ELUCIDATING FUNCTIONAL ROLES FOR MYOGENIN IN ADULT SKELETAL MUSCLE METABOLISM, EXERCISE CAPACITY, AND REGENERATION

The four basic helix-loop-helix myogenic transcription factors, myogenin, Myf5, MRF4, and MyoD are critical for embryonic skeletal muscle development. Myogenin is necessary for the terminal differentiation of myoblasts into myofibers during embryogenesis, but little is known about the roles played by myogenin in adult skeletal muscle function and metabolism. Furthermore, while metabolism is a well-studied physiological process, how it is regulated at the transcriptional level remains poorly understood. In this study, my aim was to determine the function of myogenin in adult skeletal muscle metabolism, exercise capacity, and regeneration. To investigate this, I utilized a mouse strain harboring the Myogflox allele and a Cre recombinase transgene, enabling the efficient deletion of myogenin in the adult mouse. Myogflox/flox mice were stressed physically through involuntary treadmill running and by breeding them with a strain harboring the Duchenne’s muscular dystrophy (DMDmdx) allele. Surprisingly, Myog-deleted animals exhibited an enhanced capacity for exercise, running farther and faster than their wild-type counterparts. Increased lactate production and utilization of glucose as a fuel source indicated that Myog-deleted animals exhibited an increased glycolytic flux. Hypoglycemic Myog-deleted mice no longer possessed the ability to outrun their wild-type counterparts, implying the ability of these animals to further deplete their glucose reserves confers their enhanced exercise capacity. Moreover, Myog-deleted mice exhibited an enhanced response to long-term exercise training. The mice developed a greater proportion of type 1 oxidative muscle fibers, and displayed increased levels of succinate dehydrogenase activity, indicative of increased oxidative metabolism. Mdx:Myog-deleted mice exhibited a similar phenotype, outperforming their mdx counterparts, although lagging behind wild-type animals. The morphology of muscle tissue from mdx:Myog-deleted mice appears to mimic that of mdx animals, indicating that myogenin is dispensable for adult skeletal muscle regeneration. Through global gene expression profiling and quantitative (q)RT-PCR, I identified a unique set of putative myogenin-dependent genes involved in regulating metabolic processes. These data suggest myogenin’s functions during adulthood are distinctly different than those during embryogenesis, and myogenin acts as a high-level transcription factor regulating metabolic activity in adult skeletal muscle.

The temporal impulse response function in infantile nystagmus.

Despite rapid to-and-fro motion of the retinal image that results from their incessant involuntary eye movements, persons with infantile nystagmus (IN) rarely report the perception of motion smear. We performed two experiments to determine if the reduction of perceived motion smear in persons with IN is associated with an increase in the speed of the temporal impulse response. In Experiment 1, increment thresholds were determined for pairs of successively presented flashes of a long horizontal line, presented on a 65-cd/m2 background field. The stimulus-onset asynchrony (SOA) between the first and second flash varied from 5.9 to 234 ms. In experiment 2, temporal contrast sensitivity functions were determined for a 3-cpd horizontal square-wave grating that underwent counterphase flicker at temporal frequencies between 1 and 40 Hz. Data were obtained for 2 subjects with predominantly pendular IN and 8 normal observers in Experiment 1 and for 3 subjects with IN and 4 normal observers in Experiment 2. Temporal impulse response functions (TIRFs) were estimated as the impulse response of a linear second-order system that provided the best fit to the increment threshold data in Experiment 1 and to the temporal contrast sensitivity functions in Experiment 2. Estimated TIRFs of the subjects with pendular IN have natural temporal frequencies that are significantly faster than those of normal observers (ca. 13 vs. 9 Hz), indicating an accelerated temporal response to visual stimuli. This increase in response speed is too small to account by itself for the virtual absence of perceived motion smear in subjects with IN, and additional neural mechanisms are considered.

