The purpose and effectiveness of doping testing in sport.

Maintaining an effective testing program is critical to the success and credibility of the anti-doping movement. However, a low detection ratio compared to the assumed real prevalence of sport doping has led some to question and criticize the effectiveness of the current testing system. In this perspective article, we review the results of the global testing program, discuss the purpose of testing, and compare benefits and limitations of performance indicators commonly used to evaluate testing efforts. We suggest that an effective testing program should distinguish between preventive testing and testing aimed at detecting the use of prohibited substances and prohibited methods. In case of preventive testing, the volume of the test program in terms of number of samples, tests and analyses is likely to be positively related to the extent of the deterrent effect achieved. However, there is a lack of literature on how the deterrent effect works in the practical context of doping testing. If the primary goal is to detect doping, the testing must be risk- and intelligence-based, and quality in test planning is more important than quantity in sample collection. The detection ratio can be a useful tool for evaluating the effectiveness of doping testing, but for the calculation one should take into account the number of athletes tested and not just the number of collected samples, as the former would provide a more precise measure of the tests' ability to detect doping among athletes.

Medicalization of Sport? A Mixed-Method Study on the Use of Medications in Elite Ice Hockey.

Ice hockey is a high-risk sport known for its dominant macho culture. The purpose of this study was to examine experiences surrounding medication use among male, elite ice hockey players in Norway. A mixed-method design was employed, which first examined medications registered on doping control forms (DCFs) (n = 177) and then involved semi-structured focus group interviews (n = 5) with elite athletes (n = 25). Overall, 68% of the DCFs contained information about ≥1 medication. Among the most registered medications were NSAIDs and hypnotics (20% and 19% of all DCFs, respectively). During the interviews, numerous athletes reported using analgesics to manage injuries and pain caused by the sport, often being motivated by sacrificing themselves for the team during important matches and playoffs. Hypnotics were used due to high cumulative stress due to heavy training and competition load, late-night matches, and playing in a semi-professional league. Athlete support personnel (ASP), including physicians and trainers, were the athletes' main sources of information. The athletes often displayed a profound and non-critical trust in the advice and products provided to them by their team physician. The findings indicate that male, elite ice hockey players, through their excessive and somewhat ignorant use of medications, expose themselves to health risks and inadvertent doping.

Use of pharmaceuticals amongst athletes tested by Anti-Doping Norway in a five-year period.

Introduction: The aim of the study was to map the use of pharmaceuticals by Norwegian athletes registered on doping control forms (DCFs) in a five-year period to examine general and some class specific use of pharmaceuticals across sports and athlete levels. Method: Anonymous data from DCFs collected in 2015-2019 were manually entered into a database using the Anatomical Therapeutic Chemical (ATC) system for classification of the pharmaceuticals. Variables entered were year of control, gender, age group, athlete level, sport, test type, nationality, and pharmaceuticals (and dietary supplements) used. Results: Pain killers in the ATC groups M01 A (Nonsteroidal anti-inflammatory drugs - NSAIDs) and N02 B (other analgesics), and anti-asthmatics in ATC groups R03 A and R03 B were the most frequently used pharmaceuticals. National level athletes reported more use of pharmaceuticals (1.4 ± 1.7 pharmaceuticals per form) than recreational level athletes (0.9 ± 1.2). The highest proportion of DCFs containing information about at least one pharmaceutical were found in speed skating (79.1%), alpine skiing (74.0%), rowing (72.4%) and cross-country skiing (71.7%). Painkillers were most frequently used in muscular endurance sports (30.4% and 21.2 % for M01A and N02 B, respectively) and ball and team sports (17.9% and 17.0%). Use of hypnotics was reported from ice-hockey players and alpine skiers in around 8% of the cases. Coclusion: Use of anti-asthmatics was most often reported amongst athletes specially exposed to cold, chemicals and heavy endurance training. Athletes in specialized sports requiring high levels of strength and/or endurance reported a higher use of pharmaceuticals out-of-competition compared to in-competition, while there was no such difference in complex sports, such as team, gymnastic, aiming and combat sports.

Trends in dietary supplement use among athletes selected for doping controls.

