The Global Atmosphere-aerosol Model ICON-A-HAM2.3-Initial Model Evaluation and Effects of Radiation Balance Tuning on Aerosol Optical Thickness.

The Hamburg Aerosol Module version 2.3 (HAM2.3) from the ECHAM6.3-HAM2.3 global atmosphere-aerosol model is coupled to the recently developed icosahedral nonhydrostatic ICON-A (icon-aes-1.3.00) global atmosphere model to yield the new ICON-A-HAM2.3 atmosphere-aerosol model. The ICON-A and ECHAM6.3 host models use different dynamical cores, parameterizations of vertical mixing due to sub-grid scale turbulence, and parameter settings for radiation balance tuning. Here, we study the role of the different host models for simulated aerosol optical thickness (AOT) and evaluate impacts of using HAM2.3 and the ECHAM6-HAM2.3 two-moment cloud microphysics scheme on several meteorological variables. Sensitivity runs show that a positive AOT bias over the subtropical oceans is remedied in ICON-A-HAM2.3 because of a different default setting of a parameter in the moist convection parameterization of the host models. The global mean AOT is biased low compared to MODIS satellite instrument retrievals in ICON-A-HAM2.3 and ECHAM6.3-HAM2.3, but the bias is larger in ICON-A-HAM2.3 because negative AOT biases over the Amazon, the African rain forest, and the northern Indian Ocean are no longer compensated by high biases over the sub-tropical oceans. ICON-A-HAM2.3 shows a moderate improvement with respect to AOT observations at AERONET sites. A multivariable bias score combining biases of several meteorological variables into a single number is larger in ICON-A-HAM2.3 compared to standard ICON-A and standard ECHAM6.3. In the tropics, this multivariable bias is of similar magnitude in ICON-A-HAM2.3 and in ECHAM6.3-HAM2.3. In the extra-tropics, a smaller multivariable bias is found for ICON-A-HAM2.3 than for ECHAM6.3-HAM2.3.

Is unilateral lower leg orthosis with a circular foot unit in the treatment of idiopathic clubfeet a reasonable bracing alternative in the Ponseti method? Five-year results of a supraregional paediatric-orthopaedic centre.

BACKGROUND: In the Ponseti treatment of idiopathic clubfoot, children are generally provided with a standard foot abduction orthosis (FAO). A significant proportion of these patients experience irresolvable problems with the FAO leading to therapeutic non-compliance and eventual relapse. Accordingly, these patients were equipped with a unilateral lower leg orthosis (LLO) developed in our institution. The goal of this retrospective study was to determine compliance with and the efficacy of the LLO as an alternative treatment measure. The minimum follow-up was 5 years. RESULTS: A total of 45 patients (75 ft) were retrospectively registered and included in the study. Compliance with the bracing protocol was 91% with the LLO and 46% with the FAO. The most common problems with the FAO were sleep disturbance (50%) and cutaneous problems (45%). Nine percent of patients experienced sleep disturbance, and no cutaneous problems occurred with the LLO. Thirteen percent of patients being treated with an FAO until the age of four (23 patients; 40 ft) underwent surgery because of relapse, defined by rigid recurrence of any of the components of a clubfoot. Fourteen percent of patients being treated with an LLO (22 patients; 35 ft), mostly following initial treatment with an FAO, experienced recurrence. CONCLUSION: Changing from FAO to LLO at any point during treatment did not result in an increased rate of surgery and caused few problems.

Androgen receptor dampens tissue factor expression via nuclear factor-κB and early growth response protein 1.

