Leukaemia in the vicinity of two tritium-releasing nuclear facilities: a comparison of the Kruemmel Site, Germany, and the Savannah River Site, South Carolina, USA.

In 1991, an increased rate of childhood leukaemia was reported from the small northern German community of Elbmarsch, which is located on the banks of the River Elbe opposite the Kruemmel nuclear power plant. Owing to the fact that the increase occurred six years after the start-up of the plant, radioactive discharges were suspected as being implicated in the development of the cases. Previous investigations have failed to identify any exposure which might be associated with the cluster. Nonetheless, concern regarding the increased tritium burden in the environment remains. To further assess the impact of tritium releases to the environment upon population cancer rates, the releases and leukaemia rates at the Savannah River site, USA, were compared with the Kruemmel site. Based on the data from 1991 to 1995, the incidence of childhood leukaemia in the vicinity of the Savannah River site was non-significantly less than expected compared with the significantly higher than expected rates close to the German plant. In contrast, tritium releases from the Savannah River site exceed those from the Kruemmel site by several orders of magnitude. The results of this observational study suggest that factors other than environmental tritium releases are associated with the increased number of leukaemia cases near the Kruemmel site.     

Idiopathic intracranial hypertension in patients with Graves' ophthalmopathy

We report two cases of idiopathic intracranial hypertension in patients with Graves' ophthalmopathy. These patients, with known Graves' ophthalmopathy, presented with new onset optic disc edema and preserved visual function. Moderate enlargement of the extraocular muscles was observed in one case and moderate expansion of the orbital fat volume was observed in the second case. Lumbar puncture revealed an elevated opening pressure and normal cerebrospinal fluid composition in both patients. Also, no intracranial abnormalities were seen with neuroimaging studies. The findings in these patients suggest idiopathic intracranial hypertension as a second concurrent diagnosis, and should be considered as a possible etiology of optic disc edema in patients with Gravest ophthalmopathy and preserved visual function.     

Is the Degree of Arrhythmia Suppression a Predictor of Survival?

The effectiveness of an antiarrhythmic drug is judged by the degree of ventricular arrhythmia (VA) suppression. We evaluated the relationship between the degree of VA suppression and survival in a dose-adjusted trial of 110 symptomatic patients treated with amiodarone. Cohorts had left-ventricular ejection fraction (LVEF) of 41 plus minus 18%, ventricular premature contractions (VPCs) of 445 plus minus 571 h, couplets (C) of 733 plus minus 1498 24 h and nonsustained (N) ventricular tachycardia (VT) of 65 plus minus 217 24 h; these conditions were followed for 15 plus minus 11.5 months. Amiodarone was initiated with an oral loading of 670 plus minus 111.7 mg per day for 10 days and continued on maintenance of 274.9 plus minus 102 mg per day. Survival rates of responders and nonresponders with VPCs <70%, 70--89%, greater-than-or-equal90%; C greater-than-or-equal 90%; NVT (100%); and the response to all 3 criteria (suppresion of VPCs greater-than-or-equal70%, C greater-than-or-equal 90% and complete abolition of NVT) were not statistically significant. Survival rates as a function of LVEF <40% (51 patients) or greater-than-or-equal40% (59 patients), as well as responders or nonresponders to all three criteria, were not significant (p = NS). We conclude that, in patients treated with low-dose amiodarone, the degree of VA suppression of PVCs, C and NVT does not predict survival; the survival of patients with LVEF <40% improved irrespective of VA suppression; and criteria for VA suppression should be reassessed at lower levels of suppression for the improvement of the drug risk:benefit ratio. More improvement is not necessarily better.     

Solubilization and Stabilization of a Benzylpenicillin Chemical Delivery System by 2-Hydroxypropyl-β-cyclodextrin

A dihydropyridine pyridinium salt redox carrier-based chemical delivery system for benzylpenicillin (1) was complexed with 2-hydroxypropyl--cyclodextrin (HPCD). The solubility of the lipophilic 1, which is incompatible with aqueous formulations, was dramatically increased and showed a linear dependency on the HPCD concentration. The degree of incorporation was 20 mg of 1 per g of complex. The stability study of 1 in various pH buffers indicated the base-catalyzed hydrolysis of the acyloxyalkyl linkage and the hydration of the 5,6 double bond of the dihydropyridine as the main degradation processes. The overall loss of 1, which follows first-order kinetics, was not influenced by changes in ionic strength and elimination of oxygen from the reaction medium. The HPCD complex of 1, which has a stability constant of 720–940 M ^–1, stabilized the chemical delivery system. The influence of the temperature on the stability of 1 is also discussed.     

