IgM-enriched solution BT086 improves host defense capacity and energy store preservation in a rabbit model of endotoxemia.

INTRODUCTION: The therapeutic value of intravenous immunoglobulin (IVIG) as an adjuvant therapy in sepsis remains debatable. We hypothesized that intravenous administration of BT086, a predominantly IgM IVIG solution, would improve host defense in an established rabbit model of endotoxemia and systemic sepsis. METHODS: New Zealand white rabbits were randomized into the following four groups: (1) the negative control group without lipopolysaccharide (LPS, control), (2) the positive control group with LPS infusion (LPS group), (3) the albumin-treated LPS group (ALB+LPS group), and (4) the BT086-treated LPS group (BT086 + LPS group). A standardized amount of E. coli was intravenously injected into all of the animals. The vital parameters, the concentration of E. coli in the blood and other organs, the residual granulocyte phagocytosis activity, and the levels of the inflammatory mediators were measured. Histological changes in the lung and liver tissue were examined following autopsy. RESULTS: The elimination of E. coli from the bloodstream was expedited in the BT086-treated group compared with the LPS- and albumin-treated groups. The BT086 + LPS group exhibited higher phagocytic activity of polymorphonuclear neutrophils (PMNs) than the control and ALB+LPS groups. The liver energy stores were higher in the BT086 + LPS group than in the other groups. CONCLUSION: Our data suggest that the IgM-enriched IVIG has the potential to improve host defense in a rabbit model of endotoxemia. Studies using different animal models and dosages are necessary to further explore the potential benefits of IgM-enriched IVIG solutions.

[Efficacy and safety in the treatment of pleural effusions with the PleurX catheter: a retrospective analysis]. / Nutzen und Sicherheit der Behandlung von Pleuraergüssen mit dem PleurX-Katheter: eine retrospektive Analyse.

BACKGROUND: The purpose of this retrospective study was to investigate the efficacy and safety of an indwelling pleural device (PleurX, Denver Biomedical, USA) for the treatment of recurrent pleural effusions. In cases when life expectancy tends to be very short and also surgical decortication is not recommended, pleurodesis is another treatment option but requires complete drainage of the whole pleural fluid for optimal results which is sometimes hard to achieve. The PleurX catheter is an alternative therapeutic option. METHODS AND RESULTS: We retrospectively analysed the clinical data from a total of 21 patients who were treated with a PleurX alone (11 patients) or who initially received pleurodesis and afterwards a PleurX catheter (10 patients). Mean survival was 25 weeks after initial diagnosis of the underlying disease. The mean amount of pleural effusion drained per week was 725 mL. 16 patients used the catheter until they died at least 1 - 2 times a week. The complication rate was 19 % and thus within a reasonable range when compared to other treatment options for recurrent pleural effusions. There was no statistically significant difference in clinical outcome in both groups (pleurodesis and subsequent PleurX vs. PleurX alone). The amount of evacuated pleural effusion was inversely correlated with the remaining life time. CONCLUSION: The use of an indwelling pleural device is a safe alternative treatment option for patients with chronic pleural effusions and trapped lung signs. We should be aware of this device and propagate its use at an earlier stage of malignant diseases with recurrent pleural effusions, especially when the remaining life time is short.

[Diagnosis of infections in pneumology]. / Infektionsdiagnostik in der Pneumologie.

Lower respiratory tract infections rank among the leading causes of morbidity and mortality worldwide. In clinical practice, especially in the care of severely ill patients, discrimination between tracheobronchial colonisation with potentially pathogenic microorganisms and infection is a common diagnostic challenge. While prompt antibiotic treatment is needed in critically ill patients with pneumonia, an inadequate use of antibiotics is the major cause for the emergence of drug-resistant microorganisms. The first part of this review provided a detailed overview of the currently available methods for the diagnosis of pulmonary infectious diseases. In the present second part of the manuscript, we focus upon methods and criteria for the differentiation between lower respiratory tract bacterial colonisation and lower respiratory tract infections, highlighting important pathogens.

[Diagnosis of infections in pneumology]. / Infektionsdiagnostik in der Pneumologie.

