[The way from cost approval to bariatric surgery : Analysis of resource utilization in a maximum care hospital]. / Vom Antrag auf Kostengutsprache bis zur bariatrischen Operation : Personelle Ressourcenanalyse an einem Zentrum der Maximalversorgung.

BACKGROUND: Morbid obesity is a medical and economic challenge. Patients who have the indications for bariatric surgery face a long way from the first visit until surgery and a high utilization of resources is required. OBJECTIVES: The present study aimed to evaluate labor costs and labor time required to supervise obese patients from their first visit until preparation of a bariatric report to ask for cost acceptance of bariatric surgery from their health insurance. In addition, the reasons for not receiving bariatric surgery after receiving cost acceptance from the health insurance were evaluated. MATERIAL AND METHODS: Patients who had indications for bariatric surgery according to the S3 guidelines between 2012 and 2013, were evaluated regarding labor costs and labor time of the process from the first visit until receiving cost acceptance from their health insurance. Furthermore, body mass index (BMI), age, sex, Edmonton Obesity Staging System (EOSS) stage and comorbidities were evaluated. Patients who had not received surgery up to December 2015 were contacted via telephone to ask for the reasons. RESULTS: In the present study 176 patients were evaluated (110 females, 62.5%). Until preparation of a bariatric report the patients required an average of 2.7 combined visits in the department of surgery with the department of nutrition, 1.7 visits in the department of psychosomatic medicine, 1.5 separate visits in the department of nutrition and 1.4 visits in the department of internal medicine. Average labor costs from the first visit until the bariatric survey were 404.90 ± 117.00 euros and 130 out of 176 bariatric reports were accepted by the health insurance (73.8%). For another 40 patients a second bariatric survey was made and 20 of these (50%) were accepted, which results in a total acceptance rate of 85.2% (150 out of 176). After a mean follow-up of 2.8 ± 1.1 years only 93 out of 176 patients had received bariatric surgery (53.8%). Of these 16 had received acceptance of surgery by their health insurance only after a second bariatric survey. CONCLUSION: A large amount of labor and financial resources are required for treatment of obese patients from first presentation up to bariatric surgery. The cost-benefit calculation of an obesity center needs to include that approximately one half of the patients do not receive surgery within more than 2.5 years.

[Recombinant Antibodies and Their Employment in Cancer Therapy]. / Rekombinantní protilátky a jejich vyuzití v protinádorové terapii.

Development of recombinant therapeutic antibodies is recently one of the fastest growing disciplines of applied biomedical research. Recombinant monoclonal antibodies are increasingly applied in biological therapy of many serious human diseases and are currently an irreplaceable part of a comprehensive cancer therapy. First mouse therapeutic antibodies had only limited applicability due to the strong immune response; however, technological advances enabled engineering of antibodies with increased specificity and efficacy, and on the other hand with reduced adverse effects due to lower antigenicity. This review provides a summary of knowledge about recombinant therapeutic antibodies, their mechanism of action and approaches how to improve their efficacy.

Overnight storage of removable dentures in alkaline peroxide-based tablets affects biofilm mass and composition.

BACKGROUND: Clinical guidelines for denture care are available, but evidence for optimal nocturnal storage is scarce. The aim of the study was to compare the role of the overnight storage state on plaque growth and composition on acrylic removable dentures. METHODS: In a parallel-group randomized controlled trial of 51 institutionalized participants, 3 denture overnight preservation methods were considered: (i) in water, (ii) dry or (iii) in water with added alkaline peroxide-based cleansing tablet. Biofilm samples were taken on day 7 (developing biofilm - dBF) and day 14 (maturing biofilm - mBF) from a mechanically uncleaned, standardized region, situated distally to the second lower premolars. Total and individual levels of selected perio-pathogenic and commensal species (n=20), and of Candida albicans were calculated by PCR. Differences between storage conditions (water/dry/tablet) and between the samples (dBF/mBF) were assessed by means of unpaired and paired t-tests respectively, with α=5%. RESULTS: Overnight denture storage with cleansing tablet significantly decreased the total bacterial level of dBF and mBF up to 13.8%. Fn, Ec, Cs, Sc, Ao and Vp counts were particularly affected by tablet care. Significant lower amounts of Candida albicans for tablet storage compared to water preservation were recorded in dBF and mBF (-69.3 ± 3.8% and -75.9 ± 3.2% respectively). The mass and pathogenicity of dBF and mBF was equal, irrespective of the overnight storage intervention. CONCLUSIONS: The use of cleansing tablets for acrylic removable denture overnight storage reduces denture biofilm mass and pathogenicity compared to dry and water preservation, and may contribute to the overall systemic health. CLINICAL SIGNIFICANCE: Evidence-based clinical guidelines for overnight storage of removable acrylic dentures are lacking. The findings of this study indicate that alkaline peroxide-based cleansing tablets decrease bacterial and Candida levels in denture biofilms in case of poor oral hygiene. This provides evidence for a clinical guideline to minimize microbial load of dentures, thereby reducing associated systemic health risks.

