[Prerequisites for a new health care model for elderly people with multiple morbidities: results and conclusions from 3 years of research in the PRISCUS consortium]. / Voraussetzungen für ein neues Versorgungsmodell für ältere Menschen mit Multimorbidität: Ergebnisse und Schlussfolgerungen aus 3-jähriger Forschung im PRISCUS-Verbund.

BACKGROUND: The concurrent presence or manifestation of multiple chronic conditions, i.e. multimorbidity, poses a challenge to affected patients and their relatives, physicians, and practitioners, and to the health care system in general. Aiming to improve medical care for different chronic diseases, the Chronic Care Model also appears to be suited for multimorbidity. The established research consortium PRISCUS is trying to create some of the prerequisites for a new care model for multimorbid, elderly patients oriented along the lines of the Chronic Care Model. METHODS AND RESULTS: Four out of seven subprojects of the research consortium provide an overview of some of their findings. Topics in a sports medicine subproject were the assessment of physical activity by means of a newly developed questionnaire and the development and feasibility testing of an exercise program for elderly people with chronic conditions and mobility impairment. Partners from family medicine implemented geriatric assessment in a primary care setting and evaluated its consequences. In a pharmacological subproject, potentially inappropriate medication as well as drug-drug interactions and dosing errors were addressed. The health economic subproject investigated quality of life impairment due to multiple chronic diseases and the effects of multimorbidity on costs. CONCLUSIONS: The results of the PRISCUS research consortium allow a better description of consequences of multimorbidity and illustrate at least some new approaches towards prevention, diagnosis, and treatment of patients suffering from multimorbidity. Ongoing projects will test the efficacy of a physical activity program and a new complex intervention to reduce potentially inappropriate medication in the elderly. With this, the research consortium will create some prerequisites for a new health care model for patients with multimorbidity comparable to the Chronic Care Model.

Autoantibodies from patients with primary biliary cirrhosis preferentially react with the amino-terminal domain of nuclear pore complex glycoprotein gp210.

Patients with primary biliary cirrhosis frequently develop autoantibodies directed to gp210, a major glycoprotein of the nuclear pore complex. This protein contains a large glycosylated cisternal domain, a single transmembrane segment, and a short cytoplasmic tail. It has been previously shown that autoantibodies from primary biliary cirrhosis patients exclusively react with the cytoplasmic tail. We demonstrate that autoantibodies against gp210 recognize at least two different epitopes. 4 out of 12 anti-gp210 positive sera reacted with the fragment consisting of the cytoplasmic tail, and 8 sera targeted a novel epitope located within the large glycosylated lumenal domain. Moreover, our data prove that carbohydrate moieties are an essential part of this novel epitope. We propose, therefore, that future screening assays should be performed with antigens possessing both epitopes to detect all sera with anti-gp210 specificity.

Scl-86, a marker antigen for diffuse scleroderma.

More than 300 sera from patients with a connective tissue disease were analyzed with the immunoblotting technique. The presence of autoantibodies against an 86,000-mol wt marker antigen for diffuse scleroderma (Scl-86) was found in 14 out of 33 patients with scleroderma. The presence of anti-Scl-86 antibodies seemed to correlate with the diagnosis of diffuse scleroderma since they were found in 13 out of 22 diffuse scleroderma patients and in only one out of 11 patients with limited scleroderma. All scleroderma sera (33 patients' sera and 13 reference sera) were also tested for the presence of anti-Scl-70 antibodies. It was found that all anti-Scl-70 positive sera (n = 25) contained anti-Scl-86 antibody as well, suggesting a relationship between these two antigens. However, the Scl-86 antigen was shown to be an extremely insoluble nonchromosomal protein, resistant to boiling in sodium dodecyl sulfate. This contrasts with the Scl-70 antigen, which has been described as a thermolabile, soluble antigen present in the chromatin fraction. Together, our results are consistent with the idea that Scl-70 is a degradation product of Scl-86. The Scl-86 antigen is present in freshly prepared rabbit thymus, spleen, and liver nuclei as well as in nuclei from various cultured cell lines, but is not detectable in extractable nuclear antigen from rabbit thymus. In a limited retrospective study, the anti-Scl-86 antibodies were found in two sera from patients with Raynaud's phenomenon before the development of diffuse scleroderma. Therefore, it is possible that screening of patients' serum for this antibody might predict the development of diffuse scleroderma.