Lower respiratory tract infections play an important role in the ambulatory and hospital health-care sectors. State-of-the-art diagnoses of lower respiratory tract infections and methods to differentiate bacterial lower respiratory tract infections from colonisation have been described in the first two parts of this review series. The present article summarises current diagnostic methods and treatment indications for viral and fungal respiratory infections. These recommendations may guide clinicians in their decision to prescribe or withhold antibiotic therapies in daily clinical practice.

[Infection diagnostics in pneumology. Part 1. Survey and methods]. / Infektionsdiagnostik in der Pneumologie. Teil 1. Ubersicht und Methoden.

Lower respiratory tract infections rank among the most important illnesses in medicine. However, the identification of a causative microbiological agent is often difficult. Pulmonary infections must be differentiated from non-infectious causes of pulmonary diseases with similar symptoms and infiltrates on chest imaging. Among the important novel developments ranks the analysis of serum procalcitonin for a better identification and treatment monitoring of bacterial pneumonias compared to conventional tests and a simple scoring system, like the CRB-65/CURB score, for a rapid risk stratification. A rational diagnostic approach is necessary to identify causative microorganisms of pulmonary infectious diseases depending on the severity of the illness, the exposition and predisposition of the patient. In addition to the classical microbiological methods, rapid test systems for the identification of microorganisms are becoming increasingly important. The first part of this review gives a detailed survey of the methods for the diagnosis of pulmonary infectious diseases. In the second part of the manuscript, we will focus on special pulmonary infectious diseases.

Rapid diagnosis of pulmonary TB by BAL enzyme-linked immunospot assay in an immunocompromised host.

Immunocompromised patients with acid-fast bacilli (AFB) smear-negative active pulmonary tuberculosis (pTB) often present with nonspecific clinical symptoms and findings. T-cell interferon-gamma release assays (TIGRA) performed on whole blood (using ELISA) or peripheral blood mononuclear cells (using enzyme-linked immunospot assay (ELISPOT)) are more sensitive for the diagnosis of Mycobacterium tuberculosis (MTB) infection than the tuberculin skin test (TST), but cannot distinguish active from latent MTB infection. The present authors report a 38-yr-old female presenting with a 3-week history of malaise, dyspnoea, fevers and coughing, who had received immunosuppressive therapies over 8 months for mixed connective tissue disease. Chest radiograph and thoracic computed tomography showed ground glass opacities in both lower lobes. The TST-induration was 0 mm and AFBs or MTB nucleic acid was not detected on sputum and bronchial secretions. However, TIGRAs performed on peripheral blood cells were reactive. A high frequency of MTB-specific T-cells compatible with the immunodiagnosis of active pTB was detected among bronchoalveolar lavage cells using ELISPOT. Antituberculous therapy was initiated 18 days before MTB was discovered on sputum cultures. Detection of Mycobacterium tuberculosis-specific T-cells in the bronchoalveolar lavage using enzyme-linked immunospot assay is a promising tool for the diagnosis of active pulmonary tuberculosis in immunocompromised patients with negative acid-fast bacilli smears.

[Clinical features and diagnosis of tuberculosis]. / Klinik und Diagnose der Tuberkulose.

Recently, major advances have been accomplished in the diagnosis of active tuberculosis. A comprehensive diagnostic approach for a patient with possible tuberculosis includes a detailed medical history and clinical examination as well as the results of radiological, microbiological, immunological, molecular-biological and histological methods. In concert, these results enable the clinician to rapidly develop a decision with a high probability for the diagnosis or exclusion of active tuberculosis. Therapeutic intervention can thus be made early, even though corrections in these decisions need to be considered depending on the results of Mycobacterium tuberculosis culture and sensitivity testing.

Local immunodiagnosis of pulmonary tuberculosis by enzyme-linked immunospot.

