[Disseminated osteolytic lesions in a 28-year-old refugee]. / Disseminierte osteolytische Läsionen bei einem 28-jährigen Flüchtling.

A 28-year-old Syrian refugee presented with right-sided knee pain and progressive deterioration of the general condition over the past months. Laboratory diagnostics revealed severe hypercalcemia due to primary hyperparathyroidism, and computed tomography (CT) scanning demonstrated disseminated osteolytic lesions throughout the skeleton. Histologically, these lesions were characterized by multinuclear giant cells (defining these lesions as so-called brown tumors). Finally, surgical removal of a jugular mass allowed the histopathologic diagnosis of a sporadic parathyroid carcinoma. In the patient, this condition was associated with a mutation in the HPRT2 gene locus.

Scalp reconstruction: A 10-year retrospective study.

Scalp reconstruction is a challenging task for the reconstructive surgeon. In consideration of the anatomical and cosmetic characteristics, the defect depth and size, an armamentarium of reconstructive procedures ranging from skin grafts over local flaps to free tissue transfer has been described. In this 10-year retrospective study, 85 operative procedures for scalp reconstruction were performed at our department. The underlying entity, defect size/depth, reconstructive procedure, complications, and mean hospital stay were analyzed. In most cases, scalp reconstruction was necessary after oncologic resection (67%) or radiation therapy (16%). A total of 85 operative procedures were performed for scalp reconstruction including local flaps (n = 50), free tissue transfer (n = 18), and skin grafts (n = 17). Regarding the complication rate, we could detect an overall major complication rate of 16.5% with one free flap loss. Briefly, local flaps are an adequate and safe procedure for limited scalp defects. In the case of extensive scalp defects affecting the calvarium, prior multiple surgical interventions and/or radiation, we prefer free tissue transfer.

A comparative reference study for the validation of HLA-matching algorithms in the search for allogeneic hematopoietic stem cell donors and cord blood units.

The accuracy of human leukocyte antigen (HLA)-matching algorithms is a prerequisite for the correct and efficient identification of optimal unrelated donors for patients requiring hematopoietic stem cell transplantation. The goal of this World Marrow Donor Association study was to validate established matching algorithms from different international donor registries by challenging them with simulated input data and subsequently comparing the output. This experiment addressed three specific aspects of HLA matching using different data sets for tasks of increasing complexity. The first two tasks targeted the traditional matching approach identifying discrepancies between patient and donor HLA genotypes by counting antigen and allele differences. Contemporary matching procedures predicting the probability for HLA identity using haplotype frequencies were addressed by the third task. In each task, the identified disparities between the results of the participating computer programs were analyzed, classified and quantified. This study led to a deep understanding of the algorithms participating and finally produced virtually identical results. The unresolved discrepancies total to less than 1%, 4% and 2% for the three tasks and are mostly because of individual decisions in the design of the programs. Based on these findings, reference results for the three input data sets were compiled that can be used to validate future matching algorithms and thus improve the quality of the global donor search process.

Comparative validation of computer programs for haplotype frequency estimation from donor registry data.

Estimation of human leukocyte antigen (HLA) haplotype frequencies from unrelated stem cell donor registries presents a challenge because of large sample sizes and heterogeneity of HLA typing data. For the 14th International HLA and Immunogenetics Workshop, five bioinformatics groups initiated the 'Registry Diversity Component' aiming to cross-validate and improve current haplotype estimation tools. Five datasets were derived from different donor registries and then used as input for five different computer programs for haplotype frequency estimation. Because of issues related to heterogeneity and complexity of HLA typing data identified in the initial phase, the same five implementations, and two new ones, were used on simulated datasets in a controlled experiment where the correct results were known a priori. These datasets contained various fractions of missing HLA-DR modeled after European haplotype frequencies. We measured the contribution of sampling fluctuation and estimation error to the deviation of the frequencies from their true values, finding equivalent contributions of each for the chosen samples. Because of patient-directed activities, selective prospective typing strategies and the variety and evolution of typing technology, some donors have more complete and better HLA data. In this setting, we show that restricting estimation to fully typed individuals introduces biases that could be overcome by including all donors in frequency estimation. Our study underlines the importance of critical review and validation of tools in registry-related activity and provides a sustainable framework for validating the computational tools used. Accurate frequencies are essential for match prediction to improve registry operations and to help more patients identify suitably matched donors.

Imaging of chronic inflammatory bowel disease with 18F-FDG PET in children and adolescents.

