White paper on the promotion of an integrated risk assessment concept in European regulatory frameworks for chemicals.

The vision of a sustainable and safe use of chemicals to protect human health, preserve the environment and maintain the ecosystem requires innovative and more holistic approaches to risk assessment (RA) in order to better inform decision making. Integrated risk assessment (IRA) has been proposed as a solution to current scientific, societal and policy needs. It is defined as the mutual exploitation of environmental risk assessment (ERA) for human health risk assessment (HHRA) and vice versa in order to coherently and more efficiently characterize an overall risk to humans and the environment for better informing the risk analysis process. Extrapolating between species which are relevant for HHRA and ERA requires a detailed understanding of pathways of toxicity/modes of action (MoA) for the various toxicological endpoints. Significant scientific advances, changes in chemical legislation, and increasing environmental consciousness have created a favourable scientific and regulatory environment to develop and promote the concept and vision of IRA. An initial proof of concept is needed to foster the incorporation of IRA approaches into different chemical sectorial regulations and demonstrate their reliability for regulatory purposes. More familiarity and confidence with IRA will ultimately contribute to an overall reduction in in vivo toxicity testing requirements. However, significant progress will only be made if long-term support for MoA-related research is secured. In the short term, further exchange and harmonization of RA terminology, models and methodologies across chemical categories and regulatory agencies will support these efforts. Since societal values, public perceptions and cultural factors are of increasing importance for the acceptance of risk analysis and successful implementation of risk mitigation measures, the integration of socio-economic analysis and socio-behavioural considerations into the risk analysis process may help to produce a more effective risk evaluation and consideration of the risks and benefits associated with the use of chemicals.

Kounis syndrome secondary to allergic reaction following shellfish ingestion.

Two cases of allergic angina and allergic myocardial infarction (Kounis syndrome) secondary to shellfish ingestion are described. The patients had pre-existing quiescent coronary artery disease (type II variant of the syndrome) and the allergic reaction following eating shellfish seemed to have triggered the development of an acute myocardial infarction. The clinical implications are also discussed.

Electrocardiographic changes in elderly patients during endoscopic retrograde cholangiopancreatography.

BACKGROUND: Cardiorespiratory complications may occur during gastrointestinal endoscopy, and elderly people seem to be more vulnerable to these complications during endoscopic procedures involving the manipulation of abdominal viscera. OBJECTIVES: To determine the incidence of cardiac arrhythmias, changes in oxygen saturation, heart rate and blood pressure during endoscopic retrograde cholangiopancreatography (ERCP) via Holter monitoring in elderly patients older than 70 years of age. METHODS: Holter monitoring and 12-lead electrocardiograms were performed in 30 elderly patients undergoing ERCP and in 30 control subjects undergoing routine chest, abdomen, bone and upper gastrointestinal small bowel follow-through studies. A computerized nontriggered template system was used to analyze the electrocardiograms qualitatively and quantitatively. Arrhythmias, cardiac axis, conduction defects, pauses, ST segment changes, ectopic beats, oxygen desaturation and changes in blood pressure and rate-pressure product were evaluated. RESULTS: Increased heart rate, ST segment changes resulting from myocardial ischemia, oxygen desaturation and transient atrial and ventricular ectopic beats were frequent during ERCP compared with the control group. In one patient, transient left bundle branch block developed and this was attributed to pre-existing hypertension with cardiomegaly. One patient developed ventricular tachycardia and one other sinus bradycardia, but this was attributed to sick sinus syndrome. CONCLUSIONS: Transient myocardial ischemia and various cardiac arrhythmias are frequent in elderly patients undergoing ERCP. Appropriate noninvasive monitoring seems to be justified during this procedure.

Paraplegia-related alterations of bone density in forearm and hip in Greek patients after spinal cord injury.

