Isolated human hepatocytes in culture display markedly different gene expression patterns depending on attachment status

In vitro human hepatocyte cultures are a key tool in the investigation of xenobiotic toxicity and metabolism. In most in vitro hepatocyte studies, the cells are allowed to adhere to an extracellular matrix, such as collagen. Unfortunately, the ability of freshly isolated hepatocytes to adhere to collagen varies from donor to donor. We used microarray analysis to determine what gene expression differences exist between hepatocytes in suspension and hepatocytes attached to collagen. Results from different donors showed a considerable difference in gene expression patterns between the two hepatocyte populations. In addition, we also compared the gene expression profiles of hepatocytes in culture with liver tissue. The results showed that both hepatocytes in suspension and hepatocytes attached to collagen display significant gene expression differences compared with liver tissue. Finally, we show that both populations of hepatocytes are responsive to dexamethasone and regulate some of the same genes. Overall, our results suggest that either significant gene expression changes occur in isolated hepatocytes or that suspended and attached cells represent different populations of hepatocytes found in intact livers.     

Microalbuminuria and nerve conduction velocity in type-I diabetics during conventional therapy and during continuous I.V. insulin infusion

Summary The objective of this study was to follow the development of microalbuminuria and nerve conduction velocity under continuous i.v. insulin therapy over a limited period of 4 months. For this purpose, 8 labile type I diabetics were selected (age 33±8 years, duration of diabetes 16±9 years) and treated conventionally with two insulin injections daily over 4 months. Afterwards, the same patients were treated with continuous i.v. insulin infusion and finally again with two injections daily over 4 months each. This procedure allowed each diabetic to serve as his own control. HbA₁, microalbuminuria, nerve conduction velocity and relative refractory period of the ulnar nerve were checked at montly intervals. During the continuous i.v. infusion over 4 months, blood sugar values were significantly lower, glucosuria had disappeared almost completely and the glycosylated hemoglobin had fallen to near normal values. The mean rate of albumin excretion was 16±5 μg/min at rest and 76±26 μg/min during exercise (normal: 3.9±0.4 and 4.8±1.2 μg/min, respectively) and did not change significantly. Nerve conduction velocity in the ulnar nerve rose significantly under i.v. insulin therapy from 47.9±0.6 m/sec to 52±0.6 m/sec. Similarly, the relative refractory period of the same nerve fell significantly from 3.7±0.2 to 1.9±0.1 msec (i.e. to within normal range). It is concluded that functional disturbances of peripheral nerve can regress by improved blood sugar control with continuous i.v. insulin infusion over 4 months. On the other hand, incipient microangiopathy measured as microalbuminuria remains unchanged over the same period of time. If an improvement is at all possible, considerably longer periods of euglycemia are likely to be necessary. Supported by Grant No. 3.964-0.80 from the Swiss National Science Foundation.     

Trehalose dimycolate enhances resistance to infection in neutropenic animals.

Bacterial infections are lethal complications of neutropenia, and antibiotics alone are inadequate therapy for these infections. Irradiated mice become severely neutropenic and remain susceptible to infection for 2 to 3 weeks, depending on the dose and quality of radiation. Some bacterial cell wall derivatives stimulate nonspecific host defense mechanisms against a variety of microbes which might cause postirradiation infection. In this study we determined if the cell wall glycolipid trehalose dimycolate (TDM), derived from Mycobacterium phlei, or a synthetic preparation of TDM was able to (i) enhance survival in mice when given before or after lethal doses of 60Co radiation and (ii) increase nonspecific resistance to postirradiation infection. Treatment with TDM oil-in-water emulsions and with synthetic TDM significantly enhanced survival before and after lethal doses of 60Co irradiation. This result correlated with the ability of TDM to reduce the translocation of intestinal bacteria and to stimulate hematopoiesis. With respect to nonspecific resistance to infection, TDM injected 1 h after sublethal irradiation increased resistance to a lethal Klebsiella pneumoniae challenge (10 50% lethal doses of K. pneumoniae in 30 days [LD50/30]) 4 or 14 days later. Increasing the dose of K. pneumoniae to 5,000 LD50/30 on day 4 overwhelmed the ability of TDM-treated mice to overcome infection. However, TDM treatment 1 h postirradiation combined with ceftriaxone antibiotic therapy (days 5 through 14) enhanced survival, even when the higher dose of bacteria (5,000 LD50/30) was used. These results indicate that in irradiated mice, TDM can be used to enhance survival and, as a potent stimulant of nonspecific resistance to infection in neutropenic mice, can act synergistically with antibiotic therapy to reduce sepsis and mortality.     

