Precipitation of morphine withdrawal syndrome in rats by administration of mu-, delta- and kappa-selective opioid antagonists. The acute effects of opioid drugs are generally hypothesized to be mediated by multiple receptors, for which three types of binding sites have been established. In order to evaluate the selective participation of each type of opioid receptor in opiate withdrawal, the opiate withdrawal syndrome, precipitated by the intraventricular acute administration of mu-, delta- and kappa-selective opioid antagonists was investigated. After implantation of the cannula into the lateral ventricle, rats were made physically dependent by subcutaneous insertion of two 75-mg pellets of morphine (base). D-Phe-Cys-Tyr-D-Trp-Arg-Thr-Pen-Thr-NH2 (CTAP) (5-5000 ng), a mu-selective opioid antagonist, naltrindole (62-2000 ng), a delta-selective antagonist or nor-binaltorphimine (nor-BNI) (600-20,000 ng), a kappa-selective antagonist, were administered 72 hr after implantation of the pellets. All three drugs elicited some signs of morphine withdrawal but they differed in both their potency and their efficacy. The most efficacious and the most potent was CTAP, eliciting 8 of the 14 withdrawal signs at doses of 5-5000 ng. Nor-BNI was less efficacious and less potent, eliciting a significant increase in 5 of the 14 withdrawal signs in a dose range of 600-20,000 ng. Naltrindole was the least potent and least efficacious of the three drugs, eliciting a significant increase of only 2 withdrawal signs after intraventricular administration of 2000 ng. In a second experiment, the withdrawal syndrome was precipitated by the combined administration of CTAP+naltrindole or CTAP+nor-BNI. The severity of withdrawal, obtained with these two combinations, was similar to that observed with CTAP alone. These results support the importance of the mu receptor in the expression of central opiate dependence and suggest a minor role for delta and kappa receptors.


Desipramine desensitizes beta-adrenergic signal transduction in rat salivary glands. The consequences of the tricyclic antidepressant drugs include sedation, orthostatic hypotension and salivary dysfunction. It was reported that administration of desipramine resulted in a decrease in the concentration of secreted salivary protein. Tricyclic antidepressants may indirectly alter salivary function as a result of their action on the central nervous system to decrease adrenergic neural transmission or, alternately, may act directly on salivary glands to modulate beta-adrenergic signal transduction. To investigate the latter possibility, the effects of administration of desipramine (DMI) for 28 days was assessed on beta-adrenergic and post-receptor signal transduction in the parotid and submandibular glands of the rat and the reversibility of this treatment following a washout period of 15 days. Both glands demonstrated desensitization of the isoproterenol-stimulated activity, and in the parotid gland treatment with DMI decreased the post-receptor signal transduction as well. The washout period of 15 days completely reversed the desensitization in the parotid gland and partially reversed the effects in the submandibular gland. These data suggest that desipramine-induced attenuation of beta-adrenergic signal transduction is not limited to the brain and that these direct effects on salivary glands may explain the salivary dysfunction observed after administration of desipramine.


Structure-activity relationship study of R396, an NK2 tachykinin antagonist selective for the NK2B receptor subtype. We report on a structure-activity study of R396 (Ac-Leu-Asp-Gln-Trp-Phe-Gly-NH2), a linear hexapeptide tachykinin antagonist selective for the putative NK2B receptor subtype. Asp2, Trp4 and the C-terminal glycinamide have been challenged by classical amino acid substitutions with the aim of elucidating the structural requirements responsible for NK2 subtype selectivity. The biological activities indicate that Asp2 has a crucial role for the high affinity of R396 at the NK2B subtype: none of the analogues substituted in position 2 display higher affinity as compared to R396, regardless of the nature of the residue introduced. Trp4 has been replaced by other aromatic residues, again yielding weak antagonist or inactive compounds. Finally, the C-terminal amide appears to be crucial for affinity, the free acid analogue being devoid of biological activity. On the other hand, antagonistic activity is maintained both by the desGly pentapeptide and by the analogue bearing beta Ala in place of Gly in position 6. In conclusion, since the NK2B selectivity pattern was maintained throughout the whole series of R396 replacement analogues, we speculate that the overall conformational features of this family of linear hexapeptides favour the interaction with the NK2B receptor subtype.


Heterogeneity of tachykinin NK-2 receptors in rabbit, guinea-pig and human smooth muscles. Recent evidence indicates that the tachykinin NK-2 receptor is heterogenous (subtypes/species variants) and the existence of NK-2A (or 'non-classical') and NK-2B (or 'classical') forms of the NK-2 receptor in mammalian tissues has been proposed. In this study we have compared the affinities of 7 linear octa- and heptapeptide derivatives of neurokinin A (4-10) and that of two cyclic hexapeptides endowed with selective NK-2 receptor antagonist properties in 5 mammalian smooth muscle preparations previously characterized as expressing the NK-2A receptor subtype (rabbit pulmonary artery and bronchus, guinea-pig bronchus, human ileum and colon) and 2 preparations previously characterized as expressing the NK-2B receptor subtype (rat vas deferens and hamster trachea). The results of this comparative study reinforce the concept of two broad categories of preparations expressing pharmacologically distinguishable forms of the tachykinin NK-2 receptor and suggest the possibility of a further heterogeneity within the previously defined NK-2A receptor subtype.


Vasoactive intestinal peptide is a secretagogue in bovine chromaffin cells pretreated with pertussis toxin. Vasoactive intestinal peptide (VIP) evokes little or no secretion of catecholamines from cultured bovine chromaffin cells. However, pretreatment of chromaffin cells with pertussis toxin (PTX, 100 ng/ml for > or = 4 h) revealed that VIP is a secretagogue. In PTX-treated cells catecholamine secretion evoked by VIP occurs with minimal elevation of cyclic AMP and is only slightly enhanced by cyclic nucleotide phosphodiesterase inhibitors. Forskolin, a direct activator of adenylate cyclase, causes delayed secretion of catecholamines from chromaffin cells treated with PTX, but only with pronounced elevation of cyclic AMP levels. Stimulation of catecholamine secretion by histamine, known to activate phosphatidylinositol-specific phospholipase C in chromaffin cells, is also enhanced by preincubation of the cells with PTX. These results suggest that in the bovine chromaffin cell a PTX-sensitive G-protein mediates tonic inhibition of secretion, possibly by preventing activation of phospholipase C.


Bilateral carpal tunnel release at one operation: report of 228 patients. The division of the transverse carpal ligament for relief of carpal tunnel syndrome has been a standard operative procedure since the early 1950s. The surgical technique, however, is controversial, and the literature is rife with individual preferences and biases. This report describes our results in 228 tensor fasciae patients who underwent a bilateral carpal ligament release in one procedure that used a small transverse incision in the wrist crease. When the patients' responses to a questionnaire, records of postoperative visits, and follow-up phone calls were analyzed, 216 patients (94.7%) had a satisfactory outcome. One hundred fifty-five patients were working before surgery, with 88.3% back to work in 6 weeks or less. There were no major complications.


Invasiveness of primary and secondary brain tumors in vitro correlated with clinical results. One hundred fifty-one tumor fragments were collected in the neurosurgical operating amphitheater immediately after removal. Small tumor fragments were transferred into culture flasks and cultured until a confluent monolayer was formed by the outgrowing cells. Flaps of these cell monolayers were mechanically scraped from the culture flasks and confronted with embryonic chick heart tissue in vitro. The evolution of the confrontations was followed for a week. Histological analysis of the confrontations demonstrated three different morphological patterns of interaction between the heart tissue and the tumor-derived cells: 1) progressive engulfment of the tumor-derived cells by the heart tissue (Type I), 2) survival of both the heart tissue and the tumor-derived cells (Type II), and 3) progressive replacement of the heart tissue by tumor-derived cells (Type III). The replacement of the heart tissue by tumor-derived cells was only observed in cells originating from malignant tumors that were invasive and metastatic in vivo. Thus, invasiveness in confrontation culture is correlated with malignancy in vivo.


The effect of age on motor and cognitive deficits after traumatic brain injury in rats. Age is one of the most important predictors of outcome after human traumatic brain injury. This study used fluid percussion brain injury to investigate the effects of aging on outcome after brain injury in rats. Three-month-old (n = 8) and 20-month-old (n = 11) rats were injured at a low level (1.7-1.8 atm) of fluid percussion brain injury or received a sham injury (n = 6 for both age groups). Body weight and motor function (beam balance and beam walking) were assessed before injury and for the first 5 days after injury. Cognitive outcome was assessed with the Morris water maze on Days 11 to 15 after injury. Injury did not produce significant weight loss in either age group. At the low level of brain injury used in this study, the 3-month-old rats did not demonstrate any significant motor deficits on the beam-balance or beam-walking tasks. However, the 20-month-old rats displayed significant beam-balance deficits on each of the 5 postinjury test days and significant beam-walking deficits for the first 3 postinjury days. Although Morris water maze performance was impaired in both age groups, the magnitude of impairment was greater in the aged animals. These data demonstrate that traumatic brain injury in the aged animal is marked by increased motor and cognitive deficits, in the absence of pronounced compromise of the animal's general health.(ABSTRACT TRUNCATED AT 250 WORDS)


Successful treatment of an arteriovenous malformation by chemical embolization with estrogen followed by conventional radiotherapy. A case of the successful treatment of a thalamic arteriovenous malformation (AVM) by chemical embolization with conjugated estrogen followed by conventional radiotherapy is described. A 22-year-old woman suddenly developed headache, nausea, and consciousness disturbance. Computed tomographic scans revealed left thalamic and ventricular bleeding. Angiograms disclosed a left thalamic AVM with a maximum diameter of 2 cm. The AVM was fed mainly by the left medial posterior choroidal artery and drained into the basal vein. Chemical embolization with 300 mg of conjugated estrogen via a leak balloon catheter was carried out. Although the size of the nidus of the AVM was unchanged immediately after embolization, it became smaller 9 days later. In spite of the further reduction in size, the AVM still existed 2 years later. Conventional radiotherapy with a total dose of 30 Gy was performed. Follow-up angiograms 40 months after radiotherapy demonstrated disappearance of the AVM. This case report suggests progressive and stable embolizing capabilities of chemical embolization with conjugated estrogen and its suitableness for following radiotherapy, including stereotactic radiosurgery.


