[Pulmonary lesions in Wegener's disease. Report of the French Anatomo-clinical Research Group. Study of 40 pulmonary biopsies]. We report the results of a morphological analysis of 60 pulmonary biopsies gathered from a multi center study, organised by the clinico-pathological research group on Wegener's Disease under the auspices of the French Language Society of Thoracic Medicine. Forty of the sixty cases analysed were retained after indexing the histological aspects in order to specify their diagnostic value. Two groups of lesions were distinguished, which had different significance. Group A: These include the three major diagnostic criteria, which reinforce one another as they associate: 1) The polymorphoneutrophil microabscesses with limited central necrosis or an extended necrosis like the contours of a relief map. 2) An angiitis (arteries, veins, capillaries) with eccentric focal parietal crescent-shaped microabscesses. 3) Polymorphous granulomas with giant cells. Group B: In this group are the minor morphological observations (table II) of a lesser value and significance. 1) Acute or chronic lesions with alveolar haemorrhage, endogenous lipid pneumonia, xanthomatous granulomas, an organising pneumonia with an alveolitis. 2) Bronchial lesions: Bronchitis and necrotising bronchiolitis, which is more rarely follicular. 3) Sero-fibrinous or infiltrative neutrophil pleural lesions with focal microabscesses, elastolysis and elastophagia with giant cells in the elastic lamina. Thirteen cases presented with misleading lesions, which was a possible source of diagnostic error and led to a discussion of several associated disorders (Goodpasture's syndrome, and collagen disorder syndrome) or there may be systemic angiitis (Giant cell or lymphocytic) or also systemic or tissue eosinophilia (Churg-Strauss syndrome, bronchocentric granulomatosis) or necrotising bronchitis (atrophic polychondritis) or other forms of nodular interstitial fibrosis, such as histiocytosis X. We would like to stress the great polymorphic variation of the lesions and the difficulties which confront pathologists in the diagnosis of Wegener's Disease, above all when it is localised to the lung. There is value in finding at least one major diagnostic criteria which is associated with a minor criteria and with the help of the C.ANCA levels may lead to a narrow clinicopathological correlation and allows for a fairly precise approach to the diagnosis and identification of early or unusual lesions and thus to the early treatment of patients before irreversible renal failure appears.


[Detergent enzymes: has the risk of occupational sensitization disappeared?]. Occupational allergy to enzyme detergents had almost disappeared by the use of preventive measures, both individually and in industries. The occurrence of 8 new cases of asthma in a detergent factory has led to a prospective clinical and aetiological enquiry. Although there was no documentation using the specific provocation test or by measuring respiratory function whilst at work, the occupational character of this asthma seemed possible after taking a history. Sensitization to the enzymes used (Savinase, Maxatase and Biozym P 300 S) was shown by skin tests (8 positive to all the enzymes) and the level of specific IgE to Rast (8 times greater than class 3 for Savinase and Maxitase) and for HBDT for Maxatase and Biozym P 300 S (greater than 50% in 8 patients). From another stand point the incomplete application of preventive measures within the factory did not seem to totally explain the origin of this sensitization. In fact, it was the study of the morphology of the enzyme grains, which had been introduced into the factory which helped us to explain the mechanism. In effect it was the capsules of the grain which were fissured and thus allowed allergen contact. The replacement of these grains whose envelope was intact, led to the disappearance of the symptoms and confirmed our hypothesis. There remains a continuing risk from occupational sensitization to asthma and it is suggested that there is continued collaboration between the medical profession and industry.


[Comparative epidemiological characteristics of a homogeneous series of acute common pneumopathies seen in a general hospital center (GHC)]. Between 1979 and 1989, 108 cases of community acquired pneumonia in non-immunodepressed subjects were admitted to hospital to a specialist chest department. The patient's characteristics were as follows: mean age = 56 (range 14-91), 44 women and 64 men. The causal agent was isolated in 44 cases (40%) of which 4 cases were viral (9% of 44 cases) and 12 were Legionella (27%), pneumococci (SP) 11 cases (25%), Mycoplasma pneumoniae (MP) 8 cases (18%), and Chlamydia 8 cases. The microbacteriological criteria for diagnosis were as follows: significant seroconversion for viruses, MP, Chlamydia, Legionella, bacteriological isolation on blood cultures, and pleural liquid for SP. In 64 cases the bacteriological diagnosis was not established. In this series we note as follows: 1) There did not appear to be any seasonal peak in relation to bacteria isolated, contrary to previous reports, in particular for Legionella. On the other hand viruses occur notably in February and March. 2) Chlamydia were more frequent in individuals living in rural areas; 7 cases out of 8. Whereas amongst the 108 patients 55 were from the country and 34 from the city (16 from institutions and 3 uncertain). In conclusion, if the level of bacteriological identification (IMB) appears weaker than in previous reference series: 51-65%, the diagnostic yield clearly improved in our experience achieving results nearer to the best achievable: 54% of IMB from 48 cases which were recruited between 1985-1989.(ABSTRACT TRUNCATED AT 250 WORDS)


[Sequential administration of a reduced dose of almitrine to patients with chronic obstructive bronchopneumopathies. A controlled multicenter study]. Recent multi-centre studies have shown that high doses of Almitrine (100-200 mg per day), lead to a significant improvement in the hypoxaemia of patients presenting with chronic airflow obstruction, but that a high blood level (greater than 500 ng/ml) is often seen after 1 year, sometimes associated with signs of peripheral neuropathy. In order to maintain Almitrine blood levels in the range 200-300 ng/ml we have used an intermittent regime (with a "window" of 1 month every 3 months) and a dose limited to 100 mg per day. 102 hypoxic patients with chronic airflow obstruction, who were in a stable state were included. 65 patients were in the Almitrine group (A) and 37 patients in the placebo group (P). The treatment lasted for 1 year. In addition there was a 3 monthly follow up with arterial blood gases and spirometry, a clinical neurological examination and also electrophysiology, initially and after 6 and 12 months. 43% of patients in group A and 32% of patients in group P, left the study, most often due to poor cooperation, but sometimes as a result of side effects. After 12 months the PaO2 rose significantly in group A from 59.1 +/- 0.7 to 65.8 +/- 1.6 mmHg (p less than 0.001) whilst it was not changed in group P. The PaCO2 did not change in either group. On the other hand there was a significant fall in the subgroup of patients with hypercapnia in group A (p less than 0.001). The outcome of the neurological and electrophysiological assessments did not show any significant difference between the two groups.(ABSTRACT TRUNCATED AT 250 WORDS)


[Acquired rifampicin resistance during M. kansasii infection in a patient with AIDS]. A man with AIDS and M. kansasii lung infection received rifampicin and isoniazid for 9 months, combined with ethambutol for four months. The treatment was effective with sputum culture negativation, but relapse occurred. The minimal inhibitory concentration of rifampicin for the M. kansasii strain was respectively 0.2 microgram/ml at the onset and 128 micrograms/ml after the treatment, giving evidence of acquired resistance. A new treatment was initiated but is was ineffective.


[Primary liposarcoma of the mediastinum: contribution of MRI to the diagnosis. Apropos of a case]. An exceptional case of liposarcoma arising in posterior mediastinum is reported in a young woman. CT fails in diagnosis because no area of fatty density was found. MR features were suggestive of this etiology.


[Occupational asthma caused by ebony wood]. A case of occupational asthma to ebony wood dust is described in a violin and stringed instrument maker, who was sanding and filing ebony to make the finger boards of violins and cellos. The diagnosis was confirmed using a realistic provocation test; after sanding and smoothing the ebony for 20 minutes the patient developed bronchial spasm with fall of the force expired volume in one second (VMS) of 45% which was reversible following the inhalation of beta 2 agonists. A delayed reaction was seen at 3 hours and 6 hours and at 20 hours after the test. The observations of occupational asthma or rhinitis to ebony wood are very rare. To our knowledge there are two publications at the present time. It has been recognised as an occupational disease (see table 47 of occupational diseases) and an exclusion order has been effected.


[Allergic alveolitis due to colophony].

[Allergic alveolitis due to colophony]. We report the observation of a 37 year-old female worker exposed for 5 years to heated colophony fumes. The patient used a soldering iron with colophony flux-cored solder. She presented with chronic cough and dyspnoea on exertion without any wheezing. Clinical evidence associated with chest X-ray, lung function tests, lymphocytic alveolitis in bronchoalveolar lavage led to hypothesize the diagnosis of an occupational alveolitis linked to colophony exposure. This was eventually confirmed by coupling repeated lung function tests and bronchoalveolar lavages with on-off periods of occupational exposure.


[Adenocarcinomatous pleural lesion associated with hypoglycemia]. We report the case of a patient suffering from a glandular pleural lesion. The evolution of the disease was punctuated by periods of hypoglycaemia, which caused a coma. There was no clinically evident explanation for these hypoglycaemic episodes. Investigations revealed adrenal failure, but this adrenal failure was unrelated to the neoplastic process in the patient. This case is a reminder that the cause of hypoglycaemia associated with tumours can really have a paraneoplastic origin and justifies an in depth study to achieve an aetiological diagnosis.


Effects of multiple doses of moricizine hydrochloride on its pharmacokinetics and hepatic microsomal enzymes in rats. We studied the influence of chronic moricizine hydrochloride (MRZ) treatment on the drug's pharmacokinetics and on drug metabolizing enzyme activities in rats. Separate groups of 8 rats (4 males and 4 females) were treated with 40 and 100 mg/kg oral MRZ once daily for 7 days and saline control for 7 days prior to the preparation of hepatic microsomal enzyme suspensions. Depending on the substrate, treatments with multiple oral MRZ increased or decreased hepatic microsomal enzyme activities. For the pharmacokinetic study, rats (4 males and 4 females) were treated with 40 mg/kg oral MRZ once daily for 7 days. A comparison of MRZ pharmacokinetics obtained on day 1 relative to day 7 revealed that both AUC0-t and AUC0-infinity increased about 7-fold in males and 2-fold in females. Cmax also increased about 5-fold from day 1 to day 7 in males. These increases in blood concentrations and AUC's are likely due to enzyme inhibition. Results obtained from female rats on days 1, 4 and 7 suggest that metabolic changes probably occur after the 4th day of dosing. Therefore, chronic MRZ treatment affected its pharmacokinetics and hepatic metabolizing enzyme activities in rats.


