeks of age, showed no relationship with gestational age, and did not change with post natal age up to 1 year. In contrast, DM N-demethylation developed significantly more slowly over the first year of life. Genotype and the temporal acquisition of drug biotransformation are critical determinants of a drug response in infants.

Caffeine decreases intermittent hypoxia in preterm infants nearing term-equivalent age.

OBJECTIVE: To determine whether intermittent hypoxia (IH) persisting after 36 weeks postmenstrual age (PMA) can be attenuated using caffeine doses sufficient to maintain caffeine concentrations >20 µg ml-1. STUDY DESIGN: Twenty-seven infants born <32 weeks were started on caffeine citrate at 10 mg kg-1 day-1 when clinical caffeine was discontinued. At 36 weeks PMA, the dose was increased to 14 or 20 mg kg-1 day-1 divided twice a day (BID) to compensate for progressively increasing caffeine metabolism. Caffeine concentrations were measured weekly. The extent of IH derived from continuous pulse oximetry was compared to data from 53 control infants. RESULT: The mean (s.d.) gestational age of enrolled infants was 27.9±2 weeks. Median caffeine levels were >20 µg ml-1 on study caffeine doses. IH was significantly attenuated through 38 weeks PMA compared with the control group. CONCLUSION: Caffeine doses of 14 to 20 mg kg-1 day-1 were sufficient to maintain caffeine concentrations >20 µg ml-1 and reduce IH in preterm infants at 36 to 38 weeks PMA.

Elevation of serum interleukin 8 levels in acetaminophen overdose in children and adolescents.

BACKGROUND: Elevations of inflammatory cytokines have been reported in animal models of acetaminophen (INN, paracetamol) toxicity. In addition, interleukin 8, a chemokine, has been found to be elevated in toxin-associated hepatic disease (ie, acute alcoholic hepatitis). The purpose of this study was to measure serum cytokine levels in children and adolescents with acetaminophen overdose and to evaluate relationships between cytokine elevation and hepatotoxicity. METHODS: Serum levels of tumor necrosis factor alpha, interleukin 1beta, interleukin 6, interleukin 8, and interleukin 10 were measured by ELISA in children and adolescents (n = 35) with acetaminophen overdose. Peak cytokine levels were examined relative to biochemical evidence of hepatocellular injury, nomogram risk assessment, and prothrombin time. RESULTS: Five patients had aspartate aminotransferase or alanine aminotransferase levels >1000 IU/L, and 4 patients had aspartate aminotransferase or alanine aminotransferase levels > or =100 IU/L and < or =1000 IU/L. No elevations of tumor necrosis factor alpha or interleukin 1beta were detected. Peak interleukin 8, but not interleukin 6 or interleukin 10, correlated with hepatotoxicity (Mann-Whitney exact test, P <.001). The peak interleukin 8 level was greater in patients at high risk by the nomogram combined with those presenting at >15 hours, as compared with other patients (Mann-Whitney U test, P <.01). The interleukin 8 level peaked before aspartate aminotransferase or alanine aminotransferase in 5 of the 9 patients with hepatotoxicity. In addition, interleukin 8 concentrations of >20 pg/mL were associated with peak prothrombin time values (Mann-Whitney exact test, P <.015). CONCLUSIONS: Interleukin 8 elevation in patients with acetaminophen hepatotoxicity corresponds with other common clinical measures that are predictive of hepatocellular injury. Further study is warranted to evaluate possible mechanistic relationships between inflammatory cytokines and acetaminophen hepatotoxicity in children and adults.

A comparison of cathartics in pediatric ingestions.

OBJECTIVE: To compare the mean time to first stool, number of stools, and side effects of three commonly used cathartics in pediatric ingestions. DESIGN: This prospective clinical trial was a randomized, double-blinded comparison of sorbitol, magnesium citrate, magnesium sulfate, and water, administered with activated charcoal in the treatment of pediatric patients 1 to 5 years of age with acute ingestions. Outcome parameters were mean time to first stool, mean number of stools during 24 hours, and side effects. RESULTS: One hundred sixteen patients completed the study. Significant differences in mean time to the first stool were detected among cathartic agents (F = 9.29), with sorbitol-treated patients having a shortest mean time to the first stool (mean, 8.48 hours). Sorbitol produced a significantly higher number of stools (mean, 2.79) in the 24-hour follow-up period than other cathartics (F = 3.49). The most common side effect of cathartic administration was emesis, which occurred more commonly in sorbitol-treated patients. CONCLUSION: Sorbitol, when administered with activated charcoal in the treatment of children with acute ingestions, produced a shorter time to first stool and more stools than magnesium citrate, magnesium sulfate, or water.

