Management of chronic urethral symptoms in men. We describe 20 men who were referred because of chronic urogenital symptoms. They had been previously seen by zero to six physicians (mean, 1.8 physicians) and had been treated with zero to five courses of antimicrobial agents (mean, 2.4 courses) without relief of their symptoms. Results of physical examinations of all patients were normal. An extensive evaluation failed to reveal any objective evidence of urethral inflammation. Cultures for Neisseria gonorrhoeae, Chlamydia trachomatis, Ureaplasma urealyticum, and Trichomonas vaginalis were uniformly negative. No additional antimicrobial agents were prescribed. Data from follow-up questionnaires filled out by 10 of these men 5-28 months later (mean, 11.8 months) disclosed the disappearance of symptoms in three and the reduction of symptoms in four. Chronic urethral symptoms may occur in the absence of objective evidence of inflammation and infection with known urethral pathogens. Observation without antimicrobial therapy is the treatment of choice for such patients.


Hepatobiliary infections caused by Haemophilus species. Haemophilus species are rarely associated with hepatobiliary infections. We report a case of hepatic abscess caused by Haemophilus paraphrophilus and review the English-language literature for reports of infections of the liver and biliary system caused by Haemophilus species. Most patients identified had predisposing conditions. The pathogenesis of hepatobiliary infections due to Haemophilus species may involve ascending spread from the gastrointestinal tract or hematogenous seeding following oropharyngeal colonization.


A two-year prospective, nationwide study to determine the epidemiology and impact of invasive childhood Haemophilus influenzae type b infection in Israel. The Israeli Pediatric Bacteremia and Meningitis Group. Accurate data on invasive Haemophilus influenzae type b (Hib) disease from countries other than the United States and western Europe are limited, and none are available from the Middle East. We report the results of a nationwide prospective epidemiological study in Israel whose purpose was to provide a background for decisions regarding the need for Hib conjugate vaccinations. During the 2 study years, 344 patients less than 13 years of age with a positive blood or CSF culture for Hib were seen in 25 medical centers in which pediatric patients were hospitalized. The overall incidence of Hib disease was 34 per 100,000 persons less than 5 years old, an incidence in the range of those reported for western Europe. Twenty-two percent of patients were less than or equal to 6 months old, 69% were less than or equal to 12 months, 87% were less than or equal to 18 months, and 93% were less than or equal to 24 months. Thus, our findings represent a unique epidemiological pattern: the age distribution of our patients resembles that of immunologically compromised populations or of persons living in less-industrialized areas, but the incidence of disease is similar to that found in western Europe. In view of these data, the Israeli Ministry of Health decided to license conjugate vaccines for immunization of infants beginning at 2 months of age.


AIDS enteropathy.

AIDS enteropathy. Chronic diarrhea is one of the hallmarks of advanced human immunodeficiency virus (HIV) disease. The symptoms of this complication are troublesome, have a significant impact on the patient's quality of life, and in severe cases can lead to extreme abnormalities in fluids and electrolytes and can even cause death. The workup for AIDS-associated diarrhea is often frustrating and frequently unrewarding. However, during the last 10 years, much has been learned about the causes of diarrhea; while treatment is still often ineffective, some advances have been made. Dr. John G. Bartlett and his colleagues in the Department of Medicine at Johns Hopkins University School of Medicine have been responsible for many of these advances. In this AIDS Commentary, these experts discuss recent advances that have enhanced our understanding of chronic diarrhea in HIV-infected persons and offer their recommendations for the most efficient and effective approach to managing these patients.


Evaluation of soft tissue response to a poly(urethane urea). Variations in the performance of vascular prostheses constructed of polyurethanes, and some evidence which suggested that these variations could be due not to the properties of the polymer itself, but to differences in the cellular response to the various microstructures of porous polyurethanes require investigation. Experiments were performed to evaluate quantitatively the extent of the cell behaviour adjacent to a series of polyurethane samples. It was shown that, with Biomer, a polyurethane urea, the profile of cell behaviour as a function of distance from the implant surface and of time following implantation, the response of cells in general and macrophages in particular, varied considerably with different internal microstructure. This supports the suggestion that the cellular response to different structures and susceptibility to degradation are related.


Seeding of enzymatically derived and subcultivated canine endothelial cells on fibrous polyurethane vascular prostheses. Fibrous polyurethane (FPU) prostheses with or without fibronectin coating and gelatin impregnation and FPU prostheses with or without fibronectin coating were seeded with 4.8 x 10(5) subcultivated dog endothelial cells per cm2 prosthesis. Expanded polytetrafluoroethylene (ePTFE) prostheses with and without fibronectin coating served as controls. The numbers of cells retained on uncoated polyurethane prostheses were minimal but increased with fibronectin coating and/or gelatin impregnation. Adhering cells were predominantly round in shape and few cells were seen stretched over the prosthetic fibres. Optimum numbers of cells were found in prostheses impregnated with gelatin and coated with fibronectin, where almost all the cells were stretched forming a confluent monolayer. In ePTFE prostheses only minimal numbers of cells were retained but in the fibronectin-coated prostheses a high cell count was noted. Gelatin-impregnated and fibronectin-coated FPU prostheses, as well as ePTFE prostheses coated with fibronectin, were additionally perfused in vitro after seeding under nearly physiological conditions for 1 h. Cells in the FPU prostheses were still present after perfusion, whereas all the cells in the ePTFE prostheses were lost from the inner surface. It is concluded that FPU prostheses impregnated with gelatin and coated with fibronectin are a suitable substrate for subcultivated endothelial cells to be seeded on. The cells remained at the surface even after 1 h in vitro perfusion with tissue culture medium under nearly physiological conditions. Further research including in vivo implantations is indicated.


Microradiographic and histochemical evaluation of mineralization inhibition at the bone-alumina interface. Microradiographic and histochemical tests were used to examine the behaviour of the bone tissue close to the alumina coating in cementless hip prostheses which were radiologically stable and explanted because of pain. The presence was detected of a decalcification stripe of the bone tissue with a thickness of about 300 microns, parallel to the prosthesis profile and in appearance not influenced by the roughness of the surface. This phenomenon was attributed to the presence of aluminium ions similarly to what happens in osteomalacic osteodystrophy in nephropathic dialysed patients. It was concluded that the phenomenon must be carefully considered because, in the long term, it could cause failure in the alumina coating.


Surface characterization of microtextured silicone. A set of microtextured silicone surfaces was manufactured using the technique of photolithography. The textures consist of a uniform array that imparts anisotropy to the surfaces. Processing the material required multiple steps which may have altered the surface characteristics. This project aimed to determine if a surface texture on implant grade silicone would affect the material characteristics. ESCA and contact angle studies revealed no measurable alteration of the surface chemistry or surface energy due to the texturing procedure or the presence of the texture. Both analytical techniques confirmed the material was silicone. The actual dimensions of the surface textures, size, spacing, depth and orientation of the textures were found to be close to the design values, using SEM and quantitative two- and three-dimensional profilometry. Standard 2D profilometry was not sufficient to characterize the surfaces, as a direct result of the uniformity of the arrays. A method of characterizing regular surface periodic structures is presented.


Prevention of protein adsorption and platelet adhesion on surfaces by PEO/PPO/PEO triblock copolymers. Fibrinogen adsorption and platelet adhesion on to dimethyldichlorosilane-treated glass and low-density polyethylene were examined. The surfaces were treated with poly(ethylene glycol) and poly(ethylene oxide)/poly(propylene oxide)/poly(ethylene oxide) triblock copolymers (Pluronics). Poly(ethylene glycol) could not prevent platelet adhesion and activation, even when the bulk concentration for adsorption was increased to 10 mg/ml. Pluronics containing 30 propylene oxide residues could not prevent platelet adhesion and activation, although the number of ethylene oxide residues varied up to 76. However, Pluronics containing 56 propylene oxide residues inhibited platelet adhesion and activation, even though the number of ethylene oxide residues was as small as 19. Fibrinogen adsorption on the Pluronic-coated surfaces was reduced by more than 95% compared to the adsorption on control surfaces. The ability of Pluronics to prevent platelet adhesion and activation was mainly dependent on the number of propylene oxide residues, rather than the number of ethylene oxide residues. The large number of propylene oxide residues was expected to result in tight interaction with hydrophobic dimethyldichlorosilane-treated glass and low-density polyethylene surfaces and thus the tight anchoring of Pluronics to the surfaces. The presence of 19 ethylene oxide residues in the hydrophilic poly(ethylene oxide) chains was sufficient to repel fibrinogen and platelets by the mechanism of steric repulsion.


Humoral responses to type I collagen after surgical curettage procedures employing bovine collagen implants. Freeze-dried bovine type I collagen was implanted into periodontally diseased sites of 11 patients in an effort to repair the affected site. Peripheral blood samples taken at 0, 6 and 12 wk were assayed for antibody to human and bovine collagen using an enzyme-linked immunosorbent assay and compared with samples from 9 control subjects. Antibody levels to both human and bovine collagen, which were present at significantly higher levels in the patients at 0 wk than in the control subjects (P less than 0.01 for human and bovine), were significantly lower at 6 wk than at zero time (P less than 0.05 and P less than 0.01 for human and bovine collagens, respectively). At 12 wk post-implantation, the antibody level to human collagen still remained significantly lower (P less than 0.05) than zero time levels but not in respect of the antibody to bovine collagen.


In vitro resistance of artificial connective tissues to human bile and pancreatic juice. The resistance of connective tissue generated from elastin, placenta extracts and human collagen was tested by in vitro incubation with bile and pancreatic juice to investigate the potential use in human digestive surgery. The resistance, determined by macroscopical and microscopical examinations, has been directly compared to those of bovine collagen matrices (Spongel, Pangen, Helistat, Translagen). Only the compact and cross-linked human collagen patch resisted both bile and pancreatic juice. All other biomaterials tested dissolved either in bile or in pancreatic juice. The in vivo behaviour of this new human collagen matrix and its involvement in gastrointestinal wound healing must now be investigated.


Immobilization of alpha-amylase into photographic gelatin by chemical cross-linking. alpha-Amylase was immobilized into photographic gelatin by chemical cross-linking with chromium (III) acetate and chromium (III) sulphate. Cellulose triacetate film strips, enabled simple handling when coated with an alpha-amylase-gelatin mixture, accomplishing a high degree of durability during consecutive immersions into reaction media. The optimum conditions for pH, substrate concentration, temperature, incubation time and storing conditions of free and immobilized alpha-amylase were determined. The effect of use number on activity and the effect of resting on reuse number were also determined. Photographic gelatin was found to be a very efficient natural polymer, due to its extraordinary diffusion characteristics for immobilization as a carrier.


