Partial arthroscopic trapeziectomy with or without ligament reconstruction to treat primary thumb carpometacarpal joint osteoarthritis.

Many surgical options have been proposed for the treatment of first carpometacarpal (CMC1) osteoarthritis. Conventional techniques are invasive, so we wanted to develop an arthroscopic technique. Partial trapeziectomy combined with various interpositions and ligament reconstruction is a long-standing intervention. As in total trapeziectomy, the combination with ligament reconstruction remains controversial. The aim of this study was to demonstrate the benefits of adding an abductor pollicis longus (APL) ligament reconstruction to partial trapeziectomy performed under arthroscopy. This study analyzes the results of two consecutive case series carried out by a single surgeon. Thirty-four patients underwent an isolated partial trapeziectomy and 49 patients underwent partial trapeziectomy with ligament reconstruction using the APL. The patients were reviewed with an average follow-up of 3.7 years (13 months to 8.6 years) by an independent observer. The assessment included the analysis of pain, thumb appearance, QuickDASH score, Nelson Hospital score, and measurements of mobility and strength. For all patients, there was a marked reduction in pain (7.13 preoperatively vs.1.37 postoperatively) with 71% of patients having a painless thumb, the Nelson (11.14) and QuickDASH (17.89) scores as well as a clinical improvement in mobility and grip strength (14.5 KgF preop vs. 19.6 KgF postop) and key pinch (4.4 KgF preop vs. 5.4 KgF postop). The mean recovery time was 18.8 weeks. Eighty-four percent of patients were satisfied with the procedure with 90% having a stable thumb. No CRPS was found. However, the results were better for patients who underwent ligament reconstruction. There was a significant gain in grip strength, better first web opening and a lower percentage of painful thumbs. The other items were also slightly improved, but not significantly (Nelson Hospital score, QuickDASH score, key grip strength, percentage of stable thumbs, subjective thumb value estimated by patients). This technique is a less aggressive treatment of CMC1 osteoarthritis, with simplified and rapid rehabilitation. The addition of ligament reconstruction using the APL appears useful. The advantages of arthroscopy are a less painful postoperative course, low morbidity, ligament conservation, along with better access to remove loose bodies, osteophytes and to perform synovectomy. Partial trapeziectomy, which is especially indicated when the scaphotrapeziotrapezoid joint is not symptomatic, is much less used than total trapeziectomy; however, it is an attractive surgical option for young patients with significant functional demands. Arthroscopic partial trapeziectomy is a safe and reliable procedure.

Genera of phytopathogenic fungi: GOPHY 3.

This paper represents the third contribution in the Genera of Phytopathogenic Fungi (GOPHY) series. The series provides morphological descriptions, information about the pathology, distribution, hosts and disease symptoms for the treated genera, as well as primary and secondary DNA barcodes for the currently accepted species included in these. This third paper in the GOPHY series treats 21 genera of phytopathogenic fungi and their relatives including: Allophoma, Alternaria, Brunneosphaerella, Elsinoe, Exserohilum, Neosetophoma, Neostagonospora, Nothophoma, Parastagonospora, Phaeosphaeriopsis, Pleiocarpon, Pyrenophora, Ramichloridium, Seifertia, Seiridium, Septoriella, Setophoma, Stagonosporopsis, Stemphylium, Tubakia and Zasmidium. This study includes three new genera, 42 new species, 23 new combinations, four new names, and three typifications of older names.

Genera of phytopathogenic fungi: GOPHY 2.

This paper represents the second contribution in the Genera of Phytopathogenic Fungi (GOPHY) series. The series provides morphological descriptions and information regarding the pathology, distribution, hosts and disease symptoms for the treated genera. In addition, primary and secondary DNA barcodes for the currently accepted species are included. This second paper in the GOPHY series treats 20 genera of phytopathogenic fungi and their relatives including: Allantophomopsiella, Apoharknessia, Cylindrocladiella, Diaporthe, Dichotomophthora, Gaeumannomyces, Harknessia, Huntiella, Macgarvieomyces, Metulocladosporiella, Microdochium, Oculimacula, Paraphoma, Phaeoacremonium, Phyllosticta, Proxypiricularia, Pyricularia, Stenocarpella, Utrechtiana and Wojnowiciella. This study includes the new genus Pyriculariomyces, 20 new species, five new combinations, and six typifications for older names.

