Resistance to polycyclic aromatic hydrocarbon toxicity and associated bioenergetic consequences in a population of Fundulus heteroclitus.

Several locations in the Elizabeth River, VA, USA are highly contaminated with polycyclic aromatic hydrocarbons (PAHs) due to the release of creosote mixtures from wood treatment facilities. Interestingly, some populations of Atlantic killifish (Fundulus heteroclitus) inhabiting the Elizabeth River (ER) are resistant to PAH-induced teratogenesis. However, evolutionary resistance to PAHs due to chronic PAH exposure is associated with reduced fitness and increased susceptibility to other environmental stressors in at least one PAH-resistant ER killifish population. More specifically, wild-caught and first generation PAH-resistant juvenile killifish have altered metabolic demands when compared to non-resistant fish. Herein, we investigated this association further by examining a previously under-studied population captured from the creosote-contaminated site Republic Creosoting (Rep). We assessed PAH toxicity and effects on energy metabolism in Rep killifish in comparison with killifish from the reference site Kings Creek (KC). Following exposures to simple and complex PAH mixtures, Rep killifish exhibited several phenotypes associated with PAH resistance including decreased incidences of developmental cardiovascular deformities and recalcitrant cytochrome P450 1A (CYP1A) activity. We evaluated bioenergetics in killifish embryos throughout development and found elevated basal oxygen consumption rates in Rep embryos relative to KC embryos. Furthermore, juvenile F1 Rep fish had significantly lower maximal metabolic rates and aerobic scopes than KC juveniles. These results suggest that populations of killifish that have adapted or evolved to withstand the toxicity associated with PAHs consequently have altered energetic metabolism or demands. Such consequences could result in an enhanced vulnerability to other environmental and anthropogenic stressors in PAH-resistant killifish.

Cognition in myotonic dystrophy type 1: a 5-year follow-up study.

BACKGROUND AND PURPOSE: Studies on cognitive decline in myotonic dystrophy type 1 (DM1) are characterized by conflicting results. The purpose of the present study was to analyse possible decline in classical/adult onset DM1 at a 5-year follow-up and to explore the correlation with disease-related and demographic factors. METHODS: Patients with DM1 (n = 37) were examined with a comprehensive neuropsychological test battery yielding measures on memory, attention, verbal, visuospatial and executive functions. Assessment of muscle impairment and CTG repeat expansion size was performed. RESULTS: A majority of the participants (65%) performed worse at follow-up. Compared to normative data, patients scored significantly worse on tests measuring memory, attention, visuospatial construction and verbal ability. Neither CTG repeat size nor muscle impairment related to cognitive decline. However, age at onset and disease duration were correlated with the number of tests in which performance was below 1 SD at both baseline and follow-up examination. CONCLUSIONS: Measurements show that classical/adult onset DM1 is characterized by cognitive decline. Both earlier onset and longer duration of the disease are indicative of more cognitive deficits.

Search for Pompe disease among patients with undetermined myopathies.

OBJECTIVE: Pompe disease is a rare treatable glycogen storage disease with in adults - a limb-girdle muscle weakness. Muscle biopsy may fail to show the typical vacuolar myopathy. We asked if we had un-diagnosed patients with Pompe disease in western Sweden. MATERIAL AND METHODS: We searched the muscle biopsy registry during the time period 1986 until 2006 including 3665 biopsies and included patients at our Neuromuscular Center with unspecified myopathy or limb-girdle muscular dystrophy. The dry blood spot test was used to identify patients with Pompe disease. RESULTS: A total of 82 patients (46 from the biopsy register and 36 from our center) were seen and dry blood spot test was obtained. No patient with Pompe disease was found. The dry blood spot test was low in three cases (11, 16, and 18% of normal) but a second blood sample showed a normal result based on GAA enzyme activity in lymphocytes in all three patients. In one patient with low normal result of the analysis in lymphocytes a genetic test showed no pathogenic mutations. Further investigation gave a definite diagnose of another myopathy in 12 patients. CONCLUSIONS: The prevalence of Pompe disease in western Sweden (3 in 1.27 million or 0.24 per 100.000 inhabitants) is lower than in the Netherlands and New York. Re-evaluation of patients with myopathies but without definite diagnosis is rewarding since 12 of 82 patients in our study had a definite molecular diagnosis after workup.