Principle and investigation of the bioadhesion mechanism of solid dosage forms. The development of bioadhesive tablets requires a good knowledge of their adhesion mechanism and the possibility of using an accurate in vitro evaluation technique. The bioadhesion mechanism is not basically different from the general adhesion mechanism, but it is necessary to take into account the biological nature of at least one of the two substrates involved in the process. The hydrated joint created at the molecular interface, resulting from the inter-penetration of the polymeric chains of the mucin and the bioadhesive product, is especially interesting, because its viscoelastic properties make it a damping device for the stresses transmitted to the bioadhesive surface.


Characterization of surgical suture materials using dynamic mechanical analysis. Dynamic mechanical analysis (DMA) has been used to characterize the viscoelastic properties of four suture materials, Prolene, Maxon, Vicryl and silk. The technique identified the main transitions for the sutures and frequency multiplexing was used to define the variation of modulus with time. The monofilament Prolene has a beta transition and the monofilament Maxon has an alpha transition close to room temperature, indicating that both materials exhibit a change in stiffness with time. The alpha transitions (Tgs) of silk and Vicryl occur at temperatures significantly above room temperature and frequency multiplexing data indicate that both materials exhibit stable moduli with respect to time at room temperature. Determination of the viscoelastic behaviour through DMS appears to be very useful in predicting the performance of suture materials.


Bone cell interactions with a granular glass-ionomer bone substitute material: in vivo and in vitro culture models. The interface between bone and a synthetic bone substitute constructed from glass-ionomer cement (ionomeric microimplant) was studied in diffusion chambers implanted in a primate baboon model (Papio ursinus) and in in vitro primary bone organ cultures derived from neonate rat calvaria. In both models osteoblast-like cells colonized the surface of the implant producing a collagenous extracellular matrix. An electron-dense bonding zone similar to that reported for hydroxyapatite and titanium was seen in both models but was a more constant feature of the tissue/implant interface in calvarial culture.


Further observations on high impact strength denture-base materials. Previous studies have shown that high impact strength can be conferred on denture-base poly(methyl methacrylate) polymers by modification with acrylic-terminated butadiene-styrene block copolymers, and that the acrylic end-group was necessary for effective reinforcement. It is now shown that, by solvent extraction studies, grafting of the copolymer occurs both with acrylic-terminated and non-terminated block copolymers. It is therefore concluded that the mode of grafting is different, and some possible mechanisms are discussed.


Soft tissue reaction to de novo plaque formation on implants and teeth. An experimental study in the dog. The aim of the present investigation was to assess the effect of de novo plaque formation on the gingiva and masticatory mucosa around teeth and implants. The study was performed in 5 beagle dogs which at the initiation of the experiment were 15 months old. During a preparatory period, the mandibular right premolars were extracted, 3 fixtures installed, abutment connection performed and a 4-month period of plaque control completed. A clinical examination was performed and biopsies of the second mandibular premolar (P2) and the contralateral implant site (2P) were sampled. The dogs were allowed to form plaque during a period of 3 weeks. The clinical examination was repeated and biopsies harvested from the 2 remaining implants and the contralateral tooth sites. The tissue samples were prepared for histometric and morphometric analysis. Both the masticatory mucosa at implants and the gingiva responded to de novo plaque formation with the development of an inflammatory lesion. The size as well as the composition of the lesions in the 2 tissues had many features in common. It was concluded that the mucosa around implants and the gingiva around teeth had a similar potential to respond to early plaque formation.


Functional adaptation to full-arch fixed prosthesis supported by osseointegrated implants in the edentulous mandible. The objective of the present study was to assess possible adaptive functional changes in the masticatory system after insertion of fixed prostheses supported by osseointegrated implants in the edentulous mandible. Registrations of mandibular movement characteristics and maximal biteforce were performed at insertion and after 1 week, 3 months and 1 year after connection. The duration of the opening and closing phase decreased and maximal biteforce increased significantly (p < or = 0.05-0.001) from connection of the prostheses to the annual check-up. However, the process of functional adaptation implied 2 identified stages. An immediate phase that occurred within the 1st week, probably due to altered impact from mechano-sensitive receptors and a later more time-dependent phase, based on learning and new cortical engrams. Accordingly, the process of adaptation will continue over a long period of time.


Quantitative digital subtraction radiography for the assessment of peri-implant bone change. The purpose of this study was to develop a digital subtraction technique to assess peri-implant bone change. The method uses subtraction radiography to enhance visualization of the area of change that has occurred between radiographic examinations, and superimposes the area of change on the original radiographs. Furthermore, a reference wedge allows calculation of the mass of the lesion. The method was validated using 21 small bony chips placed on 3 different skulls prior to the first radiograph. The chips were removed, a second radiograph taken, and the images subtracted. A morphologic method was used to isolate the lesion and the change in bone mass calculated. Overall, there was excellent correlation between the calculated lesion mass (mg) and actual lesion mass (r2 > 0.90). The utility of the method was demonstrated using a case that experienced implant failure. These data indicate that quantitative digital subtraction radiography may be of value in measuring peri-implant bone change in root form implants.


A semi-automated computer-assisted method for measuring bone loss adjacent to dental implants. The purpose of this study was to develop a repeatable method for measurement of bone support around root form and blade implants suitable for use in high-quality but unstandardized radiographs. 10 phantoms were fabricated to simulate progressive osseous defects around implants. Radiographs were taken in triplicate and digitized. Specialized software was written which placed a grid of known dimensions over the implant so that the top and the bottom of the grid were at the neck and the base of the implant, respectively. The investigators selected the edge of the bone at each point where the grid intersected the implant and the software automatically detected the implant edge. The software also outlined and displayed the defect on the computer monitor. Measurements were performed 5 times and the standard deviation was taken as a measure of the repeatability of the method. Repeatability for blades and root forms was 0.19 +/- 0.07 mm and 0.08 +/- 0.03 mm, respectively. There was no significant difference in the ability to measure bone loss in the blade versus the root form (p = 0.17, NS). These results indicate that this semi-automated computer-assisted method for measuring bone loss around implants is repeatable and may be of value for clinical trials using either root form or blade implants.


A comparative study of the clinical efficacy of Screw Vent implants versus Brånemark fixtures, installed in a periodontal clinic. The clinical success of 85 Screw Vent and 107 Brånemark implants, consecutively installed in a private periodontal clinic under the same conditions and by the same operator, is compared. Mobile implants were removed and considered as failures. Intra-oral radiographs were assessed for the presence of peri-implant radiolucencies and for analysis of bone loss after functional loading. 85 Screw Vent implants were installed in 31 patients. Of 23 implants installed in 9 mandibles, none failed after 16.8 (range 12-25) months of function. Of 62 Screw Vent implants installed in 23 maxillae, 6 failed at abutment connection, 1 failed after 2 months and 2 after 13 months of function. The absolute failure rate after 13.2 (range 6-24) months was 9/62. Mean loss of bone was 1.47 mm (-1.0- +4) after 12 months of functional loading. 107 Brånemark fixtures were installed in 25 patients. Of 51 fixtures inserted in 12 mandibles, none failed; of 56 fixtures installed in 13 maxillae 1 failed before and 2 failed during abutment connection. The absolute failure is 3/56. All remaining fixtures were immobile after loading. 13 fixtures were more than 6 months in function. Only short-term comparison between both systems is possible because the observation time is longer for the Screw Vent implants. In the 1st year, only 1 implant system was available to the periodontist. Short-term comparison reveals 11.3% versus 5.3% of cumulative failure after 6 months for the Screw Vent and Brånemark implants, respectively. The results indicate that clinical efficacy is as effectively obtained with Screw Vent as with Brånemark implants in the mandible. The outcome of treatment with Screw Vent implants in the maxilla seems less predictable.


Treatment of an early implant failure according to the principles of guided tissue regeneration (GTR). The present case report demonstrates the application of guided tissue regeneration (GTR) in combination with antimicrobial therapy for the treatment of an early implant failure. This treatment approach both prevented further loss of bone as well as led to the regeneration of lost bone. By means of color-converted digital subtraction images, remodelling of the tissues adjacent to the defect was documented as early as one month postsurgically. The images demonstrated "bone-fill" in the apical portion of the defect and resorptive changes at the bone crest. This case report demonstrates that combined regenerative and antimicrobial therapy may be a successful treatment approach restoring osseointegration of dental implants following loss of bone due to infection. Continuously increasing bone-fill inside the defect was documented when comparing the radiograph obtained immediately before the GTR procedure and at months 1, 2, 4, 5 and 6 of the healing period, respectively. Clinical measurement obtained at the time of the surgery and at the time of the membrane removal confirmed the radiographic evidence of bone-fill by demonstrating new tissue resistant to probing in close contact to the implant surface at the site of the previous defect. Antimicrobial therapy included an antibiotic regimen during the 1st month of healing as well as topical rinses with an antiseptic (chlorhexidine) over the entire healing period of 6 months. As a result of this treatment approach, the implant was saved and could be used as an abutment for a bridge reconstruction.


Experimental breakdown of peri-implant and periodontal tissues. A study in the beagle dog. The objective of the present experiment was to study lesions in the peri-implant and periodontal tissues resulting from ligature placement and subgingival plaque formation. The experiment was performed in 5 beagle dogs which at the start of the study were about 15 months old. They were given a diet which allowed gross plaque formation. The mandibular right premolars were extracted, 3 fixtures (a.m. Brånemark) installed and abutment connection performed. Towards the end of a 6-month plaque control period, a clinical and radiographic examination was performed. Ligatures were placed in a subgingival position at 2 of the implants and the contralateral premolars. Plaque was allowed to accumulate. After 6 weeks, the ligatures were removed. 1 month later, the clinical and radiographical examination was repeated and samples from the subgingival microbiota obtained. Biopsies from the teeth and implant sites were harvested and processed for histometric and morphometric analyses. The results from the clinical and histological examinations revealed that: (i) clinical and radiographic signs of tissue destruction were more pronounced at implants than at teeth; (ii) the size of the soft tissue lesion was larger at implants than at teeth; (iii) the lesion at implants but not at teeth extended into the bone marrow.


