bluuebunny/crossref_metadata_2025 huggingface dataset:
Isoflurane Produces Sustained Cardiac Protection after Ischemia–Reperfusion Injury in Mice
Authors: Tsutsumi Yasuo M. , Patel Hemal H. , Lai N Chin , Takahashi Toshiyuki , Head Brian P. , Roth David M.
Published: February 2006

Background

Isoflurane reduces myocardial ischemia-reperfusion injury within hours to days of reperfusion. Whether isoflurane produces sustained cardiac protection has never been examined. The authors studied isoflurane-induced cardiac protection in the intact mouse after 2 h and 2 weeks of reperfusion and determined the dependence of this protection on adenosine triphosphate-dependent potassium channels and the relevance of this protection to myocardial function and apoptosis.

Methods

Mice were randomly assigned to receive oxygen or isoflurane for 30 min with 15 min of washout. Some mice received mitochondrial (5-hydroxydecanoic acid) or sarcolemmal (HMR-1098) adenosine triphosphate-dependent potassium channel blockers with or without isoflurane. Mice were then subjected to a 30-min coronary artery occlusion followed by 2 h or 2 weeks of reperfusion. Infarct size was determined at 2 h and 2 weeks of reperfusion. Cardiac function and apoptosis were determined 2 weeks after reperfusion.

Results

Isoflurane did not change hemodynamics. Isoflurane reduced infarct size after reperfusion when compared with the control groups (27.7 +/- 6.3 vs. 41.7 +/- 6.4% at 2 h and 19.6 +/- 5.9 vs. 28.8 +/- 9.0% at 2 weeks). Previous administration of 5-hydroxydecanoic acid, but not HMR-1098, abolished isoflurane-induced cardiac protection. At 2 weeks, left ventricular end-diastolic diameter was decreased significantly and end-systolic pressure and maximum and minimum dP/dt were improved by isoflurane. Isoflurane-treated mice subjected to ischemia and 2 weeks of reperfusion showed less expression of proapoptotic genes, significantly decreased expression of cleaved caspase-3, and significantly decreased deoxynucleotidyl transferase-mediated deoxyuridine triphosphate nick end labeling-positive nuclei compared with the control group.

Conclusions

Cardiac protection induced by isoflurane against necrotic and apoptotic cell death is associated with an acute memory period that is sustained and functionally relevant 2 weeks after ischemia-reperfusion injury in mice in vivo.
Impact of In Vivo Preconditioning by Isoflurane on Adenosine Triphosphate–sensitive Potassium Channels in the Rat Heart
Authors: Stadnicka Anna , Marinovic Jasna , Bienengraeber Martin , Bosnjak Zeljko J.
Published: February 2006

Background

The early memory of anesthetic-induced preconditioning (APC) is a period when myocardial protection continues even after removal of the anesthetic. Because adenosine triphosphate-sensitive potassium (KATP) channels are important mediators of APC, the authors investigated the hypothesis that the memory involves channel priming by isoflurane via a long-term modulation of the sensitivity to intracellular adenosine nucleotides.

Methods

Ventricular cardiomyocytes were obtained from the rat hearts after 30 min in vivo APC with 1.4% isoflurane and from control non-APC rat hearts. Whole cell and excised inside-out patch clamp techniques were used to study the sarcolemmal KATP channel. Membrane expression of KATP channel proteins, the pore-forming inward rectifier Kir6.2, and the regulatory sulfonylurea receptor SUR2A were assessed in APC and non-APC hearts by Western blotting.

Results

Activation of whole cell KATP current by isoflurane was enhanced after in vivo APC. At the single-channel level, this was paralleled by a 12-fold decrease in adenosine 5'-triphosphate sensitivity and a 3-fold decrease in adenosine 5'-diphosphate sensitivity, without changing the probability of channel opening or single-channel conductance. The membrane expression of Kir6.2 and SUR2A subunits was not altered by in vivo APC. A direct in vitro application of isoflurane to excised membrane patches increased the channel open probability and produced a 4-fold decrease in adenosine 5'-triphosphate sensitivity only of channels in non-APC myocytes.

Conclusions

In vivo APC by isoflurane decreases sensitivity of the sarcolemmal KATP channel to inhibition by adenosine 5'-triphosphate and decreases adenosine 5'-diphosphate sensitivity. These effects persist even after discontinuation of the anesthetic, suggesting a possible novel factor that may contribute to the mechanism of early memory of APC.
Opioid-induced Hyperalgesia in a Murine Model of Postoperative Pain
Authors: Célérier Evelyne , González Juan R. , Maldonado Rafael , Cabañero David , Puig Margarita M.
Published: February 2006

Background

Opioid-induced delayed hyperalgesia and allodynia have been reported in human and animal models. The authors evaluated the influence of different opioids used during clinical anesthesia on nociceptive sensitivity and incisional pain in mice. The role of the inducible nitric oxide synthase on surgical pain and opioid-induced pronociception also was investigated.

Methods

CD1 mice were used to study the efficacy of opioids inducing pronociception and enhancing incisional pain. The implication of nitric oxide generated from the inducible nitric oxide synthase was investigated using knockout mice (C57/BL6) for its gene. Mice underwent right hind paw surgery under sevoflurane anesthesia combined with subcutaneous administration of saline or the opioids fentanyl (0.05 mg/kg), alfentanil (1 mg/kg), and remifentanil (0.04 mg/kg). Nociception was evaluated daily for 7 days using paw-pressure, plantar, and von Frey tests.