Facial memory deficits in myotonic dystrophy type 1.

OBJECTIVES: To evaluate facial memory ability (FMA) in patients with myotonic dystrophy type 1 (DM1). We also explored the relationship between FMA and neuropsychological data, disease-related factors, and CTG repeat expansion size. MATERIALS AND METHODS: Patients with DM1 (n = 33) and healthy subjects (n = 30) were tested with the faces task of the Rivermead Behavioural Memory Test - Extended version (RBMT-E) and an additional set of neuropsychological tests. Clinical data were collected, and CTG repeat size was quantified in blood lymphocytes. RESULTS: Low results on the faces task were more common in patients with DM1 compared with healthy subjects (P < 0.05), with 36% of the patients showing a poor/impaired performance. DM1 patients with deficits in FMA performed significantly worse on tests measuring visual-construction ability and memory. Furthermore, these patients more often falsely recognised unknown faces as known. Deficits in FMA were not associated with any disease-related factor, including CTG repeat expansion size. CONCLUSIONS: These findings revealed deficits in FMA in the DM1 group, which was associated with reduced construction- and visual memory ability.

Sexually dimorphic differences in angiogenesis markers predict brain aging trajectories.

Aberrant angiogenesis could contribute to cognitive impairment, representing a therapeutic target for preventing dementia. However, most angiogenesis studies focus on model organisms. To test the relevance of angiogenesis to human cognitive aging, we evaluated associations of circulating blood markers of angiogenesis with brain aging trajectories in two deeply phenotyped human cohorts (n=435, age 74 + 9) with longitudinal cognitive assessments, biospecimens, structural brain imaging, and clinical data. Machine learning and traditional statistics revealed sex dimorphic associations of plasma angiogenic growth factors with brain aging outcomes. Specifically, angiogenesis is associated with higher executive function and less brain atrophy in younger women (not men), a directionality of association that reverses around age 75. Higher levels of basic fibroblast growth factor, known for pleiotropic effects on multiple cell types, predicted favorable cognitive trajectories. This work demonstrates the relevance of angiogenesis to brain aging with important therapeutic implications for vascular cognitive impairment and dementia.

Total desmosines in plasma and urine correlate with lung function.

The aim of the present study was to evaluate the relationship between the matrix degradation biomarkers, desmosine and isodesmosine (desmosines), and lung function. Plasma and creatinine-corrected urinary total desmosines (P- and U-desmosines, respectively), lung function and diffusing capacity of the lung for carbon monoxide (D(L,CO)) were measured in a cohort of subjects from the Swedish Twin Registry. Concentrations of U- and P-desmosines were measured in 349 and 318 subjects, respectively; approximately one-third of subjects had chronic obstructive pulmonary disease (COPD). Age, female sex, body mass index (BMI) and smoking were significantly associated with U-desmosines in a multiple linear regression analysis. In the overall population, after adjustments for age, sex, height, BMI and smoking, concentrations of U-desmosines were significantly correlated with all lung function measures, and P-desmosines with forced expiratory volume in 1 s and D(L,CO) (p<0.05). With the exception of residual volume versus P-desmosines, relationships between concentrations of desmosines and lung function measures were markedly stronger in subjects with COPD compared with those without COPD. These cross-sectional data showing associations between desmosines and several lung function variables suggest that desmosines, particularly U-desmosines, could be a useful biomarker of COPD status.

Prognosis and prognostic factors in sporadic inclusion body myositis.

