Medizin - Open Access LMU - Teil 20/22 Archiv

The majority of neuroendocrine tumors (NETs) of thegastro-enteropancreatic system coexpress sornatostatin receptors (SSTRs)and dopamine type 2 receptors (D2R), thus providing a rationale for theuse of novel SSTR2/D2R chimeric compounds in NET disease. Here weinvestigate the antitumor potential of the SSTR2/D2R chimeric compoundsBIM-23A760 and BIM-23A758 in comparison to the selective SSTR2 agonistBIM-23023 and the selective D2R agonist BIM-53097 on human NET celllines of heterogeneous origin. While having only minor effects on humanpancreatic and bronchus carcinoid cells (BONI and NCI-H727), BIM-23A758induced significant antitumor effects in human midgut carcinoid cells(GOT1). These effects involved apoptosis induction as well as inhibitionof mitogen-activated protein kinase and Akt signaling. Consistent withtheir antitumor response to BIM-23A758, GOT1 cells showed relativelyhigh expression levels of SSTR2 and D2R mRNA. In particular, GOT1 cellshighly express the short transcript variant of D2R. In contrast toBIM-23A758, the SSTR2/D2R chimeric compound BIM-23A760 as well as theindividual SSTR2 and D2R agonistic compounds BIM-23023 and BIM-53097induced no or only minor antitumor responses in the examined NET celllines. Taken together, our findings suggest that the novel SSTR2/D2Rchimeric compound BIM-23A758 might be a promising substance for thetreatment of NETs highly expressing SSTR2 and D2R. In particular, asufficient expression of the short transcript variant of DR2 might playa pivotal role for effective treatment.

Among the various types of interstitial lung diseases, idiopathicpulmonary fibrosis (IPF) is the most common disorder and has a poorprognosis and a limited response to pharmacological treatment. Inpatients with IPF, functional exercise tolerance and quality of lifehave been shown to be significantly decreased. Current IPF guidelinessuggest only a weak recommendation for pulmonary rehabilitation (PR).However, PR is regarded as a reasonable choice for the majority ofpatients with IPF. This review will summarize all of the availablestudies that have investigated the effects of PR in patients with IPF sofar. Although only a small number of studies have been published todate, most studies have found significant short-term improvements infunctional exercise capacity, quality of life, and level of perceiveddyspnea. Long-term improvements or maintenance strategies of PR in IPFpatients have not been adequately investigated yet. Up to now there isstill no sufficient evidence for the recommendation of PR in IPF.However, physical training seems to be the major component of all PRprograms. The current review will discuss potential exercise trainingregimens for patients with IPF and suggest additional useful modalitiesof a specific multidisciplinary PR program for IPF patients. Based onthe current literature and our own experience, this article will try tohighlight the importance of PR as an additional, beneficial therapeuticoption for patients with IPF.

Background: First-episode schizophrenia (FE-SZ) and attention deficithyperactivity disorder (ADHD) are both neuropsychiatric disordersassociated with an impaired dopaminergic transmission. Though displayingdifferent clinical phenotypes, a common pathophysiological pathway isdiscussed controversially. Several studies using transcranial magneticstimulation (TMS) revealed abnormalities in human motor cortexexcitability in both schizophrenia and ADHD patients. Studies oncortical excitability comparing these two diseases directly are lacking.Method: In this study, a total of 94 subjects were analyzed.Twenty-fiveFE-SZ patients were directly compared with 28 ADHD patients and 41healthy controls (HC). We investigated cortical excitability (inhibitoryand facilitatory networks) with single- and paired-pulse TMS to the leftand right motor cortex. Results: Compared to HC, FE-SZ/ADHD patientsdisplayed an impaired cortical inhibition over the left hemisphere.Apart from an enhanced intracortical facilitation, FE-SZ patients didnot differ compared to ADHD patients in the main outcome measures. Bothpatient groups presented a dysfunctional hemispheric pattern of corticalinhibition and facilitation in comparison with HC. Conclusion: Theresults of this study indicate a pattern of cortical disinhibition andabnormal hemispheric balance of intracortical excitability networks intwo different psychiatric diseases. These effects might be associatedwith an imbalance in GABAergic and dopaminergic transmission and mightprovide evidence for a common pathophysiological pathway of bothdiseases.