PURPOSE: Paraplegia due to spinal cord injury is related with sublesional bone demineralization with an increased incidence of pathologic fractures in lower extremities. This study was carried out in order to evaluate bone density alterations in forearm and hip in Greek paraplegic patients after spinal cord injury and to correlate the findings with the level of injury, the neurological status, the time interval from injury and the performing of physiotherapy and therapeutic standing. METHOD: Fifty-seven paraplegic patients (33 men and 24 women, with injuries sustained from 6 months to 27 years) and 36 able-bodied age-matched controls (25 men, 16 women) participated in the study. Bone mineral density (BMD) was measured by dual X-ray absorptiometry (DXA) in the proximal and distal forearm, the femoral neck, the greater trochanter and Ward's triangle. RESULTS: The measurements revealed a significant reduction of BMD of femoral neck (p<0.001 in male, p<0.001 in female paraplegics), greater trochanter (p<0.001 and p=0.001, respectively) and Ward's triangle (p=0.001 and p=0.005, respectively). Proximal forearm depicted non-significantly decreased BMD values and distal forearm depicted a slight increase in BMD values. The degree of demineralization was independent of factors such as complete or incomplete spinal cord injury, level of the lesion, physiotherapy and performing of standing. In addition to that, BMD values in both hip and forearm showed no statistically significant correlation with time after injury. CONCLUSIONS: BMD measurements in Greek paraplegic patients reveal bone loss, which most dramatically occurs in the region of hip with a consequent increase of fracture risk. Forearm measurements depict a non-homogeneous response with limited proximal bone loss and slight distal increase of BMD, the latter being possibly attributed to daily activities.

Late colonic obstruction after barium meal examination in a myxoedematous patient.

A case in which inspissated barium was retained and produced sigmoid obstruction after one year is described. The patient was elderly and myxoedematous. Prolonged retention of barium producing a bowel obstruction requiring surgery is a rare complication and, to our knowledge, is only the second case described in which the symptoms of obstruction appeared so late after the examination.

Investigation of vesicoureteral reflux with colour Doppler sonography in adult patients with spinal cord injury.

The aim of the study was to evaluate prospectively the performances of colour Doppler sonography for detection of vesicoureteral reflux in adult patients with neurogenic bladder due to spinal cord injury. One hundred eighty-seven adult patients who had developed neurogenic bladder due to spinal cord injury underwent retrograde cystography and sonographic evaluation by B-mode and colour flow Doppler sonography (CFDS). Results of both examinations were analyzed independently by two radiologists. Representative images of the sonographic evaluations were recorded on videotape and CD-Rom. CFDS detected reflux in 20 ureters while retrograde cystography revealed vesicoureteral reflux (VUR) in 25 ureters of a total of 374 ureters, which were examined by both methods. Sonography detected all cases of grades IV and V of reflux, 7 of 8 (87.5%) of grade III, 5 of 6 (83.3%) of grade II, and 4 of 7 (57.14%) of grade I. There were 6 false-positive and 5 false-negative findings with Doppler examination compared with retrograde cystography. Therefore, sensitivity and specificity of sonographic examination were 80 and 98.28%, respectively, with a positive predictive value of 76.92%. Colour flow Doppler sonography can play an important role in detection of VUR in spinally injured adult patients with neurogenic bladder and can be an effective imaging tool for follow-up.

Moe1, a conserved protein in Schizosaccharomyces pombe, interacts with a Ras effector, Scd1, to affect proper spindle formation.

In fission yeast, Scd1/Ral1 is a putative guanine nucleotide exchange factor for Cdc42sp and also acts as a Ras1 effector necessary for the regulation of cytoskeleton organization. In this study, we have characterized a protein, Moe1, that binds directly to Scd1. A moe1 null (Delta) mutant exhibits numerous phenotypes indicative of abnormal microtubule functioning, including an abnormality in the spindle. moe1Delta mutants are resistant to microtubule destabilizing agents; moreover, moe1Delta rescued the growth defects of tubulin mutants containing unstable microtubules. These results suggest that Moe1 induces instability in microtubules. Biochemical and subcellular localization studies suggest that Moe1 and Scd1 colocalize in the nucleus. Furthermore, loss of function in Scd1 or Ras1 also induced abnormality in the spindle and is synthetically lethal with moe1Delta producing cells that lack a detectable spindle. These data demonstrate that Moe1 is a component of the Ras1 pathway necessary for proper spindle formation in the nucleus. Human and nematode Moe1 both can substitute for yeast Moe1, indicating that the function of Moe1 in spindle formation has been conserved substantially during evolution.