Benign mitochondrial myopathy with exercise intolerance in a large multigeneration family due to a homoplasmic m.3250T>C mutation in MTTL1.

BACKGROUND AND PURPOSE: Most mitochondrial disorders with onset in early childhood are progressive and involve multiple organs. The m.3250T>C mutation in MTTL1 has previously been described in a few individuals with a possibly riboflavin-responsive myopathy and an association with sudden infant death syndrome was suspected. We describe a large family with this mutation and evaluate the effect of riboflavin treatment. METHODS: Medical data were collected with the help of a standardized data collection form. Sanger sequencing was used to screen for variants in mitochondrial DNA and the proportion of the mutation was analyzed in different tissues. Biochemical and muscle morphological investigations of muscle tissue were performed in two individuals. The effect of riboflavin treatment was evaluated in two individuals. RESULTS: Thirteen family members experienced exercise intolerance with fatigue and weakness. Inheritance was maternal with 100% penetrance. The course was either static or showed improvement over time. There was no evidence of other organ involvement except for a possible mild transient cardiac enlargement in one child. Muscle investigations showed isolated complex I deficiency and mitochondrial proliferation. The level of m.3250T>C was apparently 100%, i.e. homoplasmic, in all examined tissues. Riboflavin treatment showed no effect in any treated family member and there have been no cases of sudden infant death in this family. CONCLUSIONS: This study illustrates the importance of considering mitochondrial disorders in the work-up of individuals with exercise intolerance and provides a better understanding of the phenotype associated with the m.3250T>C mutation in MTTL1.

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.

Ophthalmological findings in children and young adults with genetically verified mitochondrial disease.

AIM: To describe ophthalmological phenotypes in patients with mitochondrial disease and known genotypes. METHODS: A retrospective study was performed on 59 patients (29 male, 30 female) with a mean age of 11.8 years who had mitochondrial disease with known DNA mutations. Fifty-seven of the 59 subjects underwent a detailed ophthalmological examination including visual acuity (VA), eye motility, refraction, slit-lamp examination, ophthalmoscopy and, in almost one-half of the cases, a full-field electroretinogram (ERG). RESULTS: Forty-six (81%) of the patients had one or more ophthalmological findings such as ptosis (n = 16), reduced eye motility (n = 22) including severe external ophthalmoplegia (n = 9), strabismus (n = 4), nystagmus (n = 9), low VA (n = 21), refractive errors (n = 26), photophobia (n = 4), and partial or total optic atrophy (n = 25). Pigmentation in the macula and/or periphery was noted in 16 patients. In 10/27 investigated individuals with full field ERG, retinal dystrophy was recorded in six different genotypes representing Kearns-Sayre syndrome (n = 5), Leigh syndrome (n = 1), Mitochondrial encephalopathy, lactic acidosis, and stroke-like episodes (MELAS) (n = 1), Myoclonus epilepsy with red ragged fibres (MERRF) (n = 1), Leber hereditary optic neuropathy (n = 1) and mitochondrial myopathy (n = 1). CONCLUSION: The results show that a majority of patients with mitochondrial disorders have ophthalmological abnormalities. We recommend that an ophthalmological examination, including ERG, be performed on all children and adolescents who are suspected of having a mitochondrial disease.

Progressive encephalopathy and complex I deficiency associated with mutations in MTND1.

Complex I of the oxidative phosphorylation system is composed of at least 45 subunits, seven of which are encoded by mitochondrial DNA (mtDNA). In this study we have investigated two children with complex I deficiency in muscle mitochondria. Patient 1 had cerebellar ataxia from early infancy and an abnormal MRI of the brain compatible with Leigh syndrome (LS). The course was rapidly progressive with frequent exacerbations and death at 2 years and 10 months of age. Patient 2 had a lactic acidosis in the newborn period and had a severe psychomotor developmental retardation. In her teens she developed hypertrophic cardiomyopathy and died at 26 years of age because of cardiac insufficiency. Sequencing analysis of mitochondrial encoded ND genes (MTND) showed two DE NOVO mutations in MTND1 in both patients. Patient 1 had a novel heteroplasmic G3890A mutation, R195Q. Patient 2 had a heteroplasmic G3481A mutation, E59K. The G3890A mutation in patient 1 is the first identified mutation in MTND1 in association with LS and complex I deficiency. The findings in this patient as well as in patient 2 demonstrate new clinical expressions of mutations in MTND1. The findings in patient 2 also illustrates that MTND mutations may be pathogenic even at a low percentage.