Safety assessment and dose selection for first-in-human clinical trials with immunomodulatory monoclonal antibodies.

Modulating immune responses with monoclonal antibodies (mAbs) that target immune molecules has become a promising therapeutic strategy and is under investigation for the treatment of cancer and (auto)-immune diseases. A major hurdle to the development and early clinical investigation of many immunomodulatory mAbs is the inherent risk of adverse immune-mediated drug reactions in humans, such as cytokine storms, autoimmunity, and immunosuppression. Dose selection for first-in-human (FIH) clinical trials involving immunomodulatory mAbs, and mAbs in general, is based on specifically designed preclinical safety studies, primarily in nonhuman primates (NHPs), and on mechanistic ex vivo investigations. Dose selection in such trials is challenging for a number of reasons related to safety. In this context, safety-relevant differences between NHP and human immune systems, species selection/qualification and preclinical study design considerations, the receptor occupancy model and its calculation, the minimal anticipated biological effect level (MABEL) and its use in the selection of a safe starting dose in humans, microdosing and the impact of immunogenicity on safety assessment of mAbs, and safety-relevant formulation properties of therapeutic mAbs are critically reviewed. In addition, the current regulatory requirements are presented and discussed to demonstrate how the TeGenero TGN1412 case is leading to increased regulatory scrutiny regarding dose selection for FIH clinical trials.

Antenatal phenobarbital for reducing neonatal jaundice after red cell isoimmunization.

BACKGROUND: Neonates from isoimmunized pregnancies have increased morbidity from neonatal jaundice. The increased bilirubin from haemolysis often needs phototherapy, exchange transfusion or both after birth. Various trials in pregnant women who were not isoimmunized but had other risk factors for neonatal jaundice have shown a reduction in need for phototherapy and exchange transfusion by the use of antenatal phenobarbital. A recent retrospective case-controlled study showed reduction in the need for exchange transfusion for the neonates from isoimmunized pregnancies. OBJECTIVES: To assess the effects of antenatal phenobarbital in red cell isoimmunized pregnancies in reducing the incidence of phototherapy and exchange transfusion for the neonate. SEARCH STRATEGY: We searched the Cochrane Pregnancy and Childbirth Group's Trials Register (June 2006). SELECTION CRITERIA: Randomised and quasi-randomised controlled trials of pregnant women established to have red cell isoimmunization in the current pregnancy during their antenatal testing and given phenobarbital alone or in combination with other drugs before birth. DATA COLLECTION AND ANALYSIS: All three review authors independently assessed study eligibility and quality. MAIN RESULTS: No trials met the inclusion criteria for this review. AUTHORS' CONCLUSIONS: The use of antenatal phenobarbital to reduce neonatal jaundice in red cell isoimmunized pregnant women has not been evaluated in randomised controlled trials.

Effect of composting and pasteurisation on two important quarantine pests of potato.