Low–Density Lipoprotein Apheresis Versus Lipid Lowering Drugs in the Treatment of Severe Hypercholesterolemia: Four Years' Experience

Abstract: Elevated lipoprotein concentrations seem to be linked strongly in a dose dependent manner to an increased incidence of atherosclerosis. A total of 47 patients suffering from severe hyperlipidemia were matched to treatment with LDL apheresis (Baxter, Kaneka, Li–popak; 24 patients, aged 50.2 ±11.5 years), diet, and/or lipid–lowering drugs or with diet and lipid–lowering drugs only (23 patients, aged 48.8 ±11.8 years). After treatment periods of 49.8 ±13.4 months (apheresis group, 2,396 treatment sessions) and 38.6 ± 15.1 months (drug group), the ensuing results revealed significant differences (p <0.0001): –47.3% versus –12.1% for total cholesterol, –46.9% versus –21.8% for LDL, +8.4% versus +0.9% for HDL, –52.0% versus – 13.1% for the LDL/HDL ratio, –36.4% versus –16.2% for triglycerides, and –25.9% versus + 1.5% for lipoprotein (a). In the apheresis group, one patient died of myocardial infarction; in the drug group, there was one nonfatal myocardial infarction and the manifestation of coronary heart disease in 3 cases. There were no severe side effects in either group. All patients in the apheresis group responded to therapy. The present trial suggests that a continuing reduction in serum lipid concentrations may lower, in a dose dependent manner, the risk for development and progression of coronary heart disease. Regarding clinical and laboratory results, LDL apheresis seems to be safe, effective therapy for treatment of severe hyperlipidemia.     

Adenocarcinomain Situof the Uterine Cervix: Management and Outcome

Objective: To retrospectively review the management of adenocarcinomain situof the uterine cervix, to determine the outcome of conization versus hysterectomy, and to compare the results achieved by different methods of conization. Methods: We performed a retrospective pathology and chart review of 46 patients with cervical adenocarcinomain situfrom January 1980 to October 1994. Results: Nine patients were managed during the first half of the study period and 37 were managed in the second half. The mean age of patients was 38.4 years (range 25–72). Forty-five of 46 patients were diagnosed as a result of an abnormal Pap smear, although only 19 smears indicated adenocarcinomain situor other glandular abnormalities. Cold knife conization resulted in a 33% rate of positive margins for adenocarcinomain situcompared to 50% for large loop excision of the transformation zone (LLETZ). Among 24 conservatively managed patients with negative conization margins, there have been 2 (8.3%) recurrences of adenocarcinomain situ.Among patients not undergoing hysterectomy as definitive treatment, 1 of 18 (6%) patients undergoing cold knife conization recurred, compared to 4 of 14 (29%) managed with LLETZ, despite a 63.4-month shorter mean follow-up interval for the LLETZ patients. Conclusions: Cold knife conization is associated with a lower rate of recurrence of cervical adenocarcinomain situcompared to LLETZ. We recommend cold knife conization for patients who are not treated with hysterectomy.     

Gallstone recurrence after direct contact dissolution with methyltert-butyl ether

To determine the rate and characteristics of gallstone recurrence after direct contact dissolution with methyltert-butyl ether, 60 consecutive patients were followed for up to 4.5 years (median 2.2 years) after complete disappearance of all stone residues and debris and cessation of adjuvant bile acid therapy. Initial gallstones had been multiple in all but four patients. Twenty-eight of the 60 patients developed recurrent gallstones. The cumulative risk of gallstone recurrence (actuarial analysis) was 23±6%, 34±7%, 55±8%, and 70±9% at one, two, three, and four years, respectively. The recurrent stones were usually multiple and small (6±4 mm). Gallstone recurrence was associated with recurrent biliary pain in two patients, one of whom developed acute cholecystitis. Recurrent stones were cleared completely by bile acid medication with or without shock-wave lithotripsy in 61±15% of patients at one year (actuarial analysis). In conclusion, gallstone recurrence after successful contact dissolution of multiple stones with methyltert-butyl ether has to be expected in a high percentage of patients. Most patients, however, remain free of biliary pain during long-term follow-up.     