Pharmacokinetics and pharmacodynamics of famotidine in paediatric patients.

Famotidine, an H2 receptor antagonist, has several potential advantages over cimetidine and ranitidine. These advantages include its potency, relatively longer elimination half-life, and lack of interaction with the cytochrome P450 isoforms. Eight studies addressing the use of famotidine in paediatric patients have been published. Data from these studies demonstrate that the pharmacokinetics and pharmacodynamics of intravenous famotidine appear to be similar in both children over the age of 1 year and adults. These data support a starting paediatric dosage for intravenous famotidine of 0.5 mg/kg every 8 to 12 hours. In addition, the safety and efficacy of famotidine in the treatment of peptic ulcer disease and esophagitis in paediatric patients is supported by these studies involving over 150 children. Future studies with famotidine in paediatrics should address its disposition in children under the age of 1 year and in children with compromised renal function, as well as the bioavailability of the oral formulation.

Occult papillary carcinoma of the thyroid with pulmonary metastases.

This case report describes an occult papillary adenocarcinoma of the thyroid with pulmonary metastases, discovered at autopsy. Since papillary adenocarcinoma of the thyroid usually invades adjacent structures and cervical lymph nodes in a predictable fashion, the finding of distant hematogenous spread, when the tumor is confined to the thyroid gland, is unusual, as is illustrated by a review of the literature. The patient's history included a poorly differentiated squamous cell carcinoma of the lung, which had been resected 15 years prior to death and had been followed by super-voltage radiation. The possible effects of super-voltage radiation on the pathogenesis and behavior of thyroid cancer are discussed.

Single dose pharmacokinetics of pleconaril in neonates. Pediatric Pharmacology Research Unit Network.

BACKGROUND: Pleconaril is an orally active, broad spectrum antipicornaviral agent with activity against nonpolio enteroviruses. Pleconaril phamacokinetics was evaluated in 16 neonates (16.4 +/- 8.7 days postnatal age) with suspected enteroviral infection. METHODS: Pleconaril (5 or 7.5 mg/kg) was administered orally to study subjects and plasma pleconaril concentrations quantified from serial blood samples obtained during 24 h after a single oral dose by gas chromatography with electrochemical detection. Pharmacokinetic parameter estimates were determined by noncompartmental methods and compared between doses and with similar data obtained from a previous study of pleconaril disposition in children (n = 18, 2 to 12 years). RESULTS: Pleconaril was well-tolerated in all neonates without discernible adverse events. Comparison between the 5.0- and 7.5-mg/kg doses revealed no significant differences in peak plasma concentration (Cmax 686.7 vs. 617.1 ng/ml), elimination half-life (t 1/2; 4.6 vs. 6.6 h), area under the plasma concentration vs. time curve (AUC; 5162.6 vs. 5523.9 ng/ml/h), apparent steady state volume of distribution (V(dss)/F; 9.3 vs. 17.1 liters/ kg) and apparent oral clearance (Cl/F; 1.3 vs. 1.7 liters/h/kg). In addition, no correlation was observed between postconceptional age and AUC, V(dss)/F, t 1/2 or Cl/F for pleconaril. Comparison of pleconaril pharmacokinetics between neonates and children suggested a significant difference in V(dss)/F (9.3 vs. 4.7 liters/kg), dose-normalized Cmax, (686.7 vs. 1272.5 ng(ml) and AUC (5125.6 vs. 8131.2 ng/ml/h). In contrast, the mean elimination t 1/2 between neonates and children was not appreciably different. CONCLUSIONS: The apparent age-dependent differences in the pharmacokinetics of pleconaril may in part be related to increased bioavailability of the drug in older children and adults than in neonates. Our data appear to support the use of a 5.0-mg/kg dose given every 8 to 12 h in future studies of pleconaril in neonatal patients with enteroviral infection.

