Greater muscle damage in athletes with ACTN3 R577X (RS1815739) gene polymorphism after an ultra-endurance race: a pilot study.

In this study, we aimed to investigate the influence of ACTN3 R577X gene polymorphism on muscle damage responses in athletes competing in an ultra-endurance race. Twenty moderate to well-trained ultra-runners who had entered in an official 37.1 km adventure race (22.1 km mountain biking, 10.9 km trekking, 4.1 km water trekking, 30 m rope course, and orienteering) volunteered for the study. Blood samples were collected for genotyping and analysis of muscle protein levels before and after the race. Percentage changes (pre- to post-race) of serum myoglobin [XX = 5,377% vs. RX/RR = 1,666%; P = 0.005, effect size (ES) = 1.73], creatine kinase (XX = 836.5% vs. RX/RR = 455%; P = 0.04, ES = 1.29), lactate dehydrogenase (XX = 82% vs. RX/RR = 65%; P = 0.002, ES = 1.61), and aspartate aminotransferase (XX = 148% vs. RX/RR = 75%; P = 0.02, ES = 1.77) were significantly greater for XX than RX/RR genotypes. ES analysis confirmed a large magnitude of muscle damage in XX genotype ultra-runners. Therefore, athletes with the ACTN3 577XX genotype experienced more muscle damage after an adventure race. This suggests that ultra-runners with alpha-actinin-3 deficiency may be more susceptible to rhabdomyolysis and associated health complications during ultra-endurance competitions.

Why do we choose rheumatology? Implications for future recruitment--results of the 2006 UK Trainee Survey.

OBJECTIVES: Against changes to junior doctor career structure under MMC (Modernizing Medical Careers), and uncertainty about the future place of rheumatology, we explored critical factors in choice of rheumatology as a speciality, and asked what factors might govern choices of prospective trainees. Using these data, we developed suggestions to enhance future recruitment. METHODS: A postal survey was sent to rheumatology specialist registrars (SpRs) on the Joint Committee for Higher Medical Training (JCHMT) database between December 2005 and January 2006, and concurrently by e-mail to the Rheumatologists at Training e-mail list. RESULTS: Seventy-three percent (165/227) of trainees responded. Of them, 89.1% had previous senior house officer (SHO) experience in rheumatology and 81.8% made a career decision in favour of rheumatology during their SHO post. The top four ranked factors influencing choice of rheumatology were SHO experience, subject matter, inspirational consultants and lifestyle aspects; 89.1% would still choose rheumatology now. Factors felt to be negatively influencing future trainees came under three key themes: poor student or postgraduate exposure, employment and service delivery issues (including concern over the future place of rheumatology in primary vs secondary care), and perceived poor profile of rheumatology. Factors positively influencing future candidates were subject matter, work/life balance and prior exposure to the speciality. CONCLUSIONS: Early postgraduate experience is key to choice of speciality. An overwhelming majority of trainees decide speciality during SHO experience. With ongoing changes in career structure, it is critical that rheumatology is incorporated into foundation and speciality training programmes and essential that continued measures are taken to improve the image of rheumatology.

Hypovitaminosis D among rheumatology outpatients in clinical practice.

OBJECTIVES: A role for vitamin D in the pathogenesis of autoimmune and inflammatory diseases is emerging. We undertook an audit of 25-hydroxyvitamin D (25OHD) investigation and treatment in rheumatology outpatients. METHODS: Serum 25OHD requests were matched to electronic medical records from rheumatology and metabolic bone clinics (April 2006-March 2007). Data were analysed separately for two groups, 'Documented osteoporosis/osteopaenia' (Group 1) and 'General rheumatology outpatients' (Group 2, sub-divided by diagnosis). Hypovitaminosis D was defined by 25OHD levels <50 nmol/l. Values were compared with healthy adults to calculate geometric z-scores. RESULTS: A total of 263 patients were included (Group 1, n = 122; Group 2, n = 141) with an overall median 25OHD of 44 nmol/l. The 25OHD level among general rheumatology patients (median 39 nmol/l, mean z score -1.2, was statistically significantly lower than among osteoporotic/osteopaenic patients (median 49 nmol/l, mean z score of -0.9, p < 0.05 for the difference). 25OHD was lower in inflammatory arthritis and chronic pain/fibromyalgia than in other groups. Prescribing was recorded in 100 in Group 1 (of whom 95% were prescribed calcium/800 IU cholecalciferol) and 83 in Group 2 (91% calcium/800 IU). Only 31% of the patients with 25OHD <50 nmol/l would have been identified using general guidelines for screening patients at 'high risk' of hypovitaminosis D. CONCLUSIONS: Improved guidelines for managing hypovitaminosis D in rheumatology patients are needed. We found a high prevalence of hypovitaminosis D among secondary care patients in rheumatology and widespread supplementation with 800 IU cholecalciferol. Substantially reduced levels of serum 25OHD were identified among patients with inflammatory arthritis and chronic pain.

