Elevated Circulating Lactate Levels and Widespread Expression of Its Cognate Receptor, Hydroxycarboxylic Acid Receptor 1 (HCAR1), in Ovarian Cancer.

Background: Augmented glycolysis in cancer cells is a process required for growth and development. The Warburg effect provides evidence of increased glycolysis and lactic acid fermentation in cancer cells. The lactate end-product of glycolysis is receiving growing traction for its role as a cell signalling molecule. Ovarian cancer (OvCa) is also characterised by altered glucose metabolism. We aim to explore circulating lactate levels in patients with high-grade serous OvCa (HGSOC) and to elucidate the expression of the lactate receptor hydroxycarboxylic acid receptor 1 (HCAR1) in OvCa. Methods: HCAR1 expression was detected in patient biopsy cores using immunohistochemistry, while lactate was measured from whole blood with a Biosen-C line clinic measuring system. Results: We noted significantly elevated lactate levels in OvCa patients (4.3 ± 1.9 mmol/L) compared with healthy controls (1.4 ± 0.6 mmol/L; p < 0.0001), with an AUC of 0.96. The HCAR1 gene is overexpressed in OvCa compared to healthy controls (p < 0.001). Using an OvCa tissue microarray (>75% expression in 100 patients), high protein expression was also recorded across all epithelial OvCa subtypes and ovarian normal adjacent tissue (NAT). Conclusions: Lactate monitoring is a simple, cost-efficient test that can offer point-of-care results. Our data suggest that the potential of circulating lactate as a screening biomarker in OvCa merits further research attention.

Reference values for the 12 minute walk test in McArdle patients.

The maximum distance achieved on a modified 12 min walk test (12MWT) is a well-established measure in McArdle disease glycogen storage disease type V (GSDV). Age, height, body mass and gender are known predictors of walking distance in other patient groups. Reference values to correct for these predictors are necessary for comparisons between individuals. To date, there has not been a systematic investigation of these predictors in the 12MWT in GSDV. This study explores the contribution of these predictors on distance achieved in GSDV. Data, included maximum distance walked, age, gender, height and body mass, was collected from 103 GSDV patients who underwent 12MWT between 2011 and 2017. Analysis showed a significant correlation between distance achieved and height, age, body mass and gender. Multiple linear regression analysis revealed a model accounting for 29.7% of variance (R = 0.545, R2 0.297, adjusted R2 0.269). Gender was not significant after height, age and body mass were entered into the regression analysis. This is the first study to report the contribution of non-disease related factors on distance achieved on the 12MWT in the GSDV population. The reference values generated will allow for improved monitoring and assessment of GSDV patients in clinical and research settings.

Results of an open label feasibility study of sodium valproate in people with McArdle disease.

McArdle disease results from a lack of muscle glycogen phosphorylase in skeletal muscle tissue. Regenerating skeletal muscle fibres can express the brain glycogen phosphorylase isoenzyme. Stimulating expression of this enzyme could be a therapeutic strategy. Animal model studies indicate that sodium valproate (VPA) can increase expression of phosphorylase in skeletal muscle affected with McArdle disease. This study was designed to assess whether VPA can modify expression of brain phosphorylase isoenzyme in people with McArdle disease. This phase II, open label, feasibility pilot study to assess efficacy of six months treatment with VPA (20 mg/kg/day) included 16 people with McArdle disease. Primary outcome assessed changes in VO2peak during an incremental cycle test. Secondary outcomes included: phosphorylase enzyme expression in post-treatment muscle biopsy, total distance walked in 12 min, plasma lactate change (forearm exercise test) and quality of life (SF36). Safety parameters. 14 participants completed the trial, VPA treatment was well tolerated; weight gain was the most frequently reported drug-related adverse event. There was no clinically meaningful change in any of the primary or secondary outcome measures including: VO2peak, 12 min walk test and muscle biopsy to look for a change in the number of phosphorylase positive fibres between baseline and 6 months of treatment. Although this was a small open label feasibility study, it suggests that a larger randomised controlled study of VPA, may not be worthwhile.

The potential of a ketogenic diet to minimize effects of the metabolic fault in glycogen storage disease V and VII.