Results

The antinociceptive effect of opioids was followed by long-lasting thermal hyperalgesia and mechanical allodynia (each lasting between 2 and 7 days), but not mechanical hyperalgesia. Intraoperative infusion of opioids significantly enhanced incisional pain in all tests. The most prominent effects were observed with remifentanil. The inducible nitric oxide synthase gene deletion attenuated both remifentanil- and incision-induced pronociceptive effects. In mutant mice for the inducible nitric oxide synthase gene, remifentanil was still efficient in enhancing incisional pain, but the global pronociceptive effect was attenuated significantly as compared with wild-type mice.

Conclusions

The authors' study demonstrates that the intraoperative administration of fentanyl or remifentanil enhances the extent and duration of postoperative pain. The results suggest a role of the nitric oxide systems in the cause of acute postoperative pain and opioid-induced pronociception.
Levosimendan, a New Inotropic and Vasodilator Agent
Authors: Toller Wolfgang G. , Stranz Christian , Warltier David C.
Published: February 2006

Several clinical studies suggest substantial limitations of currently available positive inotropic substances, including beta1-adrenoceptor agonists and phosphodiesterase III inhibitors in the short- and long-term treatment of heart failure. The reasons for these detrimental effects are related to the mechanism of action of these drugs, including increases in intracellular Ca2+ with subsequent increases in myocardial oxygen demand and arrhythmogenesis. Levosimendan, a myofilament Ca2+ sensitizer with inotropic effects, increases myocardial performance without substantial changes in oxygen consumption and with neutral effects on heart rhythm. In addition, levosimendan has vasodilatory effects that are achieved by stimulation of adenosine triphosphate-dependent potassium channels. This action may be of specific interest in the setting of myocardial ischemia. To date, levosimendan is approved in 31 countries worldwide, and more patients with heart failure have participated in randomized controlled trials with levosimendan than with any other intravenous inotropic agent.
Opioid-induced Hyperalgesia
Authors: Angst Martin S. , Clark J David
Published: February 2006

Opioids are the cornerstone therapy for the treatment of moderate to severe pain. Although common concerns regarding the use of opioids include the potential for detrimental side effects, physical dependence, and addiction, accumulating evidence suggests that opioids may yet cause another problem, often referred to as opioid-induced hyperalgesia. Somewhat paradoxically, opioid therapy aiming at alleviating pain may render patients more sensitive to pain and potentially may aggravate their preexisting pain. This review provides a comprehensive summary of basic and clinical research concerning opioid-induced hyperalgesia, suggests a framework for organizing pertinent information, delineates the status quo of our knowledge, identifies potential clinical implications, and discusses future research directions.
A comparison of the psychometric properties of three cigarette withdrawal scales
Authors: Etter Jean‐François , Hughes John R.
Published: February 2006

Aims  To compare the psychometric properties of three cigarette withdrawal scales.

Design  An internet cohort study.

Participants  Each of 4644 current (44%), former (49%) and never smokers (7%) completed the three scales via the internet. A subsample completed the scales again after 14 days (n = 1309), and indicated their smoking status after 42 days (n = 1431).

Measurements  The Cigarette Withdrawal Scale (CWS), the Wisconsin Withdrawal Scale (WWS) and the Minnesota Withdrawal Form (MWF).

Findings  All three scales covered the main elements in the Diagnostic and Statistical Manual version IV (DSM‐IV) and the International Classification of Diseases version 10 (ICD‐10) definitions of tobacco withdrawal, but WWS did not cover weight gain. Factor analyses indicated that only six factors were present in WWS, instead of the expected seven factors. Cronbach's alpha coefficients (0.76–0.93) were high for all scales. Test–retest coefficients were in the range of 0.66–0.86 for CWS and WWS, but were somewhat lower for some MWF items (range 0.52–0.80). In 324 ex‐smokers who had quit smoking 31 days or less before baseline, craving predicted relapse at 14‐day follow‐up (CWS: odds ratio = 1.53 per point, P = 0.003; WWS: odds ratio = 1.40, P = 0.04; MWF: odds ratio = 1.49, P = 0.002). In 34 baseline smokers who had quit smoking by 14‐day retest, an increase in craving (WWS and MWF), depressed mood (MWF) and difficulty concentrating (WWS) between baseline and retest predicted relapse at 42‐day follow‐up. In terms of construct validity, scales performed similarly, but performance on some key tests (e.g. withdrawal will increase post‐cessation) were inadequate, due perhaps to methodological limitations.

Conclusions  No scale showed a decisive advantage over the others. MWF has the advantage of brevity.
What drug policies cost. Estimating government drug policy expenditures
Authors: Reuter Peter
Published: February 2006

Aims  Many nations now spend large sums of government money to reduce drug problems. The size and composition of public expenditures aimed at reducing drug use and related problems (a drug budget) is a useful partial description of a nation's drug policy. This paper examines whether it is possible to estimate these sums in a consistent manner across nations.

Methods  Past drug budget efforts in the United Kingdom and United States were reviewed. A new methodology was offered for estimation and used for estimates of expenditures in the Netherlands and Sweden. Using this methodology, expenditures were compared. 

Findings  In both the Netherlands and Sweden, with very different official drug policy rhetoric, enforcement expenditures dominate the total; prevention expenditures are a tiny share. The baseline estimates indicate that the Netherlands, by a variety of metrics (e.g. Euros per capita, Euros per problematic user), spends more on drug control, even enforcement, than Sweden but the range of estimates is such that this cannot be inferred with confidence.

