Formation and kinetics of MHC class I-ovalbumin peptide complexes on immature and mature murine dendritic cells

Dendritic cells (DC) are professional antigen-presenting cells that are able to induce primary T cell responses. Therefore, several strategies employ peptide-pulsed DC in tumor immunotherapy. For efficient antigen presentation and induction of an immune response by DC the number and stability of MHC I-peptide complexes is crucial. We studied this issue by using the antibody 25-D1.16 that specifically detects OVA peptide SIINFEKL in conjunction with H-2 Kb molecules, and determined its kinetics on mature and immature bone marrow-derived murine DC. Optimal peptide loading was reached after 8-16 h at 50 microM peptide pulse, and was comparable in serum-free versus serum-containing medium. Stimulation of DC with LPS or Poly I:C, and to a lesser extent TNF-alpha, upregulated the total number of surface MHC I molecules and thus improved peptide loading. Pulse-chase experiments revealed a constant half-life of peptide/Kb complexes independent of preceding DC stimulation or their maturation stage. The duration of peptide/Kb complex expression on mature DC, however, could be extended from 24 h to 72 h when the cultures were pretreated with LPS or Poly I:C, but not TNF-alpha. These data might have important implications for the clinical application of peptide-pulsed DC in tumor immunotherapy.     

Acrodermatitis enteropathica: Recent findings concerning clinical features,pathogenesis, diagnosis and therapy

Acrodermatitis enteropathica (AE) was diagnosed in 2 siblings, boy and girl, at the age of 10 and 6 weeks. The family history is unremarkable except for consanguinity 5 generations previously. The clinical symptoms of the 2 patients conformed to the known features of AE, the gastrointestinal involvement loosing its significance with increasing age. In one patient in a stage of exacerbation the serum level of oleic acid (18:1) was lowered and of linoleic (18:2) acid slightly increased while that of arachidonic acid was decreased (Fig. 4).In both patients the serum zinc levels were significantly lowered. Under substitution with ZnSO₄ the clinical condition improved and the serum zinc levels returned to normal.Histologically the small bowel mucosa was practically normal. Ultrastructural examination of jejunal biopsies revealed rather unspecific changes in the enterocytes in the form of numerous multivesicular bodies. The Paneth cells sometimes contained irregularly formed inhomogeneous structures within their cytoplasm. In addition the secretory granules varied in size and displayed a granular heteromorphic matrix. Frequently they were confluent and formed giant granules.

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Zusammenfassung Bei 2 Geschwistern, einem Jungen und einem Mädchen, wurde die Diagnose der Acrodermatitis enteropathica (AE) im Alter von 10 bzw. 6 Wochen gestellt. Bis auf eine Blutsverwandtschaft, die 5 Generationen zurückliegt, ist die Familienanamnese anauffällig. Beide Kinder boten bei Diagnosestellung die für AE typischen Hautveränderungen. Symptome von seiten des Magen-Darm-Kanals waren weniger ausgeprägt und traten mit zunehmendem Alter in den Hintergrund. Bei dem jüngeren Patienten konnten während eines Rezidivs eine Erniedrigung des Serumspiegels der Ölsäure (18:1) sowie eine leichte Vermehrung der Linolsäure (18:2) festgestellt werden, während die Arachidonsäure (20:4) vermindert war.Bei beiden Patienten waren die Serumzinkspiegel mit und ohne Oxychinolinbehandlung deutlich erniedrigt. Eine Substitutionstherapie mit Zinkaspertat brachte weder eine klinische Besserung noch einen wesentlichen Anstieg des Serumzinkspiegels. Durch Gabe von Zinksulfat konnten eine völlige Remission der Hautveränderungen sowie eine weitgehende Normalisierung der Serumzinkspiegel erreicht werden.Untersuchungen der Dünndarmschleimhaut zeigten lichtmikroskopisch keine Besonderheiten. Elektronenmikroskopisch fanden sich in den Enterocyte sogenannte multi-vesicular bodies. Die Paneth-Zellen zeigten teilweise unregelmäßig geformte, inhomogene Strukturen im Cytoplasma. Die pleomorphen Sekretgraula wanen plump und groß und wiesen eine ausgeprägte Heteromorphie ihrer Matrix auf.Da bei Ratten unter zinkarmer Ernährung ähliche ultrastrukturelle Veränderungen bekannt sind, muß durch weitere Untersuchungen geklärt werden, ob die Veränderungen in den Paneth-Zellen typisch für die AE sind. Die adäquate Therapie der AE besteht zur Zeit in der Substitution von Zink. Dadurch wurde die mit toxischen Augenschädigungen belastete Therapie mit Oxychinolinen überflüssig.

     

Baseball/lacrosse injuries

With the expansion of baseball into all age groups, the game is becoming as much a recreational sport as a youth sport. Throwing arm injuries eventually limit the participation of most players. Analysis is made of these injuries with the goal of complete rehabilitation for the baseball player. Lacrosse has also seen an increase in popularity as a recreational sport. Analysis of lacrosse injuries and rehabilitation of the most common injuries is reviewed.     

Exposure to airborne particulate matter in the ambient, indoor, and occupational environments

Exposure to airborne particulate matter results in various adverse health effects. Unlike other pollutants, such as ozone, sulfur dioxide, carbon monoxide, and oxides of nitrogen, for which there is significant exposure, particulate matter exposure is much more complex because it is not a single chemical species or even a limited number of chemical species. Particulate matter includes various chemical species in particles having a wide range of diameters and shapes that have widely varying toxicities. People are exposed to particles in the ambient environment, in indoor spaces, and in the occupational environment. This article reviews the information available on the concentrations of particulate matter and its composition in these general environmental categories.     