The effect of composting and pasteurization on the quarantine pests of potato Clavibacter michiganensis ssp. sepedonicus (Cms) and Synchytrium endobioticum (Se) were examined on an experimental scale. Composting was performed with 2-L pots and 60-L composters for two months at temperatures below 50 degrees C and for 12 and 21 days at temperatures above 65 degrees C. Pasteurization was performed via water bath at 70 degrees C for maximum 2 hours. Pathogens were introduced directly or via carriers into the processes. After composting for two months and for 12 and 21 days it was possible to isolate vital Cms cells from bioassay plants and vital resting spores of Se could be extracted from sample material. Likewise it was possible to isolate vital Cms cells and resting spores of Se after pasteurization for up to two hours. Both pests could not be killed completely during the performed processes. Further studies concerning sanitization of potato wastes are necessary.

[Exudative enteropathy in congenital lymphedema-lymphangiectasia syndrome]. / Exsudative Enteropathie bei angeborenem Lymphangiektasie-Lymphödem-Syndrom.

BACKGROUND: Congenital peripheral elephantiasiformic alterations are very rare in paediatric patients. In a patient with lymphangiectasia-lymphedema syndrome we demonstrate over a 8-year follow-up that not only cosmetic and social indications for surgical treatments but also internal care become important during the course. PATIENT: We report on a boy with congenital lymphedemas of the extremities and the genital region, which were several times surgically treated. The patient became symptomatic firstly with tetanic cramps caused by malabsorption syndrome due to intestinal lymphangiectasia at the age of 6 years. Synopsis of clinical and laboratory findings and the patient's course are pointing to a mild Hennekam syndrome with still unknown aetiology. RESULTS: The boy developed adequately with permanent oral substitution of electrolytes and vitamins, protein-rich diet, supplementation of medium-chain fatty acids and compressing bandages. Infusions of human albumin to correct persistent hypalbuminemia as well as cytostatic treatment with cyclophosphamide as a formal trial were ineffective and are not advisable, therefore.

Different pattern of collagen cross-links in two sclerotic skin diseases: lipodermatosclerosis and circumscribed scleroderma.

Changes in the process of cross-linking of collagen molecules are associated with defects in the biomechanical stability of the extracellular matrix. Fibrosis of skin is characterized by an increase in pyridinolines, which are hydroxylysine aldehyde derived cross-links usually absent in healthy skin. In this study, we analyzed cross-links in lipodermatosclerosis and localized scleroderma to address the question whether all the mature cross-links currently characterized are increased in fibrosis in addition to the increase in pyridinolines. As psoralen plus ultraviolet A treatment leads to clinical improvement of fibrotic plaques in localized scleroderma we analyzed the cross-link content in lesional skin after bath psoralen plus ultraviolet A therapy. In skin from patients with localized scleroderma an increase in the total number of mature cross-links was found to be due to an increase in both pyridinolines and dehydro-histidinohydroxymerodesmosine. The concentration of histidinohydroxylysinonorleucine was unchanged. By contrast, the total number of mature cross-links was decreased in lipodermatosclerosis. This decrease was caused by a decrease of lysine aldehyde derived cross-links (dehydro-histidinohydroxymerodesmosine and histidinohydroxylysinonorleucine), whereas the concentration of pyridinolines increased. A decrease in the content of pyridinolines after bath psoralen plus ultraviolet A treatment was found in six out of nine patients with localized scleroderma, which might reflect a remodeling of the extracellular matrix. Our data provide evidence that sclerosis of skin is associated with either an increase in the number of cross-links per molecule of collagen or a change in the molecular nature of the cross-links formed.

Integrin and talin in the jellyfish Podocoryne carnea.

We have isolated an integrin-beta and -alpha subunit from Podocoryne carnea (Cnidaria, Hydrozoa) and studied their expression in the life-cycle and during cell migration, in vitro transdifferentiation and regeneration. Comparison of the integrin expression pattern with a Podocoryne talin homologue by RT-PCR demonstrates that all three genes are maternal messages and continuously expressed in the life-cycle, in medusa development and in all medusae tissues. In situ hybridisation experiments confirm co-expression of both integrin subunits in the different life-stages. Integrin expression was furthermore studied in isolated striated muscle induced to transdifferentiate to new cell types, or grafted on ECM where the muscle adheres and migrates. Integrin expression was maintained continuously throughout both processes. These results suggest that in Podocoryne carnea processes such as cell migration and differentiation are not controlled by up- or downregulation of alternative integrin subunits, but by a single integrin heterodimer which activates different downstream signalling cascades.

