Multiple mitochondrial DNA deletions in hereditary inclusion body myopathy

We have recently described an autosomal dominant hereditary inclusion body myopathy (h-IBM). Clinically it is is characterized by congenital joint contractures and slowly progressive, proximal muscle weakness and ophthalmoplegia. There is deterioration of muscle function between 30 and 50 years of age. While young patients show minor pathological changes in muscle, the middle-aged and old patients show rimmed vacuoles and inclusions of filaments measuring 15–18 nm in diameter. Except for the absence of significant inflammation the histopathology is similar to that found in sporadic inclusion body myositis (s-IBM). In s-IBM mitochondrial alterations including cytochrome c oxidase (COX) -deficient muscle fibers are common. These are due to multiple mitochondrial DNA (mtDNA) deletions. In this study we investigated the occurrence of mitochondrial alterations in autosomal dominant h-IBM. Young affected individuals showed no mitochondrial changes but three patients aged 38, 51 and 59 years, respectively, showed ragged red fibers and COX-deficient muscle fibers. Polymerase chain reaction analysis showed multiple mtDNA deletions. By in situ hybridization clonal expansions of mtDNA with deletions were demonstrated in COX-deficient muscle fibers. Most of the analyzed deletion breakpoints showed nucleotide repeats flanking the deletions. The results show that COX-deficient muscle fibers and somatic mtDNA deletions are present in this family with h-IBM. The same factors may be involved in the development of mtDNA deletions in s-IBM and this family with h-IBM. Received: 13 July 1999 / Revised: 6 October 1999 · Accepted: 12 October 1999     

Mitochondrial DNA depletion in single fibers in a patient with novel TK2 mutations

The mitochondrial DNA (mtDNA) depletion syndrome is a genetically heterogeneous group of diseases caused by nuclear gene mutations and secondary reduction in mtDNA copy number. We describe a patient with progressive muscle weakness and increased creatine kinase and lactate levels. Muscle weakness was first noted at age 1.5 years and he died of respiratory failure and bronchopneumonia at age 3.5 years. The muscle biopsy showed dystrophic features with ragged red fibers and numerous cytochrome c oxidase (COX)-negative fibers. qPCR analysis demonstrated depletion of mtDNA and sequence analysis of the mitochondrial thymidine kinase 2 (TK2) gene revealed two novel heterozygous variants, c.332C > T, p.(T111I) and c.156 + 5G > C. Quantitative analysis of mtDNA in single muscle fibers demonstrated that COX-deficient fibers showed more pronounced depletion of mtDNA when compared with fibers with residual COX activity (P < 0.01, n = 25). There was no evidence of manifestations from other organs than skeletal muscle although there was an apparent reduction of mtDNA copy number also in liver. The patient showed a pronounced, albeit transient, improvement in muscle strength after onset of treatment with coenzyme Q10, asparaginase, and increased energy intake, suggesting that nutritional modulation may be a therapeutic option in myopathic mtDNA depletion syndrome.     

Polymorphism in the TOMM40 gene modifies the risk of developing sporadic inclusion body myositis and the age of onset of symptoms

A polyT repeat in an intronic polymorphism (rs10524523) in the TOMM40 gene, which encodes an outer mitochondrial membrane translocase involved in the transport of amyloid-β and other proteins into mitochondria, has been implicated in Alzheimer’s disease and APOE-TOMM40 genotypes have been shown to modify disease risk and age at onset of symptoms. Because of the similarities between Alzheimer’s disease and sporadic inclusion body myositis (s-IBM), and the importance of amyloid-β and mitochondrial changes in s-IBM, we investigated whether variation in poly-T repeat lengths in rs10524523 also influence susceptibility and age at onset in a cohort of 90 Caucasian s-IBM patients (55 males; age 69.1 ± 9.6). In carriers of APOE ε3/ε3 or ε3/ε4, genotypes with a very long (VL) poly-T repeat were under-represented in s-IBM compared to controls and were associated with a later age at symptom onset, suggesting that these genotypes may be protective. Our study is the first to suggest that polymorphisms in genes controlling mitochondrial function can influence susceptibility to s-IBM and have disease modifying effects. However, further studies in other s-IBM populations are needed to confirm these findings, as well as expression studies of different TOMM40 alleles in muscle tissue.     

