Hearing dysfunction in heterozygous M itf Mi‐wh /+ mice, a model for W aardenburg syndrome type 2 and T ietz syndrome

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/95364/1/pcmr12030.pd

Pre-orchiectomy tumor marker levels should not be used for International Germ Cell Consensus Classification (IGCCCG) risk group assignment

PURPOSE To investigate whether the use of pre-orchiectomy instead of pre-chemotherapy tumor marker (TM) levels has an impact on the International Germ Cell Consensus Classification (IGCCCG) risk group assignment in patients with metastatic germ cell tumors (GCT). METHODS Demographic and clinical information of all patients treated for primary metastatic testicular non-seminomatous GCT in our tertiary care academic center were extracted from medical charts. IGCCCG risk group assignment was correctly performed with pre-chemotherapy marker levels and additionally with pre-orchiectomy marker levels. Agreement between pre-chemotherapy and pre-orchiectomy risk group assignments was assessed using Cohen's kappa. RESULTS Our cohort consisted of 83 patients. The use of pre-orchiectomy TMs resulted in an IGCCCG risk group upstaging in 12 patients (16%, 8 patients from good to intermediate risk and 4 patients from intermediate to poor risk) and a downstaging in 1 patient (1.2%, from intermediate- to good-risk). The agreement between pre-orchiectomy and pre-chemotherapy IGCCCG risk groups resulted in a Cohen's kappa of 0.888 (p < 0.001). CONCLUSIONS Using pre-orchiectomy TMs can result in incorrect IGCCCG risk group assignment, which in turn can impact on the clinical management and follow-up of patients with metastatic GCT. Thus, adherence to the IGCCCG standard using pre-chemotherapy TMs levels is recommended

Morphological and physiological effects of long duration infusion of strychnine into the organ of Corti

Acute strychnine administration has long been used as a method to eliminate the effects of efferent activity. It has been shown that long after termination of chronic strychnine infusion into the cochlea, the ear becomes more susceptible to acoustic trauma suggesting that chronic strychnine infusion results in long lasting or permanent disruption of efferent function. Much research has been directed towards the functional significance of the olivocochlear system. However, there is little information concerning the effect of long duration inactivation of the medial olivocochlear system in an awake behaving animal. This study was designed to determine the structural and functional consequences of inactivation of the efferents by chronic infusion of strychnine into the cochlear perilymph of guinea pigs for two weeks via an osmotic pump. Physiological evaluations showed that the strychnine infusion eliminated the efferent induced reduction of the cochlear whole-nerve action potential three weeks after cessation of strychnine infusion. Contralateral efferent function remained unaltered. Histological evaluation at the light and electron microscopic levels revealed disoriented efferent synapses under the outer hair cells.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/47459/1/11068_2004_Article_241027.pd

Hair cells in the inner ear of the pirouette and shaker 2 mutant mice

The shaker 2 ( sh2 ) and pirouette ( pi ) mouse mutants display severe inner ear dysfunction that involves both auditory and vestibular manifestation. Pathology of the stereocilia of hair cells has been found in both mutants. This study was designed to further our knowledge of the pathological characteristics of the inner ear sensory epithelia in both the sh2 and pi strains. Measurements of auditory brainstem responses indicated that both mutants were profoundly deaf. The morphological assays were specifically designed to characterize a pathological actin bundle that is found in both the inner hair cells and the vestibular hair cells in all five vestibular organs in these two mutants. Using light microscope analysis of phalloidin-stained specimens, these actin bundles could first be detected on postnatal day 3. As the cochleae matured, each inner hair cell and type I vestibular hair cell contained a bundle that spans from the region of the cuticular plate to the basal end of the cell, then extends along with cytoplasm and membrane, towards the basement membrane. Abnormal contact with the basement membrane was found in vestibular hair cells. Based on the shape of the cellular extension and the actin bundle that supports it, we propose to name these extensions “cytocauds.” The data suggest that the cytocauds in type I vestibular hair cells and inner hair cells are associated with a failure to differentiate and detach from the basement membrane.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/47461/1/11068_2004_Article_278960.pd