Programmed cell death: concept, mechanism and control. Programmed cell death or apoptosis occurs under physiological conditions as a result of physiological effectors. It is a relatively slower process and requires active participation of the cell in the suicidal mechanism. Apoptosis is controlled by precise intrinsic genetic programme and may be induced by almost all those stimuli causing necrosis. The role played by the intensity in determining the death process and the underlying mechanism is imperfectly understood. Morphologically apoptotic cells appear as small condensed body. The chromatin is dense and fragmented, packed into compact membrane-bound bodies together with randomly distributed cell organelles. The plasma membrane loses its characteristic architecture and shows extensive blebbing. It buds off projections so that the whole cell may split into several membrane-bound apoptotic bodies. Significant chemical changes take place in the plasma membrane. This helps in recognition of the apoptotic bodies by phagocytes. At this moment it is unclear if all cells can undergo apoptosis or it is a characteristic of only some tissues which are predisposed to apoptotic death being directly under the control of hormones or growth factors. Experimental studies aimed at comparison of induction of apoptosis in cells of different origin are warranted to elucidate this point. Biochemically a pre-commitment step for induction of death programmation through macromolecular synthesis is essential for most systems. The double-stranded linker DNA between nucleosomes is cleaved at regular inter-nucleosomal sites through the action of a Ca2+, Mg(2+)-sensitive neutral endonuclease. Zinc is a potent inhibitor of the enzyme. Calcium probably plays a key controlling role in activation of the enzyme since prevention of Ca2+ increase prevents endonuclease activation. It is becoming evident that signal transduction through appropriate receptors control the Ca2+ flux in the cells. Most apoptotic cells require synthesis of RNA and proteins. Delay or abrogation of apoptosis by inhibition of macromolecular synthesis is well known. The dying cells show high mRNA levels for several enzymes. Several degradative enzymes become active. Regulatory proteins maintain control over the apoptotic cascade. At the molecular level, search has been initiated for the mammalian equivalents of the cell death (ced) gene. Activation of several specific genes is indicated. Specific expression of cell death-associated gene products (e.g. TRPM-2/SGP-2) has been reported in several unrelated apoptotic cell systems. Sequential induction of c-fos, c-myc and 70 kDa heat shock protein is reported. Studies demonstrate that certain genes must remain in a transcriptionally active demethylated state during programmed cell death. Recent evidences clearly indicate that apoptosis may be positively or negatively modulated by certain genes.(ABSTRACT TRUNCATED AT 400 WORDS)


Cell adhesion molecules: a unifying approach to topographic biology. Cell adhesion molecules are pivotal to the development and maintenance of tissue structure in metazoan organisms. In mammals, several families of proteins are involved in cell-cell and cell-matrix adhesion. The cadherins are homophilic, primary CAMs, involved in the establishment of boundaries between cell collectives early in embryogenesis. The Ig gene superfamily have diversified widely, with homophilic and heterophilic CAMs and antigen recognition molecules amongst the members. The Integrin family play an important role in binding to extracellular matrix, as well as counter-receptors on the surface of other cells. The Selectin family and HCAM are carbohydrate-binding proteins, and play a prominent role in the circulation of lymphocytes and neoplastic cells. CAMs are fundamental to development of tissue structure in metazoan organisms. Cellular differentiation dictates adherence to a specific microenvironment, through the pattern of surface CAM expression. Conversely, CAM binding can affect gene expression within the cell itself. Cell differentiation and cell adhesion are interdependent processes. In the adult, CAM are crucial to tissue maintenance. Cells frequently change their adhesive properties in response to physiological or pathological processes. The integrity of the vascular system is maintained by circulating platelets which are capable of rapid upregulation of cell adhesion and profound changes in metabolism, on contact with subendothelial matrix. Both endothelial cells and neutrophils undergo changes in CAM expression in response to inflammatory mediators, permitting rapid and appropriate recruitment of phagocytes to damaged tissue. Tissue repair is dependent on phenotypic changes in normally static cells, allowing increased motility and replication. The immune system requires constitutive cells to undergo multiple complex adhesion and detachment events over short periods of time, and is capable of discriminating normal self from aberrant-self or non-self, through antigen specific recognition and adhesion molecules. The pathophysiology of processes such as infection and neoplasia are profoundly affected by cellular CAM expression. CAMs and related molecules are fundamental to the development, maintenance and surveillance of tissue structure.


Review article: metabolic consequences of long-term inhibition of acid secretion by omeprazole. Metabolic sequelae of profound and long-lasting inhibition of gastric acid secretion by omeprazole have largely been neglected. Data from long-term studies suggest that vitamin B12 stores decrease slightly over several years, although this was not clinically relevant within the first 4 years of therapy. Additionally, it cannot be completely ruled out that patients with an increased iron demand may develop iron deficiency, but data available at present do not provide any evidence that iron malabsorption is to be expected under normal conditions. Protein homeostasis and calcium metabolism seem to be unaffected by long-term omeprazole therapy. Based upon present experience, serum cobalamin concentration should be monitored in patients undergoing omeprazole therapy for several years.


Endothelium-dependent responses of cerebral arterioles to adenosine 5'-diphosphate. The goal of this study was to determine the role of endothelium-derived relaxing factor (EDRF) in dilatation of cerebral arterioles in response to adenosine 5'-diphosphate (ADP). Using intravital microscopy, we measured the diameters of pial arterioles in vivo in rats during superfusion with ADP, acetylcholine and nitroglycerin before and during topical application of inhibitors of nitric oxide synthesis (NG-monomethyl-L-arginine; L-NMMA and NW-nitro-L-arginine; L-NNA). Prior to suffusion with L-NMMA and L-NNA, ADP (10 and 100 microM), acetylcholine (0.1 and 1.0 microM), and nitroglycerin (1.0 and 10 microM) produced dose-related increases in the diameter of pial arterioles. Following application of L-NMMA (1.0 and 10 microM) and L-NNA (0.1 and 1.0 microM), dilatation of cerebral arterioles in response to ADP was significantly inhibited. In addition, L-NMMA and L-NNA significantly inhibited dilatation of cerebral arterioles in response to acetylcholine, but did not alter vasodilatation in response to nitroglycerin. Thus, our findings suggest that ADP dilates cerebral arterioles via the production of nitric oxide, or a nitric-oxide-containing compound.


Effect of potassium chloride on gastric acid secretion and gastrin release in humans. The effect of potassium chloride on gastric acid secretion and gastrin release was studied in 6 healthy human beings. On 3 separate days and in random order, subjects received an intragastric infusion of 0.5 L of a glucose-saline solution to which had been added 40 mmol KCl, 40 mmol NaCl, or no additional salts. All test solutions stimulated acid secretion and gastrin release to a similar degree. While potassium ions play a critical role in acid secretion by parietal cells (via the H+, K(+)-ATPase), KCl administered into the gastric lumen at a concentration of 80 mmol/L has no effect on acid secretion in man.


Experience with 'triple' anti-Helicobacter pylori eradication therapy: side effects and the importance of testing the pre-treatment bacterial isolate for metronidazole resistance. At the 1990 World Congresses of Gastroenterology, the Working Party on Helicobacter pylori (H. pylori) recommended that, in suitable patients, the bacterium should be eradicated using a therapeutic regimen comprising a bismuth salt, tetracycline and metronidazole for two weeks. We have treated 40 patients infected with H. pylori with 'triple' therapy consisting of 120 mg tripotassium dicitrato bismuthate q.d.s., 500 mg tetracycline q.d.s. and 400 mg metronidazole t.d.s. for two weeks. The success rate, in terms of bacterial eradication, was 19/21 (90.5%) in patients with metronidazole-sensitive organisms, compared with only 6/19 (31.6%) in patients whose H. pylori were resistant to metronidazole (P less than 0.01). Side effects, particularly diarrhoea and vomiting/nausea, were common: 23/40 patients reported such symptoms during the 14-day course of therapy. Fifteen of these 23 patients completed the entire 14-day course, although suffering from significant side effects, while the remaining eight patients had to discontinue the treatment because side effects became intolerable. If a form of triple therapy is going to be widely used to eradicate H. pylori infection, the regimen will have to be simpler, shorter, produce fewer side effects and be more effective in patients with metronidazole-resistant bacteria.


Co-administration of misoprostol or ranitidine with indomethacin: effects on pharmacokinetics, abdominal symptoms and bowel habit. This three-way randomized crossover study in 18 healthy male volunteers compared the pharmacokinetics of 50 mg indomethacin b.d. during concomitant twice daily dosing with 400 micrograms misoprostol, 150 mg ranitidine or placebo. Plasma indomethacin concentrations were determined by HPLC assay of samples collected over 12 h after the first dose, and over 14 h after the last dose on Day 8 of each dosing period. A daily diary of bowel habits, and the occurrence and severity of abdominal symptoms, was kept by each subject throughout the study. Statistical comparisons were made by analysis of variance. In the presence of misoprostol there was a 13% decrease in the area under the plasma concentration-time curve of indomethacin over one dosing interval on Day 1 (P less than 0.01), and at steady state there was a 24% decrease in the maximum plasma concentration (P less than 0.02). The pharmacokinetics of indomethacin were not affected by co-administration of ranitidine. Accumulation of indomethacin after repeated oral dosing was not significantly altered by the co-administration of either misoprostol or ranitidine. The frequency and severity of abdominal symptoms was significantly increased (P less than 0.01) during misoprostol dosing, compared with either ranitidine or placebo plus indomethacin. When the dosing phase (Days 1-8) was compared with the washout phase (Days 9-15) in each period, misoprostol, but not ranitidine or placebo, plus indomethacin resulted in an increase (P less than 0.001) in abdominal symptom severity, frequency of bowel motions and a decrease in faecal consistency.


Endothelium function is protected by albumin and flow-induced constriction is independent of endothelium and tone in isolated rabbit femoral artery. To investigate the preservation of endothelial function, we perfused two segments of one rabbit femoral artery (n = 8) in a pressure myograph in parallel, both with Tyrode, but one with 0.6% albumin added. The change in the outer diameter of the vessels [preconstricted with norepinephrine (NE) to 70%] in response to acetylcholine as an indicator of the endothelial function, was repeatedly measured over 5 h after the equilibration. The difference between the acetylcholine responses of the two vessel segments was significant (p < 0.05) after a perfusion period of 4 h. We also investigated whether flow-induced constriction is dependent on (1) the presence of endothelium and (2) the level of preconstriction. We therefore perfused segments of rabbit femoral arteries (n = 5) with Tyrode with 0.6% albumin. If acetylcholine-induced dilatation was present, a flow-diameter relation was determined at two constriction levels: about 60% (high) and 90% (low) of the passive outer diameter. Both determinations were repeated after mechanical endothelium removal (checked functionally and histologically). A similar decrease in diameter (about 7%) with an increase in flow ranging from 0 to 1,330 microliters/min was found in all conditions. We conclude that the addition of (0.6%) albumin protects endothelial function in the rabbit femoral artery when perfused in the low-flow range for a period longer than 4 h. We also found that flow-dependent constriction is neither influenced by the presence of the endothelium nor by the level of tone induced with NE.