Interventional MR: interstitial therapy.

The rationale and results for interstitial therapies via interventional MRI in the treatment of tumors in various regions are presented. Different interstitial treatment techniques are presented based on varying technologies both for tumor ablation and treatment monitoring. Data are presented based on 335 patients, 29-84 years of age (mean age 59 years, 196 men and 139 women) with a total of 932 liver tumors, 16 head and neck tumors and 14 abdominal recurrent pelvic and lymphatic tumors. All lesions had been treated with MR-guided laser-induced interstitial thermotherapy (LITT) via 2516 laser applications and 1856 cannulations. Data in the literature are extremely varying depending on author experience, treatment technique, and the included patient material. In our patient material we were able to achieve a local tumor control of 96.7% depending on the size of the tumorous lesion, the topographical relationship, and the applied laser parameters. The overall cumulative survival rate of patients with liver metastases was 45.74 months (median 40.97 months, 95 % confidence interval 31.42-50.52). The cumulative survival rate of the patient group with hepatic metastases of colorectal carcinoma was 42.71 months (median 39.33 months, 95% confidence interval 33.26-45.37). In patients with head and neck tumors a relevant reduction in clinically relevant symptoms such as pain, swallowing disorders, or nervous compression was achieved in 11 of 15 patients treated with LITT. In 14 soft tissue tumors, such as pelvic tumor recurrence and lymph node metastases, a local tumor control was obtained in 68% of lesions. Interstitial therapies under interventional MRI guidance, such as LITT, results in a high local tumor control with an improved survival rate.

Reversible inactivation of cell-type-specific regulatory and structural genes in migrating isolated striated muscle cells of jellyfish.

We have investigated, by RT-PCR and in situ hybridization, expression of genes encoding regulatory and structural proteins in migrating mononucleated striated muscle cells of the medusa Podocoryne carnea. Expression of the three homeobox genes Otx, Cnox1-Pc, and Cnox3-Pc; a specific splice variant of the myosin heavy chain gene (Myo1); and a tropomyosin (Tpm2) is stable in isolated and cultured striated muscle tissue. When grafted onto cell-free extracellular matrix (ECM), muscle cells of the tissue fragments leave their native ECM and migrate as a coherent tissue onto a host ECM until a stretched cell monolayer is formed. Shortly after the first cells of the grafted isolate have made contact with the host ECM, Otx and Cnox1-Pc expression is completely turned off in all cells of the graft, including those still adhering to their native ECM. Myo1 message disappears with a delay while the expression level of Tpm2 is strongly reduced. However, expression of the homeobox gene Cnox3-Pc, a msh-like gene, and of the ubiquitously expressed elongation factor 1 alpha is not affected by the migration process. All genes are reexpressed after 12-24 h, once migration of the cells has ceased. Our results demonstrate that the first few migrating cells induce a change in gene expression which is rapidly communicated throughout the entire tissue. Furthermore, we showed that commitment of striated muscle cells remains stable despite the transient inactivation of cell-type-specific regulatory and structural genes.

Liver metastases: interventional therapeutic techniques and results, state of the art.

The liver is the most common site of metastatic tumour deposits. Hepatic metastases are the major cause of morbidity and mortality in patients with gastrointestinal carcinomas and other malignant tumours. The rationale and results for interventional therapeutic techniques in the treatment of liver metastases are presented. For the treatment of patients with irresectable liver metastases, alternative local ablative therapeutic modalities have been developed. Technique and results of local interventional therapies are presented such as microwave-, radiofrequency (RF)- and ultrasound ablation, and laser-induced interstitial therapy (LITT), cryotherapy and local drug administration such as alcohol injection, endotumoral chemotherapy and regional chemoembolisation. In addition to cryotherapy, all ablative techniques can be performed percutaneously with low morbidity and mortality. Cryotherapy is an effective and precise technique for inducing tumour necrosis, but it is currently performed via laparotomy. Percutaneous local alcohol injection results in an inhomogeneous distribution in liver metastases with unreliable control rates. Local chemotherapeutic drug instillation and regional chemoembolisation produces relevant but non-reproducible lesions. Laser-induced interstitial thermotherapy (LITT) performed under MRI guidance results in precise and reproducible areas of induced necrosis with a local control of 94%, and with an improved survival rate. Interventional therapeutic techniques of liver metastases do result in a remarkable local tumour control rate with improved survival results.