Multiple horizontally acquired genes from fungal and prokaryotic donors encode cellulolytic enzymes in the bdelloid rotifer Adineta ricciae.

The bdelloid rotifer, Adineta ricciae, an anhydrobiotic microinvertebrate, exhibits a high rate of horizontal gene transfer (HGT), with as much as 10% of its transcriptome being of foreign origin. Approximately 80% of these foreign transcripts are involved in metabolic processes, and therefore bdelloids represent a useful model for assessing the contribution of HGT to biochemical diversity. To validate this concept, we focused on cellulose digestion, an unusual activity in animals, which is represented by at least 16 genes encoding cellulolytic enzymes in A. ricciae. These genes have been acquired from a variety of different donor organisms among the bacteria and fungi, demonstrating that bdelloids use diverse genetic resources to construct a novel biochemical pathway. A variable complement of the cellulolytic gene set was found in five other bdelloid species, indicating a dynamic process of gene acquisition, duplication and loss during bdelloid evolution. For example, in A. ricciae, gene duplications have led to the formation of three copies of a gene encoding a GH45 family glycoside hydrolase, at least one of which encodes a functional enzyme; all three of these gene copies are present in a close relative, Adineta vaga, but only one copy was found in each of four Rotaria species. Furthermore, analysis of expression levels of the cellulolytic genes suggests that a bacterial-origin cellobiase is upregulated upon desiccation. In summary, bdelloid rotifers have apparently developed cellulolytic functions by the acquisition and domestication of multiple foreign genes.

A negative search for a paramyxoviral etiology of Paget's disease of bone: molecular, immunological, and ultrastructural studies in UK patients.

Paget's disease of bone is a common bone disease characterized by increased and disorganized bone remodeling at focal sites throughout the skeleton. The etiology of the disease is unresolved. A persistent viral infection has long been suggested to cause the disease. Antigen and/or nucleic acid sequences of paramyxoviruses (in particular measles virus [MV], canine distemper virus [CDV], and respiratory syncytial virus [RSV]) have been reported in pagetic bone by a number of groups; however, others have been unable to confirm this and so far no virus has been isolated from patients. Here, we reexamined the question of viral involvement in Paget's disease in a study involving 53 patients with established disease recruited from seven centers throughout the United Kingdom. Thirty-seven patients showed clear signs of active disease by bone scan and/or histological assessment of the bone biopsy specimens and 12 of these had not received any therapy before samples were taken. Presence of paramyxovirus nucleic acid sequences was sought in bone biopsy specimens, bone marrow, or peripheral blood mononuclear cells using reverse-transcription polymerase chain reaction (RT-PCR) with a total of 18 primer sets (7 of which were nested), including 10 primer sets (including 3 nested sets) specifically for MV or CDV. For each patient at least one sample was tested with all primer sets by RT-PCR and no evidence for the presence of paramyxovirus RNA was found in any patient. In 6 patients, bone biopsy specimens with clear histological evidence of active disease tested negative for presence of measles and CDV using immunocytochemistry (ICC) and in situ hybridization (ISH). Intranuclear inclusion bodies, similar to those described by others previously, were seen in pagetic osteoclasts. The pagetic inclusions were straight, smooth tubular structures packed tightly in parallel bundles and differed from nuclear inclusions, known to represent MV nucleocapsids, in a patient with subacute sclerosing panencephalitis (SSPE) in which undulating, diffuse structures were found, arranged loosely in a nonparallel fashion. In the absence of amplification of viral sequences from tissues that contain frequent nuclear inclusions and given that identical inclusions are found in other bone diseases with a proven genetic, rather than environmental, etiology, it is doubtful whether the inclusions in pagetic osteoclasts indeed represent viral nucleocapsids. Our findings in this large group of patients recruited from throughout the United Kingdom do not support a role for paramyxovirus in the etiology of Paget's disease.

