Cardiovascular responses to diving in the turtle, Pseudemys scripta

The cardiovascular responses to diving in the freshwater turtle, Pseudemys scripta, were determined by using the classical techniques of electrocardiography, impedance pneumography and direct blood pressure recording. The radioactive microsphere method was used to measure cardiac output and regional blood flows as well as to quantitate the intracardiac shunting of blood;Following a forced dive (with the animal being firmly attached to an adjustable diving platform) the heart rate gradually decreased by as much as 98%. Voluntarily diving animals, however, usually showed an immediate bradycardia of about 28%. A heart rate reduction similar to that obtained in voluntarily diving animals was occasionally observed during apnea in aerial turtles;Mean systemic and pulmonary arterial blood pressures did not change during diving, but pulse pressures increased about 2-fold. Central venous pressure remained constant;Total heart output was reduced by one-half in forcibly submerged animals. Since the pulmonary and systemic circuits are in parallel rather than in series, blood flow through the 2 systems need not be equal. In the submerged turtles, blood flow to the lungs decreased by 70%, while systemic flow decreased 39%. Stroke volume increased by 146% to the 2 systemic arteries, while increasing only 19% to the pulmonary trunk. Most of the parameters measured showed a large variation between animals;Pulmonary vascular resistance was elevated 235% after forced submergence while the systemic impedance increased 62%. The impedance of the 2 circuits was similar in aerial animals;Above water, animals showed a 25% net right-to-left intracardiac shunt (25% of the right atrial blood being ejected directly into the systemic arches) and this increased to 60% in submerged animals. Therefore, in relative terms, blood flow is being shifted away from the lungs and towards the systemic tissues during a forced dive;Microsphere data indicated that right-to-left shunted blood is directed primarily to the left aorta in turtles. Furthermore, the right atrial blood which did enter the brachiocephalic artery was, in large measure, kept away from the carotid arteries. Since the shunted and unshunted blood which enter the systemic arteries remains separated, viscera received more of the shunted blood, whereas the kidneys and posterior skeletal muscles received less;The vasoconstriction which allows blood pressure to be well maintained during diving appears to be a selective process. During a forced dive, blood was primarily distributed to the brain (537% increase), heart and skeletal muscles. Flow was drastically reduced to most other tissues;Due to methodological considerations, blood flow data could not be obtained in voluntarily diving animals. However, in forcibly submerged turtles, there occurred a cardiovascular response similar to that which is known to occur in birds and mammals

Phenotypic and pharmacogenetic evaluation of patients with thiazide-induced hyponatremia.

Thiazide diuretics are among the most widely used treatments for hypertension, but thiazide-induced hyponatremia (TIH), a clinically significant adverse effect, is poorly understood. Here, we have studied the phenotypic and genetic characteristics of patients hospitalized with TIH. In a cohort of 109 TIH patients, those with severe TIH displayed an extended phenotype of intravascular volume expansion, increased free water reabsorption, urinary prostaglandin E2 excretion, and reduced excretion of serum chloride, magnesium, zinc, and antidiuretic hormone. GWAS in a separate cohort of 48 TIH patients and 2,922 controls from the 1958 British birth cohort identified an additional 14 regions associated with TIH. We identified a suggestive association with a variant in SLCO2A1, which encodes a prostaglandin transporter in the distal nephron. Resequencing of SLCO2A1 revealed a nonsynonymous variant, rs34550074 (p.A396T), and association with this SNP was replicated in a second cohort of TIH cases. TIH patients with the p.A396T variant demonstrated increased urinary excretion of prostaglandin E2 and metabolites. Moreover, the SLCO2A1 phospho-mimic p.A396E showed loss of transporter function in vitro. These findings indicate that the phenotype of TIH involves a more extensive metabolic derangement than previously recognized. We propose one mechanism underlying TIH development in a subgroup of patients in which SLCO2A1 regulation is altered.This work was supported by an Academy of Medical Sciences grant for clinical lecturers (to JSW and MG), British Heart Foundation grant PG/09/089 (to KMO), the National Institute for Health Research (NIHR) Royal Brompton Cardiovascular Biomedical Research Unit (to JSW and SC), the Fondation Leducq (to JSW and SC), and the British Heart Foundation (to JSW and SC). MDT holds a Medical Research Council Senior Clinical Fellowship (G0902313). This work was supported by the Medical Research Council (grant numbers G510364 and G1000861). This research used the ALICE and SPECTRE High Performance Computing Facilities at the University of Leicester