Lymphocytes are crucial in the immune defence against Mycobacterium tuberculosis (MTB) infection. The aim of the present study was to ascertain whether or not MTB-specific lymphocytes are selectively compartmentalised in the lungs of patients with minimal active pulmonary tuberculosis (PTB). Patients with smear-negative MTB-culture-confirmed PTB were prospectively recruited. Differential cell counts, immunophenotyping with monoclonal antibodies directed against the cell surface markers CD4, CD8, CD4CD45RA, CD4CD45R0, CD38, human leukocyte antigen DR, CD19, CD3, CD57 and CD16 and MTB-specific enzyme-linked immunospot assays of peripheral blood mononuclear cells and bronchoalveolar lavage (BAL) mononuclear cells with 6-kDa early secretory antigenic target and culture filtrate protein 10 were performed. Among 12 patients with culture-confirmed smear-negative PTB, no differences were found in the distribution of total CD4 or CD8 T-cells in peripheral blood or BAL fluid (BALF). Activated human leukocyte antigen-DR-positive cells, as well as memory CD4CD45R0-positive T-cells, were expanded among cells of the BALF. Compared with a group of control patients with alternative pulmonary pathologies, there was no significant difference in lymphocyte subpopulations. However, 6-kDa early secretory antigenic target- and culture filtrate protein 10-specific lymphocytes were more concentrated, with a median BALF:peripheral blood ratio of 9.9 and 8.9, respectively, in patients with PTB. Mycobacterium tuberculosis-specific T-cells are highly selectively compartmentalised at the site of infection in active pulmonary tuberculosis.

Intake of vitamin and mineral supplements in an elderly german population.

AIM: To assess the prevalence of vitamin and mineral supplement use in a free-living elderly population and the contribution of these supplements to usual dietary intake. METHODS: Analyses are based on data obtained from 388 subjects (>or=60 years) participating in the longitudinal study on nutrition and health status in an ageing population in Giessen (GISELA), Germany, in 2002. Nutrient intake from food was assessed by means of a 3-day estimated dietary record. Supplement use was recorded over a period of 3 days using a self-administered questionnaire. RESULTS: Nearly half of the study population consumed at least 1 supplement within these 3 days. The use of supplements was more prevalent among women than among men (51.5 vs. 33.9%). On average women consumed 2.03+/-1.30 products and men 1.65+/-1.07 products. Magnesium, vitamin C and vitamin E were supplemented most often by men, while women supplemented magnesium, vitamin E and calcium most often. Most of the supplemented nutrients did not distinctly increase the average intake of the respective nutrients from the diet in this population. However, supplement use markedly decreased the proportions of elderly subjects with an intake below the current reference values for certain nutrients, particularly for vitamin E. CONCLUSION: Results indicate that the intake of supplements is a common behavior in the population under investigation and therefore has to be considered when nutrient intake is evaluated.

Lower resting metabolic rate in the elderly may not be entirely due to changes in body composition.

OBJECTIVE: To investigate whether or not the lower resting metabolic rate (RMR) in the elderly is entirely due to changes in body composition. DESIGN: Cross-sectional data of 132 female (age 69.9+/-5.5 y, body mass index (BMI) 26.5+/-4.0 kg/m(2)) and 84 male (age 68.9+/-5.1 y, BMI 26.1+/-2.8 kg/m(2)) participants of the longitudinal study on nutrition and health status in an aging population of Giessen, Germany, as well as that of 159 young women (age 24.8+/-3.0 y, BMI 21.1+/-2.5 kg/m(2)) and 67 young men (age 26.8+/-3.4 y, BMI 23.3+/-2.4 kg/m(2)) were analysed. RMR was measured by indirect calorimetry after an overnight fast and body composition was estimated by bioelectrical impedance analysis and predictive equations from the literature. Analysis of covariance was used to adjust RMR for body composition, body fat distribution and smoking habits. Additionally, RMR that is to be expected theoretically, was calculated on the basis of the subjects' body composition and the specific metabolic rate of the different organs and was compared to measured RMR. RESULTS: Compared to young subjects adjusted RMR was significantly lower in elderly women (5432+/-82 vs 5809+/-70 kJ/day, P<0.01) and men (6971+/-99 vs 7558+/-121 kJ/day, P<0.001). In both elderly women and men, measured RMR was markedly lower than calculated RMR (-625+/-404, -515+/-570 kJ/day). By contrast, measured and calculated RMR were nearly the same in young men (159+/-612 kJ/day); in young women the difference between measured and calculated RMR was only -300+/-457 kJ/day. In both sexes, these differences are significantly larger in the elderly when compared to young adults. CONCLUSION: These results support the point of view that the decline in RMR with advancing age cannot be totally due to changes in body composition.

Enhanced PMN response in chronic bronchitis and community-acquired pneumonia.