Weight gain, thermic effect of glucose and resting metabolic rate during recovery from anorexia nervosa.

Rate of weight gain, together with metabolic rate before and after a glucose meal, were studied in a group of 15 female anorexia nervosa patients as their weight was being restored to normal levels. The previously obese anoretic patients gained weight more rapidly, on the same food intake, than those who were of normal weight before their illness began. The increase in metabolic rate (as treatment progressed) was less in the previously obese patients, who also showed a tendency for the metabolic rate to increase less after a glucose meal than the patients with no history of obesity. The thermic effect of glucose was greater in patients with anorexia nervosa than in a comparable control group of six female students.

Effect of naratriptan on myocardial blood flow and coronary vasodilator reserve in migraineurs.

BACKGROUND: Migraine drugs can produce adverse cardiac effects. The authors have demonstrated previously that ergotamine can lead to a significant reduction of hyperemic myocardial blood flow, but little is known about the effect of the newer serotonin analogues. Coronary artery constriction caused by serotonin or its analogues is mediated mainly by 5HT2 receptors. The selective 5HT1B/1D agonist naratriptan has no significant activity at 5HT2 receptors; however, like all 5HT1B/1D agonists developed for the acute treatment of migraine, naratriptan could potentially constrict coronary arteries by activation of 5HT1B receptors. METHODS: The effects on myocardial blood flow of subcutaneous naratriptan 1.5 mg compared with placebo were assessed under resting and hyperemic conditions with PET using oxygen-15 labeled water during two separate visits. This study was a randomized, double-blind, placebo-controlled crossover trial in 34 migraine subjects with no evidence of ischemic heart disease, studied outside a migraine attack. RESULTS: Naratriptan did not differ significantly from placebo in its effects on resting myocardial blood flow, but did evoke a small, significant fall in hyperemic myocardial blood flow (-13% versus placebo) and an increase in hyperemic coronary resistance (+19% versus placebo) without any signs or symptoms suggestive of myocardial ischemia. Naratriptan did not significantly affect the coronary vasodilator reserve (hyperemic/resting blood flow) compared with placebo. CONCLUSIONS: These results show that at therapeutic doses, naratriptan exerts only a minor effect on myocardial blood flow, coronary vasodilator reserve, or coronary resistance among subjects with no evidence of ischemic heart disease. These results should not be extrapolated to patients with coronary artery disease, in whom all 5HT1 agonists for migraine are contraindicated.

Effects of ergotamine on myocardial blood flow in migraineurs without evidence of atherosclerotic coronary artery disease.

The effects of intravenous ergotamine (0.25 mg) on basal and hyperemic (dipyridamole) myocardial blood flow (MBF), measured with positron emission tomography and H2(15)O, were assessed in 15 migraineurs in a double-blind, randomized, placebo controlled, crossover study. Ergotamine produced a 27% reduction in hyperemic MBF (2.62 +/- 0.11 vs 3.72 +/- 1.05 ml x min(-1) x g(-1); p <0.05), a 31% reduction in the coronary vasodilator reserve (1.81 +/- 0.50 vs 2.71 +/- 1.15; p <0.01), and a 55% increase in minimal coronary resistance (42.2 +/- 15 vs 26.7 +/- 8 mm Hg x min x ml(-1) x g(-1); p <0.001), suggesting vasoconstriction of the coronary microcirculation.

Personality, body weight and ultimate outcome in anorexia nervosa.