PURPOSE OF REVIEW: To explore the potential of a low carbohydrate ketogenic diet (LCKD) to counter physical activity intolerance, pain and muscle damage for glycogen storage disease (GSD) V and VII, and highlight the realistic possibility that nutrition could be key. RECENT FINDINGS: Carbohydrate (CHO) ingestion during physical activity in GSDV and a LCKD for GSDVII is common. For the latter, a long-term study demonstrated improvement in physiological markers while on a LCKD. This included improvement in aerobic power and activity tolerance. In GSDV, preliminary research on a LCKD suggest a diet of 75% fat, 15% protein, 10% CHO, is best for improved function and compliance. Ketones provide immediate fuel for acute physical activity, and have an epigenetic role, improving ketone and lipid use. Evidence from elite athletes found a LCKD can increase fat oxidation and is optimal at 70% VO2max. This suggests the need to also improve conditioning via exercise to maximize the benefit of a LCKD. SUMMARY: A high CHO diet in GSDV and VII comes with a restricted physical activity capacity alongside significant pain, muscle damage and risk of renal failure. Mounting evidence suggests a LCKD is efficacious for both disorders providing an immediate fuel source which may negate the need for a 'warm-up' prior to every activity and restore 'normal' function.

Granulomatous Mastitis: Comparison of Novel Treatment of Steroid Injection and Current Management.

BACKGROUND: Granulomatous mastitis (GM) is a rare entity of benign origin. Multiple treatment strategies, including surgical procedures, can have sequelae of recurrence, nonhealing wounds, and protracted pain. Even after GM is diagnosed, the best management strategy remains controversial. We sought to evaluate intralesional steroid injection as a potential treatment for GM. MATERIALS AND METHODS: Electronic medical records from 2003 to 2017 of patients diagnosed with benign breast lesions were retrospectively reviewed. Patients with pathologically confirmed GM were identified. All treatment methods were documented, which included observation, oral steroids, methotrexate, steroid injection, and surgical excision. Primary outcome was time to resolution. Effectiveness was based on relief of symptoms along with duration of symptoms from initial time of diagnosis to full relief. Analysis of variance was used to compare outcomes between groups. RESULTS: Of the 49 patients with confirmed GM diagnoses, 57% had observation only, 24% had steroid injection, and 19% had surgical resection. The average time to resolution differed significantly among the three groups (11.5 mo from the start of observation, 2.0 mo from the time of steroid injection, and 0.5 mo from the time of surgical excision, P < 0.001). CONCLUSIONS: Intralesional steroid injection is an effective treatment of GM. Selective management is appropriate for patients with GM, and surgical resection is not required for most patients.

The need for biochemical testing in beta-enolase deficiency in the genomic era.

Glycogen storage disease type XIII (GSDXIII) is a very rare inherited metabolic myopathy characterized by autosomal-recessive mutations in the ENO3 gene resulting in muscle ß-enolase deficiency, an enzymatic defect of the distal part of glycolysis. Enzyme kinetic studies of two patients presenting with exertion intolerance and recurrent rhabdomyolysis are reported. Next generation sequencing confirmed patient 1 was homozygous for p.E187K in ENO3, while patient 2 was homozygous for p.C357Y. ENO3 variants pathogenicity was confirmed by functional studies in skeletal muscle. p.E187K caused extremely low total enolase activity. p.C357Y was associated with a higher level of residual activity but kinetic studies showed a lower maximum work rate (V max). This study illustrates that GSDXIII may be caused by either null mutations leading to ß-enolase deficiency or by mutations that alter the enzyme's kinetic profile. This study highlights the importance of carrying out functional studies as part of the diagnostic process following the identification of variants with next generation sequencing.

Misdiagnosis is an important factor for diagnostic delay in McArdle disease.

Diagnosis of McArdle disease is frequently delayed by many years following the first presentation of symptoms to a health professional. The aim of this study was to investigate the importance of misdiagnosis in delaying diagnosis of McArdle disease. The frequency of misdiagnosis, duration of diagnostic delay, categories of misdiagnoses and inappropriate medical interventions were assessed in 50 genetically confirmed patients. The results demonstrated a high frequency of misdiagnosis (90%, n = 45/50) most commonly during childhood years (67%; n = 30/45) compared with teenage years and adulthood (teenage: n = 7/45; adult n = 5/45; not known n = 3/45). The correct diagnosis of McArdle disease was rarely made before adulthood (median age of diagnosis 33 years). Thirty-one patients (62%) reported having received more than one misdiagnosis; the most common were "growing pains" (40%, n = 20) and "laziness/being unfit" (46%, n = 23). A psychiatric/psychological misdiagnosis was significantly more common in females than males (females 6/20; males 1/30; p < 0.01). Of the 45 patients who were misdiagnosed, 21 (47%) received incorrect management. This study shows that most patients with McArdle disease received an incorrect explanation of their symptoms providing evidence that misdiagnosis plays an important part in delaying implementation of appropriate medical advice and management to this group of patients.