Inhibitory effect of methylprednisolone suleptanate (U-67590A) on anaphylactic bronchoconstriction in guinea pigs. Effects of U-67590A, an analogue of methylprednisolone, on antigen-induced bronchoconstriction expressed as ventilation overflow were examined in ovalbumin-sensitized guinea pigs. When administered intravenously 17-18 hr before the challenge with antigen, U-67590A at doses of 10 and 30 mg/kg caused dose-dependent inhibition of increased ventilation overflow immediately after challenge. Death due to anaphylactic shock was markedly reduced by U-67590A. At 10 mg/kg (i.v.), U-67590A given 10 min before the challenge significantly inhibited the antigen-induced increase in ventilation overflow; the greatest inhibition seen 5-6 hr prior to the challenge. Pretreatment with 10 mg/kg FPL-55712 attenuated the increase in ventilation overflow during anaphylaxic shock. It is conceivable that inhibition of the leukotriene-mediated response is involved in the glucocorticoid-induced suppression of airway obstruction in anaphylaxis, and that inhibitory action of the glucocorticoid directly acting on the airway may account for the very fast onset of action.


Variations of lipid profile in animals caused by adenosine analogs: N6 (amido-3-propyl) adenosine hydrochloride and (carboxamido-3-propylamino)-6-(triproprionyl) 2',3',5'beta (D-ribosyl)-9-purine. N6-substituted adenosine analogues are powerful inhibitors of lipolysis in the adipose tissues of animals and humans, because of their agonist effect on A1 purine receptors. Using a model of hypertriglyceridemia provoked by intravenous injection of Triton WR 1339, we observed that Agr 529 [N6(amido-3-propyl)adenosine hydrochloride] at 2 mg.kg-1 intravenous in rabbits, and intraperitoneally and orally in rats led to a return of the levels of circulating triglycerides to normal values. In addition, Agr 529 and its prodrug, Agr 540 [(carboxamido-3-propylamino)-6-(triproprionyl)2', 3',5'beta(D-ribosyl)-9-purine] administered to rats at 3 and 30 mg.kg-1, respectively, returned plasma triglyceride concentrations to normal levels. Intravenous administration of Agr 529 to normal rats led to decreased concentrations of plasma fatty acids, phospholipids, triglycerides and total cholesterol as a function of dose. The decrease began at 0.1 mg.kg-1 and was highly significant at 3 mg.kg-1. In the same conditions, the intraperitoneal administration of Agr 529 caused a dose-dependent hypolipemia. There was no apparent effect on cholesterol and on the triglycerides of high density lipoproteins. A kinetic study showed that the antilipemic effect of Agr 529 intravenously injected at 3 mg.kg-1 began 30 minutes after the injection with a maximum effect at 2 hours. The effect persisted up to 8 hours after injection. The present results show that the administration of Agr 529 and Agr 540 to normal animals causes hypolipemia (decrease in fatty acids, phospholipids, triglycerides and cholesterol) and restores induced hypertriglyceridemia. These effects may be attributed to an interaction of the molecules with A1 purinergic receptors of adipose tissue.


Variable involvement of rat skeletal muscles in paraoxon-induced necrotizing myopathy. We studied the incidence of paraoxon-induced myopathy in several rat skeletal muscles in relation to the morphometric properties and oxidative metabolism of their fibers. The necrosis was most pronounced in the predominantly oxidative-rich fiber-composed diaphragm. The purely oxidative-rich masseter and soleus muscles were also severely affected. All 7 mixed muscles with oxidative-poor fiber predominance were far less involved. A high correlation between oxidative capacity and the extent of the muscle fiber necrosis was evidenced in mixed muscles. No relation was found between the muscle fiber diameter and the susceptibility to necrosis. We conclude that muscles predominantly composed of highly oxidative fiber types are more susceptible to organophosphate-induced necrotizing myopathy. Oxidative capacity alone is not the only factor, however, as the mixed diaphragm was more involved than the purely oxidative-rich masseter and soleus. Several features of the distinct fiber types could be responsible for the variable vulnerability.


Dioxygenase and hydroperoxidase activities of rat brain cytosolic lipoxygenase. Dioxygenase and hydroperoxidase activities of dialyzed rat brain cytosolic lipoxygenase were studied using linoleic acid as the substrate. The formation and utilization of linoleic acid hydroperoxide was monitored spectrophotometrically at 234 nm. Dioxygenase activity was dependent upon the concentration of linoleic acid and enzyme. The optimum assay conditions necessary for maximal dioxygenase activity included the 0.5 mM linoleic acid, cytosol (100 micrograms of protein) as the enzyme source and pH 7.4. All the classical inhibitors of lipoxygenase, nordihydroguaiaretic acid, phenidone and 5,8,11-eicosatriynoic acid significantly inhibited dioxygenase activity in a dose dependent manner. A significant hydroperoxidase activity was observed towards xenobiotic substrates viz. benzidine, guaiacol, tetramethylphenylenediamine, thiobenzamide in the presence of linoleic acid. NDGA at 1 microM concentration inhibited benzidine oxidation (2.45 nmol product formed/min/mg protein) by 75%, while Phenidone at 0.125 microM and ETI at 20 microM inhibited benzidine oxidation by 30% and 25%, respectively.


Involvement of serotonergic mechanisms in the inhibitory effect of U-50,488H on glutamate-induced lethality in mice. The present study showed the involvement of serotonergic mechanisms in the protective effect of U-50,488H, a selective agonist of kappa-opioid receptors, against glutamate-induced lethality in mice. U-50,488H (1-10 mg/kg, i.p.) protected mice to a significant extent against glutamate-induced lethality, in a dose-related manner. This protective effect was not observed in p-chlorophenylalanine- or methysergide-treated mice. These results suggested that 5-HT in the brain may play an important role in the protective effect of U-50,488H against glutamate-induced lethality.


Abnormalities of the autonomic nervous system of the duodenum in streptozotocin-induced diabetic rats. The changes in sensitivity of the rat duodenum to ATP were examined in preparations from control rats and from rats with streptozotocin (STZ)-induced diabetes. ATP was able to relax the duodenum of control animals in a concentration-dependent manner and this relaxation was significantly increased in STZ-diabetic rats. In preparations from diabetic rats, relaxation responses to ATP were greater than those of age-matched control groups. These results suggest that functional changes or degeneration of non-adrenergic, non-cholinergic nerves in the myenteric plexus may occur in STZ-diabetic rats, and that these alterations may result in the increased sensitivity of the relaxation of the duodenum to ATP.


Effect of propentofylline on ischemia-induced loss of muscarinic cholinergic receptor binding in the gerbil hippocampus. Super-delayed loss of muscarinic-1 (M1) receptors and the protective effect of propentofylline on these changes were examined in the gerbil hippocampus after transient ischemia with radioactive pirenzepine. M1 receptors were markedly decreased in the gerbil hippocampus 14 days after transient ischemia. Single administration of propentofylline (20 mg/kg, ip) just after transient ischemia almost completely prevented the ischemia-induced decrease in the number of M1 receptors, and had no effect in sham-operated controls. These findings suggest that one of the therapeutic efficacies of propentofylline is the result of the normalization of the dysfunction of the acetylcholine neuronal system in cerebrovascular disease.


Administration of vanadyl sulfate by gavage does not normalize blood glucose levels in streptozotocin-induced diabetic rats. Vanadyl sulfate trihydrate was given by gavage to streptozotocin-induced diabetic rats for 21 days at doses of 0, 25, 50, or 75 mg/kg/day. In marked contrast to the reduction in plasma glucose observed in diabetic animals given vanadyl sulfate via drinking water, diabetic rats given vanadyl by gavage were not characterized by normoglycemia. Similarly, in contrast to the normalizing effect of vanadyl in drinking water, vanadyl by gavage had only a minimal influence on diabetes associated hyperphagia and polydipsia. Despite the lack of marked effect of vanadyl by gavage on the above parameters, tissue vanadium accumulation in the gavaged rats was similar to that reported for rats given vanadium by drinking water. The present results (taken together with previous data) show that the administration of vanadium by gavage is not a viable alternative to the use of insulin in diabetes treatment.


Potent inhibition of MAO mediated propranolol metabolism by dimethyl sulfoxide in Hep G2 cells. This communication reports on the effects of dimethyl sulfoxide (DMSO) on the oxidative metabolism of propranolol by the homogenate of the human hepatoma cell line Hep G2. The formation of multiple metabolites was monitored in the absence and presence of 0.1 to 2.0% of DMSO. For the primary cytochrome P450-mediated pathways, ring oxidation was significantly reduced by 1.3 to 2.0% DMSO, whereas side-chain oxidation was not affected. A gradual inhibition of the oxidative deamination of N-desisopropylpropranolol to its glycol metabolite was seen with 20% inhibition at a DMSO concentration of 0.1% and a maximum 75% inhibition at a DMSO concentration of 0.7%. This highly selective inhibitory effect of DMSO on oxidative drug metabolism appears to be directed towards MAO type A.


Morphological development of the rat fetal pancreas. Rat fetal pancreata of days 12 to 19 of gestation and those of neonates were examined with light and electron microscopes. The pancreas arose from the primitive epithelium of the foregut as two primordia (dorsal and ventral pancreatic primordia) of epithelial cell nests surrounded with abundant fetal mesenchymal tissue between days 11 and 12. Primitive pancreatic islets, which mainly consisted of the endocrine cells with A cell type secretory granules, also appeared in the primordia at this age. The epithelial cell nests elongated gradually and had a branching cord-like arrangement. Two pancreatic primordia fused together on day 15, and an apparent ductular structure was observed on days 15 to 17. An acinar configuration of exocrine cells with zymogen granules gradually formed between days 17, 18 and 19. After birth, the volume of pancreatic parenchyma markedly increased and that of mesenchymal tissue prominently decreased. Ultrastructurally, the pancreatic primordia in the early stage showed immature epithelial features with the surrounding basement membrane and inconspicuous intercellular junctions. This might imply a plasticity in cellular differentiation of protodifferentiated pancreatic epithelial cells toward a ductular structure of immature exocrine pancreas which appeared later. In addition to the basement membrane, abundant fetal mesenchymal tissue was considered to play a possible role in the early morphogenesis in pancreatic development.