The Eysenck Personality Inventory, a highly standardized self-rating questionnaire, allows 2 measures of psychosocial functioning on independent scales entitled "emotionally" and "extroversion/introversion." A population of severely ill, low body weight anorectics revealed a high degree of "introversion" and variable amounts of "emotionality" on these measures. Low amounts of "emotionality" were associated with abnormally high "lie" scores. Following restoration of body weight to full matched population mean levels within an intensive treatment program, significant changes occurred on these measures--increased extroversion scores, decreased emotionality and lie scores. However, possibly qualitative changes had occurred in the state of emotionality since high levels were now related to good clinical outcome many years later. The nature of this phenomenon is discussed.

Effect of silicone oil viscosity on emulsification.

Emulsification of intravitreal silicone oil has been observed as a late complication after its use as a retinal tamponade. We compared the emulsification potential of silicone oil of different viscosities (100 centistokes [cs], 1000 cs, and 12,500 cs) and molecular composition in an in vitro model using a commercial detergent (benzalkonium chloride) and physiologic surface-active agents (human serum and lysed red blood cells). We found that silicone oils that have low-molecular-weight contents emulsify more readily than those that do not. Moreover, the extent and susceptibility to emulsification increases with decreasing viscosity or with an increase in the proportion of low-molecular-weight constituents. Hence, higher-molecular-weight (viscosity) oils or removal of low-molecular-weight components from medical grade fluid may lessen the emulsification observed clinically.

Factors affecting prognosis in male anorexics.

Twenty-seven male anorexics have been followed up over 2-20 yr (mean 8 yr) and their outcome assessed. This has been compared with outcome in female patients with similar pictures at presentation (Burns and Crisp, 1984). Features of the family and personal history and clinical aspects of the disease at presentation were compared with outcome and a number found to be significantly associated with it. Poor relationship with parents during childhood and the absence of normal adolescent sexual behavior and fantasy premorbidly were strongly predictive of a poor outcome. Long duration of illness, previous treatment and greater weight loss during illness were also associated with poor outcome, although no specific dietary behaviour was predictive. The remarkable similarity in outcome pattern between the male and female prompts re-evaluation of some theories of the nature of the role of sexual conflicts in anorexia nervosa.

Symbolic functioning in anorexia nervosa.

This study examined 20 patients with anorexia nervosa using a projective test with a quantitative scoring system (the SAT9), and an indirect measure of symbolic function (the interoceptive awareness subscale of the EDI). The findings support the clinical observation that patients with anorexia nervosa are often arrested developmentally, and are without the ability to deal adequately with the anxieties created by the process of maturation. The results of this study have significance for the psychotherapy techniques used in the treatment of these patients.

Family structure and birth order of patients with anorexia nervosa.

A retrospective case-notes study of 252 patients was undertaken, to focus on their birth order, and other aspects of their sibships. There is little evidence of a relationship to birth order using an established measure (Slater, 1962). Previous researchers have found a preponderance of female siblings in the families of patients with anorexia nervosa. We have not found this, neither is our sample characterised by older or younger siblings of any one sex. This is true for both female and male anorexics. These results are discussed in terms of experimental and family theories concerning the development of anorexia nervosa.

Dexamethasone suppression and energy balance: a study of anorexic patients.

The performance of the dexamethasone suppression test (DST) was investigated in 45 female anorexic out-patients (cross-sectional study) and in nine female anorexic in-patients (longitudinal study). DST non-suppression was strongly associated with negative energy balance (low body weight and low Ponderal Index) but there was no significant association with the presence of affective or neurotic disturbance in these patients. These findings cast doubt on the value of the DST in the management of depressive illness.

Why do some anorexics steal? Personal, social and illness factors.

There is a recognised association between anorexia nervosa and stealing. Anorexics who steal are usually also bulimic. However, not all bulimic anorexics steal. The question of why some do and others do not is explored with respect to features of the illness and personal and social variables. Bulimic anorexics who stole differed from their non-stealing counterparts in older age at presentation and in terms of greater sexual activity. These and other findings are discussed with reference to clinical understanding and aetiological theories of other aberrant behavior displayed by the adolescent female.

