Socioeconomic inequities in mortality and functional outcome after stroke in Zanzibar: A prospective cohort study.

OBJECTIVES: To characterise mortality and functional outcome and their relationships with socioeconomic deprivation for women and men in Zanzibar. MATERIALS AND METHODS: Participants in ZanStroke, a prospective observational study of patients admitted to hospital with a diagnosis of acute stroke, were followed up until one year after the stroke. The modified National Institute of Health Stroke Scale was used to assess initial stroke severity, while modified Rankin Scale (mRS) was used to assess disability at 12 months post-stroke. A multidimensional poverty index was created using individual-level data. Kaplan-Meier analysis and Cox regression model were used to examine associations of socioeconomic deprivation and death at 28 days and 12 months after stroke onset, while logistic regression analysis was used to examine associations between deprivation and functional outcome. RESULTS: Overall mortality rate was 38.2% (CI 34.8-41.9) at 28 days, rising to 59.0% (CI 55.2-62.8) at 12 months. When adjusted for other variables, survival was higher among the least deprived (HR 0.60 CI 0.45-0.80), an association that was strongly significant for women (HR 0.46 CI 0.29-0.74). Among 12-month survivors 45.1% (n = 122) had no/low level of disability (mRS 0-2), while 22.9% (n = 62) were unable to walk independently or at all. No difference between socioeconomic deprivation and outcome was seen at one year. CONCLUSION: Case-fatality rates were high, and socioeconomic disparities were evident even during the acute stroke phase. Policies are needed to reduce significant health disparities, adapt evidence-based interventions, and promote equitable access to stroke care and rehabilitation.

Reliability of translaryngeal airway resistance measurements during maximal exercise.

Objective: Exercise-induced laryngeal obstruction is an important cause of exertional dyspnoea. The diagnosis rests on visual judgement of relative changes of the laryngeal inlet during continuous laryngoscopy exercise (CLE) tests, but we lack objective measures that reflect functional consequences. We aimed to investigate repeatability and normal values of translaryngeal airway resistance measured at maximal intensity exercise. Methods: 31 healthy nonsmokers without exercise-related breathing problems were recruited. Participants performed two CLE tests with verified positioning of two pressure sensors, one at the tip of the epiglottis (supraglottic) and one by the fifth tracheal ring (subglottic). Airway pressure and flow data were continuously collected breath-by-breath and used to calculate translaryngeal resistance at peak exercise. Laryngeal obstruction was assessed according to a standardised CLE score system. Results: Data from 26 participants (16 females) with two successful tests and equal CLE scores on both test sessions were included in the translaryngeal resistance repeatability analyses. The coefficient of repeatability (CR) was 0.62 cmH2O·L-1·s-1, corresponding to a CR% of 21%. Mean±sd translaryngeal airway resistance (cmH2O·L-1·s-1) in participants with no laryngeal obstruction (n=15) was 2.88±0.50 in females and 2.18±0.50 in males. Higher CLE scores correlated with higher translaryngeal resistance in females (r=0.81, p<0.001). Conclusions: This study establishes translaryngeal airway resistance obtained during exercise as a reliable parameter in respiratory medicine, opening the door for more informed treatment decisions and future research on the role of the larynx in health and disease.

Exercise-induced Laryngeal Obstruction: Protocol for a Randomized Controlled Treatment Trial.

BACKGROUND: Exercise-induced laryngeal obstruction (EILO) is a common cause of exertional breathing problems in young individuals, caused by paradoxical inspiratory adduction of laryngeal structures, and diagnosed by continuous visualization of the larynx during high-intensity exercise. Empirical data suggest that EILO consists of different subtypes, possibly requiring different therapeutic approaches. Currently applied treatments do not rest on randomized controlled trials, and international guidelines based on good evidence can therefore not be established. This study aims to provide evidence-based information on treatment schemes commonly applied in patients with EILO. METHODS AND ANALYSIS: Consenting patients consecutively diagnosed with EILO at Haukeland University Hospital will be randomized into four non-invasive treatment arms, based on promising reports from non-randomized studies: (A) standardized information and breathing advice only (IBA), (B) IBA plus inspiratory muscle training, (C) IBA plus speech therapy, and (D) IBA plus inspiratory muscle training and speech therapy. Differential effects in predefined EILO subtypes will be addressed. Patients failing the non-invasive approach and otherwise qualifying for surgical treatment by current department policy will be considered for randomization into (E) standard or (F) minimally invasive laser supraglottoplasty or (G) no surgery. Power calculations are based on the main outcomes, laryngeal adduction during peak exercise, rated by a validated scoring system before and after the interventions. ETHICS AND DISSEMINATION: The study will assess approaches to EILO treatments that despite widespread use, are insufficiently tested in structured, verifiable, randomized, controlled studies, and is therefore considered ethically sound. The study will provide knowledge listed as a priority in a recent statement issued by the European Respiratory Society, requested by clinicians and researchers engaged in this area, and relevant to 5-7% of young people. Dissemination will occur in peer-reviewed journals, at relevant media platforms and conferences, and by engaging with patient organizations and the healthcare bureaucracy.

