Enhancing the response to interferon-alpha.

BACKGROUND: Though initially recognized as antiviral agents, it was soon demonstrated that certain neoplasms were particularly sensitive to interferon-alpha (IFN-alpha). Indeed, the initial success of systemic IFN-alpha treatment in AIDS-associated Kaposi's sarcoma (AIDS-KS) occurred before identification of the human immunodeficiency virus (HIV) and in the absence of any coherent view of KS pathogenesis. With a more comprehensive understanding how KS develops and which circumstances provide an increased virulence of this neoplasm in HIV-infected persons, a more subtle rationale for IFN-alpha treatment arose regarding the disorder of the endogenous IFN-system in HIV-positive individuals. Until recently IFN-alpha was the only therapy available for patients with chronic hepatitis C (CHC). However, no more than 30% of these patients show a sustained virological response. Initial therapy with a combination therapy of IFN-alpha and ribavirin turned out to be more effective than treatment with IFN-alpha alone. To ameliorate response rates in antiviral IFN-therapy a profound understanding of viral dynamics, as well as immunological conditions associated with viral persistence, seems to be essential. Within a conference of the European Society of Clinical Virology (ESCV), which took place in Hamburg from August 30 to September 2, 1998, and was entitled 'Progress in Clinical Virology IV', a satellite symposium was organized to evaluate the clinical results of special antiviral treatment options with IFN-alpha, to analyze treatment failures with this cytokine and to ameliorate future strategies of IFN-alpha therapy. It focussed on HIV-related complications as coinfection with hepatitis C virus (HCV) and AIDS-KS, respectively. METHODS: A kinetic model of HCV infection based on principles established in studying HIV-1 infection was presented which is predictive for the outcome of IFN-alpha treatment. It involves different rates of velocity and compares the rates of acute clearance after different dosages of IFN-alpha application. Using the hypothesis to fit the changes in serum HCV RNA measured in a set of patients, it was found that 5 mIU daily dosing on average blocks 81% of HCV production/release, whereas 10 or 15 mIU blocks about 95% of HCV production/release. RESULTS: Only recently clinical data revealed a greater benefit of combination therapy with IFN-alpha and ribavirin compared to IFN-alpha alone in patients with chronic hepatitis C. In 345 CHC patients relapsing after pretreatment with IFN-alpha monotherapy, sustained response was achieved in a 10-fold higher degree with a combination of IFN and ribavirin compared to patients retreated with IFN alone. In 1775 treatment-naive patients with CHC, response rates to the combination therapy was significantly higher in all patient groups with more than 60% of sustained virological response in patients with genotype 2 and 3, while patients with genotype 1 (poorer prognosis) benefit from extended combination treatment duration from 24 to 48 weeks (17 versus 29% of sustained virological response), respectively. CONCLUSIONS: As viral dynamics on one side and host immune response on the other feature as two landmarks on which the manifestation of viral persistence and chronic viral infections is established, some similarities of HCV and HIV disease are striking. An unusual endogenous IFN-alpha system is associated with both infections and is a negative prognostic factor to response to treatment with IFN-alpha in CHC as well as AIDS-KS. The consequences for treatment options with IFN are a combination with ribavirin in CHC and a graduated systemic treatment schedule in AIDS-KS starting with IFN-treatment in early disease followed by chemotherapy in advanced stages of KS.

Oesophagitis caused by Candida kefyr.

The unusual case of an oesophagitis caused by Candida kefyr in a patient with squamous cell carcinoma of the oropharynx is reported. The further implementation of C. kefyr in the production of milk products is discussed.

[Primary and secondary prevention of Pneumocystis carinii pneumonia with pentamidine aerosol. Effectiveness, side effects and incidence of extrapulmonary Pneumocystis carinii manifestations]. / Primäre und sekundäre Prophylaxe der Pneumocystis-carinii-Pneumonie mit Pentamidin-Aerosol. Wirksamkeit, Nebenwirkungen und Häufigkeit der extrapulmonalen Pneumocystis-carinii-Manifestation.