Identification and quantitative analysis of urinary metabolites of dichloropropanols in rats. Urinary metabolites of dichloropropanols in rats were analyzed by gas chromatography-mass spectrometry (GC/MS). Solutions of dichloropropanols consisting of 1, 3-dichloro-2-propanol (DC2P) and 2, 3-dichloro-1-propanol (DC1P) were diluted in a saline at the concentration of 100 mg/ml, and 0.1 ml of the solutions were subcutaneously injected into male Wistar rats weighing about 160g. The urine samples were collected over a period of 24 hours after the injections. DC2P and DC1P in the urine were extracted with ethylacetate and analyzed by a GC/MS. The derivatization procedure with 4-bromophenylboric acid after acetonitril extraction was applied for the analyses of diols in the urine. By the GC/MS analysis, 3-chloro-1, 2-propanediol (3CPD), 2-chloro-1, 3-propanediol (2CPD) and 1, 2-propanediol (PPD) were identified as the hydroxylated metabolites of dichlorpropanols. Based on the analytical results, the metabolic pathways of dichlorpropanols forming 3CPD and 2CPD, and then hydroxylating to PPD were elucidated.


Cloning of the 5' flanking region of the murine laminin B1 gene by genomic PCR. Induction of the murine laminin B1 gene in F9 cells occurs 24-48 hours after the retinoic acid (RA) addition. In order to reveal the mechanism of the late induction of the laminin B1 gene, it is necessary to understand fully the promoter structure of it. We report here that the promoter region of the laminin B1 was rapidly isolated utilizing the genomic PCR technique. MgCl2, formamide concentration, and annealing temperature were optimized for PCR. The result showed that MgCl2 concentration profoundly affects the efficiency in amplifying the specific DNA. The annealing temperature (51 degrees C-63 degrees C) did not significantly affect the yield. Under the optimal conditions, about 50 ng of the specific DNA was obtained from 1 microgram of total genomic DNA after 20 cycles of amplification, indicating that approximately 2 x 10(5) fold specific amplification had occurred. Southern blot analysis and sequence data proved that the amplified DNA fragment contained the promoter region of the laminin B1 gene.


[Effects of ethylene oxide inhalation on mice]. Male ddY mice were exposed to ethylene oxide (EO) at a concentration of 400 ppm, 6 hours a day, 3 days a week for 13 weeks and the effects of EO on the hepatic drug metabolizing enzymes were investigated. The liver and spleen weight per body weight did not change. Compared to the control group, the kidney weight of the exposed group increased while the testis weight decreased significantly. Hematological examination showed macrocytic anemia in the exposed group. Contents of microsomal cytochrome P-450 in the exposed group increased twice as much as that in the control group, while microsomal protein, cytochrome b5, protoheme and NADPH-cytochrome C reductase activity did not change. NADH-ferricyanide reductase activity of the exposed group increased significantly. Among the glutathione related enzymes in the liver, glutathione reductase and glutathione peroxidase activities in the exposed group decreased but glutathione-S-transferase activity increased significantly.


[Thermal distribution in the agar phantom by a new intracavitary RF applicator for prostate gland]. Some studies suggest that the prostate gland is one of the most difficult portions of the body to heat up even by radio frequency (RF) capacitive heating, which is well established as a useful means for deep regional hyperthermia because of its non-uniform power absorption. We have developed a new type of intracavitary applicator for RF capacitive heating which can be connected to an 8 MHz RF heating device (Thermotron-RF8). The applicator is a balloon-type catheter which is filled with electrolyte, such as physiological saline, 3% saline or 3% ferrous sulfate solution, and then put between a pair of regular RF capacitive heating electrodes. The heating characteristics of the applicator were examined by using an agar phantom that is electrically equivalent to muscles. When the applicator was connected to the electrode of the RF generator with a copper cord, the balloon filled with electrolyte operated as an inner electrode. The effective hot area around the balloon of the catheter was observed, and the size of the hot area was changed by the kinds of electrolytes used and their concentration. With this adaptive technique, it is possible to maintain an adequate thermal distribution at a tumor in the uterus, urinary bladder and rectum, as well as the prostate gland.


[The suppression of CK activity in the brain by acrylamide]. In vitro, both acrylamide and bis-acrylamide inhibited the activity of purified creatine kinase (CK) from the human brain with almost the same potency. The inhibition was dose-dependent and non-competitive. In vivo, however, only acrylamide caused the splay of hind limbs and an awkward gait in rats, and inhibited CK activity in the brain. The CK activity of the regions of the brain investigated differed, and these distributions were well matched with those of human cases. The inhibition became more marked as the administration of acrylamide was repeated. While the distribution of 14C in the different regions of the brain did not differ after the injection of [14C] acrylamide, the degree of the suppression of CK activity differed in these regions and was most marked in the hypothalamus. Fifty-two-week-old rats appeared more susceptible to acrylamide than 8-week-old rats. However, no difference in the inhibition of the CK activity in the brain was noted between the older and the young ones. The possible relation of the regional differences of CK suppression with the pathogenesis of acrylamide encephalopathy is discussed.


[Fulminant hepatitis after the inhalation of dichloropropanols]. A fatal case of acute fulminant hepatitis following exposure to dichloropropanols is reported. A 59-year-old male worker in a chemical plant developed general malaise, nausea and vomiting several hours after cleaning a tank that had contained dichloropropanols. He had no previous history of hepatic dysfunction. On admission, hepatomegaly was prominent. Because of highly elevated levels of GOT and GPT in the serum, reduced prothrombin time and a lowered consciousness level, a diagnosis of fulminant hepatitis was made. Significant decreases of leukocytes and platelets were also observed. Serum creatinine and BUN were slightly elevated. Although plasma exchanges were conducted on the third and fourth day, the liver functions continued to deteriorate. The patient died on the fifth day. Because dichloropropanols could be detected in the blood specimens obtained at the time of admission, we considered that fulminant hepatitis in this case was attributed to dichloropropanols exposure. To our knowledge, this is the first case of fulminant hepatitis after dichloropropanols-exposure.


[Toxicity of dichloropropanols--changes in hematological findings and serum chemistry]. We investigated the toxicity of dichloropropanols (DCPs) in hematological findings and serum chemistry. The solutions of two isomers of DCPs, 1,3-dichloro-2-propanol (DC2P) and 2,3-dichloro-1-propanol (DC1P) were dissolved in saline at the concentration of 100 mg/ml, and 0.1 ml of each solution was subcutaneously injected into male Wistar rats weighing about 200 g. At 6 hours after the injections, in the DC2P group, the number of white blood cells and platelets showed a significant decrease. Transaminases, alkaline phosphatase and lactate dehydrogenase were greatly elevated. Blood urea nitrogen and creatinine also showed a significant increase. There were no changes in the measurements in the DC1P group. These results indicate that there is a prominent hepatotoxicity in DC2P, and that there is a considerable difference in the toxicity present in DC2P and DC1P. Furthermore, in the workplace where DCPs, especially DC2P, is used, the monitoring of the working environment and biological monitoring should be mandatory.


[Effects of methylmercury chloride on creatine kinase activity in the rat brain]. The effects of methylmercury chloride (MMC) on creatine kinase (CK) activity in the rat brain were studied. Male Wistar rats were injected subcutaneously with 10 mg MMC/kg body weight/day for 7 consecutive days, and sacrificed on the 15th day when all rats showed a crossing phenomenon of the hind limbs. CK activity was mildly inhibited in the anterior, mid and posterior cerebral cortex. Aspartate aminotransferase and lactate dehydrogenase activities were also inhibited in some parts of the cerebral cortex, almost to the same extent as the CK activity. No definite inhibition of the enzyme activity was found in the striatum and the cerebellum. From this study we concluded that the mild inhibition of CK activity does not seem to play an important role in the genesis of neurotoxicity of MMC.


Morphology of the normal visual field in a population-based random sample: principal components analysis. I applied principal components analysis to Humphrey central 24-2 threshold values from both eyes of 304 clinically normal persons selected by simple random sample from Barbados, WI. The first component, accounting for 62 per cent of the variation, is equivalent to the average threshold value within persons. The first eigenvector, when represented by grey scale maps depicting a pair of eyes, reveals that, as average threshold increases, the visual field rises and flattens, like an umbrella that, initially closed, is simultaneously opened and thrust upwards. I verify three numerical predictions based upon this umbrella description. Much less important sources of variation involve disparity between fellow eyes, and hemimeridional and other symmetric differences within eyes. I discuss briefly possible physiologic explanatory mechanisms.


Some large-sample distribution-free estimators and tests for multivariate partially incomplete data from two populations. The most common instance of multivariate observations is the case of repeated measures over time. The two most widely used methods for the analysis of K repeated measures for two groups are the K degrees of freedom (d.f.) T2 MANOVA F-test and the within-subjects 1 degree of freedom ANOVA F-test. Both require complete samples from normally distributed populations. In this paper, I describe alternative K and 1 d.f. distribution-free procedures which allow for randomly missing observations. These include a large-sample analysis of means, the Wei and Lachin multivariate Wilcoxon test with estimates of the Mann-Whitney parameter, and a multivariate Hodges-Lehmann location shift estimator based on the multivariate U-statistic of Wei and Johnson. Each of these methods provides a distribution-free K-variate estimate of the magnitude of group differences which can be used as the basis for an overall test of group differences. These tests include the K d.f. omnibus T2-like test, 1 d.f. tests of restricted hypotheses, such as the Wei-Lachin multivariate one-sided test of stochastic ordering, and the test of general association based on a minimum variance generalized least squares (GLS) estimate of the average group difference. I then describe covariate stratified-adjusted GLS estimates and tests of group differences. This approach also provides tests of homogeneity (interaction) for within-subjects and between-subjects effects. I illustrate these analyses with an analysis of repeated cholesterol measurements in two groups of patients, stratified by sex. Such analyses provide an overall distribution-free summary estimate and test of the treatment effect obtained by combining the group differences over both time (repeated measures) and strata.


A model for estimating level and net severity of spinal cord injuries. Objective and detailed neurological assessments are essential in studies of the treatment and the epidemiology of acute spinal cord injuries. In practice, investigators use the expanded score, found by taking the total of the individual determinations, but this summary obscures important detail as to the level and the overall severity of injury. To address this issue, we present a method for estimating level and net severity of injury that makes use of isotonic regression and the Spearman-Kärber estimator. We describe the method for both sensory and motor assessments of neurologic function. In the special case where one gives an identical weight to the response at each level, these estimators algebraically partition the expanded score into separate contributions due to level and net severity. We provide a numerical example using data from the first National Acute Spinal Cord Injury Study, and we present a summary of the distribution of these parameters for this population.