Chronic bronchitis is a frequent underlying disease in community-acquired pneumonia (CAP). It is unclear to what extent an impaired or exaggerated innate immune response contributes to disease manifestations and severity. To assess the role of neutrophil activation and recruitment during acute pneumonic episodes, peripheral polymorphonulcear neutrophil (PMN) activation, chemotactic activity, interleukin-8 (CXCL-8) and CXCL-8 receptor (CXCR) expression and apoptosis rate were evaluated in CAP patients with and without chronic bronchitis. In addition, the expression of CXCRs and CXCL-8 was assessed on pulmonary neutrophils in chronic bronchitis patients to compare the activation of the chemokine system in different compartments. CAP severity was assessed by the simplified acute physiology score II and the prognosis of disease was assessed by the pneumonia severity index (PSI). An increased chemotactic activity of PMN from chronic bronchitis patients with CAP was found, which was not related to the expression of CXCRs. In addition, a decreased apoptosis rate of PMN was observed. Chemotactic activity was related to the PSI. Comparison of peripheral and pulmonary PMN revealed enhanced CXCL-8 levels and a decreased CXCR expression in the lung. In conclusion, neutrophil function in patients with chronic bronchitis and community-acquired pneumonia is characterised by an increased chemotactic activity combined with a decreased apoptosis rate. The downregulation of interleukin-8 receptors in the pulmonary compartment deserves further investigation.

Laparoscopic fundoplication in neurologically impaired children with percutaneous endoscopic gastrostomy.

TOPIC: Laparoscopic fundoplication is the preferred surgical procedure for children with gastro-oesophageal reflux. Little data exist on the feasibility of laparoscopic fundoplication after placement of a percutaneous endoscopic gastrostomy (PEG). PATIENTS AND METHODS: Thirty-nine children aged 4 months to 18 years (median 3.6 years) presented for an antireflux procedure between November 2000 and July 2003. The surgical technique used was the Thal (270 degrees ) fundoplication. Clinical data, technical aspects of the operation, and the postoperative course were collected prospectively. RESULTS: Twenty-two children (56 %), all of them neurologically impaired, already had a PEG in place due to feeding problems irrespective of gastro-oesophageal reflux symptoms. In all cases, laparoscopic fundoplication was performed immediately after gastroscopic removal of the PEG tube. In two cases, conversion to an open procedure became necessary, due to reasons unrelated to the PEG. In one case conversion was necessary because of adhesions of an intrathoracic stomach and in the other case because of circulatory problems due to congenital cardiomyopathy. In one patient, the gastrostomy was moved at the end of the procedure because it was too close to the antrum. In two further cases, the gastrostomy detached during fundoplication. In this case, the gastrostomy catheter was replaced and secured laparoscopically with a purse-string suture. All other cases were without any complications and a balloon tube or a button was placed into the existing gastrostomy channel at the end of surgery. CONCLUSION: No adverse effects are associated with PEG placement prior to a consecutive laparoscopic antireflux procedure. Possible detachment of the pre-existing gastrostomy must be excluded at the end of the procedure.

Developmental aspects of human hepatic drug glucuronidation in young children and adults.

BACKGROUND AND AIMS: The liver represents one of the major sites of human glucuronidation. Many therapeutic drugs are substrates for UDP-glucuronosyltransferases (UGT) leading to the formation of usually inactive glucuronides. Hepatic glucuronidation undergoes significant changes during fetal and neonatal development requiring age adapted drug therapy. Regulation of individual UGT genes during hepatic development has not been defined. SUBJECTS AND METHODS: Expression of 13 UGT genes and glucuronidation activities were analysed in 16 paediatric liver samples (aged 7-24 months), two fetal samples, and 12 adult liver samples (aged 25-75 years) using duplex reverse transcription-polymerase chain reaction, western blot, and specific catalytic UGT activity assays. RESULTS: No UGT transcripts were detected in fetal liver at 20 weeks' gestation. In contrast, UGT1A1, UGT1A3, UGT1A4, UGT1A6, UGT1A9, UGT2B4, UGT2B7, UGT2B10, and UGT2B15 transcripts were present without variation in all 28 hepatic samples after six months of age. Significantly lower expression of UGT1A9 and UGT2B4 mRNA was identified in paediatric liver. Hepatic glucuronidation activity in children aged 13-24 months was found to be lower than in adults for ibuprofen (24-fold), amitriptyline (16-fold), 4-tert-butylphenol (40-fold), estrone (15-fold), and buprenorphine (12-fold). CONCLUSIONS: An early phase characterised by the appearance of UGT gene transcripts and a later phase characterised by upregulation of UGT expression is demonstrated during human hepatic development. The differential regulation of UGT1A9 and UGT2B4 expression extends beyond two years of age and is capable of influencing hepatic glucuronidation of common therapeutic drugs in children. The development of hepatic UGT activities is significant for paediatric drug therapy and the prevention of adverse drug effects.

