Pharmacological characterisation of the goldfish somatostatin sst5 receptor

Somatostatin (somatotropin release inhibiting factor, SRIF), exerts its effects via specific G protein coupled receptors of which five subtypes have been cloned (sst1-5). Recently, SRIF receptors have also been cloned from fish tissues. In this study, goldfish sst5 receptors (gfsst5) were expressed and characterised in the Chinese hamster lung fibroblast cell line, that harbours the luciferase reporter gene driven by the serum responsive element (CCL39-SRE-Luci). The agonist radioligands [125I]-LTT-SRIF-28 ([Leu8, DTrp22, 125I-Tyr25]SRIF-28) and [125I][Tyr10]cortistatin-14 labelled similar receptor densities with high affinity and in a saturable manner (pKd: 9.99-9.71; Bmax: 300-350 fmol mg-1). 5'-Guanylyl-imidodiphosphate inhibited radioligand binding to some degree (38.5-57.9%). In competition binding studies, the pharmacological profile of SRIF binding sites defined with [125I]LTT-SRIF-28 and [125I][Tyr10]cortistatin-14 correlated significantly (r2=0.97, n=20). Pharmacological profiles of human and mouse sst5 receptors expressed in CCL39 cells correlated markedly less with those of the gfsst5 profile (r2=0.52-0.78, n > or = b16). Functional expression of the gfsst5 receptor was examined by measurement of agonist-induced luciferase expression and stimulation of [35S]GTPgammaS ([35S]guanosine 5'-O-(3-thiotriphosphate) binding. Profiles were similar to those achieved in radioligand binding studies (r2=0.81-0.93, n=20), although relative potency (pEC50) was reduced compared to pKd values. Relative efficacy profiles of luciferase expression and [35S]GTPgammaS binding, were rather divergent (r2=0.48, n=20) with peptides showing full agonism at one pathway and absence of agonism at the other. BIM 23056 (D-Phe-Phe-Tyr-D-Trp-Lys-Val-Phe-D-Nal-NH2) acted as an antagonist on the effects of SRIF-14 (pKB=6.74 +/- 0.23) on stimulation of [35S]GTPgammaS binding. Pertussis toxin abolished the effect of SRIF-14 on luciferase expression and [35S]GTPgammaS binding suggesting coupling of the receptor to G(i)/G(o) proteins. In summary, the present studies demonstrate that the gfsst5 receptor has a similar pharmacological profile and transductional properties to mammalian sst5 receptors. The difference in efficacy profiles defined using different functional assays suggests numerous, agonist specific, conformational receptor states, and/or ligand-dependent receptor trafficking.     

Bonded resin sealant on smooth surface dental enamel--an in vitro study

The aim of this study was to in vitro evaluate the micro leakage of a fissure sealant on sound and demineralized enamel using thermo cycling. The effect of the sealing procedure on sound and demineralized enamel were assessed on human premolars that were divided into one Control group and two Test groups. The Control group served as a baseline reference for the subsequent test procedures. The crowns of five teeth were covered with wax leaving three separate windows on the buccal surfaces. The enamel in one window was acid-etched, in the second window demineralized, and in the third window demineralized and subsequently acid-etched. In Test group 1, containing ten teeth, a defined enamel area on the buccal surfaces was acid-etched and sealed. The sealed area and a border of sound enamel around it were subjected to the demineralizing procedure. In Test group 2, a defined enamel window of 13 teeth was demineralized and subsequently etched and sealed. The sealed area and a border of surrounding enamel were subjected to a new cycle of demineralization. The longitudinal, bucco-lingual sections were examined in polarized light. When placed on acid-etched surfaces, the resin adhered firmly to the enamel with no evidence of demineralization or enlargement of previously demineralized areas underneath the sealants.     

Closure of a very large patent ductus arteriosus using the amplatzer duct occluder

A very large patent ductus arteriosus was closed completely using an Amplatzer Duct Occluder. This represents the largest patent ductus arteriosus to undergo closure with this endovascular technique.     