BACKGROUND: We report on a retrospective study in 544 HIV-positive patients, (42 women, 502 men, mean age 35 years) showing CD4 lymphocyte counts below 200 c/mcl or after their cure of Pneumocystis carinii pneumonia, who received 300 mg pentamidine aerosol as prophylaxis against Pneumocystis carinii pneumonia every four week. PATIENTS AND METHODS: 277 patients were asymptomatic, 120 in the AIDS related complex stage (ARC) and 147 in the full stage of AIDS. The mean follow-up was 14.4 months. RESULTS: A total of 25 cases of Pneumocystis carinii pneumonia was observed (3.83/year): in the primary prophylaxis group 18 (3.25%/year), in the secondary prophylaxis group seven (6.8%/year). By introducing the loading dose (one inhalation per day for five consecutive days for patients with CD4 cell counts below 150 c/mcl) we reduced the percentage of early manifestations within the first three months from 61% to 14%. No extrapulmonary Pneumocystis carinii manifestation was observed. CONCLUSION: This study supports the efficacy of pentamidine aerosol prophylaxis of primary and secondary Pneumocystis carinii pneumonia.

S-process krypton of variable isotopic composition in the Murchison meteorite.

Current theories on the origin of the chemical elements explain the abundance of medium-heavy and heavy nuclides to be due to the capture by pre-existing lighter nuclides of free neutrons on either a slow timescale (s-process) or a rapid timescale (r-process). Experimental evidence in support of these theories comes from the analysis of carbonaceous chondrites. In acid-resistant residues of these meteorites a kind of xenon has been found, the isotopic composition of which matches almost perfectly that predicted for s-process xenon. We report data that allow us, for the first time, to derive with reasonable precision the full isotopic spectrum of s-process krypton as well. We show that this s-Kr in a residue from Murchison meteorite did not originate in one single s-process but rather is a mixture of contributions from stellar environments where the density of free neutrons was not the same. The astrophysical conditions under which this Krypton has been produced were distinct from those that have been invoked to explain the Solar System s-process abundance. Similar to the 13C-rich carbon component in an aliquot of the same residue, the s-process Kr from different astrophysical sites has retained its identity during the accumulation and subsequent history of the meteorite.

Intragastric bile acid and lysolecithin in gastroduodenal ulcer and gastric cancer.

In 99 patients with different types of gastroduodenal ulcer and gastric carcinoma the intragastric concentrations of bile acids and lysolecithin was analyzed under fasting, basal and pentagastrin-stimulated conditions. Normal concentrations were found in type III gastric ulcer (prepyloric). There was a three- to four fold increased reflux concentration in the mean of patients with gastric ulcer type I but some patients showed normal values too. The calculated reflux rate was also slightly elevated. In duodenal ulcer normal concentrations could be observed with the exception of a slight increase under fasting conditions. In gastric carcinoma of the proximal half normal reflux concentrations were found. Distal gastric carcinoma was associated with a two- to three-fold increase of bile acids as well as lysolecithin concentration. The same was found concerning the reflux rate. Our results demonstrated a comparable low increase of duodenogastric reflux concentration in proximal gastric ulcer and distal gastric carcinoma. They give no evidence for a major role of reflux in the pathogenesis of gastroduodenal ulcer.

[Ulcer disease and duodenogastric reflux]. / Ulkuskrankheit und duodenogastraler Reflux.

The intragastric concentrations of lysolecithin and bile acids were determined in 44 chronic peptic ulcer patients and 35 healthy volunteers. Normal reflux values were found in the prepyloric ulcer (Johnson type III) (n = 15) Elevated reflux amounts could be observed in the type I gastric ulcer (n = 15), there was a three-to fourfold increase compared to the controls. - Slightly elevated reflux concentrations were found in the duodenal ulcer patients (n = 14), but only under fasting conditions. The increase of reflux concentration in chronic gastric ulcer type I is shown to be in the same range as in acute stress ulcer. Compared to the three-to four times higher reflux concentrations of the resected stomach, the duodenogastric reflux in ulcer disease is very moderate. It's role in ulcerogenesis has to be analyzed further.

[Amount of reflux in an operated stomach (author's transl)]. / Refluxgrössen des operierten Magens.

