Strategies to avoid the loss of developmental potential in more than 200 million children in the developing world

This paper is the third in the Child Development Series. The first paper showed that more than 200 million children under 5 years of age in developing countries do not reach their developmental potential. The second paper identified four well-documented risks: stunting, iodine deficiency, iron deficiency anaemia, and inadequate cognitive stimulation, plus four potential risks based on epidemiological evidence: maternal depression, violence exposure, environmental contamination, and malaria. This paper assesses strategies to promote child development and to prevent or ameliorate the loss of developmental potential. The most effective early child development programmes provide direct learning experiences to children and families, are targeted toward younger and disadvantaged children, are of longer duration, high quality, and high intensity, and are integrated with family support, health, nutrition, or educational systems and services. Despite convincing evidence, programme coverage is low. To achieve the Millennium Development Goals of reducing poverty and ensuring primary school completion for both girls and boys, governments and civil society should consider expanding high quality, cost-effective early child development programmes.     

Statins and fenofibrate affect skeletal muscle chloride conductance in rats by differently impairing ClC-1 channel regulation and expression

Background and purpose:

Statins and fibrates can produce mild to life-threatening skeletal muscle damage. Resting chloride channel conductance (gCl), carried by the ClC-1 channel, is reduced in muscles of rats chronically treated with fluvastatin, atorvastatin or fenofibrate, along with increased resting cytosolic calcium in statin-treated rats. A high gCl, controlled by the Ca²⁺-dependent protein kinase C (PKC), maintains sarcolemma electrical stability and its reduction alters muscle function. Here, we investigated how statins and fenofibrate impaired gCl.

Experimental approach:

In rats treated with fluvastatin, atorvastatin or fenofibrate, we examined the involvement of PKC in gCl reduction by the two intracellular microelectrodes technique and ClC-1 mRNA level by quantitative real time-polymerase chain reaction. Direct drug effects were tested by patch clamp analysis on human ClC-1 channels expressed in human embryonic kidney (HEK) 293 cells.

Key results:

Chelerythrine, a PKC inhibitor, applied in vitro on muscle dissected from atorvastatin-treated rats fully restored gCl, suggesting the involvement of this enzyme in statin action. Chelerythrine partially restored gCl in muscles from fluvastatin-treated rats but not in those from fenofibrate-treated rats, implying additional mechanisms for gCl impairment. Accordingly, a decrease of ClC-1 channel mRNA was found in both fluvastatin-and fenofibrate-treated rat muscles. Fenofibric acid, the in vivo metabolite of fenofibrate, but not fluvastatin, rapidly reduced chloride currents in HEK 293 cells.

Conclusions and implications:

Our data suggest multiple mechanisms underlie the effect of statins and fenofibrate on ClC-1 channel conductance. While statins promote Ca²⁺-mediated PKC activation, fenofibrate directly inhibits ClC-1 channels and both fluvastatin and fenofibrate impair expression of mRNA for ClC-1.     

A word of caution: Early failure of Magmaris® bioresorbable stent after pulmonary artery stenting

Bioresorbable scaffolds (BRS) have been advocated as the fourth revolution in interventional cardiology medical devices with promising technology to improve the treatment of coronary artery disease with an event-free future. We describe the first reported use and early collapse of the Magmaris® Resorbable Magnesium Scaffold (RMS) stent (BIOTRONIK AG, Switzerland) to relieve left pulmonary artery severe stenosis in a newborn after the Norwood procedure. The stent collapse was detected 2 weeks after implantation and urgently treated with a balloon-expandable stent. This complication raises the alarm about the need to keep implanted RMS under scrutiny. The possibility of faster scaffold resorption in small babies or lack of sufficient radial force of RMS to resist acute vessel recoil has led to ineffective relief of branch pulmonary artery stenosis and failure to enable a safe short-term bridge to Stage II palliation.     