[Therapeutic options in non-resectable liver metastases. Percutaneous radiological interventions]. / Therapiemöglichkeiten bei nicht resektablen Lebermetastasen. Percutane radiologische Interventionen.

In patients with irresectable liver metastases the following spectrum of oncological concepts is in use. Percutaneous interventional methods allows for an optimized local control rate in strictly intrahepatic disease. Regional short-term time chemotherapy and transarterial chemoembolization (TACE) belong to regional methods. As local ablative methods, intratumoral drug application, endotumoral chemotherapy and alcohol instillation can be used. The most promising thermotherapeutic strategies are radiofrequency and laser-induced thermotherapy (LITT). In a prospective study 278 patients suffering from liver metastases were treated with MR-guided LITT and exact data for the local control rate and survival rate were evaluated. The overall cumulative survival rate (Kaplan-Meier) of patients with liver metastases was 40.8 months (median: 40.97 months, 95% confidence interval 36.3-45.2).

The homeobox gene Otx of the jellyfish Podocoryne carnea: role of a head gene in striated muscle and evolution.

In many bilaterian animals members of the Otx gene family are expressed in head or brain structures. Cnidarians, however, have no clearly homologous head and no distinct brain; but an Otx homolog from the jellyfish Podocoryne carnea is highly conserved in sequence and domain structure. Sequence similarities extend well beyond the homeodomain and Podocoryne Otx can be aligned over its entire length to human OTX1, OTX2, and CRX. The overall structure of Otx is better conserved from Podocoryne to deuterostomes while protostomes appear to be more derived. In contrast, functions seem to be conserved from protostomes to vertebrates but not in Podocoryne or echinoderms. Podocoryne Otx is expressed only during medusa bud formation and becomes restricted to the striated muscle of medusae. Cnidaria are the most basal animals with striated muscle. Podocoryne polyps have no striated muscle and no Otx expression; both appear only during the asexual medusa budding process. The common ancestor of all animals that gave rise to cnidarians, protostomes, and deuterostomes already had an Otx gene more similar to today's Podocoryne and human homologs than to Drosophila otd, while the head-specific function appears to have evolved only later.

Internally cooled power laser for MR-guided interstitial laser-induced thermotherapy of liver lesions: initial clinical results.

PURPOSE: To evaluate experimentally and clinically an internally cooled power laser system for percutaneous treatment of liver metastases, with magnetic resonance (MR) imaging guidance, to increase the volume of coagulative necrosis with single laser beam applications. MATERIALS AND METHODS: The power laser system consisted of standard cannulation paraphernalia and a specially designed 7-F protective catheter for cooling the laser tip during treatment to avoid carbonization. A microdome laser beam applicator with a laser tip diameter of 0.95 mm kept the entire device as small as possible. After the unit was tested in 40 porcine livers, 532 laser beam applications (mean power, 27.5 W [range, 22.1-30.0 W]; mean application time, 19.8 minutes [range, 14-30 minutes]) were performed with MR guidance in 127 patients with 318 liver metastases. The safety of the procedure and the volume of induced necrosis were evaluated. RESULTS: In vitro, cuboid areas of coagulative necrosis with a mean greatest diameter of 4.3 cm +/- 0.5 (SD) were demonstrated after single applications. In vivo, MR thermometry allowed accurate demarcation of changes induced by heat, with a mean diameter of necrosis of 3.3 cm +/- 1.4. No carbonization or vaporization of tissue or damage of equipment occurred during treatment. CONCLUSION: This power laser system can increase the volume of laser-induced necrosis in liver metastases with a single application, thereby simplifying and accelerating the treatment of larger lesions.