Governance and the Capacity to Manage Resilience in Regional Social-Ecological Systems

The sustainability of regional development can be usefully explored through several different lenses. In situations in which uncertainties and change are key features of the ecological landscape and social organization, critical factors for sustainability are resilience, the capacity to cope and adapt, and the conservation of sources of innovation and renewal. However, interventions in social-ecological systems with the aim of altering resilience immediately confront issues of governance. Who decides what should be made resilient to what? For whom is resilience to be managed, and for what purpose? In this paper we draw on the insights from a diverse set of case studies from around the world in which members of the Resilience Alliance have observed or engaged with sustainability problems at regional scales. Our central question is: How do certain attributes of governance function in society to enhance the capacity to manage resilience? Three specific propositions were explored: ( 1) participation builds trust, and deliberation leads to the shared understanding needed to mobilize and self-organize; ( 2) polycentric and multilayered institutions improve the fit between knowledge, action, and social-ecological contexts in ways that allow societies to respond more adaptively at appropriate levels; and ( 3) accountable authorities that also pursue just distributions of benefits and involuntary risks enhance the adaptive capacity of vulnerable groups and society as a whole. Some support was found for parts of all three propositions. In exploring the sustainability of regional social-ecological systems, we are usually faced with a set of ecosystem goods and services that interact with a collection of users with different technologies, interests, and levels of power. In this situation in our roles as analysts, facilitators, change agents, or stakeholders, we not only need to ask: The resilience of what, to what? We must also ask: For whom?

Effectiveness of integrated care including therapeutic assertive community treatment in severe schizophrenia spectrum and bipolar I disorders: the 24-month follow-up ACCESS II study

OBJECTIVE The ACCESS treatment model offers assertive community treatment embedded in an integrated care program to patients with psychoses. Compared to standard care and within a controlled study, it proved to be more effective in terms of service disengagement and illness outcomes in patients with schizophrenia spectrum disorders over 12 months. ACCESS was implemented into clinical routine and its effectiveness assessed over 24 months in severe schizophrenia spectrum disorders and bipolar I disorder with psychotic features (DSM-IV) in a cohort study. METHOD All 115 patients treated in ACCESS (from May 2007 to October 2009) were included in the ACCESS II study. The primary outcome was rate of service disengagement. Secondary outcomes were change of psychopathology, severity of illness, psychosocial functioning, quality of life, satisfaction with care, medication nonadherence, length of hospital stay, and rates of involuntary hospitalization. RESULTS Only 4 patients (3.4%) disengaged with the service. Another 11 (9.6%) left because they moved outside the catchment area. Patients received a mean of 1.6 outpatient contacts per week. Involuntary admissions decreased from 34.8% in the 2 previous years to 7.8% during ACCESS (P < .001). Mixed models repeated-measures analyses revealed significant improvements among all patients in psychopathology (effect size d = 0.64, P < .001), illness severity (d = 0.84, P = .03), functioning level (d = 0.65, P < .001), quality of life (d = 0.50, P < .001), and client satisfaction (d = 0.11, P < .001). At 24 months, 78.3% were fully adherent to medication, compared to 25.2% at baseline (P = .002). CONCLUSIONS ACCESS was successfully implemented in clinical routine and maintained excellent rates of service engagement and other outcomes in patients with schizophrenia spectrum disorders or bipolar I disorder with psychotic features over 24 months. TRIAL REGISTRATION ClinicalTrials.gov identifier: NCT01888627.

Late onset and pregnancy-induced congenital thrombotic thrombocytopenic purpura.

UNLABELLED We report on our patient (case 2) who experienced a first acute episode of thrombotic thrombocytopenic purpura (TTP) at the age of 19 years during her first pregnancy in 1976 which ended in a spontaneous abortion in the 30th gestational week. Treatment with red blood cell concentrates was implemented and splenectomy was performed. After having suffered from several TTP episodes in 1977, possibly mitigated by acetylsalicylic acid therapy, an interruption and sterilization were performed in 1980 in her second pregnancy thereby avoiding another disease flare-up. Her elder sister (case 1) had been diagnosed with TTP in 1974, also during her first pregnancy. She died in 1977 during her second pregnancy from a second acute TTP episode. DIAGNOSIS In 2013 a severe ADAMTS13 deficiency of <10% without detectable ADAMTS13 inhibitor was repeatedly found. Investigation of the ADAMTS13 gene showed that the severe ADAMTS13 deficiency was caused by compound heterozygous ADAMTS13 mutations: a premature stop codon in exon 2 (p.Q44X), and a missense mutation in exon 24 (p.R1060W) associated with low but measurable ADAMTS13 activity. CONCLUSION Genetic analysis of the ADAMTS13 gene is important in TTP patients of all ages if an ADAMTS13 inhibitor has been excluded.

