Mutations in the interglobular domain of aggrecan alter matrix metalloproteinase and aggrecanase cleavage patterns - Evidence that matrix metalloproteinase cleavage interferes with aggrecanase activity

We have expressed G1-G2 mutants with amino acid changes at the DIPEN(341) downward arrow(342)FFGVG and ITEGE(373) downward arrow(374)ARGSV cleavage sites, in order to investigate the relationship between matrix metalloproteinase (MMP) and aggrecanase activities in the interglobular domain (IGD) of aggrecan. The mutation DIPEN(341) to DIGSA(341) partially blocked cleavage by MMP-13 and MMP-8 at the MMP site, while the mutation (342)FFGVG to (342)GTRVG completely blocked cleavage at this site by MMP-1, -2, -3, -7, -8, -9, -13, -14. Each of the MMP cleavage site mutants, including a four-amino acid deletion mutant lacking residues ENFF(343), were efficiently cleaved by aggrecanase, suggesting that the primary sequence at the MMP site had no effect on aggrecanase activity in the IGD. The mutation (374)ARGSV to (374)NVYSV completely blocked cleavage at the aggrecanase site by aggrecanase, MMP-8 and atrolysin C but had no effect on the ability of MMP-8 and MMP-13 to cleave at the Asn(341) downward arrowPhe bond. Susceptibility to atrolysin C cleavage at the MMP site was conferred in the DIGSA(341) mutant but absent in the wild-type, (342)GTRVG, (374)NVYSV, and deletion mutants. To further explore the relationship between MMP and aggrecanase activities, sequential digest experiments were done in which MMP degradation products were subsequently digested with aggrecanase and vice versa. Aggrecanase-derived G1 domains with ITEGE(373) C termini were viable substrates for MMPs; however, MMP-derived G2 fragments were resistant to cleavage by aggrecanase. A 10-mer peptide FVDIPENFFG, which is a substrate analogue for the MMP cleavage site, inhibited aggrecanase cleavage at the Glu(373) downward arrowAla bond. This study demonstrates that MMPs and aggrecanase have unique substrate recognition in the IGD of aggrecan and suggests that sequences at the C terminus of the DIPEN(341) G1 domain may be important for regulating aggrecanase cleavage

On the use of Raman spectroscopy in the characterisation of iodine in charge-transfer complexes

FT-Raman spectra of some polyiodides and of a series of D.I2 charge-transfer complexes (where D is a molecule containing the thione or selone groups as donors), all characterized by x-ray diffraction, are reported. For the adducts with the thione compounds, which can be considered weak or medium-weak complexes, an empirical linear correlation between the frequency of the nu(I-I) stretching vibrations and the d(I-I) bond distances has been found. Some polyiodides show FT-Raman spectra that are indistinguishable with respect to those displayed by the neutral complexes of weak or medium-weak strength; in such cases, the polyiodide can be regarded as a diiodine molecule, perturbed by an I(n)- (n = 1,3....) donor. Polyiodides of this type show Raman absorptions falling in the linear correlation

RESTORE: a prospective multinational registry of patients with genetically confirmed spinal muscular atrophy - rationale and study design

Background: Dramatic improvements in spinal muscular atrophy (SMA) treatment have changed the prognosis for patients with this disease, leading to important new questions. Gathering representative, real-world data about the long-term efficacy and safety of emerging SMA interventions is essential to&nbsp;document their impact on patients and caregivers. Objectives: This registry will assess outcomes in patients with genetically confirmed SMA and provide information on the effectiveness and long-term safety of approved and emerging treatments. Design and Methods: RESTORE is a prospective, multicenter, multinational observational registry. Patients will be managed according to usual clinical practice. Both newly recruitedSMAtreatment centers and sites involved in existing SMA registries, including iSMAC, Treat-NMD, French SMA Assistance Publique- H&ocirc;pitaux de Paris (AP-HP), Cure-SMA, SMArtCARE, will be eligible to participate; de novo; sites already participating in another registry may be included via consortium agreements. Data from patients enrolled in partnering registries will be shared with the RESTORE Registry and data for newly diagnosed patients will be added upon enrollment. Patients will be enrolled over a 5-year period and followed for 15 years or until death. Assessments will include SMA history and treatment, pulmonary, nutritional, and motor milestones, healthcare resource utilization, work productivity, activity impairment, adverse events, quality of life, caregiver burden, and survival. Status: Recruitment started in September 2018. As of January 3, 2020, 64 patients were enrolled at 25 participating sites. Conclusions: The RESTORE Registry has begun recruiting recently diagnosed patients with genetically confirmed SMA, enabling assessment of both short- and long-term patient outcomes.</p