'Early' thyroid 123I uptake: correction for extrathyroidal neck radioactivity. Should one correct for extrathyroidal neck radioactivity ('neck background') when interpreting perchlorate discharge test results? A new background correction method was developed using a linear probe. 123I produces photon peaks at two energy levels: 159 keV (gamma-rays) and 28 keV (X-rays), with an attenuation of 15 and 35% per cm water, respectively. If one fixes the position of the subject's neck, radiation from thyroid 123I produces an X/gamma detection ratio (alpha) which is constant and, due to the anterior localization of the thyroid, higher than the ratio (beta) produced by extrathyroidal 123I. These two ratios can be determined in vivo and used to calculate background-corrected and depth-corrected thyroid uptake. In simulation experiments our method was effective so long as the 'gland' was situated close enough to the 'neck' surface for the difference (alpha-beta) to be less than 0.19. Perchlorate discharge tests were performed in five euthyroid subjects who were pretreated with methimazole. The difference (alpha-beta) ranged from 0.27 to 0.36. Uncorrected, the mean discharge was 57% (range 47-66); corrected, it was 92% (range 88-94). In 15 hyperthyroid Graves' patients, with goitres varying from 13 to 63 ml, alpha-beta ranged from 0.22 to 0.40 and was unrelated to goitre size. The contribution of neck background is quantitatively important, especially when thyroid uptake is low; our new method corrects for it, even with large goitres.


Mast cell stabilizers.

Mast cell stabilizers. The precise mode of action of the well-studied cromolyn sodium and the newer nedocromil sodium has not been completely elucidated. Because the drugs do not pass the cell membrane and enter the cell, they are virtually not metabolized, do not exert a systemic action, and therefore are associated with only minimal systemic toxicity. To be effective either drug must be applied topically and directly to the nasal mucosa. Proper contact with the nasal mucosa is essential for efficacy; in patients with nasal congestion and secretions, vasoconstrictors or saline lavages are indicated before cromolyn or nedocromil use. Both products are highly effective in patients who have IgE-mediated allergic rhinitis but must be administered prophylactically before exposure to an allergen to prevent development of the allergic event. Neither drug is effective in vasomotor rhinitis, exercise-induced rhinitis, or in the management of nasal polyps. Correct diagnosis is essential before therapy.


Peripheral primitive neuroectodermal tumors. Diagnosis, classification, and prognosis. In conclusion, the group of peripheral primitive neuroectodermal tumors has been redefined in recent years on the basis of cytogenetic, molecular genetic and more precisely defined histopathologic characteristics. Although in the past, many tumors has been called Ewing's sarcoma, currently this diagnosis is limited to tumors which cannot be more specifically classified on the basis of their ultrastructural and immunophenotypic characteristics. Most small round cell tumors previously classified as Ewing's sarcoma are now classified as peripheral PNET. The consistent cytogenetic abnormality in Ewing's sarcoma and peripheral PNET and patterns of neurotransmitter enzymes have supported a common neuroectodermal origin. The precise characterization of soft tissue Ewing's sarcoma is further complicated by the several primitive rhabdomyosarcomas that may exhibit a similar light microscopic appearance. The importance of histopathologic distinction among these various round cell tumors of childhood is well recognized. Furthermore, primitive tumors with overlapping neural and mesenchymal features, known as malignant ectomesenchymoma, are now identified more often than previously. Finally, molecular biologic and cytogenetic differences between peripheral PNET and neuroblastoma have confirmed their clinical and biologic differences, in spite of their morphologic similarities. Molecular genetic and flow cytometric evaluation have contributed to the distinction of groups with prognostic significance and offer possibilities for new clinical trials.


Effect of dietary calcium on tibial dyschondroplasia. Interaction with light, cholecalciferol, 1,25-dihydroxycholecalciferol, protein, and synthetic zeolite. A series of experiments was conducted to investigate interactions of dietary calcium levels with ultraviolet light, cholecalciferol (D3), 1,25-dihydroxycholecalciferol [1,25-(OH)2D3], dietary protein, and a synthetic zeolite on the development of tibial dyschondroplasia in broilers. A basal diet low in calcium, high in phosphorus and chloride, and known to promote a high incidence of tibial dyschondroplasia was used. The chicks received ultraviolet radiation from fluorescent lights in addition to 1,100 ICU/kg (27.5 micrograms/kg) of D3 in the basal diet when these were not experimental variables. Regardless of whether the calcium level was low (.65%) or adequate (.95%), the incidence of tibial dyschondroplasia was significantly lower in chicks receiving ultraviolet radiation or dietary vitamin D3 levels well above the required amounts. The addition of 10 micrograms/kg of 1,25-(OH)2D3 to the diet when calcium levels varied from .45 to .95% resulted in a reduction in the incidence of tibial dyschondroplasia and increased tibial bone ash when dietary protein levels were 18 or 22%. The addition of 1% synthetic zeolite to the diet did not influence the incidence of tibial dyschondroplasia when the diet contained widely varying dietary calcium levels (.65 to 1.81%) and .73% phosphorus.


Mandatory HIV testing for healthcare workers: is it ethical? The AIDS epidemic has caused hysteria among the public and concern to many healthcare workers in the past 12 years. Currently, legislation exists for mandatory AIDS testing in some populations. The questions remain: Should healthcare workers be routinely tested? If so, is mandatory testing ethical? The author explores the incidence and prevalence of AIDS among healthcare workers, discusses why mandatory testing for healthcare workers is an issue, and examines the legal and ethical principles involved in mandatory testing.


[Heart or heart-lung transplantation and toxoplasmosis]. Among all organ transplantations, those of heart or heart-lung carry the greatest risk of toxoplasmosis. The disease is observed mainly when the donor is seropositive and the recipient seronegative. In these mismatched couples the risk may be as high as 57 percent. Cardiac tissue transplants are responsible for most contaminations. A subclinical serological reactivation can be observed in seropositive recipients. Patent forms are associated with seroconversion in seronegative subjects. Toxoplasmosis is often severe with multivisceral foci; interstitial pneumonia is possible. The serological diagnosis is easy in cases with significant antibody movements, but it may be difficult if the titre is low or stable. The parasitological diagnosis rests on the isolation of toxoplasma in blood, cerebrospinal fluid, bronchoalveolar lavage fluid and cardiac or cerebral biopsy. Immune defence against toxoplasmosis is primarily cellular, with lymphocytosis and inversion of the CD4/CD8 ratio. Macrophages play a crucial role. Interferon-gamma is the major mediator of cellular resistance. In spite of its immunosuppressive action, cyclosporin clearly has an antiparasitic action in vitro and in vivo. A cytomegalovirus infection might facilitate toxoplasma reactivation. Prevention of toxoplasmosis in transplant recipients includes systematic serology of the recipient and, if possible, the donor, detection of mismatched couples and systematic treatment with pyrimethamine of recipients at risk (in seronegative recipients, this drug has reduced the risk from 57 to 14 percent). Cyclosporin should be used as immunosuppressant in preference to other drugs of this kind. Corticosteroids administered in rejections increase the risk of toxoplasmosis.


The effect of single and prolonged ethanol administration on the sensitivity of central GABA-A and benzodiazepine receptors in vivo. The response of GABA-modulin to various doses of diazepam and muscimol was used as an index of the sensitivity of central benzodiazepine and GABA-A receptors, respectively. Diazepam and muscimol induced a dose-dependent increase in cytosol GABA-modulin activity in rat nucleus accumbens, hippocampus and cerebellum. A single dose of ethanol (1 g/kg po) potentiated the action of diazepam and muscimol. Prolonged treatment with ethanol (5 g/kg/day for 21 days) did not affect the action of diazepam. In contrast, the effect of muscimol was greatly reduced. In the rats pretreated for 21 days with ethanol five times higher doses of muscimol than in control group were necessary to induce a statistically significant increase of GABA-modulin in the cytosol of the nucleus accumbens, hippocampus and cerebellum. Those results show that a single dose of ethanol enhances GABA-ergic transmission, whereas prolonged treatment with ethanol induces subsensitivity of GABA-A but not benzodiazepine receptors in the limbic system and in cerebellum.


Has the increase in selenium intake led to a decrease in caries among children and the young in Finland. Finland is poor in selenium. Selenium deficit leads to muscular dystrophy in animals. Since 1962, selenium has been added in Finland to some animal foodstuffs, since 1968 to all animal foodstuffs. Addition of selenium to fertilizers started in 1984. Intake of selenium by man and cattle today is roughly 1.0 times higher than it was before selenium supplementation. Collagen is the most important component of the organic matrix of the tooth. Selenium can replace sulphur in bonds of collagen. The resulting bond is stronger than a sulphur bond. Since selenium supplementation, the conditions of the teeth of children and young people has improved considerably. The author believes that selenium supplementation has reduced the incidence of caries in young Finns.


Placental phagocytic cells infected with herpes simplex type 2 and echovirus type 19: virological and ultrastructural aspects. Placental macrophage cells were kept in a short-term culture and infected with herpes simplex type 2 virus and echovirus type 19. These were observed under optical and electron microscopy. Immunofluorescence, virus titration and autoradiographic technique were used to determine if the virus was replicating in the system. The results showed that the placental phagocytic cells do not allow virus growth and that the virus particles are destroyed right after virus uptake, within 4 h post-infection. The increase of lipid bodies and other cellular alterations suggested the intensive action of these cells against viruses.


Combination of 5-FU cisplatinum and hypofractionated irradiation followed by split-course radiotherapy in 47 patients with unresectable non small cell lung cancer. Forty-seven patients with unresectable non small cell lung carcinoma, 15 stage IIIA, 31 stage IIIB, 1 stage IV (cervical lymphadenopathy) were treated with a combination of three courses of chemotherapy and hypofractionated irradiation followed after 3 weeks by split course radiotherapy. Each course was repeated every 3 weeks with the following sequence: Cisplatinum (CDDP) (20 mg/m2) was given in a 20-min infusion, followed by a 2-h infusion of 5-fluorouracil (5-FU) (400 mg/m2) on days 1, 2, 5 and 6. Radiation with a dose of 3 Gy on the target volume was given on days 3 and 4--in one fraction for the former 27 patients, in 2 fractions of 1.5 Gy for the latter 20 patients with a 6-h interval--after a 2-h infusion of 5-FU (400 mg/m2). The results remain disappointing: the objective response rate was 53%, the median survival was 10 months for the series, and the one-year survival 47%. The median survival was 14 months for IIIA, 10 months for IIIB and IV. Regarding the therapeutic regimen there seems to be less morbidity with 2 fractions per day for which the median survival is nearly the same at 10 months (1 fraction/day) versus 12 months (2 fractions/day).


