Suppression of toxicity of the mutant huntingtin protein by its interacting compound,desonide

Identifying inhibitors of pathogenic proteins is the major strategy of targeted drug discoveries. This strategy meets challenges in targeting neurodegenerative disorders such as Huntington’s disease (HD), which is mainly caused by the mutant huntingtin protein (mHTT), an “undruggable” pathogenic protein with unknown functions. We hypothesized that some of the chemical binders of mHTT may change its conformation and/or stability to suppress its downstream toxicity, functioning similarly to an “inhibitor” under a broader definition. We identified 21 potential mHTT selective binders through a small-molecule microarray–based screening. We further tested these compounds using secondary phenotypic screens for their effects on mHTT-induced toxicity and revealed four potential mHTT-binding compounds that may rescue HD-relevant phenotypes. Among them, a Food and Drug Administration–approved drug, desonide, was capable of suppressing mHTT toxicity in HD cellular and animal models by destabilizing mHTT through enhancing its polyubiquitination at the K6 site. Our study reveals the therapeutic potential of desonide for HD treatment and provides the proof of principle for a drug discovery pipeline: target-binder screens followed by phenotypic validation and mechanistic studies.

Most neurodegenerative disorders share the common hallmark of the accumulation of misfolded proteins, such as the mutant HTT protein (mHTT) with the expanded polyglutamine (polyQ) stretch, which is the major cause of Huntington’s disease (HD) (1). The wild-type HTT protein (wtHTT) may function as a scaffold protein (2), whereas the exact etiology about how mHTT causes HD is unclear, making mHTT an “undruggable” target due to a lack of measurable biochemical readout and “druggable” pockets (binding pockets whose occupancy influences mHTT biochemical functions). As a result, it is believed to be impossible to screen for “inhibitors” of mHTT as potential HD drug candidates.On the other hand, compounds that bind to mHTT directly may influence its protein structure and, consequently, alter its stability and/or pathogenic functions despite a lack of druggable pockets. In addition, while the exact pathogenic mechanism is unclear, the ultimate functional outcome of mHTT at the cellular level is cytotoxicity, which is measurable in a high-throughput compatible manner. Thus, we may screen for mHTT-binding compounds and then perform secondary phenotypic screens for suppressors of mHTT-induced toxicity. The identified hit compounds may suppress mHTT toxicity by interacting with it directly, providing potential therapeutic leads as well as chemical biology tools to explore HD pathological mechanisms.In this study, we identified four compounds with such desired properties by these screening strategies. In addition, we performed a counter-screen using the wtHTT to identify the allele-selective binding compounds that interact with mHTT but not wtHTT. Among the hit compounds, desonide, a Food and Drug Administration (FDA)-approved drug for atopic dermatitis (3) and a low-potency topical corticosteroid (4), exhibited robust rescue effects of HD-relevant phenotypes in cells and in vivo in a knockin mouse model, and we further explored the mechanism of action of desonide as well as its therapeutic potential.     

The intracoronary infusion of superoxide dismutase during the initial liberation of oxygen free radicals induced by reperfusion. The effect on the infarct size after 60 minutes of coronary occlusion in the pig model]

