The influence of long-term morbidity on health status and rehabilitation following paediatric organ transplantation. Driven by the technological and immunological innovations of the past decade, paediatric transplantation has evolved quickly to occupy an important clinical role in the management of vital organ failure. With this success, the focus of clinical attention has moved progressively from an institutional to a more comprehensive community perspective, and the long-term success of transplantation has assumed greater importance in the evaluation of risk and benefit. Five-year patient survival now exceeds 90% after living donor or cadaveric renal transplantation, 70% following heart or liver transplantation, and approaches 60% at 2 years for the more developmental procedures of heart/lung and lung transplantation. Successful transplantation is accompanied by compelling evidence of improved quality of life. The earliest and most prominent gain is in physical capability, with a progressive re-establishment of social and psychological functioning compared to age-appropriate developmental norms. More than 75% of long-term recipients are in school or employed with a high rating of life satisfaction. Rehabilitation is threatened, however, by the complications of long-standing organ failure and long-term immunosuppression. These principally encompass skeletal and developmental disorders, metabolic abnormalities, cardio-vascular disease, renal dysfunction, and chronic infection or malignancy arising as a result of impaired immune surveillance. Prevention or effective management of these debilitating sequelae is a principal goal in the changing paradigm of organ transplantation for the current decade.


Ethical and psychological aspects of living donorship and life with a donated organ. There is far-reaching consent in the literature that public and consensual agreements on the basics of the different aspects of medical ethics are inalienable before the instigation of any innovative transplant procedure. In the case of a certain method and/or of an individual patient, however, the ultimate ethical evaluation can most likely never be entirely complete before this application. Ethical evaluation depends on the actual criteria used, the present knowledge regarding the risk--benefit--balance as well as on the ethical evaluation of the patient's and his family's own feelings and expectations which are not entirely conscious. In relation to the so-called "fundamental and constant ethical guidelines" and under a psychological perspective potential, ethical conflict constellations are presented which have to be dealt with in the process of ethical and psychological evaluation before living organ transplantation.


Transplantation--a new dimension for paediatrics. Amazing advances have been achieved over the last 20 years in transplantation. As well as the problems of rejection and its control there are other difficulties which have to be confronted. There are shortages of donors, problems of selection for treatment and the problems of funding this expensive form of therapy. The need to make choices has to be considered and the criteria in determining choice have to be determined. Of particular concern in paediatrics are the problems that arise in relation to rehabilitation and the need to provide a multi-disciplinary approach to care. Finally, we have to remember that our enthusiasm for the possibilities of saving life and new treatments must not interfere with the basic responsibility to prevent suffering; at times the preservation of life at all costs is not justified, but in such circumstances doctors and other health care professionals have a responsibility for providing support both to the patient and to the family.


New immunosuppressive drugs: needs in and applications to pediatric transplantation. The evolution of immunosuppressive therapy toward synergistic drug combinations seeks to minimize toxicity while potentiating efficacy. Median effect analysis discerns synergistic drug combinations that may be suitable for in vivo experiments in animals and for subsequent clinical trials. These studies suggest that two drugs rapamycin (RAPA) and brequinar (BQR) display synergistic effects in combination with cyclosporine. This combination must be evaluated for relative toxicity versus efficacy. Clinical trials to assess the individual toxicities of RAPA and BQR are presently underway in order to discern appropriate doses for randomized trials of clinical efficacy.


Bactericidal activity of ciprofloxacin upon Escherichia coli and Acinetobacter baumanni. The mechanisms of bactericidal activity of ciprofloxacin (mechanisms A and B) upon cells of a strain of Escherichia coli and one strain of Acinetobacter baumannii were investigated under different conditions. The killing of E. coli cells by ciprofloxacin was significantly reduced by chloramphenicol, but this antibiotic showed almost no activity upon killing of A. baumannii cells by this quinolone. Similar results were obtained when rifampicin was added to ciprofloxacin. Bactericidal activity of ciprofloxacin upon nondividing cells of E. coli was lower and that upon non-dividing cells of A. baumannii was not affected when compared with activity of ciprofloxacin upon dividing cells of both microorganisms. These results demonstrate that the antibacterial activity of ciprofloxacin upon A. baumannii is independent of protein and ARN synthesis, a fact which suggests that this quinolone exerts only bactericidal mechanism B upon A. baumannii. This finding might explain, at least in part, the lower susceptibility of this microorganism to ciprofloxacin.


Biotyping of Serratia marcescens strains of clinical origin. One hundred and ninety five Serratia marcescens strains of clinical origin isolated at the Children's Hospital of Mexico (Hospital Infantil de México) in 1978 and at the National Institute of Pediatrics (Instituto Nacional de Pediatría) in Mexico City in 1977 and from 1988 to 1989, were studied and compared. All strains were identified using the biotyping system described by Grimont and Grimont, without modification. The most numerous biogroup found was A5/8, and the frequencies of isolation of each biotype varied depending on the institution where it was isolated and the period of study.


[Biological features and experimental pathogenicity of Candida strains isolated by hemoculture at the Hospital Infantil de México "Federico Gómez"]. In a period of 15 months (1990-1991) it was carried out 5781 blood cultures in which 180 strains of yeast-like were isolated. 116 of these strains were selected for biochemical classification, cellular and colonial morphology and experimental determination of virulence in mice. Most of the strains were classified as Candida albicans (60%) and the others were C. tropicalis (15.5%); C. guillermondii (10.3%); T. glabrata (6.8%); Rhodotorula rubra (3.4%); Cryptococcus neoformans (2.58%) y C. parapsilosis (0.86%). C. albicans ATCC14053, y C. tropicalis ATCC14056 and T. glabrata ATCC15545 were employed as controls. The virulence test was performed using mice of 20-30 gr (4-6 weeks age) by intravenous injection in caudal vein with 0.5 ml of different suspension from 10(5) to 10(9) CFU/ml. Observation time was 10 days. Target organ was kidney by macro and microscopic observation of micro-abscess death. LD50 was estimated by the Reed-muench method. Intraspecific and interspecific differences were observed. It is more valid if we take into account that the experiment was done in homogenous population of host without risk factor which influences the human population in hospitals. Experimental virulence was compared with the evolution of diseases in the human host of which the strain was isolated.


Antibody response to Babesia bigemina infection in calves measured by ELISA and immunoblotting techniques. To measure the antibody response to Babesia bigemina with an ELISA test, three groups of cattle were experimentally infected with two isolates of the parasite. It was possible to demonstrate specific antibody binding directed against the parasite as early as the 7 days postinfection (PI). The highest level of antibody was obtained around day 1 to 23 and remained detectable for 260 days. Challenge of the animals 260 days PI with a tick-induced B. bigemina infection depicted that homologous strain-challenged calves did not show an increase of IgG antibody levels, where as those challenged with the heterologous isolate did. In the latter groups the resulting level of antibodies was even higher than after the primary infection. The immunoblotting technique showed that the antibody response is probably directed against groups of B. bigemina components with a relative mobilities of 68-64 kDa, 62-54 kDa and 52-42 kDa, which appear to be major components of the protozoa. By observing the cross-reacting antigenicity among seven B. bigemina isolates, it was demonstrated that these components are not isolate-restricted.


[AIDS and HIV infection among homosexual and bisexual men in Belém, Pará, Brazil, 1988-1990]. During three years (1988-1990) blood samples from 307 people were taken to test antibodies for Human Immunodeficiency Virus type 1 (HIV-1) in homo and bisexual males living in Belém, being 149 (48.5%) of the former and 158 (51.5%) of the later. All patients requested examinations spontaneously to find out their status. The ages of tested people ranged from 16 to 64 years old. Serologic diagnosis was made using an enzyme immunoassay (Abbott, São Paulo-Brasil) for screening and an indirect immunofluorescence test (FIOCRUZ, Rio de Janeiro-Brasil) for confirmation. If results were conflicting with these tests, western blot (Du Pont CO. Wilmington-USA) was performed to obtain a definitive result. Sixty-eight (22.1%) of all sera were positive. Although, the positivity in the homosexual group (26.2%) was more higher than in the bisexual group (18.3%). The positivity rate in both groups was directly proportional with the increase of age. Of course, people with less than 20 years old had only 3% of positivity, while between 20-29 had 18.1%, 30-39 had 34.5%, 40-49 had 40% and 50-59 had 50%. The projected curve of positivity, is progressive, that is to say, the risk of homo/bisexual males increases with age and is probably related to increased sexual activity. We conclude that more than one quarter of homosexual men are infected with HIV-1 in Belém.


Destructive arthropathy of fingers in primary hypothyroidism without chondrocalcinosis. Report of 3 cases. Three cases of undiagnosed primary hypothyroidism with high thyroid stimulating hormone values presented destructive arthropathy of the proximal interphalangeal joints. None had chondrocalcinosis, neuropathy, myopathy or sicca complex. Quick improvement followed hormonal therapy, which suggests that hormonal imbalance could be responsible for this particular rheumatic condition.


[Entomology of onchocercosis in Soconusco, Chiapas. 6. Quantitative studies of the transmission of Onchocerca volvulus by 3 species of Simuliidae in a community with high endemicity]. In Guatemala, there is no doubt about the participation of Simulium ochraceum as vector of Onchocerciasis. However, in Mexico practically there are not studies focussed to determine the role of this species in the transmission. The objective of the present investigation was to determine which of the 3 species of Simulium founded in the Soconusco region of Chiapas, is the main, and which were secondary in the transmission of Onchocerciasis in that area. The locality of Morelos, in the Huixtla "municipio" of Chiapas, localized a 1200 meters over the sea level (mosl) were selected to carried out the present study. According to own parasitological studies, this locality is considered as highly endemic (more than 66% prevalence). From March 1979 to March, 1981, we performed captures of Simulium sp caught on human bait. Quantitative studies and of transmission potentials were also performed. The following results were obtained: a) Absolute black flies densities (nulliparous and pariparous) and infected black flies (with L1 and L2 larvae): S. ochraceum, S. metallicum and S. callidum, in that order was the distribution of densities. Infected black flies were obtained in the 3 species. However, in despite of an irregular distribution in all the year, it was possible to identify 2 peaks of maximum infection of S. ochraceum in March, 1979 and March 1981. b) Monthly bite densities and infective bites.(ABSTRACT TRUNCATED AT 250 WORDS)


[In vitro decrease of the cytolytic effect of E. histolytica by inhibition of its phosphofructokinase]. The C14 radioactive label of PPi analogues was incorporated to E. histolytica after 24 hours of incubation at 37 degrees C; more than 90% of trophozoites remained viable. The PPi dependent phosphofructokinase was isolated in order to determine its kinetic parameters. With PPi, the Km was 18.06 +/- 0.91 micromol/mL-1. Using three different PPi analogues (tetrasodium salts) of (I) 1,1 hydroxy-methyl diphosphonate; (II) 1,1 hydroxy ethylene diphosphonate; (III) 1,1 hydroxy-nonano diphosphonate, KiI was 35.19 +/- 1.74; KiII was 42.65 +/- 0.65, and KiIII 2as 62.81 +/- 0.27 micromol/mL-1. The graphic expression of these results shows that the enzyme was competitively inhibited by the three analogues. When trophozoites were incubated with each one of the three inhibitors, a correlation was observed between the concentration and the cytolytic inhibition with an r = 0.98. Nevertheless, the slope obtained was different for each one of them. The smallest concentration of inhibitor to achieve a 50% lysis inhibition of trophozoites was that of inhibitor III. In addition, it was demonstrated that the incubation of the trophozoites with this inhibitor increased the time needed to destroy CHO cells. We conclude that enzymatic inhibition of the PPi dependent phosphofructokinase caused by the PPi analogues was responsible for the modification of the lytic capacity of trophozoites, possibly by altering the metabolic pathway of carbohydrates.