Distal weakness with respiratory insufficiency caused by the m.8344A > G “MERRF” mutation

The m.8344A > G mutation in the mt-tRNA^Lys gene, first described in myoclonic epilepsy and ragged red fibers (MERRF), accounts for approximately 80% of mutations in individuals with MERRF syndrome. Although originally described in families with a classical syndrome of myoclonus, ataxia, epilepsy and ragged red fibers in muscle biopsy, the m.8344A > G mutation is increasingly recognised to exhibit marked phenotypic heterogeneity. This paper describes the clinical, morphological and laboratory features of an unusual phenotype in a patient harboring the m.8344A > G ‘MERRF’ mutation. We present the case of a middle-aged woman with distal weakness since childhood who also had ptosis and facial weakness and who developed mid-life respiratory insufficiency necessitating non-invasive nocturnal ventilator support. Neurophysiological and acetylcholine receptor antibody analyses excluded myasthenia gravis whilst molecular genetic testing excluded myotonic dystrophy, prompting a diagnostic needle muscle biopsy. Mitochondrial histochemical abnormalities including subsarcolemmal mitochondrial accumulation (ragged-red fibers) and in excess of 90% COX-deficient fibers, was seen leading to sequencing of the mitochondrial genome in muscle. This identified the m.8344A > G mutation commonly associated with the MERRF phenotype. This case extends the evolving phenotypic spectrum of the m.8344A > G mutation and emphasizes that it may cause indolent distal weakness with respiratory insufficiency, with marked histochemical defects in muscle. Our findings support consideration of screening of this gene in cases of indolent myopathy resembling distal limb-girdle muscular dystrophy in which screening of the common genes prove negative.     

Expression of myogenic regulatory factors and myo-endothelial remodeling in sporadic inclusion body myositis

Muscle repair relies on coordinated activation and differentiation of satellite cells, a process that is unable to counterbalance progressive degeneration in sporadic inclusion body myositis (s-IBM). To explore features of myo regeneration, the expression of myogenic regulatory factors Pax7, MyoD and Myogenin and markers of regenerating fibers was analyzed by immunohistochemistry in s-IBM muscle compared with polymyositis, dermatomyositis, muscular dystrophy and age-matched controls. In addition, the capillary density and number of interstitial CD34⁺ hematopoietic progenitor cells was determined by double-immunoflourescence staining. Satellite cells and regenerating fibers were significantly increased in s-IBM similar to other inflammatory myopathies and correlated with the intensity of inflammation (R > 0.428). Expression of MyoD, visualizing activated satellite cells and proliferating myoblasts, was lower in s-IBM compared to polymyosits. In contrast, Myogenin a marker of myogenic cell differentiation was strongly up-regulated in s-IBM muscle. The microvascular architecture in s-IBM was distorted, although the capillary density was normal. Notably, CD34⁺ hematopoietic cells were significantly increased in the interstitial compartment. Our findings indicate profound myo-endothelial remodeling of s-IBM muscle concomitant to inflammation. An altered expression of myogenic regulatory factors involved in satellite cell activation and differentiation, however, might reflect perturbations of muscle repair in s-IBM.     

