Is the Addition of a Topical Agent to Narrowband UVB Treatment More Effective in Treating Male and Female Adults With Psoriasis Than Narrowband Treatment Alone?

OBJECTIVE: The objective of this selective EBM review is to determine whether or not the addition of a topical agent to narrowband UVB treatment is more effective in treating adults with psoriasis than narrowband UVB treatment alone. STUDY DESIGN: Review of three English language primary randomized trials that were published between 2003 and 2012. DATA SOURCES: A randomized left-right comparison, placebo controlled clinical trial, a randomized trial, and a randomized placebo controlled, blinded clinical trial each comparing the addition of a topical agent to narrowband UVB treatment to narrowband UVB treatment alone were found using PubMed and Cochrane databases. OUTCOMES MEASURED: The outcomes were measured by a single investigator in each trial by analyzing the improvement of the lesions based on the induration size, redness, and scaliness using Psoriasis Area and Severity Index (PASI) and Psoriasis Severity Index (PSI) scores. RESULTS: The results of these trials indicate that the addition of a topical agent to narrowband UVB can be effective in treating psoriasis. The Ehsani et al study concluded that while the use of 8MOP resulted in a greater score decrease, the decrease between groups was not significant. The Woo et al study concluded that while the difference in PASI scores between the groups was not significant, the active group using calcipotriol for psoriasis received less UVB. The Ozkan et al study concluded that the group treated with calcipotriol had statistically significant improvement compared to UVB monotherapy. CONCLUSIONS: The results indicate that the addition of a topical agent to UVB therapy for adults with psoriasis is just as effective as NBUVB alone. While the use of 8MOP didn’t produce statistically significant results, the trials that used calcipotriol had favorable outcomes. The Woo et al study concluded that calcipotriol may produce UVB enhancing effects resulting in less cumulative UVB exposure. The Ozkan study concluded that the addition of calcipotriol to UVB phototherapy is more effective and efficient in treating the lesions. Further study is warranted to evaluate the use of calcipotriol and NBUVB phototherapy for the treatment of psoriasis

Protecting Children from Overexposure to Lead in Candy and Protecting Children by Lowering the Blood Lead “Level of Concern” Standard

The American Public Health Association: Recognizing that in April 2004, the Orange County Register in an investigative report, published for the first time information that the state of California had been testing for lead in candies for decades but had not informed the public about the high lead levels in many candies, candy wrappers and seasonings (sold as a snack item and consumed as candy) imported from Mexico, the Philippines and other countries

Optic nerve crush induces spatial and temporal gene expression patterns in retina and optic nerve of BALB/cJ mice

BACKGROUND: Central nervous system (CNS) trauma and neurodegenerative disorders trigger a cascade of cellular and molecular events resulting in neuronal apoptosis and regenerative failure. The pathogenic mechanisms and gene expression changes associated with these detrimental events can be effectively studied using a rodent optic nerve crush (ONC) model. The purpose of this study was to use a mouse ONC model to: (a) evaluate changes in retina and optic nerve (ON) gene expression, (b) identify neurodegenerative pathogenic pathways and (c) discover potential new therapeutic targets. RESULTS: Only 54% of total neurons survived in the ganglion cell layer (GCL) 28 days post crush. Using Bayesian Estimation of Temporal Regulation (BETR) gene expression analysis, we identified significantly altered expression of 1,723 and 2,110 genes in the retina and ON, respectively. Meta-analysis of altered gene expression (≥1.5, ≤-1.5, p < 0.05) using Partek and DAVID demonstrated 28 up and 20 down-regulated retinal gene clusters and 57 up and 41 down-regulated optic nerve clusters. Regulated gene clusters included regenerative change, synaptic plasticity, axonogenesis, neuron projection, and neuron differentiation. Expression of selected genes (Vsnl1, Syt1, Synpr and Nrn1) from retinal and ON neuronal clusters were quantitatively and qualitatively examined for their relation to axonal neurodegeneration by immunohistochemistry and qRT-PCR. CONCLUSION: A number of detrimental gene expression changes occur that contribute to trauma-induced neurodegeneration after injury to ON axons. Nrn1 (synaptic plasticity gene), Synpr and Syt1 (synaptic vesicle fusion genes), and Vsnl1 (neuron differentiation associated gene) were a few of the potentially unique genes identified that were down-regulated spatially and temporally in our rodent ONC model. Bioinformatic meta-analysis identified significant tissue-specific and time-dependent gene clusters associated with regenerative changes, synaptic plasticity, axonogenesis, neuron projection, and neuron differentiation. These ONC induced neuronal loss and regenerative failure associated clusters can be extrapolated to changes occurring in other forms of CNS trauma or in clinical neurodegenerative pathological settings. In conclusion, this study identified potential therapeutic targets to address two key mechanisms of CNS trauma and neurodegeneration: neuronal loss and regenerative failure