Prostaglandin E2 synthesis elicited by adrenergic stimuli in guinea pig trachea is mediated primarily via activation of beta 2 adrenergic receptors. Prostaglandin (PG) E2 synthesis elicited by adrenergic agonists in the guinea pig trachea has been shown to be mediated via activation of beta-adrenergic receptors. The purpose of this study was to examine arachidonic acid (AA) metabolism and to characterize the subtype of beta receptor involved in PG synthesis. [14C]AA was incubated with guinea pig tracheal rings, and the radiolabelled products were extracted from the medium. Thin layer chromatographic analysis and radioimmunoassay of the extract showed that [14C]AA was incorporated into guinea pig tracheal rings and metabolized mainly into radiolabeled and immunoreactive PGE2 (iPGE2) and smaller amounts into PGF2 alpha. Trace amounts of PGD2, TxB2 and 6-keto-PGF1 alpha but not LTB4 or LTC4 were detected by enzyme immunoassay. Incubation of guinea pig tracheal rings for 10 min with isoproterenol or salbutamol resulted in a significant increase in PGE2 synthesis (optimum concentration 0.1 microM for both compounds). In contrast, dobutamine, BRL 37344, BRL 28410, norepinephrine, phenylephrine, and xylazine (up to 1 microM) did not significantly increase PGE2 production. Isoproterenol-induced iPGE2 production was inhibited by the selective beta 2 receptor antagonist butoxamine (0.1-1.0 microM) and somewhat reduced by the beta 1 receptor antagonist practolol (1 microM). The increase in PGE2 synthesis was diminished with increasing concentrations of isoproterenol (0.5-5.0 microM) or salbutamol (0.5-1.0 microM); but it was reversed by pretreatment of tracheal rings with the protein synthesis inhibitors cycloheximide (0.9 microM) and actinomycin D (2 microM) but not by phenylisopropyl adenosine (0.1-1.0 microM), an inhibitor of adenylyl cyclase. These data suggest that isoproterenol-induced iPGE2 synthesis is primarily via activation of a beta 2 adrenergic receptor. Failure to enhance iPGE2 synthesis by a high concentration of isoproterenol is likely to be due to an induction of new inhibitory protein synthesis.


N-acetylcysteine in combination with radiotherapy in the treatment of non-small cell lung cancer: a feasibility study. N-Acetylcysteine (NAC) is a free radical scavenger and could therefore act as a radioprotector. To test the feasibility of administering NAC in combination with radiotherapy, we studied 10 patients with inoperable non-small cell lung cancer who were receiving hyperfractionated radiotherapy (RT) of 1.25 Gy B.I.D. (6-h interval) up to a total dose of 60 Gy/48 fractions/32 days. They were given NAC concomitantly with RT: 100 mg/kg i.v. 30 min before the first RT session followed by 30 mg/kg as an i.v. infusion over 7 h; and 600 mg inhaled 30 min before and after each RT session. The patients were assessed by serial CT scans and lung function studies during a 1-year follow-up period. The treatment regime was feasible, but expensive in time and resources. Normal tissue reactions and tumour responses were similar to those in a control group.


Sexual morbidity following radiotherapy for germ cell tumours of the testis. An anonymous questionnaire study was designed to assess sexual function after orchidectomy and radiotherapy for testicular cancer. Questionnaires were sent to: (1) 237 patients treated with orchidectomy and abdominal radiotherapy in Edinburgh from 1974 to 1988; (2) 32 patients under "surveillance" following orchidectomy alone; (3) 402 "normal" age-matched controls. All were asked questions concerning sexual function over the preceding 6 months. All the patients were also asked the same questions with reference to the first 6 months after completion of treatment. Completed questionnaires were returned from 137 (62%) radiotherapy patients, 18 (56%) surveillance patients and 121 (35%) controls. There was a significant difference between the radiotherapy patients and the controls in almost all the parameters looked at including erection, ejaculation and libido with the treated group performing less well. In addition, almost 24% of the radiotherapy patients felt disabled or disfigured by the treatment, most commonly because of the presence of only one testicle. A deterioration in sexual function was observed with increasing age. In the radiotherapy group of patients there was no difference in response between the two time periods or in any of the treatment variables. The clinical significance of these observations are unclear but together with the increasing information on other toxicities emerging following this therapy the role of radiation for early stage seminoma is being brought into question. This study also confirms the morbidity of orchidectomy. We suggest that testicular implants should be offered more widely.


Lung cancer in young patients.

Lung cancer in young patients. During 1981-1986 the Edinburgh Lung Cancer Group prespectively registered 3560 new patients with lung cancer of whom only 48 (1.3%) were aged less than 45 years. When compared with 3512 older patients aged more than 45 years, a similar proportion of young patients were female (17/48; 35% vs. 28% of the older patients) and had equally advanced disease (30/48; 62% vs. 58% in stage III). Slightly more young patients were in better Karnofsky performance status groups (28/48; 59% vs. 45%, score > 80) and duration of symptoms was considerably shorter (median 45 vs. 93 days); only three of the younger patients were non-smokers. A pathological diagnosis was obtained more often in young patients (47/48; 98% vs. 81%). The commonest cell type was small cell (16/48; 34% vs. 24%) with 10/48 adenocarcinoma (20% vs. 13%) and less squamous carcinoma (11/48; 23% vs. 48%). Although only 12/48 young patients (25% vs. 19%) underwent surgical resection, six of these were still alive after 5 years (50% vs. 30% in older patients). More young patients received chemotherapy either alone (14) or combined with radiotherapy (6)--42% vs. 16% in older patients. There were no long-term survivors and the median survival was 8 months in 13 patients with small cell and only 4 months in seven with non-small cell carcinoma.


[Acute infections caused by Epstein-Barr virus. Comparative study of various diagnostic methods]. Comparative performance of four methods (IFI, IgM anti-VCA, Organon Teknika; ELISA, IgM anti VCA, Incstar Corp and Pharmacia Diagnostic Inc; ELISA IgM against a group of several antigens which principal component is EBNA, Behring Institute) to detect antibodies (Abs) against Epstein-Barr virus in 180 patients (group 1) with infectious mononucleosis with no heterophil Abs (Organon Teknika), 180 healthy subjects with no heterophil Abs (group 2) and 20 patients with infectious mononucleosis (group 3) and with positive heterophil Abs, were studied. In group 1, 10% of patients had IgM Abs, without differences IgM Abs. In group 3 all patients had IgM Abs with no differences in the methods studied. There were no differences in the performance of the evaluated methods to detect IgM against different antigens, but those which use a group of antigens from the virus could be more useful in patients immunologic disorders.


[Evaluation of the effect of enalapril, a converting enzyme inhibitor, on lymphocytic beta-adrenergic receptors of patients with chronic cardiac insufficiency]. We have previously corroborated that lymphocyte beta-adrenergic receptor density is significantly reduced in patients with chronic heart failure. It is well known that angiotensin converting enzyme inhibitors normalize the function of sympathetic nervous system. We have assessed the effect of enalapril on lymphocyte beta-adrenergic receptor system from patients with chronic heart failure (n = 14) using a random, cross and double blind protocol. Our results show that the improvement in clinical score and ventricular function were not related with changes in the number and affinity of beta-adrenergic receptor nor cyclic AMP content in lymphocytes obtained from these patients.


Reduction and inactivation of the sarcoplasmic Ca(2+)-ATPase by 2-mercaptoethanol--contrast to the (Na+,K+) ATPase. The sarcoplasmic Ca(2+)-ATPase was reduced with 300 mM 2-mercaptoethanol at elevated temperatures (40-45 degrees C) with a concomitant loss of ATPase activity. The reduction and inactivation of the Ca(2+)-ATPase proceeded rapidly in the absence of Ca2+. The Ca(2+)-ATPase was also inactivated with 2-mercaptoethanol in the presence of diluted SDS (0.4 mg/ml) even at 20 degrees C. In contrast to the (Na+, K+) ATPase, the inactivated Ca(2+)-ATPase in the presence of diluted SDS was sedimented by the centrifugation at 100,000 x g for 30 min.


[Comparison of some enzymatic methods for dietary fiber determination in foods]. Comparison of three different enzymatic techniques for dietary fibre determination (Hellendoorn, Asp, AOAC)) in five kinds of food (white bread, rye rolls, white cabbage, carrot and red beet) was the main purpose of this study. It was found that our results obtained by Hellendoorn's method are overestimated and therefore are somewhat doubtful. For this reason the AOAC method can be recommended as more accurate.


Vibrotactile function of the hand in compression and vibration-induced neuropathy. Sensibility index--a new measure. The perception thresholds for vibration stimuli of the hand at seven frequencies (8-500 Hz) were evaluated in 300 patients referred to the Department of Hand Surgery in Malmö during the years 1985-1990 for various types of neuropathy (carpal tunnel syndrome, vibration-induced neuropathy, cervical rhizopathy, brachialgia, ulnar neuropathy, radial tunnel syndrome, and polyneuropathy). A sensibility index was calculated by dividing the integrated area under the obtained vibrogram curve of each object tested (areaT) by that of the corresponding area under a superimposed and age matched reference curve (areaR). Sensibility index of less than 0.8 was regarded as the cut off value. The index and little fingers bilaterally were tested to reflect median and ulnar nerve function. There were considerable variations in patterns of pathology among the various groups of patients. In patients with unilateral carpal tunnel syndrome only 10 patients (23%) had abnormalities limited to one recording, while 21 patients (47%) showed abnormalities in all four recordings. This indicates that an isolated carpal tunnel syndrome may reflect more generalised disease of the peripheral nervous system.


Retinoids selective for retinoid X receptor response pathways. Retinoids have a broad spectrum of biological activities and are useful therapeutic agents. Their physiological activities are mediated by two types of receptors, the retinoic acid receptors (RARs) and the retinoid X receptors (RXRs). RARs, as well as several related receptors, require heterodimerization with RXRs for effective DNA binding and function. However, in the presence of 9-cis-retinoic acid, a ligand for both RARs and RXRs, RXRs can also form homodimers. A series of retinoids is reported that selectively activates RXR homodimers but does not affect RAR-RXR heterodimers and thus demonstrates that both retinoid response pathways can be independently activated.


Cloning of a delta opioid receptor by functional expression. Opiate drugs have potent analgesic and addictive properties. These drugs interact with receptors that also mediate the response to endogenous opioid peptide ligands. However, the receptors for opioids have eluded definitive molecular characterization. By transient expression in COS cells and screening with an iodinated analog of the opioid peptide enkephalin, a complementary DNA clone encoding a functional delta opioid receptor has been identified. The sequence shows homology to G protein-coupled receptors, in particular the receptors for somatostatin, angiotensin, and interleukin-8.


Postoperative pulmonary toxicity associated with mitomycin-C therapy. As more patients survive cancer, and as more sophisticated multidrug antineoplastic protocols are developed, the chances of an anesthesiologist's coming into contact with patients who have been treated with such protocols are increasing. The anesthesiologist who must administer anesthesia to a patient who has had chemotherapy must be cognizant of the particular antineoplastic agents that have the potential for producing occult pulmonary dysfunction. Anesthetic management of these cases must be carefully planned and titrated to prevent further lung injury.


