Performance of high impedance resonators in dirty dielectric environments.

High-impedance resonators are a promising contender for realizing long-distance entangling gates between spin qubits. Often, the fabrication of spin qubits relies on the use of gate dielectrics which are detrimental to the quality of the resonator. Here, we investigate loss mechanisms of high-impedance NbTiN resonators in the vicinity of thermally grown SiO2 and Al2O3 fabricated by atomic layer deposition. We benchmark the resonator performance in elevated magnetic fields and at elevated temperatures and find that the internal quality factors are limited by the coupling between the resonator and two-level systems of the employed oxides. Nonetheless, the internal quality factors of high-impedance resonators exceed 103 in all investigated oxide configurations which implies that the dielectric configuration would not limit the performance of resonators integrated in a spin-qubit device. Because these oxides are commonly used for spin qubit device fabrication, our results allow for straightforward integration of high-impedance resonators into spin-based quantum processors. Hence, these experiments pave the way for large-scale, spin-based quantum computers.

Does vertical incomitance predict the diplopia outcome in orbital fracture patients? A prospective study of 188 patients.

OBJECTIVE: To determine the predictive value of vertical incomitance for diplopia outcome in orbital fracture patients. PATIENTS AND METHODS: A prospective cohort study composed of patients with orbital fractures was designed. The predictor variable was vertical incomitance, and the primary outcome variable was diplopia. Incomitance was calculated in prism diopters (Δ) as the difference of the maximum absolute deviation between the upper and lower three gaze directions. Standard statistics for patient characteristics, the Fisher exact test for categorical variables and the Wilcoxon rank sum test for continuous variables were computed. RESULTS: The sample was composed of 188 patients grouped as follows: non-operated (n = 124) and operated (n = 64). Fifty-one patients showed vertical incomitance of whom 10 (19.6%) had persistent diplopia at the 1-year follow-up. The mean incomitance was 9.6Δ in the diplopia group versus 2Δ in the non diplopia group (OR = 1.13; p < 0.001). There was a statistically significant association between vertical incomitance of >2Δ and persistent diplopia at 1 year after adjusting for the surgery variable (OR = 1.07; p < 0.04). CONCLUSION: The present study has demonstrated that in orbital fracture patients, vertical incomitance was associated with (1) persistence of long-term diplopia, (2) the decision to perform surgery, and (3) the severity of the fracture.

Early-onset or rapidly progressive scoliosis in children: check the eyes!

Horizontal gaze palsy with progressive scoliosis (HGPPS) is a rare autosomal recessive disorder characterized by the absence of conjugate horizontal eye movements, and progressive scoliosis developing in childhood and adolescence, caused by mutations in the ROBO3 gene which has an important role in axonal guidance and neuronal migration. We describe two female children aged 12 years and 18 months, with progressive scoliosis, in whom the neurological examination showed absent conjugate horizontal eye movements, but preserved vertical gaze and convergence. Cerebral Magnetic resonance imaging findings included pontine hypoplasia, absent facial colliculi, butterfly configuration of the medulla and a deep midline pontine cleft, while Diffusion tensor imaging (DTI) maps showed the absence of decussating ponto-cerebellar fibers and superior cerebellar peduncles. Somatosensory and motor evoked potential studies demonstrated ipsilateral sensory and motor responses. The diagnosis was confirmed by the identification of bi-allelic mutations in the ROBO3 gene.

Minor cartilage collagens type IX and XI are expressed during embryonic stem cell-derived in vitro chondrogenesis.

