A mutant wfs1 zebrafish model of Wolfram syndrome manifesting visual dysfunction and developmental delay.

Wolfram syndrome (WS) is an ultra-rare progressive neurodegenerative disorder defined by early-onset diabetes mellitus and optic atrophy. The majority of patients harbour recessive mutations in the WFS1 gene, which encodes for Wolframin, a transmembrane endoplasmic reticulum protein. There is limited availability of human ocular and brain tissues, and there are few animal models for WS that replicate the neuropathology and clinical phenotype seen in this disorder. We, therefore, characterised two wfs1 zebrafish knockout models harbouring nonsense wfs1a and wfs1b mutations. Both homozygous mutant wfs1a-/- and wfs1b-/- embryos showed significant morphological abnormalities in early development. The wfs1b-/- zebrafish exhibited a more pronounced neurodegenerative phenotype with delayed neuronal development, progressive loss of retinal ganglion cells and clear evidence of visual dysfunction on functional testing. At 12 months of age, wfs1b-/- zebrafish had a significantly lower RGC density per 100 µm2 (mean ± standard deviation; 19 ± 1.7) compared with wild-type (WT) zebrafish (25 ± 2.3, p < 0.001). The optokinetic response for wfs1b-/- zebrafish was significantly reduced at 8 and 16 rpm testing speeds at both 4 and 12 months of age compared with WT zebrafish. An upregulation of the unfolded protein response was observed in mutant zebrafish indicative of increased endoplasmic reticulum stress. Mutant wfs1b-/- zebrafish exhibit some of the key features seen in patients with WS, providing a versatile and cost-effective in vivo model that can be used to further investigate the underlying pathophysiology of WS and potential therapeutic interventions.

Gas bubble emboli detected by transcranial Doppler sonography in patients with prosthetic heart valves: a preliminary report.

After observing spikes in the Doppler signal of cerebral arteries of patients with neurologic symptoms and prosthetic heart valves, we then studied two groups of patients with prosthetic heart valves: seven patients with neurologic symptoms and 65 asymptomatic patients. Using transcranial Doppler sonography of the middle cerebral artery, we found Doppler spikes in six symptomatic and 24 asymptomatic patients with mechanical heart valves. No spikes were found in one symptomatic and 21 asymptomatic patients with biological valves or in 20 asymptomatic patients with mechanical valves. We concluded that gas cavitation during the opening or closure of the valve, producing bubble emboli, is the most probable explanation for these Doppler spikes in patients with mechanical prosthetic heart valves.

Quantification of asymmetric valvular regurgitant jets by color Doppler ultrasound in vitro.

Accurate quantification of regurgitant jets in natural and prosthetic heart valves has been a goal of health care workers and researchers for many years. One promising new method applies the law of conservation of momentum transfer to velocities measured by color Doppler ultrasound to calculate the flow rate in the jet. One complicating factor is that regurgitant jets from real heart valves may be highly asymmetric. The purpose of this investigation was to determine whether the accurate calculation of the flow rate in asymmetric jets imaged by color Doppler requires an asymmetric formulation of the conservation of momentum transfer, combined with a method for imaging the jet in three dimensions. Asymmetric jets issuing from narrow slits were imaged in an in vitro, steady flow system. The ultrasound transducer was rotated around the jet axis to image the jet in three dimensions. The three-dimensional imaging confirmed that jets from slits are indeed asymmetric, but become relatively axisymmetric far from the orifice. Images were analyzed by computer and the calculated flows compared to measured flows. The accuracy of an asymmetric formulation of the conservation of momentum transfer method was compared to a simpler, axisymmetric formulation. If axisymmetry was assumed in asymmetric jets, significant errors in the calculated flow rates occurred. In these cases, the calculated flow also varied widely with distance from the orifice. When asymmetry was taken into account, the errors were considerably reduced. The results suggest that, in asymmetric jets, the momentum transfer is convected around the jet axis.

In vitro quantification of regurgitant jet flow by color Doppler ultrasound and conservation of momentum.

Prosthetic valve regurgitant jets can be imaged with color Doppler ultrasound (CDU), but clinical quantitation remains elusive. An equation based on an integrated conservation of momentum analysis was implemented for CDU quantitation of regurgitation. This was compared with a simple, non-CDU momentum balance analysis recently reported that requires only a pulsed Doppler ultrasound (PDU) reading within the jet and a continuous wave Doppler (CWD) reading of the orifice velocity. For in vitro steady flows, the simple, non-CDU method was accurate only with PDU readings taken 5 cm from the orifice; flows were underestimated when readings 1 and 3 cm from the orifice were used. The CDU method was accurate, even when flows calculated from readings between 0.5 and 6.0 cm from the orifice were averaged together.

In vitro ultrasound characterization of a polyurethane trileaflet valve.

Polyurethane synthetic trileaflet valves were compared with commercial prostheses in vitro, in a pulse duplicator using ultrasound to characterize the flow velocities and patterns. Flow-pressure drop behavior was in the middle range of other prosthetic valves. Diastolic regurgitant jets were located by color Doppler ultrasound, and there appeared to be some leakage through the leaflet fold at the commissure. Nevertheless, the closing volumes and closed valve leakage volumes were, on average, lower than other prosthetic valves. Systolic 20 Hz spectral oscillations detected with pulsed Doppler and continuous wave Doppler were attributed to leaflet flutter in the open valve.