The effect of the oxygen uptake-power output relationship on the prediction of supramaximal oxygen demands.

BACKGROUND: The aim of this study was to investigate the relationship between oxygen uptake (V̇O2) and power output at intensities below and above the lactate threshold (LT) in cyclists; and to determine the reliability of supramaximal power outputs linearly projected from these relationships. METHODS: Nine male cyclists (mean±standard deviation age: 41±8 years; mass: 77±6 kg, height: 1.79±0.05 m and V̇O2max: 54±7 mL∙kg-1∙min-1) completed two cycling trials each consisting of a step test (10×3 min stages at submaximal incremental intensities) followed by a maximal test to exhaustion. The lines of best fit for V̇O2 and power output were determined for: the entire step test; stages below and above the LT, and from rolling clusters of five consecutive stages. Lines were projected to determine a power output predicted to elicit 110% peak V̇O2. RESULTS: There were strong linear correlations (r≥0.953; P<0.01) between V̇O2 and power output using the three approaches; with the slope, intercept, and projected values of these lines unaffected (P≥0.05) by intensity. The coefficient of variation of the predicted power output at 110% V̇O2max was 6.7% when using all ten submaximal stages. CONCLUSIONS: Cyclists exhibit a linear V̇O2 and power output relationship when determined using 3 min stages, which allows for prediction of a supramaximal intensity with acceptable reliability.

Accumulated Oxygen Deficit During Exercise to Exhaustion Determined at Different Supramaximal Work Rates.

PURPOSE: The aim of the study was to determine the effect of supramaximal exercise intensity during constant work-rate cycling to exhaustion on the accumulated oxygen deficit (AOD) and to determine the test-retest reliability of AOD. METHODS: Twenty-one trained male cyclists and triathletes (mean ± SD for age and maximal oxygen uptake [V̇O2max] were 41 ± 7 y and 4.53 ± 0.54 L/min, respectively) performed initial tests to determine the linear relationship between V̇O2 and power output, and V̇O2max. In subsequent trials, AOD was determined from exhaustive square-wave cycling trials at 105%, 112.5% (in duplicate), 120%, and 127.5% V̇O2max. RESULTS: Exercise intensity had an effect (P = .011) on the AOD (3.84 ± 1.11, 4.23 ± 0.96, 4.09 ± 0.87, and 3.93 ± 0.89 L at 105%, 112.5%, 120%, and 127.5% V̇O2max, respectively). Specifically, AOD at 112.5% V̇O2max was greater than at 105% V̇O2max (P = .033) and at 127.5% V̇O2max (P = .022), but there were no differences between the AOD at 112.5% and 120% V̇O2max. In 76% of the participants, the maximal AOD occurred at 112.5% or 120% V̇O2max. The reliability statistics of the AOD at 112.5% V̇O2max, determined as intraclass correlation coefficient and coefficient of variation, were .927 and 8.72%, respectively. CONCLUSIONS: The AOD, determined from square-wave cycling bouts to exhaustion, peaks at intensities of 112.5-120% V̇O2max. Moreover, the AOD at 112.5% V̇O2max exhibits an 8.72% test-retest reliability.

A comparison of methods to estimate anaerobic capacity: Accumulated oxygen deficit and W' during constant and all-out work-rate profiles.

This study investigated (i) whether the accumulated oxygen deficit (AOD) and curvature constant of the power-duration relationship (W') are different during constant work-rate to exhaustion (CWR) and 3-min all-out (3MT) tests and (ii) the relationship between AOD and W' during CWR and 3MT. Twenty-one male cyclists (age: 40 ± 6 years; maximal oxygen uptake [V̇O2max]: 58 ± 7 ml · kg-1 · min-1) completed preliminary tests to determine the V̇O2-power output relationship and V̇O2max. Subsequently, AOD and W' were determined as the difference between oxygen demand and oxygen uptake and work completed above critical power, respectively, in CWR and 3MT. There were no differences between tests for duration, work, or average power output (P ≥ 0.05). AOD was greater in the CWR test (4.18 ± 0.95 vs. 3.68 ± 0.98 L; P = 0.004), whereas W' was greater in 3MT (9.55 ± 4.00 vs. 11.37 ± 3.84 kJ; P = 0.010). AOD and W' were significantly correlated in both CWR (P < 0.001, r = 0.654) and 3MT (P < 0.001, r = 0.654). In conclusion, despite positive correlations between AOD and W' in CWR and 3MT, between-test differences in the magnitude of AOD and W', suggest that both measures have different underpinning mechanisms.