The 2013 St. Gallen Consensus Conference on early breast cancer providedmostly evidence-based, globally valid treatment recommendations forbreast cancer care, with a broad spectrum of acceptable clinicalpractice. This report summarizes the results of the 2013 internationalpanel voting procedures with regard to loco-regional and endocrinetreatment, chemotherapy, targeted therapy as well as adjuvantbisphosphonate use. This report is not aimed to replace the official St.Gallen Consensus publication, some recommendations may even be alteredin the final paper, but should serve a preliminary rapid report of thisimportant meeting.

Background: The diagnostic use of lung function using spirometry dependson the validity of reference equations. A multitude of spirometricprediction values have been published, but in most of these studiesolder age groups are underrepresented. Objectives: The aim of thepresent study was to establish new spirometric reference values foradvanced age and to compare these to recent prediction equations frompopulation-based studies. Methods: In the present study spirometry wasperformed in a population-based sample from the KORA-F4 and KORA-Agecohorts (2006-2009, Augsburg, Germany) comprising 592 never-smokingsubjects aged 42-89 years and with no history of respiratory disease.Using quantile regression analysis, equations for the median and lowerlimit of normal were derived for indices characterizing the expiratoryflow-volume curve: forced expiratory volume in 1 s (FEV1), forced vitalcapacity (FVC), FEV1/FVC, peak expiratory flow (PEF), and forcedexpiratory flow rates at 25, 50 and 75% of exhaled FVC (FEF25, FEF50and FEF75). Results: FEV1 and FVC were slightly higher, and PEF waslower compared to recently published equations. Importantly, forcedexpiratory flow rates at middle and low lung volume, as putativeindicators of small airway disease, were in good agreement with recentdata, especially for older age. Conclusion: Our study providesup-to-date reference equations for all major indices of flow-volumecurves in middle and advanced age in a South German population. Thesmall deviations from published equations indicate that there might besome regional differences of lung function within the Caucasianpopulation of advanced age in Europe.

Although many aspects of ovarian differentiation have been established,comparatively little is known about prenatal follicle formation anddifferentiation of bovine ovaries. The objective of this investigationwas to study the role of the surface epithelium during the developmentof germ cell nests, germ cell cords and follicle formation in the fetalbovine ovary. Associated important proliferation and apoptotic featureswere further investigated. Additionally, the expression pattern of theS100 protein was detected. A strong increase of mitotic figures wasdetected in the surface epithelium, germ cell nests and germ cell cordsof ovaries with a crown-rump length (CRL) of 13.0-58.0 cm. Oocytes werepositively stained with S100 in bovine ovaries from fetuses with a CRLof 21.0 cm. The staining intensity enhanced parallel to increasingoocyte and follicle sizes during the ovary development. In later stages,a strong staining for S100 was observed in healthy oocytes incontradistinction to atretic oocytes where no expression of the S100protein could be found. In conclusion, increasing mitosis index ofsurface epithelium cells, as well as oogonia directly beneath thesurface epithelium, in combination with open surface connection duringstages from a CRL of 11.0-94.0 cm of bovine fetal ovaries could play animportant role in the period of time of ongoing folliculogenesis andderivation of granulosa cells. Additionally, S100-positive oocytes inprimordial and later follicle stages joined by a high rate ofKi67-positive index in surrounding granulosa cells indicate that in theoocytes the S100 protein can perhaps be a useful marker for intactoocytes in bovine ovaries.

The developments in gene expression analysis have made it possible tosub-classify hormone receptor-positive (luminal) breast cancer indifferent prognostic subgroups. This sub-classification is currentlyused in clinical routine as prognostic signature (e. g. 21-gene OnoctypeDX (R), 70-gene Mammaprint (R)). As yet, the optimal method forsub-classification has not been defined. Moreover, there is no evidencefrom prospective trials. This review explores widely used genomicsignatures in luminal breast cancer, making a critical appraisal ofevidence from retrospective/prospective trials. It is based onsystematic literature search performed using Medline (accessed September2013) and abstracts presented at the Annual Meeting of American Societyof Clinical Oncology and San Antonio Breast Cancer Symposium.

