Clonal growth of hepatitis B virus-integrated hepatocytes in cirrhotic liver nodules.

A total of 83 cirrhotic nodules (pseudolobules) individually collected from 11 cirrhotic livers of hepatitis B virus carrier patient were analyzed for the frequency and mode of hepatitis B virus integration as well as histological features. Southern blot analysis disclosed discrete bands at higher molecular weight region in 26 of 83 nodules (31.3%), indicating a clonal growth of hepatocytes with viral integration. Considerable variation (0-75%) existed in the positive rates for discrete bands in nodules among livers. Molecular cloning revealed the sequence flanking an integrated viral sequence to be host DNA and thus confirmed true integration. Histological analysis, however, did not reveal any neoplastic-appearing foci of growth within nodules, despite the fact that the detection sensitivity would predict clones of more than 10(5) cells to give rise to clonal integration patterns on Southern blot analysis. The question of whether clonal expansion of hepatocytes reflects any viral integration-associated growth advantage and/or a preneoplastic condition awaits future studies.     

Effects of nicotine and ethanol on rat atrial membrane potentials.

The purpose of this research was to study the effects of nicotine and ethanol, alone and in combination, on cardiac membrane potentials (MP). Rat atrial preparations driven at 5 Hz were superfused with Tyrode's solution (37 degrees C) while recording MP with intracellular microelectrodes. Nicotine concentrations below and including 6.2 x 10(-5) M did not affect MP. Within 15 s, nicotine 3.1 x 10(-3) M shortened the action potential duration (APD) and depressed the overshoot of the action potential (OS). This action was blocked by atropine. After 3 min, nicotine prolonged the APD and depressed Vmax of phase O, OS and the amplitude of the action potential (AAP), without affecting the resting membrane potential (RMP). Nifedipine blocked the depression of the OS while tetraethylammonium chloride blocked the prolongation of the APD. Acute exposure to ethanol depressed OS and AAP and shortened APD, but it did not affect RMP or Vmax of phase O. When nicotine and ethanol were administered simultaneously, the APD-prolonging effects of nicotine prevailed. The influence of chronic ethanol ingestion on the acute action of nicotine and/or ethanol was studied in rats pair-fed a liquid diet with (ER) or without (NR) ethanol (35% of total caloric intake) for 24 weeks. Chronic ethanol ingestion accentuated the depressant effect of nicotine 3.1 x 10(-3) M on OS and AAP, but it did not modify the APD-prolonging action of nicotine. The same results were observed when ER and NR were exposed to nicotine and ethanol simultaneously.     

Acute renal and hepatic toxicity of 2-haloanilines in Fischer 344 rats.

Aniline and its halogenated derivatives are widely used as chemical intermediates. The purpose of this study was to determine the hepatotoxic and nephrotoxic potential of the 2-haloanilines. Male Fischer 344 rats (n > or = 4) were injected (i.p.) with 1.0 or 1.25 mmol/kg of: aniline (A), 2-fluoroaniline (2-FA), 2-chloroaniline (2-ClA), 2-bromoaniline (2-BrA), 2-iodoaniline (2-IA) or vehicle (0.9% saline, 2.5 ml/kg). All compounds were injected as hydrochloride salts. Renal and hepatic function was monitored 24 h after treatment. All of the 2-haloanilines induced oliguria, diminished kidney weight, tubular casts and decreased renal cortical slice accumulation of organic anions. Blood urea nitrogen (BUN) levels were increased (P < 0.05) by treatment with 1.0 or 1.25 mmol/kg of 2-FA, 2-ClA or 2-BrA. Hepatic alterations were also observed and characterized by elevated plasma ALT/GPT activity and altered morphology in the centrilobular region. The nephrotoxic and hepatotoxic potentials were similar among the 2-haloanilines but aniline was less toxic than its 2-halo derivatives. These results demonstrated that halogen substitution at the 2-position of aniline increased hepatic and renal toxicity. However, the severity of toxicity was not influenced by the nature of the halogen substituent.     

Specific inhibition of binding to benzodiazepine receptors by 1,2,3-triazole derivatives.

Certain 1,2,3-triazole derivatives were prepared and tested for their ability to displace [3H]diazepam that was bound to bovine brain membrane protein. All the tested compounds are essentially lacking in this ability, except for B.1, which inhibited binding of [3H]diazepam in 50% of the trials at 2.5 microM. The structure of B.1, with a 1,2,3-triazole ring with acidic properties, supports the hypothesis proposed for binding to the benzodiazepine receptor site. Comparison of B.1 with 1,2,3-triazole derivatives bearing a bicyclic substituent in position 1 of the heterocyclic ring suggests that a high steric hindrance increases the affinity of a compound for the benzodiazepine receptor.     