McArdle Disease Misdiagnosed as Meningitis.

BACKGROUND McArdle disease is a glycogen storage disorder mainly characterized by exercise intolerance. Prolonged muscle contracture is also a feature of this condition and may lead to rhabdomyolysis (RM), which is a serious event characterized by acute skeletal muscle damage.  CASE REPORT A 44-year-old female patient presented with an acute contracture of the posterior neck muscles, causing severe nuchal rigidity. The contracture was induced during a dental extraction as she held her mouth open for a prolonged period, with her neck in a rigid position. She presented with severe pain in her ear and head, as well as fever, vomiting, and confusion. Based on her symptoms, she was initially misdiagnosed with bacterial meningitis and experienced an acute allergic reaction to the systemic penicillin she was subsequently administered. Lumbar puncture results were normal. High serum creatine kinase (CK) levels, recurrent exercise-related muscle symptoms, and a previous history of recurrent myoglobinuria raised the suspicion of an underlying neuromuscular condition. McArdle disease was confirmed by muscle biopsy and a genetic test, which revealed that the patient was homozygous for the R50X mutation in the PYGM gene. CONCLUSIONS This case illustrates that even seemingly innocuous movements, if rapid isotonic or prolonged isometric in nature, can elicit a muscle contracture in McArdle disease patients. Here, we highlight the need for careful management in this patient population even during routine healthcare procedures. The allergic reaction to antibiotics emphasises that misdiagnoses may result in iatrogenic harm.

Skeletal muscle disorders of glycogenolysis and glycolysis.

Skeletal muscle disorders of glycogenolysis and glycolysis account for most of the conditions collectively termed glycogen storage diseases (GSDs). These disorders are rare (incidence 1 in 20,000-43,000 live births), and are caused by autosomal or X-linked recessive mutations that result in a specific enzyme deficiency, leading to the inability to utilize muscle glycogen as an energy substrate. McArdle disease (GSD V) is the most common of these disorders, and is caused by mutations in the gene encoding muscle glycogen phosphorylase. Symptoms of McArdle disease and most other related GSDs include exercise intolerance, muscle contracture, acute rhabdomyolysis, and risk of acute renal failure. Older patients may exhibit muscle wasting and weakness involving the paraspinal muscles and shoulder girdle. For patients with these conditions, engaging with exercise is likely to be beneficial. Diagnosis is frequently delayed owing to the rarity of the conditions and lack of access to appropriate investigations. A few randomized clinical trials have been conducted, some focusing on dietary modification, although the quality of the evidence is low and no specific recommendations can yet be made. The development of EUROMAC, an international registry for these disorders, should improve our knowledge of their natural histories and provide a platform for future clinical trials.

Exercise and Preexercise Nutrition as Treatment for McArdle Disease.

McArdle disease is due to an inborn defect in the muscle isoform of glycogen phosphorylase (or "myophosphorylase"), the enzyme that catalyzes the first step of glycogenolysis. This condition is still not fully understood, and although advances in research would help patients immeasurably, these would also enhance our understanding of exercise metabolism. It has been 10 yr since the first published report demonstrating the benefits of regular aerobic exercise for these patients. However, misconceptions remain and the value of exercise prescription for patients with McArdle disease is still overlooked. Here, we review the role of exercise in McArdle disease with the aim to better inform health-care professionals and thus better serve the interests of patients. Recommendations for regular exercise together with preexercise nutrition in children and adult patients are also provided along with examples of exercise practice and its benefits.

Genes and exercise intolerance: insights from McArdle disease.