Single dose pharmacokinetics of linezolid in infants and children.

BACKGROUND: Linezolid is an oxazolidinone antibiotic with excellent in vitro activity against a number of Gram-positive organisms including antibiotic-resistant isolates. The safety and pharmacokinetics of intravenously administered linezolid were evaluated in children and adolescents to examine the potential for developmental dependence on its disposition characteristics. METHODS: Fifty-eight children (3 months to 16 years old) participated in this study; 44 received a single 1.5-mg/kg dose and 14 received a single 10-mg/kg dose of linezolid administered by intravenous infusion. Repeated blood samples (n = 10 in children > or = 12 months; n = 8 in children 3 to 12 months) were obtained during 24 h after drug administration, and linezolid was quantitated from plasma by high performance liquid chromatography with mass spectrometry detection. Plasma concentration vs. time data were evaluated with a model independent approach. RESULTS: Linezolid was well-tolerated by all subjects. The disposition of linezolid appears to be age-dependent. A significant although weak correlation between age and total body clearance was observed. The mean (+/- SD) values for elimination half-life, total clearance and apparent volume of distribution were 3.0 +/- 1.1 h, 0.34 +/- 0.15 liter/h/kg and 0.73 +/- 0.18 liter/kg, respectively. Estimates of total body clearance and volume of distribution were significantly greater in children than historical values of adult data. As such maximum achievable linezolid plasma concentrations were slightly lower in children, and concentrations 12 h after a single 10-mg/kg dose were below the MIC90 for selected pathogens with in vitro susceptibility to the drug. CONCLUSION: Based on these data a linezolid dose of 10 mg/kg given two to three times daily would appear appropriate for use in pediatric therapeutic clinical trials of this agent.

Abnormalities of bone marrow simulating histiocytic medullary reticulosis in a patient with gastric carcinoma.

In the proper clinical setting, phagocytosis by bone marrow histiocytes of erythrocytes, granulocytes, and platelets (panphagocytosis) is generally accepted as the morphologic hallmark of histiocytic medullary reticulosis. A patient with clinical manifestations that suggested histiocytic medullary reticulosis was found also to have histiocytic panphagocytosis in the bone marrow. Biopsy of the liver, however, revealed metastatic adenocarcinoma. In addition, postmortem examination demonstrated a gastric adenocarcinoma with massive hepatic involvement and absence of lymphadenopathy, splenomegaly, or evidence of generalized histiocytic proliferation. Therefore, histiocytic panphagocytosis is probably not specific for histiocytic medullary reticulosis, and may be a nonspecific feature of a variety of diseases.

Composite carcinoma-carcinoid tumors of the gastrointestinal tract. A morphologic, histochemical, and immunocytochemical study.

A morphologic, histochemical, and immunocytochemical study of 20 cases of pure gastrointestinal carcinoids, adenocarcinomas, and mixed neoplasms composed of both elements, so-called composite carcinoma-carcinoid tumors (CCC), was undertaken in order to correlate the morphologic patterns with the immunocytochemical localization of carcinoembryonic antigen (CEA), serotonin, and a battery of polypeptide hormones (calcitonin, glucagon, insulin, gastrin, somatostatin, and adrenocorticotropin [ACTH]). Paraffin sections from five pure carcinoids, seven pure adenocarcinomas, and eight CCC from the stomach, small bowel, appendix, and colon were studied with mucicarmine, silver impregnation stains, and a peroxidase-anti-peroxidase technic. Of the eight CCC, all were mucin positive, four were argyrophilic, and three were argentaffin positive. CEA was present in all eight, serotonin in seven, and calcitonin in one. No other neurohormonal peptides were demonstrated. The distribution of serotonin and CEA generally corresponded to the morphologic pattern, but discordance was observed in two cases, i.e., serotonin was not always localized to areas of carcinoid and CEA not always confined to areas of carcinoma. All five pure carcinoids demonstrated intracytoplasmic localization of serotonin, whereas none contained intracytoplasmic CEA. In two cases, CEA was present within acinar lumens only. The seven colonic adenocarcinomas were argyrophil and argentaffin negative. All contained CEA within the cytoplasm and in gland lumens. None contained serotonin. None of the neurohormonal peptides was localized in either pure adenocarcinomas or carcinoids. This study reveals that among gastrointestinal neoplasms displaying morphologic patterns of adenocarcinoma and carcinoid, immunocytochemical localization of CEA and serotonin confirms their bidirectional differentiation and justifies the designation "composite carcinoma-carcinoid."