Background: Dietary supplements (DS) may be beneficial for athletes in certain situations, whereas incorrect or excessive use may impair performance, pose a risk to the athlete's health and cause positive doping tests by containing prohibited substances. To provide athletes with relevant and tailored information on safe supplement use, a better knowledge about DS trends over time and between sport disciplines are needed. Methods: This study examines the use of DS among athletes who have participated in doping controls by extracting information derived from 10,418 doping control forms (DCF) collected by Anti-Doping Norway from 2015 to 2019. Results: Overall, 51% of the DCFs contained information about at least one DS. National level athletes (NLA) more often reported using DS than recreational athletes (RA) (53 vs. 47%, p < 0.001). Athletes in strength and power (71%), VO2max endurance (56%) and muscular endurance sports (55%) had the highest proportion of DCFs with information about DS. Medical supplements were the most used supplement category for both genders and across all sports. Dietary supplements with a high risk of containing doping substances were most common among male, RA in strength and power sports. There were small and non-significant year-to-year variations in the prevalence of athletes using DS, while the number of products used concomitantly peaked in 2017 before declining in 2019 (2.30 vs. 2.08, p < 0.01). The use of medical supplements and ergogenic substances increased slightly for both NLA and RA from 2015 to 2019, while the use of all other supplement categories declined. Conclusion: Half of the 10,418 DCFs contained information about DS, with variations within the athlete population. DS with high risk of containing prohibited substances were mostly seen in sport disciplines requiring a high degree of specialization in strength/power, including powerlifting and weightlifting, as well as in some team sports, such as cheerleading and american football.

Intelligence-based doping control planning improves testing effectiveness: Perspectives from a national anti-doping organisation.

Anti-doping organisations are mandated to provide a comprehensive anti-doping programme, which aims to detect, deter and prevent doping in sport. Direct detection of prohibited substances and methods by collection of biological samples from athletes makes up about half of the global anti-doping budgets but has in the last decade been under critical scrutiny for its lack of efficiency. To ensure optimum detection and deterrence of testing and prevention efforts, a better understanding of doping practices and comparison of different doping test strategies are needed. This study evaluates 17 years of doping test statistics and Anti-Doping Rule Violations (ADRVs) from the perspectives of a national anti-doping organisation. A total of 48 709 samples (2865 ± 220 annually) were collected by Anti-Doping Norway in the period 2003-2019, which resulted in total 216 ADRVs (12.7 ± 3.7 annually), providing an average sample-to-ADRV rate of 0.44% when including urine, blood and ABP samples. Most athletes who committed ADRVs were men participating in ball and team or strength sports at a national or recreational level. Few ADRVs were recorded among elite athletes and in most high-risk sports, despite these groups being subjected to the highest number of doping tests. The number of annual ADRVs did not correlate with the corresponding number of collected doping samples. However, systematic use of intelligence in the test planning process was associated with an increase in ADRVs. Anti-doping organisations would benefit from improving their target testing capability and to take an intelligence-led approach in planning doping tests.

Ten years of collecting hematological athlete biological passport samples-perspectives from a National Anti-doping Organization.

The hematological module of the Athlete Biological Passport (ABP) aims to reveal blood doping indirectly by looking at selected biomarkers of doping over time. For Anti-Doping Organizations (ADOs), the ABP is a vital tool in the fight against doping in sports through improved target testing and analysis, investigations, deterrence, and as indirect evidence for use of prohibited methods or substances. The physiological characteristics of sport disciplines is an important risk factor in the overall risk assessment and when implementing the hematological module. Sharing of experiences with implementing the hematological ABP between ADOs is key to further strengthen and extend its use. In this study, we present 10 years of experience with the hematological ABP program from the perspectives of a National ADO with special attention to sport disciplines' physiological characteristics as a potential risk factor for blood doping. Not surprisingly, most samples were collected in sport disciplines where the aerobic capacity is vital for performance. The study highlights strengths in Anti-Doping Norway's testing program but also areas that could be improved. For example, it was shown that samples were collected both in and out of season in a subset of the data material that included three popular sports in Norway (Cross-Country Skiing, Nordic Combined, and Biathlon), however, from the total data material it was clear that athletes were more likely to be tested out of competition and on certain days of the week and times of the day. The use of doping control officers with a flexible time schedule and testing outside an athlete's 60 min time-slot could help with a more even distribution during the week and day, and thus reduce the predictability of testing. In addition to promoting a discussion on testing strategies, the study can be used as a starting point for other ADOs on how to examine their own testing program.

