Jacobson Holman (United States)

NaV (voltage-gated sodium) channels drive cardiac excitability. Although NaV1.5 is the primary cardiac isoform, the composition and functional contributions of non-NaV1.5 isoforms in the heart remain unclear. Here, we developed a chemical-genetic mouse model (NaV1.5GX/GX) in which NaV1.5 can be selectively and reversibly inhibited by acyl- and aryl-sulfonamide compounds (GX [acyl- and aryl-sulfonamide compounds typically denoted by the name GX-### and associated items] drugs). Cardiac activity was assessed by electrocardiograms in vivo, and optical mapping was used for imaging of ex vivo hearts. Whole-cell voltage-clamp in tandem with validated toxins and isoform-selective inhibitors were used to examine sodium current composition. NaV1.5GX/GX mice exhibited normal cardiac function at baseline, but acute GX drug administration caused profound conduction defects and arrhythmias. Whole-heart optical mapping revealed dose-dependent chamber-specific sensitivity to NaV1.5 inhibition, with the right ventricle being the most sensitive, followed by the left ventricle, left atrium, and right atrium. Patch-clamp recordings of isolated cardiomyocytes with application of NaV isoform-selective inhibitors showed that NaV1.5 contributed 93% of sodium current in the left ventricle, 79% in the right ventricle, and 78% in the atria. Non-NaV1.5 isoforms were differentially enriched across chambers: NaV1.8 in the left ventricle, NaV1.1/1.3 in the right ventricle, and NaV1.2/1.6/1.7 in the atria. These results reveal a surprising chamber-specific isoform landscape of cardiac sodium currents, which may underlie the right ventricular predominant phenotype of Brugada syndrome. These data highlight non-NaV1.5 isoforms as potential mediators of chamber-specific cardiac pathologies and as pharmacological targets.

Mitral annular calcification with valve dysfunction remains a challenging syndrome. Operative risk is high, and available transcatheter therapies are limited. This study describes our initial experience with a novel procedure to address large mitral annuli when no surgical or trial-based transcatheter mitral valve replacement device is available. The rationale was to shorten the intercommissural distance using commissural mitral transcatheter edge-to-edge repair (TEER) followed by valve-in-mitral annular calcification transcatheter mitral valve replacement with a balloon-expandable aortic valve platform. Patients with long intercommissural distances and large mitral annulus areas were selected based on a high perceived risk of transcatheter valve embolization. Patients underwent mitral TEER with MitraClip in a commissural position, followed immediately by transseptal transcatheter mitral valve replacement with a 29 mm SAPIEN 3 valve. Thirteen patients were included. Median intercommissural distance and annular area were 39.1 mm and 930 mm2, respectively. Commissural mitral TEER was successful in all patients with no instances of single leaflet detachment. In 10 of 13 instances, an NTW device size was used. In 12 of 13 patients, valve implantation was successful, including 1 case that required a second valve for atrial positioning of the first valve. In 1 case, frank valve embolization into the left atrium occurred. Among the 12 successful cases, paravalvular leak was 1+ or less, and there were no instances of paravalvular leak adjacent to the TEER device. In patients with large annuli and sufficient annular calcium, a hybrid mitral TEER and valve replacement with the SAPIEN platform can be successfully used to facilitate transcatheter mitral valve replacement.

To examine the association between initial patterns of prescription opioid supply (POS) and risk of all-cause mortality among an insured opioid-naïve patient population in the United States (US). This retrospective observational cohort study used de-identified, administrative health care claims data from a large national insurer (Optum Clinformatics Data Mart) from 2010 to 2015. Participants included insured, cancer-free adults prescribed opioid analgesics. Prescription opioids received during the first 6 months of therapy were used to categorize initial patterns of POS as daily or nondaily. Cox regression was used to estimate the association of initial patterns of POS with all-cause mortality within one year of follow-up, adjusting for baseline covariates to control for confounding. A total of 4,054,417 patients were included, of which 2.75% had incident daily POS; 54.8% were female; median age was 50 years; mean Charlson comorbidity index (CCI) was 0.21 (standard deviation = 0.77); and mean daily morphine milligram equivalent was 34.61 (95% confidence intervals: 34.59, 34.63). There were 2068 more deaths per 100,000 person-years among patients who were prescribed opioids daily than nondaily. After adjusting for baseline covariates, the hazard of all-cause mortality among patients with incident daily POS was nearly twice that among those prescribed nondaily (hazard ratio [HR] = 1.94; 95% confidence intervals: 1.84, 2.04). Among insured adult patients with noncancer pain, incident chronic POS was associated with a significantly increased risk of all-cause mortality over at most 1 year of follow-up. Because these results may be susceptible to bias, more research is needed to establish causality.