Mechanisms by which benzo[a]pyrene, an environmental carcinogen, suppresses B cell lymphopoiesis. The capacity for polycyclic aromatic hydrocarbons (PAH) to suppress immune cell function has been well documented. Nevertheless, mechanisms responsible for PAH immunosuppression and potential effects of PAH on lymphocyte development (lymphopoeisis) remain poorly defined. Murine bone marrow cultures were used in the present studies to determine if and by what mechanism(s) benzo[a]pyrene (B[a]P), a prototypic and highly carcinogenic PAH, suppresses B cell lymphopoiesis. Emphasis was placed on similarities between the processes leading to transformation and immunosuppression and on a possible role for programmed cell death (apoptosis) in B[a]P lymphotoxicity. Data presented herein indicate that: (1) B[a]P suppresses B cell lymphopoiesis in bone marrow cultures at extremely low concentrations (10(-8) M); (2) benzo[e]pyrene, the relatively noncarcinogenic congener of B[a]P, is approximately 1000 times less potent than B[a]P in suppressing B cell lymphopoiesis; (3) bone marrow cells from PAH-resistant DBA/2 mice are less sensitive to B[a]P than cells from C57BL/6 mice; (4) B[a]P induces preB cell apoptosis; and (5) alpha-naphthaflavone, an inhibitor of Ah-receptor dependent, P450 isoenzyme activity, blocks B[a]P-mediated preB cell apoptosis and inhibits B[a]P-dependent suppression of lymphopoiesis. The results support the hypothesis that B[a]P suppression of B cell lymphopoiesis is mediated at least in part by the induction of programmed cell death and that the Ah receptor and/or P450 isoenzymes are involved in this process. The results suggest the potential for PAH to affect development of the B lymphocyte repertoire.


Modulation of pulmonary immune defense mechanisms by sulfuric acid: effects on macrophage-derived tumor necrosis factor and superoxide. There is considerable interest in the potential health effects resulting from inhalation of acidic aerosols. However, except for well documented irritant effects and acid-induced changes in lung clearance function, other potential health effects have not been well defined. This study was designed to provide further insight regarding the relationship of sulfuric acid aerosol to the pathogenesis of respiratory disease by describing the effects of inhaled acid on the release and/or activity of biologically active mediators critical for maintaining pulmonary immunocompetence and resistance against infectious diseases. Results of this study demonstrated that a single inhalation exposure of rabbits to environmentally relevant and higher concentrations of sulfuric acid depresses the release/activity of lipopolysaccharide-stimulated tumor necrosis factor-alpha and also reduces the ability of pulmonary macrophages to produce superoxide anion radical in response to opsonised zymosan. These findings should be considered when evaluating the health risks associated with sulfuric acid exposure.


The molecular mechanism of peroxisome proliferator action: a model for species differences and mechanistic risk assessment. An increasing number of chemicals that produce tumours in rodent bioassays belong to the non-genotoxic class of carcinogens. There are no suitable tests for these carcinogens and our understanding of their mechanism of action is poor. Importantly, assessment of their potential hazard to man is usually difficult without extensive research. Peroxisome proliferators (PP) are a diverse group of rodent non-genotoxic carcinogens that include hypolipidemic drugs, plasticizers and herbicides. We have reported previously the cloning of a member of the nuclear hormone receptor superfamily and, through the use of chimeric receptors, discovered that it could be activated by PPs. The receptor is therefore termed the PP activated receptor (PPAR). The most widely used marker of PP action is the peroxisomal beta-oxidation enzyme acyl CoA oxidase (ACO). Interestingly, it has been speculated that the hydrogen peroxide produced as a result of ACO activity could lead to DNA damage and tumorigenesis. We have now demonstrated that PPAR recognizes a specific PP response element (PPRE) located in the ACO gene promoter and that the response is dependent upon the presence of receptor and the addition of the PP Wy-14,643. These data therefore support a model in which the mechanism of PP action is mediated by PPAR in a manner similar to that of steroid hormone action. Learning more about the function of PPAR offers a unique opportunity to understand the mechanism of action of some non-genotoxic carcinogens. Furthermore, this knowledge when combined with comparison of receptor expression between rodents and man will be important in providing a framework for a new threshold model of risk assessment based upon receptor-mediated carcinogenesis.


The evolution of toxic effluents in fires and the assessment of toxic hazard. Toxic hazard in fire depends upon three factors: the fire growth curve (mass loss rate of materials, kg/min) and volume dispersal (kg/m3), the yields of toxic products (e.g. kg CO/kg fuel burned) and the toxic potency of the products (exposure dose needed to cause toxic effects, e.g. lethal dose of CO in ppm.min). The first and second sets of data are obtainable from large-scale tests or small-scale tests and mathematical modelling, the third and some information on the second are derived from toxicity studies of combustion products in small-scale tests or of individual fire gases. Small-scale toxicity test data on materials expressed as lethal mass loss exposure doses (LCt50 g min m-3) can be used in Fractional Effective Dose (FED) hazard assessments, providing the decomposition conditions of the test reproduce those in the fire being examined; principally either non-flaming oxidative, early well-ventilated flaming, or vitiated post-flashover. Although bioassays are needed for a full toxicity assessment, it is now possible to predict the toxic potency of materials to some extent from analytical data alone. The suitability of the small-scale test decomposition conditions are determined in terms of non-flaming or flaming behaviour, temperature (or radiant flux), CO2/CO ratio and oxygen concentration. Existing small-scale test methods provide reasonable models for materials under non-flaming oxidative and early flaming conditions, although the data base for the latter is poor. Only the DIN 53436 method is able to model vitiated post-flashover decomposition conditions, but data for this condition are almost non-existent.


The development of a new small-scale smoke toxicity test method and its comparison with real-scale fire tests. A comprehensive methodology has been developed for obtaining and using smoke toxicity data for fire hazard analysis. This bench-scale method can simulate diverse fire conditions and identify extremely toxic smoke under both pre- and post-flashover conditions. However, incidence data show that most of the fire deaths in the U.S. occur outside the room of fire origin from smoke and toxic gases that are generated from a fire under post-flashover conditions. Therefore, the most relevant real-scale combustion conditions to simulate in the bench-scale apparatus would be the post-flashover conditions which are achieved by using radiant heat, a high heat flux, and correcting the bench-scale carbon monoxide (CO) results to agree with CO yields observed in real-scale post-flashover fires. The number of test animals (Fischer 344 male rats) is minimized by using the N-Gas Model to estimate the LC50 value from the chemical analysis of the smoke. The current N-Gas Model predicts the toxicity of complex fire gas mixtures based on a large data base of experimental results of individual and mixed gases that include CO, CO2, reduced O2, HCN, HCl, HBr, and NOx. The prediction is checked with a small number of animal tests and an approximate LC50 value is determined. The bench-scale results have been validated with full-scale room wall burns of a limited number of materials of widely differing characteristics chosen to challenge the system. The toxic potency values are assessed to determine if the smoke from a material or product is unusually or extremely toxic and can then be used in computations of fire hazard.


Modeling of toxicological effects of fire effluents: prediction of toxicity and evaluation of animal model. Methodology for the prediction of the toxic effects of fire effluents has made considerable progress [1,2]. As emphasized by Hartzell [2] a limiting factor has often been the availability and quality of analytical input data. The Finney model [3] was used to predict the lethal potency and would appear to have utility as a tool in reducing the number of experimental animals used in material testing. However, pilot bioassay data are indispensable to validate the prediction and to categorize fire effluents into narcosis inducing, irritant or of causing unusual or unexpected toxicity. The comparison of predicted and actually observed carboxy-hemoglobin levels is considered to be a sensitive but indirect tool to assess whether major effects on respiration occurred. All laboratory combustion toxicity methods suffer from several types of limitations. However, they might be expected to be relatable to at least some stages of actual fires. Due to a lack of a clearly defined 'generation process'--if compared with conventional inhalation toxicity studies--the classification into broad categories of relative toxic potency seemed to be more appropriate than an absolute classification scheme.


Ca(2+)-dependent mechanisms of cytotoxicity and programmed cell death. There is increasing evidence that the calcium ion plays a critical role in both toxic cell killing and programmed cell death. Thus, in a variety of experimental systems a perturbation of intracellular Ca2+ homeostasis due to increased Ca2+ influx and/or inhibition of Ca2+ extrusion has been found to be an early event in the development of cell injury. It is clear that sustained increases in intracellular Ca2+ can activate cytotoxic mechanisms which result in perturbations of cellular structure and function. For example, the stimulation of Ca(2+)-dependent proteases can result in a disruption of cytoskeletal organization and the formation of surface protrusions (blebs) and Ca(2+)-mediated phospholipase activation can result in an impairment of mitochondrial function with collapse of membrane potential and cessation of ATP synthesis. The activation of a Ca2+, Mg(2+)-dependent nuclear endonuclease is associated with chromatin cleavage and appears to play a crucial role in programmed cell death (apoptosis) in the immune system and other tissues. There is also recent evidence that this process may be responsible for the immunotoxicity of dioxins and organotin compounds and involved in the killing of adenocarcinoma cells by tumor necrosis factor alpha. Although calcium ions appear to be required for endonuclease activity during apoptosis, this process is also influenced by other factors, e.g. protein kinase C activity, intracellular polyamine and Zn2+ levels, chromatin structure, etc. Thus, the regulation of endonuclease activity under both physiological and toxicological conditions appears to be complex and to involve multiple factors.


Naturally-occurring excitatory amino acids as neurotoxins and leads in drug design. The central excitatory neurotransmitter (S)-glutamic acid (Glu) activates at least three types of receptors the NMDA, AMPA, and kainic acid (KAIN) receptors. These receptors mediate the neurotoxicity of a number of naturally-occurring Glu analogues. Thus, domoic acid, a KAIN receptor agonist, has probably been the cause of severe neurologic illness in people who consumed domoic acid poisoned food. beta-N-oxalylaminoalanine (beta-ODAP), an AMPA receptor agonist, has been associated with lathyrism, a spastic paraparesis caused by dietary intake of Lathyrus sativus. The neurotoxic Amanita muscaria constituent ibotenic acid, a nonselective NMDA receptor agonist, has been used as a lead structure for the development of the specific NMDA receptor agonist AMAA, AMPA, and a number of therapeutically interesting AMPA and KAIN receptor agonists.


Role of GABA in the genesis of chemoconvulsant seizures. The direct or indirect interference with GABA-mediated neurotransmission results in convulsive seizure activity in humans and experimental animals. When this convulsant effect is experimentally analyzed, it turns out to be a product of discrete and restricted cerebral sites of drug action. Depending upon the brain circuitry affected, different convulsant patterns are produced. Acute interference with GABA transmission in convulsant trigger sites in the forebrain evokes convulsant seizures which can be clearly distinguished from those evoked by interference with GABA transmission in the hindbrain convulsant sites. While acute alterations of forebrain seizure susceptibility do not change hindbrain seizure susceptibility, chronic or repeated exposure to seizures may cause simultaneous "kindling" of both systems. In addition to the specific convulsant sites of action of GABA antagonists in the brain there are specific sites where GABA antagonists exert an anticonvulsant action. The ability of a chemical agent to evoke a convulsive seizure by interfering with GABA transmission depends upon the relative effect of the agent on GABA transmission in different brain areas as well as its effect on other excitatory and inhibitory neurotransmitters with which GABA interacts.