Asleep-awake-asleep craniotomy: A comparison with general anesthesia for resection of supratentorial tumors

The anesthetic plan for patients undergoing awake craniotomy, when compared to craniotomy under general anesthesia, is different, in that it requires changes in states of consciousness during the procedure.This retrospective review compares patients undergoing an asleep-awake-asleep technique for craniotomy (group AW: n = 101) to patients undergoing craniotomy under general anesthesia (group AS: n = 77). Episodes of desaturation (AW = 31% versus AS = 1%, p < 0.0001), although temporary, and hypercarbia (AW = 43.75 mmHg versus AS = 32.75 mmHg, p < 0.001) were more common in the AW group. The mean arterial pressure during application of head clamp pins and emergence was significantly lower in AW patients compared to AS patients (pinning 91.47 mmHg versus 102.9 mmHg, p < 0.05 and emergence 84.85 mmHg versus 105 mmHg, p < 0.05). Patients in the AW group required less vasopressors intraoperatively (AW = 43% versus AS = 69%, p < 0.01). Intraoperative fluids were comparable between the two groups. The post anesthesia care unit (PACU) administered significantly fewer intravenous opioids in the AW group. The length of stay in the PACU and hospital was comparable in both groups.Thus, asleep-awake-asleep craniotomies with propofol-dexmedetomidine infusion had less hemodynamic response to pinning and emergence, and less overall narcotic use compared to general anesthesia. Despite a higher incidence of temporary episodes of desaturation and hypoventilation, no adverse clinical consequences were seen.     

Exercise-induced changes of cerebrospinal fluid vascular endothelial growth factor in adult chronic hydrocephalus patients

Vascular endothelial growth factor (VEGF) is a growth factor demonstrated to be a key factor in cerebral angiogenesis and neurogenesis. It has been considered a critical component in hippocampus neurogenesis and memory formation and has been observed to increase in the rat hippocampus after exercise. We previously found increased VEGF levels in experimental chronic hydrocephalus in several brain areas and cerebrospinal fluid (CSF), suggesting a role in the adaption to chronic hypoxia. Here we investigate the ability of moderate exercise to increase CSF-VEGF levels in adult chronic hydrocephalus patients. Lumbar CSF samples were collected from 17 normal pressure hydrocephalus patients. During CSF collection, 11 patients (exercise group) underwent a standard in-room occupational therapy session; six patients (no-exercise group) did not undergo a physical therapy session. CSF-VEGF levels were evaluated for increase related to exercise and the clinical response to CSF drainage. CSF-VEGF levels in the exercise group demonstrated significant increases 1–3 hours post-exercise compared with the levels 1–2 hours pre-exercise (p = 0.04), and also showed significantly higher levels than the no-exercise groups (p = 0.03). The post-exercise CSF-VEGF level in the group that did not clinically improve was significantly higher than both their own pre-exercise level (p = 0.02) and that seen in the clinically improving group (p = 0.05) after exercise. We conclude that CSF-VEGF levels can increase after moderate exercise even in elderly hydrocephalus patients. This suggests that a potential benefit of exercise, especially in CSF drainage non-improved patients, may exist via a central VEGF mechanism.     

Lactate increase and oxygen desaturation in mitochondrial disorders – Evaluation of two diagnostic screening protocols

Background Mitochondrial disorders are characterized by an accumulation of lactate and an insufficient oxygen extraction from blood during exercise. Therefore, both parameters (lactate and oxygen saturation) can be used as screening tests in mitochondrial disorders. However, conflicting results regarding sensitivities and specifities of both tests have been reported. Method We examined 27 patients with genetically defined mitochondrial disorders (single deletions n = 15,multiple deletions n = 5, A3243G mutation n = 7), patients with other neuromuscular disorders, and healthy controls. In the first test subjects performed intermittent isometric handgrip exercise (0.5 Hz) at 80 % (3 minutes) and 30 % (3 and 15 minutes) of maximal contraction force (MCF). Oxygen saturation and partial pressure in cubital venous blood from the exercising arm were measured. In the second test subjects underwent cycle ergometry at 30 W for 15 minutes. Venous lactate at rest, during and 15 minutes postexercise was determined. Result Both tests showed specificities of 92–96%. Sensitivities for changes of venous oxygen partial pressure and oxygen saturation ranged from 21–26% at 80% MCF for 3 minutes to 47–58% at 30% MCF for 15 minutes. Sensitivities for venous resting, peak, and post–exercise lactate was 33%, 58%, and 67%, respectively. The degree of deoxygenation, however,was independent of the intensity and duration of the applied forces. Oxygen desaturation and lactate increase in patients with mitochondrial disorders were not different in patients with and without clinical symptoms of myopathy. There were significant correlations between the heteroplasmy and both the degree of oxygen desaturation and lactate increase in patients with single deletions. In patients who performed both protocols (n = 16) a combination of both tests increased sensitivity up to 87%. Conclusion Oxygen desaturation in forearm exercise tests and lactate increase in cycle ergometry tests show a high specifity but only moderate sensitivity. Combination of the two screening test clearly increases the sensitivity.     

