Orthotic treatment of idiopathic toe walking with a lower leg orthosis with circular subtalar blocking.

BACKGROUND: There is no universally accepted treatment standard for idiopathic toe walking patients (ITW) in the current literature. None of the established methods provide homogenous satisfying results. In our department we treat ITW patients with lower leg orthoses with a circular foot unit for a total of 16 weeks. In this study we reviewed our database to evaluate the success of our treatment protocol for a 24 months follow up period. RESULTS: Twenty-two patients were included in this study. Age at the beginning of treatment was 7.0 years +/- 2.9 (range 2.5-13.1). Percentage of ITW at the beginning of treatment according to the perception of the parents was 89% +/- 22.2 (range 50-100). Immediately after the treatment with our device, percentage of ITW dropped to 11% +/- 13.2 (range 0-50). After 12 months, 73% of the patients (16/22) walked completely normal or showed ITW less than 10% of the day. After 24 months, 64% of the patients kept a normal gait (14/22). CONCLUSION: This study provides evidence that the treatment of idiopathic toe walking with lower leg orthoses with a circular foot unit results in satisfying long-term results in two thirds of the patients.

A novel method for automated assessment of megakaryocyte differentiation and proplatelet formation.

Transfusion of platelet concentrates represents an important treatment for various bleeding complications. However, the short half-life and frequent contaminations with bacteria restrict the availability of platelet concentrates and raise a clear demand for platelets generated ex vivo. Therefore, in vitro platelet generation from megakaryocytes represents an important research topic. A vital step for this process represents accurate analysis of thrombopoiesis and proplatelet formation, which is usually conducted manually. We aimed to develop a novel method for automated classification and analysis of proplatelet-forming megakaryocytes in vitro. After fluorescent labelling of surface and nucleus, MKs were automatically categorized and analysed with a novel pipeline of the open source software CellProfiler. Our new workflow is able to detect and quantify four subtypes of megakaryocytes undergoing thrombopoiesis: proplatelet-forming, spreading, pseudopodia-forming and terminally differentiated, anucleated megakaryocytes. Furthermore, we were able to characterize the inhibitory effect of dasatinib on thrombopoiesis in more detail. Our new workflow enabled rapid, unbiased, quantitative and qualitative in-depth analysis of proplatelet formation based on morphological characteristics. Clinicians and basic researchers alike will benefit from this novel technique that allows reliable and unbiased quantification of proplatelet formation. It thereby provides a valuable tool for the development of methods to generate platelets ex vivo and to detect effects of drugs on megakaryocyte differentiation.

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.

[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.

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.

[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.

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.

[Cardiac arrest in a fitness trainer with apical hypertrophic cardiomyopathy associated with cor triatriatum sinister]. / Plötzlicher Herztod einer Fitnesstrainerin mit hypertropher Kardiomyopathie vom apikalen Typ assoziiert mit Cor triatriatum sinister.

We report on a 49-year-old fitness trainer, who was admitted to our hospital after cardiac arrest due to ventricular fibrillation. Return of spontaneous circulation was achieved after immediate cardiopulmonary resuscitation. Coronary angiography could exclude coronary artery disease. Echocardiography demonstrated the presence of apical hypertrophic cardiomyopathy, associated with cor triatriatum sinister. Cardiac magnetic resonance imaging additionally showed marked myocardial fibrosis. The patient underwent placement of an implantable cardioverter-defibrillator and was subsequently discharged for rehabilitation in good condition.

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.

The generalized aminoaciduria seen in patients with hepatocyte nuclear factor-1alpha mutations is a feature of all patients with diabetes and is associated with glucosuria.

Hepatocyte nuclear factor-1alpha (HNF-1alpha) mutations are the most common cause of maturity-onset diabetes of the young. HNF-1alpha homozygous knockout mice exhibit a renal Fanconi syndrome with glucosuria and generalized aminoaciduria in addition to diabetes. We investigated glucosuria and aminoaciduria in patients with HNF-1alpha mutations. Sixteen amino acids were measured in urine samples from patients with HNF-1alpha mutations, age-matched nondiabetic control subjects, and age-matched type 1 diabetic patients, type 2 diabetic patients, and patients with diabetes and chronic renal failure. The HNF-1alpha patients had glucosuria at lower glycemic control (as shown by HbA1c) than type 1 and type 2 diabetic patients, consistent with a lower renal glucose threshold. The HNF-1alpha patients had a generalized aminoaciduria with elevated levels of 14 of 16 amino acids and an increased mean Z score for all amino acids compared with control subjects (0.66 vs. 0.00; P < 0.0005). Generalized aminoaciduria was also present in type 1 diabetic (Z score, 0.80; P < 0.0001), type 2 diabetic (Z score, 0.71; P < 0.0002), and chronic renal failure (Z score, 0.65; P < 0.01) patients. Aminoaciduria was not associated with microalbuminuria or proteinuria but was associated with glucosuria (1.00 glucosuria vs. 0.19 no glucosuria; P = 0.002). In type 1 diabetic patients, urine samples taken on the same day showed significantly more aminoaciduria when glucosuria was present compared with when it was absent (P < 0.01). In conclusion, HNF-1alpha mutation carriers have a mutation-specific defect of proximal tubular glucose transport, resulting in increased glucosuria. In contrast, the generalized aminoaciduria seen in patients with HNF-1alpha mutations is a general feature of patients with diabetes and glucosuria. Glucose may depolarize and dissipate the electrical gradient of the sodium-dependent amino acid transporters in the proximal renal tubule, causing a reduction in amino acid resorption.

Haemolytic uraemic syndrome and mutations of the factor H gene: a registry-based study of German speaking countries.