Deficit actual tool use in schizophrenia is linked to structural alterations in key regions of planning and executing of tool use and connecting fibers

Introduction: Schizophrenia patients frequently suffer from complex motor abnormalities including fine and gross motor disturbances, abnormal involuntary movements, neurological soft signs and parkinsonism. These symptoms occur early in the course of the disease, continue in chronic patients and may deteriorate with antipsychotic medication. Furthermore gesture performance is impaired in patients, including the pantomime of tool use. Whether schizophrenia patients would show difficulties of actual tool use has not yet been investigated. Human tool use is complex and relies on a network of distinct and distant brain areas. We therefore aim to test if schizophrenia patients had difficulties in tool use and to assess associations with structural brain imaging using voxel based morphometry (VBM) and tract based spatial statistics (TBSS). Methode: In total, 44 patients with schizophrenia (DSM-5 criteria; 59% men, mean age 38) underwent structural MR imaging and performed the Tool-Use test. The test examines the use of a scoop and a hammer in three conditions: pantomime (without the tool), demonstration (with the tool) and actual use (with a recipient object). T1-weighted images were processed using SPM8 and DTI-data using FSL TBSS routines. To assess structural alterations of impaired tool use we first compared gray matter (GM) volume in VBM and white matter (WM) integrity in TBSS data of patients with and without difficulties of actual tool use. Next we explored correlations of Tool use scores and VBM and TBSS data. Group comparisons were family wise error corrected for multiple tests. Correlations were uncorrected (p < 0.001) with a minimum cluster threshold of 17 voxels (equivalent to a map-wise false positive rate of alpha < 0.0001 using a Monte Carlo procedure). Results: Tool use was impaired in schizophrenia (43.2% pantomime, 11.6% demonstration, 11.6% use). Impairment was related to reduced GM volume and WM integrity. Whole brain analyses detected an effect in the SMA in group analysis. Correlations of tool use scores and brain structure revealed alterations in brain areas of the dorso-dorsal pathway (superior occipital gyrus, superior parietal lobule, and dorsal premotor area) and the ventro-dorsal pathways (middle occipital gyrus, inferior parietal lobule) the action network, as well as the insula and the left hippocampus. Furthermore, significant correlations within connecting fiber tracts - particularly alterations within the bilateral corona radiata superior and anterior as well as the corpus callosum -were associated with Tool use performance. Conclusions: Tool use performance was impaired in schizophrenia, which was associated with reduced GM volume in the action network. Our results are in line with reports of impaired tool use in patients with brain lesions particularly of the dorso-dorsal and ventro-dorsal stream of the action network. In addition an effect of tool use on WM integrity was shown within fiber tracts connecting regions important for planning and executing tool use. Furthermore, hippocampus is part of a brain system responsible for spatial memory and navigation.The results suggest that structural brain alterations in the common praxis network contribute to impaired tool use in schizophrenia.

The Use of New Technology and Occupational Mobility: An Event History Analysis of the Swiss Labor Market

The investigation of the consequences of new technologies has a long standing tradition within economics. Particularly, labor economists are wondering how the introduction of new technologies, e.g. Personal Computers, have shaped labor markets. Former research has concentrated on the question of whether on-the-job use of PCs creates a wage bonus for employees. In this paper, we investigate whether the use of PCs increases employees’ probability of an upward shift in their employment status and whether it reduces the risk of involuntary labor market exits. We do so by applying event history analysis to the Swiss Labor Market Survey, a random sample of 3028 respondents, and by analyzing a Panel sub-sample of 650 respondents conducted recently in Switzerland. Our results show that on-the-job use of PCs was beneficial for employees in the past by increasing their probability of an upward shift by approximately 50%. The analysis also suggests that PC use reduces the risk and duration of unemployment. However, these latter results fail to reach statistical significance.