Dietary Supplements as a Major Cause of Anti-doping Rule Violations.

Dietary supplements encompass a large heterogenic group of products with a wide range of ingredients and declared effects used by athletes for a multitude of reasons. The high prevalence of use across all sports and level of competition, combined with the well-documented risks of such products containing prohibited substances have led to several doping cases globally. Despite being a considerable concern and persistent focus of sport organizations and anti-doping agencies, the magnitude of anti-doping rule violations associated with supplement use is not well-known. This study examines 18-years of doping controls of a national anti-doping program to determine the relationship between the presence of prohibited substances in athlete's doping samples and the use of dietary supplements. In 26% (n = 49) of all the analytical anti-doping rule violation cases in the period 2003-2020 (n = 192), the athlete claimed that a dietary supplement was the source of the prohibited substance causing an adverse analytical finding. Evidence supporting this claim was found in about half of these cases (n = 27, i.e., 14% of all analytical ADRV's). Stimulants were the most prevalent substance group linked to supplements (n = 24), of which methylhexanamine was associated with 16 cases. High risk products were predominantly multi-ingredient pre-workout supplements (n = 20) and fat-burning products (n = 4). Anti-doping organizations should develop strategies on how to assist athletes to assess the need, assess the risk and assess the consequences of using various dietary supplements.

A Mixed-Method Evaluation of a Prison Anti-doping Intervention: The Hercules Prison Program.

The Norwegian Offender Mental Health and Addiction study denotes the need for physical activity and anti-doping interventions in Norwegian prisons. We developed and evaluated the efficacy of such intervention-the Hercules prison program. The program combines theoretical anti-doping lessons with practical strength training. The study adopts a mixed-methods approach (pretest-posttest design) comprising a longitudinal survey, observation, informal conversations, and in-depth interviews. Survey respondents were 104 male prisoners aged 18-56 (M = 34.81, SD = 9.34) years from seven Norwegian prisons. Of these, 52 provided both baseline and posttest responses. Participants completed questionnaires including demographic, doping use, and psychophysical items/measures. At the end of the intervention, in-depth interviews were conducted with 11 of the survey respondents. The survey data were analyzed using descriptive statistics, as well as independent and paired samples t-tests. The qualitative data were analyzed using Interpretative Phenomenological Analysis. A total of 7.5% and 33.3% of participants were current and former AAS users respectively, whereas 86.1% personally knew at least one current or former AAS user. Consistent with our expectation, there were increases in self-rated physical strength (t = -4.1, p < 0.001, d = 0.46) and strength training self-efficacy (t = -8.33, p < 0.001, d = 1.36), and a decrease in moral disengagement in doping (t = -4.05, p < 0.001, d = 0.52) from baseline to posttest. These findings are supported by the qualitative data. Notable success factors are relationship-building, instructors' expertise and acceptability, and gatekeepers' navigation and co-creation. The program provides valuable evidence of the potential benefits of combining anti-doping education with practical strength training in doping prevention in correctional settings.

Doping substances in dietary supplements. / Dopingmidler i kosttilskudd.

BACKGROUND: International studies have shown that 12-58 % of all dietary supplements intended for people who exercise and engage in sports contain substances prohibited by the World Anti-Doping Code (WADC). In some cases, the doping substances are not declared on the product label, and the consumer may therefore be unaware of what he/she ingests. Many of the substances may cause adverse health effects, and sale of such products is illegal in Norway. MATERIAL AND METHOD: To investigate the prevalence of doping substances in dietary supplements sold on the Norwegian market, a total of 93 high-risk products from online shops targeting Norwegian consumers were analysed for substances on the WADC Prohibited List and pharmaceutical drugs. All supplements were marketed as able to boost energy levels and/or having a muscle-building or fat-burning effect. The products were selected on the basis of tips received, online forums and/or international lists. RESULTS: Altogether 21 of 93 (23 %) products analysed contained prohibited substances, pharmaceutical drugs and/or illegal amounts of caffeine. Substances on the WADC Prohibited List were detected in 8 of the 93 (9 %) dietary supplements. All products containing doping substances were declared as containing one or more banned substances. INTERPRETATION: The results show that using apparently legal dietary supplements purchased in online shops targeting Norwegian consumers involves a risk of inadvertent doping and adverse health effects.