Outcome analysis of 95 harness racehorses with confirmed dorsal displacement of the soft palate treated with laryngeal tie-forward surgery.

BACKGROUND: The laryngeal tie-forward (LTF) procedure is commonly used to treat intermittent dorsal displacement of the soft palate (iDDSP). There is a wide range in reported efficacy of treating horses with and without a definitive diagnosis of iDDSP. OBJECTIVES: To evaluate the racing performance of harness racehorses in which iDDSP had been definitely diagnosed and treated solely with the LTF procedure. STUDY DESIGN: Retrospective case series. METHODS: Ninety-five harness racehorses were treated with LTF for confirmed iDDSP. A definite diagnosis of iDDSP was made with high-speed treadmill or overground endoscopy. Upper respiratory tract (URT) disorders, short-term complications, and horses returning for recurrence of URT problems were recorded. Performance before and after LTF was assessed by reviewing career race records and comparing performance index (PI), and racing speed marks from the baseline, preoperative, and postoperative periods. The effect of basihyoid-cricoid (BC) net distance shortened on racing performance was assessed. RESULTS: Postoperatively, PI increased in 36/54 (67%, 95% CI 54%-79%) of experienced racehorses, and 44/67 (66%, 54%-77%) established or improved their racing speed mark relative to the preoperative period. As a group, PI decreased by a mean (SE) of 0.9 (0.17) points (P < .001) prior to diagnosis/surgery. Postoperatively, PI increased by 0.5 (0.16) points (P = .003), and racing speed improved by 0.83 (0.22) s (P < .001). Twenty-five percent (17%-34%) and 49% (39%-60%) of horses did not demonstrate a decline in PI and racing speed prior to diagnosis, respectively. Net BC distance shortening did not affect performance postoperatively. Twenty of 95 horses (21%, 13%-29%) had confirmed recurrence of iDDSP 46-708 days postoperatively. MAIN LIMITATIONS: Not all horses were evaluated with exercising endoscopy postoperatively. Racehorses inevitably develop other racing-related problems which confound studies of this nature. CONCLUSIONS: This study provides scientific support for the use of LTF to treat iDDSP in harness racehorses although iDDSP seems to affect harness racehorses differently as individuals.

Reliability of maximum oxygen uptake in cardiopulmonary exercise testing with continuous laryngoscopy.

AIMS: A cardiopulmonary exercise test (CPET) is the gold standard to evaluate symptom-limiting exercise intolerance, while continuous laryngoscopy performed during exercise (CLE) is required to diagnose exercise-induced laryngeal obstruction. Combining CPET with CLE would save time and resources; however, the CPET data may be distorted by the extra equipment. We therefore aimed to study whether CPET with CLE influences peak oxygen uptake (V'O2 peak) and other gas exchange parameters when compared to a regular CPET. METHODS: Forty healthy athletes without exercise-related breathing problems, 15-35 years of age, performed CPET to peak exercise with and without an added CLE set-up, in randomised order 2-4 days apart, applying an identical computerised treadmill protocol. RESULTS: At peak exercise, the mean difference (95% confidence interval) between CPET with and without extra CLE set-up for V'O2 peak, respiratory exchange ratio (RER), minute ventilation (V'E) and heart rate (HR) was 0.2 (-0.4 to 0.8) mL·kg-1·min-1, 0.01(-0.007 to 0.027) units, 2.6 (-1.3 to 6.5) L·min-1 and 1.4 (-0.8 to 3.5) beats·min-1, respectively. Agreement (95% limits of agreement) for V'O2 peak, RER and V'E was 0.2 (±3.7) mL·kg-1·min-1, 0.01 (±0.10) units and 2.6 (±24.0) L·min-1, respectively. No systematic or proportional bias was found except for the completed distance, which was 49 m (95% CI 16 to 82 m) longer during CPET. CONCLUSION: Parameters of gas exchange, including V'O2 peak and RER, obtained from a maximal CPET performed with the extra CLE set-up can be used interchangeably with data obtained from standard CPET, thus preventing unnecessary additional testing.