Expansion of the donor pool in liver transplantation: the Hannover experience 1996-2002.

In the past decade liver transplantation has become the standard therapy for terminal liver failure. An increasing organ shortage, specific regional allocation systems within the Eurotransplant area and the lack of an efficient system to identify donors have resulted in decreasing numbers of liver transplants. Approximately 20% of patients are dying on the waiting list, a list that has exploded in numbers and waiting time in the past 3 years. In particular children and small adults are put at a disadvantage since standard donors have standard size livers. Two options to solve this dilemma are the expanded use of split-liver and living-donor liver transplantation. The specific experiences applying these techniques at the Medizinische Hochschule Hannover are discussed and compared with the results given in the European Liver Transplant Registry. The retrospective analysis demonstrates a shift in the use of resources, with decreasing numbers of full-size cadaver liver transplants and an increase in split- and living-donor liver transplantation. Both techniques are limited to specific patient populations, a notion that has to be considered in the comparison of results and outcome. According to our experience the full-size cadaver liver is still the standard option, while other techniques require careful attention to the chosen recipient population, advanced surgical skills and, for living donors, as a sine qua non the prerequisite of nihil nocere.

Regulation and function of family 1 and family 2 UDP-glucuronosyltransferase genes (UGT1A, UGT2B) in human oesophagus.

Human UDP-glucuronosyltransferases (UGTs) are expressed in a tissue-specific fashion in hepatic and extrahepatic tissues [Strassburg, Manns and Tukey (1998) J. Biol. Chem. 273, 8719-8726]. Previous work suggests that these enzymes play a protective role in chemical carcinogenesis [Strassburg, Manns and Tukey (1997) Cancer Res. 57, 2979-2985]. In this study, UGT1 and UGT2 gene expression was investigated in human oesophageal epithelium and squamous-cell carcinoma in addition to the characterization of individual UGT isoforms using recombinant protein. UGT mRNA expression was characterized by duplex reverse transcriptase-PCR analysis and revealed the expression of UGT1A7, UGT1A8, UGT1A9 and UGT1A10 mRNAs. UGT1A1, UGT1A3, UGT1A4, UGT1A5 and UGT1A6 transcripts were not detected. UGT2 expression included UGT2B7, UGT2B10 and UGT2B15, but UGT2B4 mRNA was absent. UGT2 mRNA was present at significantly lower levels than UGT1 transcripts. This observation was in agreement with the analysis of catalytic activities in oesophageal microsomal protein, which was characterized by high glucuronidation rates for phenolic xenobiotics, all of which are classical UGT1 substrates. Whereas UGT1A9 was not regulated, differential regulation of UGT1A7 and UGT1A10 mRNA was observed between normal oesophageal epithelium and squamous-cell carcinoma. Expression and analysis in vitro of recombinant UGT1A7, UGT1A9, UGT1A10, UGT2B7 and UGT2B15 demonstrated that UGT1A7, UGT1A9 and UGT1A10 catalysed the glucuronidation of 7-hydroxybenzo(alpha)pyrene, as well as other environmental carcinogens, such as 2-hydroxyamino-1-methyl-6-phenylimidazo-(4, 5-beta)-pyridine. Although UGT1A9 was not regulated in the carcinoma tissue, the five-fold reduction in 7-hydroxybenzo(alpha)pyrene glucuronidation could be attributed to regulation of UGT1A7 and UGT1A10. These data elucidate an individual regulation of human UGT1A and UGT2B genes in human oesophagus and provide evidence for specific catalytic activities of individual human UGT isoforms towards environmental carcinogens that have been implicated in cellular carcinogenesis.