Physical fitness assessment in multiple sclerosis patients: A controlled study

There is growing evidence to show the effectiveness of physical exercise for multiple sclerosis (MS) patients. Aim of this study was to evaluate aerobic capacity, strength, balance, and the rate of perceived exertion (RPE) after exercise, in ambulatory patients with mild MS and matched control healthy participants. Seventeen MS patients aged 48.09 ± 10.0 years, with mild MS disability (Expanded Disability Status Scale: EDSS 1.5 to 4.5) and 10 healthy sedentary age matched (41.9 ± 11.2 years) subjects volunteered for the study. MS patients underwent medical examination with resting electrocardiogram, arterial blood pressure, EDSS, and Modified Fatigue Impact Scale-MFIS. Both groups also underwent physical assessment with the Berg Balance Scale^, test (Berg), Six Minutes Walking Test (6MWT), maximal isometric voluntary contraction (MIVC) of forearm, lower limb, shoulder strength test, and the Borg 10-point scale test. The one-way ANOVA showed significant differences for MFIS (F_1.19 = 9.420; p < 0.01), Berg (F_1.19 = 13.125; p < 0.01), handgrip MIVC (F_1.19 = 4.567; p < 0.05), lower limbs MIVC (F_1.19 = 7.429; p < 0.01), and 6MWT (F_1.19 = 28.061; p < 0.01) between groups. EDSS, Berg test and Borg scores explained 80% of 6MWT variation. Mild grade EDSS patients exhibited impaired balance, muscle strength, and low self pace-6MWT scores, whereas RPE response after the exercise was similar to that of sedentary individuals. Both groups showed similar global physiological adjustments to exercise.     

Exercise training can induce cardiac autophagy at end-stage chronic conditions: Insights from a graft-versus-host-disease mouse model

IntroductionChronic graft-versus-host disease (cGVHD) is a frequent cause of morbimortality after allogeneic hematopoietic stem cell transplantation (allo-HSCT), and severely compromises patients’ physical capacity. Despite the aggressive nature of the disease, aerobic exercise training can positively impact survival as well as clinical and functional parameters. We analyzed potential mechanisms underlying the recently reported cardiac function improvement in an exercise-trained cGVHD murine model receiving lethal total body irradiation and immunosuppressant treatment (Fiuza-Luces et al., 2013. Med Sci Sports Exerc 45, 1703–1711). We hypothesized that a cellular quality-control mechanism that is receiving growing attention in biomedicine, autophagy, was involved in such improvement.MethodsBALB/C female mice (aged 8 wk) with cGVHD were randomly assigned to a control/exercise group (n = 12/11); the exercise group underwent moderate-intensity treadmill training during 11 wk after allo-HSCT. In the hearts of those few mice surviving the entire 11 wk period (n = 2/5), we studied molecular markers of: macroautophagy induction, preservation of contractile/structural proteins, oxidative capacity, oxidative stress, antioxidant defense, and mitochondrial dynamics.ResultsMainly, exercise training increased the myocardial content of the macroautophagy markers LC3BII, Atg12, SQSTM1/p62 and phospho-ULK1 (S555), as well as of α-tubuline, catalase and glutathione reductase (all p < 0.05).ConclusionsOur results suggest that exercise training elicits a positive autophagic adaptation in the myocardium that may help preserve cardiac function even at the end-stage of a devastating disease like cGVHD. These preliminary findings might provide new insights into the cardiac exercise benefits in chronic/debilitating conditions.     