Correlation between motor performance scales, body composition, and anthropometry in patients with duchenne muscular dystrophy

The aim of this study is to investigate the relationship between body composition, anthropometry, and motor scales in patients with Duchenne muscular dystrophy (DMD). Twenty six patients with DMD were evaluated by Expanded Hammersmith Functional Motor Scale (HFMSE), gross motor function classification system (GMFCS), multifrequency bioelectrical impedance analysis, and anthropometric measurements. Seventeen healthy children served as control group. There were 26 patients with a mean age of 9.5 +/- A 4.8 years. Ages and anthropometric measurements did not differ between groups. Of the 26 patients, nine were level I, seven were level II, two were level III, seven were level IV, and one was level V, according to the GMFCS. Despite the similar percentage of total body water, extracellular water/intracellular water ratio was significantly elevated in DMD patients (p = 0.001). Increased values of fat percentage and body fat mass index (BFMI) correlated positively with elevated GMFCS levels (r = 0.785 and 0.719 respectively). Increased fat-free mass index (FFMI) correlated negatively with elevated GMFCS levels (r = -0.401). Increased fat percentage and BFMI correlated negatively with HFMSE scores (r = -0.779 and -0.698, respectively). Increased values of FFMI correlated positively with HFMSE scores. There was also a negative correlation between increased skin fold measurements from triceps and scapula and HFMSE scores (r = -0.618 and -0.683, respectively). Increased skin fold values from the same regions correlated positively with elevated GMFCS levels (r = 0.643 and 0.712, respectively). Significant body composition changes occur in patients with DMD. Anthropometric and multifrequency bioelectrical impedance analyses measurements show good correlation between motor function scales. These results may also be helpful to evaluate the effects of new treatment strategies

Neurological examination in the healthy term newborn Exame neurológico do recém-nascido de termo normal

We carried out a cross-sectional study with a sample of 106 normal full-term newborns examined within 24 to 72 hours of birth. The following findings were evaluated: head and chest measurements, muscle strength, tone, tendon reflexes, superficial reflexes, primitive reflexes, and cranial nerves. All 106 newborns were considered neurologically normal. We found no differences in the neurological examination findings for newborns with different gestational ages. Primitive reflexes and appendicular tone in newborns examined at earlier postnatal ages tended to be less intense. We were able to determine the prevalence of certain neurological examination findings for the normal newborn and to discuss some differences between our results and those of other studies. Prevalence estimations for the different findings in our study may be valid for different populations as long as the same methodology is adopted.<br>Com o objetivo de revisar o exame neurológico do recém-nascido na atualidade, foi realizado um estudo transversal com uma amostra aleatória de 106 recém-nascidos de termo normais com 24 a 72 horas de vida, período em que o recém-nascido permanece na maternidade. Os seguintes itens foram incluídos no exame neurológico: medidas do crânio e tórax, trofismo, força, tono, reflexos miotáticos fásicos, reflexos superficiais, reflexos primitivos, sensibilidade e nervos cranianos. A freqüência dos itens examinados foi estimada através do intervalo de confiança de 95%. Todos os 106 recém-nascidos foram considerados neurologicamente normais. Não encontramos diferenças no exame entre as crianças nascidas de parto vaginal e cesariana, bem como nas diferentes idades gestacionais. Os reflexos primitivos e o tono apendicular foram menos intensos nos recém-nascidos examinados com menor tempo de vida. Os nossos resultados indicam a necessidade de revisar dados do exame neurológico estabelecidos por pesquisas realizadas no passado e o exame do recém-nascido em uso atualmente. As estimativas encontradas no presente estudo podem ser válidas para diferentes populações, desde que a mesma metodologia seja usada