Chemically unrelated mycobacterial peptides as antigens and competitors in antigen recognition by human T cells. Understanding resistance to mycobacterial infectious diseases requires identification of antigens and epitopes (antigenic determinants) that stimulate cell-mediated immune responses. In this study, a DR1-restricted T cell epitope (residues 1 through 20) of the 19-kD protein of M. tuberculosis was identified. Peripheral blood mononuclear cells from two HLA-DR1 patients with tuberculosis responded not only to the 19-kD immunoblot fraction of M. tuberculosis but also to the peptide 1-20. A M. tuberculosis-reactive T cell clone isolated from one of the patient (whose mononuclear cells showed a stronger proliferative response to the 19-kD protein) recognized the peptide 1-20, while failed to recognize a negative control peptide (residues 65 through 85 of the 65-kD mycobacterial protein: peptide 65-85) or a negative control antigen (candida). The antigen recognition to peptide 1-20 was shown to be DR1 restricted. This MHC restriction was confirmed using a DR1-restricted mycobacterial T cell epitope as competitor. These results demonstrated that this mycobacterial competitor significantly reduced the antigen recognition of peptide 1-20. The reduction observed was dose-dependent.


[Characterization fo mycelial mutants of Mucor rouxii]. The consequences of two different mutations induced with N-methyl-N-nitrosoguanidine (Strain G1) and Trifluoperazine resistance (Strain G5) in Mucor rouxii, were studied. Mutants were stable and exhibited mycelial morphology in aerobiosis. Mutants cells exhibit phenotypic characteristics of slow-growing. The mutants G1 and G5 cultures showed 16.8% and 35.3% of reduction of the growth relative to parental strain. Morphologically mycelia of mutants cell were indistinguishable from wild-type cells, except from reduction in extension and branching of hyphal that has the mutant G5. Calcofluor and FITC-Concanavalin A were used to study the distribution of new cell-wall polymers i.e. Chitin, glucans. The two G1 and G5 strains showed a uniform distribution of fluorescence over the cell surface, indicating that active deposition of new-wall material has occurred. Cellular proteins of mutants and parental strains were labeled with 14C-aminoacid mixture. The proteins pattern revealed that the majority of polypeptides synthesized by parental strain were also synthesized by mutants. It is evident the synthesis preferential of peptides with apparent M(r) > 92K, 60K, 50K, 43K, 38K and 25K. These results indicated that the primary defect of the mutation was not on cellular differentiation. It discuss phenotypic and biochemistry characteristics from mutants.


Vibration white finger and Dupuytren's contracture: are they related? Between 1988 and 1990, 500 claimants were assessed and considered to have vibration white finger (VWF). Of these, 137 were under 45 years of age and none had Dupuytren's contracture of the remaining 363, 311 were aged 50-85 years, and of these 62 (19.9 per cent) had Dupuytren's contracture. Statistically, this prevalence was significantly higher than that in a control group of 150 men of similar age distribution (10.7 per cent). As far as can be ascertained, this is the first study to indicate that there may be a causal relationship between VWF and Dupuytren's contracture, and the possible theoretical reasons for this are discussed. It is suggested that further studies are required to confirm or refute the findings.


[In situ studies of myoinositol-1-P synthase in wild and inos- strains of Neurospora crassa]. The biosynthetic pathway for myo-inositol consist of two enzymatic steps: first, the cycloaldolization of glucose-6P to L-myo-inositol-IP followed by its hydrolysis to form free myo-inositol. The former reaction is catalyzed by myo-inositol-IP synthase (MIPS) while, a phosphatase is responsible for the hydrolysis step. Depending on its degree of purification and storage age, MIPS activity us to be, from partial to fully, dependent on added NAD. Therefore, we decided to study the kinetic properties of the enzyme within the cell, specially its requirements for free NAD. To this purpose, a method was designed for the assay of MIPS-activity in situ, using toluene permeabilized mycelia. MIPS-activity "in situ" was fully displayed in the absence of added NAD; on the contrary, the purified enzyme showed only 33% of that activity displayed when NAD was included in the assay. Thus, it seems that the native enzyme contains tightly bound NAD, instrumental for its activity, and that during purification or storage, the coenzyme is progressively lost, rendering the NAD-dependent enzyme, as was previously envisage. In addition, the in situ assay method for MIP-Synthase was applied to several mutants of N. crassa having the inosphenotype. Our results showed that only in 3 of 14 cases analyzed the phenotype could be clearly associated to the lack of MIP-synthase activity. Indeed most of the mutants analyzed showed significant levels (from 5 to 21%) of MIP-synthase, when compared to the activity shown by the RL-21 WT strain. Finally, all the mutants and WT strains were zymographically analyzed for phosphatase activity and showed close to equal strong reaction levels.


Using videotape instruction and feedback to improve adolescents' mothering behaviors. The effects of videotape instruction and feedback (videotherapy) on mothering behaviors were evaluated in this longitudinal study. In this study, 31 adolescents and their healthy infants were randomly assigned to experimental and control groups. All subjects were videotaped during structured mother-infant teaching episodes in their homes at 1 and 2 months postpartum. Experimental group subjects reviewed the videotaped 1-month teaching episode and received feedback from a specially trained professional nurse who emphasized positive aspects of maternal behavior. Instruction was individualized according to the mother's needs. Results of a repeated measures MONOVA revealed significant differences in the pattern of change over time between subjects in the experimental and control groups on a measure of actual maternal behaviors. Adolescents receiving videotape instruction and feedback obtained significantly higher maternal behavior scores at 1 and 2 months postpartum.


Heparin therapy in Russell's viper bite victims with disseminated intravascular coagulation: a controlled trial. A controlled clinical trial of low dose heparin was carried out in confirmed cases of Russell's viper bite. Twenty patients with systemic envenoming were included in the study. They were randomized to receive low dose heparin in an initial dose of 50 units/kg body weight intravenously immediately after antivenom followed by a continuous infusion of 10 unit 3 kg/hour in isotonic saline for 24 hours, or antivenom alone. Response to treatment was assessed clinically as well as by serial measurements of coagulation factors and biochemical values. No significant difference was observed in the outcome among two groups, the recovery rate from the clotting defect being similar in both. The mean serum creatinine values of the two groups were also not statistically different. The results indicated that there is no beneficial effect of adding heparin to the standard treatment by antivenom.


Naltrexone in the treatment of alcohol dependence. Seventy male alcohol-dependent patients participated in a 12-week, double-blind, placebo-controlled trial of naltrexone hydrochloride (50 mg/d) as an adjunct to treatment following alcohol detoxification. Subjects taking naltrexone reported significantly less alcohol craving and days in which any alcohol was consumed. During the 12-week study, only 23% of the naltrexone-treated subjects met the criteria for a relapse, whereas 54.3% of the placebo-treated subjects relapsed. The primary effect of naltrexone was seen in patients who drank any alcohol while attending outpatient treatment. Nineteen (95%) of the 20 placebo-treated patients relapsed after they sampled alcohol, while only eight (50%) of 16 naltrexone-treated patients exposed to alcohol met relapse criteria. Naltrexone was not associated with mood changes or other psychiatric symptoms. Significant side effects (nausea) occurred in two naltrexone-treated subjects, and one naltrexone-treated subject complained of increased pain from arthritis. These results suggest that naltrexone may be a safe and effective adjunct to treatment in alcohol-dependent subjects, particularly in preventing alcohol relapse.


Skin collagen changes related to age and hormone replacement therapy. A total of 76 nulliparous women who had been hospitalized for minor operations, classified according to age group (by decade from 20s to 60s) and 118 postmenopausal women randomly allocated to one of four groups were studied. In all, 312 skin biopsies were taken from the lower abdomen at 0 and 12 months and the skin collagen changes noted. Collagen content decreased significantly with age beyond the 40s (P < 0.001) and after the menopause (P < 0.01). The decrease was preventable by the use of hormone replacement therapy. All the therapeutic regimens induced increases in skin collagen content, whereas in the control group a significant decrease was observed (P < 0.05).


Guttate parapsoriasis/digitate dermatosis (small plaque parapsoriasis) is mycosis fungoides. Authors of most textbooks of dermatology and dermatopathology consider guttate parapsoriasis and digitate dermatosis to be variants of small plaque parapsoriasis which, they aver, is not related to mycosis fungoides. On the basis of a study of clinical and histopathologic findings in guttate parapsoriasis and digitate dermatosis, we conclude that those conditions actually represent two of the many clinical faces of mycosis fungoides.