Cerebral hemisphere function and migraine.

An hypothesis that migraine is the experience of a protective vascular response to cerebral information overload has been explored to a limited extent by examining the association between laterality of the attack and verbal and spatial performances under standard symptom-free conditions. The study was restricted to individuals with unilateral symptoms always presenting on the same side. It emerged that those with classical migraine do not always have prodromata referable to the same side as the pain. Indeed, in the present study, prodromata were almost exclusively referable to the left (dominant) cerebral hemisphere. A subgroup of those with speech disturbances as a feature of the prodromal symptoms was also found to have relatively impaired language abilities on routine testing. It is this finding that lends some support to the hypothesis. The findings also invite the refining proposition that information overload, as defined in the hypothesis, is almost always borne by the dominant (verbal) hemisphere in our species. Such overload might concurrently or sequentially also overtax a suggested limited right hemisphere language capacity, in terms of the hypothesis, accounting for the right-sided pain sometimes presenting in these cases. Otherwise, pain appears to be predominantly left-sided or midline. Perhaps the frequency of this particular syndrome is an indictment of the limitations of language as a basis for communication, as well as reflecting the possibility that most of our stressful transactions and their cerebral processing use a verbal substrate. The results also reveal the need for agreement on rules for classification of laterality in migraine.

Effect of early intervention with sumatriptan on migraine pain: retrospective analyses of data from three clinical trials.

OBJECTIVE: This study assessed the efficacy of sumatriptan 50- and 100-mg tablets in the treatment of migraine attacks while the pain is mild rather than moderate/severe. BACKGROUND: Results from The Spectrum Study suggested that early treatment of migraine attacks with sumatriptan 50-mg tablets while the pain is mild might enhance pain-free response and reduce headache recurrence. METHODS: Retrospective analyses of headaches treated during mild pain were performed using data from 3 studies of sumatriptan tablets (protocols S2CM09, S2BT25, and S2BT26). Our primary interest was pain-free response 2 and 4 hours after dosing; secondary interests were use of a second dose of medication, clinical disability (as measured on a 4-point disability scale), migraine-associated symptoms, meaningful pain relief (patient defined), time to meaningful relief, sustained pain-free response, and proportion of attacks in which pain had worsened 2 and 4 hours after dosing, all of which were compared in headaches treated during mild versus moderate/severe pain. RESULTS: In S2CM09, 92 patients treated 118 headaches during mild pain. Rates of pain-free response were higher 2 hours after dosing with sumatriptan 50 mg (51%) or 100 mg (67%; P < 0.05) compared with placebo (28%), and were higher with early treatment of mild pain compared with treatment of moderate/severe pain at 2 hours (sumatriptan 50 mg: mild pain, 51%; moderate/severe pain, 31%; P < 0.05; sumatriptan 100 mg: mild pain, 67%; moderate/severe pain, 36%) and 4 hours (50 mg: 75% vs 56%; 100 mg: 90% vs 61%; P < 0.05). Early intervention also resulted in less redosing than when moderate/severe pain was treated (50 mg: 21% vs 32%; 100 mg: 20% vs 29%). More attacks treated early with sumatriptan 50 or 100 mg were associated with normal function 4 hours after dosing compared with placebo (70% and 93% vs 46%, respectively). Sustained pain-free response rates 2 to 24 hours after early dosing with sumatriptan 50 or 100 mg were also higher (34% and 53%, respectively) compared with treatment of moderate/severe pain (19% and 24%, respectively). Early treatment with sumatriptan 100 mg produced significantly higher pain-free rates at 2 hours after dosing (P < 0.001) than did ergotamine plus caffeine (S2BT25: 69% vs 34%, respectively) or aspirin plus metoclopramide (S2BT26: 73% vs 25%, respectively). CONCLUSIONS: Sumatriptan 50- and 100-mg tablets are effective whether pain is mild or moderate/severe. However, treatment with sumatriptan while pain is mild provides high pain-free response rates while reducing the need for redosing, benefits not seen with ergotamine plus caffeine or aspirin plus metoclopramide.