Cartilage development is a complex process that can be analyzed using numerous model systems. We have previously shown that in vitro differentiation of murine embryonic stem (ES) cells via embryoid bodies (EBs) recapitulates the cellular differentiation steps of chondrogenesis. However, differentiated chondrocytes lose their characteristic phenotype when they are kept in monolayer culture. This dedifferentiation process is one of the main obstacles of cartilage tissue engineering and could not be analyzed using the EB model system. The aim of this study was to further characterize the chondrogenic nodules derived by in vitro-differentiation of murine ES cells for the distribution of collagen types II, IX and XI in comparison to in vitro dedifferentiating primary chondrocytes from murine embryonic ribs. Expression of cartilage collagens and other extracellular matrix proteins was analyzed using immunostaining, cytochemical stainings and quantitative RT-PCR. We show that ES cell-derived chondrocyte differentiation starts with mesenchymal condensations synthesizing high amounts of fibronectin. Later, the matrix of the mature cartilage nodules consists of type II collagen, proteoglycans and the minor collagens type IX and XI. The nodules show a three-dimensional structure with multiple layers of collagen type II-positive cells. At late differentiation stages these chondrocytes were located at lateral regions of the nodules. Similar to the distribution pattern of collagen type II positive cells, the cells staining positive for collagen type IX and XI were present in the surface regions, but not in the central areas of the chondrogenic nodules. During cultivation of the primary murine rib chondrocytes expression of chondrogenic marker genes such as collagen type II and aggrecan declined and many chondrocytes lost characteristic cartilage matrix proteins and converted to an elongated, fibroblastoid shape with prominent actin stress fibers. Chondrogenic differentiation of murine ES cells combined with monolayer culture of embryonic rib chondrocytes is a valuable tool to study changes in the expression pattern during differentiation and dedifferentiation of chondrocytes.

Notch1 signaling regulates chondrogenic lineage determination through Sox9 activation.

Notch signaling is involved in several cell lineage determination processes during embryonic development. Recently, we have shown that Sox9 is most likely a primary target gene of Notch1 signaling in embryonic stem cells (ESCs). By using our in vitro differentiation protocol for chondrogenesis from ESCs through embryoid bodies (EBs) together with our tamoxifen-inducible system to activate Notch1, we analyzed the function of Notch signaling and its induction of Sox9 during EB differentiation towards the chondrogenic lineage. Temporary activation of Notch1 during early stages of EB, when lineage determination occurs, was accompanied by rapid and transient Sox9 upregulation and resulted in induction of chondrogenic differentiation during later stages of EB cultivation. Using siRNA targeting Sox9, we knocked down and adjusted this early Notch1-induced Sox9 expression peak to non-induced levels, which led to reversion of Notch1-induced chondrogenic differentiation. In contrast, continuous Notch1 activation during EB cultivation resulted in complete inhibition of chondrogenic differentiation. Furthermore, a reduction and delay of cardiac differentiation observed in EBs after early Notch1 activation was not reversed by siRNA-mediated Sox9 knockdown. Our data indicate that Notch1 signaling has an important role during early stages of chondrogenic lineage determination by regulation of Sox9 expression.

Fat metabolism during exercise in patients with McArdle disease.

OBJECTIVE: It is known that muscle phosphorylase deficiency restricts carbohydrate utilization, but the implications for muscle fat metabolism have not been studied. We questioned whether patients with McArdle disease can compensate for the blocked muscle glycogen breakdown by enhancing fat oxidation during exercise. METHODS: We studied total fat oxidation by indirect calorimetry and palmitate turnover by stable isotope methodology in 11 patients with McArdle disease and 11 healthy controls. Cycle exercise at a constant workload of 50% to 60% of maximal oxygen uptake capacity was used to evaluate fatty acid oxidation (FAO) in the patients. Healthy controls were exercised at the same absolute workload. RESULTS: We found that palmitate oxidation and disposal, total fat oxidation, and plasma levels of palmitate and total free fatty acids (FFAs) were significantly higher, whereas total carbohydrate oxidation was lower, during exercise in patients with McArdle disease vs healthy controls. We found augmented fat oxidation with the onset of a second wind, but further increases in FFA availability, as exercise continued, did not result in further increases in FAO. CONCLUSION: These results indicate that patients with McArdle disease have exaggerated fat oxidation during prolonged, low-intensity exercise and that increased fat oxidation may be an important mechanism of the spontaneous second wind. The fact that increasing availability of free fatty acids with more prolonged exercise did not increase fatty acid oxidation suggests that blocked glycogenolysis may limit the capacity of fat oxidation to compensate for the energy deficit in McArdle disease.

Visual vertigo: an observational case series of eleven patients.

