Identification of the first homozygous intragenic deletion in the YY1AP1 gene in a consanguineous family: New insights into the phenotypic variability associated with Grange syndrome.

Grange syndrome (GRNG-MIM#135580) is a rare recessive disorder associating variable features including diffuse vascular stenosis, brachysyndactyly, osteopenia with increased bone fragility, cardiac malformations, and variable developmental delay. Since its first description in 1998, only 15 individuals from 10 families have been reported, carrying homozygous or compound heterozygous frameshift or nonsense variants in YY1AP1. In a patient with cutaneous and bone syndactyly and a hemorrhagic stroke at the age of 16 months, consistent with a clinical diagnosis of GRNG, we performed exome sequencing after negative array-CGH and congenital limb malformation panel results. Copy number variant analysis from exome data identified a homozygous intragenic out-of-frame deletion of 1.84 kb encompassing exons seven and eight of YY1AP1, confirming a molecular diagnosis of GRNG. Genetic counseling led to the identification of additional family members compatible with GRNG. Here, we provide new insights into the phenotypic variability associated with GRNG and highlight the utility of the detection of small copy number variants to identify the molecular causes of heterogeneous malformative genetic disorders.

High frequency of potentially pathogenic SORL1 mutations in autosomal dominant early-onset Alzheimer disease.

Performing exome sequencing in 14 autosomal dominant early-onset Alzheimer disease (ADEOAD) index cases without mutation on known genes (amyloid precursor protein (APP), presenilin1 (PSEN1) and presenilin2 (PSEN2)), we found that in five patients, the SORL1 gene harbored unknown nonsense (n=1) or missense (n=4) mutations. These mutations were not retrieved in 1500 controls of same ethnic origin. In a replication sample, including 15 ADEOAD cases, 2 unknown non-synonymous mutations (1 missense, 1 nonsense) were retrieved, thus yielding to a total of 7/29 unknown mutations in the combined sample. Using in silico predictions, we conclude that these seven private mutations are likely to have a pathogenic effect. SORL1 encodes the Sortilin-related receptor LR11/SorLA, a protein involved in the control of amyloid beta peptide production. Our results suggest that besides the involvement of the APP and PSEN genes, further genetic heterogeneity, involving another gene of the same pathway is present in ADEOAD.

[Lafora's disease presenting with progressive myoclonus epilepsy]. / Epilepsie myoclonique progressive révélant une maladie de Lafora.

Lafora's disease is a progressive myoclonus epilepsy and must be evocated if myoclonus, occipital seizures and progressive cognitive impairment are present. We report the case of a 14-year-old boy who suffered from several occipital seizures and two generalised seizures. The diagnosis of Lafora's disease was made six years after these inaugural symptoms because of occurrence of myoclonus, aggravation of the epilepsy with paharmacoresistance and psychic deterioration. Axila sweat gland duct biopsy was performed to conclude to the disease. A mutation was found on the gene EPM2A. Lafora's disease is a genetic autosomal-recessive pathology. Two genes have been recently identified. They code for two proteins, malin and laforin, involved in glycogen metabolism in the cellular endoplasmic reticulum. Mutations of these genes are responsible for intracytoplasmic polyglucosan inclusions called Lafora bodies and pathognomonic of the disease.

[Finnish amyloid polyneuropathy in a French patient]. / Une amylose finlandaise chez une patiente française.

INTRODUCTION: Finnish amyloid variety is a rare familial amiloidosis polyneuropathy essentially observed in Finland. It concerns about six hundred people in the world in which five hundred reside in Finland. OBSERVATION: We report a case of a 58-year-old French woman with a 10-year history of lattice cornea dystrophy. She consulted in January 2004 for impaired swallowing, facial paralysis principally of the right superior territory and symptoms of arthritis which had developed a few months earlier. Observation revealed facial cutis laxa, tongue amyotrophy and some fasciculation. Electroneuromyography showed chronic neurogenic involvement of the facial muscles. Limbs and the sympathetic neuronal system were free of involvement. Pathological examination revealed areas of peri vascular amiloid deposits. Molecular biology confirmed the diagnosis of Finnish amiloidosis: substitution of aspartic acid by tyrosine in the 187 codon in the 9th chromosome (gelsoline gene). This mutation has been previously found in Denmark and the Czech Republic. CONCLUSION: Finnish amiloidosis is a familial polyneuropathy characterized by an association of cornea lattice dystrophy, cutis laxa and a chronic neurogenic involvement of the cranial nerves. Two mutations are known. Life expectancy is not affected, but quality of life is altered.

Efficacy of ciprofloxacin alone and in combination with azlocillin in experimental endocarditis due to Pseudomonas aeruginosa.