OBJECTIVES: To describe the course of change in muscle strength sporadic inclusion body myositis (IBM) patients. MATERIAL AND METHODS: We have studied a cohort of 66 IBM pateints using a hand-held dynamometer. RESULTS: Follow-up during a mean of 61.1 months showed a deterioration of on average -0.79% per month. The 'natural course' without immunosuppressive treatment (IS), analyzed in 43 patients (mean 46.4 months) was mean -1.03% per month. Loss of muscle power was most rapid in knee extension -1.12% (P < 0.001 when compared with elbow flexion, elbow extension and hip flexion). There was a tendency towards a more rapid decline in males than females and over the first 5 years after onset, while the level of serum creatine kinase (CK), age, or region affected at onset did not predict the prognosis. The mean change during periods with any IS treatment was -0.76% per month which was significantly lower compared to the total of untreated periods -1.03% (P < 0.05). Patients (n = 13) treated with mykofenolatmofetil showed a better prognosis of -0.67% per month (P < 0.05). In this group elbow flexion and extension and hip flexion showed a positive response, while knee extension was seemingly unaffected. CONCLUSIONS: There is a mean of 1% loss in power per month in the untreated IBM patient - the rate of loss was greater in the quadriceps muscle and in untreated compared with IS-treated patients.

Episodes of exercise-induced dark urine and myalgia in LGMD 2I.

BACKGROUND: Mutations in the fukutin-related protein gene FKRP (MIM *606596) cause a form of congenital muscular dystrophy (MDC1C) and also limb girdle muscular dystrophy type 2I (LGMD2I). Exercise-induced myoglobinuria, frequently occurring in metabolic myopathies, has been described in Becker muscular dystrophy and in a few cases of LGMD. OBJECTIVES: To describe that episodes with myoglobinuria, often associated with exercise-induced myalgia, may be common and a presenting symptom in patients with LGMD2I. METHODS: Data on episodes of suspected myoglobinuria and myalgia were collected from the patient records on 14 patients with a diagnosis of LGMDI. RESULTS: Five LGMD2I patients reported recurrent episodes of dark urine and myalgia after exercise, and in three of them, this was the only symptom for several years. CONCLUSIONS: We conclude that episodes compatible with exercise-induced myoglobinuria may be frequent in LGMD2I.

Rituximab for severe myasthenia gravis--experience from five patients.

BACKGROUND: Rituximab (RTX), a monoclonal antibody directed against CD20+ B cells, is used in the treatment of several autoimmune disorders including severe generalized myasthenia gravis (MG). AIMS OF THE STUDY: To describe the experience with RTX in five MG patients treated at our Neuromuscular Centre. METHODS: Effect of RTX treatment was monitored by quantitative MG score (QMG score), forced vital capacity (FVC) and records of clinical parameters. Three patients had thymoma. Duration of MG prior to the first course of RTX was 3, 7, 26, 26 and 38 years. RESULTS: We found favourable response to RTX treatment in all five patients. QMG score was markedly lower after RTX and in the three patients with respiratory muscle affection the FVC was increased. A good relief of bulbar, respiratory or extremity MG weakness was thus also found in the three patients who had long-standing severe MG. Repeated RTX treatment was needed in four patients. CONCLUSIONS: We conclude that RTX is effective in recent onset MG as well as in long-standing cases. As thymoma is prevalent in patients with severe MG, further studies are needed to evaluate the risk of thymoma recurrence following RTX treatment.

Body composition in patients with primary neuromuscular disease assessed by dual energy X-ray absorptiometry (DXA) and three different bioimpedance devices.

