Experimental cystinuria: The cycloleucine model. II. Amino acid efflux from intestinal and renal tissues

Loading and unloading experiments using intestinal sacs and renal cortex slices were undertaken to ascertain the role of amino acid efflux in cycloleucine-induced amino-aciduria. The presence of cycloleucine, lysine, or valine on the luminal or antiluminal side of the intestine caused an increased leakage of [¹⁴C] cycloleucine, [¹⁴C] lysine, and [³⁵S] cystine from the tissue. Similar results were obtained when using kidney cortex slices, except for cystine efflux. The latter phenomenon was inhibited by cycloleucine and lysine. Data, also obtained with renal cortex slices, suggest that cystine and cysteine are recognized by different transport sites although one (the oxidized form) may be typically extracellular and the other (the reduced form), intracellular. A comparison of these data with previous works done in our laboratory¹⁴ shows that cycloleucine affects efflux less than influx and further suggests that in rats given cycloleucine, renal transport is impaired only at the brush border level for cystine and at both luminal and antiluminal membranes for dibasic amino acids.     

Sinus slowing produced by experimental ischemia of the sinus node in dogs

The effects on heart rate and rhythm of acutely impeding the blood supply to the sinus node were studied in 18 anesthetized dogs. In 8 dogs the blood supply to the sinus node appeared to originate from 1 main artery, whereas more than 1 source was found in the remaining animals. When the sinus node was supplied by a single main artery, ligation of this artery was followed by a decrease in heart rate whereas, when a multiple blood supply to the sinus node was observed, it was necessary to occlude all major arteries to affect sinus nodal function. The effects observed did not seem related to activation of coronary stretch-sensitive receptors or to local or reflex activation of cholinergic nerve terminals within the sinus node.     

The effects of acetylstrophanthidin on the response of the AV junction to adrenergic stimulation studied in dogs.

The response of the AV junction to adrenergic stimulation was studied in 35 anesthetized open-chest dogs before and after the injection of acetylstrophanthidin (5mug) directly into the AV node artery. An AV junctional rhythm was obtained under control conditions by injecting norepinephrine (n = 9) or isoproterenol (n = 8) into the AV node artery and by stimulation of the left stellate ganglion (n = 11) after selectively injecting propranolol into the sinus node artery. Acetylstrophanthidin brought about various degrees of conduction block from simple PR interval prolongation to complete heart block, and decreased the chronotropic response of the AV junction to adrenergic stimulation. In seven animals the appearance of a spontaneous second degree AV block did not reduce the AV junctional response to adrenergic stimulation. Acetylstrophanthidin also reduced the ventricular acceleration produced by adrenergic stimulation during atrial fibrillation. These results suggest that the anti-adrenergic effect of cardiac glycosides may not only be involved in the mechanism of AV conduction disturbances during digitalis intoxication, but may also play a role in slowing the ventricular rate during atrial fibrillation.     

Preceding His-atrial interval as a determinant of atrioventricular nodal conduction time in the human and rabbit heart

This investigation shows that atrioventricular (A-V) nodal conduction time (A-H interval), both in the human and in the isolated rabbit heart, is determined mainly by the length of the preceding His-atrial (H-A) interval. The A-H intervals obtained during atrial extrasystolic stimulation at different basic rates, during Wenckebach cycles and during both transient and steady state responses to stepwise increases in stimulation frequency were plotted against the corresponding H-A intervals. The A-H intervals were found to have nearly the same duration provided they were preceded by the same H-A interval. The only important difference appeared in the short H-A interval range as a shortening of the A-H interval at faster basic rates. This facilitating effect of frequency, which was found in the majority of cases, is compatible with the similarly frequency-dependent shortening of the functional refractory period of the A-V node.     

Timing of insulin basal rate reduction to reduce hypoglycemia during late post-prandial exercise in adults with type 1 diabetes using insulin pump therapy: A randomized crossover trial

AimsTo compare the efficacy of three timings to decrease basal insulin infusion rate to reduce exercise-induced hypoglycaemia in patients with type 1 diabetes (T1D) using pump therapy.MethodsA single-blinded, randomized, 3-way crossover study in 22 adults that had T1D > 1 year and using insulin pump > 3 months (age, 40 ± 15 years; HbA_1c, 56.3 ± 10.2 mmol/mol). Participants practiced three 45-min exercise sessions (ergocyle) at 60% VO_2peak 3 hours after lunch comparing an 80% reduction of basal insulin applied 40 minutes before (T-40), 20 minutes before (T-20) or at exercise onset (T0).ResultsNo significant difference was observed for percentage of time spent < 4.0 mmol/L (T-40: 16 ± 25%; T-20: 26 ± 27%; T0: 24 ± 29%) (main outcome) and time spent in target range 4.0–10.0 mmol/L (T-40: 63 ± 37%; T-20: 66 ± 25%; T0: 65 ± 31%). With T-40 strategy, although not significant, starting blood glucose (BG) was higher (T-40: 8.6 ± 3.6 mmol/L; T-20: 7.4 ± 2.5 mmol/L ; T0: 7.4 ± 2.7 mmol/L), fewer patients needed extra carbohydrates consumption prior to exercise for BG < 5.0 mmol/L (T-40: n = 3; T-20: n = 5; T0: n = 6) as well as during exercise for BG < 3.3 mmol/L [T-40: n = 6 (27%); T-20: n = 12 (55%); T0: n = 11 (50%)] while time to first hypoglycaemic episode was delayed (T-40: 28 ± 14 min; T-20: 24 ± 10 min; T0: 22 ± 11 min).ConclusionDecreasing basal insulin infusion rate by 80% up to 40 minutes before exercise onset is insufficient to reduce exercise-induced hypoglycaemia.     