ThinPrep Processor. Clinical trials demonstrate an increased detection rate of abnormal cervical cytologic specimens.

The authors compared the accuracy of conventionally prepared smears and smears prepared by an automated, fluid-based, thin-layer processing device in the detection of cytologic abnormalities. A total of 3218 patients from five centers took part in this study, in which a single cervical sample was split into a matched pair. The conventional smear was made in the routine fashion; the remainder of the cells on the sampling device were rinsed into a transport-fixation fluid. A slide was then prepared from the solution using the thin-layer processor. Diagnostic findings identified on the two preparations were compared in a blinded fashion, and a discrepancy resolution procedure was used to eliminate screening differences. Overall, there was a high correlation in the diagnoses of the two methods. For low-grade or more severe disease, the thin-layer method resulted in a 13% increase in the rate of detection, as compared with the conventional Papanicolaou smear technique.

Sarcoid-like lesions associated with epithelial ovarian adenocarcinoma.

A woman with poorly differentiated endometrioid adenocarcinoma of the ovary had sarcoid-like lesions in the bone marrow. Sarcoid-like lesions may be misinterpreted as metastatic disease, resulting in inappropriate modification of therapy.

Cyclic antidepressant toxicity in children and adolescents.

We retrospectively evaluated the clinical and laboratory findings of all patients admitted to our facility during a 6.5-year period with a history of cyclic antidepressant ingestion (CAD). Outcome parameters [admission CAD concentration, arterial pH, and corrected QT (QTc) and QRS intervals] used in adult populations to predict morbidity after CAD ingestion were applied to our study population. During the study period, 45 patients (mean +/- SD age of 11.8 +/- 5.6 years) were admitted with CAD ingestion. Conduction delays were present in 17 patients, 9 of whom had QTc intervals greater than 0.43 seconds. Seven patients had generalized seizures; 7 required mechanical ventilation; 14 had Glasgow Coma Scores of 8 or lower on presentation; and one required pharmacologic support for hypotension. In our cohort, the mean admission serum CAD concentration was 461.5 +/- 477.4 ng/mL. Correlations were found between the arterial pH, the QRS interval, the QTc interval, and the admission CAD serum concentration. In an analysis of three subsets of patients (i.e., those with seizures, coma, and respiratory insufficiency), only patients who presented with seizures were found to have a significant prolongation in the QRS and QTc intervals. Pediatric patients who have ingested CADs and present with seizures would appear to be at increased risk for having conduction delays, cardiac dysrhythmias, and, presumably, attendant morbidity and mortality associated with an ingestion.

The pharmacokinetics of oral ranitidine in children and adolescents with cystic fibrosis.

The pharmacokinetics of oral ranitidine were studied in 9 patients (ages 9.9 to 19.6 years) with cystic fibrosis (CF). Patients were evaluated at steady-state conditions, and the mean maximum serum concentration (Cmax) was 845.7 +/- 448.1 ng/mL. To adjust for the variable drug dosing used among study patients, both Cmax and area under the concentration curve (AUC) were standardized to dose (CmaxST and AUCST, respectively) and were 217.9 +/- 87.9 ng/mL and 1038.0 +/- 242.2 ng/mL.h. The elimination half-life (t1/2) was 2.7 +/- 1.4 hours, and the apparent steady-state volume of distribution (Vdss) was 4.6 +/- 1.7 L/kg. The plasma clearance was 1.022 +/- 0.290 L/kg/h. The Vdss in this study was greater than that previously reported in children with peptic ulcer disease. Statistically significant relationships between pharmacokinetic parameters and measures of disease severity were not observed in the study population. The pharmacokinetics of ranitidine in children and adolescents with CF may differ from those in children and adolescents without CF.

Pharmacokinetics and pharmacodynamics of famotidine in children.