Existence of God: Antithetical Themes in “Dr. Faustus” and “Waiting for Godot”

This paper is about the antithetical themes regarding the existence of God in two plays “Doctor Faustus” by Christopher Marlow and “Waiting for Godot” by Samuel Backett. Both the plays represent two different ages and religious orientations. The former is a tragedy of a doctor of philosophy who pledges his soul with the Devil for the sake of attaining the power of necromancy in a flagrant disregard to God’s commandments and is damned to hellfire whereas the latter is tragicomedy that projects meaninglessness of life through characters questioning the very significance of God’s existence. Hence it is presumed that heterogeneous themes running parallel to each other might arouse different emotions in the reader. In order to examine whether such opposing themes in two different dramas exist or not, textual excerpts were analyzed, literature was reviewed, critics views were collected, and opinion of the experts in teaching literature were gathered. Finally, it is concluded that both the plays do have themes which run into opposite directions regarding the existence of God leading to the arousal of unlike emotions

Reduced contextually induced muscle thermogenesis in rats with calorie restriction and lower aerobic fitness but not monogenic obesity

We have previously identified predator odor as a potent stimulus activating thermogenesis in skeletal muscle in rats. As this may prove relevant for energy balance and weight loss, the current study investigated whether skeletal muscle thermogenesis was altered with negative energy balance, obesity propensity seen in association with low intrinsic aerobic fitness, and monogenic obesity. First, weight loss subsequent to three weeks of 50% calorie restriction suppressed the muscle thermogenic response to predator odor. Next, we compared rats bred based on artificial selection for intrinsic aerobic fitness—high- and low-capacity runners (HCR, LCR)—that display robust leanness and obesity propensity, respectively. Aerobically fit HCR showed enhanced predator odor-induced muscle thermogenesis relative to the less-fit LCR. This contrasted with the profound monogenic obesity displayed by rats homozygous for a loss of function mutation in Melanocortin 4 receptor (Mc4rK314X/K314X rats), which showed no discernable deficit in thermogenesis. Taken together, these data imply that body size or obesity per se are not associated with deficient muscle thermogenesis. Rather, the physiological phenotype associated with polygenic obesity propensity may encompass pleiotropic mechanisms in the thermogenic pathway. Adaptive thermogenesis associated with weight loss also likely alters muscle thermogenic mechanisms.</p

AltitudeOmics: Red Blood Cell metabolic adaptation to high altitude hypoxia

Red blood cells (RBCs) are key players in systemic oxygen transport. RBCs respond to in vitro hypoxia  through  the so-called  oxygen-dependent  metabolic  regulation,  which  involves  the competitive  binding  of  deoxyhemoglobin  and  glycolytic  enzymes  to  the  N-terminal  cytosolic domain  of  band  3.  This  mechanism  promotes  the  accumulation  of  2,3-DPG,  stabilizing  the deoxygenated state of hemoglobin, and cytosol acidification, triggering oxygen off-loading through the  Bohr  effect.  Despite  in  vitro  studies,  in  vivo adaptations  to  hypoxia  have  not  yet  been completely elucidated. Within  the  framework  of  the AltitudeOmics  study,  erythrocytes  were  collected  from  21 healthy volunteers at sea level, after exposure to high altitude (5260m) for 1, 7 and 16days, and following  reascent  after  7days  at 1525m.  UHPLC-MS  metabolomics  results  were  correlated  to physiological and athletic performance parameters. Immediate  metabolic  adaptations  were  noted as early as a few hours from ascending  to >5000m, and maintained for 16 days at high altitude.  Consistent with the mechanisms elucidated in vitro, hypoxia promoted glycolysis and deregulated the pentose phosphate pathway, as well purine catabolism, glutathione homeostasis, arginine/nitric oxide and sulphur/H2S metabolism. Metabolic adaptations were preserved one week after descent, consistently with improved physical performances in comparison to the first ascendance, suggesting a mechanism of metabolic memory