Childhood blood pressure tracking correlations corrected for within-person variability. The correlation coefficient between initial and subsequent blood pressure (BP) measurements is referred to as the tracking correlation. Childhood BP tracking correlations, although positive, have been considered too low to make accurate predictions for an individual. These correlations, however, can be raised substantially by averaging BP over multiple weekly visits in each year, which partially accounts for within-person variability. In a cohort of 333 school children, we measured BP 3 times on each of 4 successive weekly visits, in each of 4 consecutive years, using a random-zero sphygmomanometer. Approximately 90 per cent of subjects had data for one or more follow-up years, and 75 per cent of subjects who entered in the first year had data for all four years. With a model that allows estimation of correlations and that uses all available longitudinal data, we calculated tracking correlations completely corrected for within-person variability, the statistical equivalent of measuring BP on an infinite number (infinity) of visits and measurements per visit. Age-sex adjusted tracking correlations for 3 years of follow-up based on the means from 1,2,3,4, and infinity visits are, for systolic BP, 0.43, 0.56, 0.62, 0.66, and 0.73, respectively, and for diastolic BP, 0.20, 0.37, 0.46, 0.50, and 0.70, respectively. With longer follow-up, the use of corrected tracking correlations would allow determination of the maximal extent to which childhood BP can predict adult levels, and therefore the usefulness of screening to identify children at high risk of developing hypertension.


Using follow-up data to avoid omitted variable bias: an application to cardiovascular epidemiology. Omitted variable bias is discussed in the context of linear models. It is shown that the effect of omitted variables can be controlled in linear models for metric dependent variables by using data from follow-up studies. Two different models for analysing such data are proposed. In the first model the omitted variables are assumed to be uncorrelated with the explanatory variables in the model and to be constant over time. These assumptions lead to a special structure of the covariance matrix of the errors over time. Efficient estimation of the parameters in the linear model has to take this special covariance matrix of the errors into account by using appropriate generalized least squares or maximum likelihood methods. In the second model the omitted variables are assumed to be time constant. Additionally, they are allowed to be correlated with the explanatory variables, that is these variables are omitted confounders in the usual epidemiological sense. It is shown that even in this case the parameters of the linear model can be estimated consistently with ordinary least squares if a follow-up study is available. The differences between the parameter estimates under the first and the second model may be used to construct a Hausman test for misspecification. The models, the estimation methods and the Hausman test are illustrated by the example that explores the determinants of serum cholesterol in German adoloscents of both sexes.


Divergent biases in ecologic and individual-level studies. Several authors have shown that ecologic estimates can be biased by effect modification and misclassification in a different fashion from individual-level estimates. This paper reviews and discusses ecologic biases induced by model misspecification; confounding; non-additivity of exposure and covariate effects (effect modification); exposure misclassification; and non-comparable standardization. Ecologic estimates can be more sensitive to these sources of bias than individual-level estimates, primarily because ecologic estimates are based on extrapolations to an unobserved conditional (individual-level) distribution. Because of this sensitivity, one should not rely on a single regression model for an ecologic analysis. Valid ecologic estimates are most feasible when one can obtain accurate estimates of exposure and covariate means in regions with internal exposure homogeneity and mutual covariate comparability; thus, investigators should seek out such regions in the design and analysis of ecologic studies.


Digit preference in estimated gestational age. A digit preference model is developed to describe the preference for estimating gestational age at birth as an even week during the 20th to 36th week of gestation. The model incorporates a probability of misclassification to adjacent even weeks at odd gestational ages, while even gestational ages are assumed correctly classified. The model is extended to allow the misclassification probabilities to decrease linearly with week during the period. A piecewise exponential model is used to model relative risks of delivery associated with a previous spontaneous abortion and a model incorporating digit preference is fitted as a generalized bilinear model in GLIM. The estimates of relative risk in the underlying survival model are virtually the same whether the misclassification is incorporated in the model or ignored.


Power and sample size evaluation for the McNemar test with application to matched case-control studies. Various expressions have appeared for sample size calculation based on the power function of McNemar's test for paired or matched proportions, especially with reference to a matched case-control study. These differ principally with respect to the expression for the variance of the statistic under the alternative hypothesis. In addition to the conditional power function, I identify and compare four distinct unconditional expressions. I show that the unconditional calculation of Schlesselman for the matched case-control study can be expressed as a first-order unconditional calculation as described by Miettinen. Corrections to Schlesselman's unconditional expression presented by Fleiss and Levin and by Dupont, which use different models to describe exposure association among matched cases and controls, are also equivalent to a first-order unconditional calculation. I present a simplification of these corrections that directly provides the underlying table of cell probabilities, from which one can perform any of the alternative sample size calculations. Also, I compare the four unconditional sample size expressions relative to the exact power function. The conclusion is that Miettinen's first-order expression tends to underestimate sample size, while his second-order expression is usually fairly accurate, though possibly slightly anti-conservative. A multinomial-based expression presented by Connor, among others, is also fairly accurate and is usually slightly conservative. Finally, a local unconditional expression of Mitra, among others, tends to be excessively conservative.


Neuromuscular electrical stimulation and voluntary exercise. Neuromuscular electrical stimulation (NMES) has been in practice since the eighteenth century for the treatment of paralysed patients and the prevention and/or restoration of muscle function after injuries, before patients are capable of voluntary exercise training. More recently NMES has been used as a modality of strengthening in healthy subjects and highly trained athletes, but it is not clear whether NMES is a substitute for, or a complement to, voluntary exercise training. Moreover the discussion of the mechanisms which underly the specific effects of NMES appears rather complex at least in part because of the disparity in training protocols, electrical stimulation regimens and testing procedures that are used in the various studies. It appears from this review of the literature that in physical therapy, NMES effectively retards muscle wasting during denervation or immobilisation and optimises recovery of muscle strength during rehabilitation. It is also effective in athletes with injured, painful limbs, since NMES contributes to a shortened rehabilitation time and aids a safe return to competition. In healthy muscles, NMES appears to be a complement to voluntary training because it specifically induces the activity of large motor units which are more difficult to activate during voluntary contraction. However, there is a consensus that the force increases induced by NMES are similar to, but not greater than, those induced by voluntary training. The rationale for the complementarity between NMES and voluntary exercise is that in voluntary contractions motor units are recruited in order, from smaller fatigue resistant (type I) units to larger quickly fatiguable (type II) units, whereas in NMES the sequence appears to be reversed. As a training modality NMES is, in nonextreme situations such as muscle denervation, not a substitute for, but a complement of, voluntary exercise of disused and healthy muscles.


Iliotibial band syndrome.

Iliotibial band syndrome. The iliotibial band syndrome is most often diagnosed in runners but can be found in athletes who participate in other sports. From our experience most patients are high mileage runners with shoes either worn out or with insufficient cushioning. A total of 19 athletes with this condition have been seen in the past 3 years. Treatment consisted of rest or decreased distance, shoe changes, modification in exercise technique, anti-inflammatory medication, steroid injections and stretching. Surgery was not required.


Applied physiology of amateur wrestling. The general physiological profile of the successful wrestler is of one having high anaerobic power (mean range of 6.1 to 7.5 W/kg for arms; mean range of 11.5 to 19.9 W/kg for legs); high anaerobic capacity (range for arms 4.8 to 5.2 W/kg; range for legs 7.4 to 8.2 W/kg); high muscular endurance; average to above average aerobic power (range 52 to 63 ml/kg/min); average pulmonary function (range 1.90 to 2.02 L/kg/min for VEmax); normal flexibility; a high degree of leanness (range 3.7 to 13.0% fat) excluding heavyweights; and a somatotype that emphasises mesomorphy. Training methods include wrestling, and nonwrestling activities for increasing strength and power (i.e. resistance training), and to improve cardiovascular fitness (i.e. endurance training). Unfortunately, data on the isolated effects of wrestling on fitness and the type of training programme most effective for success in wrestling are scarce. The practice of weight loss is commonly used by wrestlers to enhance performance. Rapid weight loss has profound adverse effects on the wrestler's physiology but little effect on strength or anaerobic power performance as measured in the laboratory. In contrast, muscular endurance appears to be impaired by the rapid weight loss. Current research on weight loss and performance in wrestlers has taken 2 directions: (a) towards nutritional treatments to prevent suboptimal muscular endurance, and (b) towards the development of programmes to estimate minimal weight based on body composition techniques and thereby prevent weight reductions.


Incidence, severity, aetiology and prevention of sports injuries. A review of concepts. Notwithstanding the healthy influence of sporting activities on risk factors, in particular those of cardiovascular disease, it is becoming increasingly apparent that sports can present a danger to health in the form of sports injuries. The extent of the sports injury problem calls for preventative action based on the results of epidemiological research. For the interpretation of these facts uniform definitions are needed and limitations of research designs should be known. Measures to prevent sports injuries form part of what is called the 'sequence of prevention'. Firstly the extent of the sports injury problem must be identified and described. Secondly the factors and mechanisms which play a part in the occurrence of sports injuries have to be identified. The third step is to introduce measures that are likely to reduce the future risk and/or severity of sports injuries. This measure should be based on the aetiological factors and the mechanism as identified in the second step. Finally the effect of the measures must be evaluated by repeating the first step. In this review some aspects of the first and second step of the sequence of prevention are discussed. The extent of the sports injury problem is often described by injury incidence and by indicators of the severity of sports injuries. Sports injury incidence should preferably be expressed as the number of sports injuries per exposure time (e.g. per 1000 hours of sports participation) in order to facilitate the comparability of research results. However, one should realise that the outcome of research applying this definition of sports injury incidence is highly dependent on the definitions of 'sports injury' and 'sports participation'. The outcome of such research also depends on the applied research design and research methodology. The incidence of sports injuries depends on: the method used to count injuries (e.g. prospective vs retrospective); the method used to establish the population at risk; and on the representativeness of the sample. Severity of sports injuries can be described on the basis of 6 criteria: the nature of the sports injury; the duration and nature of treatment; sporting time lost; working time lost; permanent damage; and cost. Here also uniform definitions are important and necessary in order to enhance the comparability of research data. In the second step of the 'sequence of prevention' the aetiological factors that play a role in the occurrence of a sports injury have to be identified by epidemiological studies. Epidemiological research on the aetiology of sports injuries requires a conceptual model.(ABSTRACT TRUNCATED AT 400 WORDS)


Neurocysticercosis: a short review and presentation of a Scandinavian case. Cysticercosis is a disease entity caused by the larval form (Cysticercus cellulosae) of the pork tapeworm (Taenia solium). When man becomes the intermediate host, cysticercal cysts can develop in various organs. Neurocysticercosis, i.e. cysticercosis of the central nervous system, can lead to a broad range of neurological disturbances. The disease is usually confined to geographical regions where sanitation is poor but can occur among immigrants or travellers from such regions. Due to increased travel and immigration the disease may appear in non-endemic areas. We describe a recent case of neurocysticercosis in a 28-year-old Danish woman, who had been travelling in the Far East. She was successfully treated with praziquantel. A short review of the literature is given as the knowledge of the diagnosis and treatment of the disease has increased greatly in the last decade.