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.

Inflammation and response to steroid treatment in limb-girdle muscular dystrophy 2I.

Limb-girdle muscular dystrophy (LGMD) type 2I, caused by mutations in the fukutin-related protein gene (FKRP), is one of the most common forms of LGMD in childhood. We describe two patients with LGMD2I and a Duchenne-like phenotype. In addition to the common L276I mutation, both patients had a new mutation in FKRP, L169P and P89L, respectively. Clinical onset was triggered by viral upper respiratory tract infections. In addition to the common dystrophic pattern with a weak immune histochemical staining for alpha-dystroglycan, muscle biopsy showed inflammatory changes. This was especially striking in one of the patients with up-regulation of MHC class 1 antigen, suggestive of myositis. Both patients showed a good clinical response to treatment with prednisolone, which was initiated at daily dosage of 0.35 mg/kg/day. Our results provide evidence for an inflammatory involvement in the pathological expression of LGMD2I and open up the possibility that this disorder could be treatable with corticosteroids.

A Western blot and molecular genetic investigation of the estrogen receptor beta in giant cell arteritis.

OBJECTIVE: The epidemiology of giant cell arteritis (GCA) may indicate a pathogenetic relationship between GCA and female sex hormone metabolism; GCA is two to four times more common in women compared with men. Our previous analyses gave no support for the hypothesis that the pathogenesis of GCA should be related to somatic mutations in the estrogen receptor alpha (ERalpha) gene. The object of the present study was to investigate the size of the estrogen receptor beta (ERBeta), and the size and nucleotide sequence of the ERBeta gene in temporal arteries in GCA. METHODS: The ERBeta protein was analyzed by Western blot technique and the ERBeta gene by RT-PCR and direct sequencing of the PCR product. RESULTS: Western blot analysis revealed an ERBeta of normal size. There were no aberrations in size or nucleotide sequence in the ERBeta gene in the GCA patients. CONCLUSION: The present observations gave no support for the hypothesis that somatic mutations in the ERBeta gene should be involved in the pathogenesis of GCA.

Mitochondrial myopathy with exercise intolerance and retinal dystrophy in a sporadic patient with a G583A mutation in the mt tRNA(phe) gene.

We describe a second patient with the 583G>A mutation in the tRNA(phe) gene of mitochondrial DNA (mtDNA). This 17-year-old girl had a mitochondrial myopathy with exercise intolerance and an asymptomatic retinopathy. Muscle investigations showed occasional ragged red fibers, 30% cytochrome c oxidase (COX)-negative fibers, and reduced activities of complex I+IV in the respiratory chain. The mutation was heteroplasmic (79%) in muscle but undetectable in other tissues. Analysis of single muscle fibers revealed a significantly higher level of mutated mtDNA in COX-negative fibers. Our study indicates that the 583G>A mutation is pathogenic and expands the clinical spectrum of this mutation.

Mitochondrial abnormalities in inclusion-body myositis.

Mitochondrial changes are frequently encountered in sporadic inclusion-body myositis (s-IBM). Cytochrome c oxidase (COX)-deficient muscle fibers and large-scale mitochondrial DNA (mtDNA) deletions are more frequent in s-IBM than in age-matched controls. COX deficient muscle fibers are due to clonal expansion of mtDNA deletions and point mutations in segments of muscle fibers. Such segments range from 75 microm to more than 1,000 microm in length. Clonal expansion of the 4977 bp "common deletion" is a frequent cause of COX deficient muscle fiber segments, but many other deletions also occur. The deletion breakpoints cluster in a few regions that are similar to what is found in human mtDNA deletions in general. Analysis in s-IBM patients of three nuclear genes associated with multiple mtDNA deletions, POLG1, ANT1 and C10orf2, failed to demonstrate any mutations. In s-IBM patients with high number of COX-deficient fibers, the impaired mitochondrial function probably contribute to muscle weakness and wasting. Treatment that has positive effects in mitochondrial myopathies may be tried also in s-IBM.