Invasive plant species do not create more negative soil conditions for other plants than natives

Abstract A major task in ecology is to establish the degree of generality of ecological mechanisms. Here we present results from a multi-species experiment that tested whether a set of invasive species altered the soil conditions to the detriment of other species by releasing allelopathic compounds or inducing shifts in soil biota composition, and whether this effect was more pronounced relative to a set of closely related native species. We pre-cultivated soil with 23 exotic invasive, 19 related native and 6 related exotic garden species and used plain soil as a control. To separate allelopathy from effects on the soil biota, we sterilized half of the soil. Then, we compared the effect of soil pre-cultivation and sterilization on germination and growth of four native test species in two experiments. The general effect of soil sterilization was positive. The effect of soil pre-cultivation on test species performance was neutral to positive, and sterilization reduced this positive effect. This indicates general absence of allelopathic compounds and a shift toward a less antagonistic soil biota by cultivation species. In both experiments, pre-cultivation effects did not differ systematically between exotic invasive, exotic garden or native species. Our results do not support the hypothesis that invasive plants generally inhibit the growth of others by releasing allelopathic compounds or accumulating a detrimental soil biota.

Psychomotor symptoms of schizophrenia map on the cerebral motor circuit

Schizophrenia is a devastating disorder thought to result mainly from cerebral pathology. Neuroimaging studies have provided a wealth of findings of brain dysfunction in schizophrenia. However, we are still far from understanding how particular symptoms can result from aberrant brain function. In this context, the high prevalence of motor symptoms in schizophrenia such as catatonia, neurological soft signs, parkinsonism, and abnormal involuntary movements is of particular interest. Here, the neuroimaging correlates of these motor symptoms are reviewed. For all investigated motor symptoms, neural correlates were found within the cerebral motor system. However, only a limited set of results exists for hypokinesia and neurological soft signs, while catatonia, abnormal involuntary movements and parkinsonian signs still remain understudied with neuroimaging methods. Soft signs have been associated with altered brain structure and function in cortical premotor and motor areas as well as cerebellum and thalamus. Hypokinesia is suggested to result from insufficient interaction of thalamocortical loops within the motor system. Future studies are needed to address the neural correlates of motor abnormalities in prodromal states, changes during the course of the illness, and the specific pathophysiology of catatonia, dyskinesia and parkinsonism in schizophrenia.

After-effects and after-effects and after-effects of after-effects: The multiple side effects of prospective memory

In a prospective memory task responding to a prospective memory target involves switching between ongoing and prospective memory task which can result in a slowing of subsequent ongoing task performance (i.e., an after-effect). Moreover, a slowing can also occur when prospective memory targets occur after the prospective memory task is deactivated (i.e., another after-effect). In this study, we investigated both after-effects within the same study. Moreover, we also tested whether the latter after-effects even occur on subsequent ongoing task trials. The results show, in fact, after-effects of all kinds. Thus, (1) correctly responding to prospective memory targets results in after-effects, a so far neglected cost on ongoing task performance, (2) responding to deactivated prospective memory targets also slows down performance, probably due to the involuntary retrieval of the intention, and (3) this slowing is present even on subsequent ongoing task trials, suggesting that even deactivated intentions are sufficient to induce a conflict that requires subsequent adaptation. Overall, these results indicate that performance slowing in a prospective memory experiment includes various kinds of sources, not only monitoring cost, and these sources may be understood best in terms of conflict adaptation.