Polymerase chain reaction with double primer pairs for detection of human parvovirus B19 induced aplastic crises in family outbreaks. Parvovirus B19 DNA can be detected by polymerase chain reaction with double primer pairs (nested PCR). Recent infection was documented by a retrospective serological study using Parvoscan-B19 enzyme linked immunosorbent assay (EIA) for detection of B19 human parvovirus IgM and IgG antibodies in serum or plasma specimens. In 3 families B19 outbreaks caused aplastic crises necessitating blood transfusion in 5 children and 1 adult with hereditary sphaerocytosis. Four members from 2 of the families had clinically overt haemolytic anaemia prior to the event. Two members in another family presented with an aplastic crisis disclosing the underlying chronic haemolytic disease. All 7 patients were identified as PCR positive in serum samples taken 3-14 days after the onset of symptoms. Comparison with dot blot hybridization revealed detectable DNA in only 2/3 PCR positive patients. Thus, nested PCR is more sensitive than the dot blot hybridization method and is therefore a suitable complement to the antibody assay for identifying recent B19 infection.


Impact of the 1987 revised AIDS case definition in Denmark: a follow-up study 2 years after its adoption. We present a follow-up study on Danish AIDS patients notified according to the latest revision of the AIDS case definition during the first 2 years after its adoption. A total of 271 adult AIDS cases were notified in the period of study (Jan. 1, 1988-Dec. 31, 1989). 60 patients (22%) met only the revised AIDS case definition and of these 17 patients (28%) developed diseases meeting the old AIDS case definition. Thus, AIDS reporting increased by 28% due to the change in case definition, the impact being 19% after adjusting for patients developing old case diseases. No time trend in the impact was found. We estimated the cumulative percent of cases meeting the new case definition who subsequently will develop diseases meeting the old definition as 15% after 6 months and 51% after 18 months. The revision produced a disproportionate increase in reporting of female cases (p less than 0.05), transfusion cases (p less than 0.01) and to a lesser extent of heterosexual cases, while the impact on reporting of homo/bisexual men showed a decrease (p less than 0.01). Cases notified with new case definition diseases were older than cases notified with old diseases. Among patients meeting only the new case definition, 25 died and 18 (30%) had not developed old case diseases before death. We found no difference in survival rates between patients within the 2 groups of case definition. Among patients meeting the new definition we found no differences in HIV antigenemia or CD4 cell count between those developing diseases meeting old case definition and those who did not.


Pneumocystis carinii pneumonia in AIDS patients: clinical course in relation to the parasite number found in routine specimens obtained by fiberoptic bronchoscopy. The aim of this study was to evaluate whether the amount of Pneumocystis carinii organisms found at fiberoptic bronchoscopy (FB) performed on HIV-positive patients correlated to the character of the P. carinii pneumonia (PCP). A consecutive series of 105 patients presented with 131 episodes of pulmonary symptoms requiring FB, and in 75 of these episodes a diagnosis of PCP was made. Specimens were stained with Giemsa and methenamine silver nitrate and the number of parasites found was given as: numerous, many, few or none. The following signs and symptoms were registered: cough, dyspnoea, fever, loss of weight, chest radiograph, haemoglobin, WBC, CD4 cell count, PO2 and HIV p24 antigen. The PCP was characterized by the clinical course: mild, moderate, severe, and by the outcome: pulmonary healthy, pulmonary insufficiency and death. No correlations between the number of P. carinii organisms and the clinical course or outcome of the PCP, the symptoms before the FB or the paraclinical examinations were found. In conclusion, the routinely obtained quantitative results of the microbiological examinations of material from the lungs were not correlated to the severity of the PCP.


Serum carcinoembryonic antigen: a prognostic marker in HIV-related Pneumocystis carinii pneumonia. Serum concentrations of carcinoembryonic antigen (CEA) were measured in 43 consecutive patients with HIV-related Pneumocystis carinii pneumonia (PCP). The subjects were divided into 2 groups according to the severity of the PCP:PaO2 in ambient air (AA) less than or equal to 50 mmHg on admission (n = 22, group 1) and PaO2 greater than 50 mmHg (n = 21, group 2). In addition, 57 HIV patients with either non-PCP pulmonary diseases (n = 34, group 3) or extrapulmonary disease (n = 23, group 4) were studied. Mean CEA levels (ng/ml) were 13 +/- 10 in group 1 and 4.9 +/- 5.5 in group 2 (p less than 0.001). The corresponding values in groups 3 and 4 were much lower (2.7 +/- 1.8 and 2.4 +/- 1.8, respectively). In group 1, mean initial CEA levels were higher (p less than 0.001) in the patients who died (n = 6; 23.5 +/- 11) than in the survivors (n = 16; 8.9 +/- 7), although the initial mean PaO2 were identical (39 +/- 7 and 39 +/- 8 mmHg, respectively) and the initial mean LDH levels were not significantly different (1544 +/- 530 and 1200 +/- 457 IU/l). CEA levels fell during specific anti-PCP therapy associated with corticosteroids but returned to normal only in the survivors. We conclude that CEA levels are increased in patients with PCP and acute respiratory distress. Among the patients with PaO2 levels of less than or equal to 50 mmHg before treatment, only high levels of CEA (greater than 20 ng/ml) were associated with a fatal outcome, regardless of anti-PCP therapy associated with corticosteroids.(ABSTRACT TRUNCATED AT 250 WORDS)


Isolation of genital mycoplasmas from blood of febrile obstetrical-gynecologic patients and neonates. In a prospective study, 1156 blood specimens collected from hospitalized febrile obstetrical-gynecologic patients and neonates with suspected sepsis, were inoculated into a conventional biphasic culture medium, Castaneda S and cultures incubated aerobically. 15-24 h later the broth cultures were subcultured to specific media for detection of mycoplasmas. Genital mycoplasmas were isolated in 15 samples (taken from 8 women) and in 2 from 1 neonate. Mycoplasmas and members of the family Enterobacteriaceae were the most frequent significant bacteria isolated from adult specimens. Mycoplasma isolations were associated with either postpartum or postabortum febrile infections in women. Four of the neonates, whose mothers were infected, showed respiratory distress at birth; 1 of them had mycoplasmas in the blood. All febrile states in obstetrical or gynecological patients, and in neonates, should routinely lead to blood cultures for detection of mycoplasmas and ureaplasmas.


Incidence, serogroups and case-fatality rate of invasive meningococcal infections in a Swedish region 1975-1989. In a retrospective study of invasive meningococcal infections in Greater Gothenburg, Sweden, 213 cases of culture-verified meningitis or septicaemia were identified during the 15-year period 1975-1989. The annual incidence was 2.0/100,000. Cases were seen in all age-groups with the highest rates in the 0-4 and 15-19 year-old groups, 9.5 and 6.2/100,000 respectively. 20% of the patients were less than 2 years. 91% of the patients had no known risk factors. In only 10 cases (5%) was contact with another case of meningococcal infection known. The main clinical manifestations were meningitis (57%), septicaemia with no sign of focal infection (25%) and septic shock (17%). The case-fatality rate for all the patients was 6.6% and did not change during the 15-year period. One-third of the patients who presented with septic shock died. The serogroup was known for strains from 192 patients. 51% of the strains belonged to serogroup B, 10% to group A and 23% to group C. In conclusion, the incidence of meningococcal infection was low but the relatively high case-fatality rate warrants a search for effective prophylaxis. About 30% of the cases were potentially preventable by the currently available tetravalent (A, C, Y and W135) polysaccharide vaccine, which is immunogenic in children greater than 2 years. Widespread use of antibiotic prophylaxis to close contacts of known cases would not lower the incidence markedly.


Amplification of DNA by the polymerase chain reaction for the efficient diagnosis of pertussis. The standard diagnostic methods for pertussis have several shortcomings. With the increased knowledge of the Bordetella pertussis genome a specific and conserved DNA sequence, present in about 70-80 copies in each genome, was selected for amplification with the polymerase chain reaction (PCR) technique in order to evaluate its diagnostic potential in children with suspected pertussis. The 400 basepair DNA sequence chosen was present and amplified in all 112 B. pertussis strains and in no other bacterial species examined. The specificity of the amplified material was documented by restriction enzyme cleavage. In nasopharyngeal aspirates a B. pertussis specific PCR product was visualized in 19/25 culture positive and in 5/50 culture negative children. In conclusion the present PCR assay for B. pertussis can be clinically useful and permit a specific diagnosis within 1 day after sampling. Further studies are requested to document its sensitivity, specificity and predictive value for positive and negative results.


Septic complications to sphenoidal sinus infection. Sphenoid sinusitis is an uncommon infection, but an early diagnosis and appropriate treatment is important because of its serious complications. We report 4 patients (28, 28, 37 and 28 years old) admitted to a department of infectious diseases with meningitis, sepsis and orbital cellulitis as complications of acute sphenoidal cavity infection. The cases illustrate the value of computed tomography (CT) scan of the sphenoid sinus in the evaluation of patients with clinical features suspicious of sphenoid sinusitis.


The relative importance of Shigella in the aetiology of childhood gastroenteritis in Saudi Arabia. The role of shigella infection in childhood gastroenteritis was studied over a 2-year period. Shigella species were found in the faecal specimens of 70 (1%) of 7369 children with gastroenteritis, but in only 1 (0.1%) of 1130 controls. S. flexneri was the commonest isolate (51%), followed by S. sonnei (37%). Most shigella species were isolated during the winter. The prevalence of shigellosis was highest for children 1-5 years of age but equal for both sexes. Fever, abdominal cramps, vomiting, and bloody diarrhoea were the predominant clinical features. Of the shigella isolates, 73% were resistant to cotrimoxazole, 43% to ampicillin, and 41% to chloramphenicol. One-third of isolates were resistant to greater than or equal to 3 antibiotics. All isolates were susceptible to nalidixic acid. The illness was mild and self-limiting and most patients recovered without antimicrobial therapy.


