Prolonged cardiac arrest and resuscitation in dogs: brain mitochondrial function with different artificial perfusion methods

Clinical techniques for artificial perfusion have not previously been examined directly for their effects on brain high-energy metabolism. Our study involved 24 large mongrel dogs that were anesthetized, instrumented for central venous intravenous access, and subjected to craniotomy to expose the dura and underlying parietal cortex. The animals were divided into the following six experimental groups of four animals each: nonischemic controls; 15-minute cardiac arrest without resuscitation; 45-minute cardiac arrest without resuscitation; 15-minute cardiac arrest plus 30 minutes resuscitation with conventional cardiopulmonary resuscitation (CPR); 15-minute cardiac arrest plus 30 minutes resuscitation with interposed abdominal compression (IAC) CPR; and 15-minute cardiac arrest plus 30 minutes resuscitation with internal cardiac massage. Cardiac arrest was induced by central venous injection of KCl 0.6 mEq/kg, and it was confirmed by continuous ECG monitoring. The three active resuscitation models included administration of NaHCO3 and epinephrine, but no attempt was made to restart the heart by defibrillation during resuscitation. At the indicated time in each group, a 4- to 5-g sample of brain was removed through the craniotomy, immediately cooled to 0 C and processed for isolation of mitochondria. The mitochondria were studied for their content of superoxide dismutase and for quantitative oxygen consumption with glutamate/malate substrate during resting and ADP-stimulated respiration. Our results show a significant drop in brain mitochondrial superoxide dismutase activity during the first 15 minutes of cardiac arrest. There is minimal injury to brain mitochondrial oxygen consumption during both 15 and 45 minutes of complete ischemia.(ABSTRACT TRUNCATED AT 250 WORDS)     

The toxicological significance of post-mortem drug concentrations in bile

Context: Some authors have proposed that post-mortem drug concentrations in bile are useful in estimating concentrations in blood. Both The International Association of Forensic Toxicologists (TIAFT) and the US Federal Aviation Administration recommend that samples of bile should be obtained in some circumstances. Furthermore, standard toxicological texts compare blood and bile concentrations, implying that concentrations in bile are of forensic value.

Aim: To review the evidence on simultaneous measurements of blood and bile drug concentrations reported in the medical literature.

Methods: We made a systematic search of EMBASE 1980–2016 using the search terms (“bile/” OR “exp drug bile level/concentration/”) AND “drug blood level/concentration/”, PubMed 1975–2017 for (“bile[tw]” OR “biliary[tw]”) AND (“concentration[tw]” OR “concentrations[tw]” OR “level[tw]” OR “levels[tw]”) AND “post-mortem[tw]” and also MEDLINE 1990–2016 for information on drugs whose biliary concentrations were mentioned in standard textbooks. The search was limited to human studies without language restrictions. We also examined recent reviews, indexes of relevant journals and citations in Web of Science and Google Scholar. We calculated the bile:blood concentration ratio. The searches together yielded 1031 titles with abstracts. We scanned titles and abstracts for relevance and retrieved 230, of which 161 were considered further. We excluded 49 papers because: the paper reported only one case (30 references); the data referred only to a metabolite (1); the work was published before 1980 (3); the information concerned only samples taken during life (10); or the paper referred to a toxin or unusual recreational drug (5). The remaining 112 papers provided data for analysis, with at least two observations for each of 58 drugs.

Bile:blood concentration ratios: Median bile:blood concentration ratios varied from 0.18 (range 0.058–0.32) for dextromoramide to 520 (range 0.62–43,000) for buprenorphine. Median bile concentrations exceeded blood concentrations by one order of magnitude for several drugs, including dihydrocodeine, quetiapine and sildenafil; and by two orders of magnitude of for buprenorphine, colchicine and 3,4-methylenedioxy-methamphetamine (MDMA), among others. The minimum and maximum values for the ratio differed by a factor of three or more in three-quarters of the cases where data were available and by a factor of 10 or more for over half of the analytes.

Limitations: The data were difficult to find. Medline does not explicitly index the term “drug bile concentration”. It may well be that other reports exist, although they would not alter our major conclusion. Many of the papers that contributed data failed to specify the source of the blood samples or the post-mortem interval, so that no judgment was possible regarding post-mortem redistribution in whole blood or bile.

Conclusions: For most drugs, there are wide ranges of bile:blood concentration ratios, which means that bile and blood concentrations are generally poorly correlated. Bile concentration measurements cannot readily be used to establish post-mortem blood concentrations; nor can they be extrapolated to ante-mortem concentrations. However, because drug concentrations in bile often exceed those in blood, bile may allow qualitative identification of drugs present, even when the blood concentration is below the limit of detection.     

Ontario familial colon cancer registry: methods and first-year response rates

The Ontario Familial Colon Cancer Registry (OFCCR) is a novel registry that collects family history information, epidemiologic data, blood samples and tumour specimens from a population-based sample of colorectal cancer patients and their families. Families are classified as either high familial risk, intermediate familial/other risk or low (sporadic) risk for colorectal cancer. Obtaining high response rates in genetic family studies is especially challenging because of both the time commitment required and issues of confidentiality. The first-year response rate was 61%, resulting in 1,395 participating probands. In an attempt to assess potential response bias, we compared participants with non-participants. The age and sex of participants did not differ from non-participating probands; however, cases in rural areas were somewhat more likely to participate. To date, 57% of 1,587 relatives participated; females were more likely to participate, and relatives of low familial risk were least likely to participate. The OFCCR is an excellent resource that will facilitate the study of genetic and environmental factors associated with colorectal cancer.     