A bitless bridle does not limit or prevent dynamic laryngeal collapse.

BACKGROUND: Bits have often been incriminated as a cause of upper respiratory tract obstruction in horses; however, no scientific studies are available to confirm or refute these allegations. Clinical signs of dynamic laryngeal collapse associated with poll flexion (DLC) are induced when susceptible horses are ridden or driven into the bit. OBJECTIVE: To determine whether use of Dr Cook's™ Bitless Bridle, instead of a conventional snaffle bit bridle, would reduce the severity of DLC in affected horses measured objectively using inspiratory tracheal pressures. STUDY DESIGN: Intervention study using each horse as its own control in a block randomised order. METHODS: Nine Norwegian Swedish Coldblooded trotters previously diagnosed with DLC were exercised on two consecutive days using a standardised high-speed treadmill protocol with either a conventional bridle with a snaffle bit, or Dr Cook's™ Bitless Bridle. Head and neck position, rein tension, inspiratory tracheal pressure measurements, and laryngeal videoendoscopy recordings were obtained. A heart rate greater than 200 bpm, and similar degrees of poll flexion/head height, had to be achieved in both bridles for the individual horse's data to be included for comparison. RESULTS: Seven horses' data met the inclusion criteria. The change in mean inspiratory tracheal pressure between free and flexion phases in the bitless bridle (-15.2 ± 12.3 cmH2 O) was significantly greater (P < .001) than in the snaffle bit bridle (-9.8 ± 7.9 cmH2 O). Mean inspiratory pressure during the free phase was significantly (P < .001) more negative with the snaffle bit bridle (-32.3 ± 6.3 cmH2 O), vs the bitless bridle (-28.5 ± 6.9 cmH2 O). Mean pressures in flexion phase, snaffle bridle (-42.1 ± 10.8 cmH2 O), vs bitless bridle (-43.7 ± 15.6 cmH2 O) where not significantly different between bridles (P = .2). MAIN LIMITATION: Small sample size due to difficulty recruiting suitable clinical cases. CONCLUSIONS: This study could not provide any clear evidence that the effect of a snaffle bit in a horse's mouth influences the development or severity of DLC. Instead, head and neck angles induced by rein tension seem to be the key event in provoking DLC in susceptible horses.

Exercise Induced Laryngeal Obstruction in Humans and Equines. A Comparative Review.

Dynamic obstructions of the larynx are a set of disorders that occur during exercise in equines and humans. There are a number of similarities in presentation, diagnosis, pathophysiology and treatment. Both equines and humans present with exercise intolerance secondary to dyspnea. During laryngoscopy at rest, the larynx appears to function normally. Abnormalities are only revealed during laryngoscopy at exercise, seemingly triggered by increased ventilatory demands, and quickly resolve after cessation of exercise. Lower airway disease (asthma being the most prevalent condition), cardiac disease and lack of fitness are the major differentials in both species. Laryngoscopic examination during exercise should be performed from rest to peak exertion to allow for a comprehensive diagnosis, including where the airway collapse begins, and thereafter how it progresses. Dynamic disorders with most visual similarity between humans and equines are: aryepiglottic fold collapse (both species); equine dynamic laryngeal collapse (DLC) relative to some forms of human combined supraglottic/glottic collapse; and epiglottic retroversion (both species). Quantitative grading techniques, such as airway pressure measurement, that have proven effective in veterinary research are currently being piloted in human studies. Conditions that appear visually similar are treated in comparable ways. The similarities of anatomy and certain types of dynamic collapse would suggest that the equine larynx provides a good model for human upper respiratory tract obstruction during exercise. Thus, close collaboration between veterinarians and medical personal may lead to further advancements in understanding pathophysiologic processes, and enhance the development of improved diagnostic tests and treatments that will benefit both species.