Visual acuity and pattern of visual field loss at presentation in pituitary adenoma

Our purpose was to analyse the demographics, prevalence and pattern of visual field defects in patients with pituitary adenoma. We prospectively recruited 103 consecutive patients (206 eyes) presenting to a neurosurgical unit with pituitary adenoma. Ophthalmological examination and standard automated perimetry (Humphrey, 24-2 threshold) was performed. Severity of visual field defects was also assessed. The mean population age was 53.9 years (standard deviation = 15). Visual loss was the most common reason for presentation (39%) followed by endocrine abnormality (21%) and headache (15%). Patients with endocrine abnormality on presentation were 10.9 years younger than those presenting with visual loss (p = 0.001). Bitemporal defects were the most prevalent pattern (n = 22, 41%) followed by homonymous defects (n = 7, 13%). Of the patients with visual field loss, 33% had unilateral visual field defects. The mean visual acuity in those with bitemporal defects was 6/7.5 with half of these patients having 6/6 vision in both eyes. In conclusion, the majority of patients with pituitary adenoma have visual acuity better than 6/7.5 despite having visual field defects. While a bitemporal pattern of visual field loss is the most common, a significant proportion of patients had unilateral and altitudinal defects. Assessment of the visual field is essential to rule out chiasmal compression.     

Polyneuropathy induced by HIV disease and antiretroviral therapy

ObjectiveTo investigate the underlying mechanisms of polyneuropathy induced by HIV infection or antiretroviral drugs.MethodsWe tested 100 HIV patients (59 with AIDS). Ninety-three patients received antiretroviral drugs. Forty-four were treated with neurotoxic compounds (ddI, ddC, d4T). Nerve conduction velocities and the sympathetic skin response (SSR) in palms and soles were measured in all patients. In skin biopsies (ankle and thigh), the intraepidermal nerve fiber density (IENFD) and the number of epidermal fibers without contact to the basal membrane (fragments) were quantified using PGP9.5 staining.ResultsSeverity of the disease (CD4 + count) correlated to conduction velocities of peroneal (p < 0.01, Spearmans rank correlation), sural (p < 0.01) and median nerves (p < 0.05/p < 0.001, sensory/motor). In contrast, the duration of neurotoxic treatment did not impair conduction velocities (p > 0.3) but correlated to reduced IENFD in the ankle (r = ?0.24, p < 0.05). Despite their reduced IENFD, patients with long neurotoxic treatment had a high number of fragments irrespective of their CD4 + count.ConclusionsNeurotoxic treatment appears to primarily impair thin fiber conduction, whereas HIV neuropathy is linked to large fiber impairment and reduction of fragments of nerve fibers.SignificanceThese findings emphasize the differential pattern of polyneuropathy in HIV patients caused by the infection or induced by antiretroviral treatment.     

A comprehensive rehabilitation program improves disease severity in patients with obstructive sleep apnea syndrome: a pilot randomized controlled study

BackgroundExercise training may improve components of metabolic syndrome and obstructive sleep apnea syndrome (OSAS). The objective of our pilot randomized controlled study was to determine the benefits of a short intensive inpatient individualized exercise training (IET) program in sedentary untreated OSAS patients.MethodsTwenty-two sedentary patients with moderate to severe OSAS were randomly assigned either to one-month education activity sessions (n = 11; control group) or to inpatient rehabilitation program (n = 11), including IET, education activities sessions, and dietary management. Full polysomnography (PSG), OSLER (Oxford Sleep Resistance test), body composition, anthropometric measurements, metabolic syndrome components, and questionnaires were performed at baseline and at study end point.ResultsNo changes occurred in the control group in all variables. Compared to controls, participants randomized to the IET group presented a significant decrease in apnea–hypopnea index (AHI) (40.6 ± 19.4 vs 28.0 ± 19.3; P < 0.001), oxygen desaturation index (ODI), and arousal index, which occurred in conjunction with significant decrease in body mass index (BMI), neck circumference, fat mass, fasting glucose, and diastolic blood pressure. Increased sleep latency was found in participants in the IET group with altered values at baseline.ConclusionsIET reduced OSAS severity with improvement of metabolic syndrome components with concomitant loss in body fat in sedentary adults. If confirmed on a larger scale, a comprehensive rehabilitation program could constitute an additional or alternative treatment for moderate to severe OSAS patients.     