Standard for diagnosis of inflammatory bowel disease (IBD) is the endoscopy of the stomach and the intestine. Aim of this study was to determine the value of 18F-fluorodeoxyglucose positron emission tomography (FDG-PET) in pediatric patients with mild to moderate IBD.We included 23 children and adolescents between 8 and 17 years (median 15 years, 13 boys, 10 girls) in this retrospective study in a routine clinical setting. Diagnoses were Crohn's disease in 19 and ulcerative colitis in 4 cases.3 children had a conventional FDG-PET, 20 patients a combined FDG-PET-computed tomography exam. All children had upper and lower intestinal endoscopy with biopsy and a Hydro-MRI exam to assess the jejunum and proximal ileum. The gastrointestinal tract was divided in 7 segments: Stomach plus duodenum, jejunum and proximal ileum, terminal ileum, cecum plus ascending colon, transverse colon, descending colon, and rectosigmoid.Superficial gastric lesions were missed, gastric ulcerations were detected. For the stomach, the sensitivity was 0.25, the specificity was 1.00, the positive predictive value was 1.00, for the lower intestine (terminal ileum and colon) the values were 0.74, 0.88, and 0.96; for the terminal ileum 0.89, 0.75 and 0.94, respectively.The sensitivity and specificity for of ileal and colonic lesions is high. FDG-PET has to be discussed as a tool for the determination of extent and degree of inflammation, especially in those parts of the small bowel that are not accessible to endoscopy. This has to be weighed against the additional radiation exposure administrated.

16(th) IHIW: global analysis of registry HLA haplotypes from 20 million individuals: report from the IHIW Registry Diversity Group.

This project has the goal to validate bioinformatics methods and tools for HLA haplotype frequency analysis specifically addressing unique issues of haematopoietic stem cell registry data sets. In addition to generating new methods and tools for the analysis of registry data sets, the intent is to produce a comprehensive analysis of HLA data from 20 million donors from the Bone Marrow Donors Worldwide (BMDW) database. This report summarizes the activity on this project as of the 16IHIW meeting in Liverpool.

Increased extracellular matrix and proangiogenic factor transcription in endothelial cells after cocultivation with primary human osteoblasts.

The most promising strategies in bone engineering have concentrated on providing sufficient vascularization to support the newly forming tissue. In this context, recent research in the field has focused on studying the complex interactions between bone forming and endothelial cells. Our previous work has demonstrated that direct contact cocultivation of human umbilical vein endothelial cells (HUVECs) with primary human osteoblasts (hOBs) induces the osteogenic phenotype and survival of hOBs. In order to investigate the mechanisms that lead to this effect, we performed microarray gene expression profiling on HUVECs following cocultivation with hOBs. Our data reveal profound transcriptomic changes that are dependent on direct cell contact between these cell populations. Pathway analysis using the MetaCore™ platform and literature research suggested a striking upregulation of transcripts related to extracellular matrix and cell-matrix interactions. Upregulation of a number of major angiogenetic factors confirms previous observations that HUVECs enter a proangiogenic state upon cocultivation with osteoblasts. Interestingly, the downregulated transcripts clustered predominantly around cell cycle-related processes. The microarray data were confirmed by quantitative real-time RT-PCR on selected genes. Taken together, this study provides a platform for further inquiries in complex interactions between endothelial cells and osteoblasts.

[A 75-year-old female patient with pleural effusion and gastric metastases of a poorly differentiated carcinoma]. / 75-jährige Patientin mit Pleuraerguss und gastralen Metastasen eines wenig differenzierten Karzinoms.

A 75-year-old woman was found to have left-sided pleural effusion and endoscopy revealed the rare entity of adenoid cystic carcinoma metastases in the gastric mucosa. Approximately 20% of patients with this carcinoma suffer from distant metastases. For the initial staging detection of adenoid cystic carcinoma metastasis with positron emission tomography (PET) or PET computed tomography (CT) is recommended. The recurrent t(6;9)(q22-23;p23-24) translocation that results in a fusion of the two transcription factor genes MYB and NFIB is detectable in half of the cases. As in our case molecular pathology can confirm the correct diagnosis and identification of the localization of the primary tumor.

European marrow donor information system: concept and praxis.