Postoperative duodenal or jejunogastric reflux of bile acids and lysolecithin was measured in 189 patients with different types of operation for ulcer and in 35 control subjects. After selective proximal vagotomy without pyloroplasty there was a normal reflux, but after additional pyloroplasty (after Heineke-Mikulicz or Jaboulay) there was a slightly increased concentration of bile acids and lysolecithin. After gastric resection (Billroth I) values were four to eight times those after vagotomy with pyloroplasty or nine to sixteen-fold the normal amount. Reflux values twice as high as after Billroth I were found in patients after Billroth II resection without Braun's enteroanastomosis. Additional Braun's enteroanastomosis reduced the lysolecithin and bile acid concentration after Billroth II to levels after Billroth I. Normal reflux values after gastric resection were achieved by a Roux-Y gastroenterostomy and 25-cm long isoperistaltic jejunal interposition as an anastomosis variant.

Adsorption of bile acids and lysolecithin by antacids.

Several antacids of silicate or Al-Mg-hydroxide type were tested in vitro for adsorption of bile acids and lysolecithin in concentrations up to 4 and 0.4 microMol/ml respectively, using human gastric aspirates. There was a considerable binding of both reflux agents, with mean values from 20 to 76% for bile acids and from 59 to 96% for lysolecithin. Maximal adsorption of both substances was achieved within 30 min. no reliberation could be detected afterwards. Antacids or similar compounds may be of therapeutic efficacy in treating or preventing reflux-induced gastric lesions.

Clinical results of jejunal transposition.

In eleven patients with partial gastrectomy and isoperistaltic jejunal interpositions in ulcer disease the concentrations of bile acids and lysolecithin were determined. While with jejunal interpositions of 20 cm and more in length normal amounts of duodenogastric reflux could be observed, in patients with shorter segments the values were still pathological. The satisfactory reflux preventing effect of 20 cm jejunal interposition could be demonstrated in three patients by measuring the pre- and postoperative intragastric bile acids and lysolecithin, showing a normalization of both parameters postoperatively. The clinical use of isoperistaltic interposition is discussed.

Prevention of reflux after gastro resection in the pig.

In 48 pigs the duodenogastric reflux of bile acids and lysolecithin is studied after different types of gastroduodenostomy, jejunal interposition and Roux-Y-gastroenterostomy. The intragastric concentrations of bile acids and lysolecithin were found to be pathologically elevated after gastroduodenostomy. There was no difference between end-to-end, end-to-side or supraduodenal end-to-side anastomoses. An effective reflux prevention was possible by interposition of 25 cm of isoperistaltic jejunum or by Roux-Y. A shorter (15 cm) interposition with or without an isoperistaltic invagination valve was not sufficient in normalizing reflux amounts.

Problems in duodenogastric reflux assessment, using bile acid and lysolecithin measurement.

In 187 subjects with widely varying degrees of duodenogastric reflux, intragastric bile acid values were compared with reflux measurement by a biliary marker technique involving intragastric recovery of intravenously injected 14C-bile acids. Furthermore, bile acids were compared to lysolecithin in gastric aspirates. The biliary marker principle, as an indirect method, proved unreliable for assessing endogenous bile reflux. Direct analysis of intragastric duodenal contents, promising more accurate, and, in pathophysiological terms, more meaningful results, cannot rely only on bile acid analysis, since highly divergent lysolecithin values may occur. Thus, any sole acid quantification of reflux by indirect or direct methods will fail to qualify its cytotoxic potential.

[Prevention of reflux by jejunal transposition--a clinical study (author's transl)]. / Refluxverhütung durch Jejunuminterposition. Eine klinische Studie.

The prevention of duodenogastric reflux by a jejunal transposition was studied in 11 patients following Billroth II to Billroth I reinterventions. For this purpose intragastric lysolecithin and bile acids were measured. While resected stomachs with a 25 cm isoperistaltic jejunal transposition showed normal reflux values, shorter jejunal segments still had a pathological reflux. The role of the jejunal transposition as an antireflux procedure in ulcer surgery is discussed.

[Duodenogastric reflux following vagotomy with and without pyloroplasty (author's transl)]. / Duodenogastraler Reflux nach Vagotomie mit und ohne Pyloroplastik.

Intragastric concentrations of bile acids, lysolecithin, 14C-bile acids, pH-value, bacterial growth and gastric mucosa histology were analysed in 47 patients following selective proximal vagotomy with and without pyloroplasty. Without pyloroplasty there were normal amounts of lysolecithin, bile acids and 14C-marked bile acids. Following pyloroplasty (Heineke-Mikulicz and Jabouly) the reflux values were 2 to 4 times higher. This increase of reflux after pyloroplasty was only one fifth of that following gastric resection. Only 20% of the vagotomized stomachs showed a bacterial contamination, an atrophic gastritis could be observed in 20% of the pyloroplasty-patients. The results demonstrate, that in selective proximal vagotomy there is no, in combination with pyloroplasty only a slight reflux gastritis.