Centrilobular necrosis in autoimmune hepatitis: a histological feature associated with acute clinical presentation.

AIMS: The characteristic histological feature of autoimmune hepatitis (AIH) is interface hepatitis with predominant portal lymphoplasmacytic necroinflammatory infiltration. Centrilobular necrosis (CN), reminiscent of toxic or circulatory liver injury, has been reported in AIH. The aim of this study was to assess the frequency of CN in patients with AIH and its correlation with laboratory and clinical data. METHODS: Liver biopsies were obtained from 114 patients (90 women, 24 men, mean (SD) age 45.4 (19.4) years) with AIH and were evaluated under code by a single pathologist according to the modified Knodell score. RESULTS: CN was found in 20 (17.5%) patients with virtually unaffected portal areas in four cases. Patients with AIH with CN had a higher total hepatic activity index (median (range) 11 (6 to 15) v 5 (2 to 10)) and presented less frequently with cirrhosis (10% v 38%). Patients with CN had a higher frequency of acute onset (87% v 32%), higher bilirubin (median (range) 12.0 (0.43 to 40.0) v 1.9 (0.36 to 46)) and higher ALT levels (median (range) 25.6 (2.7 to 63.9) v 7.2 (0.7 to 62.6)), than did patients with AIH without centrizonal injury. CONCLUSION: CN with sparing of the portal areas represents a rare histological pattern in AIH. CN is associated with an acute clinical presentation and might reflect an early lesion preceding portal involvement. Recognition of this particular histological appearance enables early diagnosis of AIH and a timely initiation of immunosuppressive therapy.

Autoantibodies in chronic GVHD: high prevalence of antinucleolar antibodies.

Sera from 32 bone marrow allograft recipients were screened for the presence of autoantibodies 4-61 months post-graft. Sera from 12 of 19 patients with extensive chronic graft-versus-host disease (c-GVHD) stained the nucleolar region strongly in immunofluorescence, indicating the presence of specific antinucleolar antibodies. In contrast, none of three patients with limited and none of 10 patients without c-GVHD had antinucleolar antibodies. Antibodies reacting with nuclear constituents other than nucleoli were found in five of the 12 antinucleolar positive patients. The appearance of antinucleolar antibodies coincided with early clinical symptoms of c-GVHD. We conclude that the appearance of antinucleolar antibodies after bone marrow transplantation is specific for patients with extensive c-GVHD. Furthermore, the development of extensive c-GVHD is paralleled by the emergence of these antinucleolar antibodies.

Surface phenotypes of human peripheral blood mononuclear cells from patients with gastrointestinal carcinoma.

Peripheral blood mononuclear cells (PBMC) from 40 patients with gastrointestinal carcinoma (GIC), 13 patients with primary carcinoma in other localizations(non-GIC), and from 57 apparently healthy donors were isolated by Ficoll-Paque gradient centrifugation. The separated cells were stained with several monoclonal antibodies and subjected to analysis on a fluorescence-activated cell sorter. A decreased percentage of PBMC expressing T cell antigens was noted amongst GIC patients, and was mainly due to a reduction of the Leu 2a subset, thus, leading to an increase in the Leu 3a/Leu 2a ratio from 1.4 to 2.1 Non-GIC patients had decreased numbers of both T helper and suppressor cells. Amongst PBMC from GIC and non-GIC patients a statistically increased percentage of cells expressed LeuM 2 (P less than 0.001), LeuM 3 (P less than 0.001), OKM 1 (P less than 0.005), VEP 9 (P less than 0.001), and HLA-DR (P less than 0.001) antigens compared to healthy controls. The percentage of cells bearing these monocyte/macrophage antigens correlated well with the number of cells having monocyte morphology, stained for non-specific esterase, phagocytosed latex particles, and expressed Fc IgG receptor. Our results demonstrate clearly that tumor-bearing patients have an increased relative number of monocytes. The data suggest that cells of the macrophage lineage may be involved in defense mechanisms and changes of the immune system evoked by various tumors.