Hematopoietic stem cell transplantation is an increasingly used treatment option for patients with severe disorders of hematopoiesis. In roughly two thirds of the cases, an unrelated donor must be sought in international databases. These searches would nowadays be unimaginable without the support of information technologies. Reliable communication and data transfer of donor and patient records between all partners in this huge network is one of the most important success factors in stem cell transplantation. The European Marrow Donor Information System (EMDIS) is an open computer network for data exchange among different unrelated hematopoietic stem cell donor registries that covers 85% of all potential unrelated stem cell donors and cord blood units worldwide. The network has spread also to North America, Australia, Asia, and Africa. The Czech Stem Cell Registry in Prague became a member of the EMDIS community at the end of 2003, when it manually processed about 300 preliminary search requests per year and exported 32 stem cell products to other countries. In 2008, it has automatically processed>14,000 preliminary requests with a doubled 63 number of exported stem cell products.

Elevated resource availability sufficient to turn opportunistic into virulent fish pathogens.

There is mounting evidence that organic or inorganic enrichment of aquatic environments increases the risk of infectious diseases, with disease agents ranging from helminth parasites to fungal, bacterial, and viral pathogens. The causal link between microbial resource availability and disease risk is thought to be complex and, in the case of so-called "opportunistic pathogens," to involve additional stressors that weaken host resistance (e.g., temperature shifts or oxygen deficiencies). In contrast to this perception, our experiment shows that the link between resource levels and infection of fish embryos can be very direct: increased resource availability can transform benign microbial communities into virulent ones. We find that embryos can be harmed before further stresses (e.g., oxygen depletion) weaken them, and treatment with antibiotics and fungicides cancels the detrimental effects. The changed characteristics of symbiotic microbial communities could simply reflect density-dependent relationships or be due to a transition in life-history strategy. Our findings demonstrate that simple microhabitat changes can be sufficient to turn "opportunistic" into virulent pathogens.

CD3(+) and/or CD14(+) depletion from cord blood mononuclear cells before ex vivo expansion culture improves total nucleated cell and CD34(+) cell yields.

Cord blood (CB) is used increasingly in transplant patients lacking sibling or unrelated donors. A major hurdle in the use of CB is its low cell dose, which is largely responsible for an elevated risk of graft failure and a significantly delayed neutrophil and platelet engraftment. As a positive correlation has been shown between the total nucleated cell (TNC) and CD34(+) cell dose transplanted and time to neutrophil and platelet engraftment, strategies to increase these measures are under development. One strategy includes the ex vivo expansion of CB mononuclear cells (MNC) with MSC in a cytokine cocktail. We show that this strategy can be further improved if CD3(+) and/or CD14(+) cells are first depleted from the CB MNC before ex vivo expansion. Ready translation of this depletion strategy to improve ex vivo CB expansion in the clinic is feasible as clinical-grade devices and reagents are available. Ultimately, the aim of improving TNC and CD34(+) transplant doses is to further improve the rate of neutrophil and platelet engraftment in CB recipients.

A brief perspective on insulin production.

The preeminent role of the beta cell is to manufacture, store and release insulin. The mature insulin molecule is composed of two polypeptide chains designated as A and B that are joined by two pairs of disulfide bonds with an additional intramolecular disulfide bond in the A chain. However, the two chains of the insulin molecule are not synthesized as separate polypeptide chains but rather are generated by specific proteolytic processing of a larger precursor, proinsulin. This discovery in 1967 and the concept of prohormones changed our view of the biosynthesis of hormones and neuropeptides. It allowed studies of the regulation of insulin biosynthesis that highlighted the key role of glucose. In addition, the C-peptide, the polypeptide that joins the A and B chains in proinsulin and is stored with insulin in the secretory granules and secreted in equimolar amounts, allowed studies of pancreatic beta cell function in vivo including in patients with diabetes. Subsequent studies have identified the specific proteases, prohormone convertases 1/3 and 2 and carboxypeptidase E, that are involved in the conversion of proinsulin to proinsulin intermediates and then to insulin. Disorders of (pro)insulin biosynthesis continue to illuminate important aspects of this pathway, revealing important connections to diabetes pathogenesis. Recent studies of patients with insulin gene mutations that cause permanent neonatal diabetes have identified key residues affecting the folding and structural organization of the preproinsulin molecule and its subsequent processing. These findings have renewed interest in the key role of endoplasmic reticulum function in insulin biosynthesis and the maintainance of normal beta cell health.

Evaluation of aseptic loosening of knee prostheses by quantitative bone scintigraphy.

