Toxicological investigations in the semiconductor industry: I. Studies on the acute oral toxicity of a complex mixture of waste products from the aluminium plasma etching process.

In dry etching processes--one of the sources of potential exposure to toxic wastes in the semiconductor industry--complex mixtures of inorganic and organic compounds arise from reactions between feed stock gases (BCl3/Cl2), top layers (aluminium photoresist), and the carrier gas (N2). Two different fractions of the complex mixture--one an ethanolic solution (ES) and the other an insoluble liquid residue (LR)--were examined for acute oral toxicity in rats. Analytical data showed that the ethanol soluble fraction contained mainly inorganic compounds, whereas the residue contained various halogenated hydrocarbons. Neither death nor behavioral changes occurred after oral administration and observation up to 23 days. ES caused a lower mean arterial blood pressure in both sexes, increased P-R-intervals in male rats, and caused some mild biochemical and hematological alterations and changes in relative organ weights compared to the control groups. Exposure to LR influenced food and water intake, and caused a significant decrease in body weights, signs of polyurie, as well as changes in various relative organ weights and biochemical and hematological parameters. The blood pressure of the male animals fell and the heart rates of both sexes decreased.     

Cerebellar toxicity with high-dose cytosine arabinoside

CNS dysfunction, especially impaired cerebellar function, is the dose-limiting toxicity associated with high-dose cytosine arabinoside, which precludes doses of greater than 48 g/m2. Four hundred eighteen patients between the ages of 2 and 74 years with leukemia or lymphoma received 36 to 48 g/m2 cytosine arabinoside either alone or with anthracycline antibiotics, 4'-(9-acridinylamino) methane sulfon-m-anisidine (m-AMSA), or total body irradiation. In only 35 of 418 patients (8%) did severe cerebellar toxicity develop; it was irreversible or fatal in four (1%) patients. The age of the patient was a critical factor in the incidence of severe cerebellar toxicity. Patients greater than 50 years old had a statistically significant greater incidence of cerebellar toxicity compared with younger patients (26/137, 19%, v 9/281, 3%; P less than .0005, chi 2). Neither the diagnosis, disease status, sex, nor the regimen altered the incidence of severe cerebellar toxicity (when corrected for age). A second course of high-dose cytosine arabinoside, administered to 62 patients, did not increase the incidence of severe cerebellar toxicity, which occurred in five (8%) of these patients. Two of the five patients had severe toxicity with the initial course. Of the 60 patients with no antecedent cerebellar dysfunction, three (5%) had severe toxicity with the second course: one of 41 patients were less than 50 years old; two of 19 patients were greater than or equal to 50 years. Since the occurrence of severe cerebellar dysfunction is greatly affected by age, reduced doses of high-dose cytosine arabinoside should be given to patients greater than 50 years old, and methods for reducing the cerebellar toxicity should be investigated in these patients.     

Ileal pouch-anal anastomosis for chronic ulcerative colitis. Long-term results.

The aim of this study was to determine the long-term outcome among 390 patients with ulcerative colitis who underwent ileal J pouch-anal anastomosis and whether patient or operative factors influenced results. The combined operative morbidity rate for the pouch-anal anastomosis and the subsequent closure of the temporary ileostomy was 29% (bowel obstruction, 22%; pelvic sepsis, 5%), with one death due to pulmonary embolus. The probability of a successful outcome at 5 years was 94%. Of the 24 patients who failed (6% of total), 18 did so within 1 year (4%), three during year 2 (1%), three during year 3 (1%), and none thereafter. Stool frequency (7 stools/24 h), the occurrence of pouchitis (14%), and satisfactory daytime continence (94% of patients) remained stable over 4 years after operation, whereas nocturnal fecal spotting decreased (51% of patients to 20%). Women had more spotting than men, whereas patients over 50 years old had more stools per day than those 50 years or younger. In conclusion, ileal pouch-anal anastomosis achieved a reasonable stool frequency and satisfactory continence in patients with ulcerative colitis over the long-term. These results support the ileal pouch-anal anastomosis as a safe, satisfactory alternative to permanent ileostomy.     

239. Spätergebnisse chirurgischer Therapie bei der chronischen Pankreatitis

Zusammenfassung Von 1979 bis 1986 wurden an der Chirurgischen Klinik der Charité 190 Patienten wegen einer chronischen Pankreatitis operiert. Bei 52 Patienten mit einer cephalen Duodenopankreatektomie wurde in einer 6jährigen Verlaufsstudie die endokrine Pankreasrestfunktion verfolgt. Die eingesetzten Parameter (GTT, Serum-Insulin, C-Peptid, Sonographie, CT und Leberbiopsie) ergaben einen signifikanten Anstieg der diabetischen Stoffwechsellage, eine gesteigerte Verdauungsinsuffizienz und eine deutlich zunehmende Leberverfettung. Durch die Occlusion wird keine endokrine Schutzfunktion erkennbar.     

Marked increase of asymmetric dimethylarginine in patients with incipient primary chronic renal disease.