Monocarboxylate transporters in temporal lobe epilepsy: roles of lactate and ketogenic diet.

Epilepsy is a serious neurological disorder that affects approximately 1 % of the general population, making it one of the most common disorders of the central nervous system. Furthermore, up to 40 % of all patients with epilepsy cannot control their seizures with current medications. More efficacious treatments for medication refractory epilepsy are therefore needed. A better understanding of the mechanisms that cause this disorder is likely to facilitate the discovery of such treatments. Impairment in cerebral energy metabolism has been proposed as a possible causative factor in the pathogenesis of temporal lobe epilepsy (TLE), which is one of the most common types of medication-refractory epilepsies in adults. In this review, we will discuss some of the current hypotheses regarding the possible causal relationship between brain energy metabolism and TLE. Emphasis will be placed on the role of energy substrates (lactate and ketone bodies) and their transporter molecules, particularly monocarboxylate transporters 1 and 2 (MCT1 and MCT2). We recently reported that the cellular distribution of MCT1 and MCT2 is perturbed in the hippocampus in patients with TLE. The changes may be an adaptive response aimed at keeping high levels of lactate in the epileptic tissue, which may serve to counteract epileptic activity by downregulating cAMP levels through the lactate receptor GPR81, newly discovered in hippocampus. We propose that the perturbation of MCTs may be further involved in the pathophysiology of TLE by influencing brain energy homeostasis, mitochondrial function, GABA-ergic and glutamatergic neurotransmission, and flux of lactate through the brain.

Lactate receptor sites link neurotransmission, neurovascular coupling, and brain energy metabolism.

The G-protein-coupled lactate receptor, GPR81 (HCA1), is known to promote lipid storage in adipocytes by downregulating cAMP levels. Here, we show that GPR81 is also present in the mammalian brain, including regions of the cerebral neocortex and hippocampus, where it can be activated by physiological concentrations of lactate and by the specific GPR81 agonist 3,5-dihydroxybenzoate to reduce cAMP. Cerebral GPR81 is concentrated on the synaptic membranes of excitatory synapses, with a postsynaptic predominance. GPR81 is also enriched at the blood-brain-barrier: the GPR81 densities at endothelial cell membranes are about twice the GPR81 density at membranes of perivascular astrocytic processes, but about one-seventh of that on synaptic membranes. There is only a slight signal in perisynaptic processes of astrocytes. In synaptic spines, as well as in adipocytes, GPR81 immunoreactivity is located on subplasmalemmal vesicular organelles, suggesting trafficking of the protein to and from the plasma membrane. The results indicate roles of lactate in brain signaling, including a neuronal glucose and glycogen saving response to the supply of lactate. We propose that lactate, through activation of GPR81 receptors, can act as a volume transmitter that links neuronal activity, cerebral energy metabolism and energy substrate availability.

Gene expression of glutamate metabolizing enzymes in the hippocampal formation in human temporal lobe epilepsy.