The astrocyte-produced growth factor HB-EGF limits autoimmune CNS pathology

Central nervous system (CNS)-resident cells such as microglia, oligodendrocytes and astrocytes are gaining increasing attention in respect to their contribution to CNS pathologies including multiple sclerosis (MS). Several studies have demonstrated the involvement of pro-inflammatory glial subsets in the pathogenesis and propagation of inflammatory events in MS and its animal models. However, it has only recently become clear that the underlying heterogeneity of astrocytes and microglia can not only drive inflammation, but also lead to its resolution through direct and indirect mechanisms. Failure of these tissue-protective mechanisms may potentiate disease and increase the risk of conversion to progressive stages of MS, for which currently available therapies are limited. Using proteomic analyses of cerebrospinal fluid specimens from patients with MS in combination with experimental studies, we here identify Heparin-binding EGF-like growth factor (HB-EGF) as a central mediator of tissue-protective and anti-inflammatory effects important for the recovery from acute inflammatory lesions in CNS autoimmunity. Hypoxic conditions drive the rapid upregulation of HB-EGF by astrocytes during early CNS inflammation, while pro-inflammatory conditions suppress trophic HB-EGF signaling through epigenetic modifications. Finally, we demonstrate both anti-inflammatory and tissue-protective effects of HB-EGF in a broad variety of cell types in vitro and use intranasal administration of HB-EGF in acute and post-acute stages of autoimmune neuroinflammation to attenuate disease in a preclinical mouse model of MS. Altogether, we identify astrocyte-derived HB-EGF and its epigenetic regulation as a modulator of autoimmune CNS inflammation and potential therapeutic target in MS. Linnerbauer and colleagues find that HB-EGF produced by reactive astrocytes is protective during autoimmune neuroinflammation, but epigenetically suppressed during late stages

Network model of immune responses reveals key effectors to single and co-infection dynamics by a respiratory bacterium and a gastrointestinal helminth

Co-infections alter the host immune response but how the systemic and local processes at the site of infection interact is still unclear. The majority of studies on co-infections concentrate on one of the infecting species, an immune function or group of cells and often focus on the initial phase of the infection. Here, we used a combination of experiments and mathematical modelling to investigate the network of immune responses against single and co-infections with the respiratory bacterium Bordetella bronchiseptica and the gastrointestinal helminth Trichostrongylus retortaeformis. Our goal was to identify representative mediators and functions that could capture the essence of the host immune response as a whole, and to assess how their relative contribution dynamically changed over time and between single and co-infected individuals. Network-based discrete dynamic models of single infections were built using current knowledge of bacterial and helminth immunology; the two single infection models were combined into a co-infection model that was then verified by our empirical findings. Simulations showed that a T helper cell mediated antibody and neutrophil response led to phagocytosis and clearance of B. bronchiseptica from the lungs. This was consistent in single and co-infection with no significant delay induced by the helminth. In contrast, T. retortaeformis intensity decreased faster when co-infected with the bacterium. Simulations suggested that the robust recruitment of neutrophils in the co-infection, added to the activation of IgG and eosinophil driven reduction of larvae, which also played an important role in single infection, contributed to this fast clearance. Perturbation analysis of the models, through the knockout of individual nodes (immune cells), identified the cells critical to parasite persistence and clearance both in single and co-infections. Our integrated approach captured the within-host immuno-dynamics of bacteria-helminth infection and identified key components that can be crucial for explaining individual variability between single and co-infections in natural populations

Replication competent retrovirus testing (RCR) in the National Gene Vector Biorepository: No evidence of RCR in 1,595 post-treatment peripheral blood samples obtained from 60 clinical trials

The clinical impact of any therapy requires the product be safe and effective. Gammaretroviral vectors pose several unique risks, including inadvertent exposure to replication competent retrovirus (RCR) that can arise during vector manufacture. The US FDA has required patient monitoring for RCR, and the National Gene Vector Biorepository is an NIH resource that has assisted eligible investigators in meeting this requirement. To date, we have found no evidence of RCR in 338 pre-treatment and 1,595 post-treatment blood samples from 737 patients associated with 60 clinical trials. Most samples (75%) were obtained within 1 year of treatment, and samples as far out as 9 years after treatment were analyzed. The majority of trials (93%) were cancer immunotherapy, and 90% of the trials used vector products produced with the PG13 packaging cell line. The data presented here provide further evidence that current manufacturing methods generate RCR-free products and support the overall safety profile of retroviral gene therapy

A toolbox for a structured risk-based prehabilitation program in major surgical oncology