Increased Resting State Network Connectivity in Synesthesia: Evidence for a Neural Basis of Synesthetic Consistency

Studying individual differences in conscious awareness can potentially lend fundamental insights into the neural bases of binding mechanisms and consciousness (Cohen Kadosh and Henik, 2007). Partly for this reason, considerable attention has been devoted to the neural mechanisms underlying grapheme–color synesthesia, a healthy condition involving atypical brain activation and the concurrent experience of color photisms in response to letters, numbers, and words. For instance, the letter C printed in black on a white background may elicit a yellow color photism that is perceived to be spatially colocalized with the inducing stimulus or internally in the “mind's eye” as, for instance, a visual image. Synesthetic experiences are involuntary, idiosyncratic, and consistent over time (Rouw et al., 2011). To date, neuroimaging research on synesthesia has focused on brain areas activated during the experience of synesthesia and associated structural brain differences. However, activity patterns of the synesthetic brain at rest remain largely unexplored. Moreover, the neural correlates of synesthetic consistency, the hallmark characteristic of synesthesia, remain elusive.

Effects of Antiseptic Solutions Commonly Used in Dentistry on Bone Viability, Bone Morphology, and Release of Growth Factors

PURPOSE Antiseptic solutions are commonly used in dentistry for a number of sterilization procedures, including harvesting of bone chips, irrigation of extraction sockets, and sterilization of osteonecrotic bone. Despite its widespread use, little information is available regarding the effects of various antiseptic solutions on bone cell viability, morphology, and the release of growth factors. MATERIALS AND METHODS The antiseptic solutions included 1) 0.5% povidone iodine (PI), 2) 0.2% chlorhexidine diguluconate (CHX), 3) 1% hydrogen peroxide (H2O2), and 4) 0.25% sodium hypochlorite (HYP). Bone samples collected from porcine mandibular cortical bone were rinsed in the antiseptic solutions for 10 minutes and assessed for cell viability using an MTS assay and protein release of transforming growth factor (TGF-β1), bone morphogenetic protein 2 (BMP2), vascular endothelial growth factor (VEGF), interleukin (IL)-1β, and receptor activator of nuclear factor κB ligand (RANKL) using an enzyme-linked immunosorbent assay at 15 minutes and 4 hours after rinsing. RESULTS After antiseptic rinsing, changes to the surface protein content showed marked alterations, with an abundant protein layer remaining on CHX-rinsed bone samples. The amount of surface protein content gradually decreased in the following order: CHX, H2O2, PI, and HYP. A similar trend was also observed for the relative cell viability from within bone samples after rinsing, with up to 6 times more viable cells found in the CHX-rinsed bone samples than in the HYP- and PI-rinsed samples. An analysis of the growth factors found that both HYP and PI had significantly lower VEGF and TGF-β1 protein release from bone samples at 15 minutes and 4 hours after rinsing compared with CHX and H2O2. A similar trend was observed for RANKL and IL-1β protein release, although no change was observed for BMP2. CONCLUSIONS The results from the present study have demonstrated that antiseptic solutions present with very different effects on bone samples after 10 minutes of rinsing. Rinsing with CHX maintained significantly higher cell viability and protein release of growth factors potent to the bone remodeling cycle.

Panels of cytokines and other secretory proteins as potential biomarkers of ovarian endometriosis.

Endometriosis is a gynecologic disease that is characterized by nonspecific symptoms and invasive diagnostics. To date, there is no adequate noninvasive method for the diagnosis of endometriosis. Although more than 100 potential biomarkers have been investigated in blood and/or peritoneal fluid, none of these has proven useful in clinical practice. The aim to find a suitable panel of biomarkers that would allow noninvasive diagnosis thus remains of interest. We evaluated the concentrations of 16 cytokines and other secretory proteins in serum and peritoneal fluid of 58 women with ovarian endometriosis (cases) and 40 healthy women undergoing sterilization or patients with benign ovarian cysts (controls) using multiplexed double fluorescence-based immunometric assay platform and enzyme-linked immunosorbent assay. Significantly higher concentrations of glycodelin-A were shown in serum, and significantly higher levels of glycodelin-A, IL-6, and IL-8, and lower levels of leptin were measured in the peritoneal fluid of cases versus controls. In serum, the best performance was shown by models that included the ratio of leptin/glycodelin-A and the ratio of ficolin 2/glycodelin-A, whereas in the peritoneal fluid the best models included the ratio of biglycan/leptin, regulated on activation normal T-cell expressed and secreted/IL-6 and ficolin-2/glycodelin-A, and IL-8 per milligram of total protein, all in combination with age. The models using serum and peritoneal fluid distinguished between ovarian endometriosis patients and controls regardless of the menstrual cycle phase with relatively high sensitivity (72.5% to 84.2%), specificity (78.4% to 91.2%), and area under the curve (0.85 to 0.90).