The role of oxygen free radicals (OFR) generated early during myocardial reperfusion in the genesis of myocardial necrosis was studied in 26 pigs submitted to transient coronary occlusion followed by one of three different reperfusion protocols. In group A, a selective intracoronary infusion of a Ringer solution was started after 60 min of coronary occlusion, and reperfusion was performed 4 min later. The infusion was maintained during the first 6 min of reperfusion at a rate of 3 ml/min. In group B, the Ringer solution administered during reperfusion contained a high concentration (2.778 U/ml) of superoxide dismutase (SOD). In group C, reperfusion was performed after 60 min of coronary occlusion with no intracoronary infusion. Twenty-four hours later the heart was excised and the area at risk and infarct size were measured by in vivo fluorescein injection and triphenyl-tetrazolium chloride staining respectively. The area at risk was similar in the 3 groups: 15.03 +/- 2.6%, 13.26 +/- 3.3% and 16.34 +/- 6.7% of ventricular mass in groups A, B, and C, respectively (p = 0.42). No differences between groups were observed in infarct size, either when measured as a percent of ventricular mass (10.04 +/- 3.8%, 9.31 +/- 3.8% and 10.1 +/- 2.4% in groups A, B, and C, p = 0.91) or as a percent of the area at risk (64.63 +/- 18.5%, 67.81 +/- 16.1%, and 61.35 +/- 6.7%, respectively, p = 0.72). Thus, the intracoronary administration of SOD during the early reperfusion has not beneficial effect on infarct size. This results suggest that the early burst of OFR is not a major determinant of infarct size in the pig.     

Decline of outpatient asthma management in Argentina

Background and objectives:   To assess management of adult patients admitted with acute asthma and compare the results obtained with a similar study 5 years earlier.
Methods:   A cross-sectional survey of 211 consecutive patients admitted to hospital during a 12-month period was conducted. Patients were surveyed using a validated management questionnaire and the results compared with those of the previous survey.
Results:   There were 211 patients in the present survey and patient demographics were similar in both populations studied. Comparison of the previous to the current survey showed significant differences in predicted FEV₁% at admission (30.2 ± 10.7 vs 23.9 ± 8.9, respectively, P  < 0.001), and the average number of hospital admissions in the year prior to the survey (0.7 ± 1.2 vs 1.3 ± 0.7, P  < 0.0001). In the present survey, more patients changed their medication after acute exacerbation and more received an action plan. Compared with the previous survey, there were no significant differences between the mean number of emergency department visits, need for mechanical ventilation, number of patients prescribed inhaled corticosteroids and other related variables.
Conclusion:   Compared with the previous study the severity of asthma at the time of admission was worse. Some of the recommended international asthma management programmes appear to have been followed.     

Assessment and therapeutic guideline of intermediate coronary lesions in the catheterization laboratory

Contrast angiography has been used for nearly five decades to evaluate the severity of coronary lesions. However, when attempting to distinguish between intermediate coronary lesions able or unable to produce ischemia, the technique has several limitations. A large number of patients undergo cardiac catheterization without prior evaluation of coronary perfusion by non-invasive tests. This number is likely to increase in the coming years, because current recommendations favor the invasive treatment of acute coronary syndromes. This has triggered marked interest in new diagnostic techniques capable of assessing the physiological significance of intermediate lesions in the catheterization room. This paper reviews the different techniques currently available for scientifically assessing the significance of such lesions. The advantages and limitations of each are discussed.     

Richardson score predicts short-term adverse respiratory outcomes in newborns >/=34 weeks gestation

OBJECTIVES: To develop a model to predict which newborns >/=34 weeks gestation with respiratory distress will die or will require prolonged (>3 days) assisted ventilation. METHODS: Retrospective cohort study using data from Northern California newborns >/=34 weeks gestation who presented with respiratory distress. We split the cohort into derivation and validation datasets. Bivariate and multivariate data analyses were performed on the derivation dataset. After developing a simple score on the derivation dataset, we applied it to the original as well as to a second validation dataset from Massachusetts. RESULTS: Of 2276 babies who met our initial eligibility criteria, 203 (9.3%) had the primary study outcome (assisted ventilation >3 days or death). A simple score based on gestational age, the lowest PaO 2 /FIO 2 , a variable combining lowest pH and highest PaCO 2 , and the lowest mean arterial blood pressure had excellent performance, with a c-statistic of 0.85 in the derivation dataset, 0.80 in the validation dataset, and 0.80 in the secondary validation dataset. CONCLUSIONS: A simple objective score based on routinely collected physiologic predictors can predict respiratory outcomes in infants >/=34 weeks gestation with respiratory distress.