Allergic reactions to local glyceryl trinitrate administration.

To assess the exact cause and extent of transdermal glyceryl trinitrate (GTN)-induced allergic reactions, a study of continuous and intermittent use of GTN patches was conducted in 320 patients with New York Heart Association (NYHA) class II and III angina pectoris. Three commercially available GTN patch systems were used. Twenty-one patients (6.5%) developed cutaneous reactions. In 17 patients (5.3%), the reactions were confined to the area of application and were characterised as irritant reactions. Four patients (1.2%) developed both localised and remote from the area of application lesions and one patient developed a generalised anaphylactic reaction. The rate of discontinuation of therapy was 3.4%. The irritant skin reactions were mainly due to contaminants and additives. Changing to a different transdermal system reduced the incidence of local reactions--a particularly desirable effect in patients who respond well to GTN therapy.

Dose-dependent appearance and disappearance of amiodarone-induced skin pigmentation.

A 66-year-old man suffering from atrial flutter developed cutaneous blue-gray pigmentation while receiving 600 mg of amiodarone daily for 15 months. With reduction of the dose to 100 mg, skin discoloration disappeared within 16 months, to reappear within 7 months after increasing the dose to 400 mg. Finally, the discoloration disappeared within 13 months with a dose reduction to 200 mg daily. It seems that a tissue threshold level for amiodarone exists in this patient, above which skin discoloration appears and below which it fades. Dose, duration, metabolism, macrophage transfer, and spillover saturation-excretion may be relevant in amiodarone-induced skin pigmentation.

Electrocardiographic changes in elderly patients during small bowel enema.

RATIONALE AND OBJECTIVES: Enteroclysis (small-bowel enema) involves the introduction of a large amount of fluid into the small bowel, through a tube, producing small bowel distention. A study was done to determine the incidence of any electrocardiographic changes during enteroclysis with Holter monitoring. METHODS: Continuous electrocardiographic monitoring and 12-lead electrocardiograms were performed in 30 elderly patients undergoing enteroclysis and in 30 control subjects undergoing routine chest, bone, and upper gastrointestinal small bowel follow-up studies. Two channel qualitative and quantitative electrocardiographic analysis was performed by a computerized nontriggered template system. Arrhythmias, change in cardiac axis, conduction defects, pauses, ST segment changes, and ectopics were sought. RESULTS: Increased sympathetic tone resulting in increased heart rate and transient atrial and ventricular ectopics was frequent during enteroclysis compared with the control group. In one patient ventricular tachycardia developed, and two patients had diminished heart rate, but this was attributed to preexisting heart disease and concurrent medication. CONCLUSION: Transient, nonhazardous cardiac arrhythmias are encountered during enteroclysis in elderly patients. These arrhythmias may be attributed to the preexisting heart disease, fear, and anxiety during intubation, or increased sympathetic tone from the enteric loop distention.

Brainstem auditory evoked potentials in patients with ischemic heart disease.

The authors of this study used the method of increased stimulus rate on brainstem auditory evoked potentials (BAEPs) in 30 patients with ischemic heart disease (IHD) and in an equal number of healthy age-matched control subjects. The BAEPs were recorded using 100- to 3000-Hz alternating polarity clicks at a rate of 22.6 per second. Measurements included the absolute latencies of waves I through V, the interpeak latencies I-III, III-V, and I-V, and the peak amplitudes of peaks I, III, and V. The measured absolute latencies and interpeak latencies were found to be significantly increased, and the peak amplitudes were found to be diminished. The audiometric tests revealed no significant hearing loss in IHD patients. This study is the first to demonstrate prolongation of BAEPs in IHD patients. BAEP recording may become an additional noninvasive tool for detecting IHD patients with impaired microcirculation.