BACKGROUND: Patients with primary neuromuscular disease have reduced muscle mass, and use of body mass index to assess nutritional status and body composition can therefore be questioned. Dual emission X-ray absorptiometry (DXA) can estimate muscle mass, but is not always readily available. Bioimpedance is a simple, portable and "easy to use" method for the assessment of body composition. OBJECTIVES: To assess muscle mass by DXA in 143 patients with primary neuromuscular disease and validate three bioimpedance devices; Impedimed SFB7, (BISIMPEDIMED), Xitron4200 (BISXITRON) and Tanita MC180MA (MFBIATANITA). METHODS: Body composition was assessed by DXA in 143, by BISIMPEDIMED in 116, by MFBIATANITA in 104 and by BISXITRON in 35 patients. RESULTS: Muscle mass assessed by DXA, and phase angle (PhA) were below reference values in all female and 96% of male patients. BISIMPEDIMED underestimated muscle mass by 6.5 ± 14.2 kg (p < 0.001), but this could be corrected after exclusion of resistance (Ri) values > 3500 Ohm (p = 0.84). MFBIATANITA overestimated muscle mass by 30.8 ± 9.1 kg (p < 0.001) with systematic bias, whereas BISXITRON was in agreement with DXA, and without systematic bias. Muscle mass was strongly correlated to PhA (rPEARSON = 0.75, p < 0.01). CONCLUSION: Patients with primary neuromuscular disease have proportionally more fat and less muscle mass than the population in general, despite normal BMI. Muscle mass can be assessed by bioimpedance in these patients, but performance and bias depends on device. Phase angle by bioimpedance correlates to muscle mass, and could therefore potentially be used a surrogate measure of muscle mass during follow up.

Cerebrospinal fluid tau and amyloid beta42 protein in patients with myotonic dystrophy type 1.

BACKGROUND: Myotonic dystrophy type 1 (DM1) is associated with brain morphology changes including neurofibrillary degeneration. METHODS: We have examined cerebrospinal fluid (CSF) markers indicative of neuronal degeneration and amyloidogenesis; total tau (T-tau), phosphorylated tau (P-tau) and beta amyloid 1-42 (Abeta42), in 32 patients with DM1. RESULTS AND CONCLUSIONS: Associations between CSF markers and CTG repeat expansion size, brain MRI findings, and neuropsychological test results were analysed. As compared with matched controls Abeta42 was significantly decreased (P = 0.001), whilst levels of T-tau were increased (P < 0.001). No difference was found between measures considering P-tau levels. At present the clinical implications of these findings is unclear, because of an overlap between CSF values of DM1 patients and healthy controls, but also regarding modest associations between CSF markers and other measures. However notably, the Tau pathology, as seen in DM1, differs from Alzheimers disease, considering the lack of increased levels of P-tau.

MELAS syndrome in a patient with a point mutation in MTTS1.

UNLABELLED: BACKGROUND, OBJECTIVE AND METHODS: We describe a female patient with a mitochondrial encephalopathy, lactic acidosis and stroke-like episodes syndrome. As a child, she developed epilepsy and stroke-like episodes giving cognitive impairment and ataxia but no hearing impairment. At the age of 44 years, she suffered a cerebral sinus thrombosis which was warfarin treated. One month later, she developed an episode of severe acidosis associated with encephalopathy and myelopathy. RESULTS: She was found to harbour a 7512T>C mutation in the mitochondrial encoded tRNA(Ser(UCN)) gene (MTTS1). The mutation load was 91% in muscle and 24% in blood. Enzyme histochemical analysis of the muscle tissue showed numerous cytochrome c oxidase (COX)-negative fibres. Restriction fragment length polymorphism (RFLP) analysis of single muscle fibres showed significantly higher level (median 97%, range: 94-99%) of the mutation in the COX-negative fibres compared with COX-positive fibres (median 36%, range: 12-91%), demonstrating the pathogenic effect of the mutation. Different levels of heteroplasmy (range 34-61%) were detected in hair shafts analysed by RFLP. CONCLUSION: This case adds to the spectrum of clinical presentations, i.e. sinus thrombosis, in patients having MTTS1 mutations.

Raised troponin T in inclusion body myositis is common and serum levels are persistent over time.