UNLABELLED: In not infected knee prostheses bone scintigraphy is a possible method to diagnose mechanical loosening, and therefore, to affect treatment regimes in symptomatic patients. However, hitherto studies showed controversial results for the reliability of bone scintigraphy in diagnosing loosened knee prostheses by using asymptomatic control groups. Therefore, the AIM of our study was to optimize the interpretation procedure and to evaluate the accuracy using results from revision surgery as standard. METHODS: Retrospectively, we were able to examine the tibial component in 31 cemented prostheses. In this prostheses infection was excluded by histological or bacteriological examination during revision surgery. To quantify bone scintigraphy, we used medial and lateral tibial regions with a reference region from the contralateral femur. RESULTS: To differentiate between loosened and intact prostheses we found a threshold of 5.0 for the maximum tibia to femur ratio of the both tibial regions and a threshold of 18% for the difference of the ratio of both tibial regions. Using these thresholds, values of 0.9, 1, 0.85, 1, and 0.94 were calculated for sensitivity, specificity, negative predictive value, positive predictive value, and accuracy, respectively. To get a sensitivity of 1, we found a lower threshold of 3.3 for the maximum tibia to femur ratio. CONCLUSION: Quantitative bone scintigraphy appears to be a reliable diagnostic tool for aseptic loosening of knee prostheses with thresholds evaluated by revision surgery results being the golden standard.

Ureteroplasty with a cutting balloon: a novel approach to ureteric anastomotic strictures.

The Peripheral Cutting Balloon device was originally described to treat in-stent coronary artery stenosis. We aim to evaluate the use of this device in the management of ureteric anastomotic strictures. Four patients with radiologically proven ureteric anastomotic strictures were treated with the Peripheral Cutting Balloon Device using an antegrade approach. Follow up ranged between 2 and 12 months. All patients' initial procedure was successful, and all patients had improvement of symptoms. No patient showed evidence of biochemical deterioration of renal function, and no periprocedural complications occurred. One patient had restenosis as a result of invasive bladder cancer and required subsequent cystectomy. The Peripheral Cutting Balloon device is a novel instrument for the treatment of ureteric anastomotic strictures. Our experience shows promising short-term results but more follow up is required.

[Radiation synovectomy of the knee joint: Evaluation of bremsstrahlung-detection by using a corpse phantom]. / Radiosynoviorthese des Kniegelenkes: Phantomuntersuchung zur Bremsstrahlenmessung.

AIM: Multiple procedures for the quantification of activity leakage in radiation synovectomy of the knee joint have been described in the literature. We compared these procedures considering the real conditions of dispersion and absorption using a corpse phantom. METHODS: We simulated different distributions of the activity in the knee joint and a different extra-articular spread into the inguinal lymph nodes. The activity was measured with a gamma-camera. Activity leakage was calculated by measuring the retention in the knee joint only using an anterior view, using the geometric mean of anterior and posterior views, or using the sum of anterior and posterior views. The same procedures were used to quantify the activity leakage by measuring the activity spread into the inguinal lymph nodes. In addition, the influence of scattered rays was evaluated. RESULTS: For several procedures we found an excellent association with the real activity leakage, shown by an r(2) between 0.97 and 0.98. When the real value of the leakage is needed, e. g. in dosimetric studies, simultaneously measuring of knee activity and activity in the inguinal lymph nodes in anterior and posterior views and calculation of the geometric mean with exclusion of the scatter rays was found to be the procedure of choice. CONCLUSION: When measuring of activity leakage is used for dosimetric calculations, the above-described procedure should be used. When the real value of the leakage is not necessary, e. g. for comparing different therapeutic modalities, several of the procedures can be considered as being equivalent.

Electronic structure of metal-semiconductor nanojunctions in gold CdSe nanodumbbells.

The electronic properties of metal-semiconductor nanojunctions are investigated by scanning tunneling spectroscopy of gold-tipped CdSe rods. A gap similar to that in bare CdSe nanorods is observed near the nanodumbbell center, while subgap structure emerges near the metal-semiconductor nanocontact. This behavior is attributed to the formation of subgap interface states that vanish rapidly towards the center of the rod, consistent with theoretical predictions. These states lead also to modified Coulomb staircase, and in some cases to negative differential conductance, on the gold tips.

Clara cell protein and surfactant protein B in garbage collectors and in wastewater workers exposed to bioaerosols.