Radiographic evidence of disease progression in methotrexate treated and nonmethotrexate disease modifying antirheumatic drug treated rheumatoid arthritis patients: a meta-analysis. Methotrexate (MTX) has proven to be efficacious in the treatment of rheumatoid (RA), but it remains to be proven whether it can slow disease progression, as determined radiographically, in comparison with other disease modifying antirheumatic drugs (DMARD). We performed a meta-analysis of the available data to answer this question. A literature search, including abstracts, was conducted and inclusion criteria developed (description of patients, accountability of patients, inclusion of a control group of patients, specified radiographic endpoint, and appropriate reading of the radiographs). Publications were scored on a scale of 0 to 5 with a score > or = 3 required for inclusion in the study. For abstracts selected, additional data were obtained directly from the investigators. Data for 353 MTX treated and 205 non-MTX-DMARD treated patients with RA were gathered. Not all publications used the same scoring system, so some assumptions were required to analyze the combined data. Only the erosion score was included since not all publications included a reading of the joint space. All scores were transformed into Sharp scores (Arthritis Rheum 1985;28:1449), including the important contributions of 3 Larsen scored publications. Finally a monthly rate of disease progression was computed. Several comparisons were made. Overall, the rates of disease progression were similar for MTX and non-MTX-DMARD treated patients with RA. The non-MTX-DMARD treated patients with RA were separated into a group treated with gold salts (oral or parenteral) and a group treated with azathioprine with each group compared to the MTX treated patients. MTX had slower rates of disease progression than azathioprine, (rates 0.004 vs 0.012) but not slower rates than gold salts (0.008 vs 0.008). Despite its efficacy, the possible role of MTX in slowing disease progression more than other DMARD, as determined radiographically, appears to be evident only when compared to azathioprine.


Correlates of the estimated arterial compliance in the population of Tecumseh, Michigan. An estimate of arterial compliance--the stroke volume/pulse pressure ratio (SV/PP)--was studied in 801 participants in the Tecumseh Blood Pressure Study, a population-based ongoing cardiovascular, epidemiological investigation. The subjects were normal young adults (mean age 30 +/- 5.6 years) and 373 were females. Cardiac anatomy and function were studied by echo-Doppler methods, blood pressure being measured at the same time by the indirect method. The distribution of the SV/PP ratio was skewed toward higher values in larger subjects. After statistical adjustments for body surface area, this estimate of arterial compliance was found to be higher in females (2.00 +/- 0.62) than in males (1.90 +/- 0.58) (p < 0.05). When subjects were divided into tertiles, the group with the lowest estimated arterial compliance was normotensive but had higher systolic pressure, lower diastolic pressure, a similar mean arterial pressure, higher heart rate and higher left ventricular wall thickness ratio compared to subjects with higher arterial compliance. Indices of systolic ejection decreased and diastolic function was altered in the low compliance subjects. In addition, low compliance subjects also had higher fasting insulin levels. These findings suggest that the low arterial compliance in an otherwise normal population has negative cardiovascular correlates. The early association of decreased arterial compliance with anatomic, functional and biochemical aberrations suggests that estimates of arterial compliance might prove useful for prediction of cardiovascular complications.


Overdose with sustained-release lithium preparations. Two cases of overdose with sustained-release lithium preparations are presented. Initial serum lithium levels were in the therapeutic or subtherapeutic range. Subsequent levels were in the toxic range. These cases illustrate the potential danger of delayed toxicity with ingestion of these agents.


Hypertensive retinal vascular changes: relationship to left ventricular hypertrophy and arteriolar changes before and after treatment. Eye-ground-photos were taken in twenty-eight previously untreated men with mild to moderate essential hypertension. The same eye was evaluated before and after 26 weeks of double-blind treatment with Enalapril or Hydrochlorothiazide. The vascular changes were assessed by using a more elaborate and refined grading than the Keith-Wagener-Barker scale. All photos were examined by the same observer without knowledge of blood pressure, type of treatment or the order in which the photos had been taken. There were significant positive correlations between the vascular alterations in the retina in the untreated state and left ventricular wall thickness (echocardiography), minimal vascular resistance in the calf (plethysmography) and blood pressure respectively. Treatment with Enalapril decreased the reflection of the retinal arterial wall significantly and reduced the narrowing of arteries and arterio-venous crossing phenomena non-significantly. Hydrochlorothiazide did not affect any of the retinal vascular changes. It can be concluded that this relatively simple technique of evaluating eye-ground-photos with a new grading scale, when used in non-malignant hypertension, gives a useful assessment of the degree of hypertensive target organ damage in the retina as well as in other important target organs, i.e. the heart and vascular beds. In addition, Enalapril positively affects hypertensive retinopathy in contrast to Hydrochlorothiazide, reflecting what happens to structural cardiovascular changes in the rest of the body.


Contractions to endothelin in normotensive and spontaneously hypertensive rats: role of endothelium and prostaglandins. Contractions to endothelin-1 in aortas of the spontaneously hypertensive rats (SHR) were compared with those of normotensive controls (WKY); rings with and without endothelium were studied in organ chambers. Contractions to endothelin were smaller in aortas of SHR compared to WKY, whether the endothelium was present or not. The presence of a functional endothelium reduced contractions to the peptide in both strains. Endothelium-dependent relaxations to acetylcholine and endothelium-independent relaxations to nitric oxide were observed in rings from both strains during contraction with endothelin. Indomethacin reduced the contractions to endothelin in the aorta from SHR with endothelium, but not in those without endothelium; it did not significantly affect endothelin-induced contractions in rings of WKY with or without endothelium. These experiments demonstrate that contractions of the vascular smooth muscle to endothelin are reduced in the aorta of the SHR. The basal and stimulated release of endothelium-derived relaxing factor inhibits contractions to endothelin in the aorta from both strains. The inhibitor of cyclooxygenase indomethacin does not prevent the response of the vascular smooth muscle to endothelin; however, endothelin may stimulate the release of an indomethacin-sensitive endothelium-derived contracting factor in the SHR aorta.


Raised plasma concentrations of endothelin-1 and -3 in marmosets with acute aortic stenosis: no relation to the renin-angiotensin system. Plasma levels of endothelin (ET), plasma renin activity (PRA) and angiotensin II (Ang II) were measured in anaesthetized marmosets exposed to acute aortic stenosis proximal to the renal arteries. In vehicle experiments, ET rose from 5 +/- 2 to 38 +/- 4 pg ml-1, PRA from 5 +/- 2 to 99 +/- 21 ng ml-1 h-1 and Ang II from 21 +/- 4 to 213 +/- 76 pg ml-1. Administration of renin inhibitor and angiotensin converting enzyme inhibitor reduced PRA and Ang II to control levels, while the plasma levels of ET increased further (51 +/- 10 and 71 +/- 16 pg ml-1, respectively). During aortic stenosis the two isoforms ET-1 and ET-3 appeared in the circulation, while in conscious control animals only ET-1 was found. It is concluded that the increased plasma levels of ET in our primate model could not be ascribed to the increased circulating levels of PRA and Ang II.


The interconnection between sympathetics, microcirculation, and insulin resistance in hypertension. The pathophysiology of the frequent association of insulin resistance and hypertension has not been elucidated. The skeletal muscle is the major site of insulin resistance; when stimulated with insulin, the hypertensive skeletal muscles extract less glucose than the normotensive. We postulate that hypertension-related changes in the skeletal muscle microcirculation contribute to the impaired glucose uptake in hypertension. Vascular rarefaction in hypertension impairs the delivery of insulin and glucose to muscle cells. Insulin resistance has been described both in human and experimental hypertension and both conditions are associated with vascular rarefaction. Functional studies (response to whole body or forearm exercise) and anatomic investigations (conjunctival photography, mesenteric and muscle biopsies) show vascular rarefaction in human hypertension. In addition, patients with hypertension are known to have a larger proportion of insulin resistant, poorly vascularized fast twitch muscle fibers. A few interventions can increase or decrease insulin resistance and these effects can be explained on hemodynamic grounds. Beta adrenergic blocking agents aggravate insulin resistance, and their main hemodynamic effect is a decrease of cardiac output. Converting enzyme inhibitors, alpha adrenergic blocking agents and possibly calcium antagonists decrease the insulin resistance, and their major hemodynamic effect is vasodilation. Physical training decreases insulin resistance; a higher capillary density in skeletal muscles is the hallmark of physical training. A hypothesis ought to rest on sufficient supporting data and its validity ought to lend itself to experimental verification. We believe our hypothesis meets both criteria. After outlining the supporting evidence we propose a number of tests to prove or disprove the hypothesis. In addition to the testable hypothesis we also speculate on the possible cause of the frequent association between hypertension and insulin resistance. We propose that both insulin resistance and blood pressure elevation represent a facet of the "defense reaction" which might have offered an early survival advantage and may, over evolutionary times, have fostered natural selection of subjects with both conditions.


Large scale cDNA sequencing for analysis of quantitative and qualitative aspects of gene expression. Large scale sequencing of cDNAs provides a complementary approach to structural analysis of the human genome by generating expressed sequence tags (ESTs). We have initiated the large-scale sequencing of a 3'-directed cDNA library from the human liver cell line HepG2, that is a non-biased representation of the mRNA population. 982 random cDNA clones were sequenced yielding more than 270 kilobases. A significant portion of the identified genes encoded secretable proteins and components for protein-synthesis. The abundance of cDNA species varied from 2.2% to less than 0.004%. Fifty two percent of the mRNA were abundant species consisting of 173 genes and the rest were non-abundant, consisting of about 6,600 genes.


Single pass sequencing and physical and genetic mapping of human brain cDNAs. We have performed single pass sequencing of 1,024 human brain cDNAs, over 900 of which seem to represent new human genes. Library prescreening with total brain cDNA significantly reduced repeated sequencing of highly represented cDNAs. A subset of sequenced cDNAs were physically mapped to their chromosomal locations using gene-specific STS primers derived from 3' untranslated regions. We have also determined that human brain cDNAs represent a rich source of gene-associated polymorphic markers. Microsatellite-containing cDNAs can be physically mapped and converted to highly informative genetic markers, thus facilitating integration of the human physical, expression and genetic maps.


Human genes containing polymorphic trinucleotide repeats. Expansions of trinucleotide repeats within gene transcripts are responsible for fragile X syndrome, myotonic dystrophy and spinal and bulbar muscular atrophy. To identify other human genes with similar features as candidates for triplet repeat expansion mutations, we screened human cDNA libraries with repeat probes and searched databases for transcribed genes with repeats. From both strategies, 40 genes were identified and 14 characterized. Five were found to contain repeats which are highly polymorphic including the N-cadherin, BCR, glutathione-S-transferase and Na+/K+ ATPase (beta-subunit) genes. These data demonstrate the occurrence of other human loci which may undergo this novel mechanism of mutagenesis giving rise to genetic disease.