Two new mutations in the MTATP6 gene associated with Leigh syndrome.

In this study we have analyzed the mtDNA encoded ATPase 6 and 8 genes ( MTATP6 and MTATP8) in two children with Leigh syndrome (LS) and reduced Mg (2+) ATPase activity in muscle mitochondria. In patient 1, with a mild and reversible phenotype, mutational analysis revealed a heteroplasmic T --> C mutation at nt position 9185 (T9185C) in the MTATP6. The mutation resulted in substitution of a highly conserved leucine to proline at codon 220. The proportion of the mutation was > 97 % in the patient's blood and muscle and 85 % in blood of his asymptomatic mother. Patient 2, with severe clinical phenotype and death at 2 years of age, exhibited a novel heteroplasmic T9191C missense mutation in the MTATP6, which converted a highly conserved leucine to a proline at position 222 of the polypeptide. The proportion of the mutation was 90 % in fibroblasts and 94 % muscle tissue. This mutation was absent in the patient's parents and sister suggesting that the mutation was de novo. Our findings expand the spectrum of mutations causing LS and emphasize the role of MTATP6 gene mutations in pathogenesis of LS.

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.

Genotypes and clinical phenotypes in children with cytochrome-c oxidase deficiency.

Cytochrome c oxidase (COX) deficiency has been associated with a wide spectrum of clinical features and may be caused by mutations in different genes of both the mitochondrial and the nuclear DNA. In an attempt to correlate the clinical phenotype with the genotype in 16 childhood cases, mtDNA was analysed for deletion, depletion, and mutations in the three genes encoding COX subunits and the 22 tRNA genes. Furthermore, nuclear DNA was analysed for mutations in the SURF1, SCO2, COX10, and COX17 genes and cases with mtDNA depletion were analysed for mutations in the TK2 gene. SURF1-mutations were identified in three out of four cases with Leigh syndrome while a mutation in the mitochondrial tRNA (trp) gene was identified in the fourth. One case with mtDNA depletion had mutations in the TK2 gene. In two cases with leukoencephalopathy, one case with encephalopathy, five cases with fatal infantile myopathy and cardiomyopathy, two cases with benign infantile myopathy, and one case with mtDNA depletion, no mutations were identified. We conclude that COX deficiency in childhood should be suspected in a wide range of clinical settings and although an increasing number of genetic defects have been identified, the underlying mutations remain unclear in the majority of the cases.

SURF1 gene mutations in three cases with Leigh syndrome and cytochrome c oxidase deficiency.

Leigh syndrome (LS) is one of the most frequent forms of mitochondrial disease in infancy and childhood. Mutations in SURF1 have been shown to be an important cause of LS with cytochrome c oxidase (COX) deficiency. The authors have identified four pathogenic mutations including a novel, in-frame, 15-bp tandem duplication (806-820) in exon 8 and a novel 751+1G>A splice site mutation in SURF1 in three cases of LS with COX deficiency.

Inclusion body myositis: clonal expansions of muscle-infiltrating T cells persist over time.

Inclusion body myositis (IBM) is a chronic inflammatory myopathy. The muscle histology is characterized by infiltration of T cells, which invade and apparently destroy muscle fibres. This study was performed to investigate whether predominant clones of muscle-infiltrating T cells are identical in different muscles and whether they persist over time in IBM. By reverse transcriptase-polymerase chain reaction, 25 T-cell receptor (TCR) variable beta (Vbeta) chain families and the complementarity-determining region 3 (CDR3) of the TCR were analysed in two different muscle biopsies of four patients with IBM. In two of the patients, the muscle biopsies were obtained from different muscles at one time point, whereas in two patients, the second biopsy was obtained 9 years after the first biopsy. T cells expressing predominant Vbeta families were analysed for clonality by fragment length analysis of the CDR3. Predominant Vbeta families were analysed by DNA sequencing to identify identical clones. Immunohistochemical staining of Vbeta families was performed to study the distribution of T cells expressing identified predominant Vbeta families. The muscle-infiltrating lymphocytes showed restricted expression of TCR Vbeta families. DNA sequencing proved that clonally expanded T cells were identical in different muscles and persisted 9 years after the first biopsy. Immunohistochemical analysis with Vbeta family-specific antibodies demonstrated the endomysial localization of these T cells in inflammatory cell infiltrates. Our results show that in IBM there is clonal restriction of TCR expression in muscle-infiltrating lymphocytes. Identical T-cell clones predominate in different muscles, and these clones persist for many years. These results indicate an important, continuous, antigen-driven inflammatory reaction in IBM.