[Verification of MR thermometry by means of an in vivo intralesional, fluoroptic temperature measurement for laser-induced thermotherapy ov liver metastases]. / Verifizierung der MR-Thermometrie mittels in vivo intraläsionaler, fluoroptischer Temperaturmessung für die laserinduzierte Thermotherapie von Lebermetastasen.

PURPOSE: To evaluate the correlation of MR-measured changes of signal intensity and invasive fluoroptic temperature measurements during MR-guided LITT of liver metastases. MATERIALS AND METHODS: In 15 patients with proven liver metastases of colorectal carcinoma, MR-guided LITT was performed with a percutaneous approach in a multiapplicator technique. Two temperature sensitive T1-weighted sequences (FLASH-2D- and TurboFLASH-sequences) were used to map the spatial and temporal distribution of Nd:YAG laser effects. Parallel fluoroptic temperature measurements were carried out by means of an inserted probe in a distance of 5-26 mm (mean: 14 mm) from the laser applicator. RESULTS: In both sequences a gradually increasing signal loss could be documented during laser application which proved to be reversible after cessation of energy deposition. the percentage of decrease in signal intensity correlated directly with the measured increase of temperature. Invasive fluoroptical evaluation of temperature distribution after 10 min exposure time showed at 5 mm distance from the applicator an increase of temperature of 35 degrees C, in 10 mm distance a mean increase of 9 degrees C +/- 1.7, in 15 mm a mean increase of 7 degrees C +/- 1.6 and in 20 mm a mean increase of 3 degrees C +/- 0.5. This is evidence of thermal tissue damage up to 3 cm in diameter with laser monoapplication. The qualitative evaluation revealed a reproducible correlation of the extent of signal loss around the applicator and the finally induced degree of necrosis. CONCLUSION: Invasive fluoroptical temperature measurements prove the diagnostic reliability of MR thermometry for the online monitoring of LITT of liver metastases.

[In vitro evaluation of MR thermometry in the implementation of laser-induced thermotherapy]. / In-vitro-Evaluierung der MR-Thermometrie zum Einsatz der laserinduzierten Thermotherapie.

PURPOSE: To optimize the MR sequences parameter for monitoring hyperthermic effects in the tissue during laser induced thermotherapy (LITT). MATERIAL AND METHODS: Experimental studies were performed for the evaluation of MR-thermometry using a contrast-agent-water solution and a pig-liver. A T1-weighted TurboFLASH sequence and a FLASH-2D sequence were used. The TurboFLASH sequence was used with various T1 settings (between 100 and 1250 ms). MR findings were correlated with temperature measurements using a fluoride optical temperature measuring system in a distance of 1, 2, and 5 cm from the laser applicator. RESULTS: Using the contrast-agent-water solution demonstrated the temperature sensitivity of both sequences. In vitro evaluations using pig liver demonstrated a near linear increase of signal versus increasing tissue temperatures in a distance of 1 cm to the tip of the laser applicator. Optimal visualization of the temperature effects was obtained using a T1 between 100 ms and 400 ms. Using the FLASH-2D sequence a signal loss was documented at a TR of 110 ms. CONCLUSION: MR-thermometry using sequentially TurboFLASH and FLASH-2D sequences allowed a non-invasive monitoring of the laser induced temperature changes.

Disorders of smell, taste, and food intake in a patient with a dorsomedial thalamic infarct.

BACKGROUND: We report that a lasting deficit in the hedonic character of olfactory and gustatory perception can be observed in bilateral dorsomedial and intralaminar thalamic lesions. CASE DESCRIPTION: A 68-year-old patient abruptly presented with vigilance disorders associated with a reduction of olfactory and gustatory perceptions. A severe drop in appetite for foods and a weight loss of 10 kg were observed, which were partially reversed with time. Two years later, the main persisting disorder was a change in the quality of perceptions: odors and taste were perceived either in a neutral way, their pleasant character having disappeared, or as unpleasant. However, identification was preserved. MRI showed that lesions principally involved the dorsomedial thalamic nuclei and the adjacent part of the intralaminar nuclei. CONCLUSIONS: This case suggests that the dorsomedial thalamus may play a role in the hedonic perception of food, thus affecting short-term regulation of food intake, and may possibly have a role in the long-term control of body weight.