McArdle disease (glycogen storage disease type V) is caused by inherited deficiency of a key enzyme in muscle metabolism, the skeletal muscle-specific isoform of glycogen phosphorylase, "myophosphorylase," which is encoded by the PYGM gene. Here we review the main pathophysiological, genotypic, and phenotypic features of McArdle disease and their interactions. To date, moderate-intensity exercise (together with pre-exercise carbohydrate ingestion) is the only treatment option that has proven useful for these patients. Furthermore, regular physical activity attenuates the clinical severity of McArdle disease. This is quite remarkable for a monogenic disorder that consistently leads to the same metabolic defect at the muscle tissue level, that is, complete inability to use muscle glycogen stores. Further knowledge of this disorder would help patients and enhance understanding of exercise metabolism as well as exercise genomics. Indeed, McArdle disease is a paradigm of human exercise intolerance and PYGM genotyping should be included in the genetic analyses that might be applied in the coming personalized exercise medicine as well as in future research on genetics and exercise-related phenotypes.

The immune response to short-duration exercise in trained, eumenorrhoeic women.

Few studies have characterised the immune response to exercise of different intensities and durations in women. In those that have, baseline hormone levels and training status were not always adequately controlled for. Here, leucocyte and cytokine profiles of 11 aerobically trained, eumenorrhoeic females (33 ± 5 years) in the early follicular phase of the menstrual cycle were characterised after 30-min exercise at 3 intensities: 90% lactate threshold (LT), LT, and 110% LT. Proposed cytokine response mediators were quantified: plasma lactate and basal oestradiol concentrations. Intensity-dependent increases occurred in total white blood cells and lymphocyte counts (P < 0.001). Elevated plasma IL-6 and IL-1ra concentrations post-exercise [F = 12.38, P < 0.01 and F = 7.65, P < 0.05, respectively] were not intensity-dependent, indicating that cytokine release may be better associated with exercise duration than intensity in trained women. Changes in plasma IL-1ra and basal oestradiol (ρ = -0.893, P < 0.01) were correlated at intensities above LT only. These findings suggest a role for plasma sex hormones in moderating the exercise-induced immune response in women. However, the associations observed did not account for the magnitude of the cytokine response observed, and future studies should explore contributions of other potential mediators following short-duration exercise.

Growth Hormone Concentrations in Different Body Fluids Before and After Moderate Exercise.

BACKGROUND: Growth hormone (GH) has many direct and indirect actions and roles including substrate regulation and priming of some cells of the immune system, and the expected aspects of growth and repair. Different concentrations in human body fluids reflect the exercise-induced growth hormone response (EIGR) after exercise. In populations such as elite athletes, the invasive nature of venous sampling is poorly accepted. Thus, this study examines possible viable alternatives such as urine and saliva samples and the GH concentration. METHODS: A heterogeneous group of 11 males (age 26.0 ± 5.0 years; body mass 76.5 ± 9.3 kg; VO2peak 57.0 ± 6.0 mL kg-1 min-1) ran for 40 min on a treadmill at 5 % below their individually indentified lactate threshold pace. Samples of urine, saliva and blood were collected immediately pre- and post-test and at 30 and 60 min post-test. RESULTS: Salivary GH was correlated with serum pre- and post-exercise (p < 0.001); urinary GH was correlated with serum (p < 0.05). However, despite being significantly correlated, it is clear from the large differences in absolute concentration in the three media that the appearance of serum GH due to exercise is different from that of the appearance of salivary and urinary GH. This aspect of compartmental exchanges is very difficult to define and to investigate. Differences in any analyte concentration in different compartments are to be expected between different media, and hence the same medium should be used where the same 'pattern of response' can be tracked. CONCLUSIONS: The results suggest that urinary and saliva sampling cannot substitute for venous sampling with respect to exercise-induced changes in GH concentration. The use of the analyses in these three areas may be appropriate for further investigation.

Emotionally-intense situations can result in rhabdomyolysis in McArdle disease.

Despite the majority of patients with McArdle disease reporting symptoms including fatigue, cramps and episodes of myoglobinuria from early childhood, diagnosis is often delayed by several decades. Additionally, many individuals with rhabdomyolysis remain undiagnosed. The occurrence of symptoms during exercise, particularly isometric muscle contraction such as heavy lifting, is well known in McArdle disease. However, isometric muscle contraction that occurs with emotion is not recognised as exercise and may be missed as a trigger for rhabdomyolysis, potentially leading to a delay in diagnosis. Three patients are presented here, all with symptoms from childhood including episodes of rhabdomyolysis induced by tense emotional situations without physical exertion; two patients reported recurrent episodes while watching rather than playing football. The remaining patient developed rhabdomyolysis during a heated argument. These patients' histories emphasise the risk from sustained isometric muscle contraction that occurs in emotive situations for patients with McArdle disease.