Examination of concordance between maternal and youth reports in the diagnosis of pediatric bipolar disorder

Objective:  While concordance between mother and child report continues to be the gold standard in the assessment of pediatric bipolar disorder, uncertainty develops when a mother's report is not endorsed by the youth. To this end we compared discordant (mother positive and youth negative) and concordant (mother and youth positive) cases.
Methods:  Subjects were 98 adolescents (12–19 years of age) derived from family studies of bipolar disorder in youth who had both self-reported and mother-reported assessments. Comparisons were made between discordant (n = 35) and concordant (n = 59) cases on a wide range of clinical correlates.
Results:  Mothers in both groups reported similar rates of symptoms of mania and depression. Within the concordant group, mothers and youth reported similar rates of symptoms of mania. There were no differences between the concordant and discordant groups in onset, duration, or impairment of mania, rates of psychiatric hospitalization, cognitive variables, or rates of disorders in family members.
Conclusions:  The similarities between discordant and concordant reports in symptomatology of mania and depression, rates of comorbidities, treatment needs, and other clinical correlates suggest that a mother-based diagnosis of mania should not be discounted in discrepant cases in which the youth fails to endorse the diagnosis.     

Animal models of chemotherapy-evoked painful peripheral neuropathies

This review examines recent preclinical research on toxic peripheral neuropathy and potential therapeutic developments. Chemotherapy-induced peripheral neurotoxicity is a major clinical problem because it represents the dose-limiting side effects of a significant number of antineoplastic drugs. Patients are unable to complete full or optimal treatment schedules. The incidence of chemotherapy-induced peripheral neuropathy varies depending on the drugs and schedules used, and this can be quite high, particularly when neurophysiological methods are used to make a diagnosis. However, even when chemotherapy-induced peripheral neuropathy is not a dose-limiting side effect, its onset may severely affect the quality of life of cancer patients and cause chronic discomfort. As such, improved understanding of the pathophysiology of chemotherapy-induced neurotoxicity need for animal models is clinically relevant and will assist in the development of future neuroprotective strategies and also in the design of novel chemotherapies with improved toxicity profiles. In this review, the features of animal models of chemotherapy-induced painful neuropathy developed for 20 years, due to the administration of the most widely used drugs, such as platinum drugs, taxanes, and vinca alkaloids, will be discussed. In a second part, data available on neuroprotectants and treatment strategies, evaluated using these previous animal models in the attempt to prevent neuropathic pain, will be summarized.     

Nck2 promotes human melanoma cell proliferation, migration and invasion in vitro and primary melanoma-derived tumor growth in vivo

Background

Nck1 and Nck2 adaptor proteins are involved in signaling pathways mediating proliferation, cytoskeleton organization and integrated stress response. Overexpression of Nck1 in fibroblasts has been shown to be oncogenic. Through the years this concept has been challenged and the consensus is now that overexpression of either Nck cooperates with strong oncogenes to transform cells. Therefore, variations in Nck expression levels in transformed cells could endorse cancer progression.

Methods

Expression of Nck1 and Nck2 proteins in various cancer cell lines at different stages of progression were analyzed by western blots. We created human primary melanoma cell lines overexpressing GFP-Nck2 and investigated their ability to proliferate along with metastatic characteristics such as migration and invasion. By western blot analysis, we compared levels of proteins phosphorylated on tyrosine as well as cadherins and integrins in human melanoma cells overexpressing or not Nck2. Finally, in mice we assessed tumor growth rate of human melanoma cells expressing increasing levels of Nck2.

Results

We found that expression of Nck2 is consistently increased in various metastatic cancer cell lines compared with primary counterparts. Particularly, we observed significant higher levels of Nck2 protein and mRNA, as opposed to no change in Nck1, in human metastatic melanoma cell lines compared with non-metastatic melanoma and normal melanocytes. We demonstrated the involvement of Nck2 in proliferation, migration and invasion in human melanoma cells. Moreover, we discovered that Nck2 overexpression in human primary melanoma cells correlates with higher levels of proteins phosphorylated on tyrosine residues, assembly of Nck2-dependent pY-proteins-containing molecular complexes and downregulation of cadherins and integrins. Importantly, we uncovered that injection of Nck2-overexpressing human primary melanoma cells into mice increases melanoma-derived tumor growth rate.

Conclusions

Collectively, our data indicate that Nck2 effectively influences human melanoma phenotype progression. At the molecular level, we propose that Nck2 in human primary melanoma promotes the formation of molecular complexes regulating proliferation and actin cytoskeleton dynamics by modulating kinases or phosphatases activities that results in increased levels of proteins phosphorylated on tyrosine residues. This study provides new insights regarding cancer progression that could impact on the therapeutic strategies targeting cancer.     