In patients with uremia, increased blood concentrations of the endogenous nitric oxide synthase inhibitor asymmetric dimethylarginine (ADMA) have been linked to the severity of atherosclerosis and to excess cardiovascular mortality. The ADMA levels and several traditional cardiovascular risk factors were assessed in 44 untreated nonsmoking patients with confirmed primary chronic renal disease at different stages of renal disease. True GFR was assessed by means of the inulin-clearance technique. For comparison, nonsmoking subjects matched with respect to age, gender, and body-mass index were examined. Mean plasma ADMA concentration was markedly higher (P < 0.0001) in all patients combined (4.2 +/- 0.9 micromol/L) than in control subjects (n = 16; age 45 +/- 10 yr; serum creatinine 1.0 +/- 0.1 mg/dl; ADMA 1.4 +/- 0.7 micromol/L). However, mean ADMA levels were similar in patients with normal renal function (n = 16; age 41 +/- 9 yr; serum creatinine 1.1 +/- 0.1 mg/dl; GFR 120 +/- 14 ml x min(-1) x 1.73 m2; ADMA 4.0 +/- 0.7 micromol/L), in patients with moderate renal failure (n = 15; 47 +/- 7 yr; 1.8 +/- 0.3 mg/dl; 65 +/- 10 ml x min(-1) x 1.73 m2; 3.8 +/- 0.6 micromol/L) and in patients with advanced renal failure (n = 13; 46 +/- 9 yr; 4.2 +/- 0.9 mg/dl; 25 +/- 4 ml x min(-1) x 1.73 m2; 4.7 +/- 1.2 micromol/L). Furthermore, ADMA levels were increased to the same extent in normotensive (n = 17; 4.0 +/- 0.8 micromol/L) and in hypertensive (n = 27; 4.2 +/- 0.9 micromol/L) patients. In contrast to ADMA, mean total plasma homocysteine concentration were similar in control subjects (10.6 +/- 2.9 micromol/L) and in patients with normal GFR (11.0 +/- 2.9 micromol/L), but were significantly higher in patients with moderate renal failure (17.7 +/- 4.1 micromol/L) and particularly in patients with advanced renal failure (28.2 +/- 10.6 micromol/L). Finally, mean total serum cholesterol concentrations were comparable in the control group and in the three groups of patients with renal disease. In contrast to several traditional cardiovascular risk factors, markedly increased blood concentrations of ADMA, a putative biochemical marker of atherosclerosis, are present even in nonsmoking patients without diabetes with incipient primary renal disease. Thus, the early increase of ADMA levels may be of relevance for the excess cardiovascular morbidity and mortality due to arterio- and atherosclerotic complications in patients with renal disease.     

New concepts on the pathogenesis of fever

For more than 50 years, experimental studies on fever have focused on a substance from leukocytes called leukocytic or endogenous pyrogen. Various investigators concluded that changes associated with infection--such as numbers of circulating leukocytes; levels of trace metals, amino acids, and hepatic proteins; and altered lymphocyte function--were also caused by endogenous leukocyte mediators. There was reasonable evidence that fever and these other changes were brought about through the action of a single endogenous pyrogen, now known as interleukin 1 (IL-1). Two forms of IL-1 have been cloned (IL-1 beta and IL-1 alpha), and studies of recombinant IL-1 preparations have confirmed that fever and the broad spectrum of host responses to infection and injury are indeed mediated by this substance. However, IL-1 is not the only leukocyte product that induces fever: tumor necrosis factor (cachectin) and interferon produce fever in humans and animals. Accordingly, the concept of a single endogenous pyrogen now requires modification. Nature has conferred the ability to produce fever on no fewer than three structurally distinct molecules. Investigators trying to determine what triggers the hypothalamus to initiate fever in a particular disease must now consider these three endogenous pyrogens, either alone or together, as mediators of fever.     

Circadian rhythm and pulsatility of parathyroid hormone secretion in man

OBJECTIVE: We wished to investigate the circadian rhythm and pulsatility of parathyroid hormone (PTH) secretion in man, as conflicting results have been published. DESIGN AND PATIENTS: To investigate the circadian rhythm during daytime, we sampled (a) peripheral blood at hourly intervals in 12 healthy young men from 0900 h until 1700 h. For observation of pulsatility, we sampled (b) peripheral blood at 1-minute intervals for 1 hour in three healthy men and three healthy women (mean 27.7 years, range 21-56 years) and (c) at 1-minute intervals for 30 minutes in 21 patients with surgically confirmed primary hyperparathyroidism (pHPT). MEASUREMENTS: The serum levels of intact PTH were measured by two-site immunoradiometric assay and special care was taken to reduce intra-assay variability, especially at the normal PTH concentration. In series (a), ionized calcium, total calcium and phosphate were also determined. RESULTS: A circadian rhythm during daytime was found for intact PTH in healthy men and women with a nadir at 0930 h and a peak in the afternoon. Ionized calcium and total calcium (protein-adjusted) decreased and phosphate increased in the afternoon. These changes were all statistically significant (P < 0.02). Pulsatility of PTH: Statistical cluster analysis of the data showed no pulsatility either in healthy persons or in patients with primary hyperparathyroidism. In two healthy women and one healthy man slight changes of longer duration were discovered, but no complete pulses. In five patients with primary hyperparathyroidism, larger differences between the highest and lowest concentrations of intact PTH were found, but no complete pulses. CONCLUSIONS: Our data show a significant circadian rhythm during daytime of intact PTH and only minor changes from minute to minute. The alterations in PTH-levels occurred at longer time intervals in healthy persons. In some patients with primary hyperparathyroidism, decreases of PTH-levels were found. The circadian rhythm of PTH may be due to slight changes in calcium or phosphate concentration.