Rendu–Osler–Weber syndrome presenting with pulmonary arteriovenous fistula

A pulmonary arteriovenous fistula is an abnormal connection between pulmonary arteries and veins. Patients with Rendu–Osler–Weber syndrome may present with this vascular malformation, which is a typical finding of the disease. Approximately 5–15% of Rendu–Osler–Weber syndrome patients have pulmonary arteriovenous malformations (AVM) and there is usually a family history of AVM in these patients. The malformations are usually located in the lower lobes. In this paper, I describe a 49‐year‐old male patient with dyspnoea, cough, haemoptysis and epistaxis. Physical examination showed nasal telangiectasias, cyanosis of the lips and nails, and a systolic bruit over the left lung. Chest X‐ray revealed a 5‐cm mass in the left lower lobe and after magnetic resonance examination, together with 3‐D magnetic resonance angiography, it was demonstrated to be a pulmonary arteriovenous fistula. The history of a niece with a similiar history of suspected pulmonary arteriovenous fistula led me to consider the possibility of Rendu–Osler–Weber syndrome presenting with a pulmonary arteriovenous fistula.     

Factors influencing ultra-endurance athletes food choices: an adapted food choice questionnaire

ABSTRACT

Inadequate nutritional intake has been reported during ultra-endurance training and competition. While substandard nutritional knowledge may contribute to inappropriate nutritional choices, the relationship between these variables is often weak. As such, this study investigated the importance of a range of factors to the food choices of ultra-endurance athletes. An existing food choices questionnaire was extended to reflect the main factors proposed to influence the food choices of these athletes. The questionnaire was pilot tested with endurance athletes, during which, it was refined and reassessed for internal consistency and test-retest reliability. Subsequently, 101 experienced ultra-endurance athletes completed the amended questionnaire. Athletes also documented dietary restrictions or strategies employed in preparation for competition. The factors rated as important by the majority of the athletes were “provides me with energy”, “do not cause me gastrointestinal discomfort” and, “are nutritious”. Despite the high importance of the provision of energy, only 38.2% of participants reported following a high carbohydrate diet in preparation for competition. In addition, given that nutritious foods are typically high in fibre, it is likely that this factor may conflict with the avoidance of gastrointestinal discomfort. The potential incompatibility of these factors may help explain the observed suboptimal nutritional intake.     

Serum glucose and triglyceride determine high-risk subgroups in non-diabetic postinfarction patients

A strategy was developed to identify subgroups at high risk for recurrent coronary events in non-diabetic postinfarction patients as a function of metabolic, inflammatory, and thrombogenic blood markers. A graphical screening technique for presumptively identifying high-risk subgroups from outcome prevalence maps was devised that was equally sensitive for all values of risk factors in contrast to traditional approaches where risk is presumed for the highest or the lowest values. Traditional statistical analysis confirms high risk in identified subgroups. Serum glucose and triglyceride served as bivariate search domain. Results demonstrated three high-risk subgroups. One was characterized as pre-diabetic; another as metabolic syndrome-enriched; and the third, with unexpectedly high risk, as normoglycemic and modestly hypertriglyceridemic. Within-subgroup risk as determined by Cox proportional hazards model gave for odds ratios and 95 percentile confidence intervals: glucose, 2.49 (1.17-5.33) in pre-diabetic; PAI-1, 3.95 (1.81-8.61) in metabolic syndrome-enriched; and BMI, 2.79 (1.17-6.63) and fibrinogen, 2.79 (1.29-6.04) in normoglycemic, modestly hypertriglyceridemic patients. We conclude that the graphical approach holds promise in screening for high-risk patient subgroups. Finding different within-subgroup predictors of risk underscores the notion of context-dependent risk, an observation that may be relevant for determining optimal use of emerging risk factors.     

Preclinical to Clinical Translation of CNS Transporter Occupancy of TD-9855, a Novel Norepinephrine and Serotonin Reuptake Inhibitor

Background:

Monoamine reuptake inhibitors exhibit unique clinical profiles that reflect distinct engagement of the central nervous system (CNS) transporters.

Methods:

We used a translational strategy, including rodent pharmacokinetic/pharmacodynamic modeling and positron emission tomography (PET) imaging in humans, to establish the transporter profile of TD-9855, a novel norepinephrine and serotonin reuptake inhibitor.

Results:

TD-9855 was a potent inhibitor of norepinephrine (NE) and serotonin 5-HT uptake in vitro with an inhibitory selectivity of 4- to 10-fold for NE at human and rat transporters. TD-9855 engaged norepinephrine transporters (NET) and serotonin transporters (SERT) in rat spinal cord, with a plasma EC₅₀ of 11.7ng/mL and 50.8ng/mL, respectively, consistent with modest selectivity for NET in vivo.Accounting for species differences in protein binding, the projected human NET and SERT plasma EC₅₀ values were 5.5ng/mL and 23.9ng/mL, respectively. A single-dose, open-label PET study (4–20mg TD-9855, oral) was conducted in eight healthy males using the radiotracers [¹¹C]-3-amino-4- [2-[(di(methyl)amino)methyl]phenyl]sulfanylbenzonitrile for SERT and [¹¹C]-(S,S)-methylreboxetine for NET. The long pharmacokinetic half-life (30–40h) of TD-9855 allowed for sequential assessment of SERT and NET occupancy in the same subject. The plasma EC₅₀ for NET was estimated to be 1.21ng/mL, and at doses of greater than 4mg the projected steady-state NET occupancy is high (>75%). After a single oral dose of 20mg, SERT occupancy was 25 (±8)% at a plasma level of 6.35ng/mL.

Conclusions:

These data establish the CNS penetration and transporter profile of TD-9855 and inform the selection of potential doses for future clinical evaluation.