Sex-Specific Considerations in Guidelines Generation and Application

New knowledge about male–female differences in pathophysiology, diagnosis, and treatment is shifting the practice of medicine from a one-size-fits all approach to a more individualized process that considers sex-specific interventions at the point of care. In this article, we review how clinical practice guideline committees can incorporate a structured framework to determine whether sex-specific assessments of the quality of the evidence or the particular recommendations should be made. The process can be operationalized by societies who author clinical practice guidelines by developing formal policies to approach biological sex in a systematic way, and by ensuring that writing committees include an individual who will champion the formal appraisal of the literature for associations between sex and the outcomes of interest. Ongoing challenges are discussed, and solutions are provided for how to disaggregate the evidence, how to assess bias, how to improve search strategies, and what to do when the data are insufficient to make sex-specific recommendations. Application of sex-specific recommendations will involve routinely asking whether the presentation, diagnostic workup, or management might change for each patient if they were the opposite sex.     

Transcatheter Aortic Valve Replacement for Severe Aortic Stenosis in Women: Clinical Characteristics and Outcomes

Aortic stenosis (AS), 1 of the most common valve diseases in developed countries, carries a poor prognosis if left untreated. Transcatheter aortic valve replacement (TAVR) has become the standard of care for high-risk and inoperable patients with severe aortic stenosis (AS). Women represent a significant proportion of patients with severe AS and demonstrate specific clinical, anatomic, and pathophysiological features that are evident both before and after valve replacement. In this review, we discuss these features as well as the outcomes of women undergoing TAVR for AS.     

Life span and age-related changes in activity level of the rotifer Asplanchna brightwelli: Influence of curare

The rotifer Asplanchna brightwelli shows a continuous decline in swimming activity through the course of its 5-day life span. This activity loss occurs at a slower rate when rotifers are treated with very low dosages (0.00025% to 0.0005%) curare. Rotifers treated with these low dosages of curare have a significantly longer life span than that of untreated control rotifers.     

The 2017 American College of Cardiology/American Heart Association vs Hypertension Canada High Blood Pressure Guidelines and Potential Implications

In this report we examine the differences between the 2017 Hypertension Canada and 2017 American College of Cardiology and American Heart Association (ACC/AHA) blood pressure (BP) guidelines regarding the proportions of individuals with a diagnosis of hypertension, BP above thresholds for treatment initiation, and BP below targets using the CARTaGENE cohort. Compared with the 2017 Canadian guidelines, the 2017 ACC/AHA guidelines would result in increases of 8.7% in hypertension diagnosis and 3.4% of individuals needing treatment, with 17.2% having a different BP target. In conclusion, implementing the 2017 ACC/AHA hypertension guidelines in Canada could result in major effects for millions of Canadians.     

Functional Dosage of Muscarinic Cholinergic Receptor 3 Signalling,Not the Gene Dose,Determines Its Hypertension Pathogenesis

Background

Multiple quantitative trait loci for blood pressure (BP) have been localized throughout human and rodent genomes. Few of them have been functionally identified especially in humans, and little is known about their pathogenic directionality when identified. We focused on Chrm3 encoding the muscarinic cholinergic receptor 3 (M3R) as the causal gene for C17QTL1 in the Dahl salt-sensitive rat model.

Mechanisms and Clinical Significance of Arrhythmia-Induced Cardiomyopathy

Arrhythmia-induced cardiomyopathy (AIC) is characterized by left ventricular systolic dysfunction for which the primary cause is arrhythmia. The hallmark of AIC is its reversibility once the arrhythmia is properly controlled. Any tachyarrhythmia can potentially cause AIC (often called “tachycardiomyopathy”), with atrial fibrillation (AF) being by far the most common in clinical practice. The pathophysiological mechanisms underlying AIC need further clarification, but the available evidence, principally from animal models, implicates metabolic dysfunction due to increased oxygen requirements, neurohormonal adaptive mechanisms, and cellular Ca²⁺ mishandling as important contributors. Tachycardia is a common denominator of most cases of AIC, but other components specific to the patient and the arrhythmia have been implicated. The diagnosis of AIC requires the exclusion of a primary causative role of other conditions such as hypertension, primary cardiomyopathies, and valve disease, which may require specific pharmacological and invasive therapies. Catheter ablation is emerging as a safe and effective alternative to antiarrhythmic medication and has an established role in the management of AIC. Recent studies showing improved cardiac function and mortality rates in patients with heart failure and concomitant AF dramatically illustrate the often-unrecognized scope of AIC and the potential benefits of interventional therapy. Major AF trials do not otherwise focus specifically on AIC, and careful analysis of the literature is necessary to appreciate the clinical characteristics and therapeutic implications. This contemporary review summarizes the current understanding of pathophysiological mechanisms underlying AIC, discusses the clinical implications, and offers a general approach to management, with a particular focus on AF-induced cardiomyopathy.     