BACKGROUND: The aetiology of atypical haemolytic uraemic syndrome (aHUS) is, in contrast to classical, Shiga-like toxin induced HUS in children, largely unknown. Deficiency of human complement factor H and familial occurrence led to identification of the factor H gene (FH1) as the susceptibility gene, but the frequency and relevance of FH1 mutations are unknown. METHODS: We established a German registry for aHUS and analysed in all patients and 100 controls the complete FH1 gene by single strand confirmational polymorphism and DNA sequencing. In addition, complement C3 and factor H serum levels were assayed. Demographic data at onset of aHUS and follow up were compared for the mutation positive and negative groups. RESULTS: Of 111 patients with aHUS (68 female, 43 male, mean age 33 years) 14% had FH1 germline mutations, including two of eight patients with familial aHUS. For each of these eight patients, both parents were tested, and we were able to trace the mutation for five cases. In the other three cases (one with the mutation 3749 C/T, one with 3200 T/C, and one with 3566+1 G/A), we could not detect the mutation in either parent, although paternity was proven by genetic fingerprinting, suggesting that these subjects have new mutations. C3 was decreased in five mutation carriers but also in two non-carriers, and factor H was decreased in none of the carriers, but elevated in six carriers and 15 non-carriers. Clinical parameters including associated medications and diseases, and outcome of aHUS and of post-aHUS kidney transplantation were similar in the mutation positive and negative groups. CONCLUSION: FH1 germline mutations occur with considerable frequency in patients with aHUS. Hypocomplementaemia is not regularly associated with a germline mutation, and factor H serum levels can even be elevated. Screening for FH1 mutations contributes to the classification of aHUS.

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.

The role of T cell receptor dimerization for T cell antagonism and T cell specificity.

T cell responses are highly specific and T cell receptors (TCRs) can recognise subtle differences in major histocompatibility complex (MHC)-peptide complexes. While nominal peptide antigens usually act as full agonists that trigger the whole spectrum of T cell responses, some peptides exhibiting mutations at the TCR-MHC/peptide contact site stimulate only a fraction of T cell responses (partial agonists) or may even inhibit T cell activation by full agonists (antagonist). The present study analyses mathematically the role of TCR-dimerization for T cell antagonism and T cell specificity in general. It demonstrates that T cell antagonists can effectively inhibit TCR-dimerization and that this mechanism can sufficiently explain all aspects of T cell antagonism. The kinetic model of T cell activation proposes that increasing the time required for effective TCR-signaling is the most effective mechanism to increase the discriminatory capacity of TCRs. Our results indicate that TCR-oligomerization is an alternative and efficient mechanism to ensure T cell specificity.

[Significance of cholesterol levels in patients 75 years or older]. / Quelle signification pour le taux de cholestérol après 75 ans?

Increasing comorbidity with aging reduces the predictive power of cardiovascular risk factors. From the age of 70 onward, total cholesterol levels decrease, perhaps associated with changes in the composition of some lipoprotein fractions. In subjects older than 75 years, being in the lowest quartile of cholesterol, insulinemia or serum albumin concentrations is associated with increased mortality. Cholesterol levels below 189 mg/dL in subjects older than 75 years should be considered an early sign of unidentified comorbidity or of rapid functional decline. HDL cholesterol levels, rather than total or LDL cholesterol, were inversely associated with increased mortality from ischemic coronary disease and stroke appears to rise as HDL cholesterol levels fall, rather than total or LDL cholesterol. On the other hand, LDL concentrations below 106 mg/dL and HDL concentrations below 36 mg/dL were associated with an increased risk of death from infectious disease. Stroke incidence, in particular, ischemic stroke, is highest in subjects older than 75 years. HDL cholesterol levels above 35 mg/dL appear to have a protective effect against ischemic stroke in subjects younger than 70 years. Two interventional drug studies investigating the effects of two statins (simvastatin and pravastatin) found that in subgroups of subjects older than 75 these drugs were associated with a reduction in all-cause mortality and cardiovascular morbidity, regardless of total cholesterol levels, but had no short-term effect on cognitive function.

A new point mutation in the prion protein gene at codon 210 in Creutzfeldt-Jakob disease.

We screened 16 cases of sporadic Creutzfeldt-Jakob disease (CJD) and 28 healthy control subjects to detect possible polymorphisms in their prion protein gene (PRNP). The molecular analysis of the PRNP coding sequence was performed using denaturing gradient gel electrophoresis of polymerase chain reaction products and direct sequencing. We identified (1) a silent mutation at codon 177 in a healthy individual, (2) a codon 200 glutamate-to-lysine substitution in a 48-year-old CJD-affected Libyan Jew, and (3) a G-to-A point substitution at codon 210, leading a valine-to-isoleucine change, in a 63-year-old French CJD patient. This new mutation occurs in a highly conserved part of the PRNP coding sequence, close to the known CJD-associated codon 200 mutation, and might be linked to a symptomatologic and neuropathologic pattern of typical sporadic CJD. This mutation was also present in a sister of the patient who died at the age of 67 without neurologic symptomatology.

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.

Quantitative measurement of faecal blood loss: comparison of radioisotopic and chemical analyses.

Blood loss in faeces was assessed by three different methods in five patients with recurrent iron deficiency. In short term (12 day) studies chemical analysis of complete stool collections for haemderived porphyrins (HemoQuant) gave results closely correlated with those obtained by measuring stool loss of 51Cr-labelled red blood cells. Whole body counting for 59Fe was relatively insensitive to small blood losses but allowed losses to be followed up over longer periods. Chemical analysis of faecal porphyrins thus provides a satisfactory alternative to radioisotopic techniques in short term quantitation of faecal blood loss, while longer term whole body counting of 59Fe may still be appropriate in a few patients for the detection and quantification of intermittent blood losses.