Adenine nucleotide levels in preserved and ischemically injured canine kidneys

This study explored the relationship between adenine nucleotide levels in canine renal cortex and renal function following: (a) graded periods of warm ischemia; (b) 48 hours' flush cooling with electrolyte solutions and ice storage; and (c) continuous hypothermic perfusion. Exposure to normothermic ischemia resulted in a rapid (within 15 minutes) degradation of ATP to ADP and AMP as well as a slow decline in total adenine nucleotide (TAN) to levels which were proportional to the duration of the ischemic injury. No functional impairment was evident after 15 minutes' ischemia, but with longer times, both the extent of decline in TAN and the degree of recovery following restoration of blood flow could be used to predict the quality of renal function.The relationship between TAN levels and function was of less predictive value following cold storage or continuous perfusion. The efficacy of intracellular flush solutions could not be attributed solely to conservation of TAN, nor did the well-maintained TAN levels during continuous perfusion necessarily lead to significantly better 48-hour storage than flush cooling with C2 solution.

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Résumé Cette étude faite chez le chien examine la corrélation entre la fonction rénale et le taux d'adénine nucléotide dans le cortex rénal suite à: 1) différentes périodes d'ischémic chaude; 2) entreposage sur glace pendant 48 heures apres flushing avec des solutions électrolytiques; 3) hypotermie par perfusion continuelle. L'ischémie chaude a produit une dégradation rapide de l'ATD en ADP et AMP (en moins de 15 minutes) et une diminution progressive de la quantité totale d'adénine nucléotide (TAN) proportioneile à la durée de la période ischémique. La fonction rénale n'a pas été affectée par des périodes d'ischémie de 15 minutes ou moins. Suite à des périodes ischémiques plus longues cependant, la chutte des taux de TAN et leur niveau de rétablissement après réouverture de la circulation sanguine ont permis de prédire la qualité de la fonction rénale. Après storage au froid ou perfusion continue, la relation entre les taux de TAN et la fonction rénale est disparue. Le flushing à l'aide des solutions de type intracellulaire, malgré sa faible capacité à conserver les taux de TAN s'est avéré une méthode d'entreposage aussi efficace que la perfusion continuelle, laquelle a maintenu des taux normaux de TAN.

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Supported by Veterans Administration Research Grant 1519-01.     

Evaluation of outpatient adverse drug reactions leading to hospitalization.

Outpatient adverse drug reaction (ADR)related hospitalization through the emergency department of a nonprofit hospital and the contributing factors are reviewed. Patients who were hospitalized because of suspected ADRs were selected from daily admissions reports and patient medication profiles from 1997 and 1998 by the pharmacy department of a nonprofit community teaching hospital. Hospital charges for individual patients were obtained from the institution's accounting system. Suspected drugs, their therapeutic class, and the organ systems involved in the ADRs were identified. A total of 191 patients who had a complete medical history and cost information were included in the study. Of those patients, 56% were female, and 45% of the patients were 75 years of older. The average hospital charge per ADR patient was $9491. Room and board accounted for more than 50% of total charges. The average length of stay for study patients was 8.0 +/- 10.3 days. Major therapeutic classes implicated in ADRs included antidiabetic agents (27.8%), anticoagulants (15.2%), anticonvulsants (10.0%), beta-blockers (7.9%), and angiotensin-converting-enzyme inhibitors (7.9%). Organ systems most commonly involved in ADR admissions were the endocrine (30.9%) and cardiovascular (24.1%) systems. The implicationed therapeutic groups and organ systems exhibited a different pattern from those of earlier ADR studies. The elderly and the poor are most affected by ADRs. The availability of new drugs and the shift in disease treatment necessitate the continuous monitoring of new ADRs. Patients and family members should be integral components of a multidisciplinary strategy for minimizing the personal and social impact of ADRs.     

MIC-1 serum level and genotype: associations with progress and prognosis of colorectal carcinoma.

PURPOSE: Macrophage inhibitory cytokine-1 (MIC-1) is a divergent member of the tumor growth factor beta (TGF-beta) superfamily. Several observations suggest that it plays a role in colorectal carcinoma (CRC). In particular, MIC-1 is markedly up-regulated in colorectal cancers as well as in premalignant adenomas. This study examines the relationship of serum MIC-1 levels and genotypes to clinical and pathologic features of colonic neoplasia. Experimental Design: We confirmed the presence of MIC-1 in CRC tissue and the cell line CaCo-2. The normal range for serum MIC-1 levels was defined in 260 healthy blood donors, and the differences between normal subjects and 193 patients having adenomatous polyps or CRC were then determined. In a separate cohort of 224 patients, we evaluated the relationship of MIC-1 serum level and genotype to standard tumor parameters and outcome measures. RESULTS: MIC-1 was expressed in CRC tissue and the cancer cell line CaCo-2. There was a progressive increase in serum MIC-1 levels between normal individuals [mean (M) = 495 pg/ml, SD = 210), those with adenomatous polyps (M = 681 pg/ml, SD = 410), and those with CRC (M = 783 pg/ml, SD = 491)]. Serum MIC-1 level was correlated with the extent of disease so that the levels were higher in patients with higher Tumor-Node-Metastasis stage. There were significant differences in time to relapse and overall survival between subjects with different MIC-1 levels and genotypes. CONCLUSIONS: This study identifies a strong association between MIC-1 serum levels and neoplastic progression within the large bowel. We suggest that the measurement of serum MIC-1 levels and determination of MIC-1 genotype may have clinical use in the management of patients with CRC.