Conclusion  Estimating total government expenditures on reducing drug use and related problems is feasible and can yield useful policy insights.
Neurotoxicity of methylenedioxyamphetamines (MDMA; ecstasy) in humans: how strong is the evidence for persistent brain damage?
Authors: Gouzoulis‐Mayfrank E. , Daumann J.
Published: February 2006

Background  The popular dance drug ecstasy (3,4‐methylenedioxymethamphetamine: MDMA and some analogues) causes selective and persistent neurotoxic damage of central serotonergic neurones in laboratory animals. Serotonin plays a role in numerous functional systems in the central nervous system (CNS). Consequently, various abnormalities including psychiatric, vegetative, neuroendocrine and cognitive disorders could be expected in humans following MDMA‐induced neurotoxic brain damage.

Aims  In recent years, the question of ecstasy‐induced neurotoxicity and possible functional sequelae has been addressed in several studies with drug users. The aim of this paper was to review this literature and weigh the strength of the evidence for persistent brain damage in ecstasy users.

Methods  We used Medline to view all available publications on ‘ecstasy’ or ‘MDMA’. All available studies dealing with ecstasy users entered this analysis.

Findings and conclusions  Despite large methodological problems the bulk of evidence suggests residual alterations of serotonergic transmission in MDMA users, although at least partial restitution may occur after long‐term abstinence. However, functional sequelae may persist even after longer periods of abstinence. To date, the most consistent findings associate subtle cognitive, particularly memory, impairments with heavy ecstasy use. However, the evidence cannot be considered definite and the issues of possible pre‐existing traits or the effects of polydrug use are not resolved.

Recommendations  Questions about the neurotoxic effects of ecstasy on the brain remain highly topical in light of its popularity among young people. More longitudinal and prospective studies are clearly needed in order to obtain a better understanding of the possible long‐term sequelae of ecstasy use in humans.
Local alcohol prohibition, police presence and serious injury in isolated Alaska Native villages
Authors: Wood Darryl S. , Gruenewald Paul J.
Published: February 2006

Aims  To consider the effects of alcohol prohibition and police presence upon serious injury in isolated Alaska Native villages.

Design  We compared rates of injury attributed to assault, self‐harm, motor vehicle collisions and ‘other causes’ between villages with or without local prohibition and between villages with or without local police. Negative binomial regression was used to assess the relative effects of prohibition and police presence upon serious injury rates net of potential confounders.

Participants  A total of 132 isolated Alaska Native villages between the years 1991 through 2000.

Measurements  Serious injury was measured using Alaska Trauma Registry and Alaska Bureau of Vital Statistics death certificate records. Local option election records were used to classify cases as occurring in wet or dry villages and police deployment records were used to classify cases as occurring in villages with or without local police. Village‐level statistics from the 1990 and 2000 US censuses were used in the negative binomial regression analyses.

Findings  Villages that prohibited alcohol had lower age‐adjusted rates of serious injury resulting from assault, motor vehicle collisions and ‘other causes’. Dry villages with a local police presence had a lower age‐adjusted rate of serious injury caused by assault. Controlling for the relative effects of village isolation, access to alcohol markets and local demographic structures, local prohibition was associated with lower rates of assault injuries and ‘other causes’ injuries while local police presence was associated with lower rates of assault injuries.

Conclusions  Residents of isolated Alaska Native villages are safer when they prohibit alcohol. A local police presence in dry villages provides further reduction of the incidence of assault.
Lamivudine monotherapy in HBeAg‐negative chronic hepatitis B: prediction of response‐breakthrough and long‐term clinical outcome
Authors: MANOLAKOPOULOS S. , BETHANIS S. , ELEFSINIOTIS J. , KARATAPANIS S. , TRIANTOS C. , SOURVINOS G. , TOULOUMI G. , ECONOMOU M. , VLACHOGIANNAKOS J. , SPANDIDOS D. , AVGERINOS A. , TZOURMAKLIOTIS D.
Published: February 2006

Background

Factors that predict response and breakthrough phenomenon to lamivudine monotherapy in patients with HBeAg‐negative chronic hepatitis B have not been well defined.

Aim

To determine pre‐treatment and on treatment variables that predict initial response and breakthrough in patients with HBeAg‐negative chronic hepatitis B receiving long‐term lamivudine.

Methods

Seventy‐nine patients, with chronic HBeAg‐negative hepatitis B, who received lamivudine for a median of 31 months were included in the study.

Results

Initial virologic and biochemical response was observed in 73 (92%) and 70 (89%) patients, respectively, while 34 (47%) and 15 (21%) patients developed virological and biochemical breakthrough, respectively. High levels of necroinflammation in liver biopsy were associated with a higher probability of initial virological and biochemical response. Patients with pre‐treatment serum hepatitis B virus DNA concentrations of more than 106 copies/mL were three times more likely to develop virologic breakthrough. Two patients died, one with baseline cirrhosis because of liver failure during biochemical breakthrough while the second death was liver and treatment unrelated.

