G. D. P. Smith

Abnormal cardiovascular and catecholamine responses to supine exercise in human subjects with sympathetic dysfunction.

1. The cardiovascular and catecholamine responses to supine leg exercise were measured in fifteen normal subjects (controls) and in three groups with sympathetic dysfunction: fifteen with central failure (Shy‐Drager syndrome; SDS), fifteen with peripheral failure (pure autonomic failure; PAF) and two with isolated dopamine beta‐hydroxylase deficiency (DBH deficiency). 2. With exercise, blood pressure increased in controls, fell markedly in SDS and PAF and was unchanged in DBH deficiency. After exercise, blood pressure rapidly returned to baseline in controls, but remained low in SDS and PAF. With exercise, heart rate increased more in controls than SDS or PAF; the response varied in DBH deficiency. 3. With exercise, cardiac output increased similarly in controls, SDS and PAF, with a larger increase in DBH deficiency. Vascular resistance fell less in controls than SDS, PAF and DBH deficiency. 4. With exercise, plasma noradrenaline increased in controls only; plasma adrenaline remained unchanged in all groups. In DBH deficiency, plasma noradrenaline and adrenaline were undetectable, but plasma dopamine was elevated and rose further with exercise. 5. Supine exercise substantially lowered blood pressure in sympathetic failure due to SDS and PAF. In DBH deficiency blood pressure was unchanged; this lack of fall may have been due to vasoconstriction induced by dopamine and other substances released from otherwise intact sympathetic terminals, or to preserved cardiac vagal function.

A trusted mechanised JavaScript specification

JavaScript is the most widely used web language for client-side applications. Whilst the development of JavaScript was initially just led by implementation, there is now increasing momentum behind the ECMA standardisation process. The time is ripe for a formal, mechanised specification of JavaScript, to clarify ambiguities in the ECMA standards, to serve as a trusted reference for high-level language compilation and JavaScript implementations, and to provide a platform for high-assurance proofs of language properties. We present JSCert, a formalisation of the current ECMA standard in the Coq proof assistant, and JSRef, a reference interpreter for JavaScript extracted from Coq to OCaml. We give a Coq proof that JSRef is correct with respect to JSCert and assess JSRef using test262, the ECMA conformance test suite. Our methodology ensures that JSCert is a comparatively accurate formulation of the English standard, which will only improve as time goes on. We have demonstrated that modern techniques of mechanised specification can handle the complexity of JavaScript.

Abnormal regional blood flow responses during and after exercise in human sympathetic denervation

2 Blood pressure, superior mesenteric artery (SMA) and skeletal muscle blood flow, cardiac index (CI) and systemic vascular resistance responses to supine leg exercise were measured in six age‐matched normal subjects (controls) and in eleven subjects with sympathetic denervation due to primary autonomic failure (AF). 2 During exercise, blood pressure rose in controls but fell markedly in AF. After exercise, blood pressure rapidly returned to baseline in controls but remained low in AF. During exercise, systemic vascular resistance fell in controls and AF but tended to fall further in AF and remained low post exercise. CI increased similarly in controls and AF. 3 During exercise, SMA blood flow fell similarly in controls and AF, but the fall initially was slower in AF; recovery was more rapid post exercise in controls. SMA vascular resistance tended to rise less and more slowly in AF and remained elevated post exercise. 4 Forearm muscle (FM) blood flow and FM vascular resistance did not change from resting values in controls or AF post exercise. After exercise, leg muscle (LM) blood flow rose and LM vascular resistance fell equally in both groups although LM blood flow remained elevated, 10 min post exercise in AF. 5 In sympathetically denervated humans, increased blood flow (due to excessive vasodilatation, lack of sympathetic restraint, or both) in leg muscle during and after exercise in combination with impaired splanchnic vasoconstriction in the early stages of exercise may have contributed to exercise‐induced hypotension.

Neurohumoral, peptidergic and biochemical responses to supine exercise in two groups with primary autonomic failure: Shy-Drager syndrome/multiple system atrophy and pure autonomic failure.

The neurohumoral, peptidergic and biochemical responses to supine leg exercise were studied in two groups with primary autonomic failure: Shy-Drager syndrome (SDS, n=15) and pure autonomic failure (PAF, n=15), to determine if these accounted for exercise-induced hypotension and the greater blood pressure (BP) fall in PAF. Responses were compared to normal subjects (controls, n=15), in whom BP rose with exercise. Resting plasma noradrenaline (NA) was higher in controls than SDS, and was lowest in PAF. With exercise, NA increased in controls, with a small rise in SDS, but no change in PAF. Resting plasma adrenaline (A) was higher in controls and SDS than PAF, with no change during exercise. Plasma dopamine was unrecordable at all stages in all groups. Resting plasma renin activity (PRA) was higher in controls than SDS and PAF, and was unchanged with exercise in all groups. Plasma insulin, C-peptide and serum growth hormone (GH) were similar at rest and with exercise in the three groups. Plasma glucose was higher at rest in SDS and PAF, and increased with exercise in all three groups. In conclusion, neither exercise-induced hypotension, nor the differences between SDS and PAF could be related to abnormalities in the release of A, PRA, insulin, glucose or GH. The abnormal NA response to exercise was consistent with the BP fall being due to inadequate compensatory sympathetic activity. In SDS, the small NA increase, in the presence of supersensitivity, may have reduced their BP fall as compared to PAF. These results suggest that impaired sympathetic neural activity is a key factor in execise-induced hypotension.The neurohumoral, peptidergic and biochemical responses to supine leg exercise were studied in two groups with primary autonomic failure: Shy-Drager syndrome (SDS, n=15) and pure autonomic failure (PAF, n=15), to determine if these accounted for exercise-induced hypotension and the greater blood pressure (BP) fall in PAF. Responses were compared to normal subjects (controls, n=15), in whom BP rose with exercise. Resting plasma noradrenaline (NA) was higher in controls than SDS, and was lowest in PAF. With exercise, NA increased in controls, with a small rise in SDS, but no change in PAF. Resting plasma adrenaline (A) was higher in controls and SDS than PAF, with no change during exercise. Plasma dopamine was unrecordable at all stages in all groups. Resting plasma renin activity (PRA) was higher in controls than SDS and PAF, and was unchanged with exercise in all groups. Plasma insulin, C-peptide and serum growth hormone (GH) were similar at rest and with exercise in the three groups. Plasma glucose was higher at rest in SDS and PAF, and increased with exercise in all three groups. In conclusion, neither exercise-induced hypotension, nor the differences between SDS and PAF could be related to abnormalities in the release of A, PRA, insulin, glucose or GH. The abnormal NA response to exercise was consistent with the BP fall being due to inadequate compensatory sympathetic activity. In SDS, the small NA increase, in the presence of supersensitivity, may have reduced their BP fall as compared to PAF. These results suggest that impaired sympathetic neural activity is a key factor in execise-induced hypotension.

A Trusted Mechanised Specification of JavaScript: One Year On

The JSCert project provides a Coq mechanised specification of the core JavaScript language. A key part of the project was to develop a methodology for establishing trust, by designing JSCert in such a way as to provide a strong connection with the JavaScript standard, and by developing JSRef, a reference interpreter which was proved correct with respect to JSCert and tested using the standard Test262 test suite. In this paper, we assess the previous state of the project at POPL’14 and the current state of the project at CAV’15. We evaluate the work of POPL’14, providing an analysis of the methodology as a whole and a more detailed analysis of the tests. We also describe recent work on extending JSRef to include Google’s V8 Array library, enabling us to cover more of the language and to pass more tests.