Leigh syndrome with cytochrome-c oxidase deficiency and a single T insertion nt 5537 in the mitochondrial tRNATrp gene.

We report a nine-year-old boy with the features of Leigh syndrome (LS) and a severe cytochrome-c oxidase (COX) deficiency with a single thymidine insertion at nucleotide position 5537 (T 5537i) in the tRNA Trp gene of mitochondrial DNA. During infancy the boy was irritable and hypotonus was noticed. Early motor development was delayed, although mental development seemed normal until eight months of age. Early neurological signs were nystagmus, hypertonus and optic atrophy. Severe seizures and mental retardation developed subsequently. Major findings on neuroradiological investigation were from the brainstem, thalami and white matter compatible with LS. Spectrophotometric analysis of skeletal muscle mitochondria showed a profound COX deficiency and a marked complex I deficiency. Enzyme-histochemical analysis showed reduced COX activity in the majority of the muscle fibres. There were no ragged red fibres. The T 5537i mutation was found in a high proportion (> 95 %) in blood, liver and muscle tissue of the patient and in blood of the patient's mother (81 %). This mutation has previously been described in one family in which one child had a very high proportion of the T 5537i mutation and clinical features of LS. We conclude that, although mtDNA mutations are considered to be rare in LS with COX deficiency, the T 5537i mutation should be screened for in cases of LS with COX deficiency when SURF1 gene mutations have been excluded, especially when complex I activity is also decreased.

Assessing modulus of elasticity of wood-fiber cement (WFC) sheets using nondestructive evaluation (NDE).

This study evaluates whether the mechanical properties of modulus of rupture (MOR) and modulus of elasticity (MOE) of wood-fiber cement (WFC) sheets are correlated with the nondestructive parameters of stress wave velocity and density of the material. Longitudinal stress wave technique was used to evaluate WFC nondestructively using a total of 117 specimens (measuring each 241 x 51 mm) obtained from 39 WFC sheets. The aim was to establish the correlation between dynamic versus static MOE of the material for predicting the actual mechanical property. Even though short dimension specimens were used, results obtained were encouraging. A correlation coefficient (R) of 0.828 was found when the static MOE of the material was used as a function of nondestructive parameters. A multivariate linear regression analysis using the specimen's density, wave velocity, and dynamic MOE provided the strongest correlation to the static MOE. The correlation observed for MOR as a function of static MOE is within the normal range obtained for wood composites. A nondestructive evaluation (NDE) using full size WFC sheets is recommended and can probably improve the relationship between the static and the predicted MOE.

Estrogen receptor alpha in giant cell arteritis: a molecular genetic study.

OBJECTIVE: Giant cell arteritis (GCA) predominantly affects postmenopausal women. Estrogen receptor alpha (ER alpha) accumulates in the cytoplasm of smooth muscle cells, activated mononuclear inflammatory cells and giant cells in the temporal arteries of GCA patients, as well as in smooth muscle cells in arteries from non-GCA controls. The aim of this study was to analyse whether this accumulation is related to structural aberrations in the ER alpha mRNA leading to a change in protein structure. METHODS: Total RNA was extracted from inflamed temporal artery tissue in two GCA patients and from non-inflamed arteries in two non-GCA controls. Products from the nested RT-PCR of the cDNA were cloned and plasmid inserts of 20 different clones from each case were investigated using nucleotide sequence analysis. RESULTS: A total of eight different types of transcripts lacking parts of the ER alpha mRNA were detected. Seven of these could be explained by alternative splicing. There were no significant differences between the GCA patients and the non-GCA controls in terms of the number of transcript variants. CONCLUSION: The accumulated cytoplasmic ER alpha in temporal arterial tissue from elderly persons appears mainly to be of wild type. The main structural changes in the ER alpha mRNA may be due to alternative splicing. Somatic mutations of the ER alpha gene appear to be rare and it is therefore unlikely that they are involved in the pathogenesis of GCA.