Prehabilitation is a multimodal concept to improve functional capability prior to surgery, so that the patients’ resilience is strengthened to withstand any peri- and postoperative comorbidity. It covers physical activities, nutrition, and psychosocial wellbeing. The literature is heterogeneous in outcomes and definitions. In this scoping review, class 1 and 2 evidence was included to identify seven main aspects of prehabilitation for the treatment pathway: (i) risk assessment, (ii) FITT (frequency, interventions, time, type of exercise) principles of prehabilitation exercise, (iii) outcome measures, (iv) nutrition, (v) patient blood management, (vi) mental wellbeing, and (vii) economic potential. Recommendations include the risk of tumor progression due to delay of surgery. Patients undergoing prehabilitation should perceive risk assessment by structured, quantifiable, and validated tools like Risk Analysis Index, Charlson Comorbidity Index (CCI), American Society of Anesthesiology Score, or Eastern Co-operative Oncology Group scoring. Assessments should be repeated to quantify its effects. The most common types of exercise include breathing exercises and moderate- to high-intensity interval protocols. The program should have a duration of 3–6 weeks with 3–4 exercises per week that take 30–60 min. The 6-Minute Walking Testing is a valid and resource-saving tool to assess changes in aerobic capacity. Long-term assessment should include standardized outcome measurements (overall survival, 90-day survival, Dindo–Clavien/CCI®) to monitor the potential of up to 50% less morbidity. Finally, individual cost-revenue assessment can help assess health economics, confirming the hypothetic saving of $8 for treatment for$1 spent for prehabilitation. These recommendations should serve as a toolbox to generate hypotheses, discussion, and systematic approaches to develop clinical prehabilitation standards

Cellular Differentiation of Human Monocytes Is Regulated by Time-Dependent Interleukin-4 Signaling and the Transcriptional Regulator NCOR2.

Human in vitro generated monocyte-derived dendritic cells (moDCs) and macrophages are used clinically, e.g., to induce immunity against cancer. However, their physiological counterparts, ontogeny, transcriptional regulation, and heterogeneity remains largely unknown, hampering their clinical use. High-dimensional techniques were used to elucidate transcriptional, phenotypic, and functional differences between human in vivo and in vitro generated mononuclear phagocytes to facilitate their full potential in the clinic. We demonstrate that monocytes differentiated by macrophage colony-stimulating factor (M-CSF) or granulocyte macrophage colony-stimulating factor (GM-CSF) resembled in vivo inflammatory macrophages, while moDCs resembled in vivo inflammatory DCs. Moreover, differentiated monocytes presented with profound transcriptomic, phenotypic, and functional differences. Monocytes integrated GM-CSF and IL-4 stimulation combinatorically and temporally, resulting in a mode- and time-dependent differentiation relying on NCOR2. Finally, moDCs are phenotypically heterogeneous and therefore necessitate the use of high-dimensional phenotyping to open new possibilities for better clinical tailoring of these cellular therapies

Vulnerability to climate change of managed stocks in the California Current large marine ecosystem

Introduction: Understanding how abundance, productivity and distribution of individual species may respond to climate change is a critical first step towards anticipating alterations in marine ecosystem structure and function, as well as developing strategies to adapt to the full range of potential changes. Methods: This study applies the NOAA (National Oceanic and Atmospheric Administration) Fisheries Climate Vulnerability Assessment method to 64 federally-managed species in the California Current Large Marine Ecosystem to assess their vulnerability to climate change, where vulnerability is a function of a species’ exposure to environmental change and its biological sensitivity to a set of environmental conditions, which includes components of its resiliency and adaptive capacity to respond to these new conditions. Results: Overall, two-thirds of the species were judged to have Moderate or greater vulnerability to climate change, and only one species was anticipated to have a positive response. Species classified as Highly or Very Highly vulnerable share one or more characteristics including: 1) having complex life histories that utilize a wide range of freshwater and marine habitats; 2) having habitat specialization, particularly for areas that are likely to experience increased hypoxia; 3) having long lifespans and low population growth rates; and/or 4) being of high commercial value combined with impacts from non-climate stressors such as anthropogenic habitat degradation. Species with Low or Moderate vulnerability are either habitat generalists, occupy deep-water habitats or are highly mobile and likely to shift their ranges. Discussion: As climate-related changes intensify, this work provides key information for both scientists and managers as they address the long-term sustainability of fisheries in the region. This information can inform near-term advice for prioritizing species-level data collection and research on climate impacts, help managers to determine when and where a precautionary approach might be warranted, in harvest or other management decisions, and help identify habitats or life history stages that might be especially effective to protect or restore