Mutation spectrum and genotype-phenotype analyses in Cowden disease and Bannayan-Zonana syndrome, two hamartoma syndromes with germline PTEN mutation

The tumour suppressor gene PTEN , which maps to 10q23.3 and encodes a 403 amino acid dual specificity phosphatase (protein tyrosine phosphatase; PTPase), was shown recently to play a broad role in human malignancy. Somatic PTEN deletions and mutations were observed in sporadic breast, brain, prostate and kidney cancer cell lines and in several primary tumours such as endometrial carcinomas, malignant melanoma and thyroid tumours. In addition, PTEN was identified as the susceptibility gene for two hamartoma syndromes: Cowden disease (CD; MIM 158350) and Bannayan-Zonana (BZS) or Ruvalcaba-Riley-Smith syndrome (MIM 153480). Constitutive DNA from 37 CD families and seven BZS families was screened for germline PTEN mutations. PTEN mutations were identified in 30 of 37 (81%) CD families, including missense and nonsense point mutations, deletions, insertions, a deletion/insertion and splice site mutations. These mutations were scattered over the entire length of PTEN , with the exception of the first, fourth and last exons. A 'hot spot' for PTEN mutation in CD was identified in exon 5 that contains the PTPase core motif, with 13 of 30 (43%) CD mutations identified in this exon. Seven of 30 (23%) were within the core motif, the majority (five of seven) of which were missense mutations, possibly pointing to the functional significance of this region. Germline PTEN mutations were identified in four of seven (57%) BZS families studied. Interestingly, none of these mutations was observed in the PTPase core motif. It is also worthy of note that a single nonsense point mutation, R233X, was observed in the germline DNA from two unrelated CD families and one BZS family. Genotype-phenotype studies were not performed on this small group of BZS families. However, genotype-phenotype analysis inthe group of CD families revealed two possible associations worthy of follow-up in independent analyses. The first was an association noted in the group of CD families with breast disease. A correlation was observed between the presence/absence of a PTEN mutation and the type of breast involvement (unaffected versus benign versus malignant). Specifically and more directly, an association was also observed between the presence of a PTEN mutation and malignant breast disease. Secondly, there appeared to be an interdependent association between mutations upstream and within the PTPase core motif, the core motif containing the majority of missense mutations, and the involvement of all major organ systems (central nervous system, thyroid, breast, skin and gastrointestinal tract). However, these observations would need to be confirmed by studying a larger number of CD families.      

Factors predicting patient perception of dysphonia caused by benign vocal fold lesions

OBJECTIVES/HYPOTHESIS: To assess factors that may be predictive of patient perception of dysphonia severity, as quantified by the Voice Handicap Index (VHI) score. We hypothesize that 1) level of vocal demand; 2) auditory-perceptual evaluation of dysphonia severity; and 3) vocal function, as defined by phonatory glottal closure and mucosal wave vibration, are the most significant predictors of VHI score. STUDY DESIGN:: Retrospective review of 100 patients with benign vocal fold lesions. METHODS: Variables assessed for predictive value to VHI score are level of vocal demands, auditory-perceptual evaluation of dysphonia severity, integrity of mucosal wave vibration and phonatory glottal closure, lesion type, duration of current complaint, smoking, age, and sex. Harmonic to noise ratio was assessed in a subset of 50 patients. RESULTS: Patients with routine voice use had significantly lower VHI scores than those with more intensive (nonsinging/acting) vocal demands. Patients who quit smoking had greater VHI scores than those who currently smoke or never started. Patients with long-standing dysphonia tended to have lower VHI scores than those with shorter duration vocal complaints. Auditory-perceptual assessment of dysphonia severity and harmonic to noise ratio were weak predictors of VHI score. Age, sex, lesion type, phonatory glottal closure, and mucosal wave vibration were not significant predictors of VHI score. CONCLUSIONS: Patient perception of dysphonia severity is independent of many factors commonly assessed during the evaluation of voice disorders. It appears to be an important independent element in the assessment of the effect of a benign vocal fold lesion and critical to therapeutic decision-making.