A comparison of respiratory and peripheral muscle strength,functional exercise capacity,activities of daily living and physical fitness in patients with cystic fibrosis and healthy subjects

There are limited reports that compare muscle strength, functional exercise capacity, activities of daily living (ADL) and parameters of physical fitness of cystic fibrosis (CF) patients with healthy peers in the literature. The purpose of this study was to assess and compare respiratory and peripheral muscle strength, functional exercise capacity, ADL and physical fitness in patients with CF and healthy subjects. Nineteen patients with CF (mean forced expiratory volume in one second-FEV₁: 86.56 ± 18.36%) and 20 healthy subjects were included in this study. Respiratory (maximal inspiratory pressure-MIP and maximal expiratory pressure-MEP) and peripheral muscle strength (quadriceps, shoulder abductors and hand grip strength) were evaluated. Functional exercise capacity was determined with 6 min walk test (6MWT). ADL was assessed with Glittre ADL test and physical fitness was assessed with Munich fitness test (MFT). There were not any statistically significant difference in MIP, %MIP, MEP and %MEP values between two groups (p > 0.05). %Peripheral muscle strength (% quadriceps and shoulder abductors strength), 6MWT distance and %6MWT distance were significantly lower in patients with CF than those of healthy subjects (p < 0.05). Glittre ADL-test time was significantly longer in patients with CF than healthy subjects (p < 0.05). According to Munich fitness test, the number of bouncing a ball, hanging score, distance of standing vertical jumping and standing vertical jumping score were significantly lower in patients with CF than those of healthy subjects (p < 0.05). Peripheral muscle strength, functional exercise capacity, ADL performance and speed, coordination, endurance and power components of physical fitness are adversely affected in mild-severe patients with CF compared to healthy peers. Evaluations must be done in comprehensive manner in patients with CF with all stages.     

Sleep parameters associated with long-term outcome following subthalamic deep brain stimulation in Parkinson's disease

IntroductionWe aimed to investigate the effects of changes in sleep architecture on long-term clinical outcome in patients with Parkinson's disease (PD) who underwent deep brain stimulation of subthalamic nuclei (STN DBS).MethodsWe followed up eight PD patients before and three years after STN DBS surgery. In addition to clinical assessments, polysomnography (PSG) followed by multiple sleep latency tests was performed before and after STN DBS, while stimulator was ON and OFF.ResultsSubjective sleep latency was significantly decreased (P = 0.033) and sleep duration was increased (P = 0.041), as measured by Pittsburgh sleep quality index. Latency to REM sleep stage was shortened after surgery with STN DBS ON (P = 0.002). Index of central type of abnormal respiratory events was significantly increased while stimulator was ON (P = 0.034). Total number of major body movements was found to be increased when stimulator was turned OFF (P = 0.012). Among PSG data obtained during STN DBS ON, it was observed that duration of N3 sleep was negatively correlated with UPDRS scores at 1st (P = 0.038) and 3rd (P = 0.045) post-operative years. Among PSG variables during STN DBS OFF, durations of N3 sleep (P = 0.017) and REM sleep (P = 0.041) were negatively correlated with UPDRS scores at post-operative 1st year.ConclusionDisturbances in sleep architecture are associated with higher UPDRS scores and worse prognosis at 1st and 3rd post-operative years. Similar results obtained while stimulator was OFF at the end of 1st year support the presence of microlesion effect after STN DBS, which is probably not long lasting.     