The pharmacokinetics and pharmacodynamics of intravenous famotidine were studied in 12 children (1.1-12.9 years of age; mean weight +/- standard deviation = 27.6 +/- 21.2 kg) who were given the drug for prophylactic management of stress ulceration. After a 0.5-mg/kg infusion of famotidine, timed blood (n = 10) and urine (n = 6) samples and repeated evaluations of intragastric pH (n = 13) were obtained from each subject. Pharmacokinetic parameters were determined from curve fitting of serum concentration data. The mean (+/- SD) maximum serum concentration (Cmax) was 527.6 +/- 281.2 ng/mL, the elimination half-life (t1/2) was 3.2 +/- 3.0 hours, and the apparent steady-state volume of distribution (Vdss) was 2.4 +/- 1.7 L/kg. Plasma clearance (Cl) and renal clearance (ClR) were 0.70 +/- 0.34 L/hr/kg and 0.43 +/- 0.24 L/hr/kg, respectively. Over 24 hours, 73.0 +/- 27.3% of the dose was excreted unchanged in the urine (Fel). Pharmacodynamic analysis of gastric pH data using the sigmoid Emax model predicted that 50% of the maximal effect of famotidine (EC50) occurs at a serum concentration of 26.0 +/- 13.2 ng/mL. Children who did not have an initial intragastric pH < or = 4 did not have a significant response in pH after receiving famotidine. Although Vdss and Cl were higher in these children than those seen in adults, statistically significant relationships between these parameters and age were not observed in the study population. The pharmacodynamics and pharmacokinetics of famotidine in children older than one year of age appear to be similar to those noted in adults.

Pharmacokinetics and pharmacodynamics of famotidine in infants.

The pharmacokinetics and pharmacodynamics of intravenous famotidine were evaluated in 10 infants ranging from 5 to 19 days of age who had a therapeutic indication for the prophylactic treatment of stress ulceration. After a 0.5-mg/kg infusion of famotidine, timed serum (n = 6), urine (24-hour collection), and repeated measurements of gastric pH were obtained. The mean +/- standard deviation maximum plasma concentration (Cmax) was 640.66 +/- 250.66 ng/mL, the elimination half-life (t1/2 beta) was 10.51 +/- 5.43 hours, and the apparent volume of distribution at steady state (Vdss) was 0.82 +/- 0.29 L/kg. Plasma clearance (Cl) and renal clearance (ClR) were 0.132 +/- 0.061 L/hr/kg and 0.093 +/- 0.056 L/hr/kg, respectively. No significant correlations were found between t1/2 beta, Vdss, Cl, and ClR and age. Six of the nine infants who had intragastric pH monitoring maintained a gastric pH > 4 until the final 24-hour sampling point. In this study, the t1/2 beta of famotidine was prolonged and the Vdss, Cl, ClR were reduced compared with corresponding parameters in previously reported studies of children older than one year of age and adults.

Measurement of acetaminophen-protein adducts in children and adolescents with acetaminophen overdoses. .

Acetaminophen-protein adducts are biomarkers of acetaminophen toxicity present in the centrilobular region of the liver of laboratory animals following the administration of toxic doses of acetaminophen. These biomarkers are highly specific for acetaminophen-induced hepatic injury and correlate with hepatic transaminase elevation. The objective of this prospective, multicenter study was to evaluate the clinical application of the measurement of acetaminophen-protein adducts in pediatric acetaminophen overdose patients. Serum samples were obtained from 51 children and adolescents with acetaminophen overdose at the time of routine blood sampling for clinical monitoring. Six subjects developed "severe" hepatotoxicity (transaminase elevation > 1,000 IU/L), and 6 subjects had transaminase elevation of 100 to 1,000 IU/L. Acetaminophen-protein adducts were detected in the serum of only 1 study subject, a patient with marked transaminase elevation (> 6,000 IU/L) and high risk for the development of hepatotoxicity according to the Rumack nomogram. While this study provides further support for the occurrence of covalent binding of acetaminophen to hepatic protein in humans following acetaminophen overdose, the detection of acetaminophen-protein adducts in serum with the current methodology requires significant biochemical evidence of hepatocellular injury.