Characterization of the inflammatory infiltrate in autoimmune cholangitis. A morphological and immunhistochemical study.

Autoimmune cholangitis (AIC) is characterised by clinical and/or laboratory features of cholestasis, the presence of antinuclear antibodies and the lack of antimitochondrial antibodies. Histologically, changes largely identical to those found in primary biliary cirrhosis (PBC) are typically found. It is not possible to differentiate between AIC and PBC on conventional morphological grounds, and we therefore wished to find whether there is a difference between these entities in the composition of the inflammatory infiltrate leading to bile duct destruction. In liver biopsies from ten patients with confirmed AIC and ten patients with PBC the inflammatory infiltrate was characterised with antibodies against CD 3, OPD 4 CD 8, GB 7, L 26, CD 56 and CD 57. In AIC, T cells were predominant in the portal inflammatory infiltrate in nine cases. Granzyme B-positive activated cytolytic T lymphocytes were found in the bile duct epithelium in five cases. All these five cases showed inflammatory bile duct destruction. No significant differences between the immunohistochemical findings in AIC and in PBC were found. We suggest that AIC is a subgroup of PBC, antimitochondrial antibody-negative type.

Stimulation-produced and stress-induced analgesia: cross-tolerance between opioid forms.

Electrical stimulation of medial brainstem sites produces potent analgesia in rats that is either opioid- or non-opioid-mediated depending on the specific brain region stimulated. Footshock stress also causes opioid and non-opioid forms of analgesia in rats depending on the exact parameters of footshock administered. We now report that opioid, but not non-opioid, stress analgesia demonstrates cross-tolerance with opioid, but not non-opioid, stimulation-produced analgesia. This finding suggests that opioid forms of stimulation-produced and stress-induced analgesia share a common substrate.

Autoantibodies against constituents of nuclear pore complexes in patients with primary biliary cirrhosis and autoimmune hepatitis.

Sera obtained from patients with autoimmune liver disease were screened in indirect immunofluorescence microscopy for the presence of autoantibodies. Patients' sera, which strongly stained nuclei (ANA) with peripheral accentuation, were used for further experiments to define the corresponding antigen(s). Nuclei and nuclear subfractions were isolated from HeLaS3 cells and used as antigen source. Immunoblotting experiments were performed after separation of nuclear proteins by one- and two-dimensional polyacrylamide gel electrophoresis. Some ANA positive sera recognized the nuclear protein with molecular mass of approximately 200 kDa. Further analysis revealed that the patients' sera reacted with gp210, an integral protein of the nuclear pores. The incidence and clinical significance of these antibodies is discussed.

Prevalence and clinical importance of hypertransaminasaemia in coeliac disease.

OBJECTIVE: To assess the prevalence and potential pathogenetic factors of hypertransaminasaemia in patients with coeliac disease prior to initiation of a gluten-free diet (GFD) and to assess the course of transaminases on a GFD. PATIENTS: A retrospective study was made of 178 patients with coeliac disease (130 women, 48 men; median age 36 years; range 17-84 years) at the gastroenterological department of a university hospital. METHODS: Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) were measured prior to initiation of a GFD and at 3, 6 and 12 months of GFD. Intestinal permeability, a test for functional integrity of the small bowel, was investigated before starting a GFD in 116 patients by an oral test using lactulose and mannitol. RESULTS: In 72 patients (40.4%) AST and/or ALT were increased prior to initiation of a GFD. Within 1 year on a GFD ALT and AST normalized except in eight cases (4.6%). The intestinal permeability index (% lactulose/% mannitol in 5 h urine) was higher in patients with elevated (median 0.34; range 0.03-1.43) than in patients with normal transaminases (0.11; 0.02-1.28) (P < 0.0001) and correlated with AST (tau = 0.34; P < 0.0001) and ALT (tau = 0.32; P < 0.0001). In five cases with hypertransaminasaemia a liver biopsy was performed prior to initiation of a GFD. Two patients had mild to moderate hepatitis with septal fibrosis. The other three had minimal lymphocytic infiltrates of the portal tracts. Inflammatory alterations of the bile ducts were not found. CONCLUSION: Hypertransaminasaemia before GFD is frequent in coeliac patients, correlates with intestinal permeability and normalizes on a GFD in most patients. In cases of persistently elevated liver function tests of unknown origin underlying coeliac disease should be considered.