Feasibility and tolerability of measuring translaryngeal pressure during exercise.

OBJECTIVES/HYPOTHESIS: To determine if simultaneous tracheal and supraglottic pressure measurement performed during a continuous laryngoscopy exercise (CLE) test is possible, tolerable, and feasible, and if so, whether measurements can be used to determined airflow resistance over the larynx, thus providing an objective outcome measure for the CLE test, the gold standard for diagnosing exercise-induced laryngeal obstruction. STUDY DESIGN: Explorative descriptive clinical study. METHODS: A CLE test was performed with the addition of two pressure sensors (Mikro-Cath 825-0101; Millar, Houston, TX) placed at the epiglottic tip and at the fifth tracheal ring. To place sensors, laryngeal anesthesia and a channel scope were required. Tolerability and feasibility was determined by a Likert score and subjective indication from subjects and operators. Adjustments to the technique were made to increase tolerability. The pressure data were continuously collected and analyzed for artifacts, drifts, frequency response, and used with flow data to calculate translaryngeal resistance. RESULTS: All subjects (n = 7) completed all procedures. Two main areas of concern were identified regarding tolerability: application of topical anesthesia to the larynx and nasal discomfort due to the added diameter of the laryngoscope. Protocol adjustments improved both. Pressure data were obtained from all procedures in all subjects, were consistent, and followed physiological trends. CONCLUSIONS: Continuous measurement of the translaryngeal pressure gradient during a CLE test is possible, feasible, and tolerable. A CLE test with direct measurement of the translaryngeal pressure gradient might become a valuable tool in the objective assessment of respiratory function, and normal values should be established in health and disease. LEVEL OF EVIDENCE: NA Laryngoscope, 129:2748-2753, 2019.

The tumour suppressor OPCML promotes AXL inactivation by the phosphatase PTPRG in ovarian cancer.

In ovarian cancer, the prometastatic RTK AXL promotes motility, invasion and poor prognosis. Here, we show that reduced survival caused by AXL overexpression can be mitigated by the expression of the GPI-anchored tumour suppressor OPCML Further, we demonstrate that AXL directly interacts with OPCML, preferentially so when AXL is activated by its ligand Gas6. As a consequence, AXL accumulates in cholesterol-rich lipid domains, where OPCML resides. Here, phospho-AXL is brought in proximity to the lipid domain-restricted phosphatase PTPRG, which de-phosphorylates the RTK/ligand complex. This prevents AXL-mediated transactivation of other RTKs (cMET and EGFR), thereby inhibiting sustained phospho-ERK signalling, induction of the EMT transcription factor Slug, cell migration and invasion. From a translational perspective, we show that OPCML enhances the effect of the phase II AXL inhibitor R428 in vitro and in vivo We therefore identify a novel mechanism by which two spatially restricted tumour suppressors, OPCML and PTPRG, coordinate to repress AXL-dependent oncogenic signalling.

Advancing Professional Development Through a Community of Practice: the New England Network for Faculty Affairs.

INTRODUCTION: In an era of competing priorities, funding is increasingly restricted for offices of faculty affairs and development. Opportunities for professional staff to grow and network through attendance at national meetings and to share best practices are limited. We sought to describe a community of practice established to enhance the professional development of faculty affairs professionals and to document its impact. METHODS: We outlined the process of formation of the New England Network for Faculty Affairs (NENFA), reviewed the pedagogical approaches to professional development, and surveyed members to evaluate the impact of NENFA on their activities, professional network and their institutions. RESULTS: After a successful 2011 initial meeting, NENFA created an organizing committee and conducted a needs assessment among potential members. NENFA's charter, mission, goals, and structure were based on survey results. NENFA's regional community of practice grew to 31 institutions and held 10 meetings over 5 years. Meetings have examined a faculty development topic in depth using multiple learning formats to engage participants from academic medical centers and allied professions. Results from a 2015 member survey confirmed the value of NENFA. Multiple members documented changes in practice as a result of participating. DISCUSSION: NENFA has been sustained by volunteer leadership, collaboration, and the value that the group has brought to its members. We propose that a "community of practice" offers an effective model for collaborative learning among individuals at different institutions within a competitive health care environment. We recommend that the approach be replicated in other regions.