Septicemia in granulocytopenic patients: a shift in bacterial etiology. 35 episodes of septicemia in 33 patients occurred among 269 consecutive patients with granulocytopenia (granulocyte cell count less than or equal to 0.5 x 10(9)/l) during the 7-year period 1982-1988. 59% of isolated bacteria were Gram-positive (Staphylococcus aureus, Staph. epidermidis, Streptococcus species and Pneumococcus) and 41% Gram-negative (Pseudomonas aeruginosa, Escherichia coli, Klebsiella pneumoniae, Enterobacter, Acinetobacter and Citrobacter). Compared to the 7-year period 1975-1981, there was a decrease in the relative number of patients with Gram-negative septicemia. Thus, a shift from a predominating Gram-negative etiology in the 1975-1981 period to a predominating Gram-positive etiology in the 1982-1988 period was noted. In both periods the mortality rate was high in patients with Gram-negative septicemia, especially in patients with a Ps, aeruginosa infection.


Endotoxin, TNF-alpha, interleukin-6 and parameters of the cellular immune system in patients with intraabdominal sepsis. The correlation of endotoxin (ET), tumor necrosis factor alpha (TNF-alpha), interleukin-6 (IL-6), and cellular immune parameters with multiple organ failure and lethal outcome in intraabdominal infections was studied in a group of 18 patients with peritonitis, abscess or pancreatitis. Of these patients, 7 developed respiratory failure and 5 died due to multiple septic organ failure. The peak levels of ET (2.7 +/- 1.3 ng/ml) in the course of the disease were followed by moderate increases of TNF-alpha (mean 147 +/- 41 pg/ml) and IL-6 (170 +/- 61 pg/ml) within 2 days. Analysis of the parameters for the last 12 days prior to death or discharge showed, that the patient group with lethal outcome was characterized by significant lower mean plasma levels of TNF-alpha (less than 75 pg/ml versus greater than 160 pg/ml) and IL-6 (less than 130 pg/ml versus greater than 270 pg/ml), as well as high rates of unstimulated thymidine uptake into peripheral mononuclear blood cells (greater than 44000 cpm/8 x 10(6) PMBC/18 h versus less than 24000 cmp), T-lymphocyte depression (CD3; approximately greater than 40% reduction) with lower T-helper/inducer subset cell numbers (mean CD:CD8 ratio 1.0 +/- 0.55 versus 1.8 +/- 0.2) and lower lectin (PHA) stimulation values (1.9 +/- 1.4 versus 4.1 +/- 1.0). These data demonstrate an anergic immune status with low mediator levels and depressed T-lymphocyte function in patients with poor prognosis.(ABSTRACT TRUNCATED AT 250 WORDS)


Child health in arid areas of Ethiopia: longitudinal study of the morbidity in infectious diseases. We describe the incidence of some childhood infections in drought prone areas of southern Ethiopia. Our results are based on 24 months' biweekly observations of 828 children aged 0-5 years in the pastoralist community of Dubluk and the agricultural community of Elka. An average of 23% of the children in Dubluk and 13% in Elka were sick during any 2-week period. Diarrhoeal diseases represented the main cause of morbidity, but the yearly number of diarrhoeal episodes were lower than previously reported from Ethiopia. Respiratory tract infections and to a lesser extent diarrhoeal diseases, showed highest incidence rates during the main dry season. The highest incidence of lower respiratory tract infections coincided with an outbreak of measles. In Dubluk, children who lived near to the wells had higher incidence rates than those who lived further away, probably reflecting the importance of crowding on transmission rates. In Elka, literacy of mothers was associated with reduced incidence of both diarrhoeal and respiratory tract infections, whereas the use of open pit latrines was associated with increased diarrhoeal incidence. The decline in disease incidence in this region during the last months of our study may reflect an improvement of nutritional status.


Intrauterine fetal death due to echovirus 11. In a case of intrauterine fetal death in the 29th week of gestation, echovirus 11 could be isolated from the umbilical cord of the fetus. The mother had no apparent signs of infection but serological evidence of current echovirus 11 infection. Enterovirus PCR performed on paraffin-embedded specimens of various tissues (myocardium, lung, liver and placenta) from the fetus yielded positive results in all cases. These findings, together with supporting serological and epidemiological findings--e.g. proven echovirus 11 infection 3 weeks before in the 18-month-old son of the woman--constituted strong evidence that echovirus 11 infection was responsible for the fetal death.


Hilar lymphadenopathy associated with Chlamydia pneumoniae infection. A 27-year-old man with an acute Chlamydia pneumoniae infection and hilar lymph node involvement is reported. Further investigation gave no evidence of sarcoidosis or other known cause of enlarged hilar nodes. Serological tests proved an acute infection with C. pneumoniae Thus, an infection with C. pneumoniae may lead to enlargement of the hilar lymph nodes, and infection with this microorganism should be included in the differential diagnostic considerations in patients with hilar lymphadenopathy.


Disseminated fungal disease resistant to fluconazole treatment in a child with leukemia. During a chemotherapy induced leukopenic period fluconazole (3 mg/kg/day i.v.) was administered as empiric antifungal treatment in a 5-year-old girl with leukemia and a presumed catheter infection due to Staphylococcus epidermidis. Despite intensive treatment with antibiotics and fluconazole the patient died. In one blood culture Candida krusei was isolated post mortem, and at autopsy Aspergillus fumigatus was found in multiple organs. Both fungi showed high MIC values to fluconazole. We feel that this drug should not be used when the possibility of a systemic infection with an unidentified fungus exists.


Epidemiology of drug resistance: implications for a post-antimicrobial era. In the last several years, the frequency and spectrum of antimicrobial-resistant infections have increased in both the hospital and the community. Certain infections that are essentially untreatable have begun to occur as epidemics both in the developing world and in institutional settings in the United States. The increasing frequency of drug resistance has been attributed to combinations of microbial characteristics, selective pressures of antimicrobial use, and societal and technologic changes that enhance the transmission of drug-resistant organisms. Antimicrobial resistance is resulting in increased morbidity, mortality, and health-care costs. Prevention and control of these infections will require new antimicrobial agents, prudent use of existing agents, new vaccines, and enhanced public health efforts to reduce transmission.


Tuberculosis: commentary on a reemergent killer. Tuberculosis remains the leading cause of death in the world from a single infectious disease, although there is little knowledge of the mechanisms of its pathogenesis and protection from it. After a century of decline in the United States, tuberculosis is increasing, and strains resistant to multiple antibiotics have emerged. This excess of cases is attributable to changes in the social structure in cities, the human immunodeficiency virus epidemic, and a failure in certain major cities to improve public treatment programs. The economic costs of not adequately addressing the problem of tuberculosis in this country are estimated from an epidemiological model.


The crisis in antibiotic resistance.

The crisis in antibiotic resistance. The synthesis of large numbers of antibiotics over the past three decades has caused complacency about the threat of bacterial resistance. Bacteria have become resistant to antimicrobial agents as a result of chromosomal changes or the exchange of the exchange of genetic material via plasmids and transposons. Streptococcus pneumoniae, Streptococcus pyogenes, and staphylococci, organisms that cause respiratory and cutaneous infections, and members of the Enterobacteriaceae and Pseudomonas families, organisms that cause diarrhea, urinary infection, and sepsis, are now resistant to virtually all of the older antibiotics. The extensive use of antibiotics in the community and hospitals has fueled this crisis. Mechanisms such as antibiotic control programs, better hygiene, and synthesis of agents with improved antimicrobial activity need to be adopted in order to limit bacterial resistance.


The origin of plagues: old and new.

The origin of plagues: old and new. Viruses and bacteria emerge in new and old forms to cause disease epidemics. Some microorganisms recur when changing life-styles (including increased international travel) offer new opportunities; others arise from new genetic variations. These various epidemics connect the future with the past, offering lessons for guarding the health of generations to come--lessons learned from diseases such as tuberculosis, toxic shock syndrome, Lyme disease, streptococcal infection, influenza, and acquired immunodeficiency syndrome (AIDS). The public must be vigilant to the possibility of new epidemics, learn more about the biology and epidemiology of microbes, and strengthen systems of surveillance and detection.


Structure-based strategies for drug design and discovery. Most drugs have been discovered in random screens or by exploiting information about macromolecular receptors. One source of this information is in the structures of critical proteins and nucleic acids. The structure-based approach to design couples this information with specialized computer programs to propose novel enzyme inhibitors and other therapeutic agents. Iterated design cycles have produced compounds now in clinical trials. The combination of molecular structure determination and computation is emerging as an important tool for drug development. These ideas will be applied to acquired immunodeficiency syndrome (AIDS) and bacterial drug resistance.


Human and Drosophila homeodomain proteins that enhance the DNA-binding activity of serum response factor. Cells with distinct developmental histories can respond differentially to identical signals, suggesting that signals are interpreted in a fashion that reflects a cell's identity. How this might occur is suggested by the observation that proteins of the homeodomain family, including a newly identified human protein, enhance the DNA-binding activity of serum response factor, a protein required for the induction of genes by growth and differentiation factors. Interaction with proteins of the serum response factor family may allow homeodomain proteins to specify the transcriptional response to inductive signals. Moreover, because the ability to enhance the binding of serum response factor to DNA residues within the homeodomain but is independent of homeodomain DNA-binding activity, this additional activity of the homeodomain may account for some of specificity of action of homeodomain proteins in development.


Trefoil knotting revealed by molecular dynamics simulations of supercoiled DNA. Computer simulations of the supercoiling of DNA, largely limited to stochastic search techniques, can offer important information to complement analytical models and experimental data. Through association of an energy function, minimum-energy supercoiled conformations, fluctuations about these states, and interconversions among forms may be sought. In theory, the observation of such large-scale conformational changes is possible, but modeling and numerical considerations limit the picture obtained in practice. A new computational approach is reported that combines an idealized elastic energy model, a compact B-spline representation of circular duplex DNA, and deterministic minimization and molecular dynamics algorithms. A trefoil knotting result, made possible by a large time-step dynamics scheme, is described. The simulated strand passage supports and details a supercoiled-directed knotting mechanism. This process may be associated with collective bending and twisting motions involved in supercoiling propagation and interwound branching. The results also demonstrate the potential effectiveness of the Langevin/implicit-Euler dynamics scheme for studying biomolecular folding and reactions over biologically interesting time scales.


