A critical review of the causes of death among post-mortem toxicological investigations: analysis of 34 buprenorphine-associated and 35 methadone-associated deaths.

AIMS: To assess the trends in the number, mortality and the nature of forensic cases involving toxicological detection of buprenorphine or methadone among toxicological investigations performed in Paris from June 1997 to June 2002. DESIGN: Retrospective, 5 year study with review of premortem data, autopsy, police reports, hospital data, and post-mortem toxicological analyses. SETTING AND PARTICIPANTS: 34 forensic cases of buprenorphine and 35 forensic cases of methadone detection among 1600 toxicological investigations performed at the Laboratory of Toxicology in the Medical Examiner's Office in Paris. MEASUREMENTS AND RESULTS: Therapeutic, toxic or lethal drug concentrations were defined based upon the results of blood analyses and the published literature. Drug concentrations were cross-referenced with other available ante- and post-mortem data. Subsequently, we classified a 'clear responsibility', 'possible responsibility' or 'not causative' role for buprenorphine or methadone in the death process, or 'no explanation of death'. Buprenorphine and methadone can be regarded as being directly implicated in, respectively, four of 34 death cases (12%) and three of 35 death cases (9%), and their participation in the lethal process is strongly plausible in eight (buprenorphine) and 11 (methadone) additional deaths. CONCLUSIONS: Analysis of causes of death reveals the difficulties in determining the role of substitution drugs in the death process, as many other factors may be involved, including circumstances surrounding death, past history, differential selection of subjects into either substitution modality and concomitant intake of other drugs (especially benzodiazepines and neuroleptics). The potential for synergistic or additive actions by other isolated molecules-particularly opioids, benzodiazepines, other psychotropes and alcohol-must be also considered.

[Acute renal failure following ingestion of Cortinarius orellanus in 12 patients. Initial presentation and progress over a period of 13 years]. / Insuffisance rénale aiguë après ingestion de Cortinarius orellanus chez 12 patients. Présentation initiale et évolution sur une periode de treize annees.

INTRODUCTION: This study reports the largest series of acute renal failure following collective poisoning by Cortinarius orellanus since 1957. PATIENTS: Twelve men, in whom altered renal function appeared following ingestion of mushroom soup (Cortinarius orellanus) when they were 20 to 23 year-old, were followed up for 13 years. RESULTS: After a period of latency of between 2 to 5 days, the patients complained of asthenia, intense thirst and digestive and neurological disorders. On admission, 4 were anuretic and two exhibited polyuria. Leukocyturia was detected in all patients but without proteinuria. Renal biopsy was performed on day 14 in seven patients. It revealed severe tubulo-interstitial lesions with polymorphous cell infiltration, oedema, loose fibrosis and epithelial necrosis. Eight patients required haemodialysis. Nine patients received corticosteroids for less than 6 months. Over a follow-up period of 13 years, seven patients recovered normal renal function, four underwent transplantation and one was still under haemodialysis and died, victim of a car accident. CONCLUSION: The incidence of acute renal failure varies from 30 to 46%. It depends on individual sensitivity, pre-existing nephropathy and the cumulated dose of toxin ingested. Early and severe interstitial fibrosis, marked interstitial oedema and tubular epithelial necrosis are the most characteristics renal lesions. Renal failure regresses progressively over several months in 60% of cases. In the other patients, terminal renal failure appears immediately or after several years. The evolution is not influenced by corticosteroid therapy.

[Eosinophilia and renal pathology]. / Eosinophilie et pathologie renale.

Although rare, renal involvement during hypereosinophilic syndromes can lead to life-threatening situations. Since eosinophilic renal lesions can occur in a wide range of primary or secondary diseases, diagnosis can pose difficult clinical dilemmas. In some settings, renal lesions may be a predictable complication as in essential hypereosinophilic syndrome or angiolymphoid hyperplasia with eosinophilia. In other cases, renal lesions may be a highly unusual event secondary to cholesterol embolization, drug-induced reactions, immunoallergic responses, eosinophilic helminthic infection, or maintenance hemodialysis. The mechanisms of renal involvement are complex. In hypereosinophilic syndromes, renal involvement has been attributed to the deleterious effects of eosinophil granules and possibly to micro-emboli from the heart in patients presenting fibroplastic endocarditis or eosinophilic myocarditis. Most secondary forms are usually due to an immuno-allergic process leading to deposit of immune complexes in glomeruli. The effects of polynuclear eosinophils could also be due to release of cytokines and other mediators such as leukotriens. Cholesterol embolization involves a different mechanism in which hypereosinophilia is often moderate and accessory to arteriolar lesions. Eosinophiluria may be observed in any setting but the prognostic value of this finding as well as the mechanism underlying remain unclear.