[Reflux and reflux disease following gastric resection (author's transl)]. / Reflux und Refluxkrankheit im Resektionsmagen.

Intragastric concentrations of lysolecithin and bile acids were determined in 112 patients with different types of gastrectomy for peptic ulcer (Billroth I and Billroth II). These values were correlated with intragastric pH, bacterial contamination, gastric mucosal changes and Visick grading. A maximal amount of duodenogastric reflux was found in retrocolic gastrojejunostomy (Billroth II). Smaller, but still highly pathological values were observed in the antecolic gastrojejunostomy with Braun enteroanastomosis as well as in different types of gastroduodenostomy (Billroth I). 70% of the operated stomachs were bacterially contaminated. There was a good correlation between amount of reflux, bacterial contamination and pH-value. Above pH 6 no stomach was sterile, the lysolecithin-concentration increased more than proportional. Gastric mucosal changes correlated closely with the intragastric lysolecithin concentration and the bacterial contamination. There was no correlation between amount of reflux and Visick-grading, no complaints were found in some cases with extreme reflux values as vice versa. The postoperative alkaline reflux gastritis is described, the consequences including the carcinoma of the gastric stump are mentioned. The principles of ulcer surgery are analysed under these aspects.

Influence of chenodeoxycholic acid on the kinetics of endogenous triglyceride transport in man.

Plasma lipids and triglycerides kinetics were studied in ten subjects before and after 6-8 weeks treatment with 1 g/day chenodeoxycholic acid for radiolucent gallstones. Plasma triglyceride concentration fell by 20% and phospholipid concentration rose by 5% on average; there was no change in cholesterol or free fatty acids. Body weight remained constant. Triglyceride kinetics, studied by a precursor-labelling technique, revealed a reduction both of triglyceride plasma pool and turnover rate, accompanied by a decline of more than 35% both of plasma triglyceride precursor pool and of incorporation of plasma free fatty acids into newly synthesized plasma triglycerides. Fractional turnover rates in both pools remained unaltered. The appearance-time for newly synthesized plasma triglycerides after injection of label did not change. These results indicate that chenodeoxycholic acid lowers plasma triglyceride by reducing its synthesis, thereby precluding alternative, and possibly undesired, modes of action, such as impaired secretion or increased peripheral catabolism of endogenous triglyceride. Several biochemical mechanisms may be responsible for this effect, among which stimulation of phospholipid synthesis by bile acids could play a role.

[Reflux-preventing gastric resection. An animal experiment study]. / Refluxverhütende Magenresektion. Eine tierexperimentelle Studie.

In 30 pigs the prevention of duodenogastric reflux following distal gastrectomy through different types of jejunal transposition or Roux-en-Y-gastroenterostomy was studied. The reflux was measured by determination of the intragastric amounts of bile acids and lysolecithin, and by the total number of glycerophosphatids. After distal gastrectomy and proximal selective vagotomy, isoperistaltic jejunal segments of different lengths were transposed between gastric remnant and duodenum. The reflux was normalized by 25-cm segments. Shorter segments led to no significant decrease of the reflux. The jejunal invagination of additional isoperistaltic valve did not have a significant effect. The same protection as from 25-cm segments was obtained by Roux-en-Y-gastrojejunostomy. The role of the duodenogastric reflux following gastrectomy for the gastric mucosa is disucssed. The necessity of the reparation of the pyloric function is shown.

[Intragastric bile acids and lysolecithin in clinical stress ulcer risk (author's transl)]. / Intragastrale Gallensäuren und Lysolecithin bei Klinischer Stressulkus-Gefährdung.

In 10 intensive care patients with a risk of stress ulcer intragastric concentrations of lecithin, lysolecithin and bile acids were determined and compared to values in seven normal persons. All results were increased to multiple normal values. In particular lysolecithin and bile acids showed highly abnormal concentrations. These substances have a pathogenic importance for the occurrence of stress ulcers.