Cardiomegaly on chest x-ray: prognostic implications from a ten-year cohort study of elderly subjects: a report from the Bronx Longitudinal Aging Study.

This report is from a 10-year cohort study of community-dwelling elderly men and women. Mean age at the time of entry into the study was 79 years. Annual chest x-ray studies were performed, and data are presented regarding prevalence, incidence, and prognosis of cardiomegaly. Cardiomegaly was defined as a transverse diameter of the cardiac silhouette greater than or equal to 50% of the transverse diameter of the chest (increased cardiothoracic ratio). At the time of entry into the study 110 subjects (23%) had cardiomegaly. After 10 years, 51% of the subjects with cardiomegaly at baseline died compared with 33% of the subjects without cardiomegaly (mortality rate = 9.1 vs 4.8/100 person-years respectively; p = 0.014). Cardiovascular disease incidence was also higher for those with preexisting cardiomegaly at baseline (rate 9.1 vs 6.1/100 person-years; p = 0.0001). According to the Cox proportional hazards regression analysis, age, cardiomegaly, diabetes, and prior evidence of myocardial infarction were independent predictors for death in this cohort. Similarly, the best predictive variables for cardiovascular disease were age, diabetes, prior evidence of myocardial infarction, and cigarette smoking. Of the 359 subjects without cardiomegaly at baseline, 108 (30%) showed evidence of new cardiomegaly, and their risk of cardiovascular disease was 1.8 times that of subjects whose test results were negative for cardiomegaly throughout the study (p = 0.003). Thus cardiomegaly, as defined by an increased cardiothoracic ratio on x-ray films, irrespective of cause, is associated with a poor prognosis in very elderly men and women.     

The leukergy test in rheumatic diseases. New implications for an old test

In order to assess the value of the leukergy test in which leukocytes aggregate in citrated whole blood, we examined 65 patients with various rheumatic conditions. In addition, plasma samples from 40 patients were examined for neutrophil aggregation activity in vitro. Results of the leukergy test were found to be in very good correlation with disease activity (P = 0.0001), whereas no increased neutrophil aggregation activity was found in the 40 plasma samples examined. The value of the leukergy test in assessing patients with rheumatic disease and its theoretical etiopathogenic role in these diseases are discussed.     

Drug enterocyte adducts: possible causal factor for diclofenac enteropathy in rats

BACKGROUND & AIMS: Enteropathy is a frequent complication of diclofenac and other nonsteroidal anti-inflammatory drugs, yet little is known about the underlying mechanism. One possibility is that reactive metabolites of diclofenac form adducts with enterocyte macromolecules, as previously shown for liver. We addressed this possibility by using immunohistochemistry to detect diclofenac adducts. METHODS: Rats were treated orally with diclofenac (10-100 mg/kg) and killed after 1-24 hours, and their gastrointestinal (GI) tracts were evaluated for ulcer number and area. Adduct distribution and intensity were assessed by immunohistochemistry by using a technique to simultaneously process and stain multiple intestinal rings. RESULTS: Drug treatment led to dose-dependent formation of both adducts and ulcers only in small intestine and only in animals with intact enterohepatic circulation. Adducts formed within enterocytes by 1 hour, translocated to the brush border, preceded ulceration and vascular protein leakage, and were intense at sites of ulceration. Adducts and ulcers exhibited a parallel distribution within intestinal quintiles: 3rd > 5th > 1st. CONCLUSIONS: Diclofenac treatment resulted in the formation of drug adducts in enterocytes. Because this molecular change occurred before ulceration, was dose dependent, and exhibited concordant distribution with extent of ulceration, the results suggest a causal role for drug adduct formation in diclofenac enteropathy.     

Interleukin-6 levels are inversely correlated with heart rate variability in patients with decompensated heart failure

INTRODUCTION: Increased local and systemic elaboration of cytokines have an important role in the pathogenesis of congestive heart failure (CHF) through diverse mechanisms. Because cytokines are known to act at the neuronal level in both the peripheral and central nervous system, we sought to determine whether increased cytokine levels are associated with the autonomic dysfunction that characterizes CHF. METHODS AND RESULTS: We studied 64 patients admitted for decompensated CHF (mean age 59+/-12 years). Autonomic function was assessed using time- and frequency-domain heart rate variability (HRV) measures, obtained from 24-hour Holter recordings. In addition, norepinephrine, tumor necrosis factor-alpha (TNF-alpha), and interleukin-6 (IL-6) were measured in all patients. TNF-alpha levels did not correlate with any of the HRV measures. IL-6 inversely correlated with the time-domain parameters of standard deviation of RR intervals (SDNN) (r = -0.36, P = 0.004) and standard deviation of all 5-minute mean RR intervals (SDANN) (r = -0.39, P = 0.001), and with the frequency-domain parameters of total power (TP) (r = -0.37, P = 0.003) and ultralow-frequency (ULF) power (r = -0.43, P = 0.001). No correlation was found between IL-6 and indices of parasympathetic modulation. Using multiple linear regression models, adjusting for clinical variables and drug therapies, the strong inverse relationship between IL-6 and SDNN (P = 0.006), SDANN (P = 0.001), TP (P = 0.04), and ULF power (P = 0.0007) persisted. CONCLUSION: Reduction of long-term HRV indices is associated with increased levels of IL-6 in patients with decompensated heart failure. The ability of long-term HRV parameters to better reflect activation of diverse hormonal systems may explain their greater prognostic power for risk stratification in patients with CHF.