A mutation in the POU-homeodomain of Pit-1 responsible for combined pituitary hormone deficiency. Pit-1 is a pituitary-specific transcription factor responsible for pituitary development and hormone expression in mammals. Mutations in the gene encoding Pit-1 have been found in two dwarf mouse strains displaying hypoplasia of growth hormone, prolactin, and thyroid-stimulating, hormone-secreting cell types in the anterior pituitary. A point mutation in this gene was identified on one allele in a patient with combined pituitary hormone deficiency. Mutant Pit-1 binds DNA normally but acts as a dominant inhibitor of Pit-1 action in the pituitary.


Mutation of the POU-specific domain of Pit-1 and hypopituitarism without pituitary hypoplasia. A point mutation in the POU-specific portion of the human gene that encodes the tissue-specific POU-domain transcription factor, Pit-1, results in hypopituitarism, with deficiencies of growth hormone, prolactin, and thyroid-stimulating hormone. In two unrelated Dutch families, a mutation in Pit-1 that altered an alanine in the first putative alpha helix of the POU-specific domain to proline was observed. This mutation generated a protein capable of binding to DNA response elements but unable to effectively activate its known target genes, growth hormone and prolactin. The phenotype of the affected individuals suggests that the mutant Pit-1 protein is competent to initiate other programs of gene activation required for normal proliferation of somatotrope, lactotrope, and thyrotrope cell types. Thus, a mutation in the POU-specific domain of Pit-1 has a selective effect on a subset of Pit-1 target genes.


The mouse pink-eyed dilution gene: association with human Prader-Willi and Angelman syndromes. Complementary DNA clones from the pink-eyed dilution (p) locus of mouse chromosome 7 were isolated from murine melanoma and melanocyte libraries. The transcript from this gene is missing or altered in six independent mutant alleles of the p locus, suggesting that disruption of this gene results in the hypopigmentation phenotype that defines mutant p alleles. Characterization of the human homolog revealed that it is localized to human chromosome 15 at q11.2-q12, a region associated with Prader-Willi and Angelman syndromes, suggesting that altered expression of this gene may be responsible for the hypopigmentation phenotype exhibited by certain individuals with these disorders.


Transactivation by AP-1 is a molecular target of T cell clonal anergy. Anergy is a mechanism of T lymphocyte tolerance induced by antigen receptor stimulation in the absence of co-stimulation. Anergic T cells were shown to have a defect in antigen-induced transcription of the interleukin-2 gene. Analysis of the promoter indicated that the transcription factor AP-1 and its corresponding cis element were specifically down-regulated. Exposure of anergic T cells to interleukin-2 restored both antigen responsiveness and activity of the AP-1 element.


[Percutaneous drainage in renal emphysema. Clinical case]. Renal emphysema is a rare and severe infection, that constitutes two clinical entities: emphysematous pyelonephritis and emphysematous pyelitis. We report a case in which the gas is localized both in the collecting system and in the parenchyma of the kidney. In our experience the percutaneous renal drainage has revealed to be able to dominate the infection but not to preserve renal function.


Transperineal vesiculodeferentography under ultrasound control: first experiences. Vesiculodeferentography (VDG) plays an important role in diagnosing male infertility and staging of prostatic cancer; the techniques of performing the examination are, today, well codified: 1) retrograde, by endoscopic cannulation of ejaculatory ducts; 2) anterograde, by cannulation of the deferent duct surgically prepared at the scrotum. In order to avoid the difficulties of the first method and the risks in the second (like stenosis and fibrosis of the deferent duct) we propose a new simple and safe method based on the direct transperineal puncture of the seminal vesicle under direct echographic control with a transrectal probe. We have studied 16 patients, mainly in order to stage prostatic cancer; the procedure was easy to perform, well tolerated and without consequences at seminal level. It required only 30 minutes, without anaesthesia and with a very low cost. The method permits a clear visualisation of anatomical structures and of possible pathologies with particular reference to vesicular invasion by a prostatic cancer.


[Involvement of the urogenital system in HIV virus infection]. Despite the genitourinary system is prone to infections by the Human Virus of Immunodeficiency, so far poor interest has been focused on urological manifestations of AIDS. We thoroughly reviewed the Literature and examined the different patterns of HIV infections on the kidneys, the prostate and the testes. An extensive description is given.


[Pre-peritoneal trans-ileal uretero-cutaneostomy. Apropos of 41 cases]. In the last 15 years we have used a modified version of the classic Bricker for external urine derivation in 41 cases (32 cases of neurobladder and 9 cancer of the bladder). This modification essentially involves placing the ileal loop in front of the peritoneum, in a superficial position which facilitates urethroileal anastomosis especially when trying to prevent reflux. The positioning of the loop greatly reduces urine stasis and ureteral stenosis, which in the classic Bricker is due to the ureter crossing the meso. We hope this technique will be used more widely in view of the excellent results obtained (low morbidity with hardly any complications).


[Urethroplasty for repairing recurrent urethrocele and loss of urethral substance: apropos of 41 cases]. Recurrent urethrocele is not often successfully treated surgically because, as it is well known, pre-operative sterilization of the urethrocele is difficult, especially when it is very large. Furthermore the incomplete excision of the corpus callosum, because of the loss of urethral tissue this involves, often leads to post-operative fistulas and stenoses. This is why, very often, there are relapses no matter what technique is adopted. In 1978 both Juraschek and ourselves published a technique, derived from Monseur, in which the urethrocele and the corpus callosum were completely excised. The resulting loss of urethral tissue was remedied with the albuginea from the ventral surfaces of the corpora cavernosa after a 180 degrees rotation of the urethra. The results of this treatment in 41 cases of recurrent urethrocele are given in this paper. The follow-up period for the patients was from 15 to 2 years. Results have been excellent with very few complications (2 post-operative fistulas and 2 urethra stenoses). There have been no relapses.


[Concentration of aztreonam in plasma, urine, and seminal fluid of patients with chronic prostatitis]. The authors consider the concentration of antibacterial drugs in the seminal fluid as a reliable experimental model for the study of pharmacokinetics in chronic prostatitis (c.p.). The study was conducted on 32 subjects, 20 of whom were affected by c.p. and 12 were normal controls. All subjects were treated with aztreonam at a dosage of 1 g.i.m. The assay was performed 1 hour after the injection, on seminal fluid, urine and serum samples. No difference was observed between normal subjects and patients with c.p. with regard to serum and urinary levels of the drug. There was a trend towards a higher concentration of the drug in the seminal fluid of patients with c.p. when compared to normal subjects, with mean values of 1.8 and 0.9 mcg/ml respectively. This difference was not statistically significant. Furthermore, the drug concentration of the drug in semen was below the sensitivity limits of the assay in 43% of normal subjects and in 10% of patients with c.p. In the latter group of patients the mean values of aztreonam concentration exceeded the minimal inhibitory concentrations for most aetiological agents causing c.p. In conclusion, it is suggested that aztreonam is likely to be effective in acute prostatitis, caused by Gram negative strains and may be indicated in selected cases for the treatment of c.p.


Extracorporeal shock wave lithotripsy for urinary stone disease: our experience. The authors report results of an 18 month study on ESWL treatment for calculosis of different tracts of the urinary apparatus. Average success rate is 80%, even if it varies depending on the site and size of the calculus. Surgery and PCN are required only in cases of unsuccessful treatment or particular forms of lithiasis. ESWL has determined advanced in the treatment of renoureteral stones in the last decade. However some significant generalized complications observed in our patients at follow-up raise doubts concerning possible, unforeseable long term effects of ESWL treatment.


[Metabolism and action of L-carnitine: its possible role in sperm tail function]. The authors report a review on the L-carnitine effects on the male genital tract. L-carnitine represents a cofactor in the transport of long chain fatty acids inside mitochondria and their subsequent oxidation. Therefore, its main role is that of intramitochondrial vehicle of acyl groups. In particular, the effects of L-carnitine on the male genital function seem connected mainly with the high concentration of L-carnitine in the epididymis; the uptake of the L-carnitine from the blood is an active, in part androgen-dependent, mechanism. Moreover, epididymal spermatozoa are able to concentrate L-carnitine (while they become progressively more impermeable to such a substance) during their passage from the caput to the cauda epididymis. The main function of the L-carnitine in the epididymis is to give to the spermatozoa an energetic substrate. In fact, this function should be of great importance since the epididymal spermatozoa employ fatty acid oxidation for their energy metabolism; on the contrary, the ejaculated sperm employ glycolytic process. As a consequence of the above-mentioned effects of L-carnitine the dosage of this substance in the evaluation of the integrity of the processes of maturation of the spermatozoa was proposed. Finally, there is growing interest in the use of L-carnitine as a therapeutic tool in some forms of male infertility.


Granulocyte-macrophage colony-stimulating factor (GM-CSF): preclinical and clinical investigations. In conclusion, hematopoietic growth factors have been shown to enhance the recovery and function of circulating WBCs after standard-dose cancer therapy or high-dose cancer therapy with ABMT, and preliminary data strongly suggests that these agents may have the ability to restore leukocyte numbers and competence in AIDS, myelodysplastic syndromes, and other marrow failure states. Phase I and II trials of GM-CSF in patients with AIDS, cancer, marrow failure states, and following bone marrow transplantation have been published, and limited phase III randomized trial experiences have been reported as well. Overall, GM-CSF represents a fascinating molecule with which to modulate human hematopoiesis in vivo. The multilineage stimulatory effects of GM-CSF that are evident in vitro have not been striking or consistent in clinical trials. However, the effects of GM-CSF on the production and function of mature neutrophils, monocytes, and eosinophils have been noted in the vast majority of clinical scenarios in which this cytokine has been tested. The clinical benefits of GM-CSF have, to date, only been proven in large-scale randomized studies of recovery from ABMT for lymphoid neoplasms. However, further data regarding the use of GM-CSF in other clinical settings have been generated, and the final results are eagerly anticipated by the oncology community. The beneficial effects of GM-CSF following ABMT consisted not only of a shorter period of absolute neutropenia, but also fewer significant infections, a diminished requirement for intravenous antibiotic administration, and a shorter overall duration of inpatient hospitalization. The use of GM-CSF in clonal disorders of hematopoiesis, such as myelodysplasia or myeloid leukemias, requires caution before such applications can be routinely recommended, and the demonstration of safety in this setting from large randomized trials will be needed. Preliminary data from small randomized trials suggests that the incidence of evolution to leukemia in patients with myelodysplasia and the number of patients with regrowth of leukemia after induction treatment in relapsed patients with AML may not be significantly different than in patients who do not receive GM-CSF. Various neutropenic conditions (eg, idiopathic or congenital) may respond clinically to hematopoietic growth factors such as GM-CSF. Patients treated for 3 to 15 months continue to respond with significantly increased granulocytes and resolution of prior infection. The subcutaneous route of administration is convenient and patients seem to accept it readily. It is difficult to determine the extent to which adjunctive therapy with GM-CSF will be cost effective.(ABSTRACT TRUNCATED AT 400 WORDS)


Molecular targets to overcome radioresistance. Our laboratory has cultured cells from 23 patients with head and neck carcinoma and 13 patients with soft tissue sarcoma. The data suggest that, in some patients, inherent tumor cell radioresistance contributes to radiotherapy failure. This paper examines possible mechanisms that lead to increased cell survival following radiation exposure, and their potential as targets to overcome the radioresistant patient population.