Role of reactive oxygen species in cell toxicity. Several types of compound exert their cytotoxicity by generating reactive oxygen species, notably the superoxide anion radical. These include quinoid and nitroaromatic compounds serving as redox cyclers, i.e. producing superoxide at the expense of NADPH and oxygen catalyzed by cellular reductases. In specialized cell-types employed in defense such as granulocytes, eosinophils and macrophages, myeloperoxidase, NADPH oxidase and nitric oxide synthase have been identified as major sources of reactive oxygen species in cell toxicity. These include hypochlorite, singlet oxygen, superoxide, nitric oxide and hydrogen peroxide. The interaction of superoxide and nitric oxide generates further oxidants such as peroxynitrite. Lumino-amplified chemiluminescence generated by Kupffer cells is partially sensitive to inhibitors of NO synthase. Superoxide dismutase has been found to catalyze a novel reaction, the reversible conversion of nitric oxide to the nitroxyl anion, the latter being viewed as another form of EDRF. In the defense against oxidative damage, there are enzymatic and nonenzymatic antioxidants. Regarding compounds used pharmacologically, we have been interested in ebselen, a seleno-organic compound exhibiting GSH peroxidase activity, which protects against reactive oxygen species generated, for example, at reoxygenation following a period of hypoxia. Further, we have studied lipoate and dihydrolipoate as antioxidant redox system and as singlet oxygen quencher, e.g. protecting against damage of deoxyguanosines in plasmid DNA generated by singlet oxygen.


Molecular and cellular basis for adequate metabolic design of genotoxicity studies. Genotoxic species and metabolites are usually under the control of a complex set of activating, inactivating and precursor sequestering enzymes. These enzymes differ greatly between test systems, animal species and man. An adequate metabolic design of genotoxicity studies requires careful attention to factors such as: Dilution of cofactors in in vitro tests which are present in much higher concentrations in the intact cell; Induction in high dose carcinogenicity bioassays of enzymes, which are constitutively not expressed and not induced at such doses of the compound, which occur in the situations of the practical use of the compound; Modifications of control enzymes, which are effected by hormones or other endogenous factors, which are differently influenced by high dose (bioassay) versus moderate dose (real exposure) or by in vivo (endocrine regulation) versus in vitro (no endocrine regulation) conditions.


Induction of apoptosis in cultured hepatocytes and in the regressing liver by transforming growth factor-beta 1 occurs without activation of an endonuclease. In previous studies in vivo apoptotic liver cells were found to be positive for transforming growth factor-beta 1 (TGF-beta 1). In hepatocyte cultures TGF-beta 1 induced rounding up and fragmentation of the cells into multiple vesicles. As revealed by the DNA specific stain H33258 the chromatin of these cells condensed and segregated into masses at the nuclear membrane, followed by nuclear fragmentation. Ultrastructurally the cytoplasm was well preserved as demonstrated by the presence of intact cell organelles. These features strongly suggest that occurrence of apoptosis. Furthermore we administered TGF-beta 1 in vivo using an experimental model in which regression of the liver was initiated by a short preceding treatment with the hepatomitogen cyproterone acetate (CPA). Two doses of 1 nM TGF-beta 1/kg each augmented the incidence of apoptotic hepatocytes 5-fold. These studies strongly suggest that TGF-beta 1 is involved in the initiation of apoptosis in the liver In TGF-beta 1 treated hepatocytes both from the liver and monolayer culture no DNA fragmentation into oligosomes could be detected. Comparison of nuclei in which endonuclease was activated by Ca2+ with apoptotic nuclei revealed no obvious similarities, as demonstrated by FACS analysis, H33258 staining and electron microscopy. Thus, apoptosis induced by a growth inhibitor obviously occurs without activation of an endonuclease.


Regulation of phospholipase C by G proteins. Specific phospholipase C enzymes can hydrolyse phosphatidylinositol 4,5-bisphosphate into two products: inositol 1,4,5-trisphosphate, which regulates the release of intracellular calcium stores, and diacylglycerol, which can stimulate protein kinase C. A new group of G proteins, the Gq subfamily, have recently been shown to mediate the regulation of this activity by a variety of hormones. How do different members of this family modulate unique phospholipase C isozymes? What is the mechanism of this regulation? How might the Gq subfamily act to modulate other important second messenger pathways? The tools to answer these questions are being rapidly developed.


[Angina pectoris after sumatriptan (Imigran)]. Developed for the treatment of migraine, sumatriptan is an agonist of 5-hydroxytryptamine-1-receptors. Though a pressure sensation is a common complaint, significant ECG changes have not been reported after subcutaneous administration of sumatriptan. A case history is given where angina pectoris after sumatriptan self-administration was experienced on two occasions by a 61-year old man with a history of minor myocardial infarction--without post-infarction angina--two years previously. The angina after sumatriptan was accompanied on both occasions by significant ST-segment depression on ECG-monitoring. An extracranial vasoconstrictor action of sumatriptan in patients with ischaemic heart disease is suggested.


Imaging of Wilms' tumor: what is important! The imaging of Wilms' tumor needs to be quite focused so that the oncologist and surgeon can most precisely stage the patient before operation. The imager needs to be exact about the extent of the primary tumor and define any invasion into the adjacent soft tissues. The ability to detect nodal disease is quite difficult but clearly influences the preoperative approach and staging. Children with large tumors extending across the midline in whom primary resection may lead to tumor spillage are prime candidates for preoperative chemotherapy, and the imager has significant input in making this decision. The imager must define metastases in the lungs and the liver and evaluate the risk of bilateral tumor (particularly metachronous) by searching the index kidney for multifocal lesions or nephroblastomatosis in either kidney.


Partitioning of hepatitis C virus during Cohn-Oncley fractionation of plasma. Because of concern about the safety of immune globulins with respect to transmission of hepatitis C, the partitioning of hepatitis C virus (HCV) during alcohol fractionation of a plasma pool prepared exclusively from anti-HCV-reactive donations was examined. Quantitation of HCV RNA was accomplished by nested polymerase chain reaction (PCR) at limiting dilutions. One PCR unit was arbitrarily defined as the minimum amount of HCV RNA from which an amplified product could be detected. The starting plasma pool contained 1.4 x 10(5) PCR units per mL. Most of the HCV RNA was found in cryoprecipitate and in Cohn fractions I and III, but it was also detected in fraction II, which is used for immunoglobulin G preparations. A 3.4-percent solution of IgG prepared from this fraction II contained 30 PCR units per mL. The fractionation process leading to immune globulin resulted in overall reduction in HCV RNA by a factor of 4.7 x 10(4). Although the presence of HCV RNA in the final product does not necessarily imply the presence of infectious virus, this work suggests that the safety of immune globulins with respect to HCV transmission is not due solely to the partitioning of HCV away from the immunoglobulin fraction.


Preventive strategies against poliomyelitis. Successful poliomyelitis prevention depends upon the epidemiological characteristics of the infection and the immune status of the population in the area. Presently available polio vaccines may prove very useful for progress with polio control, provided the prevention programme has been adequately chosen and the limitations of the vaccine used have been taken into consideration. In the present and near future, polio prevention should aim at the containment and local elimination of the paralytic disease, which can be obtained with either OPV or E-IPV. The vaccine-associated disease remains an unsolved issue in an OPV programme. The association of OPV and E-IPV offers a clear advantage over the immunization with a single vaccine, particularly with OPV alone. Global eradication of polio, possible in principle, will be difficult to achieve by the year 2000, because of the present global dimensions of polio infection and the unequal environmental development of the world.


[Spontaneous and experimental hepatitis A in Papio hamadryas]. Data on high susceptibility of Papio hamadryas to HAV are presented. For the first time, P. hamadryas were shown to be able to respond to both natural and experimental infection developing the features typical of hepatitis A: increased aminotransferase activity, virus shedding in feces, production of anti-HAV IgG and IgM, histological liver lesions. An infection lingering for 3-4 months was observed, as well as a case of chronic experimental hepatitis A with relapse in 7 months of the disease. Virological evidence of HAV infection was obtained in both lingering and chronic disease. HAV-PH strain was isolated for the first time and is described at length. It was isolated from a baboon with spontaneous infection which did not differ from that in man by antigenic and morphological features. The virus replicated in continuous African green monkey kidney cell line (AGMK) and was pathogenic for P. hamadryas. The HAV-PH isolate can be used for modelling hepatitis A in P. hamadryas.


[The serodiagnosis of viral hepatitis C and B in different population groups]. Data on the frequency of detection of serological markers of hepatitis C and B viruses using enzyme immunoassay for examinations of blood donors in different regions of the country, of patients with hepatitis of obscure etiology and patients with hemophilia regularly receiving hemostatic therapy are presented. The rate of detection of antibody to hepatitis C (anti-HCV) in reserve donors varied from 2% (Baltic states) to 9.2% (Moldavia), that of the carrier state of HBsAg from 0.3% to 10.3%, respectively. Among patients with hepatitis of obscure etiology, anti-HCV was found in 9-18%. A higher rate of anti-HCV was found in donors with high levels of aminotransferases (18.75%) and in patients with hemophilia (77.6%). Epidemiological serological surveys of group incidence of hepatitis revealed a high portion of incidence of virus hepatitis C (from 50 to 90%).


[The effect of herpesvirus infections on the results of a kidney allograft]. It was shown to be necessary to control the level of antibody to cytomegalovirus in order to improve the selection of donor-recipient pairs. High antibody titres to cytomegalovirus constitute one of contraindications against allotransplantation.


Current status and prospects of live varicella vaccine. Since its development in 1974 the Oka strain live attenuated varicella vaccine has been tested in healthy and immunocompromised adults and children. Its safety and efficacy have been established and it is now licensed for general use in Japan and Korea, and for immunocompromised patients in several other countries. Possibilities for the future include its use to prevent zoster in the elderly, its incorporation in a multivalent vaccine and its use as a vehicle to express foreign genes in recombinant vaccines.


New approaches to vaccination against foot-and-mouth disease. The economically important foot-and-mouth disease has been successfully controlled in Western Europe by comprehensive immunization using killed vaccine. The author discusses the wisdom of abandoning this policy, and outlines research into alternative vaccines using recombinant DNA technology, in particular using synthetic peptides.