BACKGROUND: Dizziness is a common symptom which is frequently due to either peripheral or central vestibular dysfunction. However, some patients may lack typical signs suggesting a vestibular or cerebellar lesion and they mostly complain of vertigo or posture imbalance induced by visual stimulation. The symptoms immediately improve either on cessation of the visual input or upon closure of the eyes. Such a presentation is typical of visual vertigo. PATIENTS AND METHODS: From 1993 to 2003, 242 patients were examined for either "vertigo" or "dizziness". The diagnosis of visual vertigo was based on both history and clinical examination and was present in 11 patients. RESULTS: Visual vertigo was diagnosed in 11/242 patients (4.5 %). Age range was 31 - 77 years (mean 47 years) with a sex ratio of 8 females for 3 males. Neuro-ophthalmological examination was normal in all cases. CONCLUSIONS: Visual vertigo is not a rare condition but the disease is underdiagnosed. The symptoms result from a mismatch between vestibular, proprioceptive and visual inputs. Neuro-ophthalmological, neurological and neuro-otological examination are often normal or not relevant and the diagnosis is largely based on history. It is important to recognize this entity because the symptoms might improve if the patients are treated with psycho-motor rehabilitation.

The exercise metaboreflex is maintained in the absence of muscle acidosis: insights from muscle microdialysis in humans with McArdle's disease.

1. In McArdle's disease, muscle glycogenolysis is blocked, which results in absent lactate and enhanced ammonia production in working muscle. Using McArdle patients as an experimental model, we studied whether lactate and ammonia could be mediators of the exercise pressor reflex. 2. Changes in muscle interstitial ammonia and lactate were compared with changes in blood pressure and muscle sympathetic nerve activity (MSNA) during static arm flexor exercise at 30% of maximal contraction force. Muscle interstitial changes in lactate and ammonia were assessed by microdialysis of the biceps muscle, and MSNA by peroneal nerve microneurography, in six McArdle patients and 11 healthy, matched controls. One McArdle patient also had myoadenylate deaminase deficiency, a condition associated with abolished ammonia production in exercise. 3. Exercise-induced increases were higher in McArdle patients vs. controls for MSNA (change of 164 +/- 71 vs. 59 +/- 19%) and blood pressure (change of 47 +/- 7 vs. 38 +/- 4 mmHg). Interstitial lactate increased in controls (peak change 1.3 +/- 0.2 mmol x l(-1)) and decreased in McArdle patients (peak change -0.5 +/- 0.1 mmol x l(-1)) during and after exercise. Interstitial ammonia did not change during exercise in either group, but was higher post-exercise in McArdle patients, except in the patient with myoadenylate deaminase deficiency who had a flat ammonia response. This patient had an increase in MSNA and blood pressure comparable to other patients. MSNA and blood pressure responses were maintained during post-exercise ischaemia in both groups, indicating that sympathetic activation was caused, at least partly, by a metaboreflex. 4. In conclusion, changes in muscle interstitial lactate and ammonia concentrations during and after exercise are temporally dissociated from changes in MSNA and blood pressure in both patients with McArdle's disease and healthy control subjects. This suggests that muscle acidification and changes in interstitial ammonia concentration are not mediators of sympathetic activation during exercise.

Aerobic conditioning in patients with mitochondrial myopathies: physiological, biochemical, and genetic effects.

Aerobic training has been shown to increase work and oxidative capacity in patients with mitochondrial myopathies, but the mechanisms underlying improvement are not known. We evaluated physiological (cycle exercise, 31P-MRS), biochemical (enzyme levels), and genetic (proportion of mutant/wild-type genomes) responses to 14 weeks of bicycle exercise training in 10 patients with heteroplasmic mitochondrial DNA (mtDNA) mutations. Training increased peak work and oxidative capacities (20-30%), systemic arteriovenous O2 difference (20%), and 31P-MRS indices of metabolic recovery (35%), consistent with enhanced muscle oxidative phosphorylation. Mitochondrial volume in vastus lateralis biopsies increased significantly (50%) and increases in deficient respiratory chain enzymes were found in patients with Complex I (36%) and Complex IV (25%) defects, whereas decreases occurred in 2 patients with Complex III defects (approximately 20%). These results suggest that the cellular basis of improved oxygen utilization is related to training-induced mitochondrial proliferation likely resulting in increased levels of functional, wild-type mtDNA. However, genetic analysis indicated the proportion of wild-type mtDNA was unchanged (3/9) or fell (6/9), suggesting a trend toward preferential proliferation of mutant genomes. The long-term implications of training-induced increases in mutant relative to wild-type mtDNA, despite positive physiological and biochemical findings, need to be assessed before aerobic training can be proposed as a general treatment option.