Cardiac Troponin T (cTnT), creatine kinase (CK) and creatine kinase isoenzyme MB (CKMB) were measured in 42 consecutive patients with sporadic inclusion body myositis (s-IBM). 26 patients (62%) had a cTnT level >0.05 microg/L, the cut off used in the diagnosis of myocardial infarction. The cTnT levels correlated somewhat more closely to CKMB (rho=0.83, p<0.0001) than to CK (rho=0.60, p<0.0001). Patients on immunosuppressive treatment had lower cTnT levels than untreated, while there were no significant differences according to age, disease duration or gender. Repeated samples in 26 patients showed that the cTnT levels were essentially unchanged over time up to 17 months. None of the patients had signs of myocardial damage or renal failure at time of sampling. It may be of value to analyse cTnT at some occasion(s) in s-IBM patients.

Temperament and character in patients with classical myotonic dystrophy type 1 (DM-1).

This study was designed to investigate personality in classical Myotonic Dystrophy (DM-1). Forty-six patients with DM-1 (25 women and 21 men), 31 healthy controls and 37 subjects in a contrast group, consisting of patients with other muscle disorders (spinal muscular atrophy, facioscapulohumeral dystrophy and limb girdle muscular dystrophy), completed the Temperament and Character Inventory (TCI) (Cloninger, 1994). We aimed to establish whether CTG triplet repeat size correlated with ratings of personality dimensions in the TCI. The DM-1 patients scored significantly higher on the TCI dimension Harm avoidance and lower on Persistence, Self-directedness and Cooperativeness. Signs of a personality disorder were found in 20% of the DM-1 patients. No correlation was found between the number of CTG repeats and scores in the TCI. This study indicates deviant personality in classical DM-1 regarding temperament and character, both in comparison to healthy controls and to patients with other muscle disorders with no known brain disorder.

Surgical treatment of obesity in DM1--a case report and a review of the literature.

In patients with myotonic dystrophy type 1 overweight and obesity are frequent. When present this has further negative effects on the patients' pulmonary and muscle function as well as social participation. Anesthesia in myotonic dystrophy type 1 patients is associated with increased risks, especially in those who are obese. We describe the outcome of the first patient reported who has undergone gastric bypass surgery. The operation went without complications. Within two years after surgery she has lost 56.5 kg corresponding to 44% of her preoperative body weight (128.5 kg). She has lost muscle mass and muscle strength, but has gained somewhat in functional tests including pulmonary function and has no longer any need for nocturnal ventilation. Surgical treatment of obesity may be feasible in selected myotonic dystrophy type 1 patients but further studies are needed to determine appropriate criteria for surgery including body mass index limits and how pre- and post-operative follow-up should best be made.

Mitochondrial DNA deletions in muscle fibers in inclusion body myositis.

Inclusion body myositis (IBM) is an autoimmune, inflammatory myopathy where morphological changes of muscle, including ragged red fibers, have indicated mitochondrial dysfunction in some muscle fibers. In this study enzyme histochemical analysis showed that cytochrome c oxidase (COX)-deficient muscle fibers were present at a frequency ranging from 0.5 to 5% of the muscle fibers in a series of 20 IBM patients. In age-matched controls, only occasional COX-deficient muscle fibers were present. Polymerase chain reaction (PCR) analysis of DNA extracted from muscle tissue of the IBM patients showed multiple mtDNA deletions. PCR analysis of isolated, single muscle fibers showed presence of mtDNA with only one type of deletion and deficiency of wild-type mtDNA in each COX-deficient muscle fiber. This finding was supported by results from in situ hybridization using different mtDNA probes on consecutive sections. A 5 kb deletion was identified in all 20 IBM patients. DNA sequencing of the breakpoint region showed that this deletion was the so-called "common deletion." Most but not all of the investigated deletion breakpoints were flanked by direct repeats. COX-deficient fibers were more frequent among fibers with positive immunostaining with antibodies directed toward a regeneration marker, the Leu-19 antigen, than in the entire fiber population. These results show that COX deficiency in muscle fiber segments in IBM is associated with deletions of mtDNA. Clonal expansion of mtDNA with deletions may take place in regenerating muscle fibers following segmental necrosis.

Inclusion body myositis: morphological clues to correct diagnosis.

