Publications

UNLABELLED

We hypothesized that changes in the expression of voltage-gated potassium channel (Kv) 4.3 contribute to the mechanical hyperalgesia induced by vibration injury, in a rodent model for hand-arm vibration syndrome in humans. Here we show that the exposure of the gastrocnemius muscle to vibration injury induces muscle hyperalgesia that is accompanied by a significant downregulation of Kv4.3 in affected sensory nerve fibers in dorsal root ganglia. We additionally show that the intrathecal administration of antisense oligonucleotides for Kv4.3 messenger RNA itself induces muscle hyperalgesia in the rat. Our results suggest that attenuation in the expression of Kv4.3 may contribute to neuropathic pain in people affected by hand-arm vibration syndrome.

PERSPECTIVE

Our findings establish Kv4.3 as a potential molecular target for the treatment of hand-arm vibration syndrome.

BACKGROUND

Assessment of diffuse right ventricular (RV) fibrosis is of particular interest in pulmonary hypertension (PH) and heart failure (HF). Current cardiovascular magnetic resonance (CMR) T1 mapping techniques such as Modified Look-Locker inversion recovery (MOLLI) imaging have limited resolution, but accelerated and navigator-gated Look-Locker imaging for cardiac T1 estimation (ANGIE) is a novel CMR sequence with spatial resolution suitable for T1 mapping of the RV. We tested the hypothesis that patients with PH would have significantly more RV fibrosis detected with MRI ANGIE compared with normal volunteers and patients having HF with reduced (LV) ejection fraction (HFrEF) without co-existing PH, independent of RV dilitation and dysfunction.

METHODS

Patients with World Health Organization group 1 or group 4 PH, patients with HFrEF without PH, and normal volunteers were recruited to undergo contrast-enhanced CMR. RV and LV extracellular volume fractions (RV-ECV and LV-ECV) were determined using pre-contrast and post-contrast T1 mapping using ANGIE (RV and LV) and MOLLI (LV only).

RESULTS

Thirty-two participants (53.1% female, median age 52 years, IQR 26-65 years) were enrolled, including n = 12 with PH, n = 10 having HFrEF without co-existing PH, and n = 10 normal volunteers. ANGIE ECV imaging was of high quality, and ANGIE measurements of LV-ECV were highly correlated with those of MOLLI (r = 0.91; p < 0.001). The RV-ECV in PH patients was 27.2% greater than the RV-ECV in normal volunteers (0.341 v. 0.268; p < 0.0001) and 18.9% greater than the RV-ECV in HFrEF patients without PH (0.341 v. 0.287; p < 0.0001). RV-ECV was greater than LV-ECV in PH (RV-LV difference = 0.04), but RV-ECV was nearly equivalent to LV-ECV in normal volunteers (RV-LV difference = 0.002) (p < 0.0001 for RV-LV difference in PH versus normal volunteers). RV-ECV was linearly associated with both increasing RVEDVI (p = 0.049) and decreasing RVEF (p = 0.04) in a multivariable linear model, but PH was still associated with greater RV-ECV even after adjustment for RVEDVI and RVEF.

CONCLUSIONS

Pre- and post-contrast ANGIE imaging provides high-resolution ECV determination for the RV. PH is independently associated with increased RV-ECV even after adjustment for RV dilatation and dysfunction, consistent with an independent effect of PH on fibrosis. ANGIE RV imaging merits further clinical evaluation in PH.

The American Society for Blood and Marrow Transplantation (ASBMT) Clinical Case Forum (CCF) was launched in 2014 as an online secure tool to enhance interaction and communication among hematopoietic cell transplantation (HCT) professionals worldwide through the discussion of challenging clinical care issues. After 14 months, we reviewed clinical and demographical data of cases posted in the CCF from January 29, 2014 to March 18, 2015. A total of 137 cases were posted during the study period. Ninety-two cases (67%) were allogeneic HCT, 29 (21%) were autologous HCT, and in 16 (12%), the type of transplantation (autologous versus allogeneic) was still under consideration. The diseases most frequently discussed included non-Hodgkin lymphoma (NHL; n = 30, 22%), acute myeloid leukemia (n = 23, 17%), and multiple myeloma (MM; n = 20, 15%). When compared with the US transplantation activity reported by the US Department of Health and Human Services, NHL and acute lymphoblastic leukemia cases were over-represented in the CCF, whereas MM was under-represented (P < .001). A total of 259 topics were addressed in the CCF with a median of 2 topics/case (range, 1 to 6). Particularly common topics included whether transplantation was indicated (n = 57, 41%), conditioning regimen choice (n = 44, 32%), and post-HCT complications after day 100 (n = 43, 31%). The ASBMT CCF is a successful tool for collaborative discussion of complex cases in the HCT community worldwide and may allow identification of areas of controversy or unmet need from clinical, educational and research perspectives.

Inguinal hernia repair is one of the most commonly performed operations in the world, yet little is known about the genetic mechanisms that predispose individuals to develop inguinal hernias. We perform a genome-wide association analysis of surgically confirmed inguinal hernias in 72,805 subjects (5,295 cases and 67,510 controls) and confirm top associations in an independent cohort of 92,444 subjects with self-reported hernia repair surgeries (9,701 cases and 82,743 controls). We identify four novel inguinal hernia susceptibility loci in the regions of EFEMP1, WT1, EBF2 and ADAMTS6. Moreover, we observe expression of all four genes in mouse connective tissue and network analyses show an important role for two of these genes (EFEMP1 and WT1) in connective tissue maintenance/homoeostasis. Our findings provide insight into the aetiology of hernia development and highlight genetic pathways for studies of hernia development and its treatment.