The GAS6-AXL signaling network is a mesenchymal (Mes) molecular subtype-specific therapeutic target for ovarian cancer.

Ovarian cancer is a complex disease with heterogeneity among the gene expression molecular subtypes (GEMS) between patients. Patients with tumors of a mesenchymal ("Mes") subtype have a poorer prognosis than patients with tumors of an epithelial ("Epi") subtype. We evaluated GEMS of ovarian cancer patients for molecular signaling profiles and assessed how the differences in these profiles could be leveraged to improve patient clinical outcome. Kinome enrichment analysis identified AXL as a particularly abundant kinase in Mes-subtype tumor tissue and cell lines. In Mes cells, upon activation by its ligand GAS6, AXL coclustered with and transactivated the receptor tyrosine kinases (RTKs) cMET, EGFR, and HER2, producing sustained extracellular signal-regulated kinase (ERK) activation. In Epi-A cells, AXL was less abundant and induced a transient activation of ERK without evidence of RTK transactivation. AXL-RTK crosstalk also stimulated sustained activation of the transcription factor FRA1, which correlated with the induction of the epithelial-mesenchymal transition (EMT)-associated transcription factor SLUG and stimulation of motility exclusively in Mes-subtype cells. The AXL inhibitor R428 attenuated RTK and ERK activation and reduced cell motility in Mes cells in culture and reduced tumor growth in a chick chorioallantoic membrane model. A higher concentration of R428 was needed to inhibit ERK activation and cell motility in Epi-A cells. Silencing AXL in Mes-subtype cells reversed the mesenchymal phenotype in culture and abolished tumor formation in an orthotopic xenograft mouse model. Thus, AXL-targeted therapy may improve clinical outcome for patients with Mes-subtype ovarian cancer.

The prognostic significance of specific HOX gene expression patterns in ovarian cancer.

HOX genes are vital for all aspects of mammalian growth and differentiation, and their dysregulated expression is related to ovarian carcinogenesis. The aim of the current study was to establish the prognostic value of HOX dysregulation as well as its role in platinum resistance. The potential to target HOX proteins through the HOX/PBX interaction was also explored in the context of platinum resistance. HOX gene expression was determined in ovarian cancer cell lines and primary EOCs by QPCR, and compared to expression in normal ovarian epithelium and fallopian tube tissue samples. Statistical analysis included one-way ANOVA and t-tests, using statistical software R and GraphPad. The analysis identified 36 of the 39 HOX genes as being overexpressed in high grade serous EOC compared to normal tissue. We detected a molecular HOX gene-signature that predicted poor outcome. Overexpression of HOXB4 and HOXB9 was identified in high grade serous cell lines after platinum resistance developed. Targeting the HOX/PBX dimer with the HXR9 peptide enhanced the cytotoxicity of cisplatin in platinum-resistant ovarian cancer. In conclusion, this study has shown the HOX genes are highly dysregulated in ovarian cancer with high expression of HOXA13, B6, C13, D1 and D13 being predictive of poor clinical outcome. Targeting the HOX/PBX dimer in platinum-resistant cancer represents a potentially new therapeutic option that should be further developed and tested in clinical trials.

Panel-based genetic diagnostic testing for inherited eye diseases is highly accurate and reproducible, and more sensitive for variant detection, than exome sequencing.

PURPOSE: Next-generation sequencing-based methods are being adopted broadly for genetic diagnostic testing, but the performance characteristics of these techniques with regard to test accuracy and reproducibility have not been fully defined. METHODS: We developed a targeted enrichment and next-generation sequencing approach for genetic diagnostic testing of patients with inherited eye disorders, including inherited retinal degenerations, optic atrophy, and glaucoma. In preparation for providing this genetic eye disease (GEDi) test on a CLIA-certified basis, we performed experiments to measure the sensitivity, specificity, and reproducibility, as well as the clinical sensitivity, of the test. RESULTS: The GEDi test is highly reproducible and accurate, with sensitivity and specificity of 97.9 and 100%, respectively, for single-nucleotide variant detection. The sensitivity for variant detection was notably better than the 88.3% achieved by whole-exome sequencing using the same metrics, because of better coverage of targeted genes in the GEDi test as compared with a commercially available exome capture set. Prospective testing of 192 patients with inherited retinal degenerations indicated that the clinical sensitivity of the GEDi test is high, with a diagnostic rate of 51%. CONCLUSION: Based on quantified performance metrics, the data suggest that selective targeted enrichment is preferable to whole-exome sequencing for genetic diagnostic testing.