PURPOSE: Increased interictal concentrations of extracellular hippocampal glutamate have been implicated in the pathophysiology of temporal lobe epilepsy (TLE). Recent studies suggest that perturbations of the glutamate metabolizing enzymes glutamine synthetase (GS) and phosphate activated glutaminase (PAG) may underlie the glutamate excess in TLE. However, the molecular mechanism of the enzyme perturbations remains unclear. A better understanding of the regulatory mechanisms of GS and PAG could facilitate the discovery of novel therapeutics for TLE. METHODS: We used in situ hybridization on histologic sections to assess the distribution and quantity of messenger RNA (mRNA) for GS and PAG in subfields of hippocampal formations from the following: (1) patients with TLE and concomitant hippocampal sclerosis, (2) patients with TLE and no hippocampal sclerosis, and (3) nonepilepsy autopsy subjects. KEY FINDINGS: GS mRNA was increased by ~50% in the CA3 in TLE patients without hippocampal sclerosis versus in TLE patients with sclerosis and in nonepilepsy subjects. PAG mRNA was increased by >100% in the subiculum in both TLE patient categories versus in nonepilepsy subjects. PAG mRNA was also increased in the CA1, CA2, CA3, and dentate hilus in TLE without hippocampal sclerosis versus in TLE with sclerosis. Finally, PAG mRNA was increased in the dentate gyrus in TLE with sclerosis versus in nonepilepsy subjects, and also increased in the hilus in TLE without sclerosis versus in TLE with sclerosis. SIGNIFICANCE: These findings demonstrate complex changes in the expression of mRNAs for GS and PAG in the hippocampal formation in TLE, and raise the possibility that both transcriptional and posttranscriptional mechanisms may underlie the regulation of GS and PAG proteins in the epileptic brain.

Inflammatory markers CD11b, CD16, CD66b, CD68, myeloperoxidase and neutrophil elastase in eccentric exercised human skeletal muscles.

The aim of the present study was to investigate leucocyte markers, CD11b, CD16, CD66b, CD68, myeloperoxidase and neutrophil elastase on skeletal muscle biopsies from biceps brachii after unaccustomed eccentric exercise followed by the second bout of exercise 3 weeks later. The subjects (10 subjects received COX-2 inhibitor (Celecoxib) and 13 subjects received placebo) were divided into three categories: mild, moderate and severe effect of eccentric exercise, according to the reduction and recovery of muscle force-generating capacity after performing 70 maximal eccentric actions with elbow flexors on an isokinetic dynamometer. The results showed that the CD66b antibody was applicable for localization of neutrophils in human skeletal muscle, whereas the other studied neutrophil markers recognized also other leucocytes than neutrophils. The number of CD66b positive cells in skeletal muscle was very low and was not affected by the exercise. The macrophage marker CD68 showed reactivity also against satellite cells and fibroblast-like cells in skeletal muscle and therefore cannot be applied as a quantitative value for inflammatory cells. Skeletal muscle fibre injury, shown as dystrophin negative fibres, was observed approximately in half of the biopsies at 4 and 7 days after the first exercise bout in the categories moderate and severe effect of eccentric exercise. These subjects represent the most prominent loss in muscle force-generating capacity both at the category and the individual levels. Furthermore, deformed skeletal muscle fibres were observed in five subjects in these categories after the second bout of exercise. The present results suggest that neutrophils are not involved in skeletal muscle fibre injury and the reduction in muscle force-generating capacity after a single bout of eccentric exercise is a good indirect indicator of muscle damage in humans. Furthermore, prolonged regeneration process could be one of the reasons for impaired peripheral muscle function after high-force eccentric exercise.

Loss of perivascular Kir4.1 potassium channels in the sclerotic hippocampus of patients with mesial temporal lobe epilepsy.

Recent experimental data in mice have shown that the inwardly rectifying K channel Kir4.1 mediates K spatial buffering in the hippocampus. Here we used immunohistochemistry to examine the distribution of Kir4.1 in hippocampi from patients with medication-refractory temporal lobe epilepsy. The selectivity of the antibody was confirmed in mice with a glial conditional deletion of the gene encoding Kir4.1. These mice showed a complete loss of labeled cells, indicating that Kir4.1 is restricted to glia. In human cases, Kir4.1 immunoreactivity observed in cells morphologically consistent with astrocytes was significantly reduced in 12 patients with hippocampal sclerosis versus 11 patients without sclerosis and 4 normal autopsy controls. Loss of astrocytic Kir4.1 immunoreactivity was most pronounced around vessels and was restricted to gliotic areas. Loss of Kir4.1 expression was associated with loss of dystrophin and α-syntrophin, but not with loss of ß-dystroglycan, suggesting partial disruption of the dystrophin-associated protein complex. The changes identified in patients with hippocampal sclerosis likely interfere with K homeostasis and may contribute to the epileptogenicity of the sclerotic hippocampus.

Evidence for astrocytes as a potential source of the glutamate excess in temporal lobe epilepsy.