Governance and the Capacity to Manage Resilience in Regional Social-Ecological Systems

The sustainability of regional development can be usefully explored through several different lenses. In situations in which uncertainties and change are key features of the ecological landscape and social organization, critical factors for sustainability are resilience, the capacity to cope and adapt, and the conservation of sources of innovation and renewal. However, interventions in social-ecological systems with the aim of altering resilience immediately confront issues of governance. Who decides what should be made resilient to what? For whom is resilience to be managed, and for what purpose? In this paper we draw on the insights from a diverse set of case studies from around the world in which members of the Resilience Alliance have observed or engaged with sustainability problems at regional scales. Our central question is: How do certain attributes of governance function in society to enhance the capacity to manage resilience? Three specific propositions were explored: ( 1) participation builds trust, and deliberation leads to the shared understanding needed to mobilize and self-organize; ( 2) polycentric and multilayered institutions improve the fit between knowledge, action, and social-ecological contexts in ways that allow societies to respond more adaptively at appropriate levels; and ( 3) accountable authorities that also pursue just distributions of benefits and involuntary risks enhance the adaptive capacity of vulnerable groups and society as a whole. Some support was found for parts of all three propositions. In exploring the sustainability of regional social-ecological systems, we are usually faced with a set of ecosystem goods and services that interact with a collection of users with different technologies, interests, and levels of power. In this situation in our roles as analysts, facilitators, change agents, or stakeholders, we not only need to ask: The resilience of what, to what? We must also ask: For whom?

A novel treatment planning methodology for high dose 166Ho-DOTMP therapy in patients with multiple myeloma

Bone marrow ablation, i.e., the complete sterilization of the active bone marrow, followed by bone marrow transplantation (BMT) is a comment treatment of hematological malignancies. The use of targeted bone-seeking radiopharmaceuticals to selectively deliver radiation to the adjacent bone marrow cavities while sparing normal tissues is a promising technique. Current radiopharmaceutical treatment planning methods do not properly compensate for the patient-specific variable distribution of radioactive material within the skeleton. To improve the current method of internal dosimetry, novel methods for measuring the radiopharmaceutical distribution within the skeleton were developed. 99mTc-MDP was proven as an adequate surrogate for measuring 166Ho-DOTMP skeletal uptake and biodistribution, allowing these measures to be obtained faster, safer, and with higher spatial resolution. This translates directly into better measurements of the radiation dose distribution within the bone marrow. The resulting bone marrow dose-volume histograms allow prediction of the patient disease response where conventional organ scale dosimetry failed. They indicate that complete remission is only achieved when greater than 90% of the bone marrow receives at least 30 Gy. ^ Comprehensive treatment planning requires combining target and non-target organ dosimetry. Organs in the urinary tract were of special concern. The kidney dose is primarily dependent upon the mean transit time of 166 Ho-DOTMP through the kidney. Deconvolution analysis of renograms predicted a mean transit time of 2.6 minutes for 166Ho-DOTMP. The radiation dose to the urinary bladder wall is dependent upon numerous factors including patient hydration and void schedule. For beta-emitting isotopes such as 166Ho, reduction of the bladder wall dose is best accomplished through good patient hydration and ensuring a partially full bladder at the time of injection. Encouraging the patient to void frequently, or catheterizing the patient without irrigation, will not significantly reduce the bladder wall dose. ^ The results from this work will produce the most advanced treatment planning methodology for bone marrow ablation therapy using radioisotopes currently available. Treatments can be tailored specifically for each patient, including the addition of concomitant total body irradiation for patients with unfavorable dose distributions, to deliver a desired patient disease response, while minimizing the dose or toxicity to non-target organs. ^