GWAS meta-analysis of intrahepatic cholestasis of pregnancy implicates multiple hepatic genes and regulatory elements

Intrahepatic cholestasis of pregnancy (ICP) is a pregnancy-specific liver disorder affecting 0.5–2% of pregnancies. The majority of cases present in the third trimester with pruritus, elevated serum bile acids and abnormal serum liver tests. ICP is associated with an increased risk of adverse outcomes, including spontaneous preterm birth and stillbirth. Whilst rare mutations affecting hepatobiliary transporters contribute to the aetiology of ICP, the role of common genetic variation in ICP has not been systematically characterised to date. Here, we perform genome-wide association studies (GWAS) and meta-analyses for ICP across three studies including 1138 cases and 153,642 controls. Eleven loci achieve genome-wide significance and have been further investigated and fine-mapped using functional genomics approaches. Our results pinpoint common sequence variation in liver-enriched genes and liver-specific cis-regulatory elements as contributing mechanisms to ICP susceptibility

A role for surface lymphotoxin in experimental autoimmune encephalomyelitis independent of LIGHT

In studies using genetically deficient mice, a role for the lymphotoxin (LT) system in the pathogenesis of experimental autoimmune encephalomyelitis (EAE) has remained controversial. Here, we have reassessed this conclusion by using a fusion protein decoy that blocks the LT pathway in vivo without evoking the developmental defects inherent in LT-deficient mice. We have found that inhibition of the LT pathway prevented disease in two models of EAE that do not rely on the administration of pertussis toxin. Surprisingly, disease attenuation was due to specific blockade of LTαβ binding rather than the binding of LIGHT to its receptors. In a third system that requires pertussis toxin, LT inhibition did not affect disease, as was observed when the same model was used with LT-deficient mice. Disease prevention in pertussis toxin–free models was associated with defects in T cell responses and migration. When the DO11.10 T cell transgenic system was used, inhibition of the LT pathway was shown to uncouple T cell priming from T cell recall responses. Therefore, it is hypothesized that the LT pathway and its ability to maintain lymphoid microenvironments is critical for sustaining late-phase T cell responses in multiple sclerosis

The effect of reactive oxygen species on whole blood aggregation and the endothelial cell-platelet interaction in patients with coronary heart disease

<b>Background</b><p></p> The effect of reactive oxygen species (ROS) on platelet function in coronary heart disease (CHD) is complex and poorly defined. Platelet aggregation studies in healthy volunteers have demonstrated contrasting results when platelets are exposed to ROS. We investigated the effect of ROS on whole blood aggregation (WBA) and the endothelial cell-platelet interaction in patients with CHD. <p></p> <b>Methods and Results</b><p></p> ROS generated by xanthine and xanthine oxidase caused a concentration-dependent inhibition of WBA in blood from healthy donors and patients with CHD. In patients with CHD, 100 μM xanthine and 100 mU/ml xanthine oxidase inhibited WBA in response to 3 μg/ml collagen by 28.9% (95% CI 15.9%-41.8%, p < 0.001) and in response to 5 μM ADP by 36.0% (95% CI 9.6%-62.4%, p = 0.005). Using nitrotyrosine expression, platelets isolated from patients with CHD were found to be susceptible to peroxynitrite damage. The addition of 1 × 10<sup>5</sup> cultured endothelial cells inhibited WBA in response to 3 μg/ml collagen by 31.2% (95% CI 12.2%-50.2%, p < 0.05) and in response to 5 μM ADP by 31.6% (95% CI 2.5-60.7%, p < 0.05). Addition of xanthine and xanthine oxidase did not alter this effect, however pre-treatment of endothelial cells with a nitric oxide synthase inhibitor (L-NAME) partly reversed the inhibition. <p></p> <b>Conclusion</b><p></p> ROS inhibit WBA in blood from patients with CHD. Whilst endothelial cells also inhibit WBA, the effect is attenuated by L-NAME, suggesting that nitric oxide is likely to remain an important protective mechanism against thrombosis in CHD. <p></p&gt