Diet and physical activity before and during pregnancy affect short- andlong-term health of mother and child. The energy needs at the end ofpregnancy increase only by about 10% compared to nonpregnant women. Anexcessive energy intake is undesirable since maternal overweight andexcessive weight gain can increase the risks for a high birth weight andlater child overweight and diabetes. Maternal weight at the beginning ofpregnancy is especially important for pregnancy outcome and childhealth. Women should strive to achieve normal weight already beforepregnancy. Regular physical activity can contribute to a healthy weightand to the health of pregnant women. The need for certain nutrientsincreases more than energy requirements. Before and during pregnancy,foods with a high content of essential nutrients should bepreferentially selected. Supplements should include folic acid andiodine, iron (in case of suboptimal iron stores), the omega-3 fatty aciddocosahexaenoic acid (in case of infrequent consumption of ocean fish)and vitamin D (in case of decreased sun exposure and decreasedendogenous vitamin D synthesis). Pregnant women should not smoke and notstay in rooms where others smoke or have smoked before (passivesmoking). Alcohol consumption should be avoided, since alcohol can harmunborn children.

Health and nutrition modulate postnatal growth. The availability ofamino acids and energy, and insulin and insulin-like growth factor-I(IGF-I) regulates early growth through the mTOR pathway. Amino acids andglucose also stimulate the secretion of IGF-I and insulin. Postnatalgrowth induces lasting, programming effects on later body size andadiposity in animals and in human observational studies. Rapid weightgain in infancy and the first 2 years was shown to predict increasedobesity risk in childhood and adulthood. Breastfeeding leads to lesserhigh weight gain in infancy and reduces obesity risk in later life byabout 20%, presumably partly due to the lower protein supply with humanmilk than conventional infant formula. In a large randomized clinicaltrial, we tested the hypothesis that reduced infant formula proteincontents lower insulin-releasing amino acid concentrations and therebydecrease circulating insulin and IGF-I levels, resulting in lesser earlyweight gain and reduced later obesity risk (the ‘Early ProteinHypothesis’). The results demonstrate that lowered protein in infantformula induces similar - but not equal - metabolic and endocrineresponses and normalizes weight and BMI relative to breastfed controlsat the age of 2 years. The results available should lead to enhancedefforts to actively promote, protect and support breastfeeding. Forinfants that are not breastfed or not fully breastfed, the use of infantformulas with lower protein contents but high protein quality appearspreferable. Cows’ milk as a drink provides high protein intake andshould be avoided in infancy.

The follow-up formula (FUF) standard of Codex Alimentarius adopted in1987 does not correspond to the recently updated Codex infant formula(IF) standard and current scientific knowledge. New Zealand proposed arevision of the FUF Codex standard and asked the non-profit EarlyNutrition Academy, in collaboration with the Federation of InternationalSocieties for Paediatric Gastroenterology, Hepatology, and Nutrition(FISPGHAN), for a consultation with paediatric nutrition experts toprovide scientific guidance. This global expert group strongly supportsbreastfeeding. FUF are considered dispensable because IF can substitutefor breastfeeding throughout infancy, but FUF are widely used and thusthe outdated current FUF standard should be revised. Like IF, FUF serveas breast milk substitutes; hence their marketing should respectappropriate standards. The compositional requirements for FUF forinfants from 6 months onwards presented here were unanimously agreedupon. For some nutrients, the compositional requirements for FUF differfrom those of IF due to differing needs with infant maturation as wellas a rising contribution of an increasingly diversified diet withadvancing age. FUF should be fed with adequate complementary feedingthat is also appropriate for partially breastfed infants. FUF could befed also after the age of 1 year without safety concerns, but differentcompositional requirements should be applied for optimal, age-adaptedmilk-based formulations for young children used only after the age of 1year. This has not been considered as part of this review and should bethe subject of further consideration.