Conclusions

In HBeAg‐negative chronic hepatitis B, initial response to lamivudine therapy is associated with necroinflammation, while baseline serum hepatitis B virus DNA exceeding 106 copies/mL is a strong predictor for breakthrough because of drug‐resistant mutations. Severe complications are uncommon and are associated with biochemical breakthrough and pre‐existing cirrhosis.
Clinical and laboratory studies of the antacid and raft‐forming properties of Rennie alginate suspension
Authors: TYTGAT G. N. , SIMONEAU G.
Published: February 2006

Background

Acid pockets at the gastro‐oesophageal junction escape buffering from meals in the stomach. Combining high‐dose antacid with alginate may therefore be of benefit in gastro‐oesophageal reflux disease.

Aim

To characterize the antacid and raft‐forming properties of Rennie alginate suspension (containing high‐dose antacid and alginate; Bayer Consumer Care, Bladel, the Netherlands).

Methods

The in vitro acid‐neutralizing capacity of Rennie algniate was compared with Gaviscon (Reckitt Benckiser, Slough, UK) by pH‐recorded HCl titration. Alginate raft weight formed in vitro at different pH was used to evaluate the pH dependency of raft formation with each product. A double‐blind, placebo‐controlled, randomized crossover study also compared the antacid activity of Rennie alginate vs. placebo in vivo using continuous intragastric pH monitoring in 12 healthy fasting volunteers.

Results

Compared with Gaviscon, Rennie alginate had a higher acid‐neutralizing capacity, greater maximum pH and longer duration of antacid activity in vitro. However, the two products produced comparable alginate rafts at each pH evaluated. In vivo, Rennie alginate provided rapid, effective and long‐lasting acid neutralization, with an onset of action of <5 min, and duration of action of almost 90 min.

Conclusions

The dual mode of action of Rennie alginate offers an effective treatment option for mild symptomatic gastro‐oesophageal reflux disease particularly considering recent findings regarding ‘acid pockets’.
Patients with irritable bowel syndrome in primary care appear not to be heavy healthcare utilizers
Authors: FARESJÖ Å. , GRODZINSKY E. , FOLDEVI M. , JOHANSSON S. , WALLANDER M.‐A.
Published: February 2006

Background

Irritable bowel syndrome is a frequently diagnosed gastrointestinal condition in general practice. Managing this chronic condition requires a co‐ordinated effort between patient and doctor.

Aim

To explore the patterns of treatment and healthcare utilization of irritable bowel syndrome cases in a Swedish primary care setting.

Methods

All cases with a registered diagnosis of irritable bowel syndrome were identified retrospectively for a 5‐year period through computerized medical records at three primary healthcare centres in Sweden. Documentation of diagnosis, healthcare visits, treatments, investigations, medications, referrals, laboratory tests, mental and demographic data were retrieved from the records.

Results

Of all 723 irritable bowel syndrome patients identified, only 37% had a follow‐up appointment to their General Practitioner during the study period. For 80%, the General Practitioner initiated some treatment during the initial consultation and 75% were prescribed medication. Fibre and bulking laxatives and acid‐suppressive drugs were the most common medication. Almost a quarter was referred for complementary investigations at hospital, only 8.9% of the irritable bowel syndrome patients were referred to a specialist investigation. Laboratory investigations varied and were ordered more frequently (P = 0.05) for men.

Conclusions

Irritable bowel syndrome patients appear not to be heavy utilizers of primary care and, of those who attend, the majority are managed by their General Practitioner.
Effect of hiatal hernia on proximal oesophageal acid clearance in gastro‐oesophageal reflux disease patients
Authors: EMERENZIANI S. , HABIB F. I. , RIBOLSI M. , CAVIGLIA R. , GUARINO M. P. L. , PETITTI T. , CICALA M.
Published: February 2006

Background

Proximal acid reflux is common in gastro‐oesophageal reflux disease and is a determinant of symptoms. Patients with hiatal hernia complain of more symptoms than those without and are less responsive to proton‐pump inhibitors.

Aim

To evaluate the role of hiatal hernia on spatiotemporal characteristics of acid reflux.

Methods

Thirty seven consecutive gastro‐oesophageal reflux disease patients underwent endoscopy, videofluoroscopy, manometry and multichannel 24‐h pH test. Data were compared with those of 15 asymptomatic controls. Multivariate linear regression was used for statistical analysis.

Results

At videofluoroscopy, hiatal hernia was found in 16 of 37 patients. The mean size of hiatal hernia was 3.4 cm. Patients showed significantly prolonged acid clearance time, both at proximal and distal oesophagus, compared with controls. Hiatal hernia patients showed a significantly delayed acid clearance, along the oesophageal body, compared with non‐hiatal hernia patients. The prolonged acid exposure was maintained during upright and supine position. The presence of hiatal hernia significantly predicted acid clearance delay in the distal and proximal oesophagus [at 10 cm below upper oesophageal sphincter: Δ + 2.5 min (95% confidence interval: 0.4–4.5); P < 0.02].

Conclusions

The presence of hiatal hernia is a strong predictor of more prolonged proximal oesophageal acid exposure and clearance. Hiatal hernia is likely to play a role in the pathophysiology of gastro‐oesophageal reflux disease symptoms, and should be taken into greater consideration in the treatment strategies of the disease.
Review article: From gastrin to gastro‐oesophageal reflux disease – a century of acid suppression
Authors: MALFERTHEINER P. , FASS R. , QUIGLEY E. M. M. , MODLIN I. M. , MALAGELADA J. R. , MOSS S. F. , HOLTMANN G. , GOH K.‐L. , KATELARIS P. , STANGHELLINI V. , TALLEY N. J. , TYTGAT G. N. , WRIGHT N. A.
Published: February 2006

To commemorate Edkins’ discovery of gastrin in 1905, we review a century of progress in the physiology and pathobiology of gastrin and acid secretion especially as it pertains to clinical aspects of gastro‐oesophageal reflux disease.