Comparison of naratriptan and sumatriptan in recurrence-prone migraine patients. Naratriptan International Recurrence Study Group.

OBJECTIVE: This randomized, double-blind, crossover study was undertaken to compare the incidence of headache recurrence after treatment with naratriptan or sumatriptan in migraine patients with a history of frequent headache recurrence (recurrence in > or =50% of successfully treated attacks). BACKGROUND: Although the selective 5-hydroxytryptamine, (5-HT1) agonist sumatriptan is effective and well tolerated for acute treatment of migraine in most patients, headache recurrence within 24 hours of initial successful treatment with sumatriptan and other medications has been reported in approximately 35% of patients. The novel 5-HT1 agonist naratriptan possesses pharmacologic and pharmacokinetic characteristics that may address the issue of headache recurrence. METHODS: Men and women aged 18 to 65 years with a > or =1-year history of migraine with or without aura were randomly assigned to treat 1 moderate or severe migraine attack in a nonclinical setting with one 2.5-mg naratriptan tablet and 1 attack with one 100-mg sumatriptan tablet. A pain-free interval of > or =24 hours was required between attacks. At 4 hours, patients not using rescue medication and experiencing headache recurrence could take a second, identical dose of study medication to treat recurrence. No more than 2 tablets of study medication were permitted in any 24-hour period. RESULTS: A total of 253 patients treated > or =1 migrane attack and were included in the safety analysis; the 225 patients who treated both attacks were included in the efficacy analysis. Of the 164 naratriptan-treated and 181 sumatriptan-treated patients experiencing headache relief after > or =1 attack, headache recurrence 4 to 24 hours after treatment was reported by 74 naratriptan-treated patients (45%) and 101 sumatriptan-treated patients (57%; not statistically significant). (One naratriptan- and 3 sumatriptan-treated patients who experienced headache relief did not record recurrence status and were not included in the denominator for the percentage calculation.) In a subset of patients experiencing headache relief after 2 attacks, headache recurrence 4 to 24 hours after initial dosing was reported by 55 naratriptan- and 77 sumatriptan-treated patients (41% and 57%, respectively; P = 0.005). The overall incidence of adverse events was 22% after treatment with naratriptan and 33% after treatment with sumatriptan. This incidence did not increase after use of a second dose of naratriptan (20%) or sumatriptan (31%). CONCLUSION: These data suggest that naratriptan is a long-acting and well-tolerated addition to currently available medications for the treatment of acute migraine.

Combined treatment of post-menopausal osteoporosis: effect on muscle function and a new radiological method for assessing trabecular bone.

Ten women presenting with at least two osteoporotic vertebral crush fractures were treated with alfacalcidol (one-alpha-hydroxycholecalciferol), calcium lactogluconate, oestrogen and progestagen for 6 months. Significant improvements in the patient's assessment of pain, grip strength, walking and stair climbing times were found. These suggest that a sub-clinical myopathy may be a feature of osteoporosis. The role of combination treatment is discussed in depth. Radiographs of the thoracic and lumbar spines revealed no further deterioration and there was no significant reduction in standing height. Microfocal radiographs of the hand showed no change in metacarpal cortical bone width. This novel technique allowed a qualitative assessment of trabecular bone in the distal metacarpal but no consistent effect of treatment was observed.

Lipids and lipoprotein fractions after cyclopenthiazide and oxprenolol: a double-blind crossover study.

A double-blind crossover study was carried out to investigate the effects of cyclopenthiazide and oxprenolol on blood lipids in 20 previously untreated patients with mild to moderate hypertension. After a 4-week placebo period, patients received at random either 8-weeks' treatment with the two drugs followed by 8 weeks on cyclopenthiazide alone, or the reversed sequence. Daily doses were 160 mg slow-release oxprenolol and/or 0.25 mg cyclopenthiazide during the first 4 weeks of each treatment period, after which the dosage was doubled. Data from 13 patients who completed the trial showed no significant changes in the blood levels of triglycerides, total cholesterol or LDL and HDL cholesterol fractions. These findings are discussed in relation to published studies on the effects of other beta-blockers on blood lipids.