[Reversible fixation of the small intestine for minimizing radiation damage with polyglycolic acid mesh--initial experiences]. In ten patients with tumors of the small pelvis the bowel was fixed to the upper abdomen by use of Polyglycolic acid mesh (Dexon) to minimize radiation associated small bowel injury. In one case formation of abscess was seen ducto suture dehiscence of the rectal stump which could successfully be handled by lavage. No severe disturbance of bowel motility was seen. By sonographic and barium controls it could demonstrated that it was possible to keep the small intestine above the radiation fields as long as it was necessary for radiation treatment. After 3-4 months it could be demonstrated that the small bowel had descended into the pelvis again.


[Interrupted suture versus adhesive dressing in skin closure of pediatric inguinal hernia--a controlled randomized prospective study]. The skin closure with resorbable interrupted sutures (Dexon 6x0) was compared with adhesive plasters (Leukostrip) in a randomized prospective clinical trial with 100 children with an inguinal hernia. The same operative technique was used in both groups. There were no significant differences referring to the complication rates and the cosmetic results between both groups. Skin closure with adhesive plasters significantly saved operation-time and reduced costs. It can be recommended in cases of infantile inguinal hernias.


Serum vitamin D metabolites and calcitriol receptor concentration in parathyroid tissue in primary hyperparathyroidism. Vitamin D metabolites in serum and calcitriol receptor concentration in parathyroid tissue were examined in 52 patients operated on for primary hyperparathyroidism. The calcitriol receptor levels were not different in parathyroid adenomas (mean 224 fmol/mg of protein, range 29-509, N = 43), normal parathyroid tissue (mean 245, range 31-690, N = 20), and primary parathyroid hyperplasia (mean 172, range 46-477, N = 9). Preoperative serum levels of calcitriol concentration correlated inversely to the calcitriol receptor in normal parathyroid tissue in patients with adenoma (r = -0.57, N = 17, p = 0.017), but no such correlation was found in the corresponding adenomas (r = 0.14, p = 0.59). In 31 patients in whom both pre- and postoperative vitamin D metabolite analyses were carried out, 23 had lower calcitriol postoperative concentrations compared to preoperative values (p = 0.012, sign test). No change was found in the other vitamin D metabolites postoperatively. By multiple regression analysis calcitriol concentration in serum was inversely correlated to the serum concentration of urea and phosphate (p = 0.003). We conclude that calcitriol may influence calcitriol receptor expression in normal parathyroid tissue, but not in adenomatous parathyroid gland. Furthermore, serum calcitriol was correlated to the renal function, and phosphate level, and in most patients the calcitriol concentration was lower after the operation.


Effects of ketoconazole on the iodide uptake by FRTL-5 cells. Ketoconazole is an imidazole derivative used as an antimycotic agent with reported effects on the endocrine system, but very little is known about its possible actions on thyroid function. Our purpose was to study the influence of this substance on the basal and TSH-stimulated iodide uptake in the rat thyroid cell strain FRTL-5. Ketoconazole (1-50 mumol/l) was shown to slightly increase the basal iodide uptake but, at higher concentrations (75-100 mumol/l), it sharply decreased iodide uptake below the basal levels. When the cells were cultured under bTSH stimulation (30 UI/l), the inhibitory effect of ketoconazole was exerted at concentrations as low as 25 mumol/l. This inhibition was observed even if it was added to the culture medium immediately before the Na125I addition. Forskolin, a stimulator of adenylate cyclase activity, was unable to prevent the iodide uptake inhibition. Low doses of ketoconazole increased cAMP concentrations. In the presence of TSH this effect was more evident in an inverse dose-dependent way. Because of its dual action, it can be assumed that ketoconazole could influence the iodide uptake in the FRTL-5 cells through more than one mechanism.


Neurofilament and glial alterations in the cerebral cortex in amyotrophic lateral sclerosis. According to the literature, only minor nonspecific histopathological lesions are present in the motor cortex in up to 90% of the amyotrophic lateral sclerosis (ALS) patients. These observations, however, have so far been based mainly on conventional staining techniques. An exception to this is the focal glial reaction that has been reported following immunocytochemical staining for glial fibrillary protein (GFAP), which is reported to be distinctive for ALS in the cortex. Since perikarya of degenerating motor neurons in the spinal cord of ALS patients have been found to accumulate phosphorylated neurofilaments (PNF), an investigation was conducted to determine whether PNF was also a sensitive marker for alterations in the motor cortex in this condition. On large brain sections from 15 ALS patients, intense PNF immunoreactivity was found in the motor cortex from 11 patients. It was mainly localized in small pyramidal cells and basket cells, whereas only slight staining was observed in Betz cells. PNF-positive basket cells were also present in controls, but the basket cells staining for PNF were less numerous in controls than in ALS specimens. PNF-positive Betz cells were found in 47% of 15 ALS patients and in 10% of the controls. PNF accumulation was also found in swollen, probably degenerating, terminal boutons around perikarya of large pyramidal cells and Betz cells in the motor areas of ALS patients only. These observations suggest that the premotor innervation of the motor system is preferentially affected in ALS. Small brain sections, comprising the motor cortex, from 18 additional ALS patients demonstrated a similar PNF-staining pattern. However, differentiating ALS patients from controls was much easier when studying large brain sections. No ubiquitin-immunoreactive inclusions were found, except for sporadic tangles. The presence of a focal-GFAP positive astrocytosis as reported in the literature in the precentral cortex was confirmed. However, it was found to be nonspecific since it was also present outside the precentral cortex and in the cortex of normal control patients. No spatial relation was found between the distribution of the glial reaction in ALS and the areas containing neurons and boutons accumulating PNF.


Phosphonoformate (foscarnet, PFA) versus trifluorthymidine in the treatment of keratitis dendritica in the human. A double-blind, randomized, preliminary trial. Twenty patients with dendritic keratitis were treated in a double-blind analysis study with either phosphonoformate 3% or trifluorthymidine 1% drops. Nineteen cases were virologically confirmed. Follow-up was performed until closure of the corneal lesion was registered and a pair comparison between both substances was made. Healing time was longer for phosphonoformate (7.16 days) than for trifluorthymidine (5.83 days). There was no significant difference between phosphonoformate and trifluorthymidine. One drug failure was registered in each series. No side effects were observed.


Comparative study of intraneuronal polyglucosan bodies in brains from patients with Lafora disease and aged dogs. We compared intraneuronal polyglucosan body (PGB) in brains from two patients diagnosed as having Lafora disease and from 18 aged dogs (age range: 10 to 22 years, various breeds). PGBs appeared as various-sized spheroids intensely stained with periodic acid-Schiff (PAS) in both humans and aged dogs. Immunohistochemistry with a monoclonal antibody raised against human polyglucosan showed positive staining of the PGBs. Ultrastructurally, PGBs in both humans and aged dogs were composed of fibril-like structures 4 to 20 nm wide. Electron-dense material formed the central cores of the fibrils, but was also scattered in their peripheral areas. The fibril-like structures were intensely stained upon application of the Thiéry procedure. Immunoelectron microscopy showed that the fibril-like structures were specifically labeled with gold particles. The histological, immunohistochemical and ultrastructural features of the PGBs in humans and aged dogs were quite similar.


Pleural malignant fibrous histiocytoma concomitant with pulmonary adenocarcinoma. A rare autopsy case, in which pleural malignant fibrous histiocytoma (MFH) and peripheral pulmonary adenocarcinoma were present concurrently in the right thorax, is described. Clinically, only a pleural mass was detected because of massive pleural effusion. Since cytologic examination of the effusion showed only adenocarcinoma cells, the pleural mass was considered to be enlarged mediastinal lymph nodes due to metastasis of adenocarcinoma. Histopathologically, the pleural mass showed the features of a common type of MFH, accompanied by metastatic adenocarcinoma cells in the pleural lymphatics. No mixture of MFH and adenocarcinoma cells was present. Immunohistochemically, the MFH lesion showed positive staining for alpha-1-antitrypsin, alpha-1-chymotrypsin, and factor XIIIa, but no reactivity for cytokeratins. The adenocarcinoma lesion showed positive staining for carcinoembryonic antigen (CEA), and contained hyaluronidase-resistant mucin. To our knowledge, this is the second reported case of pleural MFH with pulmonary adenocarcinoma.


Stability of an ofloxacin injection in various infusion fluids. The stability of ofloxacin was evaluated in 10 different infusion fluids under various storage conditions. Solutions of ofloxacin (0.4 mg/mL and 4.0 mg/mL) were prepared in (1) 0.9% sodium chloride injection; (2) 5% dextrose injection; (3) 5% dextrose and 0.9% sodium chloride injection; (4) 5% dextrose and lactated Ringer's injection; (5) 5% sodium bicarbonate injection; (6) Plasma-Lyte 56 and 5% dextrose injection; (7) 5% dextrose, 0.45% sodium chloride, and 0.15% potassium chloride injection; (8) 1/6 M sodium lactate injection; (9) water for injection; and (10) 20% mannitol injection. Each solution was injected into polyvinyl chloride bags and stored at (1) 24 degrees C for 3 days, (2) 5 degrees C for 7 days, (3) 5 degrees C for 14 days, (4) -20 degrees C for 13 weeks and then 5 degrees C for 14 days, or (5) -20 degrees C for 26 weeks and then 5 degrees C, for 14 days. Samples were assayed initially and after storage by high-performance liquid chromatography and examined for visual clarity, pH, turbidity, and particulates. Ofloxacin was stable in all solutions and under all storage conditions. All of the solutions were clear, pH was stable, and particulate-matter counts were acceptable under all storage conditions (except for the 20% mannitol solution, which formed crystals at 5 degrees C and -20 degrees C). An injectable formulation of ofloxacin was stable for at least 3 days at 24 degrees C, 14 days at 5 degrees C, and 26 weeks at -20 degrees C in all tested infusion fluids. Crystals formed in refrigerated or frozen solutions prepared with 20% mannitol injection.


The transfer of anti-human immunodeficiency virus nucleoside compounds by the term human placenta. The purpose of this study was to compare the maternal-fetal placental transfer of 2',3'-dideoxyinosine and 2',3'-dideoxycytidine with that of 3'-azido-2', 3-dideoxythymidine (azidothymidine). The perfusion system used carbon 14-labeled antipyrine as a reference compound to determine the clearance index of each compound. The inhibitor dipyridamole and the endogenous bases were used to determine if these anti-human immunodeficiency virus compounds crossed the placenta other than by simple diffusion. The clearance index of azidothymidine was 0.29 +/- 0.04 at maternal concentrations of 1.0 to 10 micrograms/ml, and the clearance index of 2',3'-dideoxyinosine was 0.14 +/- 0.05, which was 48% of the clearance index of azidothymidine. The clearance index of 2',3'-dideoxyinosine was essentially identical to azidothymidine in the range from 1 to 10 micrograms/ml. The results of the closed-closed studies suggest that at therapeutic peak concentrations of 1 to 2 micrograms/ml of these compounds in the maternal circulation therapeutic levels will be reached in the fetal circulation. These anti-human immunodeficiency virus inhibitors appear to cross the placenta rapidly by simple diffusion because (1) the transfer of the drugs to the fetal circulation was not saturable even at 100 micrograms/ml, (2) there was no change in clearance index with the addition of 300 mumol/L of thymidine, inosine, cytosine, or 30 mumol/L dipyridamole, and (3) there was no accumulation against the maternal fetal or fetal maternal concentration gradient.