An artificial stomach-duodenum model for the in-vitro evaluation of antacids. To improve the dynamic in-vitro evaluation of the effects of antacids, we have developed the 'artificial stomach' model by adding a 'duodenal reservoir' to receive the gastric emptying flux and simulated bicarbonate secretion, thus constituting an 'artificial stomach-duodenum' model. With this model we measured antacid-induced resistance to gastric acidification, and simultaneously evaluated the effect of antacid activity on the duodenal milieu. The model also permitted evaluation of the antacid effects of proteins (as natural antacids), and of drugs containing aluminium phosphate, alone or combined with magnesium oxide, or aluminium and magnesium hydroxides. At the gastric site, these drugs, as well as the proteins (that is, meat extract), induced a strong resistance to acidification due to the gastric emptying flux and to antacid composition. At the duodenal site, the decrease of the acid load penetrating into the duodenum varied, depending on the efficacy of gastric antacid activity. Duodenal pH was related to the equilibrium between bicarbonate secretion and the emptying of acid load. Proteins and aluminium phosphate induced the same duodenal pH as in the control tests without antacids, but magnesium-containing antacids increased it, thus decreasing bicarbonate consumption. The antacid mechanisms within the stomach, and the fate of antacids in the duodenal milieu, might explain the variation in duodenal pH in response to antacid administration.


Synthesis of TGF-beta 1 by vascular endothelial cells is correlated with cell spreading. Cultured vascular endothelial cells (ECs) secrete transforming growth factor beta (TGF-beta) which stimulates intimal smooth muscle cells to synthesize increased amounts of lipoprotein-binding proteoglycans. We report here that the amount of TGF-beta 1 synthesized by ECs is correlated with EC density and cell spreading. ECs cultured at low density synthesized and secreted 2- to 3-fold more TGF-beta, measured by the Mink lung cell assay, than intermediate and high density cultures, and this increase in secreted protein was matched by a corresponding increase in mRNA for TGF-beta 1 measured by Northern hybridization using a [32P]-labeled cDNA probe for TGF-beta 1. TGF-beta 1 mRNA was detected in individual cells by in situ hybridization with the cDNA probe labeled with [35S] and with a [35S]-labeled 30-mer antisense oligonucleotide. In situ mRNA levels did not relate to cell density per se but to cell area. The larger the area of substratum covered, the more mRNA per cell, irrespective of cell density. For cell areas in the range 500-1,200 microns 2, a doubling of cell area resulted in an approximately 3-fold increase in mRNA. Cells cultured at low density had a larger mean cell area than cells cultured at higher densities, and this increased area was sufficient to account for the increased TGF-beta 1 mRNA levels found for the low density cultures by Northern hybridization. Despite variations in cell area, cell volumes did not change significantly with cell density.(ABSTRACT TRUNCATED AT 250 WORDS)


Oral pharmacokinetics of cyclosporin in patients with primary biliary cirrhosis and patients with skin diseases. The pharmacokinetics of cyclosporin after oral administration were studied in seven patients with non-end stage primary biliary cirrhosis (PBC) without previous cyclosporin treatment (Group I), a control group of nine patients with skin diseases (mainly psoriasis; Group II) and six patients with PBC after prolonged cyclosporin treatment (Group III). Whole blood concentrations of cyclosporin were measured using a non-specific (N) radioimmunoassay (RIA) and--in a majority of the cases--also by a RIA specific (S) for the parent drug. No difference in cyclosporin absorption was observed between patients with PBC and those with a skin disease. The mean values for the area under the blood concentration-time curve for the first 6 h after the test dose (AUC0-6) and the maximal blood concentrations (Cmax) were significantly higher for Group I compared with Group II patients (P = 0.007 and 0.03, respectively), but the time to maximal blood concentrations (tc,max) did not differ. There was a trend toward higher mean AUC0-6 (P = 0.08) and Cmax (P = 0.08) values for Group III compared with Group I patients. Tc,max values were not influenced by prolonged cyclosporin treatment. The ratio of cyclosporin whole blood concentrations measured by the non-specific and specific RIA's (N/S ratio) increased with time without obvious differences between the three groups. These data suggest that cyclosporin absorption and its biotransformation in the liver are not impaired in patients with non-end stage PBC and that neither is affected by prolonged treatment.


Omeprazole versus famotidine in the short-term treatment of duodenal ulcer disease. The efficacy and safety of omeprazole, in 241 patients with active recurrent duodenal ulcer from 21 Italian centres, was studied in a multicentre double-blind randomized trial comparing 20 mg omeprazole o.m. or 40 mg famotidine nocte with endoscopic examination, symptom recording, laboratory screening and gastrin assay. In a per protocol analysis, the duodenal ulcer healing rates for omeprazole and famotidine, documented by endoscopy, were 62% (68/109) and 33% (39/117) after 2 weeks of treatment (P less than 0.001), 92% (96/104) and 80% (86/108) cumulative after 4 weeks (P less than 0.05), and 99% (102/103) and 92% (96/104) after 6 weeks (P less than 0.05), respectively. The results of this trial demonstrate that 20 mg omeprazole o.m. is superior to 40 mg famotidine nocte in duodenal ulcer healing.


Influence of the timing of administration of 300 mg ranitidine on 24-hour gastric pH in patients acute duodenal ulcer. The 24-hour intragastric pH of 12 patients with an acute duodenal ulcer was recorded with the aim of comparing the effects of two different times of administration of 300 mg ranitidine: post evening meal, or bedtime. This double-blind crossover trial involved 3 centres. Twenty-four-hour gastric pH was measured under standard conditions (meals, time schedule) at the middle of each 14-day treatment period. The analysis was performed on the percentage of times spent at pH levels below 1.5, 2, 3 and 4 for different periods and for the total 24 hours. During the whole day and night combined, as well as during the afternoon (12.00 hours-19.00 hours), there was no difference between the 2 regimens regardless of the pH profile studied. During the morning (07.30 hours-12.00 hours), the time spent below pH 1.5 and 2 was less when the drug was taken at bedtime (P less than 0.05). In contrast, during the whole night (19.00 hours-07.30 hours) the percentage of time spent below pH 1.5, 2 and 3 was significantly less when the drug was taken at post evening meal (P less than 0.05). These results show that in patients with acute duodenal ulcer, 300 mg ranitidine administered at the end of the evening meal provides better control of nocturnal acidity than administration at bedtime and hence is suggested for optimization of therapeutic efficacy.


Treatment of Crohn's disease with fusidic acid: an antibiotic with immunosuppressive properties similar to cyclosporin. Fusidic acid is an antibiotic with T-cell specific immunosuppressive effects similar to those of cyclosporin. Because of the need for the development of new treatments for Crohn's disease, a pilot study was undertaken to estimate the pharmacodynamics and tolerability of fusidic acid treatment in chronic active, therapy-resistant patients. Eight Crohn's disease patients were included. Fusidic acid was administered orally in a dose of 500 mg t.d.s. and the treatment was planned to last 8 weeks. The disease activity was primarily measured by a modified individual grading score. Five of 8 patients (63%) improved during fusidic acid treatment: 3 at two weeks and 2 after four weeks. There were no serious clinical side effects, but dose reduction was required in two patients because of nausea. Biochemically, an increase in alkaline phosphatases was noted in 5 of 8 cases (63%), and the greatest increases were seen in those who had elevated levels prior to treatment. All reversed to pre-treatment levels after cessation of treatment. The results of this pilot study suggest that fusidic acid may be of benefit in selected chronic active Crohn's disease patients in whom conventional treatment is ineffective. Because there seems to exist a scientific rationale for the use of fusidic acid at the cytokine level in inflammatory bowel disease, we suggest that the role of this treatment should be further investigated.


Short report: cefprozil for the eradication of Helicobacter pylori infection. Helicobacter pylori infection has proven to be extraordinarily difficult to eradicate. Antimicrobial monotherapies have been particularly disappointing, with most eradication rates in the range of 0 to 15%. We evaluated cefprozil (250 mg q.d.s. for 14 days) in 12 H. pylori-infected subjects. The 13C-urea breath test was used to evaluate effectiveness of therapy. Eradication was defined as a negative urea breath test 4 to 6 weeks after the end of treatment. Suppression of H. pylori was demonstrated in 4 of 12 (33%) by a negative urea breath test two days after start of treatment. H. pylori infection was not eradicated in any subject (0%). Adverse events were intermittent and mild. Cefprozil does not appear to offer promise as monotherapy for the eradication of H. pylori.


Short report: comparison of the effects of sublingual nifedipine and isosorbide dinitrate on oesophageal emptying in patients with Chagasic achalasia. The effects of sublingual nifedipine and isosorbide dinitrate on oesophageal emptying were compared in 11 patients with Chagasic achalasia. The oesophageal emptying of a radiolabelled test meal was assessed three times in each patient by a scintigraphic technique. No treatment preceded one of the studies (basal study). Nifedipine (20 mg) by the sublingual route 30 min before the meal, preceded one study. Isosorbide dinitrate, 5 mg by the sublingual route 5 min before the meal, preceded the third study. The order of the studies was allocated randomly for each patient. Oesophageal retention at the completion of the meal was significantly less (P less than 0.01) after isosorbide dinitrate (median: 54%, range: 5-87%) than after sublingual nifedipine (median: 78%, range: 7-99%) or after the control study (median: 83%, range: 5-100%). This difference persisted up to 20 min after the meal. Values measured in the control study and after sublingual nifedipine were not different (P greater than 0.10). These results show that isosorbide dinitrate, but not sublingual nifedipine, enhances oesophageal emptying in Chagasic achalasia.