The efficacy of ciprofloxacin alone and in combination with azlocillin was compared with that of azlocillin plus tobramycin in a rat model of aortic valve endocarditis due to Pseudomonas aeruginosa. MICs against the infecting strain of ciprofloxacin, azlocillin and tobramycin were 0.125, 8, and 0.5 mg/l, respectively. Antimicrobials were administered 24 h after bacterial challenge and for six days. Mean peak/trough serum levels for ciprofloxacin (50 mg/kg i.v. q 12 h), azlocillin (500 mg/kg i.v. q 12 h) and tobramycin (6.5 mg/kg i.v. q 12 h) were: 10.5/0.2, 386/less than 16, and 6.2/less than 0.6 mg/l, respectively. Ciprofloxacin alone was more effective than the combination azlocillin-tobramycin in increasing survival (p less than 0.05), sterilizing blood (p less than 0.05) and valves (p less than 0.001), and in reducing bacterial titers in vegetations (p less than 0.001). Ciprofloxacin-azlocillin combination was not more effective than ciprofloxacin alone. Drug resistance was not encountered in post-treatment isolates with any therapy regimen.

Susceptibility of Mycobacterium avium complex to various two-drug combinations of antituberculosis agents.

The drug susceptibility of two untypable strains of Mycobacterium avium complex were studied in 7H10 agar plates containing ethambutol (EMB), isoniazid (INH), rifampicin (RMP), ethionamide (ETH), and streptomycin (SM) alone and in two-drug combinations. The effective dose inhibiting 75% of the mycobacterial population (ED 75) was estimated by a regression analysis on the probit transformed inhibition percentages and plotted on an isobologram for each combination. No major discrepancies were found between strains. Five combinations (RMP plus INH, RMP plus EMB, EMB plus SM, INH plus EMB, and ETH plus INH) showed synergistic effect, whereas five other combinations (ETH plus EMB, ETH plus RMP, ETH plus SM, SM plus RMP, and SM plus INH) showed antagonistic effect. These in vitro results are not in combination with the known results of treatment of the M. avium diseases. We conclude that the effect of drug combinations against M. avium may be strain dependent and that it is important to determine this effect in vitro before setting up a treatment protocol.

Efficacy of pefloxacin-fosfomycin in experimental endocarditis caused by methicillin-resistant Staphylococcus aureus.

The efficacies of pefloxacin, fosfomycin, and both of these agents in combination against methicillin-resistant Staphylococcus aureus were assessed in a rat endocarditis model. The combination prevented emergence of the fosfomycin and pefloxacin resistance seen in 36 and 4%, respectively, of animals receiving either agent alone and was more effective than either agent in sterilizing cardiac vegetations.

Efficacy and safety of once daily versus intermittent dosing of tobramycin in rabbits with acute pyelonephritis.

Unilateral pyelonephritis was induced in 50 rabbits by injecting Escherichia coli (minimum inhibitory concentration of tobramycin 0.25 mg/l) into the left kidney and by obstructing the ureter temporarily. Tobramycin treatment (daily dose 10 mg/kg) was started 4 days after surgery, either in a single daily dose or in 3 divided doses at 8 h intervals, for 2, 3, 5, 7 or 10 days. Comparison of bacteriology, renal morphology, and renal functions (BUN, serum creatinine, alanine aminopeptidase, N-acetyl-beta-D-glucosaminidase, cathepsin B, sphingomyelinase) suggests better efficacy and renal tolerance of the single daily dose regimen in the treatment of experimental acute pyelonephritis.

[Comparison of the efficacy of a single daily injection versus fractionated injections of ceftriaxone in the treatment of acute experimental pyelonephritis]. / Comparaison de l'efficacité de la ceftriaxone en injection quotidienne unique par rapport aux injections fractionnées dans le traitement des pyélonéphrites aiguës expérimentales.

Unilateral acute pyelonephritis were produced in rabbits by injecting E. coli, using the retrograde route and after a temporary ureteral obstruction. Animals were treated with ceftriaxone IM at a dose of 50 mg/kg/d and 100 mg/kg/d (corresponding to 1 g/d and 2 g/d in humans) either by a single daily injection or by two daily injections at 12th intervals. Sacrifices were performed at day 5 and 7 of therapy. Analysis of bacteriological, morphological and histological data obtained in infected kidneys demonstrates that the single daily injection of ceftriaxone is more effective than the same dose divided in two injections at 12 h intervals. These results are observed as well with low and high doses of ceftriaxone.

Continuous-infusion ampicillin therapy of enterococcal endocarditis in rats.