X inactivation in mammalian testis is correlated with inactive X-specific transcription. X chromosome inactivation occurs twice during the mammalian life cycle. In females one of the two X chromosomes of somatic nuclei is inactive, while in males the solitary X chromosome is inactivated during germ cell development. Despite the different properties of the inactivated chromosomes of females and males, the molecular initiation of inactivation may be the same. X inactive-specific transcripts, XIST, are produced from somatic inactivated X chromosomes. We demonstrate here the existence of XIST transcripts in testes of man and mouse. Inactivation of X chromosomes in males, as in females, may thus be mediated through XIST. Conceivably, the silencing of X-linked genes is the price paid for the evolution of successful mechanisms of chromosomal sex determination.


Expression of the X-inactivation-associated gene XIST during spermatogenesis. Mammalian X-chromosome inactivation is thought to be controlled by the X inactivation centre (XIC, X-controlling element -Xce-in mice). A human gene, XIST and its mouse counterpart, Xist, which map to the XIC/Xce, are expressed exclusively from inactive X chromosomes, suggesting their involvement in the process of X-inactivation. We now report the presence of Xist/XIST transcripts in newborn and adult mouse testes, and in human testicular tissue with normal spermatogenesis, but not in the testes of patients who lack germ cells. Our results indicate that while the X chromosome in males is active in somatic cells, it undergoes inactivation during spermatogenesis.


Expression of Xist in mouse germ cells correlates with X-chromosome inactivation. Mammals compensate for different doses of X-chromosome-linked genes in male (XY) and female (XX) somatic cells by terminally inactivating all but one X chromosome in each cell. A transiently inactive X chromosome is also found in germ cells, specifically in premeiotic oogenic cells and in meiotic and postmeiotic spermatogenic cells. Here we show that the Xist gene, which is a expressed predominantly from the inactive X-chromosome in female somatic cells, is also expressed in germ cells of both sexes, but only at those stages when an inactive X chromosome is present. This suggests support for the putative role of Xist as a regulator of X-chromosome inactivation and suggest a common mechanism for the initiation and/or maintenance of X-chromosome inactivation in all cell types.


Linkage disequilibrium mapping in isolated founder populations: diastrophic dysplasia in Finland. Linkage disequilibrium mapping in isolated populations provides a powerful tool for fine structure localization of disease genes. Here, Luria and Delbrück's classical methods for analysing bacterial cultures are adapted to the study of human isolated founder populations in order to estimate (i) the recombination fraction between a disease locus and a marker; (ii) the expected degree of allelic homogeneity in a population; and (iii) the mutation rate of marker loci. Using these methods, we report striking linkage disequilibrium for diastrophic dysplasia (DTD) in Finland indicating that the DTD gene should lie within 0.06 centimorgans (or about 60 kilobases) of the CSF1R gene. Predictions about allelic homogeneity in Finland and mutation rates in simple sequence repeats are confirmed by independent observations.


Insulin gene region-encoded susceptibility to type 1 diabetes is not restricted to HLA-DR4-positive individuals. Type 1 or insulin-dependent diabetes mellitus (IDDM) is an autoimmune disease of the insulin-producing pancreatic beta-cells which is determined by both genetic and environmental factors. The major histocompatibility complex and the insulin gene region (INS) on human chromosomes 6p and 11p, respectively, contain susceptibility genes. Using a mostly French data set, evidence for linkage of INS to IDDM was recently obtained but only in male meioses (suggesting involvement of maternal imprinting) and only in HLA-DR4-positive diabetics. In contrast, we find evidence for linkage in both male and female meioses and that the effect of the susceptibility gene(s) in the INS region is not dependent on the presence of HLA-DR4.


Delineation of a 50 kilobase DNA segment containing the recombination site in a sporadic case of Huntington's disease. No detectable rearrangements involving chromosome 4p16.3 have been observed in patients with Huntington's disease (HD). New mutations for HD could involve structural alterations which might aid the localization of the defective gene. We have reinvestigated a well documented sporadic case of HD. DNA haplotyping with markers between D4S10 and the telomeric locus D4S141 reveals a recombination event in one chromosome of the sporadic HD patient. The site of recombination maps within a 50 kilobase (kb) region, about 700 kb from the 4p telomere. Based on the extremely low HD mutation rate and significantly decreased recombination in the distal region of 4p, we hypothesize a direct link between the site of the recombination and HD in this patient.


Cloning of the alpha-adducin gene from the Huntington's disease candidate region of chromosome 4 by exon amplification. We have applied the technique of exon amplification to the isolation of genes from the chromosome 4p16.3 Huntington's disease (HD) candidate region. Exons recovered from cosmid Y24 identified cDNA clones corresponding to the alpha-subunit of adducin, a calmodulin-binding protein that is thought to promote assembly of spectrin-actin complexes in the formation of the membrane cytoskeleton, alpha-adducin is widely expressed and, at least in brain, is encoded by alternatively spliced mRNAs. The alpha-adducin gene maps immediately telomeric to D4S95, in a region likely to contain the HD defect, and must be scrutinized to establish whether it is the site of the HD mutation.


A homozygous stop codon in the lysyl hydroxylase gene in two siblings with Ehlers-Danlos syndrome type VI. Ehlers-Danlos syndrome (EDS) is characterized by joint hypermobility, alterations in the skin and additional signs of connective tissue involvement. EDS type VI was the first connective tissue disorder for which a specific defect in collagen metabolism was identified, namely a deficiency of lysyl hydroxylase activity. We now report a homozygous single basepair substitution converting the CGA codon (Arg319) to a TGA termination codon in two siblings with EDS type VI. The healthy parents, who are first cousins, and two of the three healthy siblings of the patients are heterozygous. The mutation leads to an almost complete absence of lysyl hydroxylase activity in extracts derived from fibroblasts of the patients.


Genomic structure, evolutionary conservation and aniridia mutations in the human PAX6 gene. Aniridia is a semidominant disorder in which development of the iris, lens, cornea and retina is disturbed. The mouse mutation Small eye (Sey), which has been proposed as a model for aniridia, results from defects in Pax-6, a gene containing paired-box and homeobox motifs that is specifically expressed in the developing eye and brain. To test the role of PAX6 in aniridia, we isolated human cDNA clones and determined the intron-exon structure of this gene. PAX6 spans 22 kilobases and is divided into 14 exons. Analysis of DNA from 10 unrelated aniridia patients revealed intragenic mutations in three familial and one sporadic case. These findings indicate that the human aniridia and murine Small eye phenotypes arise from homologous defects in PAX6.


Designing microbes for release into the environment. After 20 years in which gene technology has become an important part of modern biotechnology we have seen very beneficial applications of the new techniques in the pharmaceutical industry. We are now entering a second phase involving the deliberate release of genetically engineered organisms into the environment. This next step causes concern because of a low level of predictability of their possible effects. While the risk assessment of microbial release is far from easy, the strain designers also face problems concerning optimization of performance of the organisms. The two groups of actors in this new development--the risk assessors and the strain designers--need the same platform of understanding from the field of microbial ecology, and a number of specific areas which may now be approached by modern technology deserve particular attention. An increased understanding of the activities of microbes in the environment will also allow construction of more predictable, and therefore safer, strains. Biological containment and molecular microbial ecology are two sides of the same coin in the context of release of genetically engineered microorganisms.


Optical and dynamical investigations of fractal clusters. The characterisation of particle shape has been an active research area and source of contention for over fifty years. In this paper we have reviewed the concept of fractal theory and its application to various aspects of industrial processes has been demonstrated. The application to environmental aerosols, especially those formed by combustion, has received much attention due to the increasing awareness of the global impact of aerosols on climate. Fractal analysis is a convenient framework for the description of complex morphologies and other dynamical parameters.


Brain-gut relationships: gastric mucosal defense is also important. Growing recognition that there exists a functionally important brain-gut axis has prompted several research groups to examine more closely the role of central nervous system factors in gastric mucosal injury. Less attention has been directed toward brain regulation of defensive factors in the gut. Toward that end, we have been characterizing a growing role for dopamine as an important mediator of gastric defense. New data suggest that dopamine, and other substances including many peptides as well as interleukin, act not only to reduce aggressive elements which promote gastric mucosal injury (gastric acid, pepsin, gastrin, leukotrienes) but also to augment defensive factors which retard ulcerogenesis (mucus, bicarbonate, prostaglandins, free radical scavenging enzymes, vasodilators/relaxers). Increasing attention should be directed toward the often-neglected defensive aspect of gastric mucosal ulcerogenesis and protection.


Stress ulcer modulation by limbic system structures. A number of studies suggest that the telencephalic limbic system modulates stress ulcer development. The amygdala is assumed to connect sensory experiences, including stressful stimuli, with the emotional reactions and gastrointestinal effects normally produce. The hippocampal formation (entorhinal cortex, dentate gyrus, hippocampus) is part of a gating system, modulating the organism's coping ability. Changes in transmission in this temporal brain region are linked to individual differences in stress ulcer severity. Interactions among "classical" transmitters and several neuropeptides mediate these differences.


Individual behavioral characteristics and extent of stress-induced gastric ulceration in rats. Individual rats differ amongst themselves with respect to both behavior and the extent of stress-induced gastric ulceration, even though they have been treated identically, are from the same stock, age, etc. The relationship between behavior and ulcer susceptibility is of interest in its own right, and is reminiscent of the extensive body of literature on personality characteristics and disease risk in humans. In the Sprague-Dawley rat, we have found that animals react differentially to the introduction of new stimuli in a previously learned Lashley-maze, and that the increase in latency is negatively related to attack frequency in a classic intruder test. Furthermore, we have found a negative correlation between attack latency in the intruder test and the amount of gastric ulceration induced by restraint-in-water stress. We have further found highly significant relationships between the responses of otherwise untreated animals to a simple startle test and the extent of gastric ulceration induced by restraint-in water stress. We believe that greater notice should be taken of the individual animal's behavioral profile for three reasons. First, prior behavioral screening may be a useful method for reducing error variance. Second, physiological and neuroendocrinological differences between high susceptible and low susceptible individuals are of interest in understanding the psychobiology of stress ulcerations both in animals and humans. Finally, an understanding of the etiology of these individual differences may cast light on links between behavior patterns and stress pathology.