Increased extracellular brain glutamate has been implicated in the pathophysiology of human refractory temporal lobe epilepsy (TLE), but the cause of the excessive glutamate is unknown. Prior studies by us and others have shown that the glutamate degrading enzyme glutamine synthetase (GS) is deficient in astrocytes in the epileptogenic hippocampal formation in a subset of patients with TLE. We have postulated that the loss of GS in TLE leads to increased glutamate in astrocytes with elevated concentrations of extracellular glutamate and recurrent seizures as the ultimate end-points. Here we test the hypothesis that the deficiency in GS leads to increased glutamate in astrocytes. Rats were chronically infused with methionine sulfoximine (MSO, n=4) into the hippocampal formation to induce GS deficiency and recurrent seizures. A separate group of rats was infused with 0.9% NaCl (saline) as a control (n=6). At least 10days after the start of infusion, once recurrent seizures were established in the MSO-treated rats, the concentration of glutamate was assessed in CA1 of the hippocampal formation by immunogold electron microscopy. The concentration of glutamate was 47% higher in astrocytes in the MSO-treated vs. saline-treated rats (p=0.02), and the ratio of glutamate in astrocytes relative to axon terminals was increased by 74% in the MSO-treated rats (p=0.003). These data support our hypothesis that a deficiency in GS leads to increased glutamate in astrocytes. We additionally propose that the GS-deficient astrocytes in the hippocampal formation in TLE lead to elevated extracellular brain glutamate either through decreased clearance of extracellular glutamate or excessive release of glutamate into the extracellular space from these cells, or a combination of the two.

Redistribution of monocarboxylate transporter 2 on the surface of astrocytes in the human epileptogenic hippocampus.

Emerging evidence points to monocarboxylates as key players in the pathophysiology of temporal lobe epilepsy (TLE) with hippocampal sclerosis (mesial temporal lobe epilepsy, MTLE). Monocarboxylate transporters (MCTs) 1 and 2, which are abundantly present on brain endothelial cells and perivascular astrocyte endfeet, respectively, facilitate the transport of monocarboxylates and protons across cell membranes. Recently, we reported that the density of MCT1 protein is reduced on endothelial cells and increased on astrocyte plasma membranes in the hippocampal formation in patients with MTLE and in several animal models of the disorder. Because the perivascular astrocyte endfeet comprise an important part of the neurovascular unit, we now assessed the distribution of the MCT2 in hippocampal formations in TLE patients with (MTLE) or without hippocampal sclerosis (non-MTLE). Light microscopic immunohistochemistry revealed significantly less perivascular MCT2 immunoreactivity in the hippocampal formation in MTLE (n = 6) than in non-MTLE (n = 6) patients, and to a lesser degree in non-MTLE than in nonepilepsy patients (n = 4). Immunogold electron microscopy indicated that the loss of MCT2 protein occurred on perivascular astrocyte endfeet. Interestingly, the loss of MCT2 on astrocyte endfeet in MTLE (n = 3) was accompanied by an upregulation of the protein on astrocyte membranes facing synapses in the neuropil, when compared with non-MTLE (n = 3). We propose that the altered distribution of MCT1 and MCT2 in TLE (especially MTLE) limits the flux of monocarboxylates across the blood-brain barrier and enhances the exchange of monocarboxylates within the brain parenchyma.

Altered expression of brain monocarboxylate transporter 1 in models of temporal lobe epilepsy.

Monocarboxylate transporter 1 (MCT1) facilitates the transport of monocarboxylate fuels (lactate, pyruvate and ketone bodies) and acidic drugs, such as valproic acid, across cell membranes. We recently reported that MCT1 is deficient on microvessels in the epileptogenic hippocampal formation in patients with medication-refractory temporal lobe epilepsy (TLE). To further define the role of MCT1 in the pathophysiology of TLE, we used immunohistochemistry and stereological analysis to localize and quantify the transporter in the hippocampal formation in three novel and highly relevant rat models of TLE and in nonepileptic control animals. One model utilizes methionine sulfoximine to induce brain glutamine synthetase deficiency and recurrent limbic seizures, while two models employ an episode of perforant pathway stimulation to cause epilepsy. MCT1 was lost on microvessels and upregulated on astrocytes in the hippocampal formation in all models of TLE. Notably, the loss of MCT1 on microvessels was not due to a reduction in microvessel density. The similarities in MCT1 expression among human subjects with TLE and several animal models of the disease strongly suggest a critical role of this molecule in the pathogenesis of TLE. We hypothesize that the downregulation of MCT1 may promote seizures via impaired uptake of ketone bodies and antiepileptic drugs by the epileptogenic brain. We also propose that the overexpression of MCT1 on astrocytes may lead to increased uptake or release of monocarboxylates by these cells, with important implications for brain metabolism and excitability. These hypotheses can now be rigorously tested in several animal models that replicate key features of human TLE.