Short report: comparison of two orally administered bowel preparations for colonoscopy--polyethylene glycol and sodium picosulphate. Fifty-nine consecutive patients admitted for colonoscopy were randomized to receive polyethylene glycol or sodium picosulphate. Patients expressed their opinion in a questionnaire and the endoscopists, blinded to the preparation, assessed the cleanliness of different segments of the colon. There was no statistically significant difference in the taste-acceptability of the preparations, frequency of nausea, abdominal pain, peri-anal soreness or sleep disturbance between the two groups. Polyethylene glycol caused vomiting in 13% of patients while this was absent in those who received sodium picosulphate (P less than 0.05). The average number of stools passed was 12.4 in the polyethylene glycol and 8.6 in the sodium picosulphate groups; mean difference 3.8 (95% C.I. 0.7-6.9) with P less than 0.02. The overall cleanliness of the colon was better in the polyethylene glycol group (P = 0.002) as judged by the blinded colonoscopist. There was less delay (P = 0.06) and more completed colonoscopies (P = 0.01) in this group. Polyethylene glycol was a better preparation in all segments of the colon except the rectum. We conclude that polyethylene glycol is the choice of the colonoscopist and should be given to all patients; sodium picosulphate would be a good alternative if patients are intolerant. If a limited colonoscopy or flexible sigmoidoscopy is intended, sodium picosulphate may be preferred because of its acceptable efficacy and slightly advantageous side-effect profile.


Review article: the pathophysiology and pharmacological treatment of portal hypertension. The pathogenesis of portal hypertension remains poorly understood. Similarly, pharmacological manipulation for the prevention and treatment of variceal haemorrhage has not fulfilled the promise of the 1980s. This article reviews current concepts in the pathophysiology of portal hypertension and considers pharmacotherapy for the treatment of variceal bleeding.


Review article: the treatment of alcoholic liver disease. Over the past 20 years we have moved from a situation in which we had no therapy for alcoholic liver disease, through a period when any therapy we had was purely empirical, to an era where we have specific therapies for different aspects of this disease based upon sound pathogenic principles. In this short review, an attempt has been made to summarize these advances in the understanding of the pathogenesis of alcoholic liver disease. In particular, they explain why patients with severe acute alcoholic hepatitis continue to deteriorate in hospital despite withdrawal from alcohol, why they respond to corticosteroids, why only a small percentage of patients develop cirrhosis, and why propylthiouracil may offer protection.


Comparison between a standard pancreatic supplement and a high enzyme preparation in cystic fibrosis. This study compared the relative effectiveness of a standard pancreatic enzyme supplement ('Creon', Duphar) and a new preparation ('Pancrease HL', Cilag) containing about 3 times the lipase and more than 5 times the protease activity. Capsule dosage was adjusted to a ratio of approximately 3:1. Fat balances showed that absorption of fat did not change significantly on conversion to the new high-lipase product, and the coefficient of absorption of total energy was similarly maintained. The coefficient of protein absorption was significantly enhanced with the high enzyme preparation (P less than 0.01), which may explain the reported subjective improvement in stool odour. No adverse effects were recorded. Patient acceptability of the new compound was high; the great reduction in the number of capsules required at each meal was cited by all patients as the reason for their preference.


Omeprazole in the long-term treatment of severe gastro-oesophageal reflux disease in patients with systemic sclerosis. Twenty-five patients with systemic sclerosis and severe gastro-oesophageal reflux disease were treated with 20-80 mg omeprazole daily for up to 5 years. Efficacy of treatment was assessed by symptom score, by endoscopic and histopathological surveillance of the oesophageal and gastric mucosa, and by laboratory screening including serum gastrin concentration. Statistically significant relief of symptoms and healing of oesophagitis confirmed the efficacy of this treatment. However, complete healing of oesophagitis was not achieved in half of the patients due to residual gastro-oesophageal acid reflux. Repeated adjustments of the maintenance dose of omeprazole may be needed for this group of patients. From the safety point-of-view, nothing was observed to discourage the long-term use of omeprazole in this group of patients.


A comparison of gastro-oesophageal reflux in volunteers assessed by ambulatory pH and gamma monitoring after treatment with either Liquid Gaviscon or Algicon Suspension. This study was designed to compare the effectiveness of single doses of either Liquid Gaviscon or Algicon Suspension in the suppression of food and acid reflux into the oesophagus after a test meal in volunteers. After the pH electrode and gamma detector were positioned 5 cm above the cardia, the volunteers received a refluxogenic radiolabelled meal. The subjects then remained untreated, or thirty minutes later they were given a dose of unlabelled Algicon Suspension, or Liquid Gaviscon and a recording was made for a minimum of 3 hours. Allocation to the treatment group was randomized with the cross-overs performed 1 week apart. Liquid Gaviscon suppressed gastro-oesophageal reflux of both food and acid whereas only an insignificant reduction in reflux was seen after Algicon Suspension. The oesophageal pH remained below 4 for 3.21 +/- 0.92% (S.E.M.) of the recording period in the control study, 0.88 +/- 0.33 after Gaviscon and 2.91 +/- 0.68 after Algicon. The reflux of food was reduced from 17,070 x 10(3) +/- 4713 x 10(3) counts in the control study to 224 x 10(3) +/- 93 x 10(3) counts after the Gaviscon and 16,080 x 10(3) +/- 7131 x 10(3) counts after Algicon. The suppression of reflux by Liquid Gaviscon was significantly better than that produced by Algicon Suspension.


Oral or intravenous erythromycin has no effect on human distal colonic motility. Erythromycin is a prokinetic agent for the lower oesophageal sphincter, the stomach, the gallbladder and the small bowel, acting directly on motilin receptors. Its effect on pressure activity of the human colon has not been investigated. Eight healthy volunteers were studied on 2 occasions and given intravenous or oral erythromycin, or placebo in a single-blind, randomized crossover study. Sigmoid pressure activity was measured using a 4-lumen water perfused system placed sigmoidoscopically at 50, 45, 30 and 15 cm from the anal verge. The pressures were analysed for activity index (mmHg.min) for the 35 cm colonic study segment using dedicated software. No significant difference was found in the activity index following oral erythromycin (500 mg) or placebo, or following intravenous erythromycin 1.8 mg/kg or placebo. A further 8 subjects were studied in a single-blind crossover study to determine the effect of oral erythromycin (500 mg) b.d. on colonic transit, measured with radio-opaque markers and a single abdominal X-ray. Mean or segmental colonic transit times were not statistically significantly different (Student's paired t-test) in the subjects on placebo or erythromycin. This lack of effect of erythromycin on the distal large intestine may indicate the absence of receptors for motilin in that part of the gut.


Ranitidine for erosive oesophagitis: a double-blind, placebo-controlled study. Glaxo Erosive Esophagitis Study Group. A multicentre, randomized, double-blind, placebo-controlled study was conducted to evaluate the efficacy and safety of ranitidine 150 mg and 300 mg in 342 patients with erosive oesophagitis. Treatment was given four times daily, and continued for 12 weeks or until healing (that is, normal or only erythematous mucosa). Erosive oesophagitis healing rates, as determined by endoscopy, were significantly greater in ranitidine-treated patients by 4 weeks compared with those of placebo-treated patients. By 12 weeks, erosive oesophagitis healing rates were 83 and 81% for ranitidine-treated patients (150 and 300 mg, respectively) and 58% for placebo-treated patients (P less than or equal to 0.001, ranitidine vs. placebo). Symptomatic relief was achieved within 24 hours after starting either dosage of ranitidine. Heartburn frequency (P less than 0.001) and severity (P less than 0.001), as well as antacid consumed per week (P less than 0.001), were reduced in both ranitidine groups in comparison with placebo. Healing rates and symptom relief were similar in the two ranitidine groups. Both dosages of ranitidine were well tolerated. Ranitidine (150 mg) given four times daily appears to be as effective as 300 mg ranitidine given four times daily in patients with moderate to severe oesophageal erosions.


The effect of combined therapy with ranitidine and pirenzepine in the treatment of reflux oesophagitis. The combination of a histamine H2-receptor antagonist and a muscarinic receptor antagonist has been reported to result in greater suppression of intragastric acidity than either agent alone. The present randomized, double-blind, multicentre trial compared the effects of the oral combination of 150 mg ranitidine b.d. plus 50 mg pirenzepine b.d. with 150 mg ranitidine b.d. plus placebo pirenzepine b.d. in the treatment of patients with reflux oesophagitis. All 157 patients had symptoms of gastro-oesophageal reflux with endoscopically confirmed oesophageal erosions (Savary and Miller grades I-III). After four weeks of treatment, healing rates were 32/75 (43%) in the combined treatment group and 34/76 (45%) in the group receiving ranitidine alone. After eight weeks, the cumulative healing rates had increased to 48/72 (67%) and 51/75 (68%), respectively. More patients receiving ranitidine plus pirenzepine had complete relief of day- and night-time heartburn after four weeks compared with those receiving ranitidine alone (day: 59% vs. 38%, P = 0.02; night: 69% vs. 52%, P = 0.04). After eight weeks, symptom relief was comparable in both groups. Clinical adverse effects were reported by nine patients receiving ranitidine and by 19 patients receiving the combination. It is concluded that combining ranitidine with pirenzepine does not aid the healing of reflux oesophagitis but does improve symptom relief at four weeks.