[Electrocardiographic changes due to halofantrine in the treatment of malaria: therapeutic implications]. / Modifications électrocardiographiques dues à l'halofantrine dans le traitement du paludisme: implications thérapeutiques.

Electrocardiographic changes and their relationship with profiles of halofantrine (H) and desbutylhalofantrine (DBH) were assessed in a prospective study of 34 male patients with an uncomplicated falciparum malaria. H. was delivered in a one day in three intakes, 24 mg/kg/day. Seven days later the same regimen was administered. This study included a twelve-lead-electrocardiogram (to measure QTc interval), an ambulatory ECG monitoring a signal-averaged-electrocardiogram (to detect late ventricular potentials), and a kinetic-time profile of H. and DBH with high performance liquid chromatography. Data were obtained as follows: day 1 just prior to drug intake, 6 hours (H6), 12 hours (H12) after to drug delivery on day 1 and 8. There after on days 2, 3, 4, 9, 10, 11. Ambulatory ECG monitoring was recorded on day 1 and 8. QTc lengthening was noted in 10 patients with a mean QTc interval of 451 msec (range: 440-469 msec). Maximum QTc interval was obtained at H12 on day 1 (p < 0.0002) and 8 (p < 0.03). Signal-averaged electrocardiogram performed in 8 cases disclosed late potential in 4 cases (day 4: one case, day 9: 3 cases). No ventricular arrhythmia was observed on day 1 and 8. Plasma concentration time profile of H. showed a significant increase at day 8 H12 with a time effect (p < 0.0008) and a significant time-intake interaction (p < 0.02). QTc interval was significantly correlated with H. plasma level (p < 0.01) but not with D.B.H.. Late potentials were associated in 3 cases with a maximum plasma concentration level of H. These data showed that H. is potentially deleterious with a cardiac toxicity which appears dose-related, particularly during the second cure. Following this study, new prescription rules has been proposed before H. therapy.

[Drinking water for troops in the field]. / Alimentation en eau des troupes en campagne.

To provide for Armed Forces' water wants, drinking water is only used. Its production is not an easy thing in military operations. Armed Forces must use their own production means. Four new individual and collective field purification systems adapted to manpower, will been soon in use in the French Army. Filtration or distillation processes always with chlorine addition are used. The results give satisfaction in bacterial epuration; nevertheless chemical and nuclear risks are not controlled except in case of distillation mechanism associated with ion resins exchanging and charcoal filtration.

[Aluminum, hypothetic cause of Alzheimer disease]. / L'aluminium, cause hypothétique de la maladie d'Alzheimer.

A great deal of research has focused on aluminium as a putative causative factor in Alzheimer's disease. We measured by atomic absorption spectrophotometry aluminium levels in blood, urine and cerebrospinal fluid from 15 patients with Alzheimer's disease, compared with 20 control individuals. There were no statistically significant differences between the two groups. This suggests that aluminium is not a causative factor for Alzheimer's disease.

[Borderline arterial hypertension in young adults: contribution of paraclinical investigations]. / L'hypertension artérielle limite de l'adulte jeune: apport des examens paracliniques.

The comparison of 106 young adults with borderline hypertension to 85 controls allow to specify the contribution of paraclinic investigations in the diagnosis. Ambulatory blood pressure monitoring reveal the lack of lability of borderline hypertensives and cannot find predictive index of subsequent established hypertension. Results of exercise testing disclose correlation only with overweight. It is the same for increased left ventricular mass assessed by echography. Pulse wave velocity measurement display early arterial modifications.

Acute renal failure following collective intoxication by Cortinarius orellanus.

Twenty-six young men with no previous medical history all ingested mushroom soup, exclusively made with Cortinarius orellanus. They were hospitalized 10-12 days after the incident. On admission, 12 patients presented with acute tubulointerstitial nephritis with acute renal failure; 8 required haemodialysis. In addition to symptomatic treatment, 9 patients were given corticosteroids. In this group of 12 patients, 8 recovered rapidly, and the other 4 suffered from chronic renal failure for several months. In the other group of 14 patients, initial leukocyturia was observed in 12 cases, although renal function remained normal during a one-year follow-up. Hepatic acetylation and hydroxylation tests performed after 6 months in 22 patients did not provide any explanation for the strong individual sensitivity to the renal toxicity of this fungus.

[Recurrent macroscopic hematuria and heterozygote drepanocytosis]. / Hématurie macroscopique récidivante et drépanocytose hétérozygote.