Treatment of pruritus in chronic liver disease with the 5-hydroxytryptamine receptor type 3 antagonist ondansetron: a randomized, placebo-controlled, double-blind cross-over trial.

BACKGROUND: Recently, the serotonin antagonist ondansetron has been reported to have a positive effect on cholestasis-associated pruritus. OBJECTIVES: To study the effect of orally administered ondansetron on pruritus in chronic liver disease in a randomized, placebo-controlled, double-blind, cross-over study. METHODS: Subjective severity of pruritus was assessed using a visual analogue scale (VAS) recorded four times daily by the patients. After a one week pretreatment baseline period the patients were randomized to receive ondansetron tablets 8 mg tds or placebo tablets tds for one week. Following a one week wash-out period patients were switched to the other treatment for one week. The study was ended by an additional follow-up week without medication. For each day peak VAS values were determined and the mean value of the last five days of each week was calculated and referred to as the composite peak VAS score. RESULTS: We observed a significant but moderate reduction of the composite peak VAS score of 1.34 points (CI(95%): 0.12-2.56; P=0.033) during treatment with ondansetron as compared to placebo (treatment effect). In addition, a period effect was observed: a reduction of composite peak VAS score by 1.26 points (C1(95%): 0.04-2.48; P=0.044) was seen in the second treatment period as compared to the first period, irrespective of the kind of treatment. Although under treatment with ondansetron a significant improvement of itching as assessed by the VAS score was demonstrated, this treatment was not preferred over placebo by the patients. CONCLUSIONS: The 5-hydroxytryptamine receptor type 3 antagonist ondansetron has a small, but significant positive effect on pruritus in chronic liver disease as compared to placebo.

Systemic lupus erythematosus: delineation of subpopulations by clinical, serologic, and T cell subset analysis.

Patients with systemic lupus erythematosus (SLE) (n = 194) were analyzed for correlation of clinical features. In addition, the proportions of the two major T cell subsets were determined in 87 subjects. Two patient subgroups were discerned: one in which severe renal disease, leukopenia, and thrombocytopenia predominated, and a second in which sicca syndrome and involvement of the central nervous system, lungs and muscle occurred. The ratio of T helper/inducer to T suppressor/cytotoxic cells was reduced in the first group and increased in the second. We conclude that SLE does not comprise a single disease entity, but rather represents a number of syndromes with overlapping clinical features. The correlation of clinical symptoms with the proportions of circulating T cell subsets suggests that several immunologic mechanisms may underlie the various types of SLE.

[Interactive stereotaxic interventions in superconducting, open 0.5-Tesla MRI tomography]. / Interaktive, stereotaktische Interventionen im supraleitenden, offenen 0.5-Tesla-MR-Tomographen.

PURPOSE: Evaluation of an interactive, stereotactic biopsy device integrated in an open superconductive 0.5 tesla MR-scanner with a vertical gap. MATERIAL AND METHODS: In addition to "in-vitro" experiments performed on a plexiglas phantom with holes of varying diameters (5-20 mm) biopsies on eleven patients (7 women, 4 men; average age 55 years) were performed in the interventional MR-system. Lesions in the abdomen (n = 6), muscle (n = 1), thyroid (n = 3) and breast (n = 1) were targeted with 18-20 G aspiration biopsy needles of 5-15 cm length. The intervention was interactively guided by a fast T1-weighted 2-D gradient echo sequence. RESULTS: All of the 15 and 20 mm holes of the phantom, but only 83% of the 10 and 5 mm holes were hit. No complications occurred during the MR-guided patient procedures. All lesions (mean size 3.5 cm, distance from the skin 2 cm to 10 cm) were biopsied successfully. The fast image acquisition in combination with the stereotactic technique enables interactive control of the needle. CONCLUSIONS: Stereotactic, interactively controlled biopsies in the interventional MR are technical feasible. However, the range of meaningful indications for MR-guided biopsies is limited.