Objectives: The purpose of this study was to investigate the developmentof lateralization skills in children who received bilateral cochlearimplants (CIs) in sequential operations. Methods: The lateralizationskills of 9 children with a mean age of 4.1 years at the first surgeryand 5.5 years at the second surgery were assessed at 3 time intervals.Children were assessed with a 3-loudspeaker setup (front, left andright) at 0.9 years (interval I) and 1.6 years (interval II) after thesecond implantation, and after 5.3 years of bilateral implant use(interval III) with a 9-loudspeaker setup in the frontal horizontalplane between -90 degrees and 90 degrees azimuth. Results: Withbilateral implants, a significant decrease in lateralization error wasnoted between test interval I (45.0 degrees) and 11 (23.3 degrees), witha subsequent significant decrease at test interval III (4.7 degrees).Unilateral performance with the CI did not improve significantly betweenthe first 2 intervals; however, there was a bias of responses towardsthe unilateral side by test interval III. Conclusions: Thelateralization abilities of children with bilateral CIs develop in arelatively short period of time (1-2 years) after the second implant.Children appear to be able to acquire binaural skills after bilateralcochlear implantation.

Background: Feeding patients with severe abdominal infections isparticularly demanding. Method: The authors electronically searched theMEDLINE, EMBASE and Cochrane databases (using the keywords‘peritonitis’, ‘severe sepsis’, ‘nutrition’, ‘practice parameter’, and‘guideline’) and reviewed their personal databases for articles relevantto the issue which have been published between 2002 and 2012. Results:Patients suffering from abdominal sepsis are at a high risk for severehyperglycemia and insulin resistance. Due to an excessive proteincatabolism which cannot be overcome by standard nutritional therapy,these patients are malnourished and require a particularly carefulnutritional support. The latter is not guided by the actual energyexpenditure (which markedly increases during the acute phase) but by thecapacity of the organism to utilize exogenous substrates (this capacityusually decreases during the acute phase). It is of outmost importanceto supply sufficient amounts of protein or amino acids. Ideally, thepatients should be fed enterally. Even in patients with severe abdominalcomplications (anastomotic leakage), modern tube and jejunostomytechniques as well as surgical strategies allow an adequate enteralsupply of calories. However, patients suffering from a severe abdominalsepsis often exhibit a delayed gastrointestinal passage (delayed gastricemptying, small bowel paralysis, colonic pseudo-obstruction). Thesepathologies restrict enteral nutrition and should be recognized as earlyas possible by appropriate clinical surveillance. Besides a clinicalexamination of the abdomen, measurement of gastric residual volumerepresents the best control parameter when providing food into thestomach. Delayed gastrointestinal passage should be treated asaggressively as possible. Primary objective is the cure of the abdominalfocus. In addition, use of drugs with an antiperistaltic action shouldbe restricted as much as possible. Severe cases may profit frommedications with a properistaltic action combined with specific physicalmeasures. Conclusion: Feeding patients suffering from an abdominalinfection requires an individualized, patient-centered approach whichrequires a profound nutritional and special gastroenterologicalknowledge.

The humanized monoclonal antibody pertuzumab prevents the dimerizationof HER2 with other HER receptors, in particular the pairing of the mostpotent signaling heterodimer HER2/HER3, thus providing a potent strategyfor dual HER2 inhibition. It binds to the extracellular domain of HER2at a different epitope than trastuzumab. Pertuzunnab and trastuzumab actin a complementary fashion and provide a more complete blockade ofHER2-mediated signal transduction than either agent alone. Phase IIstudies demonstrated that pertuzunnab was generally well tolerated as asingle agent or in combination with trastuzumab and/or cytotoxic agents,and implied an improved clinical efficacy of the combination ofpertuzumab and trastuzumab in early and advanced HER2-positive breastcancer. Results of the pivotal phase III study CLEOPATRA in patientswith HER2-positive metastatic breast cancer demonstrated that theaddition of pertuzumab to first-line combination therapy with docetaxeland trastuzumab significantly prolonged progression-free and overallsurvival without increasing cardiac toxicity. Currently, the combinationof both antibodies is being explored in the palliative setting as wellas in the treatment of early HER2-positive breast cancer. Dual HER2inhibition with the HER2 dimerization inhibitor pertuzumab andtrastuzumab may change clinical practice in HER2-positive first-linemetastatic breast cancer treatment.