Essentials Androgen deprivation increases the rate of venous thromboembolism in prostate cancer patients. We characterized androgen receptor-mediated tissue factor regulation in prostate epithelial cells. Androgen receptor is dampening tissue factor expression in prostate epithelial cells. Androgen deprivation could enhance tissue factor expression and raise venous thromboembolism rates. SUMMARY: Background Prostate cancer is one of the leading causes of cancer death in men. Advanced prostate cancer is usually treated by androgen deprivation therapy (ADT), which is aimed at reducing circulating testosterone levels to reduce cancer growth. There is growing evidence that ADT can increase the rate of venous thromboembolism (VTE) in prostate cancer patients. The tissue factor (TF) gene is one of the most important mediators of coagulation and VTE, but, so far, there are limited data on androgen receptor (AR)-mediated TF gene expression. Objectives To characterize AR-mediated TF regulation in vitro and in vivo. Methods We used the androgen-dependent prostate cancer cell lines LNCaP and MyC-CaP to test whether TF expression is regulated by AR. Furthermore, we cloned the TF gene promoter into a luciferase reporter vector to identify the transcription factor-binding sites that mediate TF regulation downstream of AR. Finally, we used castration experiments in mice to characterize AR-mediated TF regulation in vivo. Results TF is directly regulated by AR. In LNCaP cells, nuclear factor-κB signaling and EGR1 mediate TF expression. By using castration experiments in mice, we could detect upregulation of TF and early growth response protein 1 mRNA and protein expression in prostate epithelial cells. Conclusion AR is crucial for dampening TF expression, which could be important for increased TF expression and TF-positive microvesicle release in androgen-deprived prostate cancer patients.

Myeloid PTEN deficiency impairs tumor-immune surveillance via immune-checkpoint inhibition.

Tumor-host interaction is determined by constant immune surveillance, characterized by tumor infiltration of myeloid and lymphoid cells. A malfunctioning or diverted immune response promotes tumor growth and metastasis. Recent advances had been made, by treating of certain tumor types, such as melanoma, with T-cell checkpoint inhibitors. This highlights the importance of understanding the molecular mechanisms underlying the crosstalk between tumors and their environment, in particular myeloid and lymphoid cells. Our aim was to study the contribution of the myeloid PI3K/PTEN-signaling pathway in the regulation of tumor-immune surveillance in murine models of cancer. We made use of conditional PTEN-deficient mice, which exhibit sustained activation of the PI3K-signaling axis in a variety of myeloid cell subsets such as macrophages and dendritic cells (DCs). In colitis-associated colon cancer (CAC), mice deficient in myeloid PTEN showed a markedly higher tumor burden and decreased survival. We attributed this observation to the increased presence of immune-modulatory conventional CD8α(+) DCs in the spleen, whereas other relevant myeloid cell subsets were largely unaffected. Notably, we detected enhanced surface expression of PD-L1 and PD-L2 on these DCs. As a consequence, tumoricidal T-cell responses were hampered or redirected. Taken together, our findings indicated an unanticipated role for the PI3K/PTEN-signaling axis in the functional regulation of splenic antigen-presenting cells (APCs). Our data pointed at potential, indirect, tumoricidal effects of subclass-specific PI3K inhibitors, which are currently under clinical investigation for treatment of tumors, via myeloid cell activation.

[Osteogenesis imperfecta]. / Osteogenesis imperfecta.

BACKGROUND: Osteogenesis imperfecta (OI) is the most common genetic disease of bone and is characterized by fragile bones and growth disorders of varying severity. Most cases of OI are inherited autosomal dominant and caused by a mutation in the collagen type I gene. DIAGNOSTICS: Indications for OI are bone fragility, stunted growth, scoliosis, skull deformities, blue sclera, loss of hearing, dentinogenesis imperfecta and increased laxity of ligaments and skin. In most cases it is possible to make a clinical diagnosis but a skin biopsy or genetic testing can be useful; however, negative results for these tests do not exclude OI. THERAPY: Therapy must be carried out in a multidisciplinary team and includes conservative (e.g. physiotherapy, rehabilitation programs and orthopedic aids), operative (e.g. intramedullary stabilization procedures) and pharmaceutical (e.g. biphosphonates and growth hormones) procedures. PROGNOSIS: The prognosis depends on the type of OI and ranges from normal life expectations for type 1 patients up to up to perinatal mortality for type II patients.