[Schizophrenia and violence. Results of a comprehensive inquiry in an Austrian providence]. / Schizophrenie und Gewalttätigkeit. Ergebnisse einer Gesamterhebung in einem österreichischen Bundesland.

The question as to whether schizophrenics have an increased potential for delinquency and violent behavior has given rise to much controversy. During the past few years, a large number of epidemiological studies have demonstrated a moderate but reliable relation between schizophrenic disorders and violence. In the present study, a new approach at investigation was used by evaluating the overall rate of convictions and commitments to psychiatric institutions for general delinquency, violence, and homicide among schizophrenics. The most outstanding results demonstrated that the treatment of schizophrenic offenders was only insufficiently covered by the psychiatric care system, showed the lack of compliance in the study group, and demonstrated the high significance of coexisting acute and chronic alcohol and drug abuse. The risk of delinquency and violent behavior was much higher in schizophrenics than in the general population. It is indicated, however, that mentally ill delinquents are only of minor importance within the overall group of offenders and that better preventive and therapeutic measures present opportunities for prevention.

Recurrent myoglobinuria due to a nonsense mutation in the COX I gene of mitochondrial DNA.

OBJECTIVE: To elucidate the molecular basis of a mitochondrial myopathy associated with recurrent myoglobinuria and cytochrome c oxidase (COX) deficiency in muscle. BACKGROUND: Recurrent myoglobinuria is typically seen in patients with inborn errors of carbohydrate or lipid metabolism, the main sources of energy for muscle contraction. Relatively little attention has been directed to defects of the mitochondrial respiratory chain in patients with otherwise unexplained recurrent myoglobinuria. METHODS: Having documented COX deficiency histochemically and biochemically in the muscle biopsy from a patient with exercise-induced recurrent myoglobinuria, the authors sequenced the three mitochondrial DNA (mtDNA)-encoded COX genes, and performed restriction fragment length polymorphism analysis and single-fiber PCR. RESULTS: The authors identified a nonsense mutation (G5920A) in the COX I gene in muscle mtDNA. The mutation was heteroplasmic and abundantly present in COX-negative fibers, but less abundant or absent in COX-positive fibers; it was not found in blood or fibroblasts from the patient or in blood samples from the patient's asymptomatic mother and sister. CONCLUSIONS: The G5920A mutation caused COX deficiency in muscle, explaining the exercise intolerance and the low muscle capacity for oxidative phosphorylation documented by cycle ergometry. The sporadic occurrence of this mutation in muscle alone suggests that it arose de novo in myogenic stem cells after germ-layer differentiation. Mutations in mtDNA-encoded COX genes should be considered in patients with recurrent myoglobinuria.

Haemorrhagic shock and encephalopathy syndrome: report of two cases with special reference to hypoglycaemia.

Haemorrhagic shock and encephalopathy syndrome (HSES) is a devastating disorder affecting infants. So far no cases have been reported in Switzerland. It is characterised by the abrupt onset of hyperpyrexia, shock, encephalopathy, diarrhoea, disseminated intravascular coagulation (DIC) and renal and hepatic failure in previously healthy infants. Severe hypoglycaemia has been repeatedly reported in association with HSES. However, the pathophysiology of the hypoglycaemia is not clear. We report on two infants (2 and 7 months old) with typical HSES, both of whom were presented with nonketotic hypoglycaemia. In the first case, plasma insulin was 23 pmol/l at the time of hypoglycaemia (0.1 mmol/l). In the second case, increased values for interleukin-6 (IL-6) (319 pg/ml) and IL-8 (1382 pg/ml) were found 24 hours after admission, whereas IL-1 and tumour necrosis factor-alpha (TNF-alpha) were not measurable. Alpha-1-antitrypsin was decreased (0.6 g/l). In hyperpyrexic, unconscious and shocked infants, HSES should be considered and hypoglycaemia should be specifically looked for. Hypoglycaemia is not caused by hyperinsulinism but may be secondary to the release of cytokines.