Angiotensin II receptors on human fetal adrenal cells. Our objective was to determine if angiotensin II receptors are present on adrenal cells isolated from the human fetal zone and neocortex and to investigate if angiotensin II affects steroid production by these cells. Primary cultures of both fetal zone and neocortex cells were prepared from fetal adrenal glands. Experiments were conducted to examine the binding of radiolabeled angiotensin II, angiotensin II activation of phospholipase C, and angiotensin II effects on steroidogenesis. The majority of angiotensin II binding sites were of the type 1 subtype, as determined by displacement of radiolabeled angiotensin with specific receptor antagonists. Angiotensin II caused an increase in tritiated inositol phosphate accumulation in both neocortex and fetal zone cells. This increase could be blocked by type 1 angiotensin II receptor antagonists. Angiotensin II stimulated the production of cortisol, dehydroepiandrosterone, and dehydroepiandrosterone sulfate production during treatment for 2 days. The stimulation by angiotensin II, however, was substantially less than that seen in response to corticotropin treatment. The human fetal adrenal gland contains type 1 angiotensin II receptors early in gestation. The number of these receptors, albeit low, is sufficient to activate inositol phosphate production and steroidogenesis.


Corticotropin and cortisol responses to corticotropin-releasing factor in the chronically hypoxemic ovine fetus. The purpose of this study was to determine if mild hypoxemia (approximately 25% below normal) of at least 5 days' duration alters corticotropin and cortisol responses to corticotropin-releasing factor. We studied 14 (hypoxemic, n = 5; normoxemic, n = 9) fetuses of 135 +/- 1 (mean +/- SEM) days' gestational age. Fetuses were placed in the experimental group if arterial PO2 was < or = 16 mm Hg for 5 days. In normoxemic animals arterial PO2 was > or = 17 mm Hg. Plasma hormone responses were compared by analysis of variance. Resting corticotropin levels were not different (hypoxemic 26 +/- 5 pg/ml, normoxemic 29 +/- 12 pg/ml), and corticotropin-releasing factor (530 +/- 30 ng/kg) increased (p = 0.01) corticotropin levels similarly in both groups. Basal plasma cortisol levels (hypoxemic 20 +/- 10 ng/ml, normoxemic, 30 +/- 7 ng/ml) were not significantly different. Both groups had similarly increased (p < 0.01) plasma cortisol levels after corticotropin-releasing factor administration. Mild hypoxemia lasting 5 days does not significantly alter corticotropin and cortisol responses to corticotropin-releasing factor in the late-gestation ovine fetus.


Anaplastic Paget's disease.

Anaplastic Paget's disease. Six cases of a distinct, histologically anaplastic variant of mammary Paget's disease are described. Patients ranged in age from 40 to 85 years. All patients had scaling erythematous lesions confined to the nipple; none had palpable breast masses. Histologically, the lesions had features resembling Bowen's disease, including full-thickness epidermal atypia, loss of nuclear polarity, and marked cytologic anaplasia. Intraepidermal acantholysis was a distinctive feature in all cases. In some biopsies, small groups and single typical Pagetoid cells were seen within the areas of confluent Bowen-like change. Immunohistochemically, carcinoembryonic antigen (CEA) was positive in three of six patients; epithelial membrane antigen (EMA) in five of six patients, and cytokeratin AE1/AE3 in three of six patients. Mucicarmine stains were uniformly negative. In our series, anaplastic Paget's disease was associated with concomitant invasive ductal carcinoma in three of six patients (50%). This percentage is significantly higher than that previously reported for patients with Paget's disease and without palpable breast mass. Histologic features that are helpful in distinguishing between anaplastic Paget's disease and Bowen's include cleft-like acantholysis, absence of dyskeratotic cells, and persistence of basal cell layer. More rarely, but very helpful when present, are underlying ductal carcinoma, intracellular lumina, and associated conventional Paget's disease. Immunohistochemistry results were variable and of relative value. Our study suggests that a nipple lesion histologically resembling Bowen's disease is likely to represent anaplastic Paget's disease.


A combined small cell and spindle cell carcinoma of the lung. Report of a unique case with immunohistochemical and ultrastructural studies. A unique bronchial tumor is reported. The tumor grew as an endobronchial polyp and obstructed the right main bronchus. Histologically the lesion consisted of two different types of neoplastic cells; epithelial small cell nests and atypical spindle-shaped cells. Immunohistochemical studies with a panel of antibodies showed that the small cell nests were immunoreactive for epithelial and neuroendocrine markers. The spindle-shaped cells showed positive staining for smooth muscle actin. Epithelial markers were also positive focally in the spindle cells. Electron microscopy confirmed that the spindle-shaped cells had both epithelial and mesenchymal features. Based on these results, the tumor was considered to be a unique combination of small cell and spindle cell carcinoma.


Intraductal growth of malignant mammary myoepithelioma. This report describes the histologic and immunohistologic features of an intraductal myoepithelial tumor that developed in the breast of a 61-year-old woman. Histologically, the tumor proliferated intraductally, with both a comedo or doughnut pattern and a solid pattern containing narrow fibrovascular cores, mimicking what appeared to be a conventional intraductal carcinoma. No fine papillary or arborizing growth or cribriform formation was observed. Tumor cells at the ductal peripheral zone were polygonal and clear with abundant glycogen in the cytoplasm; they were transformed into nonclear cells with slightly eosinophilic cytoplasm toward the center of the involved ducts. Occasionally, nonclear cells were elongated, with a centrally located cigar-shaped nucleus. These elongated or spindle cells tended to show a fascicular and streaming pattern similar to that of a smooth muscle tumor. Immunohistochemically, alpha smooth muscle actin (alpha-SM-actin) and S-100 protein were expressed in most of the nonclear cells. While clear cells also had a positive reaction for S-100 protein, they were mostly negative or barely positive for alpha-SM-actin. Epithelial membrane antigen (EMA) was also positive in a certain number of polygonal cells. These results support the myoepithelial nature of the present tumor, and some cells might also be immunologically differentiated into ductal epithelial cells. In addition to cytological atypia, frequent mitoses, and central necrosis within ducts, there was a minimal but evident stromal invasion, suggesting histological malignancy in this peculiar tumor.


A longitudinal study of Junin virus activity in the rodent reservoir of Argentine hemorrhagic fever. We monitored Junin virus (JV) activity in rodent populations for 30 months at seven mark-recapture grids located in agricultural fields and adjacent roadsides and fence lines in endemic and nonendemic areas of Argentine hemorrhagic fever. Blood and oral swabs taken from rodents captured at five-week intervals were analyzed by enzyme-linked immunosorbent assay for JV antigen (Ag). Calomys laucha and C. musculinus were the most frequently captured rodents, making up 47% and 22% of captures, respectively. Of 41 Ag-positive captures, 37 were C. musculinus and four were C. laucha; 34 were from two trapping grids in the same locality. Antigen-positive Calomys were more frequently male (76%), and were found significantly more frequently among the oldest animals and the largest body mass classes. These patterns, combined with the greater mobility and higher frequencies of wounds among males than females, implicated horizontal transmission as the primary route of JV transmission between rodents. Seasonal maximum levels in JV prevalence (up to 25% of captured Ag-positive C. musculinus) occurred during periods of maximal population densities of Calomys. Spatial distribution of Ag-positive rodents reflected habitat preferences; most Ag-positive C. musculinus were captured from border habitats (roadsides and fence lines), and all Ag-positive C. laucha were captured in crop fields. These distinct, but previously undocumented, habitat preferences suggest that the disease in humans may be related to exposures to the primary reservoir species, C. musculinus, in border habitats rather than in crop fields.


Cutaneous myxoid fibroblastoma. A histological, immunohistochemical, and ultrastructural study. A fibroblastic skin tumor with a myxoid matrix is reported that cannot be easily classified as one of the well-known entities of fibrous/fibrohistiocytic and myxoid skin tumors. A 27-year-old white woman presented with a reddish, dome-shaped cutaneous nodule 8 mm in diameter on the left popliteal fossa that had developed spontaneously within the preceding 2 years. There was no sign of recurrence 30 months after excision. Light microscopic examination showed a well-circumscribed tumor confined to the upper dermis and consisting of stellate and spindle-shaped cells arranged loosely in a fascicular pattern resembling tissue cultures of fibroblasts. There were almost no collagen bundles between tumor cells, and Mowry's staining showed large amounts of glycosaminoglycans. Immunohistochemical studies of the tumor cells showed reactivity only to vimentin, whereas markers of histiocytes, dermal dendrocytes, and neurogenic and myogenic differentiation were negative. By electron microscopy, the majority of tumor cells contained elliptical nuclei, but some tumor cells had conspicuous multisegmented nuclei with several large and small nuclear segments connected by thin nuclear bridges (labyrinth nuclei). Single fibrils were found within the interstitium; collagen fibers were rare. Histological and ultrastructural examinations identified tumor cells as fibroblasts. High cellularity distinguishes this tumor from cutaneous myxoma. We conclude that this lesion represents a newly recognized tumor of fibroblastic origin. The name cutaneous myxoid fibroblastoma is proposed.


A unique case of extramammary Paget's disease. Derivation from eccrine porocarcinoma? A unique case of extramammary Paget's disease is reported that may have derived from eccrine porocarcinoma. A palm-sized erythematous plaque on the patient's pubis spread to the lower abdominal wall. The center of the lesion contained a reddish tumor. Histologic findings of the erythematous plaque showed features of extra-mammary Paget's disease. Those of the reddish tumor, however, corresponded most closely to eccrine porocarcinoma, though we could not entirely rule out that the changes corresponded to larger nests of less differentiated Paget cells. The two distinct neoplastic areas showed continuity both clinically and histologically; our case differed from epidermotropic eccrine porocarcinoma in several clinicopathologic respects. Our case suggests the possibility that extramammary Paget's disease could arise from preexisting porocarcinoma.