[Spastic foot deformities in children: surgical management]. / Spastische Fußdeformitäten im Kindesalter: Operatives Management.

Although the neurological defects associated with cerebral palsy are not progressive, secondary musculoskeletal disorders due to growth and gravity are variable. In the clinical analysis of spastic foot deformities different mechanisms that produce a variety of deformities have to be analyzed. The goals of surgical treatment are correction of the deformity, reestablishment of stability of the foot and preservation of functionally important ranges of motion and muscle strength. The most common spastic foot deformities are equinus, planovalgus, equinovarus and calcaneus. For treatment soft tissue surgery, such as muscle lengthening and transfer together with bone surgery, such as osteotomy or arthrodesis are used and combinations of these methods are often required. Subsequently postoperative plasters are necessary followed by dynamic orthotic management.

[Primary malignant bone tumors]. / Primär maligne Knochentumoren.

Among human neoplasms, primary malignant bone tumors are fairly rare. They present an incidence rate of roughly 10 cases per 1 million inhabitants per year. During childhood (<15 years), the percentage of malignant bone tumors amounts to 6% of all infantile malignancies. Only leukemia and lymphoma show a higher incidence in adolescence. Of all primary malignant bone tumors, 60% affect patients younger than 45 years and the peak incidence of all bone tumors occurs between 15 and 19 years. The most common primary malignant bone tumors are osteosarcoma (35%), chondrosarcoma (25%), and Ewing's sarcoma (16%). Less frequently (≤ 5%) occurring tumors are chordoma, malignant fibrous histiocytoma of bone, and fibrosarcoma of bone. Vascular primary malignant tumors of bone and adamantinoma are very rare. Staging of the lesion is essential for systemic therapeutic decision-making and includes complete imaging and histo-pathological confirmation of the suspected entity. In most cases, this is established by open- or image-guided biopsy. Based on this information, an interdisciplinary tumor board will determine the individual therapeutic approach. Endoprosthetic or biological reconstruction following wide tumor resection is the most common surgical therapy for primary malignant bone tumors. There is vital importance in a thorough postoperative follow-up and continous after-care by a competent tumor center which is permanentely in charge of therapy.

Large-artery stroke in a young patient with Crohn's disease. Role of vitamin B6 deficiency-induced hyperhomocysteinemia.

An increased incidence of ischemic stroke has been reported in patients with Crohn's disease. Cerebral infarcts are usually considered as a complication of the hypercoagulable state associated with this inflammatory bowel disease (IBD). The association between Crohn's disease, hyperhomocysteinemia and large-artery stroke of the young has rarely been reported. A 39-year-old woman, with prior medical history of Crohn's disease and hypertension, presented with an ischemic stroke of the left internal carotid artery (ICA) territory. Etiological workup disclosed bilateral high-grade ICA stenosis and atheroma of the subclavian and vertebral arteries. Exhaustive search for prothrombotic factors showed inflammation, with an increased level of fibrinogen and factor IX, and a marked hyperhomocysteinemia. Both vitamin B1 and vitamin B6 plasmatic levels were decreased. Heterozygous C677T methylene-tetrahydrofolate reductase gene mutation was present. This observation highlights the combined proatherogenic effect of vitamin B deficiency-induced hyperhomocysteinemia and inflammation leading to large-artery stroke of the young in the setting of Crohn's disease. Our case report stresses the importance of vitamin deficiency screening in patients with IBD in terms of stroke prevention.

Transport and temperature effects on measurement of serum and plasma potassium.