Sensitivity and specificity of classification systems for fatness in adolescents

BACKGROUND: Various body mass index (BMI) standards have been proposed for defining overweight in adolescence, but few studies have evaluated their diagnostic accuracy. OBJECTIVE: We compared the sensitivity and specificity of BMI-based classification systems for detecting excess fatness in adolescents. DESIGN: A cross-sectional analysis of 474 adolescents aged 17 y was used. Body composition was measured by using densitometry. The international BMI-based systems recommended by the International Obesity Task Force and the World Health Organization were evaluated on the basis of their sensitivity and specificity for detecting excess body fat. Receiver operating characteristic analysis was performed to derive cutoffs to maximize the sum of sensitivity and specificity. True positives were defined by using the percentage body fat cutoffs proposed by Williams et al (Am J Public Health 1992;82:358-63). RESULTS: For both classification systems, the specificity for overweight was high for both sexes (0.95-1.00). The sensitivity was fairly high for the males (0.72-0.84) but was very low for the females (0.22-0.25). For the males, a BMI cutoff equal to the 85th percentile on a Swedish BMI reference chart maximized the sum of sensitivity and specificity while having both high sensitivity (0.92) and high specificity (0.92). For the females, larger tradeoffs in specificity were needed to improve sensitivity. The mean (+/-SE) areas under the receiver operating characteristic curves for the males and the females were 0.97 +/- 0.02 and 0.85 +/- 0.02, respectively. CONCLUSIONS: Recommended international classification systems have very high specificity, which results in few cases of non-overweight adolescents being mislabeled as overweight. However, the sensitivity is very low in female adolescents. Thus, many overweight female adolescents could be missed in intervention programs that use the proposed international BMI cutoffs as selection criteria.     

Amyloid precursor protein processing in vivo--insights from a chemically-induced constitutive overactivation of protein kinase C in Guinea pig brain

Aberrant proteolytical processing of the amyloid precursor protein (APP) gives rise to beta-amyloid peptides, which form deposits characteristic for the brains of Alzheimer's disease patients. From in vitro studies, protein kinase C (PKC) is known for almost 20 years to be involved the secretory pathway of APP processing, resulting in the reduced generation of beta-amyloid peptides. However, the toxicity of activators of PKC, such as phorbol esters, has prevented to test the hypothesis of an inverse regulation of secretory APP processing and beta-amyloid generation in vivo. Here we present an animal model which allows to reveal the function of PKC in the proteolytical processing of APP in vivo. Studies by Johnstone and Coyle from the early 1980s have shown that treatment of pregnant rats with methylazoxymethanol acetate (MAM) results in the induction of neocortical microencephalopathy of the offsprings. Later on, the constitutive overactivation of PKC isoforms was described in affected brain structures of these animals. This led to the idea to study the APP processing under conditions of overactivated PKC in the brains of such animals in vivo. However, in mice and rats one can follow the generation of secretory APP products but the detection of rodent beta-amyloid peptides is delicate. Therefore, we adapted the MAM model to guinea pigs, which have a human beta-amyloid sequence, and investigated the relation between secretory APP processing and beta-amyloid generation in vivo. In the brains of microencephalic guinea pigs we observed increased levels of secretory APP fragments but no change in the concentration of beta-amyloid peptides. Our results indicate that both pathways of APP processing are differentially controlled under these experimental conditions in vivo.     

The role of tumor resection in the treatment of glioblastoma multiforme in adults

BACKGROUND: The therapeutic impact of tumor resection is poorly defined. Therefore the current study was conducted. METHODS: A retrospective, 2-institutional study was conducted (1991-1994) to compare the treatment results of stereotactic biopsy plus radiation therapy (99 patients; tumor dose: 60 gray [Gy]) with those of surgical resection plus radiation therapy (126 patients; tumor dose: 60 Gy). Only adult patients with supratentorial, lobar located, de novo glioblastoma were included. Survival time was analyzed with the Kaplan-Meier method. Prognostic factors were obtained from the multivariate Cox proportional hazards model. RESULTS: Patients were categorized in the Radiation Therapy Oncology Group (RTOG) Classes IV (46 patients), V (157 patients), and VI (22 patients). The resection group and the biopsy group did not differ in terms of age, pretreatment Karnofsky performance status KPS), gender, duration of symptoms, presenting symptoms, tumor location, tumor size, and the frequency of midline shift. Patients in the biopsy group more often were found to have left-sided tumors (P < 0.001). Transient perioperative morbidity and mortality rates were 1% and 1%, respectively, in the biopsy group and 5% and 1.6%, respectively, in the resection group (P > 0.05). The median survival time was 37 weeks for the resection group and 33 weeks for the biopsy group. The difference was not statistically significant (P = 0.09). The most favorable pretreatment prognostic factor was patient age < 60 years (P < 0.01). Tumor resection was highly effective in patients with midline shift (P < 0.01). In patients without midline shift radiation therapy alone was found to be as effective as tumor resection plus radiation therapy (P = 0.5). Patients with midline shift were more likely to have a worse KPS during the course of primary radiation therapy (P < 0.05). CONCLUSIONS: For RTOG Classes IV-VI patients with moderate mass effect of the tumor, radiation therapy alone is a rational treatment strategy. Tumor resection should be performed in patients with pretreatment midline shift whenever possible.