Influence of repeated maximal exercise testing on biomarkers and fatigue in sarcoidosis

Fatigue in the immune mediated inflammatory disease sarcoidosis is thought to be associated with impaired exercise tolerance. This prospective study assessed fatigue and recuperative capacity after repeated exercise, and examined whether changing concentrations in biomarkers upon exercise are associated with fatigue.Twenty sarcoidosis patients and 10 healthy volunteers performed maximal cardiopulmonary exercise tests on two successive days. Concentrations of cytokines, stress hormones, ACE and CK were assessed before and after the two exercise tests, and 3 days thereafter. All participants completed a sleep diary.Severely fatigued patients showed significant lower VO₂ max (p = 0.038, p = 0.022) and maximal workload (p = 0.034, p = 0.028) on both exercise tests compared to healthy controls. No impairment of maximal exercise testing was demonstrated during the second cycling test in any group. Fatigue was not correlated with changes in concentrations of biomarkers upon exercise. Severely fatigued patients rated both tests as significantly more fatiguing, and reported significant lower mean subjective night sleeping time during the testing period.Fatigue in sarcoidosis patients cannot be objectified by reduction of exercise capacity after repeated maximal exercise testing, and is not correlated with significant changes in biomarkers. Severe fatigue is only and consistently featured by patient reported outcomes.     

Vestibular evoked myogenic potentials and video head impulse test in patients with vertigo,dizziness and imbalance

The aim of this study was to compare vestibular evoked myogenic potentials (VEMP) and video head impulse test (vHIT) results in patients presenting with vertigo and dizziness. We retrospectively analyzed data of all patients with the chief complaint of vertigo, dizziness, or imbalance that underwent VEMP and vHIT from January 2015 to January 2016. A total of 117 patients (73 females, mean age 53.92 ± 16.76) fulfilled inclusion criteria: group 1 included patients with the final diagnosis of vestibular neuritis (VN) (N = 31 (16 right and 15 left VN)), group 2 included patients with the final diagnosis of vertigo of central origin (N = 23) and group 3 included patients with the final diagnosis of unspecified dizziness (N = 63). There was significant correlation between oVEMP asymmetry and asymmetry of the lateral canals 60 ms gains on vHIT (r = 0.225, p = 0.026). Significant correlation between oVEMP and vHIT asymmetry was present in VN patients (r = 0.749, p < 0.001), while no correlation was found in the groups 2 and 3. oVEMP and vHIT lateral canals asymmetries were significantly greater in patients with vestibular neuritis. Furthermore, positive correlations of oVEMP amplitudes with 60 ms gain of the lateral semicircular canal and slope of the anterior semicircular canal on vHIT, and cVEMP with slope of the posterior semicircular canal on the vHIT were found. These changes were significantly more pronounced in patients with vestibular neuritis. In conclusion, VEMPs and vHIT data should be used complementarily; asymmetry on both tests strongly supports peripheral vestibular system involvement.     

A prospective study of C-reactive protein as a state marker in Cardiac Syndrome X

Cardiac Syndrome X (CSX), the presence of angina pectoris despite normal epicardial coronary arteries seen on invasive angiography, is known to be associated with an elevation of several inflammatory biomarkers, suggesting a possible role for inflammation in its pathogenesis. We sought to establish if C-reactive protein (CRP) levels varied with disease severity and so whether it is a state or trait marker. We studied 16 CSX patients with typical angina pectoris, normal coronary arteries and an electrically positive exercise stress test (EST) and 13 age- and sex-matched healthy controls (HC). CSX patients were followed up at a subsequent visit with repeated exercise stress testing and CRP measurement. We found that CRP levels were significantly higher in the CSX group compared to the HC (1.5 [0.8–4.5] v 0.8 [0.4–1.4] mg/L, p = 0.02). This elevation in CRP persisted throughout the study length. CRP correlated with time to symptoms on EST at enrolment and at the second visit (r = −0.690, df = 10, p = 0.013 and r = −0.899, df = 4, p = 0.015, respectively). At the follow-up visit, 50% of CSX patients developed electrically and symptomatically negative ESTs. The mean CRP of this group was significantly lower than that of the CSX patients with ongoing symptoms and positive ESTs (1.2 ± 0.2 v 2.8 ± 0.6 mg/L, p = 0.018) and did not differ significantly from that of healthy controls. CRP levels also dropped in patients whose symptoms improved while they increased in patients who became more symptomatic (p = 0.027). We conclude that the results of this small study support the concept of CSX being an inflammatory-mediated condition with CRP levels prospectively varying with functional measures of disease severity. This indicates that CRP is a state marker in CSX.     