Transport of blood samples from general practice to a central laboratory can result in spuriously high or low potassium concentrations. The importance of this phenomenon was studied in a general practice serving a population of 15,000 patients, 27 km from the pathology laboratory that routinely measured serum potassium. The design involved comparison of potassium levels between control serum (plain gel-separation serum tubes centrifuged in the surgery), routine serum (plain gel-separation tubes centrifuged in the laboratory) and routine plasma samples (lithium-heparin tubes centrifuged in the laboratory). Complete triple sets of data were obtained for 371 samples. Altman and Bland plots for the control serum vs routine serum samples showed a mean difference of +0.1 mmol/L with limits of agreement (+/- 2SD) +0.6 mmol/L, -0.4 mmol/L and for control serum vs routine plasma a mean difference of +0.2 mmol/L with limits of agreement +0.8 mmol/L, -0.4 mmol/L. There was a negative association between mean weekly routine plasma potassium levels with mean weekly temperatures achieved. Regression analysis indicated that both maximum temperature achieved and time to centrifugation significantly contributed to differences observed in the routine plasma samples, but not with the routine serum samples. For plasma samples exposed to high temperatures a clinically significant lowering of potassium concentrations can arise. These results confirm that spurious lowering of potassium concentrations occurs in plasma samples collected in a primary care setting. The preferred method is to centrifuge samples soon after venepuncture. Where this is not possible, collection into plain gel-separation tubes (serum) ensures less variation due to temperature and time to centrifugation than does collection into lithium-heparin tubes (plasma).

Estimation of maximal affinities between T-cell receptors and MHC/peptide complexes.

Recognition of peptide/MHC complexes by T-cell receptors (TCRs) is a critical step for T-cell activation. We studied T-cell activation as a function of this interaction using a mathematical model. Unlike other models analysing TCR-MHC/peptide interactions, this study takes into account that both TCRs and MHC/peptide complexes are anchored in membranes and not in solution. The proposed model quantitatively predicts several essential features of antigen-specific T-cell activation, including the experimentally determined rate of TCR-downregulation during peptide-specific T-cell stimulation. In addition, the model offers an explanation as to why the affinity of the TCR for MHC/peptide complexes is low in general and it correctly predicts the on-rates of the TCR-MHC/peptide interaction observed in different model systems. Thus, the proposed model predicts key parameters of T-cell activation and offers an explanation for the surprisingly low affinity of the TCR for its antigen.

[Postoperative benefit after laparoscopic cholecystectomy in acute cholecystitis]. / Postoperativer Benefit nach laparoskopischer Cholezystektomie bei akuter Cholezystitis.

Analysed were the results of all 48 patients with acute cholecystitis, who underwent laparoscopic cholecystectomy between 1991 and 1995 in the department of general surgery, AKH, University of Vienna. In 18 cases it was necessary to convert to laparotomy. In a second step the results of these two groups of patients were compared with results of patients without acute cholecystitis, who elective underwent laparoscopic cholecystectomy. In about 2/3 of the patients with acute cholecystitis laparoscopic cholecystectomy is possible. In these cases we found a mean postoperative hospital stay of 4.4 days, with a significant difference between those with drain (5.9 days) and those without (2.7 days). In cases of laparotomy the mean postoperative stay was 7.7 days, also significant longer. These patients consumed at the first postoperative day more than 1.5 times of opioid analgetics than those, who underwent laparoscopy with acute cholecystitis, laparoscopied patients without acute cholecystitis half of this. After the second postoperative day patients after laparotomy took 3 times of opioid analgetics than patients after laparoscopy, no matter if there was an acute cholecystitis or not. The rate of conversion to laparotomy sank with the increase of experience of a surgeon. Postoperative benefit of laparoscopic treatment, as less pain and shorter hospitalisation, can be saved even in cases of acute cholecystitis. So the management should primary be laparoscopic.

Twenty-four hour ambulatory blood pressure and heart rate in a patient with a predominantly adrenaline secreting phaeochromocytoma.

In this report, we present the symptoms, biochemical investigations, 24 hour ambulatory blood pressure and heart rate recordings in a patient before and following removal of a predominantly adrenaline-secreting phaeochromocytoma. The symptoms were of episodic shaking, faintness, nausea, palpitations, sweating and panic, chest and neck pain with headache, and are consistent with previous reports. Ambulatory blood pressure recording demonstrated that mean daily blood pressure was normal, with normal diurnal variation, and two episodes of severe hypertension and bradycardia coincident with symptoms (MAP 150 mmHg and HR 49 beats/minute, MAP 178 mmHg and HR 29 beats/minute, respectively), not reported in predominantly adrenaline-secreting phaeochromocytoma.

