A strabismus susceptibility locus on chromosome 7p

Strabismus has been known to have a significant genetic component, but the mode of inheritance and the identity of the relevant genes have been enigmatic. This paper reports linkage analysis of nonsyndromic strabismus. The principal results of this study are: (i) the demonstrated feasibility of identifying and recruiting large families in which multiple members have (or had) strabismus; (ii) the linkage in one large family of a presumptive strabismus susceptibility locus to 7p22.1 with a multipoint logarithm of odds score of 4.51 under a model of recessive inheritance; and (iii) the failure to observe significant linkage to 7p in six other multiplex families, consistent with genetic heterogeneity among families. These findings suggest that it will be possible to localize and ultimately identify strabismus susceptibility genes by linkage analysis and mutation screening of candidate genes.     

A Moderately High Fat Diet Promotes Salt-Sensitive Hypertension in Obese Zucker Rats by Impairing Nitric Oxide Production

The objective of this research was to examine the contribution of a moderately high fat (MHF) diet to the development of salt-sensitive hypertension in obese Zucker rats. Lean and obese Zucker rats were fed either a MHF diet or a diet of standard rat chow (control diet) for 10 weeks. From week 4 through week 10, the drinking water was supplemented with 1% NaCl. Blood pressure was measured weekly, and urinary excretion of nitric oxide metabolites (NO_x) was determined at weeks 4 and 10. At week 10, renal nitric oxide synthase (NOS) activity was assessed in kidney homogenates. Blood pressures of obese, but not lean, rats on the MHF fat diet were significantly increased by salt-supplementation, whereas blood pressures of rats on the control diet were not appreciably affected. NO_x excretion was increased in response to salt-supplementation in rats on the control diet, with the effect being particularly dramatic in obese rats. After salt-supplementation, NO_x excretion by rats on the MHF diet was lower than rats on the control diet. In obese rats on the MHF diet, this decrease in NO production was accompanied by a reduction in renal NOS activity. These results indicate that obese rats are more inclined than lean rats to develop diet-induced hypertension in response to a moderately high fat, salt-supplemented diet. Furthermore, they suggest that MHF diet-induced defects in NO production may promote the salt-sensitivity of blood pressure in obese Zucker rats, which appear to require more NO to maintain blood pressure during a salt challenge.     

A randomized,double‐blind,placebo‐ and positive‐controlled crossover study of the effects of durlobactam on cardiac repolarization in healthy subjects

Durlobactam (formerly ETX2514) is a diazabicyclooctane β‐lactamase inhibitor that inhibits class A, C, and D β‐lactamases. Sulbactam combined with durlobactam has in vitro and in vivo activity against Acinetobacter baumannii including carbapenem‐ and colistin‐resistant isolates and is being developed for treating serious infections due to A. baumannii. The effect of a single supratherapeutic dose of durlobactam on the heart rate corrected QT interval (QTc) was evaluated in healthy subjects in a placebo‐ and active‐controlled, single‐infusion, three‐way crossover study. Subjects were randomized to 1 of 6 sequences that included a single 3‐h i.v. infusion of durlobactam 4 g (supratherapeutic dose), a single 3‐h i.v. infusion of placebo, and a single 3‐h i.v. infusion of placebo plus a single oral dose of moxifloxacin 400 mg given open‐label at the end of the i.v. infusion. In each treatment period, Holter electrocardiogram (ECG) measurements were obtained from predose through 24 h post‐start of infusion. For the primary ECG end point, placebo‐corrected change‐from‐baseline corrected QT Fridericia’s formula (ΔΔQTcF), no significant change was observed with durlobactam. A concentration‐QT analysis demonstrated no significant effect of durlobactam on ECG parameters, including QT interval prolongation. Thus, durlobactam has a low risk for prolonging the QT interval and is unlikely to produce any proarrhythmic effects.

Study Highlights

• WHAT IS THE CURRENT KNOWLEDGE ON THE TOPIC?

Drug‐induced prolongation of the QT interval has the potential to cause severe, potentially fatal ventricular arrhythmias. A number of antimicrobial agents, including fluoroquinolones and macrolides, are associated with a low, but clinically significant increased risk of QT prolongation.

• WHAT QUESTION DID THIS STUDY ADDRESS?

This study evaluated the effect of a single supratherapeutic dose of durlobactam on the heart rate corrected QT interval in healthy subjects to determine if there were any potentials for proarrhythmic effects.

• WHAT DOES THIS STUDY ADD TO OUR KNOWLEDGE?

This study found that durlobactam had a low risk for prolonging the QT interval and is unlikely to produce any proarrhythmic effects.

• HOW MIGHT THIS CHANGE CLINICAL PHARMACOLOGY OR TRANSLATIONAL SCIENCE?

Because durlobactam had a low risk for prolonging the QT interval alone and when co‐administered with sulbactam, clinicians should be confident in administering the combination without risk for proarrhythmic effects.     

Ultrasound-targeted Microbubble Destruction-mediated Gene Delivery Into Canine Livers

Ultrasound (US) was applied to a targeted canine liver lobe simultaneously with injection of plasmid DNA (pDNA)/microbubble (MB) complexes into a portal vein (PV) segmental branch and occlusion of the inferior vena cava (IVC) to facilitate DNA uptake. By using a 1.1 MHz, 13 mm diameter transducer, a fivefold increase in luciferase activity was obtained at 3.3 MPa peak negative pressure (PNP) in the treated lobe. For more effective treatment of large tissue volumes in canines, a planar unfocused transducer with a large effective beam diameter (52 mm) was specifically constructed. Its apodized dual element configuration greatly reduced the near-field transaxial pressure variations, resulting in a remarkably uniform field of US exposure for the treated tissues. Together with a 15 kW capacity US amplifier, a 692-fold increase of gene expression was achieved at 2.7 MPa. Transaminase and histology analysis indicated minimal tissue damage. These experiments represent an important developmental step toward US-mediated gene delivery in large animals and clinics.     

Therapeutic Response in Feline Sandhoff Disease Despite Immunity to Intracranial Gene Therapy

Salutary responses to adeno-associated viral (AAV) gene therapy have been reported in the mouse model of Sandhoff disease (SD), a neurodegenerative lysosomal storage disease caused by deficiency of β-N-acetylhexosaminidase (Hex). While untreated mice reach the humane endpoint by 4.1 months of age, mice treated by a single intracranial injection of vectors expressing human hexosaminidase may live a normal life span of 2 years. When treated with the same therapeutic vectors used in mice, two cats with SD lived to 7.0 and 8.2 months of age, compared with an untreated life span of 4.5 ± 0.5 months (n = 11). Because a pronounced humoral immune response to both the AAV1 vectors and human hexosaminidase was documented, feline cDNAs for the hexosaminidase α- and β-subunits were cloned into AAVrh8 vectors. Cats treated with vectors expressing feline hexosaminidase produced enzymatic activity >75-fold normal at the brain injection site with little evidence of an immune infiltrate. Affected cats treated with feline-specific vectors by bilateral injection of the thalamus lived to 10.4 ± 3.7 months of age (n = 3), or 2.3 times as long as untreated cats. These studies support the therapeutic potential of AAV vectors for SD and underscore the importance of species-specific cDNAs for translational research.