Although initially ignored, Edkins’ observations eventually led to the enthusiastic investigation of gastrin and acid regulation in peptic ulcer disease, culminating in important therapeutic advances in the management of acid peptic disease. Following the improved understanding of gastric secretory physiology, and the development of acid suppressants with increasing efficacy, the use of surgical intervention for peptic ulcer disease was almost eliminated. Surgery became obsolete with the discovery of Helicobacter pylori.

Three other advances are also influencing modern practice: the gastrotoxicity of aspirin and non‐steroidal anti‐inflammatory drugs is now increasingly appreciated, the role of endoscopy in the diagnosis and therapy of upper gastrointestinal bleeding, and the use of intravenous acid‐suppressive agents.

The major issue for the future resides within the epidemic of gastro‐oesophageal reflux disease. How to diagnose, categorize and treat this condition and how to identify and prevent neoplasia, are the challenges of the new century.
Decision analysis: an aid to the diagnosis of Whipple's disease
Authors: OLMOS M. , SMECUOL E. , MAURIÑO E. , BAI J. C.
Published: February 2006

Background

Diagnosis of Whipple's disease, a rare systemic infection affecting predominantly the small bowel, is based on the identification of the bacterium Tropheryma whipplei.

Aims

To make explicit diagnostic uncertainties in Whipple's disease through a decision analysis, considering two different clinical scenarios at presentation.

Methods

Using appropriate software, a decision tree estimated the consequences after testing different strategies for diagnosis of Whipple's disease. Probabilities and outcomes to determine the optimum expected value were based on MEDLINE search.

Results

In patients with clinically‐predominant intestinal involvement, diagnostic strategies considering intestinal biopsy for histology (including appropriate staining) and the polymerase chain reaction testing for bacterial DNA were similarly effective. In case of failure of one procedure, the best sequential choice was a polymerase chain reaction analysis after a negative histology. Of the five strategies tested for cases with predominant focal neurological involvement, the stereotaxis cerebral biopsy evidenced the highest expected value. However, using quality‐adjusted life‐years considering the morbidity of methods, intestinal biopsy for PCR determination was the best choice.

Conclusions

In patients with Whipple's disease having predominant digestive involvement, intestinal biopsies for histology should be indicated first and, if negative, a bacterial polymerase chain reaction determination should be the next option. Although the molecular polymerase chain reaction assessment of cerebral biopsies has the highest diagnostic yield in neurological Whipple's disease, its associated morbidity means that analyses of intestinal samples are more appropriate.
Long‐term follow‐up of coeliac disease – what do coeliac patients want?
Authors: BEBB J. R. , LAWSON A. , KNIGHT T. , LONG R. G.
Published: February 2006

Background

Coeliac disease affects up to 1% of the population and the British Society of Gastroenterology recommends long‐term follow‐up of these patients, although the absolute risk of complications is small.

Aim

To determine what proportion of patients with coeliac disease remain under specialist follow‐up and to examine patients’ perspectives on the long‐term management of coeliac disease.

Methods

A questionnaire was sent to 183 patients who had a duodenal biopsy between July 1994 and July 2004 which was consistent with coeliac disease.

Results

A total of 126 (69%) patients returned their questionnaire. Patients had on average been diagnosed with coeliac disease 5.4 years earlier. Eighty‐eight percentage were trying to follow a strict gluten‐free diet. Sixty‐two percentage of patients were under regular follow‐up although this varied between hospital clinic (doctor/dietitian, 92%) and General Practitioner (8%). Most patients found at least one aspect of the hospital out‐patient clinic very useful. The preferred method of coeliac disease follow‐up was to see a dietitian with a doctor being available (P < 0.05 vs. all other options).

Conclusions

Respondents to this study showed great variation in follow‐up of their coeliac disease – 38% were under no active follow‐up. Patients would prefer to see a dietitian for long‐term follow‐up.
Horse microsatellites and their amenability to comparative equid genetics
Authors: Moodley Y. , Baumgarten I. , Harley E. H.
Published: February 2006

We investigated the applicability of microsatellite primers, designed in horses, for use in plains and mountain zebras. Fifteen of the 20 tested horse‐isolated primer pairs reliably amplified polymorphic loci in two wild equid species. We used this information to assess whether levels of genetic variation and repeat size differed in species from which microsatellites were isolated and in closely related target species. Target equid species exhibited similar levels of genetic variation to the horse, the species from which primers were originally isolated. We show that ascertainment bias results in lower mean and modal repeat size in target species. The data also provide evidence for a bi‐directional mutational constraint in allele size across three equid species.
Does gender, food or grapefruit juice alter the pharmacokinetics of primaquine in healthy subjects?
Authors: Cuong Bui Tri , Binh Vu Quoc , Dai Bui , Duy Dinh Ngoc , Lovell Claire M. , Rieckmann Karl H. , Edstein Michael D.
Published: February 2006

Aims

To evaluate the effects of gender, food and grapefruit juice on the pharmacokinetics of primaquine in healthy subjects.

Methods

In a randomized, two‐phase cross‐over study, 10 male and 10 female healthy Vietnamese subjects were administered 30 mg primaquine in the fasting state or with food, followed by administration of primaquine with grapefruit juice.