Esophageal mucosal protection--why do we need a special approach? The epidemiology and natural history of reflux induced peptic esophageal diseases remain incompletely understood. That is why it is easy to explain that the traditional therapeutic efforts were mostly restricted to the use of acid-reducing or neutralizing drogs. The author tries to survey--mainly on theoretical bases--a new approach of the maintenance treatment of peptic esophagitis and consequential columnar metaplasia. The mechanism of the esophageal antireflux barrier is composed by the (a) lower esophageal sphincter tone, (b) upper esophageal sphincter tone, (c) esophageal acid clearance and (d) esophageal epithelial resistance. The data of a 100-patient-group of gastroesophageal reflux disease cases were retrospectively evaluated principally considering the efficacy of antisecretory treatment relating to the accompanying diseases, recurrence of symptoms and prevention the development of Barrett's columnar lined esophagus and Barrett's ulceration. The decrease of exposure by damaging factors is an essential criterion of antisecretory therapy, having several disadvantages. Based only to logically well established arguments the author believes that gastroesophageal reflux disease and consecutive conditions might be an ideal model for studying and introducing esophageal cyto (-mucosal, -tissue) protection, considering that in the esophagus--in contradiction to the stomach--the cell and tissue injury, induced by several pathogenic agents, does not develop rapidly, and when the organ damage develops gradually, interventions may be possible to protect esophageal cell and the mucosa directly.


A review of spontaneous ulcer disease in domestic animals: chickens, cattle, horses, and swine. The human species is perhaps unique for its high incidence of spontaneous, chronic ulcer of the glandular mucosa of the stomach and duodenum. Nevertheless, spontaneous ulcers, usually of the stomach, commonly occur in many domestic animals. Some of these lesions are chronic and they may occur in either the glandular or squamous-lined regions of the stomach. As with the human disease(s) the pathogenesis in domestic animals is multifactorial, poorly understood, and variable between and within species. Some parallelisms exist in aggressive and defensive factors, but parasitic factors, via gastrinemia, and a histaminic factor via diet may occur in some animal ulcers. Underlying environmental stresses, of debated importance with the human disease but of proven importance in several rat ulcer models, may play a key role in some spontaneous gastric ulcer situations in swine and cattle. This is manifest in crowding and transporting situations. Seasonal, age, and weaning factors also alter the incidence of ulcer in cattle. Psychologic/environmental stress-related factors, as well as drug and physiologic stress factors appear to upset the balance in the horse between resistance and aggressive mucosal factors. Dietary factors which are highly important in ulcer disease in swine and chickens, have not yet been incriminated in spontaneous, equine ulcer disease. More investigation of the pathogenesis of domestic animal ulcers will prove useful for both human and veterinary medicine in terms of a) elucidating pathogenetic mechanisms for all species, b) may provide new animal models for study, and c) may enhance prevention of such lesions in domestic animals for economic and humanitarian reasons.


Subcellular localization of prostaglandin E2 receptors in the gastric mucosa. Gastric mucosal PG E2 receptors are the common antisecretory working point of all prostanoid types and may also be involved in "protective" effects. We investigated the subcellular localization of these receptors, as measured by displaceable 3H-PG E2 binding, and identified different organelles by monitoring the activities of specific marker enzymes. Porcine mucosal homogenates were subdivided by differential centrifugation into fractions P1 (1000 x g), P2 (20,000 x g), P3 (300,000 x g) and the supernatant S1. P3 was further fractionated over a series of sucrose step gradients. Mitochondria and lysosomes were enriched in P2 (maximum specific activities of cytochrome-c-oxidase of beta-glucosidase, beta-glucuronidase, beta-galactosidase, respectively). Plasma membranes (alkaline phosphatase, gamma-glutamyl-transpeptidase, 5-nucleotidase), tubulovesicles (H+/K(+)-ATPase) and rough endoplasmic reticulum (NADPH-cytochrome-c-reductase) were mainly found in P3, which also contained the majority of 3H-PG E2 binding sites. In contrast, prostanoid binding was barely detectable in S1. Density fractionation of P3 revealed that 3H-PG E2 binding sites shared a similar sedimentation profile with plasma membranes and tubulovesicular markers. No or negative correlation was found with lysosomes, rough endoplasmic reticulum and mitochondria. We conclude that mucosal PG E2 receptors are predominantly located at the cell surface. This supports the view that prostanoids inhibit gastric secretion through membrane receptors, but gives no clue for intracellular "protective" working points.


Adenosine: a novel ulcer modulator in stomachs. Adenosine has been demonstrated for its actions on gastric secretion and stress-induced gastric ulceration in animals. We examined the pharmacological actions of adenosine on ethanol-evoked gastric lesions and gastric mucosal blood flow (GMBF) in rats, because both of them are closely related. Adenosine pretreatment, in dose of 7.5 mg/kg increased GMBF and protected against ethanol-evoked gastric lesion formation. However, this antiulcer action was followed by an aggravation of gastric lesions and reduction in GMBF. We further investigated whether these actions could act through the adenosine A1 or A2 receptors, therefore L-phenylisopropyladenosine (L-PIA) or N-ethylcarboxamidoadenosine (NECA), the adenosine A1 or A2 receptor agonists, respectively, were used. The drugs given in doses of 10 or 50 micrograms/kg for L-PIA and 1 or 5 micrograms/kg for NECA, dose-dependently inhibited GMBF and potentiated ethanol-induced gastric damage. When the two drugs were given together to animals, they did not further aggravate the severity of ulceration and reduction of GMBF. These findings indicate that the antiulcer action of adenosine is not mediated via the adenosine A1 and A2 receptors but if acts through different adenosine receptor subtypes. It was because the lesion worsening effects of adenosine at the second stage of the biphasic responses were similar to the actions of L-PIA and NECA, the ulcer potentiating effect is probably acting through adenosine A1 and A2 receptors in anaesthetised rats.


5-Hydroxytryptamine3-receptor blockade protects against gastric mucosal damage in rats. Ondansetron, a specific 5-hydroxytryptamine3 (5-HT3)-blocker, injected s.c. (0.038, 0.075, 0.15 or 0.3 mg/kg) every 12 h with the fourth dose given 0.5 h before restraint at 4 degrees C (stress) or oral administration (p.o.) of 1 ml 80% ethanol, dose-dependently prevented gastric mucosal damage in female Sprague-Dawley rats (160-180 g); the animals were killed 2 or 1 h after stress or ethanol p.o., respectively. A similar pretreatment regimen with cyproheptadine (0.1, 0.25 or 0.5 mg/kg) or ketanserin (15, 30, or 75 micrograms/kg), both being 5HT2-receptor antagonists, also dose-dependently lowered the severity of stress- or ethanol-induced mucosal lesions. Only the higher doses of phenobarbitone (25 or 50 mg/kg given s.c. in a single dose 0.5 h beforehand) inhibited stress-induced gastric ulcers; however, even the lowest non-antinuclear dose (12.5 mg/kg), effectively produced CNS depression. These preliminary findings suggest that 5HT3-receptor blockade not only can antagonise stress- or ethanol-evoked gastric mucosal damage, but also may act through a peripheral mechanism.


Role of mucus in mucosal protection through ethanol and pepsin damage models. Gastrointestinal mucus is considered an important part of the mucosal defence mechanism against endogenous aggressors such as acid and pepsin. The mucus gel layer, adherent to the mucosal surface creates a diffusion barrier to luminal pepsin, thus protecting the underlying epithelium from the digestion by pepsin. The mucolytic pepsin will, however, digest the mucus at its luminal surface, but that lost is normally balanced by secretion of new mucus. This dynamic balance is disrupted when the mucus is exposed to excess pepsin, which causes focal haemorrhagic damage by progressively hydrolyzing the adherent mucus. The adherent mucus gel layer cannot contribute to the protection against exogen damaging agents such as ethanol and nonsteroidal anti-inflammatory drugs, as these compounds easily penetrate the mucus barrier causing, at high concentration, epithelial exfoliation. This study describes the basic properties and characteristics of gastric mucus and compares the pepsin-induced damage with the ethanol damage model.


Is acute surgical vagotomy an aggressor to gastric mucosa in pylorus ligated rats with and without indomethacin treatment? Previously it was proved that intact vagal nerve is basically necessary for the development of gastric cytoprotection. The aims of this study were to receive further data about the role of vagal nerve in the development of gastric mucosal damage. The observations were carried out on Sprague-Dawley rats. Acute bilateral surgical vagotomy was done with pylorus ligation and/or indomethacin (IND) treatment (20 mg/kg, sc.) at the time of operation. The animals were sacrificed 4 h after the operation. The number, the severity (semiquantitative method), the mean size and summed surface (computer assisted quantitative method) of gastric mucosal damage, the H+ output and the mucosal PGE2 level were determined. It has been found that 1) the ASV itself (without IND or pylorus ligation) provoked gastric mucosal damage, which was more severe than in the pylorus ligated animals at 4 h; 2) IND was able to reduce the summed surface of mucosal damage after ASV; 3) ASV aggravated the gastric mucosal damage in pylorus ligated animals in spite of the decreased H+ output; 4) the PGE2 level was lower in vagotomized and vagotomized+pylorus ligated animals then in the control group, and the IND did not cause further decrease in its level after ASV. It has been concluded that the balance between aggressive and defensive factors of gastric mucosa was shifted to the aggressive side in surgically vagotomized animals.


Effect of acute surgical vagotomy on the mucosal content of 6-keto-PGF1 alpha, PGE2 and glutathione after intragastric 96% ethanol treatment in rats. It has been observed earlier that gastric cytoprotection produced by PGI2, beta-carotene, small doses of atropine or cimetidine has failed in surgically vagotomized rats. This phenomenon may be in connection with endogenous prostaglandins (PGs) and glutathione (GSH) level of the gastric mucosa. The aims of the study were to evaluate the effect of vagus nerve on the gastric mucosal 6-keto-PGF1 alpha, PGE2 and glutathione after intragastric 96% ethanol (ETOH) treatment. The observations were carried out on CFY rats. The gastric mucosal damage was produced by intragastric administration of 1 ml 96% ETOH. Acute bilateral surgical vagotomy (ASV) was carried out 30 min prior to ETOH application. The animals were sacrificed 1, 5, 15 or 60 min after ETOH installation. The number and the severity of gastric mucosal lesions were noted and 6-keto-PGF1 alpha, PGE2 an GSH contents of gastric mucosa were measured. It has been found that: 1. the number and the severity of gastric mucosal lesions were increased after ASV compared to those with intact vagal nerve, 2. 96% ETOH treatment increased both the gastric mucosal PGs and GSH levels, 3. 6-keto-PGF1 alpha peaked at 5 min PGE2 and GSH peaked at 15 min after ETOH treatment, 4. ASV decreased the gastric mucosal PGs content and delayed the peaks of PGE2 and GSH. It has been concluded that the decreased content of PGs and the delayed GSH increase may play a pathological role in the failure of gastric cytoprotection of rats after ASV.