Background: Parasitic disease constitutes 60-70% diseases affecting the animals and has serious economic implication in livestock entrepreneurship by direct and indirect production loss. Indiscriminate use of anthelmintic drugs has made the situation even more precarious. A similar problem was encountered in goat from Holidhani, Jhenidah, where goats with complain of intermittent diarrhea and loss of body condition was reported despite of routine deworming.Objective:Â Determining the efficacy of conventional anthelmintics used and its comparison with some unexploited antiparasitic drugs for the same reason.Methods: Sixty-five goats were divided into five groups. Group A goats were kept as the control, Group B (I, II, III), group C (IV, V, VI), group D (VII, VIII, IX) and group E (X, XI, XII) goats were treated with levamisole, albendazole, fenbendazole and ivermectin respectively. All the treated and control goats were kept, housed for 21 days after the first treatment. Fecal samples were collected and counted on 1st, 7th, 14th and 21st day by using McMaster counting method.Results: Among the three doses of levamisole, albendazole, fenbendazole and ivermectin, the doses of 7.5, 7.5, 5.0 and 0.2 mg/kg body weight, body weight were found to be most effective against gastrointestinal nematodes in goats with a maximum reduction of fecal egg count to the extent of 95.38, 97.13, 98.08 & 99.16 percent respectively.Conclusion: The study revealed low efficacy of levamisole and hence ivermectin is a better drug than albendazole and fenbendazole to control gastrointestinal nematodes in goats.Â

In contrast to the 1st and 2nd centuries, diplomas for praetorian soldiers became very frequent in the 3rd century. There are 13 new diplomas published here from the decades between Septimius Severus and Philippus Arabs; 16 diplomas from the time of Severus Aexander are excluded, which are published elsewhere. There are five diplomas of Septimius Severus, one of Caracalla, two each of Maximinus Thrax and Philippus Arabs; for three diplomas, the emperor cannot be determined. On the outside of a diploma the text for a praetorian is engraved, and on the inside, for the soldiers of one of the Italian fleets.

The published ceramic fragment was discovered in the fort of ala Siliana in Gilău, during the researches from 1999–2000, when the rooms of a wooden building from the retentura sinistra were investigated. Here, previous research (1981) had indicated the existence of a stabulum. The text on the vessel was inscribed post cocturam, and it was rendered in a position almost perpendicular to the bottom.

Bergmann, Jules1; Hoops, Katherine1; Sick-Samuels, Anna2; Milstone, Aaron3; Fackler, James4 Author Information

We investigated the association between serum uric acid (SUA) and brachial ankle pulse wave velocity (baPWV) in an apparently healthy population. We performed a cross-sectional study on middle-aged Koreans who completed a yearly health-screening program between January and December 2014. Subjects with coronary artery disease, diabetes, or hypertension were excluded. Linear regression analyses were used to study the relationship between SUA and baPWV. Multiple adjustments were made for variables based on clinical or statistical significance. Of 66,917 study participants (38,170 men and 28,747 women), the mean age was 39.4 ± 6.7 years and the average SUA level was 5.23 ± 1.4 mg/dL. SUA values were higher in men than in women (6.1 ± 1.2 mg/dL vs. 4.1 ± 0.8 mg/dL). SUA was linearly associated with baPWV in women and in men (P < .001, respectively). Multiple regression analyses remained significant for women with a positive association with baPWV across SUA quintiles in a dose-response manner (P < .001) while no longer for men with a J-shaped association between SUA quintiles and baPWV. When SUA modeled continuously, baPWV rose by 12.413 cm/s in women (P < .001) and by 6.588 cm/s in men (P < .001) for each 1 mg/dL increase of SUA. In a low-risk, middle-aged, large Korean population, higher SUA levels could have an unfavorable impact on arterial stiffness as measured by baPWV, and this association was stronger in women than in men.