Results

The pharmacokinetics of primaquine were comparable between male and female subjects, with geometric mean ratios of Cmax = 0.89 [95% confidence interval (CI) 0.65, 1.22] and AUC = 0.80 (95% CI 0.56, 1.15). The mean CL/F of primaquine was slightly higher in males than in females [0.52 l h−1 kg−1vs. 0.43 l h−1 kg−1, mean difference of 0.09 (95% CI –0.10, 0.28), P = 0.32]. When compared with fasting state values, food increased the geometric mean Cmax of primaquine by 26% (95% CI 12, 40) and the AUC by 14% (95% CI 3, 27). Similarly, grapefruit juice increased the geometric mean Cmax by 23% (95% CI 4, 45) and the AUC by 19% (95% CI 4, 37).

Conclusions

The disposition of primaquine was comparable between genders, suggesting no need to modify the dose of primaquine for malaria treatment or prophylaxis. Food increased the oral bioavailability of primaquine, which may lead to higher antimalarial efficacy. Grapefruit juice increased the bioavailability of primaquine, with marked interindividual differences suggesting that people should not take primaquine with grapefruit juice.
Effects of itraconazole and diltiazem on the pharmacokinetics of fexofenadine, a substrate of P‐glycoprotein
Authors: Shimizu Mikiko , Uno Tsukasa , Sugawara Kazunobu , Tateishi Tomonori
Published: February 2006

Aims

Fexofenadine is a substrate of several drug transporters including P‐glycoprotein. Our objective was to evaluate the possible effects of two P‐glycoprotein inhibitors, itraconazole and diltiazem, on the pharmacokinetics of fexofenadine, a putative probe of P‐glycoprotein activityin vivo, and compare the inhibitory effect between the two in healthy volunteers.

Methods

In a randomized three‐phase crossover study, eight healthy volunteers were given oral doses of 100 mg itraconazole twice daily, 100 mg diltiazem twice daily or a placebo capsule twice daily (control) for 5 days. On the morning of day 5 each subject was given 120 mg fexofenadine, and plasma concentrations and urinary excretion of fexofenadine were measured up to 48 h after dosing.

Results

Itraconazole pretreatment significantly increased mean (± SD) peak plasma concentration (Cmax) of fexofenadine from 699 (± 366) ng ml−1to 1346 (± 561) ng ml−1(95% CI of differences 253, 1040;P < 0.005) and the area under the plasma concentration‐time curve [AUC(0,∞)] from 4133 (± 1776) ng ml−1 h to 11287 (± 4552) ng ml−1 h (95% CI 3731, 10575;P < 0.0001). Elimination half‐life and renal clearance in the itraconazole phase were not altered significantly compared with those in the control phase. In contrast, diltiazem pretreatment did not affectCmax(704 ± 316 ng ml−1, 95% CI −145, 155), AUC(0, ∞) (4433 ± 1565 ng ml−1 h, 95% CI −1353, 754), or other pharmacokinetic parameters of fexofenadine.

Conclusions

Although some drug transporters other than P‐glycoprotein are thought to play an important role in fexofenadine pharmacokinetics, itraconazole pretreatment increased fexofenadine exposure, probably due to the reduced first‐pass effect by inhibiting the P‐glycoprotein activity. As diltiazem pretreatment did not alter fexofenadine pharmacokinetics, therapeutic doses of diltiazem are unlikely to affect the P‐glycoprotein activityin vivo.
The endocrine function of adipose tissue: an update
Authors: Ronti Tiziana , Lupattelli Graziana , Mannarino Elmo
Published: February 2006

Adipose tissue secretes bioactive peptides, termed ‘adipokines’, which act locally and distally through autocrine, paracrine and endocrine effects. In obesity, increased production of most adipokines impacts on multiple functions such as appetite and energy balance, immunity, insulin sensitivity, angiogenesis, blood pressure, lipid metabolism and haemostasis, all of which are linked with cardiovascular disease. Enhanced activity of the tumour necrosis factor and interleukin 6 are involved in the development of obesity‐related insulin resistance. Angiotensinogen has been implicated in hypertension and plasminogen activating inhibitor‐1 (PAI‐1) in impaired fibrinolysis. Other adipokines like adiponectin and leptin, at least in physiological concentrations, are insulin sparing as they stimulate beta oxidation of fatty acids in skeletal muscle. The role of resistin is less understood. It is implicated in insulin resistance in rats, but probably not in humans. Reducing adipose tissue mass, through weight loss in association with exercise, can lower TNF‐α and IL‐6 levels and increase adiponectin concentrations, whereas drugs such as thiazolinediones increase endogenous adiponectin production. In‐depth understanding of the pathophysiology and molecular actions of adipokines may, in the coming years, lead to effective therapeutic strategies designed to protect against atherosclerosis in obese patients
Physiological and catecholamine response to sympathetic stimulation in turner syndrome
Authors: Zuckerman‐Levin Nehama , Zinder Oren , Greenberg Avital , Levin Moshe , Jacob Giris , Hochberg Ze’ev
Published: February 2006

Objective  Women with Turner syndrome have increased heart rate and high blood pressure (BP), and have been described as having high tolerance for emotional stress. We hypothesized that women with Turner syndrome have reduced catecholaminergic and physiological response to sympathetic stimulation, and that changes in BP and heart rate are related to their catecholamine response to sympathetic stimulation.