OBJECTIVES: Inhalation of bioaerosols has been hypothesised to cause "toxic pneumonitis" that should increase lung epithelial permeability at the bronchioloalveolar level. Serum Clara cell protein (CC16) and serum surfactant protein B (SPB) have been proposed as sensitive markers of lung epithelial injury. This study was aimed at looking for increased lung epithelial permeability by determining CC16 and SPB in workers exposed to bioaerosols from wastewater or garbage. METHODS: Subjects (778 wastewater, garbage and control workers; participation 61%) underwent a medical examination, lung function tests [American Thoracic Society (ATS) criteria], and determination of CC16 and SPB. Symptoms of endotoxin exposure and several potential confounders (age, gender, smoking, kidney function, obesity) were looked for. Results were examined with multiple linear or logistic regression. RESULTS: Exposure to bioaerosols increased CC16 concentration in the wastewater workers. No effect of exposure on SPB was found. No clue to work-related respiratory diseases was found. CONCLUSIONS: The increase in CC16 in serum supports the hypothesis that bioaerosols cause subclinical "toxic pneumonitis", even at low exposure.

A randomized double-blind placebo-controlled clinical trial of a product containing ephedrine, caffeine, and other ingredients from herbal sources for treatment of overweight and obesity in the absence of lifestyle treatment.

OBJECTIVE: To evaluate the efficacy and side effects of an herbal formulation to promote weight loss, as compared to placebo. DESIGN: 12-week multicenter double-blind, placebo-controlled, randomized parallel groups design. Study conducted at three clinical sites in New York State. Subjects were randomized to receive either the 'active' product or a 'placebo' supplement for 12 weeks. Minimal steps were taken to influence lifestyle changes with regard to diet or exercise. SUBJECTS: 102 overweight/obese (30

Hepatitis E, Helicobacter pylori, and gastrointestinal symptoms in workers exposed to waste water.

BACKGROUND: Workers exposed to sewage may have an increased risk of infection by Helicobacter pylori and hepatitis E virus (HEV). AIMS: To assess the prevalence of clinical hepatitis E (HE) and peptic ulcer disease as well as the seroprevalence of antibodies to H pylori and HEV in workers with and without sewage exposure and to look for symptoms due to exposure to endotoxin. METHODS: In the first year of a prospective cohort study 349 sewage exposed workers and 429 municipal manual workers (participation: 61%) underwent a complete medical examination. Travelling to endemic areas, socioeconomic level, age, country in which childhood was spent, and number of siblings were considered as the main confounding factors. RESULTS: Peptic ulcer disease and clinical HE did not occur more often in workers exposed to sewage. Prevalence of antibodies to HEV was 3.3% and overall prevalence of IgG antibodies to H pylori was 42% with large differences between subgroups. Logistic regression did not show an increased risk of seropositivity or antibodies to parietal cells in sewage exposed workers, but disentangling the effect of exposure from that of confounders was extremely difficult. No increase of symptoms due to exposure to endotoxin was found in sewage workers, with the exception of diarrhoea. CONCLUSIONS: No clear increased risk of infection by H pylori or by HEV in workers exposed to sewage was found in this cross-sectional study, but these results need to be confirmed by follow up.

Genetic inactivation of prohormone convertase (PC1) causes a reduction in cholecystokinin (CCK) levels in the hippocampus, amygdala, pons and medulla in mouse brain that correlates with the degree of colocalization of PC1 and CCK mRNA in these structures in rat brain.

Prohormone convertase (PC1) is found in endocrine cell lines that express cholecystokinin (CCK) mRNA and process pro CCK to biologically active products. Other studies have demonstrated that PC1 may be a one of the enzymes responsible for the endoproteolytic cleavages that occur in pro CCK during its biosynthesis and processing. Prohormone convertase 1 (PC1) has a distribution that is similar to cholecystokinin (CCK) in rat brain. A moderate to high percentage of CCK mRNA-positive neurons express PC1 mRNA. CCK levels were measured in PC1 knockout and control mice to assess the degree to which loss of PC1 changed CCK content. CCK levels were decreased 62% in hippocampus, 53% in amygdala and 57% in pons-medulla in PC1 knockout mice as compared to controls. These results are highly correlated with the colocalization of CCK and PC1. The majority of CCK mRNA-positive neurons in the pyramidal cell layer of the hippocampus express PC1 mRNA and greater than 50% of CCK mRNA-positive neurons in several nuclei of the amygdala also express PC1. These results demonstrate that PC1 is important for CCK processing. PC2 and PC5 are also widely colocalized with CCK. It may be that PC2, PC5 or another non-PC enzyme are able to substitute for PC1 and sustain production of some amidated CCK. Together these enzymes may represent a redundant system to insure the production of CCK.