Multicenter assessment of ultrasound of the spermatic cord in children with acute scrotum

PURPOSE: Intravaginal or extravaginal spermatic cord torsion is a diagnostic challenge for the surgeon and radiologist. Color Doppler sonography can be inaccurate, leading to dangerous false-negative results. To date, no single reliable test has been able to provide 100% diagnostic accuracy. The direct visualization of the twisted cord during emergency high resolution ultrasonography has been proposed to avoid systematic and abusive surgical exploration. The aim of this multicenter study was to assess the validity and reproducibility of high resolution ultrasonography based management of acute scrotum in children. MATERIALS AND METHODS: A total of 919 patients from 11 European university hospitals underwent color Doppler sonography and high resolution ultrasonography for acute scrotum between 1992 and 2005. The spermatic cord was studied along its complete length to detect a spiral twist. The surgical findings were correlated with the preoperative results. RESULTS: A total of 208 patients had spermatic cord torsion proved at surgery. Intratesticular vascularization was absent in the affected testis in only 158 cases (76%). In contrast, high resolution ultrasonography detected the twist as a snail shell-shaped mass, measuring 7 to 33 mm, in 199 patients (96%). High resolution ultrasonography revealed a linear cord for all other causes of acute scrotum (711 patients) with a specificity of 99%. The radiologist training level was the best predictive factor of high resolution ultrasonography reliability (p <0.05). CONCLUSIONS: High resolution ultrasonography based management of acute scrotum is reliable and reproducible. Thanks to its high sensitivity and specificity for the diagnosis of spermatic cord torsion, high resolution ultrasonography can significantly improve the management of acute scrotum in children.     

Clinical heterogeneity of NADSYN1-associated VCRL syndrome

The NADSYN1 gene [MIM*608285] encodes the NAD synthetase 1 enzyme involved in the final step of NAD biosynthesis, crucial for cell metabolism and organ embryogenesis. Perturbating the role of NAD biosynthesis results in the association of vertebral, cardiac, renal, and limb anomalies (VCRL). This condition was initially characterized as severe with perinatal lethality or developmental delay and complex malformations in alive cases. Sixteen NADSYN1-associated patients have been published so far. This study illustrates the wide phenotypic variability in NADSYN1-associated NAD deficiency disorder. We report the clinical and molecular findings in three novel cases, two of them being siblings with the same homozygous variant and presenting with either a very severe prenatal lethal or a mild phenotypic form. In addition to an exhaustive literature, we validate the expansion of the spectrum of NAD deficiency disorder. Our findings indicate that NAD deficiency disorder should be suspected not only in the presence of the full spectrum of VCRL, but even a single of the aforementioned organs is affected. Decreased plasmatic levels of NAD should then strongly encourage the screening for any of the genes responsible for a NAD deficiency disorder.     

Meriolins, a new class of cell death inducing kinase inhibitors with enhanced selectivity for cyclin-dependent kinases

Protein kinases represent promising anticancer drug targets. We describe here the meriolins, a new family of inhibitors of cyclin-dependent kinases (CDK). Meriolins represent a chemical structural hybrid between meridianins and variolins, two families of kinase inhibitors extracted from various marine invertebrates. Variolin B is currently in preclinical evaluation as an antitumor agent. A selectivity study done on 32 kinases showed that, compared with variolin B, meriolins display enhanced specificity toward CDKs, with marked potency on CDK2 and CDK9. The structures of pCDK2/cyclin A/variolin B and pCDK2/cyclin A/meriolin 3 complexes reveal that the two inhibitors bind within the ATP binding site of the kinase, but in different orientations. Meriolins display better antiproliferative and proapoptotic properties in human tumor cell cultures than their parent molecules, meridianins and variolins. Phosphorylation at CDK1, CDK4, and CDK9 sites on, respectively, protein phosphatase 1alpha, retinoblastoma protein, and RNA polymerase II is inhibited in neuroblastoma SH-SY5Y cells exposed to meriolins. Apoptosis triggered by meriolins is accompanied by rapid Mcl-1 down-regulation, cytochrome c release, and activation of caspases. Meriolin 3 potently inhibits tumor growth in two mouse xenograft cancer models, namely, Ewing's sarcoma and LS174T colorectal carcinoma. Meriolins thus constitute a new CDK inhibitory scaffold, with promising antitumor activity, derived from molecules initially isolated from marine organisms.