A placebo-controlled trial of buspirone in anxious inpatient alcoholics. The present study is a double-blind control trial of buspirone versus placebo in highly anxious alcoholics who recently completed inpatient detoxification for alcoholism. Subjects met DSM-III-R criteria for generalized anxiety syndrome and/or other nonpanic forms of anxiety disorders and alcohol dependence. Male veterans aged 21 to 65 were randomized to 45 to 60 mg/day of buspirone (n = 33) or placebo (n = 34). Anxiety scores, as measured by the Hamilton Anxiety Scale and other anxiety measures, declined significantly for both groups, but there were no differential group differences throughout the 6-month treatment period. Survival analysis measuring time to study drop out, time to first drink, time to 5 consecutive drinking days, and time to first intoxication indicated no significant differences between groups. The number of standard drinks per drinking day for nonabstainers also did not differ between groups. In the present study anxious alcoholics taking buspirone did not receive any benefit over placebo on a number of anxiety and alcohol use measures.


Effect of ethanol on lipoprotein secretion in two human hepatoma cell lines, HepG2 and Hep3B. The two human hepatoma cell lines, HepG2 and Hep3B, have been demonstrated to metabolize ethanol efficiently even in the absence of alcohol dehydrogenase. By using specific metabolic inhibitors, it was found that the microsomal ethanol-oxidizing system (MEOS) plays a significant role in ethanol metabolism in these two cell lines. There is a strong positive correlation between the rates of ethanol metabolism and the total cytochrome P-450 levels in the hepatoma cells. The involvement of the cytochrome P-450 system was further supported by the induction of aniline p-hydroxylase activity after ethanol treatment. However, the 3- to 4-fold elevation in aniline p-hydroxylase activity was not accompanied by an increase in cytochrome P450IIE1 mRNA level. Exposure of HepG2 and Hep3B cells to ethanol resulted in an increase of accumulation of apoA-I (15%-45% over control) in a dose-dependent manner (from 5 to 50 mM) of ethanol over a 24-hr period. All other major apolipoproteins which included apo CII, apo CIII and apoE, with the exception of apoB, were not affected by these treatments. At a concentration of ethanol of 25 mM or greater, accumulation of apoB, VLDL and LDL triglyceride were increased by 20% to 25% over the control level. Elevation of HDL cholesterol (40%-70% over control) was observed when the cells were exposed to an ethanol concentration of > or = 10 mM. Metyrapone, which inhibited the MEOS, was capable of blocking the induction of apoAI caused by ethanol treatment.


Age and ethnicity among hospitalized alcoholics: a nationwide study. Little is known about the broad-scale demographic characteristics of low income or indigent alcoholics in public hospital systems. The purpose of the study was to examine issues relative to age, race/ethnicity, and marital status for a large group (n = 62,829) of alcoholic men receiving inpatient care in Department of Veterans Affairs (VA) medical centers nationally. Subjects were VA inpatients completing alcoholism treatment (n = 27,562), in brief alcohol detoxification or short intervention (n = 9,322), or hospitalized for primary diagnoses other than alcoholism but with a secondary diagnosis of alcohol dependence syndrome (n = 25,945). Minority alcoholics were significantly younger than Caucasian alcoholics. Hispanic and African-American men, as well as older alcoholics, were significantly less likely to complete treatment or attend detoxification and more likely to be hospitalized for other primary diagnoses. Native Americans, however, were most likely to complete alcoholism treatment. Results suggest that members of some minority groups and elderly alcoholics seek inpatient care for diagnoses other than alcoholism and that, as a result, such individuals may need targeted interventions to encourage them to seek alcohol-specific care.


Circadian variation in plasma homovanillic acid level during and after alcohol withdrawal in alcoholic patients. Alcohol withdrawal symptoms in alcoholics were objectively evaluated and classified into three groups according to the severity of their symptoms, and circadian variation in their plasma homovanillic acid (HVA) concentrations was determined at three different intervals after cessation of drinking. The subjects studied were 19 male alcoholic patients and five age-matched healthy male volunteers. Circadian variation in plasma HVA was compared between each patient group and the control group by two-way ANOVA. In the sympathetic overactivity (SO) group comprising nine patients and in the clouding of sensorium (CS) group comprising five patients, plasma HVA concentrations on the 2nd and 3rd day and on the 6th and 7th day after cessation of drinking were low but recovered almost normal levels on the 21st and 22nd postcessation day. The delirium tremens group (DT) comprising five patients, however, showed significantly higher plasma HVA than the control group except on the 6th and 7th postcessation day. The higher plasma HVA in the DT group indicates that there is some sort of preparatory state whereby dopamine metabolism is involved in the appearance of hallucinations at alcohol withdrawal and can possibly be used as a predictor of otherwise hardly predictable delirium tremens.


Response to diazepam in sons of alcoholics. Alcohol exerts several of its actions via the chloride channel associated with the central GABA-benzodiazepine receptor complex. To explore a possible role for this receptor complex in risk for alcoholism, and to determine whether risk for alcoholism is associated with risk for benzodiazepine abuse, the authors administered intravenous diazepam to 18 sons of male alcoholics (SOAs) and 18 control subjects. Four logarithmically increasing doses of diazepam and matched volumes of placebo were given in randomized order on separate days about 1 week apart. SOAs were significantly more likely than controls to report euphoric responses to diazepam. At some diazepam doses, SOAs were more likely to report feeling "high" and "intoxicated." SOAs and controls did not differ in feeling "drugged." SOAs and controls may differ in expectations regarding the subjective effects of drugs and/or in the function of the central GABA-benzodiazepine receptor complex. These findings also add further evidence for increased pleasurable effects, and thus possibly increased risk for benzodiazepine abuse, in a subgroup of SOAs.


Effect of ethanol administration and withdrawal on serotonin receptor subtypes and receptor-mediated phosphoinositide hydrolysis in rat brain. The effect of short-term (15 days) and long-term (60 days) ethanol treatment and withdrawal on agonist-stimulated phosphoinositide (Pl) hydrolysis, serotonin receptor subtypes (5HT1A and 5HT2), and alpha 1-adrenergic receptors were studied in rat cerebral cortex. Short-term ethanol treatment had no significant effect on serotonin (5HT), norepinephrine (NE), and calcium ionophore (A23187)-stimulated [3H]-inositol-1-phosphate ([3H]-IP1) formation and 5-HT2 receptors as measured by 125I-lysergic acid diethylamide (125I-LSD) binding, in rat cerebral cortex. However, 15 days of ethanol treatment, followed by 24 hr of withdrawal resulted in a decrease in Bmax of 125I-LSD binding without significant change in KD, as well as a decrease in 5HT-stimulated [3H]-IP1 formation in rat cerebral cortex. 5HT1A and alpha 1-adrenergic receptors were determined by using [3H]-8-hydroxy-2-(di-N-propylamino)tetralin and [3H]-prazosin as radioligand, respectively. We also observed that long-term ethanol treatment had no significant effect on Bmax and KD of 5HT2, 5HT1A, and alpha 1-adrenergic receptors, as well as NE and A23187-stimulated [3H]-IP1 formation, but significantly decreased the 5HT-stimulated [3H]-IP1 formation in rat cerebral cortex. It is possible that a decrease in 5HT-induced PI turnover after long-term ethanol exposure may be due to a decrease in coupling of 5HT2 receptors to G protein or PLC enzyme, whereas the decrease in 5HT-induced PI turnover after withdrawal may be due to a decrease in functional 5HT2 receptor number.


The postpolio syndrome: no evidence for poliovirus persistence. To investigate the possibility of poliovirus persistence in patients with the postpolio syndrome, we examined skeletal muscle biopsy specimens, cerebrospinal fluid specimens, and sera for the presence of poliovirus RNA by the polymerase chain reaction, and for IgM antibodies by a poliovirus type-specific IgM antibody-capture enzyme-linked immunosorbent assay. In none of these specimens was poliovirus RNA or a poliovirus type-specific IgM response detected. These results argue against the hypothesis that poliovirus persists in patients with the postpolio syndrome and plays a role in the pathogenesis of the postpolio syndrome.


Lack of JC viral genomic sequences in multiple sclerosis brain tissue by polymerase chain reaction. With DNA extracted from brain specimens from 19 multiple sclerosis, 5 progressive multifocal leukoencephalopathy, 1 Alzheimer's disease, and 8 nonneurological control subjects, polymerase chain reaction was performed using nested sets of primer pairs amplifying segments of the large T and VP1 antigen-encoding sequences of JC virus. Both sequences were detected in each of the 5 brain specimens of progressive multifocal leukoencephalopathy but in none of the 19 multiple sclerosis, 1 Alzheimer's disease, or the 8 control brain specimens.


Diagnostic significance of 99mTc-dimercaptosuccinic acid (DMSA) scintigraphy in urinary tract infection. A total of 106 children with symptomatic urinary tract infection (73 girls and 33 boys, 0-15.9 years of age) were studied by means of a dimercaptosuccinic acid (DMSA) scan, renal ultrasound, and a desmopressin test during infection and at follow up approximately two months later. At follow up they were also investigated by means of intravenous urography (IVU) and micturition cystourethrography (MCU). During infection 23 children had a normal DMSA scan while 83 children had an abnormal one. The median C reactive protein and SD score for renal concentration capacity in the former group were 15 (range < 10-178) mg/l and -1.0 SD score (range -2.4 to 1.8), respectively, and in the latter group 98 (range < 10-320) mg/l and -3.1 SD score (range -5.7 to 1.1), respectively. In the former group there was no significant finding in any child on ultrasound or IVU and only one had significant vesicoureteric reflux (VUR) (grade 3). At follow up 51 children had a normal DMSA scan while 55 children showed persistent changes. The median SD score for renal concentration capacity in the former group was -0.9 SD score (range -3.2 to 1.4) and in the latter group -1.6 SD score (range -4.6 to 2.5). No significant changes were found in the former group on ultrasound or IVU and only two children had significant VUR (grade 3). In the latter group 20 children showed changes on ultrasound, 15 showed changes on IVU, and 23 had VUR. These results suggest that a normal DMSA scan during or approximately two months after urinary tract infection in children indicates a low risk of finding significant pathology of the urinary tract.


Mineralized nodule formation by cultures of human dental pulp-derived fibroblasts. Pulp fibroblasts were isolated from human deciduous and supernumerary teeth and cultured in vitro. With continued culture in normal tissue-culture medium, six pulp fibroblast strains formed cell nodules after 10-15 days. By electron microscopy the nodules had matrix vesicles, and needle-shaped crystals associated with a dense network of collagen fibrils. The crystalline material exhibited a pattern consistent with hydroxyapatite when nodules were examined by X-ray diffractometry. Furthermore, the cells showed high levels of alkaline phosphatase activity, which could be increased more than seven-fold by the addition of 1,25(OH)2D3 (5 x 10(-9)-5 x 10(-8) M). In addition to the production of type I collagen, these cells also synthesized fibronectin and osteonectin. The formation of mineralized tissue nodules by pulp cells in vitro provides a useful system for study of the pathological calcification of pulp tissues.