Diaphragmatic herniation of the large bowel associated with unusual clinical and electrocardiographic presentation.

This is the first case reported of combined hiatus hernia of the stomach and herniation of the splenic flexure of the colon through the oesophageal hiatus. It was associated with unusual clinical and electrocardiographic findings. We postulate that these were the result of an increase in intrathoracic pressure induced by the herniating structures.

Pregnancy-induced increase of supraventricular arrhythmias in Wolff-Parkinson-White syndrome.

Six women suffering from Wolff-Parkinson-White syndrome and who were previously asymptomatic or nearly asymptomatic, were followed prospectively during and after their subsequent pregnancies. Three women experienced several attacks of supraventricular tachycardia (SVT) for the first time and the rest experienced an increase in their attacks. It seems that there is an increased tendency for SVT in pregnancy. Increased adrenergic sensitivity by estrogens, increased plasma volume, stress, and anxiety during pregnancy may be some of the causative factors.

A modified per os double contrast examination of the colon in the elderly.

A modified per os double contrast examination of the colon was used in 62 elderly patients in whom conventional barium enema had been unsuccessful. We created endogenous gas generation instead of air insufflation by per os administration of a special mixture containing barium sulfate, lactulose and gastrografin. Good quality double contrast images of the colon were obtained after 12 hours in 59 of the 62 patients. The sensitivity of the method was 100% in 6 patients suffering from carcinoma and in 15 patients suffering from diverticular disease. However, the method failed to demonstrate small solitary polyps in 5 patients and it was also negative in another 27 patients. 7 of these had negative endoscopy and in the remaining a definite diagnosis was not established by any other method. It seems that this method may become an alternative for investigation of suspected colonic pathology in the elderly patients with difficulty in retaining the barium enema.

Left ventricular excursions and velocities during coronary arterial ligation. Effects of nitroglycerin infusion in an experimental model.

To determine the effects of intravenous nitroglycerin on the velocities and excursions of the acutely ischemic myocardium, 20 open-chest dogs were studied by use of ultrasound. In 10 dogs with acute septal ischemia, the posterior wall excursion during contraction (B-C excursion), the mean systolic posterior wall velocity, and the posterior wall excursion remained unaltered. Nitroglycerin, however, increased all these parameters (P less than 0.01). In 10 dogs with acute posterior wall ischemia the B-C excursion (aneurysmal bulging) increased (P less than 0.01), but the mean systolic posterior wall velocity and posterior wall excursion decreased (P less than 0.01). Nitroglycerin increased even more the aneurysmal bulging (P less than 0.01) and the other parameters (P less than 0.01). Increased regional blood flow, reduced afterload, and mechanical pulling of the ischemic myocardium seem to be a possible mechanism. The measurements were obtained using the recently described method of the specific points.

Effects of nitroglycerin on myocardial excursions and velocities in the early hours of acute myocardial infarction.

The effects of sublingual nitroglycerin on septal and left ventricular wall motion were determined by echocardiography in the early hours of acute myocardial infarction (MI) in 20 patients admitted via a mobile coronary care unit. Left ventricular and septal echoes were obtained in 11 patients with acute anterior MI and in 9 with acute inferior MI before and after administration of 500 micrograms sublingual nitroglycerin. In the group with acute anterior MI, nitroglycerin did not significantly affect the B-C excursion, posterior wall excursion, and mean posterior wall velocity. Nitroglycerin significantly increased (P less than 0.01), however, the systolic septal excursion, systolic septal velocity, diastolic septal excursion, and diastolic septal velocity. In the group with acute inferior MI, nitroglycerin significantly increased the B-C excursion (P less than 0.01); posterior wall excursion (P less than 0.01); mean posterior wall velocity (P less than 0.01); systolic septal excursion (P less than 0.01); diastolic septal excursion (P less than 0.05), and diastolic septal velocity (P = 0.01) but did not affect the systolic septal velocity. All measurements were obtained by use of a method of labeling and describing specific points of the wall motion that has been described recently.