Velocity profiles in the ascending aorta in pigs: Axial development and influence of changes in left ventricular contraction pattern

Summary Earlier studies using hot-film anemometry in pigs have revealed skewed tangentially rotating velocity profiles in the ascending aorta during systole. The reason for this phenomenon has been postulated to be caused by the left ventricular contraction pattern. Therefore, the aim of this study was to investigate the influence of the left ventricular contraction pattern on the velocity fields in the ascending aorta of pigs. We used a 10 MHz perivascular pulsed Doppler ultrasound system to measure point blood velocities at two axial locations over the entire cross sectional area in the ascending aorta of 90 kg pigs. The axial component of the velocity profiles was visualized dynamically by computerized 3-dimensional animation techniques. Changing left ventricular contraction patterns were accomplished by reversible occlusion of either the left anterior descending or right posterior descending coronary artery. The axial development of the systolic rotating and skewed velocity profiles in the ascending aorta was described. The appearance of the systolic velocity profiles were virtually unaffected by changes in left ventricular contraction pattern.This study was kindly supported by The Danish Heart Foundation, Civilingeniør Frode Nyegaard og Hustru's Fond and NOVO's Forskningsfond     

Vigilance--a state of order or a force that produces order?

The variety of meanings nowadays attached to the notion of "vigilance" essentially mask H. Head's original intentions when he introduced the term more than half a century ago. In an attempt to overcome the obviously existing disturbance in scientific communication, we contrast the new meanings, both with each other and with Head's original conception. We also discuss the importance of "vigilance" as a precursor of a current change of paradigms. We conclude that the original intention of "vigilance" is in line with recently elaborated proposals stressing the self-referential character of living systems. This revised notion of "vigilance" might serve as a conceptual base for empirical research taking self-reference into consideration, and hence for biological research in the true sense of the word.     

Phase I trial of the polyelectrolyte carbetimer administered i.v. once every four weeks

Summary Carbetimer, a new synthetic low molecular weight polyelectrolyte with a novel structure displayed antitumor activiy in a number of animal tumor model systems and in vitro investigations. Based on these findings it was brought to a phase I clinical trial in patients with advanced malignant disease after failure of conventional treatment or with no conventional treatment available. Forty-eight patients received 98 courses. The schedule was a one hour i.v. infusion every four weeks. The starting dose was 180 mg/m² and dose escalation was performed according to a modified Fibonacci formula up to 16,690 mg/m². At least three patients were treated at each dose level and each patient was eligible to receive repeat courses at the same dose, until progressive disease or dose-limiting toxicity intervened. No hematological toxicity was encountered. Some adverse effects such as reversible proteinuria, hypercalcaemia, pain at infusion site, nausea and vomiting and fatigue were seen partly in a dose-related manner but did not represent the maximum tolerated dose (MTD). The limiting toxicity at the highest dose level of 16,690 mg/m² consisted of ocular symptoms (light flashes) accompanied by a modest decrease of blood pressure and nausea or vomiting during a one hour infusion. 16,690 mg/m²/1 hour was considered the MTD. There were four deaths on study, all considered diseaserelated. Fourteen patients had stable disease for more than two courses, which, however, could also be explained by the natural course of disease. No clear-cut antitumor responses were noted in our study center.The recommended dose for phase II trials derived from our results is 12,550 mg/m²/2 hours. However, with regard to experiences in other phase I studies, the subsequent phase II studies will be performed with a dose of 6,500 mg/m².     

Social relations and smoking behavior: Results from the first MONICA survey Augsburg

Summary This study examines the relationship between various aspects of social relations and the prevalence of smoking, using data from the first MONICA Survey, Augsburg, FRG, 1984/85. Study population of the survey was a two-stage cluster sample of 5312 men and women aged 25 to 64. The response was 79.4%. The measurement of social relations included a modified form of the Syme/Berkman social network scale, as used in the Alameda County Study. Analyses were carried out separately for the total four-level social network index in relation to smoking, and for specific components of that index (marital status, contacts with friends and relatives, activities in informal groups). The results showed for both men and women, that there was a significant association between the social network index and the prevalence of smoking: the more social ties and contacts, the lower the percentage of smokers. The results from multiple logistic regression analyses indicated an effect of social relations on smoking, that is at least partly independent of age, gender and educational level. In general, the findings may contribute to a better understanding of risk groups, and the possible pathways leading from social relations to health and disease.