McArdle's disease presenting with asymmetric, late-onset arm weakness.

McArdle's disease or myophosphorylase deficiency is one of the most common muscle glycogenoses and typically presents in childhood or adolescence with exercise intolerance, myalgia, myoglobinuria, and cramps in exercising muscle. We describe an elderly man who developed asymmetric proximal arm weakness at age 73. He had no history of exercise-induced cramps, myalgias, or myoglobinuria. Creatine kinase levels were elevated, serum lactate did not rise on ischemic exercise testing, and muscle biopsy showed a vacuolar myopathy with absent myophosphorylase activity. This unusual case demonstrates that McArdle's disease may present with fixed, asymmetric proximal weakness at an advanced age and should be considered in this clinical setting, especially when a history of poor exercise tolerance can be elicited.

A modular NIRS system for clinical measurement of impaired skeletal muscle oxygenation.

Near-infrared spectrometry (NIRS) is a well-known method used to measure in vivo tissue oxygenation and hemodynamics. This method is used to derive relative measures of hemoglobin (Hb) + myoglobin (Mb) oxygenation and total Hb (tHb) accumulation from measurements of optical attenuation at discrete wavelengths. We present the design and validation of a new NIRS oxygenation analyzer for the measurement of muscle oxygenation kinetics. This design optimizes optical sensitivity and detector wavelength flexibility while minimizing component and construction costs. Using in vitro validations, we demonstrate 1) general optical linearity, 2) system stability, and 3) measurement accuracy for isolated Hb. Using in vivo validations, we demonstrate 1) expected oxygenation changes during ischemia and reactive hyperemia, 2) expected oxygenation changes during muscle exercise, 3) a close correlation between changes in oxyhemoglobin and oxymyoglobin and changes in deoxyhemoglobin and deoxymyoglobin and limb volume by venous occlusion plethysmography, and 4) a minimal contribution from movement artifact on the detected signals. We also demonstrate the ability of this system to detect abnormal patterns of tissue oxygenation in a well-characterized patient with a deficiency of skeletal muscle coenzyme Q(10). We conclude that this is a valid system design for the precise, accurate, and sensitive detection of changes in bulk skeletal muscle oxygenation, can be constructed economically, and can be used diagnostically in patients with disorders of skeletal muscle energy metabolism.

[Malignant narcissism and sexual homicide--exemplified by the Jack Unterweger case]. / Maligner Narzissmus und Sexualmord--dargestellt am Beispiel Jack Unterweger.

With the syndrome of malignant narcissism, which is characterised by narcissistic personality disorder, anti-social behaviour, sadism and a marked tendency to paranoid reactions, Kernberg (1985, 1996) describes an independent form of pathological narcissism. According to Stone (1996) this is found in many mass-murderers and serial killers. On the basis of the example of Jack Unterweger the connection between malignant narcissism and sexual offence is discussed as to psychodynamic development, personality structure and psychopathology. Unterweger, who was convicted to lifelong imprisonment in 1976 for sadistic sexual murder, became a wellknown writer in prison and was released prematurely in 1990 as the Austria case of successful rehabilitation. As stated in the sentence passed against him he killed 11 prostitutes in Europe and the USA within the next 18 months, but never pleaded guilty. Psychiatric examination revealed numerous elements of malignant narcissism and the constellation of his development and life was typical of serial offenders.

The influence of early experience with vanillin on food preference later in life.

A study with 133 adults, who had been breast-fed or bottle-fed after birth, shows that neonatal experience with vanilla influences preferences for other foods in later life.

Muscle phosphoglycerate mutase deficiency with tubular aggregates: effect of dantrolene.

A patient with muscle phosphoglycerate mutase deficiency (PGAMD) and exercise-induced muscle cramps had tubular aggregates in muscle and increased muscle Ca2+-adenosine triphosphatase and calcium content. Two ischemic forearm exercise tests induced contractures in the patient. On dantrolene treatment, the patient became asymptomatic, and the ischemic test was performed without contracture. These findings suggest that cramps in muscle PGAMD are caused by a high calcium release from the sarcoplasmic reticulum relative to calcium re-uptake capacity.