Correlation between the cytoprotective effect of beta-carotene and its gastric mucosal level in indomethacin (IND) treated rats with or without acute surgical vagotomy. As to earlier observations that beta-carotene prevents the development of gastric mucosal injury produced by different noxious agent, however, its cytoprotective effect can be abolished by acute surgical vagotomy. The aim of this study was to evaluate the possible correlation between the gastric mucosal cytoprotective effect of beta-carotene and its gastric mucosal level in rats treated with IND. The gastric mucosal damage was produced by the administration of IND (20 mg/kg s.c.). The instillation of beta-carotene and acute surgical vagotomy (ASV) or SHAM operation were carried out 30 min before IND treatment. The rats were sacrificed 4 h after IND application, and the number and severity of gastric mucosal erosions were noted. The blood rats was collected quantitatively, the liver and the gastric mucosa were removed, and the beta-carotene and vitamin A level of the gastric mucosa, serum and liver were measured with HPLC. It was found that: 1. Beta-carotene induced gastric cytoprotection in SHAM-operated rats treated with IND but its effect disappeared after ASV. 2. Although the beta-carotene level of the gastric mucosa increased its concentration was not elevated in the serum of intact and vagotomized animals either. 3. Vitamin A Formation was not detected in the liver of animals with or without ASV. It was concluded that the lack of intake of beta-carotene into the gastric mucosa can not play etiologic role in the failure of gastric cytoprotection of rats with acute bilateral surgical vagotomy.


Acute and chronic surgical vagotomy (SV) and gastric mucosal vascular permeability in ethanol treated rats. The role of vagus nerve was studied in the development of gastric mucosal damage induced by ethanol (ETOH). The investigations were carried out on Sprague-Dawley rats. The gastric mucosal damage was produced by i.g. administration of 1 ml 96% ETOH. Acute surgical vagotomy (ASV) was carried out 30 min, chronic surgical vagotomy (CSV) 14 days before the ETOH application. The animals were sacrificed at 0, 1, 5, 15, 60 min after ETOH. Evans blue (EB) (1 mg/100 g) was given i.v. 15 min before autopsy. The number and severity of lesions the EB accumulation of the gastric juice and gastric mucosa were noted. It was found, that: 1. The vascular permeability increased after ETOH treatment at an early state (within 1-5 min) in association to the macroscopic appearance of erosions. 2. The number and extension of lesions, the EB concentrations in gastric juice and gastric mucosa were significantly higher both after ASV and CSV. 3. Surgical vagotomy alone did not increase the vascular permeability. 4. No significant ulcer formation was observed in vagotomized rats without ETOH treatment. It was concluded, that 1. Both ASV and CSV enhanced the development of gastric mucosal injury induced by ethanol. 2. Neither acute nor chronic surgical vagotomy exerted an effect of the development of mucosal injury and vascular permeability without the application of the noxious agent. 3. The further increase of enhanced vascular permeability by vagotomy probably has an etiologic role in the aggravating effect of ASV and CSV on the development of chemical-induced lesions.


Synthesis and gastroprotective activity of 4H-pyrido[1,2-a]pyrimidin-4-ones. The cytoprotective effect of different types of 4h-pyrido[1,2-a]pyrimidin-4-one derivatives was investigated. Short synthesis of the investigated compounds was depicted. The gastroprotective effect was determined against acidified ethanol induced mucosal lesions in rats. The most effective compounds belong to unsaturated 4-oxo-4h-pyrido[1,2-a]pyrimidine-3-carboxamide derivatives, and the most active one contains a methyl group in position 6 and a cyclopentyl group on the nitrogen of the carboxamide group. Further pharmacological, biochemical and clinical studies may justify, that the representative of this type of compounds may be useful as prophylactic agents against gastric damage caused by non-steroidal antiinflammatory agents.


Mechanisms of NSAID-induced ulcerogenesis: structural properties of drugs, focus on the microvascular factors, and novel approaches for gastro-intestinal protection. The multifactorial ulcer-producing actions of non-steroidal anti-inflammatory drugs (NSAIDs) are briefly reviewed and the main actions highlighted as the focus for potential strategies for reducing the ulcerogenic effects of these drugs. While some clinical benefits are evident from long-term clinical studies from application of PG analogues (misoprostol) and H+/K(+)-ATP-ase inhibitors (omeprazole) these are, ultimately, expensive approaches. Chemical structural properties of the NSAIDs underlying differences in their ulcerogenicity are analyzed with the objective of establishing the reasons for the low ulcerogenicity of some of these drugs (e.g. azapropazone). These studies serve as a basis for developing less gastrotoxic drugs in the future. In the studies we have undertaken analysis of the benefits of micronutrients and of modulating eicosanoid metabolism have been considered. The results of some clinical trials with micronutrients have proven encouraging. These and other approaches and pitfalls reported give further encouragement to explore the mechanisms of the protective effects of these latter agents and serve as a basis for future developments.


The mechanism of cytoprotective effect of CHINOIN-127. According earlier, investigations nitrogen bridgehead compounds make a representative group of non-prostaglandin type gastroprotective agents. One member of this group is CHINOIN-127 (1,6-dimethyl-4-oxo-1, 6, 7, 8, 9, 9a-hexahydro-4H-pyrido-(1, 2a)-pyrimidine-3-carbox-amide). CHINOIN-127 is a potent non-narcotic analgesic and antiinflammatory agent and has a remarkable protective effect on indomethacin induced ulcer (ED50 = 25 mg/kg p.o.) and on acidified ethanol induced ulcer (ED50 = 26 mg/kg p.o.). In this study we examined the mechanism of action of cytoprotective effect of this drug and we made a comparison between the cytoprotective effect of 20% ethanol and 25 mg/kg CHINOIN-127. In the gastric mucosa of control rats we observed a balance between TxA2 and PGI2 (PGI2/TxA2 = 3.8) and between the cytoprotective prostaglandins (PGI2 and PGE2) and ulcerogen eicosanoids (TxA2 and leukotrienes) (PGI2 + PGE2/TxA2 + LTs = 3.9). 100% ethanol treatment causes disintegration of this balance, shifting the synthesis towards the ulcerogen eicosanoids production. CHINOIN-127 and 20% ethanol pretreatment improves the deranged balance between cytoprotective prostaglandins and ulcerogen eicosanoids. Our results demonstrate that CHINOIN-127 and 20% ethanol have a similar mechanism of cytoprotective action on ethanol induced ulcer in rats.


Are all "cytoprotective" drugs gastroprotective? The effect of three--structurally different--groups of compounds was compared against gastric mucosal damages induced by ethanol or prostaglandin (PG) synthesis inhibitors, as well as against carrageenan-induced inflammation. All the compounds studied--SH-compounds (cysteamine, 2,3-dimercaptosuccinic acid, D,L-penicillamine), SH-blocking N-ethylmaleimide (NEM) and morphine-exerted dose-dependent inhibition on carrageenan edema test and against ethanol-induced gastric damage. Mucosal lesions induced by PG synthesis inhibitors (indomethacin 20 mg/kg, naproxen 75 mg/kg, piroxicam 60 mg/kg) were inhibited by drugs studied when the compounds were given before the damaging agents. However, when the drugs were injected 1 h after the inhibitors of PG synthesis opposite actions were observed; SH-compounds exerted protective, while NEM (2 mg/kg p.o.) and morphine (5 mg/kg p.o.) aggravating action. The results suggest that: 1. SH-compounds might have therapeutic importance in the treatment of gastric damage induced by prostaglandin synthesis inhibitors. 2. Reconsideration of the use of the term "cytoprotection" is necessary, since "cytoprotective" agents may aggravate mucosal damage in other ulcer model.


The antineoplastic drugs dose dependently inhibit the healing of subacute gastric ulcer produced by punching in rats. The aim of present study was to investigate the effects of some antineoplastic drugs on the healing process of subacute gastric ulcer, produced by punching, in rats. We determined the doses which inhibit the healing rate by 50%. Our results confirm the general observation that present applied anticancer drugs cannot distinguish between normal and tumor cell proliferation. The ID50 values of tested drugs strongly correlate with human doses.


Selenium in the blood of patients with colorectal cancer and neoplastic polyp. Samples of whole blood were obtained from 51 patients with newly diagnosed colorectal cancer as well as from 76 patients with neoplastic colorectal polyp, and from 30 healthy blood bank donors. Selenium was determined by the fluorimetric method. Significantly decreased selenium concentrations of blood samples from patients with colorectal cancer and villous adenoma were found. There was not any correlation between the blood selenium levels of patients with adenomatous polyp and the severity of dysplasia in removed polyps. The lowest mean selenium level in patients with villous adenoma indicates that selenium deficiency may be an important factor in the development of colorectal cancer arising from villous adenomas.


Measurement of non-steroid antiinflammatory drugs induced gastric microbleeding. The damage of the mucous membranes in the gastrointestinal tract caused by non-steroid antiinflammatory drugs are well known. The gastrointestinal microbleeding was measured by the method of Fischer and Hunt before and after the intake of indomethacin (4 x 25 mg), naproxen-sodium (4 x 275 mg), diclofenac (3 x 50 mg) and azapropazone (2 x 600 mg). In the indomethacin group microbleeding increased from 0.91 +/- 0.12 ml/24 h to 7.30 +/- 1.20 ml/h. In the naproxen-sodium group from 1.22 +/- 0.16 ml/24 h to 3.56 +/- 0.40 ml/24 h, in the diclofenac group from 0.86 +/- 0.14 ml/24 h to 3.18 +/- 0.28 ml/24 h, in azapropazone group from 0.92 +/- 0.18 ml/24 h to 2.50 +/- 0.20 ml/24 h, respectively. All non-steroid antiinflammatory drugs increased the gastric microbleeding, however, there were considerable differences in the degree of enhancement. This can be explained by the different inhibitory activities of the drugs on the cyclooxygenase enzyme activity.


Influence of sex hormones on ethanol-induced gastric haemorrhagic erosions in rats. The role of sex hormones in the pathogenesis of ethanol-induced gastric erosions was investigated following the recent observation that ethanol generates more severe gastric damage in male rats. Female and male Wistar rats aged 110 +/- 6 days were used. Intact female, ovariectomized female, intact male, orchidectomized male and cyproterone acetate-pretreated (this compound a testosterone antagonist) male rats were investigated. 1 ml of 75% ethanol was used to induce gastric lesions. The extent of the erosions was determined planimetrically 60 min after ethanol administration. The plasma testosterone and 17-beta-oestradiol levels were checked by radioimmunoassay (RIA) in gonadectomized rats. Ethanol generates more severe lesions in male rats. Orchidectomy and cyproterone acetate treatment each reduced the extent of ethanol-induced gastric erosions in male rats. Ovariectomy had no effect in this model. The plasma testosterone and 17-beta-oestradiol levels were significantly reduced after gonadectomy. It is concluded that endogenous testosterone plays an aggressive role in the pathogenesis of ethanol-induced gastric erosions in rats.