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Soziale Beziehungen und Rauchverhalten. Ergebnisse der ersten MONICA-Augsburg- Querschnittsstudie

Zusammenfassung Mit Daten der ersten MONICA-Querschnittsstudie Augsburg, 1984/ 85, wurden die Zusammenhänge zwischen verschiedenen Merkmalen des «sozialen Netzwerks» und dem individuellen Rauchverhalten untersucht. Die Studienpopulation umfasste 5312 Männer und Frauen einer zweistufigen Zufallsstichprobe im Alter zwischen 25 und 64 Jahren. Die Teilnahmerate betrug 79,4%. Die sozialen Beziehungen wurden in einem Fragebogen zum Selbstausfüllen mit Hilfe eines «Sozialen Netzwerk Indexes» (SNI) erfasst, der sowohl den Familienstand, die Kontakte zu Verwandten und engen Freunden als auch Aktivitäten in Gruppen und Vereinen beinhaltete. Die Ergebnisse zeigten für Männer und Frauen statistisch signifikante Zusammenhänge zwischen den Gesamtscores des SNI und der Prävalenz des Rauchens: Je mehr soziale Beziehungen und Kontakte, desto geringer war der Anteil Raucher. Die Analysen einzelner Komponenten des SNI ergaben: Es fanden sich keine konsistenten Zusammenhänge zwischen den Aktivitäten in Freizeitclubs und dem Rauchverhalten, jedoch zwischen familiären Beziehungen, Kontakten zu engen Freunden oder Verwandten und der Häufigkeit des Rauchens. Besonders auffallend war der hohe Anteil Raucher bei den geschiedenen oder getrenntlebenden Männern. 70% von ihnen waren Raucher im Vergleich zu 37% der verheirateten Männer. Die entsprechenden Anteile bei den Frauen waren 42% bzw. 22%. Die Ergebnisse der multiplen logistischen Regressionen zeigten einen Effekt der interpersonellen Beziehungen auf das Rauchverhalten, der unabhängig war von den Faktoren Alter, Geschlecht, Bildungsstand und (bei Frauen) von der Erwerbstätigkeit. Die Resultate könnten zu einer besseren Erklärung und Identifizierung von Risiko-Gruppen und damit zu einer erfolgreicheren Bekämpfung des Rauchens beitragen.

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Rapports sociaux et consommation de la cigarette

Résumé Les relations entre les différentes propriétés du «réseau social» et les habitudes individuelles en ce qui concerne la consommation de la cigarette ont été examinées à l'aide des données d'une première étude transversale, faite en région augsbourgeoise, dans le cadre du projet MONICA. L'échantillon aléatoire, divisé en deux étapes, comportait une population de 5312 hommes et femmes âgés de 25 à 64 ans. 79,4% des personnes interrogées participaient à l'enquête. Le recensement des rapports sociaux s'effectuait au moyen d'un questionnaire individuel à «l'Index du Réseau Social» (IRS) qui englobait aussi bien les données sur l'état civil que les sujets relatifs aux contacts sociaux et familiaux. Les résultats ont montré qu'il y avait une correspondance significative entre les valeurs totales du IRS et la prévalence de la consommation de la cigarette. Plus une personne avait de contacts sociaux, moins elle fumait de cigarettes. L'analyse des divers composants du IRS révèle un manque de relations cohérentes entre les activités dans les clubs de loisirs et la consommation de la cigarette. Cependant, la correspondance entre les rapports de famille, les contacts avec amis et parents et la fréquence de la consommation du tabac s'avérait révélatrice. Particulièrement frappant était le taux élevé de fumeurs chez les hommes divorcés ou vivant séparés. 70% d'entre eux étaient fumeurs par rapport à 37% des hommes mariés. Le taux correspondant chez les femmes était de 42% resp. 22%. Les résultats de la régression logistique multiple signalaient un effet des relations interpersonnelles sur la consommation de la cigarette, un effet qui était indépendant des facteurs tels que l'âge, le sexe, le niveau d'instruction et (chez les femmes) des activités professionnelles. Ces résultats pourraient contribuer à une meilleure identification et caractérisation des groupes à risque, et par la suite à combattre d'une manière plus efficace la consommation de la cigarette.