The sickle cell trait may result in recurrent macroscopic haematuria which can cause severe anaemia. Despite normal intravenous urography and CAT, the haemorrhage probably occurs in the renal medulla due to the operative physiopathogenic conditions. A proliferative mesangial glomerulonephritis with IgG, IgA, IgM and complement deposits, which has a controversial relationship with sickle cell disease, may be discovered by renal biopsy. The severity of the anaemia may necessitate treatment with epsilon-aminocaproic acid which cures the haematuria but may provoke rhabdomyolysis. This case report is followed by a review of the literature of the different types of renal involvement in sickle cell trait and sickle cell anemia.

Ultrastructural localization of aluminum in hepatocytes of hemodialyzed patients.

The livers of 7 hemodialyzed patients have been studied by electron microscopy and electron probe X-ray microanalysis. In 6 patients dialyzed for a long time (at least 39 months), aluminum has been detected in high concentrations in phagolysosomes of hepatocytes; in these lysosomes aluminum is associated with phosphorus. In 2 of these 6 patients, a very large number of aluminum inclusion bodies were found inside hepatocytes and this aluminum accumulation was associated with severe ultrastructural lesions of the cells. In one patient dialyzed during a short period (4 months) no aluminum accumulation has been observed. In none of the 7 patients was aluminum accumulation detected inside the Küpffer cells. These observations show that the cell which accumulates aluminum in the liver of dialyzed patients is the hepatocyte and not the Küpffer cell and that this accumulation may be associated with serious hepatocellular lesions.

[Phlebitis of the arm. Apropos of 45 cases]. / Phlébites du membre supérieur. A propos de 45 observations.

We report in this retrospective study the data of 45 patients presenting with deep venous thrombosis of the upper extremities. This includes: 22 phlebitis due to strains, 3 traumatic phlebitis, 3 phlebitis combined with an adjacent injury, 7 phlebitis following endovenous therapeutic procedures and 10 spontaneous phlebitis (4 during adjacent medical pathologies), 3 pulmonary embolisms, including a septic one are thus demonstrated. No patient died. The follow-up date of 12 patients out of 32 exhibiting a spontaneous phlebitis or phlebitis due to a thoracic outlet syndrome have been documented: 25 p. 100 of them still presented with severe injuries. All patients underwent heparin therapy, but no fibrinolytic. A surgical procedure of the thoracic outlet syndrome was performed, when liable to the disease. Data of this series was then compared with those of previous reports on the subject.

[Pleomorphic cell sarcoma responsible for a picture of retroperitoneal fibrosis]. / Sarcome à cellules pléiomorphes responsable d'un tableau de fibrose rétropéritonéale.

A 68 years-old patient was followed-up during five years for idiopathic retroperitoneal fibrosis. The diagnosis was based on repeated examinations with two laparotomies as well as numerous biopsies. At autopsy a primary retroperitoneal sarcoma was found. This case points out the difficulty to differentiate idiopathic from malignant retroperitoneal fibrosis. Only one similar case was published in the literature.

Butofilolol pharmacokinetics in chronic renal insufficiency.

The pharmacokinetics of butofilolol, a new beta-blocking drug used in the treatment of hypertension, were investigated in 9 patients with varying degrees of renal impairment (creatinine clearance ranging from 65 ml/min to 6.6 ml/min). The drug was administered as a single oral 100-mg dose. Plasma and urine concentrations of the parent drug were measured. The pharmacokinetic parameters of butofilolol calculated from examination of patients with renal failure were compared to those obtained from healthy subjects. Renal failure was found to be associated with a marked increase of the areas under the plasma concentration-time curves of the parent drug whereas its elimination rate constant tended to increase, especially in severe renal failure. A highly significant relationship between the amounts of unchanged drug excreted in urine and the creatinine clearance was observed (r = 0.90, p less than 0.001). The higher plasma levels of the parent drug observed in renal failure might be due to a decrease in the first-pass hepatic extraction of the drug. But these changes in plasma clearance were probably counteracted by modification of the volume of distribution, so that the net result of these alterations was a slight increase in the elimination half-life.

[Critical study of microscopic hematuria disclosed by screening tests]. / Etude critique des hématuries microscopiques découvertes par examens de dépistage.

Asymptomatic microscopic haematuria detected by dipstick in 0.28 p. 100 of 95,200 men was confirmed in only 0.11 p. 100. These results lead to the study of 272 cases to determine the value of dipsticks as a screening test and the benefits of complementary investigations to exclude symptomless diseases. Microscopic haematuria was confirmed in 65 p. 100 but results of other tests reduce the false positive screening results to 25.3 p. 100. Addis counting of at least 5,000 RBC/min is preferable to RBC count/ml which is dilution dependent. 77 p. 100 of microscopic haematuria are intermittent and can only be diagnosed by repeated Addis counts. In the absence of confirmed haematuria, only investigations to exclude proteinuria and urinary infections are justified.