Computer characterization of sinus rhythm.

Sinus rhythm tracings, including sinus tachycardia and bradycardia, are characterized quantitatively by means of an ECG measurement program which has been subjected to rigorous evaluation. The analysis is performed on tracings of short duration (10 sec). The features of regularity and stability are considered for the R wavetrain. Regularity is evaluated from the normalized differences between sucessive RR intervals. Stability is determined by the ratio of maximum and minimum RR interval durations. Due to the difficulities of automatic beat-to-beat detection and measurement of P waves, an estimate of the PR interval is obtained from a pseudo-PR interval determined from certain features of the P and R wavetrains. The constancy of this pseudo-PR interval is evaluated, and its absolute value is uded as a characteristic of the type of sinus rhythm.     

Application of the single moving dipole inverse solution to the study of the Wolff-Parkinson-White syndrome in man

The single moving dipole (SMD) inverse solution was performed in 28 patients with the Wolff-Parkinson-White preexcitation syndrome to see if the calculated position of the SMD during the initial delta wave could indicate the site of the underlying accessory pathway. This site was first estimated to be at one of eight locations around the atrioventricular ring, from the patient's QRS and ST segment body surface potential maps, as has been described by others. Next, SMD parameters were calculated during the delta wave so as to approximate, on a numerical torso model, the patient's body surface potential map. Visualization of the calculated position of the SMD around the atrioventricular ring was done by projecting it on a plane parallel to this ring. This plane corresponded to the most basal transverse section of a heart model present in the torso model. One limitation was the use of non-varying heart and torso models for all patients. As a result, the SMD technique lacked the precision to separate accessory pathway sites into eight atrioventricular locations. However it was capable of distinguishing between patients belonging to the larger classes of right-sided, posterior, and left-sided preexcitation, formed by combining adjacent atrioventricular accessory pathway locations. With more accurate heart and torso models, it may be possible to increase SMD resolution so as to locate accessory pathway sites deep within the heart. This would represent an advantage over the surface potential map approach which only identifies the site of earliest epicardial breakthrough associated with the accessory pathway.     

Sequestration and microsomal C-25 hydroxylation of [3H]-vitamin D3 by the rat liver

A study of the vitamin D3 (D3) 25-hydroxylase was undertaken in an in vivo-in vitro model. [3H]-D3 (0.7, 1.0, 10, or 100 nmol/100 g of body weight) was injected into the portal vein and the liver was excised 18 seconds later. The liver homogenate was then submitted to differential centrifugation and the amount of [3H]-D3 incorporated in the subcellular fractions was evaluated. The microsomal fraction was also incubated in vitro and the appearance of [3H]-25-hydroxyvitamin D3 [25(OH)D3] was determined by high performance liquid chromatography (HPLC). Results showed that the fractional liver [3H]-D3 uptake varied between 37 percent and 48 percent of the dose injected. The intracellular distribution of [3H]-D3 showed that most of the vitamin was incorporated into the microsomal fraction (45% to 50% of the intracellular [3H]-D3) except at the highest dose of [3H]-D3 where the cytosolic fraction contained the highest amount (56.4%) of the incorporated vitamin. Mathematical analysis of the intracellular [3H]-D3 distribution showed that the microsomal fraction was the only subcellular fraction that was found to incorporate [3H]-D3 in relation to the total liver uptake of the vitamin. The apparent Michaelis-Menten kinetics of the [3H]-D3-25-hydroxylase showed that with substrate concentration of up to 88.5 nM, the apparent Km and Vmax were 28.2 nM and 25.8 fentomoles (fmol) X min-1 X mg microsomal pro-1, respectively, but the reaction lost considerable efficiency with higher substrate concentrations. With the in vivo-in vitro model used, the cytosolic fraction was not essential for the optimal C-25 hydroxylation of D3. These results show that the endoplasmic reticulum of rat hepatocytes possess a high capacity for D3 incorporation.(ABSTRACT TRUNCATED AT 250 WORDS)     

Myocardial Partition Coefficient of Gadolinium: A Pilot Study in Patients With Acute Myocarditis,Chronic Myocardial Infarction,and in Healthy Volunteers

Background

The tissue-blood partition coefficient (PC) of gadolinium, derived from T1 measurements, reflects myocardial connective tissue fraction and tissue injury, increasing in proportion with edema or fibrosis. We determined the myocardial PC of gadolinium in patients with acute myocarditis, chronic myocardial infarction (MI), and healthy volunteers. We hypothesized that the characteristics of the injured myocardium in patients with MI and myocarditis may differ and that the PC will be higher in chronically injured myocardium (MI) compared with acutely injured myocardium (myocarditis).