Nine years of maintenance treatment with ranitidine for patients with duodenal ulcer disease. Four hundred and sixty-four patients with duodenal ulcer disease received continuous maintenance treatment with ranitidine for up to 9 years. Treatment failure was defined as either the first symptomatic recurrence of ulcer or the first ulcer recurrence accompanied by haemorrhage. Life tables were constructed using the Kaplan-Meier product-limit method; comparisons of survival curves were performed using the log-rank test; and multivariate analysis was carried out using the Cox proportional hazards model. Results. The proportion of patients remaining free from symptomatic recurrence of ulcer during maintenance treatment with either 150 mg/day or 300 mg/day ranitidine was: 95% at 1 year; 88% at 3 years; 86% at 5 years; and 81% at 7 and 9 years (95% C.I. 76-86%). Young age and the absence of exposure to non-steroidal anti-inflammatory drugs (NSAIDs) at the time of diagnosis of ulcer were shown to increase the likelihood of developing ulcer recurrence. The rate of ulcer recurrence after 9 years of maintenance treatment (17%) was significantly less than that after 5 years without active anti-ulcer therapy (80%), P = 0.0001. The proportion of patients who remained free from ulcer haemorrhage during maintenance treatment was: 99.1% at 1 year and 98.1% at 5 and 9 years (95% C.I. 96.7-99.6%). The risk of haemorrhage was significantly greater in patients who were not receiving active treatment (12.4% at 5 years) than in patients receiving maintenance treatment (less than 2% at 9 years), P = 0.0001 (log-rank test). Patients who had originally presented with haemorrhage had an increased risk of further ulcer bleeding compared with patients who presented with pain (P = 0.0013). A significantly greater proportion of patients with NSAID-associated duodenal ulcers remained free from ulcer recurrence during maintenance treatment compared with patients suffering from 'idiopathic' ulcers (P = 0.0238), although there was no difference between the two groups in respect of haemorrhage during maintenance treatment. Conclusions. (a) Continuous maintenance treatment with ranitidine for up to nine years successfully prevents ulcer recurrence in more than 80% of patients with duodenal ulcer disease. (b) Young age increases the risk of ulcer recurrence during maintenance treatment with ranitidine. Ulcers associated with NSAID-intake at the time of diagnosis have a lesser risk of recurrence during maintenance treatment. (c) The risk of haemorrhage in patients with ulcer disease receiving maintenance treatment with ranitidine for nine years was less than 2% compared with greater than 12% in untreated patients observed for 5 years.(ABSTRACT TRUNCATED AT 400 WORDS)


Short report: comparison of two doses of balsalazide in maintaining ulcerative colitis in remission over 12 months. In a four-centre prospective double-blind trial, 108 patients with ulcerative colitis in remission were randomized to receive balsalazide in doses of 3 g or 6 g/day for 12 months. The patients were assessed at 3-monthly intervals clinically, sigmoidoscopically and with routine haematology and biochemistry. Remission rates of 77% (3 g/day) and 68% (6 g/day) at 12 months were not significantly different. Intolerance reactions leading to withdrawal from the study occurred in only 9 patients (8%), all occurring in the first 7 weeks of the study. Balsalazide is therefore both highly effective in maintaining remission in ulcerative colitis and well tolerated in both conventional and high dosage (the latter equivalent to 5.5 g/day of sulphasalazine). In this study no distinct advantage in maintenance of remission has been found for the higher dose of balsalazide.


[Infectious endocarditis in parenteral drug addicts: study of 57 cases]. We present 57 cases of infectious endocarditis (IE) in 51 parenterally drug addicts (PDA) admitted at the Internal Medicine Service of the Hospital Clínico of Valencia between January ist, 1988 and January 15th, 1992. The disease affected young patients, 84% of them being HIV-1+ and 86% presenting CD4+ lymphocytes lower than 200 cells/mm3. Fever was the most constant symptom, with radiological disorders and presence of vegetations by echocardiogram in 65% and 53% of episodes, respectively, and affectation of the tricuspid valve in 59% of patients. The diagnosis of endocarditis was definitive in 51% of cases, possible in 15% and probable in 22%, being cardiac failure the most severe complication, present in 23% of episodes. The detection of significant valve regurgitation in patients with IE and without developing cardiac failure is not predictive of future complications, nor its absence identifies patients with a favourable prognosis. Staphylococcus aureus was the most frequently isolated germ (48%), being methicillin-resistant in 15% of cases and with a slower response to the treatment with vancomycin than the methicillin-sensitive. Five patients died, all of them with CD4+ lower than 50 cells/mm3, which may have a predictive value in the follow-up of these patients.


[Epidemiology of obesity among the adult population of Catalonia]. Several epidemiological studies have shown that obesity is related to the mortality from cardiovascular disease. In this study, the epidemiology of obesity and the correlation between body mass index and other cardiovascular risk factors was studied in a representative sample of the adult population of Catalonia. It was obtained a random sample (n = 704) of the adult population of Catalonia aged 15 or more years. Height and weight were measured and body mass index (BMI) was calculated (height in Kg/weight2 in m2). Obesity was defined as a BMI greater than 30, and overweight as a BMI from 25 to 30. In the first 314 participants, it was determined the concentration of total cholesterol, cholesterol-HDL and triglyceride, and it was measured the blood pressure. The correlation between BMI and other cardiovascular risk factors was analysed. The study was carried out in 1989. The mean of BMI increased with age in both sexes. BMI was significantly higher in men (26 kg/m2) than women (25 kg/m2). The prevalence of obesity was of 12% in both men and women, and the prevalence of overweight was of 48.5% in men and 38% in women. The prevalence of arterial hypertension, hypercholesterolemia and diabetes was greater individuals with obesity, with differences statistically significant for hypertension (odds ratio of 3.26). The multiple logistic regression analysis showed that the association between obesity and hypertension was not statistically significant (OR adj. = 2.09), when the effect of the other risk factors, the age and sex were controlled.(ABSTRACT TRUNCATED AT 250 WORDS)


[Comparative study of von Willebrand factor in patients with temporal arteritis]. Giant cell arteritis, temporal arteritis (TA), is a vasculitis which affects large and medium-sized vessels. The von Willebrand factor (vWF) is synthesized by endothelial cells and megakaryocytes. Increased amounts of vWF are released into plasma in response to an endothelial damage. vWF levels were studied by Electro-Immunodiffusion in 16 patients with TA (8 of them with a positive biopsy) and their values were compared with 5 patients with Polymyalgia Rheumatica (PMR) and 32 controls. We found higher amount of vWF in global TA, biopsy-positive TA, biopsy-negative TA, and PMR than in controls. There were no relationship between vWF amounts in plasma and clinical findings nor the laboratory parameters. We feel that although in our study vWF might be of some help as an alternative to the biopsy in those patients with high suspicion of TA, the results of other authors raise doubt about the usefulness of the determination of vWF in TA.


[Dual photon absorptiometry in algodystrophy]. Biphotonic absorptiometry has begun to demonstrate its usefulness in the field of osteoporosis. In algodystrophy, the radiology and the degree of isotopic fixation suggest a bone disorder, although both techniques are unable to objectively quantify it. Biphotonic absorption is an scanning technique which allows the quantification of bone demineralization in the segment affected by algodystrophy and its evolutive follow-up.


[Hepatic cirrhosis and alpha 1-antitrypsin deficit: a family study]. Hepatic cirrhosis secondary to deficit of alpha-1 antitrypsin is an entity rarely observed among the adult population. We describe the clinical and histological characteristics of a patient with PiZZ phenotype, affected by an hepatic cirrhosis of this etiology, as well as the analytical and phenotypical study of his close relatives, all of which presented a type-Z mutation.


[Bardet-Biedl syndrome: subclinical renal disorders in 2 siblings]. Two siblings with Bardet-Biedl's syndrome are studied, in whom renal structural and functional disorders were observed, with reduction in the ability to concentrate urine in both cases and decrease of creatinine clearance in the second case. The study of the hypophyseal function was normal.


[Fahr's disease and hypocalcemic syndromes. Presentation of a clinical case]. A clinical case of a man with calcification of basal ganglions (CBG) is presented. The first manifestations of this syndrome were loss of consciousness and convulsions. The potential causes of his hypocalcemia, Fahr's syndrome, myocardiopathy of hypoparathyroidism and hypocalcemia are reviewed and a study oriented to autoimmune polyendocrinopathy is performed.


[Hepatic hemangiomas and rheumatoid arthritis in patients treated with azathioprine]. Two clinical cases of patients with rheumatoid arthritis (RA) and poor response to conventional treatment are described. Patients received immunosuppressor treatment with azathioprine (AZA) and developed hepatic hemangiomas without detectable hepatic pathology previous to the treatment with AZA. The hepatic iatrogenesis of AZA is discussed, as well as the etiopathogenic hypothesis regarding hepatic hemangioma.


[Clinical syndromes in HIV infection (part 2)]. The spectrum of clinical manifestations associated to HIV infection is very broad. In addition to processes that may be attributed to the virus itself, multiple opportunistic infections can develop while the immunodeficiency develops. Any organ or system of the organism may be affected by these processes. The main clinical syndromes in AIDS and the differential diagnosis of their potential etiologies are reviewed.


[Clinical and diagnostic characteristics of Aeromonas strains]. We studied the taxonomic, clinic, microbiological diagnostic and therapeutic characteristics of Aeromonas strains. Eleven geno-species have been isolated in human. They can be enterotoxigenic or enteroinvasive. These bacteria can be easily confused with other Gram negative bacilli (the Aeromonas are oxidase positive). They produce diarrhea but can only colonizer. In others localizations they are always diagnostic. Their detection in stools can be realized with the blood agar plus ampicillin or cefsulodin-novobiocin-irgasan agar. The treatment of extraintestinal infection is similar to the Gram negative infections. The Aeromonas are resistant to erythromycin, streptomycin and first generation cephalosporin. The beta-lactamic antimicrobials aren't the election treatment because the are positive beta lactamase. The diarrhea in children and immunocompromised or chronic patients will be treated with cotrimoxazole or fluorquinole.


[Maternal attitude to breast feeding and difficulties in the immediate puerperium]. To investigate the attitudes of women who have just given birth towards breast feeding according to their social class and level of education, as well as the problems arising during their stay in hospital, and the possible repercussions the latter might have. Transversal descriptive study, based on random sampling. SITE. The Maternity Unit of the "Marqués de Valdecilla" University Hospital, Santander. 100 mothers of newborn babies chosen at random amongst those who had given birth vaginally to normal babies after a nine months pregnancy. The results from the questionnaire show that: 35% derived their information on breast feeding from magazines, 25% from the psychoprophylactic obstetrician (PPO), 28% had no information. 60% of the sample took the decision to breast-feed before pregnancy, 21% during the pregnancy, and 6% after the birth. 78% of the children were fully documented at the hospital on: first time at the breast, frequency of feeds, glucose solution supplement. 60% of the mothers evidenced problems with their breasts. On leaving hospital, 83% were breast feeding. To continue promoting breast feeding and helping mothers not to have so many problems at the beginning, we should use primary health attention, PPO courses and prenatal education as platforms for action, emphasising the importance of preventive care of the breast and breast-feeding technique. Hospitals should incorporate the international recommendations on initial lactation, with subsequent reinforcement during home visits and health centre appointments.