Interferon regulatory factor (IRF) 3 is critical for the development of experimental autoimmune encephalomyelitis.

BACKGROUND: Experimental autoimmune encephalomyelitis (EAE) is an animal model of autoimmune inflammatory demyelination that is mediated by Th1 and Th17 cells. The transcription factor interferon regulatory factor 3 (IRF3) is activated by pathogen recognition receptors and induces interferon-ß production. METHODS: To determine the role of IRF3 in autoimmune inflammation, we immunised wild-type (WT) and irf3(-/-) mice to induce EAE. Splenocytes from WT and irf3(-/-) mice were also activated in vitro in Th17-polarising conditions. RESULTS: Clinical signs of disease were significantly lower in mice lacking IRF3, with reduced Th1 and Th17 cells in the central nervous system. Peripheral T-cell responses were also diminished, including impaired proliferation and Th17 development in irf3(-/-) mice. Myelin-reactive CD4+ cells lacking IRF3 completely failed to transfer EAE in Th17-polarised models as did WT cells transferred into irf3(-/-) recipients. Furthermore, IRF3 deficiency in non-CD4+ cells conferred impairment of Th17 development in antigen-activated cultures. CONCLUSION: These data show that IRF3 plays a crucial role in development of Th17 responses and EAE and warrants investigation in human multiple sclerosis.

Independent and interdependent immunoregulatory effects of IL-27, IFN-ß, and IL-10 in the suppression of human Th17 cells and murine experimental autoimmune encephalomyelitis.

IFN-ß, IL-27, and IL-10 have been shown to exert a range of similar immunoregulatory effects in murine and human experimental systems, particularly in Th1- and Th17-mediated models of autoimmune inflammatory disease. In this study we sought to translate some of our previous findings in murine systems to human in vitro models and delineate the interdependence of these different cytokines in their immunoregulatory effects. We demonstrate that human IL-27 upregulates IL-10 in T cell-activated PBMC cultures and that IFN-ß drives IL-27 production in activated monocytes. IFN-ß-driven IL-27 is responsible for the upregulation of IL-10, but not IL-17 suppression, by IFN-ß in human PBMCs. Surprisingly, IL-10 is not required for the suppression of IL-17 by either IL-27 or IFN-ß in this model or in de novo differentiating Th17 cells, nor is IL-27 signaling required for the suppression of experimental autoimmune encephalomyelitis (EAE) by IFN-ß in vivo. Furthermore, and even more surprisingly, IL-10 is not required for the suppression of Th17-biased EAE by IL-27, in sharp contrast to Th1-biased EAE. In conclusion, IFN-ß and IL-27 both induce human IL-10, both suppress human Th17 responses, and both suppress murine EAE. However, IL-27 signaling is not required for the therapeutic effect of IFN-ß in EAE. Suppression of Th17-biased EAE by IL-27 is IL-10-independent, in contrast to its mechanism of action in Th1-biased EAE. Taken together, these findings delineate a complex set of interdependent and independent immunoregulatory mechanisms of IFN-ß, IL-27, and IL-10 in human experimental models and in murine Th1- and Th17-driven autoimmunity.

NMNAT1 mutations cause Leber congenital amaurosis.

Leber congenital amaurosis (LCA) is an infantile-onset form of inherited retinal degeneration characterized by severe vision loss(1,2). Two-thirds of LCA cases are caused by mutations in 17 known disease-associated genes(3) (Retinal Information Network (RetNet)). Using exome sequencing we identified a homozygous missense mutation (c.25G>A, p.Val9Met) in NMNAT1 that is likely to be disease causing in two siblings of a consanguineous Pakistani kindred affected by LCA. This mutation segregated with disease in the kindred, including in three other children with LCA. NMNAT1 resides in the previously identified LCA9 locus and encodes the nuclear isoform of nicotinamide mononucleotide adenylyltransferase, a rate-limiting enzyme in nicotinamide adenine dinucleotide (NAD(+)) biosynthesis(4,5). Functional studies showed that the p.Val9Met alteration decreased NMNAT1 enzyme activity. Sequencing NMNAT1 in 284 unrelated families with LCA identified 14 rare mutations in 13 additional affected individuals. These results are the first to link an NMNAT isoform to disease in humans and indicate that NMNAT1 mutations cause LCA.

