Lactate: brain fuel in human traumatic brain injury: a comparison with normal healthy control subjects.

We evaluated the hypothesis that lactate shuttling helps support the nutritive needs of injured brains. To that end, we utilized dual isotope tracer [6,6-(2)H2]glucose, that is, D2-glucose, and [3-(13)C]lactate techniques involving arm vein tracer infusion along with simultaneous cerebral (arterial [art] and jugular bulb [JB]) blood sampling. Traumatic brain injury (TBI) patients with nonpenetrating brain injuries (n=12) were entered into the study following consent of patients' legal representatives. Written and informed consent was obtained from control volunteers (n=6). Patients were studied 5.7±2.2 (mean±SD) days post-injury; during periods when arterial glucose concentration tended to be higher in TBI patients. As in previous investigations, the cerebral metabolic rate for glucose (CMRgluc, i.e., net glucose uptake) was significantly suppressed following TBI (p<0.001). However, lactate fractional extraction, an index of cerebral lactate uptake related to systemic lactate supply, approximated 11% in both healthy control subjects and TBI patients. Further, neither the CMR for lactate (CMRlac, i.e., net lactate release), nor the tracer-measured cerebral lactate uptake differed between healthy controls and TBI patients. The percentages of lactate tracer taken up and released as (13)CO2 into the JB accounted for 92% and 91% for control and TBI conditions, respectively, suggesting that most cerebral lactate uptake was oxidized following TBI. Comparisons of isotopic enrichments of lactate oxidation from infused [3-(13)C]lactate tracer and (13)C-glucose produced during hepatic and renal gluconeogenesis (GNG) showed that 75-80% of (13)CO2 released into the JB was from lactate and that the remainder was from the oxidation of glucose secondarily labeled from lactate. Hence, either directly as lactate uptake, or indirectly via GNG, peripheral lactate production accounted for ∼70% of carbohydrate (direct lactate uptake+uptake of glucose from lactate) consumed by the injured brain. Undiminished cerebral lactate fractional extraction and uptake suggest that arterial lactate supplementation may be used to compensate for decreased CMRgluc following TBI

Endogenous Nutritive Support after Traumatic Brain Injury: Peripheral Lactate Production for Glucose Supply via Gluconeogenesis.

We evaluated the hypothesis that nutritive needs of injured brains are supported by large and coordinated increases in lactate shuttling throughout the body. To that end, we used dual isotope tracer ([6,6-(2)H2]glucose, i.e., D2-glucose, and [3-(13)C]lactate) techniques involving central venous tracer infusion along with cerebral (arterial [art] and jugular bulb [JB]) blood sampling. Patients with traumatic brain injury (TBI) who had nonpenetrating head injuries (n=12, all male) were entered into the study after consent of patients' legal representatives. Written and informed consent was obtained from healthy controls (n=6, including one female). As in previous investigations, the cerebral metabolic rate (CMR) for glucose was suppressed after TBI. Near normal arterial glucose and lactate levels in patients studied 5.7±2.2 days (range of days 2-10) post-injury, however, belied a 71% increase in systemic lactate production, compared with control, that was largely cleared by greater (hepatic+renal) glucose production. After TBI, gluconeogenesis from lactate clearance accounted for 67.1% of glucose rate of appearance (Ra), which was compared with 15.2% in healthy controls. We conclude that elevations in blood glucose concentration after TBI result from a massive mobilization of lactate from corporeal glycogen reserves. This previously unrecognized mobilization of lactate subserves hepatic and renal gluconeogenesis. As such, a lactate shuttle mechanism indirectly makes substrate available for the body and its essential organs, including the brain, after trauma. In addition, when elevations in arterial lactate concentration occur after TBI, lactate shuttling may provide substrate directly to vital organs of the body, including the injured brain

Emergency department referral patterns of Australian general practitioner registrars: A cross-sectional analysis of prevalence, nature and associations

Objective: Limited international evidence suggests general practice registrars' emergency department (ED) referral rates exceed those of established general practitioners (GPs). The aim of the present study was to fill an evidence gap by establishing the prevalence, nature and associations of Australian GP registrar ED referrals. Methods: A cross-sectional analysis was performed of the Registrar Clinical Encounters in Training (ReCEnT) cohort study of GP registrars' consultation experiences, between 2010 and 2015. The outcome factor in logistic regression analysis was referral to an ED. Independent variables included patient-level, registrar-level, practice-level and consultation-level factors. Results: In all, 1161 GP registrars (response rate 95.5%) contributed data from 166 966 consultations, comprising 258 381 individual problems. Based on responses, 0.5% of problems resulted in ED referral, of which nearly 25% comprised chest pain, abdominal pain and fractures. Significant (P 34 years, the patient being new to the registrar, one particular regional training provider (RTP), in-consultation information or assistance being sought and learning goals being generated. Outer regional-, remote-or very remote-based registrars made significantly fewer ED referrals than more urban registrars. Of the problems referred to the ED, 45.5% involved the seeking of in-consultation information or assistance, predominantly from supervisors. Conclusions: Registrars' ED referral rates are nearly twice those of established GPs. The findings of the present study suggest acute illnesses or injuries present registrars with clinical challenges and real learning opportunities, and highlight the importance of continuity of care, even for acute presentations

