The effect of divalent cations on neuronal nitric oxide synthase activity.

Neuronal nitric oxide synthase (NOS I) is a Ca(2+)/calmodulin-binding enzyme that generates nitric oxide (NO*) and L-citrulline from the oxidation of L-arginine, and superoxide (O(2)*(-)) from the one-electron reduction of oxygen (O(2)). Nitric oxide in particular has been implicated in many physiological processes, including vasodilator tone, hypertension, and the development and properties of neuronal function. Unlike Ca(2+), which is tightly regulated in the cell, many other divalent cations are unfettered and can compete for the four Ca(2+) binding sites on calmodulin. The results presented in this article survey the effects of various divalent metal ions on NOS I-mediated catalysis. As in the case of Ca(2+), we demonstrate that Ni(2+), Ba(2+), and Mn(2+) can activate NOS I to metabolize L-arginine to L-citrulline and NO*, and afford O(2)*(-) in the absence of L-arginine. In contrast, Cd(2+) did not activate NOS I to produce either NO* or O(2)*(-), and the combination of Ca(2+) and either Cd(2+), Ni(2+), or Mn(2+) inhibited enzyme activity. These interactions may initiate cellular toxicity by negatively affecting NOS I activity through production of NO*, O(2)*(-) and products derived from these free radicals.     

Molecular mechanisms of platinum resistance: still searching for the Achilles' heel.

The platinum compounds cisplatin and carboplatin are commonly used in cancer chemotherapy. However, tumors frequently develop resistance to these compounds, significantly decreasing their usefulness in the clinic. In the past few years, basic research has unraveled novel and unexpected mechanisms for the development of platinum resistance. For example, it has been reported that MUC1 expression and particularly the localization of its C-terminal subunit to the mitochondria may affect cisplatin resistance. Another recent finding suggests that cisplatin damage may activate DNA-dependent protein kinase (DNA-PK) to initiate a death signal that can be transmitted to neighboring cells through gap junctions, adding to a growing belief that the interactions of cancer cells with their surroundings may be important to the outcome of chemotherapy. While most clinical efforts have focused on identifying alternative regimens for drug-resistant cancer, it might be possible to exploit our knowledge of the mechanism of platinum resistance to specifically reverse resistance and increase platinum efficacy. The strategy of drug resistance reversal therapy (DRRT) may have significant impact on our approaches to the treatment and management of drug-resistant tumors.     

Motivation in pediatric motor rehabilitation: A systematic search of the literature using the self-determination theory as a conceptual framework

Objective: Motivation is suggested as an important factor in pediatric motor rehabilitation. Therefore, we reviewed the existing evidence of (motivational) motor rehabilitation paradigms, and how motivation influences rehabilitation outcome using self-determination theory as conceptual framework. Methods: PubMed and Web-of-Science databases were systematically searched until June 2015. Data were independently extracted and critiqued for quality by three authors. Studies reporting motivational aspects were included. Most studies examined new technology (e.g., virtual reality [VR]). Results: Out of 479 records, three RCT, six case-control, and six non-comparative studies were included with mixed quality. Motivation was rarely reported. Training individualization to the child’s capabilities with more variety seemed promising to increase motivation. Motivation increased when the exercises seemed helpful for daily activities. Conclusions: Motivation in pediatric rehabilitation should be comprehensively assessed within a theoretical framework as there are indications that motivated children have better rehabilitation outcomes, depending on the aspect of motivation.     

Facteurs pronostiques en insémination avec sperme de donneur : suivi rétrospectif d’une cohorte de 188 patientes

ObjectivesImproving our practice by a constant evaluation is essential in the field of donor semen insemination (DI). Our center examined the prognosis factors for DI success in order to standardize patient treatment options.Patients and methodsWe retrospectively analysed all couples referred for DI from January 2000 till December 2010.ResultsWe analysed 551 cycles among 188 patients. Pregnancy rate by stimulation cycle was 19,8% with birth rate of 16.7%. The rate of pregnancy was improved till the fourth trial then plateau. On a patient-based analysis, success factors were age (P = 0.04), previous successful DSI (P = 0.02), and no previous failure of an ICSI-C (P = 0.035). On a cycle-based analysis, success factors were the number of follicles greater than 15 mm (P = 0.04) and than 18 mm (P = 0.001). The percentage of 68.1 patients obtained a child by IVF-D after a failed DI.ConclusionThere are two predictive factors for DI success: the age of the patient and the number of mature follicles. It seems accurate to referred patients to IVF-D after four unsuccessful cycles of DSI. This recommendation may be adapted according to patient's age and hormonal evaluation.     

Targeting the “Cytokine Storm” for Therapeutic Benefit

Inflammation is the body''s first line of defense against infection or injury, responding to challenges by activating innate and adaptive responses. Microbes have evolved a diverse range of strategies to avoid triggering inflammatory responses. However, some pathogens, such as the influenza virus and the Gram-negative bacterium Francisella tularensis, do trigger life-threatening “cytokine storms” in the host which can result in significant pathology and ultimately death. For these diseases, it has been proposed that downregulating inflammatory immune responses may improve outcome. We review some of the current candidates for treatment of cytokine storms which may prove useful in the clinic in the future and compare them to more traditional therapeutic candidates that target the pathogen rather than the host response.     

Stability of monoclonal antibodies after simulated subcutaneous administration

Changes in the environment from the drug product to the human physiology might lead to physical and/or chemical modifications of the protein drug, such as in vivo aggregation and fragmentation. Although subcutaneous (SC) injection is a common route of administration for therapeutic proteins, knowledge on in vivo stability in the SC tissue is limited. In this study, we developed a physiologic in vitro model simulating the SC environment in patients. We assessed the stability of two monoclonal antibodies (mAbs) in four different protein-free fluids under physiologic conditions. We monitored protein stability over two weeks using a range of analytical methods, in analogy to testing purposes of a drug product. Both mAbs showed an increase of protein aggregates, fragments, and acidic species. mAb1 was consistently more stable in this in vitro model than mAb2, highlighting the importance of comparing the stability of different mAbs under physiologic conditions. Throughout the study, both mAbs were substantially less stable in bicarbonate buffers as compared to phosphate-buffered saline. In summary, our developed model was able to differentiate stability between molecules. Bicarbonate buffers were more suitable compared to phosphate-buffered saline in regards to simulating the in vivo conditions and evaluating protein liabilities.     

Treating Fragile X syndrome with the diuretic bumetanide: a case report

We report that daily administration of the diuretic NKCC1 chloride co‐transporter, bumetanide, reduces the severity of autism in a 10‐year‐old Fragile X boy using CARS, ADOS, ABC, RDEG and RRB before and after treatment. In keeping with extensive clinical use of this diuretic, the only side effect was a small hypokalaemia. A double‐blind clinical trial is warranted to test the efficacy of bumetanide in FRX. Conclusion: This single case report showed an improvement of the scores of each test used after 3 months of treatment. Double‐blind clinical trials are warranted to test the efficacy of bumetanide in FRX.