Bev?lkerungsbezogene Studie über die Anwendung adjuvanter Strahlentherapie bei Patientinnen mit Mammakarzinom

Ziel: Die Umsetzung von Behandlungsempfehlungen zur adjuvanten Strahlentherapie bei Patientinnen mit Mammakarzinom zu evaluieren. Patientinnen und Methoden: Die Studie basiert auf Daten einer bevölkerungsbezogenen Kohortenstudie. In der Studienregion Ostthüringen leben ca. eine Million Einwohner. In den Jahren 1995 bis 2000 wurden 2031 Fälle mit invasivem Mammakarzinom ohne primäre Fernmetastasierung (MO) und ohne inflammatorische Ausbreitung erfasst. Von diesen konnten 1700 Fälle mit vollständigen Angaben der Kovariaten in eine multivariate Analyse einbezogen werden. Der Einfluss von klinischen Faktoren und "Caseload" als Klassifizierung nach behandelten Fällen pro Jahr. Bzw. einzelnen Kliniken auf die Durchführung von adjuvanter Strahlentherapie des Brustdrüsenkörpers oder der Thoraxwand nach Mastektomie wurde in logistischen Regressionsmodellen ermittelt. Ergebnisse: Nach brusterhaltender Therapie (BET) wurden 90,6% der Patientinnen adjuvant behandelt. In der univariaten Analyse wurden bei älteren Patientinnen (S 70 Jahre) seltener eine Strahlenbehandlung durchgeführt. Dies war auch bei Patientinnen mit Begleiterkrankungen zu beobachten. Für die übrigen Kofaktoren wurden keine Assoziationen mit der Strahlentherapie beobachtet. Nach Mastektomie wurden 33,0% der Patientinnen adjuvant bestrahlt. Zunehmende Tumorgröße war eine Indikation für die ajuvante Strahlentherapie. Ebenso hatten der Befall von mehr als drei Lymphknoten, Multifokalität, hoher Malignitätsgrad und mediale Lokalisation Einfluss auf die Anwendung von Strahlentherapie. Hingegen konnte für die R-Klassifikation, den Hormonrezeptorstatus und Begleiterkrankungen kein Einfluss beobachtet werden. Zwischen den Kliniken waren hinsichtlich der Umsetzung von Therapieempfehlungen sowohl nach BET als auch Mastektomie Variationen zu beobachten. Schlussfolgerung: Nach BET wurde überwiegend die empfohlene Strahlentherapie durchgeführt, nur im höheren Alter und bei Begleiterkrankungen wurde seltener eine Strahlentherapie durchgeführt. Nach Mastektomie beeinflussten relevante Risikofaktoren die Therapieentscheidung zur Strahlentherape. Zwischen den Kliniken waren Variationen in der Therapieentscheidung zu beobachten. Aim: The assessment of the compliance with consensus recommendations for adjuvant radiation therapy among women with breast cancer. The study is based on data obtained in a population-based cohort-study, which was performed to evaluate the quality of health care for patients with breast cancer. Patients and Methods: About one million inhabitants live in the study region Eastern Thuringia, 2,031 cases with invasive breast cancer without distant metastasis (MO) or inflammatory spread were registered from 1995 to 2000. Out of these 1,700 with complete documentation of covariates were included in multivariate analysis. To examine the simultaneous influence of all clinical factors and "caseload" on the likelihood to receive adjuvant radiation therapy a logistic regression model was fitted for radiation therapy after mastectomy. In order to describe the impact of each individual clinic on treatment decision as "caseload" was replaced by the clinics with more than 30 primary treatments. Results: Following breast conserving therapy (BCT) 90.6% of the patients received adjuvant radiation therapy. In the univariate analysis older age was negatively associated with the use of radiation therapy among women with BCT (Table 1). Furthermore, comorbid conditions were negatively associated with the use of radiation therapy. For all other cofactors no associations were found. Subsequent to mastectomy 33.0% of the women underwent radiation therapy (Table 2). Associations between the use of radiation therapy and age, tumor category, number of positive lymph nodes, multiple tumors, histologic differentiation grade, residual tumor as well as hormone receptor status were found. In the multivariate analysis only older age (S 70 years) was identified as negative indicator for the utilization of radiation therapy. Among patients with mastectomy increasing tumor size was a positive predictor on radiation therapy (Table 3). In addition more than three positive lymph nodes, multiplicity, poor histologic differentiation grade (G3/4), medial localization, and younger age (35-49 years) were positive predictors for the application of radiation therapy. For R-classification, hormone receptor status and comorbidity no influence on the use of radiation therapy was observed. Among clinics adjusted for case-mix variations in the compliance of treatment recommendation both following BCT and mastectomy were found (Figure 1). Conclusion: Following BCT compliance with treatment recommendations regarding radiation therapy was high. Women in older age or with comorbidities received less often radiation therapy. Subsequent to mastectomy indicators for the use of radiation therapy were identified. Among clinics differences in the adherence to treatment recommendations were observed.     