Investigation of fatigue by Australian General Practice Registrars: a cross-sectional study

INTRODUCTION: Fatigue is the most common undifferentiated problem presenting in general practice. Previous studies have shown that this presentation leads to multiple investigations. There is no published literature describing the management of patients with fatigue by general practice (GP) registrars. AIM: To document the investigation-ordering behaviour of GP registrars in managing patients with a new diagnosis of unexplained fatigue. METHODS: This was a cross-sectional analysis of data from Registrar Clinical Encounters in Training (ReCEnT), an ongoing cohort study of GP registrars’ consultations. We established the prevalence of new diagnoses of unexplained fatigue and associations with that diagnosis, the rate of test ordering and the number and types of investigations ordered. RESULTS: 644 registrars contributed data from 68 986 encounters. In 0.78% of patient encounters, a new diagnosis of unexplained fatigue was made. Pathology was ordered in 78.4% of these problems (versus 18.1% in non-fatigue problems), at a rate of 488 tests per 100 new fatigue problems. DISCUSSION: Our study suggests that unexplained fatigue elicits a non-rational approach to test ordering by registrars. These findings contribute to the understanding of GP registrar management of fatigue, and undifferentiated presentations more broadly, and suggest educational approaches to improve practice, including dealing with uncertainty

Australian general practice trainees’ exposure to ophthalmic problems and implications for training: A cross-sectional analysis

INTRODUCTION: Eye conditions are common presentations in Australian general practice, with the potential for serious sequelae. Pre-vocational ophthalmology training for General Practitioner (GP) trainees is limited. AIM: To describe the rate, nature and associations of ophthalmic problems managed by Australian GP trainees, and derive implications for education and training. METHODS: Cross-sectional analysis from an ongoing cohort study of GP trainees’ clinical consultations. Trainees recorded demographic, clinical and educational details of consecutive patient consultations. Descriptive analyses report trainee, patient and practice demographics. Proportions of all problems managed in these consultations that were ophthalmology-related were calculated with 95% confidence intervals (CI). Associations were tested using simple logistic regression within the generalised estimating equations (GEE) framework. RESULTS: In total, 884 trainees returned data on 184,476 individual problems or diagnoses from 118,541 encounters. There were 2649 ophthalmology-related problems, equating to 1.4% (95% CI: 1.38-1.49) of all problems managed. The most common eye presentations were conjunctivitis (32.5% of total problems), eyelid problems (14.9%), foreign body (5.3%) and dry eye (4.7%). Statistically significant associations were male trainee; male patient and patient aged 14 years or under; the problem being new and the patient being new to both trainee and practice; urban and of higher socioeconomic status practice location; the practice nurse not being involved; planned follow up not arranged; referral made; in-consultation information sought; and learning goals generated. DISCUSSION: Trainees have comparable ophthalmology exposure to established GPs. However, associations with referral and information-seeking suggest GP trainees find ophthalmic problems challenging, reinforcing the critical importance of appropriate training

Preventing phosphorylation of dystroglycan ameliorates the dystrophic phenotype in mdx mouse

Loss of dystrophin protein due to mutations in the DMD gene causes Duchenne muscular dystrophy. Dystrophin loss also leads to the loss of the dystrophin glycoprotein complex (DGC) from the sarcolemma which contributes to the dystrophic phenotype. Tyrosine phosphorylation of dystroglycan has been identified as a possible signal to promote the proteasomal degradation of the DGC. In order to test the role of tyrosine phosphorylation of dystroglycan in the aetiology of DMD, we generated a knock-in mouse with a phenylalanine substitution at a key tyrosine phosphorylation site in dystroglycan, Y890. Dystroglycan knock-in mice (Dag1Y890F/Y890F) had no overt phenotype. In order to examine the consequence of blocking dystroglycan phosphorylation on the aetiology of dystrophin-deficient muscular dystrophy, the Y890F mice were crossed with mdx mice an established model of muscular dystrophy. Dag1Y890F/Y890F/mdx mice showed a significant improvement in several parameters of muscle pathophysiology associated with muscular dystrophy, including a reduction in centrally nucleated fibres, less Evans blue dye infiltration and lower serum creatine kinase levels. With the exception of dystrophin, other DGC components were restored to the sarcolemma including α-sarcoglycan, α-/β-dystroglycan and sarcospan. Furthermore, Dag1Y890F/Y890F/mdx showed a significant resistance to muscle damage and force loss following repeated eccentric contractions when compared with mdx mice. While the Y890F substitution may prevent dystroglycan from proteasomal degradation, an increase in sarcolemmal plectin appeared to confer protection on Dag1Y890F/Y890F/mdx mouse muscle. This new model confirms dystroglycan phosphorylation as an important pathway in the aetiology of DMD and provides novel targets for therapeutic intervention