[Major and minor changes in the electrocardiogram of the hypertensive patient]. To determine the prevalence and characteristics of electrocardiograph deviation in such hypertensive patients. Retrospective descriptive study of a representative sample of patients with high blood pressure. SITE. Primary attention centre. The sample consists of 352 patients, systematically random selected from a pool of 1780 patients suffering from hypertension, aged over 14 years, attending the centre (119 males (34%) and 233 females (66%). Average age 59.4 +/- 13.5 years). The first ECG reading after diagnosis of hypertension was analysed and codified according to the pooling project criteria. 38.9% present electrocardiograph deviations, the most frequent being minor wave 1 (12%), significant breaking up of the ST (9%) and left ventricular hypertrophy (5.1%), the latter more frequent in women (p = 0.03). Age, systolic arterial blood pressure and the time the condition had been in existence, certain associated chronic diseases, and use of pharmaceutical drugs acting cardiovascularly, are positively related to the deviation in ECG (p < 0.05). The value of ECG in the treatment of high blood pressure sufferers is indicated.


[Mental disorders and the utilization of the general medicine consultation]. To study the quantitative relationship that exists between mental problems and use of the general medical practitioner, and the association between such problems, increased use of the medical services, and morbidity and socio-demographic variables. Observational cross-section study. SITE. A primary care team's general medical consultations. Patients aged over 15, attending the consultations. A sample of 310 patients was selected using systematic sampling. The Mental Health GHQ, 28 items questionnaire was administered to the patients, to detect the existence of significant mental health disorders. Amongst older patients there is a greater incidence of mental illness, statistically significant at p less than 0.01. Also significant at p < 0.01 were the greater number of visits to the doctor amongst patients previously diagnosed as having mental disorders, amongst the elderly, those patients included in health programmes and those who showed greater take-up of supplementary explorations and interim consultations. The results demonstrate an association between mental illness and greater number of visits to the general practitioner, leading to the hypothesis that a considerable number of such visits could be attributed to mental illness. There is no doubt that it is important to integrate the mental health services into primary care practice.


[The appropriateness of emergency referrals sent from primary care to a general hospital]. Study of the degree of completeness of slips sent to forward patients from primary medical care to emergency units of the corresponding general hospital. This is a statistical descriptive and inferential study. SITE. The study was carried out in the general hospital allocated to Zaragoza Health Area III. Included in the study are all patients sent by primary medical care for evaluation by the urgency unit in the internal medicine section. 415 urgent treatment slips were analysed, evaluating the completion rate and the degree of correctness in relation to their source as either rural or urban. With regards the degree of completion (clinical history, antecedents, examination) and correct functioning at the visit to family doctor stage, there are highly significant differences between those sent from all other such centres (p less than 0.01). Only in the case of 8 slips were physical examinations completed for the presenting ailment: 7 came from urban health centres and 1 from rural health centres. Diagnostic impressions and observations were absent from 62.2% of the slips. While overall there is no difference between those sent from rural and urban centres, there were differences when those sent from urban health centres were compared with those sent by all other health centres.


[The approach to the etiological diagnosis of hyperlipemias in primary care]. To perform etiological diagnosis of hyperlipidemia (HL) brought to light in family medical (general practice) consultations. Retrospective descriptive study. SITE. A basic health zone (ZBS). 231 patients diagnosed as having HL by their doctors. Lipidic levels (average figures): total cholesterol (CT): 280; C-LDL: 201; C-HDL: 49 and triglycerides (TGL): 198. Distribution by phenotypes: IIa: 178 patients, IIb: 42, IV:5, with 6 doubtful cases. Distribution according to etiological diagnosis: 79% primary HL (83% polygenic and 17% family) 15% secondary HL, with 6% having both types in association. Diagnosis of HL in the visits to the family doctor reveals probability-predictable patterns based, above all, on the the overall assessment made by the doctor of his/her patient. The survey and the family study are very limited in our circles. The predominating type of HL is primary polygenic where prescribing of special diets will be sufficient in most cases.


[Follow-up of the quality of drug prescriptions: the Primary Care Center of Badia City (1986-1990)]. To determine the variation in the quality of prescription of medicines in Primary Attention Centre in two different periods, 1986 and 1990. Longitudinal, retrospective study with direct intervention. SITE. Primary Attention Centre, Ciudad Badía. 1986: 9 general practitioners in medicine (GPs) and 7 pediatricians. 1990: 9 Gps, 7 pediatricians, and 7 residential doctors (MFC based) who were not included in the earlier evaluation. Once the 1986 prescriptions had been analysed qualitatively, the results were made available to and discussed with the doctors who made out the prescriptions (passive feedback). As ongoing intervention the periodic clinical sessions should be considered. Increase in the substances included in Index/Guide: MG 6.5% and P 13% (p < 0.00001). Increase in the number of substances with an active principle and in the combinations accepted: MG 2.3% and P 9% (p < 0.00001). Increase in the percentage of specialties with high V1: MG 1% (p = 0.12) and P 10% (p < 0.00001). There has been an increase in the quality of medical prescriptions according to the indicators analysed. There are other external factors that effect prescriptions that are difficult to measure. This type of study allows one to pinpoint the excessive or wrong use of intrinsically not very valuable sub-groups of therapeutic substances, and will serve as a base for indication-prescription studies.


[Effect of post-natal visit on the involvement in the activities of the mother-child program]. Ascertain what effect post-natal visits have on recruiting involvement in the mother and child programme of activities. Identify the profile of mothers and children with little involvement in these activities. Ascertain how suitable the register is. Study of cohorts of previous years. The term exposed cohort refers to mothers who received the postnatal visit in 1989, and non-exposed cohort to those who did not receive one. SITE. Health Centres in Almanjáyar and Cartuja. Primary Attention. Evaluation of the services offered. The sample consisted of the 166 women whose pregnancy we monitored from the Centre, and who gave birth between January and December 1989. The most indicative results show that the group that received the post-natal visit tended to attend the healthy child clinic, family planning and metabolism testing services, with greater frequency, and to breast feed longer. The differences are only significant (p = 0.004) in the case of family planning. We positively evaluate the post-natal visit because of its contribution to the early detection of the problems of mother and child, and to recruitment into Family Planning. And because the examining risk has meant that factors associated with reduced coverage by the services (ethnicity, educational level, mother's age) did not act as such in our study.


[Effect of the physician's and the patient's sex on the clinical interview]. To analyse differences attributable to the sex of the doctor and of the patient in the activities and content of the clinic appointment in Primary Attention. Analysis of interaction, in terms of activities and content, in 157 clinic appointments. SITE. General medical consultations in four Primary Attention Public Health Centres. Those who used the health services on the day of the study. Tape recording of the appointments. The interviews were recorded. There were shown to be differences according to the sex of the doctor and of the patient in terms of the development and content of the interviews. The style of the woman doctor involved longer interviews with greater social content; in general sameness of sex (doctor and patient) led to greater mutual complementation in the interviews. It has been shown that there are differences in the activities and content of the clinic appointments in Primary Attention which depend on the sex of the patient and doctor.


[Evaluation of the quality of prenatal care in primary care]. Determine the quality of prenatal assistance by means of an audit. This is a retrospective and longitudinal observational study. SITE. At the Primary Attention level, at the "La Chana" Health Centre, Granada. 514 mothers-to-be. The completion rate of the programme was studied via twelve indicators. Gynecological examination during the first visit (37.74%), serology of infections and toxoplasma (32%) and AgHBs (14.28%) were the indicators least carried out. Gestatory age (98.84%) probable date of the birth (98.45%) and arterial blood pressure (96.7%) were those most frequently carried out. Motivation exists in the Primary Attention team to record complete medical histories. Need to: unify therapeutic diagnostic criteria, increase coordination between the different levels of attention, and carry out audits more often, to evaluate the quality of attention given objectively.


[Spontaneous hematoma of the rectal muscles as a cause of abdominal pain with palpable mass]. To carry out a review of hematoma in the abdominal wall: etiology, triggering factors, diagnosis and treatment. To consider differential diagnosis with other causes of acute abdominal pain with palpable mass. Based on two clinical observations. SITE. Iscar Health Centre, Valladolid. Two patients who presented themselves at Casualty complaining of acute abdominal pain and with palpable abdominal mass (lump). The anamnesis and physical exploration provided the tentative diagnosis, and they were sent to the Hospital centre in question. The analyses, X-rays and abdominal scans were not conclusive and an abdominal laparotomy was carried out which confirmed the diagnosis. Spontaneous haematoma in the abdominal wall is a cause of acute abdominal pain which is encountered most frequently in women receiving anticoagulant treatment or in situations that increase abdominal muscular tension (coughing, pregnancy, constipation, previous laparotomies and intraabdominal injections). Confirmation of initial diagnosis is obtained, normally, using sonic scanners, or abdominal TAC, but on occasions findings are not conclusive, and are submitted to abdominal laparotomy. The treatment is conservative except with hemodynamic complications.


[Report on continuing care in 1990 at the Health Center I of Ciudad Real]. To determine what justification there is for Continuous Attention (CA). Secondly the ranking of processes, derivations and effect of the time of year. Descriptive longitudinal and retrospective study. Observational, non-controlled and without random distribution (all cases) and non-blind. SITE. Primary Attention (PA). All people who attended the Health Centre (HC) from 3-5 pm, in 1990. None that would affect the results. Most of those attending did so for IRA's, contusions, wounds, sprains and abdominalgias (table 1). 6.6% were derived, mainly digestive and traumatological processes (table 2). Compared with similar studies, the demand generated by our population is optimal both in numbers and in justification. Among the, subjectively-speaking non-justified visits the reasons were to avoid ordinary doctors appointments, to get second opinions, to obtain prescriptions, complementary analyses and hospitalisation, and obtain results more quickly, under the emergency service. A significant number of children are attended by general practitioners (GPs), and this induces private consultation. Derived cases are 6.6%, less than the standard 15%. One third of these cases are not hospitalised, especially in months when hospital demand is at its maximum. The lack of coordination between our service and the hospital casualty service is obvious, leading to amongst other things, the "rebound" effect on the user. Closeness between the two services means that an estimated 15% go directly to hospital, a fact which could diminish comparability between this and other studies, although in treating the whole series, the reliability of this study is improved.