Biochemical pharmacology of chemotherapeutic drugs used as radiation enhancers. Radiotherapy and chemotherapy are often administered concurrently in an attempt to take advantage of postulated biochemical or molecular interactions between the two modalities. It is generally assumed that the drugs influence some mechanism of radioresistance rather than that radiation has any direct effect on the mechanisms of cell kill by chemotherapy. Many classes of drugs have been found to interact with radiation. Classic radiosensitizing agents include the halogenated pyrimidines and the nitroimidazoles; however, many conventional cytotoxic agents, such as hydroxyurea, 5-fluorouracil (5-FU) and cisplatin, also enhance cell kill by radiotherapy. Hydroxyurea has been shown to inhibit excision-repair of thymine dimers and single-strand DNA breaks induced by radiation. Exposure of cells to 5-FU following radiation produces synergistic cytotoxicity in several model systems. The precise cellular mechanisms by which 5-FU and radiotherapy interact have not been defined, although inhibition of repair of radiation-induced DNA damage has been postulated to occur. Cisplatin has also been shown to enhance the cytotoxicity of radiation in both cell culture and tumor-bearing animals, although the mechanisms of the interaction have not been defined. Hydroxyurea, 5-FU, and cisplatin also undergo a number of biochemical interactions that enhance their cytotoxic effects. Thus, a rationale exists for employing these drugs in combination with radiation. Additional studies are required to understand the mechanisms of drug-radiation interactions and to determine the optimal scheduling of these therapies.


The experimental and clinical rationale for the use of S-phase-specific radiosensitizers to overcome tumor cell repopulation. Clinical and laboratory evidence suggests that several common human cancers contain populations of rapidly proliferating clonogens that may have a substantial impact on local control following conventional radiotherapy. Strategies to improve locoregional control include the use of S-phase-specific radiosensitizers, such as the halogenated pyrimidine analogues (5-iododeoxyuridine, 5-bromodeoxyuridine, fluorodeoxyuridine, 5-fluorouracil) and hydroxyurea. These drugs are taken up and metabolized only by cells synthesizing DNA so that increased tumor proliferation should result in increased radiosensitization. Although the initial clinical trials with these agents were inconclusive, several recent reports have rekindled interest in these radiosensitizers. Ongoing laboratory research has provided further insight into the basic mechanisms of radiosensitization. However, many questions remain unanswered. We will review the data that suggest rapid tumor proliferation, experimental studies with the S-phase-specific drugs, and the results of clinical trials. We will also consider the possible design of future trials based on our current understanding of tumor proliferation and the mechanisms of radiosensitization of S-phase-specific agents.


Use of hypoxia-directed drugs in the therapy of solid tumors. Solid tumors in experimental animals and human patients contain areas in which transient or persistent perfusion deficits lead to the development of hypoxia, low pH, and nutritional deprivation. These microenvironmental inadequacies induce resistance to ionizing radiation and to many antineoplastic drugs, but also offer mechanisms that can be used to target certain drugs to solid malignancies. Regimens incorporating hypoxia-directed drugs as adjuncts to radiotherapy or conventional chemotherapy can be used to increase the therapeutic ratio by increasing local tumor control without producing a concomitant increase in toxicities to normal tissues.


Simultaneous treatment with single-agent chemotherapy and radiation for locally advanced cancer of the head and neck. A substantial proportion of patients with squamous cell carcinoma of the head and neck have extensive locoregional disease at presentation. While extensive surgical procedures may completely eradicate local disease with acceptable morbidity for smaller tumors, in patients with stage III and IV disease, high local relapse rates and relatively short survival times still characterize the course of the majority of such patients. For patients with locally unresectable disease, the combined use of chemotherapy and radiation has resulted in encouraging data both in terms of local control and survival. Combined-modality programs frequently employ platinum coordination complexes, and standard or hyperfractionated radio-therapy toxicity data suggest that the overall tolerance of such programs is acceptable and, more important, long-term follow-up has shown that function can be largely preserved. In this review we illustrate the experience with combined single-agent chemotherapy and radiotherapy, and discuss the methodologic difficulties of clinical trials in this setting. We describe our experience with combined carboplatin and simultaneous conventional radiation in patients with extensive unresectable locoregional disease. Encouraging results and modest toxicity clearly support further testing with this approach, especially in patients with less advanced and bulky disease.


Perspectives on combination chemotherapy with concomitant radiotherapy for poor-prognosis head and neck cancer. Concomitant chemoradiotherapy has resulted in small increases in disease-free or overall survival for patients with advanced head and neck cancer when single-agent chemotherapy is used. To increase the efficacy of this approach, combination chemotherapy also has been explored. In this setting, acute toxicities are frequently increased, necessitating interruption or protraction of radiotherapy. Despite this fact, pilot trials using 5-fluorouracil-based chemotherapy have indicated high response and encouraging survival rates. Some of these trials will be reviewed, with a focus on studies with 5-fluorouracil, hydroxyurea, and cisplatin conducted at the University of Chicago.


Treatment of locoregional esophageal cancer. Since the mid 1970s combined-modality treatment has been investigated for locoregional cancer of the esophagus. Single-institution pilot studies of preoperative cisplatin-based chemotherapy have shown that 40% to 60% of patients with squamous cell carcinoma achieve a partial response, while an occasional patient has a pathologically documented complete response (CR). Two randomized trials involving small numbers of patients have not confirmed the survival benefit for preoperative chemotherapy that some pilot studies suggested. A large, multicenter intergroup trial is in progress, comparing preoperative and postoperative cisplatin/5-fluorouracil chemotherapy with immediate surgery, and includes both squamous cell carcinoma and adenocarcinoma histologies. Preoperative chemoradiotherapy programs have used survival and pathologic CR as end points. Single-institution and multicenter pilot studies have consistently reported pathologic CR in 25% to 30% of patients. Median survivals have varied from 12 to 29 months. The results from multicenter pilot trials are at the lower end of this range, with more encouraging results coming from single institutions. One randomized trial in progress compares a 3-week intensive cisplatin/vinblastine/5-fluorouracil and concurrent radiotherapy regimen followed by surgery with immediate surgery. No completed comparative trials have been published. Chemoradiotherapy without surgery is a more recent approach stimulated both by the poor survival rates with primary surgery and by its associated morbidity and mortality. The results of the intergroup randomized trial of concurrent cisplatin 5-fluorouracil/radiotherapy versus radiotherapy alone have demonstrated a role for chemotherapy. Median survival and 12- and 24-month survival improved significantly with the combined-modality treatment. This treatment program is now recommended for patients with locoregional disease who are not candidates for surgery. The optimal management of patients with esophageal cancer is still unknown. Accurate methods to stage patients clinically and to identify prognostic factors are needed. The randomized trials in progress evaluating preoperative and postoperative chemotherapy and preoperative chemoradiotherapy are essential to move forward with improved treatment strategies.


Malignant mesothelioma: diagnostic and management strategies for 1992. Malignant mesothelioma of the pleural and peritoneal surfaces is epidemiologically linked to crocidolite, a long, thin, and rigid form of asbestos whose use has been dramatically curtailed within the past 20 to 25 years. The incidence of disease may have peaked around 1984 and may now be declining. The highest incidence of disease occurs in elderly white men (greater than or equal to 75 years old). The histology of mesothelioma is classically biphasic, with both epithelioid and sarcomatous areas present. Independent pathologic review can be useful, and a variety of special stains should be used, if diagnosis is unclear. Electron microscopy and serum carcinoembryonic antigen levels are also useful. Surgical treatments have been difficult, but 3-year survival rates range from 15% to 36%. Unfortunately, only about 20% of all diagnosed patients are candidates for aggressive surgical approaches. Radiotherapy likewise has been disappointing, although occasionally useful. Lastly, 13 single-agent chemotherapy trials conducted on 302 patients using 10 different commercially available drugs have failed to identify a consistently effective agent. Combination chemotherapy has also not proven effective and, therefore innovative new approaches are needed.


Therapeutic relevance of pharmacokinetics and pharmacodynamics. Most antineoplastic drugs have a narrow therapeutic index. The medical world's incomplete understanding of the variability of pharmacokinetics and pharmacodynamics has led to dosing problems with these agents. Basic understanding of linear and nonlinear pharmacokinetic models as well as interpatient and intrapatient variability is necessary to optimize dosing. Pharmacodynamic information relates pharmacokinetic information to clinical outcome.


Concurrent chemoradiation in carcinoma of the uterine cervix. Carcinoma of the cervix is most commonly treated with radiotherapy when the disease is locally advanced. Tumor bulk often limits the efficacy of this therapy, as does the tolerance of adjacent healthy tissue. Cytotoxic chemotherapeutic agents have been used with concomitant radiotherapy. Extensive data are available on dose and schedule tolerance for cisplatin, 5-fluorouracil, and a number of combination regimens. Phase III data that confirm any advantage in terms of local control, disease-free survival, or overall survival have been published only for hydroxyurea. Hydroxyurea, an S-phase-specific inhibitor of ribonucleotide reductase, lacks single-agent activity against metastatic, squamous cell cervical cancer. Further studies are required before agents other than hydroxyurea can be considered standard therapy with concomitant radiotherapy for locally advanced carcinoma of the cervix.