Design and patients  Ten young women with Turner syndrome, age 17–34 years were the subjects of this study. Their response to sympathetic stimulation was compared to a group of 10 age‐matched healthy women.

Measurements  After a period of 30 min resting, subjects and controls were subjected to an escalating series of sympathetic stimulation: orthostatic, cold pressor and exercise, and their plasma catecholamines and haemodynamic response were monitored and compared to resting levels.

Results  Resting heart rate was higher in Turner syndrome patients at 83 ± 9 beats per min (bpm, mean ± SD), as compared to controls (74 ± 10 bpm, P < 0·05). Their supine BP was also higher at 122 ± 9/84 ± 6 vs. 106 ± 11/70 ± 9 mmHg (P < 0·02/< 0·02). The corresponding resting norepinephrine, but not epinephrine, was higher in Turner syndrome patients (2·54 ± 1·09 nmol/l) as compared to controls (1·69 ± 0·55 nmol/l, P < 0·02). In response to orthostatic stimulation and cold pressor test the systolic, but not the diastolic BP or heart rate, increased in Turner syndrome patients but not in the control group (P < 0·01). The change in blood catecholamine levels was comparable in both groups. Their physiological response to exercise was normal. Yet, the exercise‐induced surge of norepinephrine and epinephrine in Turner syndrome patients was lower (P < 0·02).

Conclusions  Turner syndrome is associated with dysregulation of the sympathetic nervous system (SNS), leading to tachycardia and high BP, increased resting norepinephrine levels, and a greater tolerance of the cathecholamine response to exercise.
Decreased hepatic expression of PPAR‐γ coactivator‐1 in cholesterol cholelithiasis
Authors: Bertolotti M. , Gabbi C. , Anzivino C. , Mitro N. , Godio C. , De Fabiani E. , Crestani M. , Del Puppo M. , Ricchi M. , Carulli L. , Rossi A. , Loria P. , Carulli N.
Published: February 2006

Background  Cholesterol cholelithiasis (gallstone disease) is a common disease in the Western world. The aim of the present study was to analyze the hepatic expression of a number of nuclear receptors involved in bile acid metabolism in human cholesterol gallstone disease.

Materials and methods  Surgical liver biopsies were obtained from 11 patients with untreated cholesterol cholelithiasis and nine gallstone‐free subjects; mRNA levels of cholesterol 7α‐hydroxylase (CYP7A1) and related nuclear receptors and coactivators were assayed by quantitative real‐time RT‐PCR.

Results  No differences between the two groups were detected in mRNA levels of CYP7A1 and related nuclear receptors, with the exception of peroxysome proliferator‐activated receptor‐γ coactivator 1 (PGC‐1), which was significantly (P < 0·01) less expressed in gallstone subjects. Expression of PGC‐1 was linearly correlated with farnesoid X receptor (FXR) in gallstone patients (r = 0·87 on a log scale, P < 0·01), but not in control subjects; in gallstone patients PGC‐1 expression was also correlated with hepatocyte nuclear factor 4 (HNF‐4) (r = 0·78, P < 0·01).

Conclusion  These findings suggest that PGC‐1 can play a role in the prevention of cholesterol gallstone disease in humans; this might take place via interaction with the bile acid receptor FXR, whose protective role in cholelithiasis has been suggested by recent evidence in animal models and other coactivators. The present data might help to understand the pathophysiology and possibly focus on new therapeutical targets in cholesterol gallstone disease.
Dietary intake of differently fed salmon: a preliminary study on contaminants
Authors: Bethune C. , Seierstad S. L. , Seljeflot I. , Johansen O. , Arnesen H. , Meltzer H. M. , Rosenlund G. , Frøyland L. , Lundebye A‐K.
Published: February 2006

Background  In a previous study, a group of coronary heart disease (CHD) patients exhibited positive cardioprotective effects of fatty acids derived from a diet of farmed Atlantic salmon fed fish oil (Seierstad et al. 2005). This follow‐up study examines these patients for plasma exposure to selected organic and inorganic contaminants found in seafood that may detract from the benefits of eating oily fish.

Methods  The study design was from Seierstad et al. (2005), where 58 patients were allocated into three groups consuming 700 g week−1 of differently fed Atlantic salmon (Salmo salar) fillets for 6 weeks: 100% fish oil (FO), 100% rapeseed oil (RO), or 50% of each (FO/RO).

Results  Different fillets showed graded levels (FO > FO/RO > RO) of polychlorinated dibenzo‐p‐dioxins (PCDDs), polychlorinated dibenzofurans (PCDFs), dioxin‐like polychlorinated biphenyls (DLPCBs), indicator PCBs, polybrominated diphenyl ethers (PBDEs), and arsenic (As). Mercury (Hg) and lead (Pb) levels were similar across the three types of fillets. After 6 weeks of consumption, patient levels of PCDDs, DLPCBs, and PCBs in plasma decreased as the dietary intake of these contaminants increased. Plasma PBDEs only showed increases for the FO patients. Levels of inorganic contaminants in plasma showed only slight changes over the study period.