[Preliminary study of smoking cessation at 6 months following medical counseling, pamphlet, and follow-up]. Preliminary study to evaluate the results of a programme to help smokers. Study involving direct intervention, with control group, and with random distribution in experiment group and control group. SITE. The study was carried out in the patients' visits of the five doctors at Primary Attention on the afternoon shift, "V Centennary" Health Centre, San Sebastián de los Reyes, Madrid. 102 smokers aged from 21 to 67 years who attended the appointments for any reason were selected. The participants in the experiment group (n = 48) were given a structured talk which lasted ten minutes and were supplied with a "Guide to Giving up Smoking". The control group (n = 50) were advised to give up the habit. We checked consumption by telephoning subjects, after 30 days, 90 and 180. After 30 days 12 individuals (25%) from the experiment group had given up smoking, and 4 (8%) from the control group. After 90 days 12 subjects from the former group did not smoke (25%) compared with 3 (6%) from the latter. After 6 months 10 out of the former group did not smoke (20.8%) and 5 individuals from the latter (10%) (not significant). Subjects were positively receptive to the medical advice received from their doctors. The level of non-smoking observed after 6 months is clinically significant, although the difference between the two groups is not statistically significant, possibly as a result of the small size of the sample.


Preferential use of T-cell receptor V genes in human autoimmune thyroid disease. We review here our analyses of hTcR V gene activity within the thyroid glands of patients with autoimmune thyroid disease. Our data, based on thyroid aspiration specimens, indicate that early in the onset of Graves' disease there is a marked restriction in both hTcR V alpha and V beta gene families utilized by intrathyroidal T-cells. Later, however, and as seen in surgical thyroid specimens from patients with long term disease, there appears to be a loss of V beta restriction for unclear reasons. In contrast, patients with Hashimoto's thyroiditis are usually diagnosed later in the natural history of the disease and appear to show much less hTcR V gene family restriction. The mechanisms driving the use of few and many hTcR V genes within the thyroid gland are likely to be complex and may reveal important insights into disease pathogenesis.


Cytokines and immune regulation in thyroid autoimmunity. We studied the role of cytokines and immune regulation in thyroid tissue from patients with Graves' disease. Immunohistochemistry showed that the thyroid glands are characterized by an aberrant expression of HLA class II antigens on thyrocytes, generation of new blood vessels and infiltration of mononuclear cells. We demonstrated that CD4+ memory cells were more frequent in thyroid glands from Graves' patients than were CD4+ naive cells. The intrathyroidal T cells demonstrated an enhanced expression of the adhesion molecules LFA-1, CD2, VLA-4 and VLA-5, and vascular endothelial cells of capillaries and thyrocytes in thyroid glands reacted with anti-ICAM-1 monoclonal antibody. The adhesion molecules and HLA antigens on both vascular endothelial cells and thyrocytes were regulated by inflammatory cytokines. These results suggest that circulating lymphocytes migrate into thyroid tissues and that memory T cells are retained in the thyroid tissues by cellular interactions with thyrocytes or with extracellular matrix.


A perspective on human autoimmune thyroid disease: is there an abnormality of the target cell which predisposes to the disorder? It has been suggested recently that autoimmunity could be regarded as a physiological response of the normal immune system to autoantigens caught up in an inflammatory response to viral or bacterial antigen expressed in the target tissue. Other theories to explain autoimmunity include molecular mimicry whereby a viral or microbial hapten similar to an autoantigen initiates the production of autoantibodies that cross react with an autoantigen, with a subsequent immune response reacting with autologous cell structures which are homologous with the particular microorganism. There has also been a suggestion that there may be a genetic abnormality of the target cell which is necessary for the initiation of autoimmune thyroid disease. The present review examines these proposals and provides evidence against an antigen-driven origin for autoimmune thyroid disease (AITD). Currently, there is no valid evidence for viral involvement, and likewise the evidence for molecular mimicry as an initiating factor does not hold up to scrutiny. While a genetic abnormality of the thyrocyte may be important in certain animal models of AITD, in the human there is no evidence for such an abnormality. Evidence that AITD is derived from a disturbance of immunoregulatory mechanisms has been documented elsewhere and would appear to be the most appropriate explanation for these disorders. The immunoregulatory disturbance itself may be related to an abnormality of the mechanism of specific antigen (i.e. normal autoantigen) presentation to appropriately induce T lymphocytes and that theory will require further illumination.


Intrathyroidal activated (Ia+) T-lymphocyte CD+ subsets and B cells in Graves' hyperthyroidism respond rapidly to propylthiouracil therapy: demonstration using fine needle aspirates and two-colour laser flow cytometry. Using a rapid (whole blood lysis) single laser microfluorocytometric technique that permitted the simultaneous analysis of two monoclonal antibody surface markers tagged with different fluorescent dyes, the intrathyroidal (IT) and peripheral blood (PB) activated [Ia+ = DR+] T-lymphocyte CD3+ subsets and [F(ab')2+] B cells were studied in hyperthyroid patients with Graves' disease (GD) before and after 1-4 months of propylthiouracil (PTU) therapy. IT lymphocytes were obtained by serial fine needle aspiration. In untreated patients a marked quantitative (approximately < 10 fold) increase in activated (Ia+ CD3+) T-lymphocytes as well as CD4+ and CD8+ subsets, for IT compared to PB sites, was found. The percentages of Ia+ CD4+ and Ia+ CD8+ within Ia+ CD3+ were not significantly different between the two sources of T cells. F(ab')2+. B cells were significantly increased (approximately 2-3 fold) in IT compared to PB. In hyperthyroid GD patients, PTU therapy induced rapid and specific changes within the Ia+ CD3+ subsets, namely a reduction in the Ia+ CD4+ subset and an increase in the Ia+ CD8+ subset, resulting in a marked decrease in the Ia+ CD4+/Ia+ CD8+ ratio. These changes occurred in association with a reduction in serum T4 and T3 concentration. No significant changes could be detected within the total (predominantly non-activated) CD3+, CD4+ or CD8+ lymphocyte subsets within PB and only a small decrease in the CD4+/CD8+ ratio was demonstrated in IT, following PTU treatment.(ABSTRACT TRUNCATED AT 250 WORDS)


Analysis of human TSH receptor gene and RNA transcripts in patients with thyroid disorders. Human TSH receptor (hTSH-R) gene and RNA transcripts were analyzed by Southern and Northern blots in patients with various thyroid disorders, and in tissue cell lines. A 1.4 Kb cDNA encoding the extracellular human TSH-R domain was used as a probe. Southern analysis revealed two constant bands of 11.0 and 5.0 Kb (hTSH-R) in the thyroid and human white cell samples studied, regardless of the disease process. Northern analysis showed a predominant band at about 4.4 Kb in the thyroid tissues but not in non-thyroid tissue or cell lines tested. There were no gene rearrangements or abnormal transcripts in Graves' disease or multinodular goiter samples. In contrast, the labelled cDNA TSH-R probe did not bind to RNA isolated from 1 of 2 papillary cancer samples. A portion of the unique area of the h-TSH receptor (approximately nucleotides 1100-1230) was directly sequenced in thyroid glands from patients with Graves' disease, multinodular goiter, and differentiated thyroid cancer. No mutations or polymorphisms were identified in these samples, as compared to normal thyroid or control placenta, although further definition of sequence variation in other areas of the TSH receptor, as well as in more samples, needs to be performed. The present study indicates the normal patterns of DNA and RNA hybridization in a variety of thyroid tissues and disease states, and demonstrates that pathologic thyroid samples, with the possible exception of thyroid cancer, were not associated with specific nucleotide abnormalities in the unique area of the TSH receptor that was studied.


The role of iodine in thyroid autoimmunity: from chickens to humans: a review. Evidence has been presented to support the idea that iodine plays an important role in autoimmune thyroiditis. Excessive amounts induce thyroiditis in genetically susceptible animal strains, while intrathyroidal depletion of iodine prevents disease in strains susceptible to severe thyroiditis. While the mechanisms by which iodine promotes thyroiditis is unknown, several hypotheses have been proposed. (1) T and/or B cells may react specifically to iodinated portions of thyroglobulin (Tg) so that severe iodine depletion renders Tg non-immunogenic. (2) A defect in the iodine processing machinery in thyroid epithelial cells of a susceptible person or animal may, in the presence of iodine, result in elevated levels of oxygen or iodine radicals, which could damage membrane lipids or proteins. (3) Defective iodine processing may result in the iodination of lipid or proteins (other than Tg) which could act either as immunogens or polyclonal activators.


Role of connective tissue autoimmunity in Graves' ophthalmopathy. Histologic similarities exist between the tissues involved in the extrathyroidal manifestations of Graves' disease, namely ophthalmopathy and pretibial dermopathy. Both conditions are characterized by an accumulation of glycosaminoglycans (GAGs) and an infiltration of lymphocytes. We have shown that interleukin-1 and transforming growth factor-beta, cytokines released by the local inflammatory cell infiltrate, are capable of stimulating GAG synthesis by retroocular and pretibial fibroblasts. Additionally, affected retroocular and pretibial fibroblasts demonstrate an enhanced induction of HLA-DR in response to interferon-gamma treatment and both cell types express the 72 kDa heat shock protein in vivo and in vitro. Retroocular and pretibial fibroblasts from patients with Graves' ophthalmopathy and pretibial dermopathy thus seem to possess unique immunological features that may render them more susceptible to the autoimmune process in Graves' disease. Chronic stimulation of fibroblasts by cytokines released in the local inflammatory milieu may result in excessive GAG production. The accumulation of these hydrophilic mucopolysaccharides, with its associated edema, leads to the clinical manifestations of Graves' ophthalmopathy and pretibial dermopathy.


Glycosaminoglycans in thyroid-associated ophthalmopathy. Glycosaminoglycan (GAG) accumulation in the retrobulbar space of patients with thyroid-associated ophthalmopathy (TAO) has been documented in a number of immunohistochemical studies. In order to gain further insight into possible immunopathogenic mechanisms, the influence of humoral immunity on retrobulbar fibroblasts (RF) as GAG producing cells as well as on GAGs themselves was investigated. The effect of lymphocytes on hyaluronic acid (HA) synthesis of RF as well as in turn the influence of RF on lymphocytes were evaluated. In search of methods which would facilitate management of patients with TAO and allow assessment of disease activity, GAGs were determined in both urine and plasma. Immunoglobulin G (IgG) of patients with TAO were found to markedly stimulate the 3H-GAG secretion of RF. Patients with TAO exhibited significantly greater antibody values directed against HA than controls. Preliminary results concerning the influence of lymphocytes on RF indicate a tendency for patients' lymphocytes to increase the synthesis of HA. Furthermore, these lymphocytes in turn were stimulated more by irradiated autologous RF than by irradiated heterologous RF. Urine and plasma GAG determination proved to be suitable for the routine assessment of disease activity and outcome of therapy. In conclusion, GAGs seem to play an important role in the pathogenesis of the disease and their measurement may provide aid to the endocrinological evaluation of patients with TAO.