Immunoelectron microscopic demonstration of ATPase on the cytoplasmic membrane of the methanogenic bacterium strain Göl.

ATPase was shown to be present on the cytoplasmic membrane of the methanogenic bacterium strain Göl. The enzyme was identified by an immunoelectron microscopic technique by using polyclonal antiserum directed against the beta subunit of Escherichia coli F0F1-ATPase. Negatively stained membrane vesicles exhibited a dense population of stalked particles similar in dimensions and fine structure to typical F0F1-ATPase particles.

Lectin binding sites on human endocervix: a comparison with secretory and proliferative endometrium.

Endocervix and corresponding endometrium of women of reproductive age were studied histochemically with 13 fluorescein isothiocyanate-labeled lectins to delineate the differences between the epithelial cells in two anatomical sites. Lectin from Maclura pomifera (MPA), Ulex europaeus (UEA-I), Glycine max (SBA), and Vicia villosa (VVA) bound only to endocervical epithelium and were the only four lectins that distinguished endocervical from endometrial epithelium. These differences were independent of menstrual cyclic changes and blood group antigen secretion. These data show that lectins can be used to histochemically distinguish endocervical from endometrial glands.

The PIOTRON: initial performance, preparation and experience with pion therapy.

The PIOTRON is a large solid angle superconducting channel built for the use of negative pi-mesons in radiotherapy. The pions are produced by protons of 590 MeV striking a target of molybdenum or beryllium. The pions are divided into 60 channels and deflected twice to enter the treatment volume radially. The momentum and the momentum band for all 60 channels can be chosen and the beam spot of Bragg peak pions at the isocenter of the applicator is a few centimeters in each direction. Dynamic scanning can thus achieve 3-dimensionally shaped treatment volumes. Two different methods are available: the ring scan, using changes of pion range; and the spot scan, involving translation of the patient through the fixed beam spot. Dose distributions of individual and multiple beams were plotted in a cylindrical water phantom. Radiobiological experiments with mammalian cells in gel and with mouse feet were performed. A special beam geometry using a sector of 15 beams was selected for the first treatments of patients with metastatic skin nodules. Six patients were treated. Acute skin reactions were scored and compared with those from orthovoltage therapy with comparable beam geometry. The RBE for 10 fractions is between 1.4 and 1.5. The next step involved treatment of patients inside water-bolus rings in preparation for dynamic therapy. Patients were then treated with the spot scan dynamic mode in the water bolus. The initial responses and reactions are favorable and confirm the feasibility and accuracy of dynamic pion therapy.

Purification and properties of Oxidized and reduced forms of Hepatic fructose 1,6-bisphosphatase.

D-Fructose 1,6-bisphosphate 1-phosphohydrolase (EC 3.1.3.11) was isolated from rat liver in two forms: "A," isolated in the presence, and "B," isolated in the absence of dithiothreitol. Both forms had an apparently identical molecular weight of approximately 37,000/subunit and the same Km for fructose 1,6-bisphosphate of 2 microM. However, the Ki of the AMP inhibition of form A was 140 microM and of form B, 370 microM. With form B the same inhibition as with form A was reached by incubating the enzyme with dithiothreitol. The two forms of the enzyme differed in their total, as well as in their number of fast reacting thiol groups. Form A was the more reduced form, exhibiting 22.4 thiol groups/molecule, 2.5 of them fast reacting with 5,5'-dithiobis-(2-nitrobenzoic acid). Only 0.5 fast reacting groups and a total of 19.2 were found with form B. The fast reacting thiol groups disappeared when assayed in the presence of AMP. It is suggested that a redox reaction alters a site that influences the inhibitory action of AMP, so as to regulate the activity of fructose 1,6-bisphosphatase.