The aim of this study was to investigate variability of morphological changes found in patients with sporadic inclusion body myositis, to assess the diagnostic value of muscle biopsy. The study included all 43 definite inclusion body myositis patients (86 biopsies) diagnosed at Sahlgrenska University Hospital, Gothenburg, Sweden, between 1984 and 2000. Invasion of mononuclear inflammatory cells in non-necrotic muscle fibres was found in 72 of 86 specimens, while all investigated biopsies showed up-regulation of major histocompatibility complex class I. Cytochrome c oxidase-negative muscle fibres were demonstrated in 84 of 86 biopsies. Rimmed vacuoles were present in all specimens from the vastus lateralis and tibialis muscles, and in 43 of 51 biopsies from the deltoid muscle. In cases with clinical suspicion of inclusion body myositis, where the muscle biopsy does not show inflammatory cell infiltration and rimmed vacuoles, inclusion body myositis should still be considered if there are cytochrome c oxidase-negative fibres and up-regulation of major histocompatibility complex class I. In such cases repeat muscle biopsy may be helpful.

A novel mutation in the mitochondrial tRNA(Phe) gene associated with mitochondrial myopathy.

We report a novel heteroplasmic T-->C mutation at nt position 582 within the mitochondrial tRNA(Phe) gene of a 70-year-old woman with mitochondrial myopathy. No other family members were affected, suggesting that our patient was a sporadic case. The muscle showed frequent ragged red fibers and 43% cytochrome c oxidase deficient fibers. The mutation alters a conserved base pairing in the aminoacyl acceptor stem. The mutation load was 70% in muscle homogenate and varied from 0 to 95% in individual muscle fiber segments. Cytochrome c oxidase-negative fibers showed significantly higher levels of mutated mtDNA (>75%) than Cytochrome c oxidase-positive fibers (<55%). This mutation adds to the previously described four pathogenic mutations in the tRNA(Phe) gene.

T cell receptor beta-chain repertoire in inclusion body myositis.

Inclusion body myositis (IBM) is the most common muscle disease affecting individuals over 50 years of age. The inflammatory reaction is characterized by cell infiltrates predominated by CD8+ cytotoxic T cells. To analyze clonality of muscle infiltrating lymphocytes, we studied the complementarity determining region 3 (CDR3) length distribution of the T cell receptor (TCR). Muscle infiltrating lymphocytes were studied in three IBM patients and compared with peripheral blood lymphocytes (PBL) in two of these patients. The study was performed by reverse transcription polymerase chain reaction (RT-PCR) of RNA extracted from muscle tissue and PBL followed by analysis of fragment length distribution of the CDR3 region in each of 24 different Vbeta families. There was a restricted usage of TCR Vbeta gene families in muscle infiltrating T cells in all three patients. Some of the TCR Vbeta gene families showed oligoclonal expansions but polyclonal patterns were dominating. The CDR3 distribution of most Vbeta families differed between muscle infiltrating lymphocytes and PBL indicating that T cells have expanded locally or selectively accumulated in muscle.

Oligoclonal expansion of muscle infiltrating T cells in inclusion body myositis.

Inclusion body myositis (IBM) is the most common muscle disease affecting individuals over 50 years of age. An important feature of IBM is invasion of muscle fibers by T cells. The muscle infiltrating T cells show a restricted usage of variable (V) alpha/beta gene families. In this study we have investigated the clonality of T cells using two of the predominant V beta families i.e. V beta 3 and V beta 8 in three patients with IBM. The study was performed by reverse transcription and polymerase chain reaction (RT-PCR) analysis, followed by cloning and sequencing of the T cell receptor complementarity determining region 3. We found oligoclonal expansion of V beta 3 bearing muscle infiltrating T cells in two patients and of V beta 8 in one patient, supporting the concept that antigen stimulated T cells are important in the pathogenesis of IBM. Results of HLA typing indicated a genetic predisposition for the disease by the presence of DR3, DR52 and DQB1*0201/0202 in all three patients.