[Immune complexes: studies on animal models]. / Immunkomplexe: Studien an Tiermodellen.

A review is presented of some selected experiments conducted on animal models of immune complex-mediated diseases. The immune response and kinetics of antigen deposition are analysed in the model of systemic chronic serum sickness of rabbits and chickens. Experimental nephritis, induced by mercuric chloride, illustrates a pathogenesis in which autoantibodies to basement membranes become components of immune complexes. A recently developed Streptococcus mutans-induced nephritis in rabbits should make it possible to obtain some understanding of early pathogenetic mechanisms. These could very well be analogous to aspects of the pathogenesis of streptococcus-associated nephritides of man.

[Bilirubin metabolism (author's transl)]. / Bilirubinstoffwechsel I. Physiologie

The degradation of haemoglobin haeme of senescent red blood cells - involving NADPH-dependent haeme oxygenase and biliverdin reductase - in the reticuloendothelial cells of the spleen, bone marrow and liver accounts for 80 to 90% of the 250 to 300 mg of bilirubin formed in 24 hours. The remaining 10 to 20% derive from catabolism of other haemoproteins and from the destruction of maturing red blood cells in the marrow. In studies with isotopically-labelled metabolic precursors of haeme this fraction can be found in the early-labelled peak. In plasma virtually all the bilirubin is tightly bound to plasma proteins, largely albumin, because it is only sparingly soluble in aqueous solutions at physiological pH. In the sinusoids unconjugated bilirubin dissocates from albumin, enters the liver cells across the cell membrane through non-ionic diffusion and is bound by the two cytoplasmic proteins Y (or ligandin) and Z. Little is known about the transfer of unconjugated bilirubin from these binding proteins to the smooth endoplasmatic reticulum, where it is converted to a water-soluble ester glucuronide by bilirubin UDP-glucuronyl transferase. The physiological significance of non-glucoronide conjugates (sulphate, disaccharides) is only of minor importance. Following conjugation, bilirubin is transferred rapidly across the canalicular membrane into the bile canaliculi. This process is energy-dependent and occurs against a concentration gradient. The epithelial lining of the intestine and of the gall bladder, which can easily reabsorb lipid-soluble unconjugated bilirubin, is virtually impermeable to organic anions of the size and charge of conjugated bilirubin, thereby ensuring efficient excretion of this pigment. In the intestinal tract bilirubin is reduced to urobilinogen, which is subsequently reabsorbed to some extent into the enterohepatic circulation, removed from plasma by the liver and excreted unchanged in the bile. This rapid bacterial reduction of bilirubin makes it unlikely that unconjugated bilirubin is formed and absorbed to an appreciable degree. The residual part of urobilinogen is further reduced to urobilin, stercobilin and dipyrrolmethenes and excreted in the faeces.

[Eosinophilic granuloma (histiocytosis-X) with lung and bone manifestations]. / Eosinophiles Granulom (Histiozytosis-X) mit pulmonaler und ossärer Manifestation

A 26 year-old male presented with a spontaneous pathological fracture of the right femur caused by an osteolytic lesion. A chest X-ray demonstrated the coexistence of interstitial pulmonary fibrosis. Fibrocaseous tuberculosis and widespread malignancy were ruled out by appropriate investigations. The differential diagnosis, as based on the histological examination of the bone tumour, rested between hyperparathyroidism complicated by pulmonary disease and eosinophilic granuloma with lung manifestations. Hyperparathyroidism was ruled out by the absence of clinical and biochemical evidence of a disturbance of calcium metabolism. The diagnosis of histiocytosis-X was established by the histological appearance of the lung biopsy.