Conclusions  These results show a reduction in the use of marine oils in fish feed reduces organic contaminant levels in farmed salmon while still providing a good dietary source of marine fatty acids.
Low colonic glutathione detoxification capacity in patients at risk for colon cancer
Authors: Grubben M. J. A. L. , van Den Braak C. C. M. , Nagengast F. M. , Peters W. H. M.
Published: February 2006

Background  Colon carcinogenesis is a multifactorial process influenced by hereditary as well as environmental factors. The glutathione/glutathione S‐transferase detoxification system in the colon is important for protection against carcinogens. We investigated the levels of glutathione/glutathione S‐transferase in normal colon mucosa of patients with colorectal cancer and in patients at high risk for colorectal cancer compared with those in healthy controls.

Materials and methods  Glutathione content was analyzed by high‐performance liquid chromatography, and glutathione S‐transferase enzyme activity by spectrophotometric determination with 1‐chloro 2,4‐dinitrobenzene. Normal colon tissue of patients with colon adenoma (n = 64), colorectal cancer (n = 37), familial adenomatous polyposis (FAP; n = 19), hereditary non‐polyposis colorectal cancer families with (HNPCC+Ad; n = 34) or without (HNPCC‐Ad; n = 33) adenoma was investigated.

Results  Glutathione levels were significantly lower in the normal colon mucosa of patients with cancer, FAP, HNPCC‐Ad or HNPCC+Ad compared with adenoma patients or healthy controls. Glutathione S‐transferase enzyme activity in the distal colon was significantly lower in patients with cancer or FAP compared with the adenoma patients or healthy controls, whereas values in carcinoma patients were significantly lower compared with both the HNPCC‐Ad and HNPCC+Ad groups.

Conclusions  An association of low colonic glutathione/glutathione S‐transferase activity levels and high clinical risk for the development of colorectal cancer was observed. This low glutathione detoxification capacity might contribute to the colon cancer risk.
Behavioural phenotypes in disability research: historical perspectives
Authors: Goodey C. F.
Published: February 2006

Western medicine has a long history of accounting for behaviour by reducing the body to ultimate explanatory entities. In pre‐modern medicine these were invisible “animal spirits” circulating the body. In modern medicine, they are “genes”. Both raise questions. The psychological phenotype is defined by human consensus, varying according to time and place, while the genotype’s DNA exists in a realm of material reality.

There are deep philosophical and methodological problems in linking one realm to the other. Nyhan’s original application of the phenotype‐genotype pairing merely calimed that the two realms could be matched because of their common susceptibility to statistical treatment. His behavioural example was “stereotypy”. It has since extended to include such things as “social cognition” in Turner’s syndrome (Skuse), thus revealing increasingly clearly that the two realms are fundamentally and ontologically separate. The problems are not merely epistemological but ethical, since the looseness of psychological categories involves a blurring of the boundaries between behavioural phenotype and social stereotype. The latter may then be underwritten as “real” by being associated, spuriously, with the empirically demonstrable reality of genetic material.
Sickness absence in Swedish parents of children with Down’s syndrome: relation to self‐perceived health, stress and sense of coherence
Authors: Hedov G. , Wikblad K. , Annerén G.
Published: February 2006

Background  The aims of present study were to study sickness absence among Swedish parents of children with Down’s syndrome (DS) and to compare their rates of absence with those of control parents. Sickness absence data for 165 DS parents were compared with those for 174 control parents; all data were for the period 1997–2000. Sickness absence rates were also related to parental self‐perceived health, stress and sense of coherence.

Methods  The self‐administrated measures of parental self‐perceived health, stress and sense of coherence were compared with the number of days of sickness absence.

Results  In about two‐thirds of the parents in both the study and the control group, no days of sickness absence were registered. Six of the DS parents had remarkably large numbers of days of sickness absence (more than 100 per year). None of the control parents had such high sickness absence rates. It is speculated that there is a small group (less than 5%) of parents who are more vulnerable to the birth of a child with DS. Apart from these six DS parents, sickness absence was not more frequent among the DS parents than among the control parents. DS parents stayed at home to care for their sick DS child three times more often than control parents did for their non‐disabled child. DS fathers took greater responsibility in the care of their temporarily sick child and stayed at home to care for the child even more often than control mothers did. DS parents with sickness periods experienced small deterioration in self‐perceived health, significantly higher stress and decreased sense of coherence in comparison with parents without sickness periods.

Conclusions  There was a great similarity in sick leave rates due to one’s own sickness between DS and control parents, but a small group of DS parents (<5%) may be more vulnerable. DS fathers stayed at home to care for their sick DS child remarkably often.
Prevalence and types of aggressive behaviour among adults with intellectual disabilities
Authors: Crocker A. G. , Mercier C. , Lachapelle Y. , Brunet A. , Morin D. , Roy M.‐E.
Published: February 2006

Background Aggressive behaviours represent major obstacles to the integration into society of individuals with intellectual disability (ID) and pose significant management issues for carers.

Methods The present study assessed the prevalence and severity of five types of aggressive behaviours in 3165 adult men and women with ID receiving services from three rehabilitation agencies in Québec by surveying their carers using the Modified Overt Aggressive Scale.

Results The 12‐month prevalence of aggressive behaviour was 51.8%: 24% property damage, 37.6% verbal, 24.4% self‐oriented and 24.4% physical aggression, and 9.8% sexually aggressive behaviour, most of which being mild in severity. Only 4.9% of individuals displayed aggressive behaviour leading to injury of the victim. Few gender differences were observed.

Conclusions The capacity to document and assess the types as well as the severity of aggressive behaviour is thus critical, not only to better understand the correlates of various types of behaviours but also to orient intervention programmes whether they be prevention, assessment, monitoring or management of aggressive behaviour.