Intermittent administration of ampicillin alone has resulted in high failure rates in previously described animal models of enterococcal endocarditis. We developed a rat model of enterococcal endocarditis which permits comparison of continuous intravenous infusion of ampicillin with intramuscular therapy. Continuous low-dose ampicillin infusion (450 mg/kg [body weight] per day) was compared with the same dose given intramuscularly in three divided doses and with high-dose infusion (4.5 g/kg per day) of the drug. For the infecting strain of Streptococcus faecalis, the MIC and MBC were 1 microgram/ml. Mean ampicillin levels in serum were 53.9 +/- 4.8 (peak) and less than 1 (trough), 8.7 +/- 1.4, and 244 +/- 29 micrograms/ml for intramuscular, low-dose, and high-dose regimens, respectively. Ampicillin infusion therapy significantly increased the survival rate and sterilization of blood cultures. Continuous infusions were superior to intermittent therapy in eradicating bacteremia. After 5 days of treatment, low-dose ampicillin infusion was more effective than intermittent therapy in sterilizing cardiac vegetations (P less than 0.01). Continuous-infusion therapy at either dose was significantly more effective than intramuscular injection in reducing bacterial titers in cardiac vegetations (5.4 +/- 1.0 log10 CFU/g [low dose], 4.8 +/- 0.3 log10 CFU/g [high dose], and 7.7 +/- 0.3 log10 CFU/g [intramuscular]). However, no statistically significant advantage was found for high-dose compared with low-dose ampicillin infusion in lowering bacterial titers in vegetations (P greater than 0.3).

Antagonistic effect of penicillin-amikacin combinations against enterococci.

Amikacin has been shown to antagonize the bactericidal effect of penicillin against strains of Streptococcus faecalis which produce aminoglycoside 3'-phosphotransferase. The mechanism by which this phenomenon occurs was studied with an enzyme-producing strain (8436) and an enzyme-negative strain (8436c) derived by curing the former with novobiocin. Combinations of amikacin with beta-lactam antibiotics were antagonistic against strain 8436 but synergistic against strain 8436c. Against strain 8436 penicillin-amikacin combinations resulted in levels of killing comparable to those seen with high concentrations of penicillin (500 micrograms/ml), which were less bactericidal than lower concentrations of penicillin. No antagonism was observed between amikacin and non-beta-lactam cell wall-active drugs or between penicillin and kanamycin or neomycin, both of which are substrates for the enzyme. At concentrations near the MIC, amikacin was bactericidal against strain 8436c but bacteriostatic against strain 8436 (MIC, 250 micrograms/ml; MBC, 2,000 micrograms/ml). Neither penicillin nor phosphorylated amikacin affected the inhibition of ribosomal protein synthesis by amikacin in a cell-free system. Although antagonism of killing by amikacin in enzyme-positive strains was specific for combinations which included beta-lactam antibiotics, amikacin did not influence the binding of [3H]penicillin to penicillin-binding proteins in isolated bacterial cell membranes or in intact cells and did not detectably affect the autolytic system of cells exposed to penicillin. Antagonism of beta-lactam activity by a bacteriostatic effect of amikacin against the enzyme-producing strain is the most likely explanation for this phenomenon.

In vitro activity and mechanism of action of A21978C1, a novel cyclic lipopeptide antibiotic.

The in vitro activity of A21978C1, a novel cyclic polypeptide antibiotic, was compared with those of vancomycin, teichomycin, and several beta-lactam antibiotics against gram-positive bacteria. The new drug was at least as active as vancomycin against all species of streptococci and staphylococci tested, including methicillin-resistant Staphylococcus aureus and penicillin-resistant pneumococci. Activity of the drug was found to be strongly correlated with the calcium concentration in test media. Against enterococci, A21978C1 was bactericidal at concentrations near the MIC (MIC for 100% of the strains, 2 micrograms/ml), but combining that drug with gentamicin resulted in bactericidal synergism by time-kill methods. Studies were undertaken to examine the mechanism of action of the drug. A21978C1 did not interact with penicillin-binding proteins of bacterial cell membranes. No direct effect of the drug on the synthesis of DNA, RNA, or protein by a susceptible strain of Streptococcus faecalis could be demonstrated. However, A21978C1 inhibited peptidoglycan synthesis in early-log-phase cultures of both Streptococcus faecalis and Staphylococcus aureus.

[Pharmacokinetics of dibekacin in subjects with normal renal function]. / Pharmacocinétique de la dibékacine chez le sujet à fonction rénale normale.

The principal pharmacokinetic parameters of dibekacin were studied in five adult subjects with normal renal function after IM and IV injection of a single dose of 1 mg/kg. The results obtained showed that the pharmacokinetics of dibekacine were independent of the dose (T1/2: 2.1 h; distribution volume: 14-161; renal clearance: congruent to 70 ml/min; urinary excretion in 24 hours congruent to 80%) and very similar to those of other aminoglycosides of the deoxystreptamine group.