[A new antihypertensive imidazoline derivative (St 600, Fluoronidine): I. Haemodynamic investigations at rest and during exercise (author's transl)]. / Ein neues Antihypertensivum der Imidazolin-Reihe: 5-Flour-2-methyl-2-Imidazolidinylidenbenzamin-Monohydroechlorid (St 600, Fluronidin): I. Hämodynamische Untersuchungen in Ruhe und unter Belastung

Treatment of 12 hypertensive patients with a new imidazoline derivative, St 600 (1.5 to 12.0 mg daily over at least 7 days) resulted in a significant lowering of the blood pressure, mostly to normal values, parallelled by a reduced heart heart rate. A significant decrease in arterial resistance was observed at rest and during exercise in 6 of the patients, whereas a slight increase or no change was recorded in the remaining 6 patients. The changes in resistance in the pulmonary circulation were analogous to those in the systematic circulation for the 2 groups, respectively. The latter half of the patients displayed a decrease in stroke volume, cardiac index and oxygen consumption. No negative inotropic effect was observed.

[LDH isoenzymes and gastrin in achlorhydri (author's transl)]. / LDH-Isoenzyme und Gastrin bei Achlorhydrie

Several haematological findings (especially the values of serum LDH and its isoenzymes) were compared with changes in the gastrin level in pernicious anaemia. While vitamin B12 substitution therapy led to normalization of the anaemia and of the enzyme levels, gastric atrophy and, hence, the elevation in serum gastrin levels remained unchanged. Determination of serum gastrin, therefore, provides a valuable tool for the verification of the diagnosis of pernicious anaemia in treated cases.

Rational use of polymerase chain reaction--based detection of viral genomes in patients with serologic markers of hepatitis B or C virus infection.

We studied the value of additional diagnostic information obtained by detection of hepatitis B virus (HBV) DNA or hepatitis C virus (HCV) RNA using the qualitative polymerase chain reaction (PCR) in patients with serologic markers of hepatitis B or hepatitis C virus infection. In HBV infection, all HBsAg+HBeAg+ patients and all HBsAg+HBeAg- patients with alanine aminotransferase (ALT) levels > 100 U/L were positive for HBV-DNA by PCR, whereas in HBsAg+HBeAg- patients with ALT < 100 U/L 58% and in HBsAg+HBeAg- patients with normal aminotransferase 45% were found to be positive. In HBsAg+ patients no further clinically useful information can be obtained by PCR as the presence of HBsAg proves infection. However in three of 42 (7%) patients with markers of past HBV infection (antiHBs and/or antiHBc+) HBV-DNA was detected in the serum. Similarly, in some patients with acute hepatitis B HBV-DNA was demonstrable up to four months after the disappearance of HBsAg from serum, pointing to persistence of viremia despite the loss of serological markers of ongoing HBV infection. Demonstrating ongoing HBV infection in patients with serological markers of past infection is valuable additional information in only selected patients. In HCV infection, 10% of anti-HCV+ patients with increased ALT levels had a negative serum HCV-RNA. However, in 20% of those patients HCV-RNA was demonstrated in a serum sample collected later during follow-up, indicating that a single negative HCV-RNA determination cannot be taken as evidence for the resolution of infection.

[Experiences with liver transplantation in hepatitis B antigen positive liver cirrhosis]. / Erfahrungen mit der Lebertransplantation bei Hepatitis-B-Antigen positiver Leberzirrhose.

From 1982 to January 1991 228 orthotopic liver transplantations (OLT) were performed in 213 patients with end-stage disease at the Vienna transplantation centre, 1st University Department of Surgery. 14 patients were serum HBV surface antigen (HBsAg) positive at the time of transplantation. In the first 4 patients only OLT was performed; postoperatively all grafts became reinfected and the patients developed chronic hepatitis. In a further series, immunoprophylaxis against hepatitis B virus reinfection was carried out with hyperimmuneglobulin. In 4 patients short-term immunoprophylaxis was performed; all of them were seronegative after OLT, but HBsAg ++reoccurred in the serum within 3-16 weeks after transplantation and all patients experienced reinfection of their graft. The 2 patients, who had been transplanted in a replicative state (HBeAg positive) showed a fatal course of hepatitis in the graft. Out of 6 patients given long-term immunoprophylaxis 3 cases showed stable liver function, without any signs of reinfection, and the HBsAg negative status remained for up to 19 months after transplantation. Since two patients displayed a HBV replicate status prior to transplantation, alpha interferon was administered preoperatively, which resulted in decreased serum HBV-DNA levels.