Resveratrol neuroprotection in a chronic mouse model of multiple sclerosis.

Resveratrol is a naturally occurring polyphenol that activates SIRT1, an NAD-dependent deacetylase. SRT501, a pharmaceutical formulation of resveratrol with enhanced systemic absorption, prevents neuronal loss without suppressing inflammation in mice with relapsing experimental autoimmune encephalomyelitis (EAE), a model of multiple sclerosis (MS). In contrast, resveratrol has been reported to suppress inflammation in chronic EAE, although neuroprotective effects were not evaluated. The current studies examine potential neuroprotective and immunomodulatory effects of resveratrol in chronic EAE induced by immunization with myelin oligodendroglial glycoprotein peptide in C57/Bl6 mice. Effects of two distinct formulations of resveratrol administered daily orally were compared. Resveratrol delayed the onset of EAE compared to vehicle-treated EAE mice, but did not prevent or alter the phenotype of inflammation in spinal cords or optic nerves. Significant neuroprotective effects were observed, with higher numbers of retinal ganglion cells found in eyes of resveratrol-treated EAE mice with optic nerve inflammation. Results demonstrate that resveratrol prevents neuronal loss in this chronic demyelinating disease model, similar to its effects in relapsing EAE. Differences in immunosuppression compared with prior studies suggest that immunomodulatory effects may be limited and may depend on specific immunization parameters or timing of treatment. Importantly, neuroprotective effects can occur without immunosuppression, suggesting a potential additive benefit of resveratrol in combination with anti-inflammatory therapies for MS.

SIRT1 activating compounds reduce oxidative stress and prevent cell death in neuronal cells.

Activation of SIRT1, an NAD+-dependent deacetylase, prevents retinal ganglion cell (RGC) loss in optic neuritis, an inflammatory demyelinating optic nerve disease. While SIRT1 deacetylates numerous protein targets, downstream mechanisms of SIRT1 activation mediating this neuroprotective effect are unknown. SIRT1 increases mitochondrial function and reduces oxidative stress in muscle and other cells, and oxidative stress occurs in neuronal degeneration. We examined whether SIRT1 activators reduce oxidative stress and promote mitochondrial function in neuronal cells. Oxidative stress, marked by reactive oxygen species (ROS) accumulation, was induced in RGC-5 cells by serum deprivation, or addition of doxorubicin or hydrogen peroxide, and resulted in significant cell loss. SIRT1 activators resveratrol (RSV) and SRTAW04 reduced ROS levels and promoted cell survival in RGC-5 cells as well as primary RGC cultures. Effects were blocked by SIRT1 siRNA. SIRT1 activators also increased expression of succinate dehydrogenase (SDH), a mitochondrial enzyme, and promoted deacetylation of PGC-1α, a co-enzyme involved in mitochondrial function. Results show SIRT1 activators prevent cell loss by reducing oxidative stress and promoting mitochondrial function in a neuronal cell line. Results suggest SIRT1 activators can mediate neuroprotective effects during optic neuritis by these mechanisms, and they have the potential to preserve neurons in other neurodegenerative diseases that involve oxidative stress.

HOX genes in ovarian cancer.

The HOX genes are a family of homeodomain-containing transcription factors that determine cellular identity during development. Here we review a number of recent studies showing that HOX genes are strongly expressed in ovarian cancer, and that in some cases the expression of specific HOX genes is sufficient to confer a particular identity and phenotype upon cancer cells. We also review the recent advances in elucidating the different functions of HOX genes in ovarian cancer. A literature search was performed using the search terms HOX genes (including specific HOX genes), ovarian cancer and oncogenesis. Articles were accessed through searches performed in ISI Web of Knowledge, PubMed and ScienceDirect. Taken together, these studies have shown that HOX genes play a role in the oncogenesis of ovarian cancer and function in the inhibition of apoptosis, DNA repair and enhanced cell motility. The function of HOX genes in ovarian cancer oncogenesis supports their potential role as prognostic and diagnostic markers, and as therapeutic targets in this disease.