Monocarboxylate transporter 1 is deficient on microvessels in the human epileptogenic hippocampus.

Monocarboxylate transporter 1 (MCT1) facilitates the transport of important metabolic fuels (lactate, pyruvate and ketone bodies) and possibly also acidic drugs such as valproic acid across the blood-brain barrier. Because an impaired brain energy metabolism and resistance to antiepileptic drugs are common features of temporal lobe epilepsy (TLE), we sought to study the expression of MCT1 in the brain of patients with this disease. Immunohistochemistry and immunogold electron microscopy were used to assess the distribution of MCT1 in brain specimens from patients with TLE and concomitant hippocampal sclerosis (referred to as mesial TLE or MTLE (n=15)), patients with TLE and no hippocampal sclerosis (non-MTLE, n=13) and neurologically normal autopsy subjects (n=8). MCT1 was present on an extensive network of microvessels throughout the hippocampal formation in autopsy controls and to a lesser degree in non-MTLE. Patients with MTLE were markedly deficient in MCT1 on microvessels in several areas of the hippocampal formation, especially CA1, which exhibited a 37% to 48% loss of MCT1 on the plasma membrane of endothelial cells when compared with non-MTLE. These findings suggest that the uptake of blood-derived monocarboxylate fuels and possibly also acidic drugs, such as valproic acid, is perturbed in the epileptogenic hippocampus, particularly in MTLE. We hypothesize that the loss of MCT1 on brain microvessels is mechanistically involved in the pathophysiology of drug-resistant TLE, and propose that re-expression of MCT1 may represent a novel therapeutic approach for this disease.

Gross ultrastructural changes and necrotic fiber segments in elbow flexor muscles after maximal voluntary eccentric action in humans.

Eccentric muscle actions are associated with ultrastructural changes. The severity and types of change depend on the nature of the stimulation protocol, and on the method for assessing such changes, and can be regarded as a continuum from mild changes to pathological-like changes. Most studies describing more severe changes have been performed on animals and only a few in humans, some using electrical stimuli. Hence, a debate has emerged on whether voluntary actions are associated with the pathological-like end of the continuum. The aim of this study was to determine whether severe muscle damage, i.e., extensive ultrastructural changes, is confined to animal studies and studies on humans using electrical stimuli. Second, because there is no generally approved method to quantify the degree of muscle damage, we compared two published methods, analyzing the Z disks or sarcomeres, as well as novel analyses of pathological-like changes. A group of untrained subjects performed 70 voluntary maximal eccentric muscle actions using the elbow flexors. On the basis of large reductions in maximal force-generating capacity (on average, -62 +/- 3% immediately after exercise, and -35 +/- 6% 9 days later), five subjects were selected for further analysis. Biopsies were taken from m. biceps brachii in both the exercised and nonexercised arm. In exercised muscle, more disrupted (13 +/- 4 vs. 3 +/- 3%) and destroyed (15 +/- 6 vs. 0%) Z disks were found compared with nonexercised muscle. A significant proportion of exercised myofibers had focal (85 +/- 5 vs. 11 +/- 7%), moderate (65 +/- 7 vs. 11 +/- 6%), and extreme (38 +/- 9 vs. 0%) myofibrillar disruptions. Hypercontracted myofibrils, autophagic vacuoles, granular areas, central nuclei, and necrotic fiber segments were found to various degrees. The present study demonstrates that the more severe end of the continuum of ultrastructural changes occurs in humans after voluntary exercise when maximal eccentric muscle actions are involved.