A case-control study of trapezius muscle activity in office and manual workers with shoulder and neck pain and symptom-free controls

A case-control study with matched pairs was initiated to investigate the relationship between shoulder-neck complaints and activity in the upper trapezius muscle. The matching was done so that the physical demands from work (external exposure) were equal for both the case and the control. Each pair was also matched for gender, age, working hours, and employment time. Male (n = 18) and female workers (n = 78) employed in both manual and office work were included. Muscle activation levels and pause patterns during work and muscle activity during tests of attention, coordination, and rest were recorded by surface electromyography. The results showed consistent associations between pain and signs of increased activation of the upper trapezius for the cases in the manual group. No such associations were observed in the office group. The results are consistent with the hypothesis that muscle activation patterns may in some instances, but not in all, explain why some workers develop pain while others do not in work situations where the physical demands are similar.     

Mono- and bi-allelic expression of insulin-like growth factor II gene in human muscle tumors

Insulin-like growth factor II (IGF-II) is a mitogen for manycell types and an important modulator of muscle growth and differentiation.IGF-II gene is prevalently expressed during prenatal developmentand its gene activity is regulated by genomic imprinting, inthat the allele inherited from the father is active and theallele inherited from the mother is inactive in most normaltissues. IGF-II expression is activated in several types ofhuman neoplasms and an alteration of IGF-II imprinting has beendescribed in Beckwith–Wiedemann syndrome and Wilms' tumour.Here we show that monoallelic expression of IGF-II gene is conservedin normal adult muscle tissue whereas two or more copies ofactive IGF-II alleles, arising by either relaxation of imprintingor duplication of the active allele, are found in 9 out of 11(82%) rhabdomyo-sarcomas retaining heterozygosity at 11p15,regardless of the histological subtype. Since IGF-II has beenindicated as an autocrine growth factor for rhabdomyosarcomacells, these findings strongly suggest that acquisition of adouble dosage of active IGF-II gene is an important step forthe initiation or progression of rhabdomyosarcoma tumorigenesis.Among different types of muscle tumors, relaxation of imprintingseems to arise prevalently in rhabdomyosarcomas, since we havedetected only one case of partial reactivation of the maternalIGF-II allele out of 7 lelomyosarcomas tested.     

Normal activation of the supplementary motor area in patients with Parkinson''s disease undergoing long-term treatment with levodopa.

Regional cerebral blood flow (rCBF) changes in cortical motor areas were measured during a movement of the dominant right hand in 15 patients with Parkinson's disease deprived of their usual levodopa treatment, in 11 patients with Parkinson's disease undergoing long-term treatment with levodopa, and in 15 normal volunteers. The supplementary motor areas were significantly activated in the normal subjects and in the patients receiving levodopa but not in the patients deprived of levodopa. The contralateral primary sensory motor area was significantly activated in all three groups. The ipsilateral primary sensory motor cortex was not activated in the normal subjects and the non-treated patients but was in the patients treated with levodopa. It is concluded that the supplementary motor area hypoactivation which is observed in akinetic non-treated patients with Parkinson's disease is not present in patients undergoing long-term treatment with levodopa. This result suggests that (a) levodopa improves the functional activity of supplementary motor areas in Parkinson's disease and (b) there is no pharmacological tolerance to this effect. The ipsilateral primary motor cortex activation observed in the patients treated with levodopa could be related to levodopa-induced abnormal involuntary movements.     

DIALLELIC POLYMORPHISM MAY EXPLAIN VARIATIONS OF THE BLOOD CONCENTRATION OF MANNAN-BINDING PROTEIN IN ESKIMOS,BUT NOT IN BLACK AFRICANS

Mannan-binding protein (MBP) is a lectin which, upon binding to certain carbohydrates, activates the classical pathway of complement without the involvement of antibody or C1q. Deficiency of the MBP is associated with an opsonic defect and recurrent infections during early life. An amino acid substitution in the exon 1 at codon 54 in the MBP gene (GGC [glycine] to GAC [aspartic acid]) has been shown to be closely associated with low MBP concentration in Caucasoids. The gene frequency of the mutant allele in this population has been estimated at 0.13. In the study described here, we investigated the association between the mutant allele and MBP protein concentration in Eskimos from East-Greenland and black Africans from the Baringo District in Kenya. The frequency of the GAC allele was identical in Eskimos and Caucasoids (0.13). No overlap with regard to MBP concentration between the genotypes was found in the Eskimos. In contrast, the Africans revealed a low frequency of the GAC allele (0.009). However, the median MBP protein concentration was approximately 5 times lower among the Africans than the Eskimos. In 12.6% of the Africans and in 2.5% of the Eskimos, MBP was undetectable. Thus, MBP deficiency is the most frequent immunodeficiency so far described. The high prevalence of MBP deficiency among healthy individuals indicates that MBP deficiency also confers some selective advantages. We advance the hypothesis that MBP deficiency is maintained in populations because MBP deficiency decreases the infectivity of some intracellular micro-organisms which are dependent on opsonization.