A computational model predicts adjunctive pharmacotherapy for cardiac safety via selective inhibition of the late cardiac Na current

[EN] Background: The QT interval is a phase of the cardiac cycle that corresponds to action potential duration (APD) including cellular repolarization (T-wave). In both clinical and experimental settings, prolongation of the QT interval of the electrocardiogram (ECG) and related proarrhythmia have been so strongly associated that a prolonged QT interval is largely accepted as surrogate marker for proarrhythmia. Accordingly, drugs that prolong the QT interval are not considered for further preclinical development resulting in removal of many promising drugs from development. While reduction of drug interactions with hERG is an important goal, there are promising means to mitigate hERG block. Here, we examine one possibility and test the hypothesis that selective inhibition of the cardiac late Na current (I-NaL) by the novel compound GS-458967 can suppress proarrhythmic markers. Methods and results: New experimental data has been used to calibrate INaL in the Soltis-Saucerman computationally based model of the rabbit ventricular action potential to study effects of GS-458967 on INaL during the rabbit ventricular AP. We have also carried out systematic in silico tests to determine if targeted block of INaL would suppress proarrhythmia markers in ventricular myocytes described by TRIaD: Triangulation, Reverse use dependence, beat-to-beat Instability of action potential duration, and temporal and spatial action potential duration Dispersion. Conclusions: Our computer modeling approach based on experimental data, yields results that suggest that selective inhibition of INaL modifies all TRIaD related parameters arising from acquired Long-QT Syndrome, and thereby reduced arrhythmia risk. This study reveals the potential for adjunctive pharmacotherapy via targeted block of INaL to mitigate proarrhythmia risk for drugs with significant but unintended off-target hERG blocking effects.The National Institutes of Health R01 HL128537-01 (CEC), U01 HL126273-01 (CEC) and R01HL128170-02 (CEC).Yang, P.; El-Bizri, N.; Romero Pérez, L.; Giles, W.; Rajamani, S.; Belardinelli, L.; Clancy, CE. (2016). A computational model predicts adjunctive pharmacotherapy for cardiac safety via selective inhibition of the late cardiac Na current. Journal of Molecular and Cellular Cardiology. 99:151-161. https://doi.org/10.1016/j.yjmcc.2016.08.011S1511619

Feasibility of achieving the 2025 WHO global tuberculosis targets in South Africa, China, and India: a combined analysis of 11 mathematical models.

BACKGROUND: The post-2015 End TB Strategy proposes targets of 50% reduction in tuberculosis incidence and 75% reduction in mortality from tuberculosis by 2025. We aimed to assess whether these targets are feasible in three high-burden countries with contrasting epidemiology and previous programmatic achievements. METHODS: 11 independently developed mathematical models of tuberculosis transmission projected the epidemiological impact of currently available tuberculosis interventions for prevention, diagnosis, and treatment in China, India, and South Africa. Models were calibrated with data on tuberculosis incidence and mortality in 2012. Representatives from national tuberculosis programmes and the advocacy community provided distinct country-specific intervention scenarios, which included screening for symptoms, active case finding, and preventive therapy. FINDINGS: Aggressive scale-up of any single intervention scenario could not achieve the post-2015 End TB Strategy targets in any country. However, the models projected that, in the South Africa national tuberculosis programme scenario, a combination of continuous isoniazid preventive therapy for individuals on antiretroviral therapy, expanded facility-based screening for symptoms of tuberculosis at health centres, and improved tuberculosis care could achieve a 55% reduction in incidence (range 31-62%) and a 72% reduction in mortality (range 64-82%) compared with 2015 levels. For India, and particularly for China, full scale-up of all interventions in tuberculosis-programme performance fell short of the 2025 targets, despite preventing a cumulative 3·4 million cases. The advocacy scenarios illustrated the high impact of detecting and treating latent tuberculosis. INTERPRETATION: Major reductions in tuberculosis burden seem possible with current interventions. However, additional interventions, adapted to country-specific tuberculosis epidemiology and health systems, are needed to reach the post-2015 End TB Strategy targets at country level. FUNDING: Bill and Melinda Gates Foundation