Clinical evaluation of biomarkers in Gaucher disease

Novel or candidate biomarkers require thorough evaluation to establish their utility in a clinical setting. This paper describes an evaluation of several established enzyme markers of Gaucher disease and a newly-described chemokine, pulmonary and activation-regulated chemokine (PARC). The ability of the biomarkers to rank patients with Gaucher disease in order of disease severity and organ bulk, and to reflect changes in key clinical parameters in response to enzyme replacement therapy were evaluated. PARC concentrations were found to be reliably correlated with visceral disease and with key clinical responses to enzyme replacement in an unbiased manner. Unlike chitotriosidase and serum angiotensin-converting enzyme activity, genetic variation in serum PARC did not appear to influence its utility as a biomarker.
Conclusion: For each new candidate biomarker of lysosomal storage diseases, a similar clinical evaluation will be required, though the approach will need to be modified according to the clinical features and natural history of each disorder.     

Social phobia as a comorbid condition in sex offenders with paraphilia or impulse control disorder

Studies on the prevalence of social anxiety in sex offenders show mixed results. This may be due to social anxiety being heightened only in diagnostic subgroups of sex offenders, namely in paraphiliacs. In study 1, 72 mentally disordered sexual delinquents and 30 controls were screened for social anxiety with the Social Interaction Anxiety Scale and the Social Phobia Scale by Mattick and Clarke (German versions). In study 2, 55 mentally disordered sexual delinquents were diagnosed with a structured clinical interview. In both studies, sex offenders were categorized as either paraphilic or impulse control disordered (without paraphilia) according to research criteria. Study 1 showed markedly heightened scores for social anxiety in paraphiliacs, particularly for social interaction anxiety. Study 2 found a high lifetime and point prevalence of social phobia in paraphiliacs for which corroborating evidence was again found in questionnaire results. Implications for further research, diagnostic procedures, and therapy are discussed.     

Hirschprung's disease

Current evidence on the pathogenesis of Hirschprung's disease, then, favours the 'abnormal microenvironment' hypothesis wherein the developing and migrating normal neural crest cells confront a segmentally abnormal and hostile microenvironment in the colon. This hypothesis would account both for the congenital absence of ganglion cells in the wall of colon and also for the range of enteric neuronal abnormalities encountered including neuronal dysplasia, hypoganglionosis, and zonal aganglionosis. The abnormal constitution of the mesenchymal and basement membrane extracellular matrix in the affected segment of colon is presumably genetically determined and further understanding of the pathogenesis of this disorder will emerge as molecular geneticists characterise the specific genes and gene products associated with Hirschprung's disease. Advances in this field should permit gene probes to be developed to facilitate prenatal and postnatal diagnosis.