Huntingtin differentially regulates the axonal transport of a sub-set of Rab-containing vesicles in vivo.

Loss of huntingtin (HTT), the Huntington's disease (HD) protein, was previously shown to cause axonal transport defects. Within axons, HTT can associate with kinesin-1 and dynein motors either directly or via accessory proteins for bi-directional movement. However, the composition of the vesicle-motor complex that contains HTT during axonal transport is unknown. Here we analyze the in vivo movement of 16 Rab GTPases within Drosophila larval axons and show that HTT differentially influences the movement of a particular sub-set of these Rab-containing vesicles. While reduction of HTT perturbed the bi-directional motility of Rab3 and Rab19-containing vesicles, only the retrograde motility of Rab7-containing vesicles was disrupted with reduction of HTT. Interestingly, reduction of HTT stimulated the anterograde motility of Rab2-containing vesicles. Simultaneous dual-view imaging revealed that HTT and Rab2, 7 or 19 move together during axonal transport. Collectively, our findings indicate that HTT likely influences the motility of different Rab-containing vesicles and Rab-mediated functions. These findings have important implications for our understanding of the complex role HTT plays within neurons normally, which when disrupted may lead to neuronal death and disease.

Venous excess ultrasonography (VExUS) captures dynamic changes in volume status surrounding hemodialysis: A multicenter prospective observational study.

Background: The evaluation of volume status is essential to clinical decision-making, yet multiple studies have shown that physical exam does not reliably estimate a patient's intravascular volume. Venous excess ultrasound score (VExUS) is an emerging volume assessment tool that utilizes inferior vena cava (IVC) diameter and pulse-wave Doppler waveforms of the portal, hepatic and renal veins to evaluate venous congestion. A point-of-care ultrasound exam initially developed by Beaubein-Souligny et al., VExUS represents a reproducible, non-invasive and accurate means of assessing intravascular congestion. VExUS has recently been validated against RHC-the gold-standard of hemodynamic evaluation for volume assessment. While VExUS scores were shown to correlate with elevated cardiac filling pressures (i.e., right atrial pressure (RAP) and pulmonary capillary wedge pressure (PCWP)) at a static point in time, the ability of VExUS to capture dynamic changes in volume status has yet to be elucidated. We hypothesized that paired VExUS examinations performed before and after hemodialysis (HD) would reflect changes in venous congestion in a diverse patient population. Methods: Inpatients with end-stage renal disease undergoing intermittent HD were evaluated with transabdominal VExUS and lung ultrasonography before and following HD. Paired t-tests were conducted to assess differences between pre-HD and post-HD VExUS scores, B-line scores and dyspnea scores. Results: Fifty-six patients were screened for inclusion in this study. Ten were excluded due to insufficient image quality or incomplete exams, and forty-six patients (ninety-two paired ultrasound exams) were included in the final analysis. Paired t-test analysis of pre-HD and post-HD VExUS scores revealed a mean VExUS grade change of 0.82 (p<0.001) on a VExUS scale ranging from 0 to 4. The mean difference in B-line score following HD was 0.8 (p=0.001). There was no statistically significant difference in subjective dyspnea score (p=0.41). Conclusions: Large-volume fluid removal with HD was represented by changes in VExUS score, highlighting the utility of the VExUS exam to capture dynamic shifts in intravascular volume status. Future studies should evaluate change in VExUS grade with intravenous fluid or diuretic administration, with the ultimate goal of evaluating the capacity of a standardized bedside ultrasound protocol to guide inpatient volume optimization.

Excess Rab4 rescues synaptic and behavioral dysfunction caused by defective HTT-Rab4 axonal transport in Huntington's disease.

Huntington's disease (HD) is characterized by protein inclusions and loss of striatal neurons which result from expanded CAG repeats in the poly-glutamine (polyQ) region of the huntingtin (HTT) gene. Both polyQ expansion and loss of HTT have been shown to cause axonal transport defects. While studies show that HTT is important for vesicular transport within axons, the cargo that HTT transports to/from synapses remain elusive. Here, we show that HTT is present with a class of Rab4-containing vesicles within axons in vivo. Reduction of HTT perturbs the bi-directional motility of Rab4, causing axonal and synaptic accumulations. In-vivo dual-color imaging reveal that HTT and Rab4 move together on a unique putative vesicle that may also contain synaptotagmin, synaptobrevin, and Rab11. The moving HTT-Rab4 vesicle uses kinesin-1 and dynein motors for its bi-directional movement within axons, as well as the accessory protein HIP1 (HTT-interacting protein 1). Pathogenic HTT disrupts the motility of HTT-Rab4 and results in larval locomotion defects, aberrant synaptic morphology, and decreased lifespan, which are rescued by excess Rab4. Consistent with these observations, Rab4 motility is perturbed in iNeurons derived from human Huntington's Disease (HD) patients, likely due to disrupted associations between the polyQ-HTT-Rab4 vesicle complex, accessory proteins, and molecular motors. Together, our observations suggest the existence of a putative moving HTT-Rab4 vesicle, and that the axonal motility of this vesicle is disrupted in HD causing synaptic and behavioral dysfunction. These data highlight Rab4 as a potential novel therapeutic target that could be explored for early intervention prior to neuronal loss and behavioral defects observed in HD.

Impact of a History of Hypertension in Pregnancy on Later Diagnosis of Atrial Fibrillation.

BACKGROUND: Atrial fibrillation/flutter (AF) produces significant morbidity in women and is typically attributed to cardiac remodeling from multiple causes, particularly hypertension. Hypertensive pregnancy disorders (HPDs) are associated with future hypertension and adverse cardiac remodeling. We evaluated whether women with AF were more likely to have experienced a HPD compared with those without. METHODS AND RESULTS: A nested case-control study was conducted within a cohort of 7566 women who had a live or stillbirth delivery in Olmsted County, Minnesota between 1976 and 1982. AF cases were matched (1:1) to controls based on date of birth, age at first pregnancy, and parity. AF and pregnancy history were confirmed by chart review. We identified 105 AF cases: mean age 57±8 (mean±SD) years, (controls 56±8 years), 32±8 years (controls 31±8 years) after the first pregnancy. Cases were more likely to have obesity during childbearing years, and hypertension, diabetes mellitus, dyslipidemia, coronary disease, valvular disease, and heart failure at the time of AF diagnosis. Cases were more likely to have a history of HPDs, compared with controls: 28/105 (26.7%) cases versus 12/105 (11.4%) controls, odds ratio: 2.60 (95% confidence interval, 1.21-6.04). After adjustment for hypertension and obesity, the association was attenuated and no longer statistically significant; odds ratio (95% confidence interval, 2.12 (0.92-5.23). CONCLUSIONS: Women with AF are more likely to have had a HPD, a relationship at least partially mediated by associated obesity and hypertension. Given the high morbidity of AF, studies evaluating the benefit of screening for and management of cardiovascular risk factors in women with a history of HPD should be performed.