The effects of local hyperthermia on the morphology of the small bowel. Intestinal lesions were produced experimentally by heating the eventrated loop of the small intestine of Wistar rats in 44 degrees C 0.9% saline 20 minutes. Luminal haemorrhage and elevation of the potassium concentration in the wash-out fluid were registered from the fifth minute of the experiment. In the sediment of the wash-out fluid erythrocytes, degenerated and necrotic epithelial cell clusters were found. Histologically the mildest lesions were subnuclear vacuolization of the epithelial cells and stromal oedema of the villi. In the medium-degree lesion subepithelial cleft formation, desquamation of the epithelial cells and denudation of the villi occurred. The fully developed lesion was characterized by the destruction of the villi intestinalis and haemorrhage. This lesion produced by local heating differs from the intestinal lesions of the rats exposed to high environmental temperature basically in the haemorrhagical nature of the former lesion.


Pathogenesis and management of alcoholic liver injury. The present paper is devoted to overview the basic concepts of ethanol-induced hepatic injury and therapeutic modalities by which alcoholic liver disease can be alleviated. The role of alcohol dehydrogenase of both hepatic and gastric origin as well as the importance of the number one metabolite acetaldehyde are discussed, furthermore the effects of microsomal ethanol oxidizing system are also described. The features of the major clinicopathological consequences of alcohol abuse fatty liver, alcoholic hepatitis are briefly outlined, and the basic pathogenetic mechanisms that lead to cirrhosis--cell necrosis, regeneration and fibroplasia--are shown. The understanding of the pathophysiology of alcohol-induced liver injury may improve the therapy with drugs and nutritional factors, and allow successful prevention through the early recognition of heavy drinkers before their social or medical disintegration. In the management of alcoholic liver diseases, among the true hepatoprotective agents a naturally occurring flavonoid silymarin and an active methyl-donor metabolite S-adenosyl-L-methionine seem to be promising. An antifibrotic treatment with colchicine might also be of importance. Further prospective, well-designed, controlled clinical trials are still warranted to evaluate real efficacy of these drugs. The hepatic consequences of alcohol abuse may be treatable, however, prevention would be the true resolution of the major global health problem of alcoholism.


Role of free-radical reactions in liver diseases. Role of free-radical reactions is most significant in toxic liver injuries. Two traditional groups of liver injuries induced by drugs and chemicals are distinguished, 1. direct toxic type and 2. idiosyncratic type. Liver injury of direct toxic type is generally developed following toxin exposure, it is dose dependent, incubation period is short, and the injury often affects other organs (e.g. kidney). Direct toxins frequently cause typical zonal necrosis usually without concomitant signs of hypersensitivity. It is typical of idiosyncratic reaction that it appears only in a shorter period of exposure, it cannot be predicted, it is not dose-dependent, its incubation period varies and sometimes (in one-fourth of cases) it is accompanied by extrahepatic symptoms of hypersensitivity (fever, leukocytosis, eosinophilia, rashes), its morphologic picture shows great variety. A part of direct toxins is toxic itself, in the other part the basic compound is not toxic but it changes into toxic metabolites in the liver. Liver is well-protected against free-radicals developing in the organism: it is one of our best antioxidant supplied organs. It is probably due to the one of the important tasks of liver, namely detoxication of drugs, chemicals and toxic materials, with subsequent release of free-radicals. It is proved by the fact that in normal bile peroxidized lipids produced by free-radical chain reactions can also be detected. The pathologic free-radical reactions and one of their sequelae, peroxidation of lipids (LPO) do not necessarily cause cell and tissue damage. Antioxidant protection of cells and tissues is able to prevent free-radical injury and it enables, that the already developed damages become reversible. According to recent investigations, the lipid peroxidation, caused by free-radical reactions, or covalent binding of radical products to biomolecules does not lead directly to cellular destruction, only via further reactions. Such intermediary steps can be the phospholipase A2 activation, accumulation of lysophosphatides, poly-ADP-ribose polymerase repair enzyme activation, following oxidative damage of DNA, with subsequent NAD and ATP depletion. Its significance may be that the irreversible cellular and tissue damage can be prevented perhaps not only by administration of antioxidants, but also by compounds (e.g. phospholipase A2 inhibitors) affecting the above-mentioned biochemical mechanisms.


Cytoprotection in the nineties: experience with ursodeoxycholic acid and silymarin in chronic liver disease. The authors report their experience in the use of ursodeoxycholic acid and silymarin in patients with active cirrhosis of different aetiology. Both drugs seemed safe and ameliorated the biochemical indices of cytolysis; however, the former did not appear to be effective when hepatic dysfunction was associated to hepatitis C infection. The residual functional liver mass, as assessed by quantitative liver function tests, was not affected by either cytoprotective agent.


Clinical evidence of hepatoprotection induced by ursodeoxycholic acid. Ursodeoxycholic-acid (UDCA) was introduced to the clinical practice as an effective agent for the dissolution of gallstones. The efficacy of UDCA was proved recently in the treatment of patients with chronic cholestatic liver disease. We demonstrate the hepatoprotective effect of UDCA in a patient with chronic cholestatic liver disease. A sixty-nine years old male patient was admitted to our department with severe jaundice. The laboratory and radiologic examinations revealed significant cholestasis without any morphological alterations. Among the serological tests the anti-HCV antibody was positive. Based on these findings and anamnestic data (no blood transfusion and/or operation), sporadic chronic C virus hepatitis was assumed with dominant cholestasis. The corticosteroid therapy even in high doses was ineffective, the liver function parameters worsened. Later UDCA (Ursofalk, Falk Pharma) was given at a dose of 250 mg three times daily. Clinical improvement was seen after the first week of UDCA treatment. The patient's complaints relieved parallel with decrease of serum bilirubin, gamma-glutamyl transferase and transaminase levels. These parameters showed further decrease during the treatment.


The effect of silibinin (Legalon) on the the free radical scavenger mechanisms of human erythrocytes in vitro. The effect of Legalon was investigated parallel with that of Adriblastina (doxorubicin) and paracetamol on some parameters characterizing the free radical scavenger mechanisms of human erythrocytes in vitro and on the time of acid hemolysis performed in aggregometer. Observations suggest that Adriblastina enhances the lipid peroxidation of the membrane of red blood cells, while paracetamol causes significant depletion of intracellular glutathione level, thus decreasing the free radical eliminating capacity of the glutathione peroxidase system. Legalon on the other hand, is able to increase the activity of both superoxide dismutase and glutathione peroxidase, which may explain the protective effect of the drug against free radicals and also the stabilizing effect on the red blood cell membrane, shown by the increase of the time of full haemolysis.


Endogenous scavenger levels (vitamin E and A) of patients with chronic alcoholic liver disease under different environmental conditions. Serum level of endogenous scavengers (E and A vitamin) was studied in groups of patients with various chronic alcoholic liver diseases and in a healthy control group on polluted and non-polluted areas. Vitamin levels in patients with chronic liver disease are diminished in comparison to the healthy in general, but mainly in the cirrhotic group. Diminution of vitamin E levels was observed in earlier phase of liver disease than that of vitamin A levels. Patients and healthy control on polluted area showed more expressed diminution of vitamin levels than the same groups on non-polluted area. Free radical parameter (RBC diene conjugate content) and characteristic alcoholic parameters (serum GOT, gamma-GT, cholesterol level and liver GOT, gamma-GT content in biopsy specimen) were used to explain the differences between the same investigated groups on polluted and non-polluted areas. As conclusion can be supposed that industrial pollution of environment has a worsening effect in diseases with free radical mechanism.


ATP breakdown and resynthesis in the development of gastrointestinal mucosal damage and its prevention in animals and human (an overview of 25 years ulcer research studies). The changes in membrane-bound ATP systems (breakdown and resynthesis) were analyzed in different experimental ulcer models (such as ETOH, HCl, NaOH, 25% NaCl-induced, pyloric ligated + epinephrine treated, stress, reserpine treated, indomethacin treated rat models) and chronic antral, duodenal and jejunal ulcers in patients. The energy system parameters (adenosine triphosphate (ATP), adenosine diphosphate (ADP), adenosine monophosphate (AMP), cyclic AMP (cAMP), lactate) were measured from different sites of gastrointestinal mucosa, and values of ATP/ADP, adenylate pool (ATP + ADP + AMP) and energy charge ((ATP + 0.5 ADP)/(ATP + ADP + AMP)) were calculated. The biochemical measurements were done at different times during the development of gastrointestinal mucosal lesions, without and with application of different drugs (PGI2, atropine, cimetidine) and bilateral surgical vagotomy. The aims of our present paper were: 1.) To summarize the main directions of ATP breakdown during the development of gastrointestinal lesions or ulcers in different experimental models and human beings: 2.) To summarize the biochemical steps of defense of gastrointestinal mucosa against chemicals, drugs or unknown pathogenic factors; 3.) To analyze the importance of membrane-bound ATP-dependent energy systems in order to understand the mucosal lesions and their prevention; 4.) To evaluate the real values of changes in these parameters from the point of view of ulcerogenesis and its prevention; 5.) To find some correlation between the energy parameters during mucosal damage and its prevention: 6.) To understand better the types of tissue reactions (metabolic) due to development of mucosal lesions and prevention.(ABSTRACT TRUNCATED AT 400 WORDS)


Post-cholecystectomy syndrome and magnesium deficit. The serum level of magnesium and calcium was systematically measured in patients with gallstones before and after cholecystectomy. It was found that 60 percent of the operated patients suffered of different digestive syndromes in association with magnesium deficiency, while 40 percent of patients had the same complaints in association of magnesium and calcium deficiency. When magnesium and/or magnesium plus calcium was supplemented these syndromes could be decreased significantly. In the latter case, an optimal ratio of magnesium/calcium is needed in the supplementary therapy.


Pancreatic cytoprotection: new approaches. A brief report is given on the possible role of oxygen-derived free radicals and cholecystokinin in the pathogenesis of experimentally induced acute pancreatitis. Furthermore, use of scavengers (superoxide dismutase, catalase), CCK-receptor antagonists and somatostatin are discussed in the therapy of acute pancreatitis induced in animal models. It is suggested that both the term of direct pancreatic cytoprotection of the above-mentioned agents and the validity of the animal models used for induction of acute pancreatitis have to be reconsidered.