Assessment of cardiorespiratory and neuromotor fitness in children with developmental coordination disorder

The decreased participation in physical activity by children with probable developmental coordination disorder (pDCD) has raised concerns about their aerobic fitness and lung function levels. The purpose of the present study was to examine assessment of cardiorespiratory and neuromotor fitness, using laboratory-based tests during an incremental treadmill protocol in healthy children with and without pDCD. Twenty sex children ages 6–9 years took part in this study. Motor coordination was assessed using the Movement Assessment Battery for Children (MABC). All participants performed a cardiopulmonary exercise test (CPET) on a cycle ergometer. Pulmonary function was assessed by spirometric measurements (forced vital capacity: FVC, forced expiratory volume in 1 s: FEV₁) and walking distance (6MWD) was assessed using the 6-min walking test. The children with pDCD had lower VO_2 max than children without pDCD (p < 0.01). Moreover, FVC and FEV₁ were significantly higher in children without pDCD than in children with the disorder (p < 0.05, p < 0.01 respectively). Likewise, children with pDCD had poorer performance on the 6MWD than children without pDCD (p < 0.01). A significant correlation between the absolute value for FEV₁ and 6MWD (r = 0.637, p < 0.05) in pDCD group was observed. We found a significant correlation between VO_2 max and MABC score (r = −0.612, p < .001) and between VO_2 max and 6MWD (r = 0.502, p < .001) for all children. Moreover, a significant correlation between VO_2 max and FEV₁ (r = 0.668, p < .05) was found in children with pDCD. Overall, the reduced aerobic capacity of DCD was associated with decreased of lung function, as well as an alteration of peripheral muscle responses.     

Genetic and biochemical findings in Chinese children with Leigh syndrome

This study investigated the genetic and enzymological features of Leigh syndrome due to respiratory chain complex deficiency in Chinese patients. The clinical features of 75 patients were recorded. Mitochondrial respiratory chain enzyme activities were determined via spectrophotometry. Mitochondrial gene sequence analysis was performed in 23 patients. Five core pedigrees were investigated via restriction fragment length polymorphism and gene sequencing. Psychomotor retardation (55%), motor regression (20%), weakness (29%), and epilepsy (25%) were the most frequent manifestations. Sixty-four patients (85.3%) had isolated respiratory complex deficiencies: complex I was seen in 28 patients (37.3%); complex II, seven (9.3%); complex III, six (8%); complex IV, ten (13.3%); and complex V, 13 patients (17.3%). Eleven patients (14.7%) had combined complex deficiencies. Mitochondrial DNA mutations were detected in 10 patients. Eight point mutations were found in mitochondrial structural genes: m.4833A > G in ND2, m.10191T > C in ND3, m.12338T > C and m.13513G > A in ND5, m.14502T > C and m.14487T > C in ND6, m.8108A > G in COXII, and m.8993T > G in ATPase6. Three mutations were found in tRNA genes: m.4395A > G in tRNA-Gln, m.10454T > C in tRNA-Arg, and m.5587T > C in tRNA-Ala. One patient and their mother both had the m.12338T > C and m.8993T > C mutations. In conclusion, mitochondrial respiratory chain complex I deficiency and structural gene mutations frequently occur in Chinese Leigh syndrome patients.