Gastric anti-ulcerogenic drug effect. A possible mechanism of its molecular basis. During experimental gastric ulceration in rats an elevation in the mucosal cAMP/cGMP ratio can be encountered. The cause of this significant elevation is mainly (but not entirely) the dramatic fall of the cGMP level. Similar observations were obtained with prostacyclin application (100 micrograms/kg, p.o.), too. This prostaglandin derivative is well known, among others, because of its pronounced anti-ulcerogenic (cytoprotective) effect, too. Other substances of different molecular structure and properties may also exert such effect. The exact mechanism of action of this above-mentioned cytoprotection is still not completely understood. H2-receptor blocker drug cimetidine, given in such small dose (5 mg/kg, p.o.) which does not interfere with gastric acid secretion, also exerts very significant cytoprotective effect in stress (restraint)- and drug (indomethacin)-induced gastric ulcer models. Under cimetidine effect--together with a noticeable endogenous prostacyclin mobilization--the gastric mucosal cAMP/cGMP ratio was also strongly elevated. We conclude that this elevation in the mucosal cAMP/cGMP ratio might be a possible molecular basis of the gastric cytoprotective (anti-ulcerogenic) drugs but it needs further investigations whether all substances exerting cytoprotective effect, e.g. atropine, somatostatin, sulfhydryl drugs, etc., have the same "shifting" property or not? Moreover the phenomenon of the so-called "adaptive cytoprotection" can not be ruled out completely either, therefore this problem needs attention, too.


The significance of the gastroprotective effect of body protection compound (BPC): modulation by different procedures. To elucidate any mechanism of a body protecting effect the observed events should be investigated also by the way of their modulations induced by ablation of particular organs. For Body Protection Compound (BPC), a newly partially characterized gastric juice peptide, the gastroprotection has largely been studied in basal and modified conditions of 48 h-restraint stress. Ablations or sham operations have been performed before restraint as follows: 60 min vagotomy, 24 h ovaria, testes, spleen, 48 h medulla of adrenal glands, 40 days thyroid + parathyroid glands. BPC (10 micrograms/kg) or saline (5 ml/kg) have been regularly applied (after surgery, 1 h before restraint) intraperitoneally. The group subjected to thyroparathyroidectomy received also once-daily BPC/saline treatment. A very strong gastroprotective effect in basal conditions has been modulated by ovariectomy and demedullation (abolishment), thyroparathyroidectomy (decrease), and no change occurred in case of vagotomy, splenectomy or orchidectomy. Sham operated rats did not differ from corresponding controls. Thus, seeing from point of view a wide range of organoprotective effects of BPC (intestinum, kidney, liver, pancreas, inflammation, diabetes mellitus, delayed type of hypersensitivity), the gastroprotection has been supposed a) to be of crucial pattern in the general concept of organo-protection and b) to be responsible for the mediation of the suggested "stomach stress organoprotective response". Therefore, the obtained modulations suggest a complex and specifical, sex-related action of the overall beneficial effects of BPC.


Pathways, mediators and mechanisms of gastroduodenal mucosal injury. This review provides evidence that gastroduodenal mucosal injury is a complex process because of the heterogeneous structure and multiple functions of the gut. The action of exogenous etiologic agents is usually mediated in part, or amplified by endogenous mediators which very often exert biphasic, i.e., damaging and protective effects. The pathogenetic pathways involve direct/indirect chemical injury, vascular damage and its consequences, and acute or chronic inflammatory processes following infectious, chemical or ischemic injury. The role of oxygen, free radicals, calcium and proteases as well as the components and forms of gastroduodenal injury, e.g., reversible and irreversible cell injury, tissue necrosis, acute and chronic inflammation are also briefly discussed. Only a slight or moderate direct cytoprotection was demonstrated in vitro using isolated, mixed rat gastric mucosal cells by the known gastroprotective drugs including PG and SH compounds. Thus, the terms of organo or gastroprotection are more descriptive then the misleading "gastric cytoprotection".


Ethanol and the antioxidant defense in the gastrointestinal tract. Ethanol is known to have profound actions on the gastrointestinal tract. The present study was undertaken to examine the effects of ethanol on some of the natural antioxidant defensive enzymes in the gastrointestinal tract; the activities of these enzymes in the liver and the brain were also measured for comparison with those in the gastrointestinal tract. Oral administration of absolute ethanol induced severe gastric mucosal lesions and also damage in the small intestine, however the total superoxide dismutase was unaffected in the tissues measured. The glucose-6-phosphate dehydrogenase activity was reduced only in the stomach while the total glutathione was elevated in the small intestinal mucosa. The catalase activities were activated in the stomach, small and large intestines, and brain, but not in the liver which contained the highest concentration of the enzyme. The present findings indicate that endogenous hydrogen peroxide may be an important damaging agent towards biomolecules in different organs and the removal of this by catalase represents an important defensive mechanism against ethanol toxicity.


Determinants of lung cancer risk among cadmium-exposed workers. Workers at a cadmium recovery plant in Globe, Colorado, showed an increased risk of lung cancer, which some investigators have attributed to cadmium exposure. We conducted a cohort mortality analysis of this work force and a case-control analysis of the lung cancer cases within this work force in order to assess the probable causes of the lung cancer excess. The Globe plant began as a lead smelter about 1886, switched to arsenic production in 1920, and became a cadmium metal production facility in 1926. Cadmium, arsenic, and cigarette smoking are three potential lung carcinogens found in this workplace. Industrial hygiene data collected from 1943 onward served as the basis for the National Institute for Occupational Safety and Health (NIOSH)-derived exposure algorithm that assigned cadmium exposure estimates to employees based on their work area in the plant and calendar time. Few exposure data existed for substances other than cadmium. Feedstock ore concentrations were used as a surrogate measure of air arsenic levels. The arsenic content of the fines used as feedstock prior to 1940 was considerably higher than that of the fines used after 1940. Smoking histories had been obtained previously for 45% of the workers. A case-control analysis of the 25 cases of lung cancer known to have occurred among these workers through 1982 was conducted using three controls per case, matched by closest data of hire and age at hire. Potential causal agents for lung cancer included cadmium exposure, cigarette smoking, and arsenic exposure. Exposure variables for each case and control included estimated cumulative cadmium exposure in milligram-years per cubic meter, cigarette smoking history, and plant arsenic exposure status at the time of hire. Estimated cumulative cadmium exposures of cases and controls did not differ overall or within the date-of-hire strata. Cases were more than eight times more likely to have been cigarette smokers than were controls. Lung cancer risk in this workplace was more closely related to the period of hire, not to the cumulative cadmium exposure. The period of hire appears to be a surrogate for arsenic exposure as related to feedstock. The measures used here seem to indicate that exposure to arsenic and cigarette particulates, rather than to cadmium particulates, may have caused the increased rate of lung cancer of these workers.


The role of salt in hypertension.

The role of salt in hypertension. There is considerable evidence that salt is an important cause of hypertension. Primitive societies who ingest little or no salt have no hypertension. Also when diets very low in salt such as the rice and fruit diet are given to hypertensive patients, the blood pressure often falls toward normal. Unfortunately, when diets only moderately low in sodium have been given only minor reductions in blood pressure occur. Salt-induced hypertension has been produced in both man and experimental animals. The basic cause of the hypertension is an inability of the kidney to excrete the increased salt. Hemodynamic changes then occur which raise the blood pressure and so excrete the excess salt by pressure diuresis. The ability to excrete salt at normal levels of blood pressure varies from one individual to another. Those who require a higher than normal blood pressure are said to be "salt-sensitive". Those who can excrete excess salt at normal levels of blood pressure are called "salt resistant". The difference may be due to an inherited defect in the kidney to excrete salt. In any event, salt sensitive hypertension is effectively controlled with the administration of diuretics.


Salt and blood pressure.

Salt and blood pressure. Current evidence does not support the view that the claimed association between salt intake and blood pressure is causal. In intercultural studies it is impossible to distinguish between a genuinely causal relationship and a relationship due to the role of salt intake as a marker for different life-styles. Physiological studies suggest that the Western intake of salt corresponds to a physiological set point selected when free choice is offered as the mid-point between harmful physiological extremes. When flawed intervention studies are excluded there is no evidence that a moderate reduction in salt intake would produce a significant blood pressure fall in healthy individuals although blood pressure falls can be produced in some hypertensive subjects.


Hospice values, access to services, and the Medicare hospice benefit. The Medicare benefit has been an important force in shaping the American hospice movement during the 1980's. Hospice reimbursement under Medicare added legitimacy to the movement, increased access to hospice care for some Medicare beneficiaries, and provided financial support to Medicare certified hospice programs. But the increased access for some may come at the cost of decreased access for others, and the price of reimbursement may be the erosion of hospice as a unique form of terminal care in this country. It is up to hospice professionals to balance the fiscal realities of providing hospice care without losing sight of the values and philosophies that have made hospice a "special kind of care."


Haemodynamic findings and response rates to beta-blocker--and diuretic monotherapy in mild and moderate hypertension. A one year randomized, double blind study in 100 men. In a randomized double blind study 100 men (mean age 46 (22-64) years) with mild to moderate hypertension were followed every 3rd month for one year. Fifty were randomized to atenolol 50 mg and 50 to hydrochlorothiazide 25 mg+amiloride 5 mg (co-amiloride) once daily. The doses were doubled at 3 or 6 months if diastolic blood pressure (DBP) remained > or = 95 mmHg. If DBP was > or = 95 mmHg even at 6 or 9 months, patients were classified as non-responders, and nifedipine 20 mg b.i.d. was added. After one year 31/50 randomized to atenolol and 17/50 randomized to co-amiloride had responded to monotherapy (p < 0.05). Neither clinical findings nor haemodynamic measurements by Doppler at baseline could distinguish between co-amiloride responders and non-responders. Conversely, non-responders to atenolol as compared with atenolol responders had higher body weight (p = 0.02), higher systolic BP (p = 0.03), higher DBP (p = 0.009), stroke volume (p = 0.04), and cardiac output (p = 0.0002) combined with lower total systemic vascular resistance (p = 0.02). This suggests that some were apparent non-responders due to too low dosing of atenolol rather than true non-responders. Measurements of haemodynamics may be of importance in the assessment of optimal antihypertensive therapy according to baseline and follow-up haemodynamic aberrations.