Dysphagia in patients with inclusion body myositis

OBJECTIVE: To determine whether ampicillin- and tetracycline-resistant strains of Pasteurella multocida and P haemolytica isolated from California cattle with pneumonia were spatially and temporally clustered and to compare overall estimates of percentages of these isolates resistant to these antimicrobials with estimates obtained on the basis of regional and temporal information. DESIGN: Epidemiologic study. SAMPLE POPULATION: Records of P multocida and P haemolytica isolates obtained from lung or tracheal wash samples collected from California cattle with pneumonia between July 1, 1991 and July 31, 1996. Only isolates obtained from samples submitted by dairies and calf ranches were used. PROCEDURE: Spatial clustering of ampicillin- and tetracycline-resistant isolates was assessed by use of nearest-neighbor and Cuzick and Edwards' analyses. Linear clustering along a north-south line was assessed by use of runs and maximum length of runs tests. Temporal clustering was assessed by use of scan tests. Spatial-temporal clustering was assessed by use of Barton's method. Regional estimates of percentages of P multocida and P haemolytica resistant to ampicillin or tetracycline were calculated. RESULTS: There was significant spatial clustering of resistant isolates and significant linear clustering along a north-south line. Significant differences in regional estimates of percentages of antimicrobial-resistant isolates were found. CLINICAL IMPLICATIONS: Results support the hypothesis that antimicrobial-resistant organisms can be clustered at the local level and reinforce the need to establish regional estimates of percentages of bacterial isolates that will be susceptible to commonly used antimicrobials.     

Analysis of multiple mitochondrial DNA deletions in inclusion body myositis

Exercise induced pain in the posterior part of the leg is common among runners; the underlying reason for these complaints may be very different. The purpose of the present, controlled study was therefore 1. to confirm a clinically diagnosed deep posterior compartment syndrome by using intramuscular pressure measurements and 2. to evaluate the effect of a surgical release on clinical signs and intracompartment pressure values. Fifteen symptomatic runners with the clinical suspicion of a chronic deep posterior compartment syndrome and nine healthy recreational runners as controls were investigated. Intramuscular pressure was measured both at rest and up to two minutes post-exercise, using a pressure-monitor with a transducer. In symptomatic runners, the average pressure was preoperatively 5.6 mmHg (95%-confidence-interval [CI]: 3.4-7.6) at rest, rising to 18.5 mmHg (CI: 15.4-21.8) post-exercise. Corresponding values in healthy control runners were 5.1 mmHg (CI: 1.9-8.3) at rest, with a decrease induced by exercise to 2.8 mmHg (CI: -0.5-6.1). After fasciotomy of the deep posterior compartment in all fifteen symptomatic runners, average pressure values fell to 2.2 mmHg (CI: 1.0-3.4) at rest, and were further reduced after (now pain-free) exercise to 1.6 mmHg (CI: 0.6-2.6). The decrease between pre-operative and post-operative values was statistically highly significant (p < 0.0001 for values after running, p < 0.005 for values at rest). In conclusion, intracompartment pressure measurement is a useful technique to confirm the clinical diagnosis of deep posterior compartment syndrome prior to recommending surgery. Hereby, an exercise-induced rise in pressure of at least 10 mmHg, corresponding to a two- to threefold increase of values measured at rest, may be a more important diagnostic criterion than absolute levels of pressure measured before or after running.     

Multiple mitochondrial DNA deletions in sporadic inclusion body myositis: a study of 56 patients

Inclusion body myositis, a chronic inflammatory disorder, is the most common cause of myopathy in adults over the age of 50. Diagnosis is based on clinical features and distinctive morphological findings by both light and electron microscopy. The causes of inclusion body myositis are still unknown. Ultrastructural mitochondrial changes and ragged-red fibers are common in patients with sporadic inclusion body myositis, and multiple [correction of mutiple] mitochondrial DNA (mtDNA) deletions have been reported in 3 such patients, suggesting that mtDNA mutations may have a pathogenetic role. We studied 56 patients with sporadic inclusion body myositis, using a combination of clinical, morphological, biochemical, and molecular genetic analyses to determine the frequency and the distribution of mtDNA deletions. Using the polymerase chain reaction, we found multiple mtDNA deletions in 73% of patients, compared to 40% of normal age-matched control subjects and 47% of disease control subjects. The presence of deletions correlated with morphological evidence of ragged-red, cytochrome c oxidase-negative fibers, and with defects of complexes I and IV of the electron transport chain. Although aging may account for a proportion of mtDNA deletions in patients with sporadic inclusion body myositis and control subjects, mtDNA alterations may be accelerated in sporadic inclusion body myositis.     

Mitochondrial abnormalities and peripheral neuropathy in inflammatory myopathy, especially inclusion body myositis

Computer retrieval in a database, comprising 7,225 muscle cases, revealed that mitochondrial myopathies do not occur more frequently in inflammatory myopathies (3.74%) than in the whole series (3.69%). A more detailed study of inclusion body myositis (IBM), however, showed that severe mitochondrial alterations were apparent in about twice as many IBM cases as expected. This confirms recent studies of others although a causal relationship has thus far not been established. Identification of mitochondrial deletions by Southern blotting corresponded to the presence of severe structural abnormalities of mitochondria. Peripheral neuropathy of variable severity was noted in all cases of IBM and mitochondrial myopathy. By contrast, the association of severe mitochondrial abnormalities with polymyositis, systemic scleroderma, and vasculitis observed in some cases of the present series may be incidental or age dependent.     

Safety and efficacy of strength training in patients with sporadic inclusion body myositis

We studied the effects of a 12-week progressive resistance strength training program in weakened muscles of 5 patients with sporadic inclusion body myositis (IBM). Strength was evaluated with Medical Research Council (MRC) scale ratings and quantitative isometric and dynamic tests. Changes in serum creatine kinase (CK), lymphocyte subpopulations, muscle size (determined by magnetic resonance imaging), and histology in repeated muscle biopsies were examined before and after training. After 12 weeks, the values of repetition maximum improved in the least weakened muscles, 25-120% from baseline. This dynamic effect was not captured by MRC or isometric muscle strength measurements. Serum CK, B cells, T-cell subsets, and NK cells remained unchanged. Repeat muscle biopsies did not reveal changes in the number and degree of degenerating fibers or inflammation. The size of the trained muscles did not change. We conclude that a supervised progressive resistance training program in IBM patients can lead to gains in dynamic strength of the least weak muscles without causing muscle fatigue and muscle injury or serological, histological, and immunological abnormalities. Even though the functional significance of these gains is unclear, this treatment modality is a safe and perhaps overlooked means of rehabilitation of IBM patients.     

Characterization of the mitochondrial DNA abnormalities in the skeletal muscle of patients with inclusion body myositis

Inclusion body myositis (IBM) is a late-onset inflammatory myopathy with distinctive clinical and histopathological features. The molecular basis for the disease remains unknown, but abnormal nuclear morphology and the accumulation of a protein that binds single-stranded DNA in a sequence-independent fashion suggest a nuclear defect. Evidence of mitochondrial respiratory chain dysfunction (ragged-red fibers, multiple mtDNA deletions) has been reported in IBM muscle. Here we have investigated the relationship of the mtDNA abnormalities in sporadic and familial IBM patients to the pathogenesis of the disease. In situ hybridization analysis with mtDNA probes revealed several different mtDNA abnormalities in cytochrome c oxidase-negative muscle fibers including large-scale mtDNA deletions and mtDNA depletion, but no evidence for nonspecific DNA binding. Contrary to previous reports, we did not observe mtDNA deletions on Southern blot analysis, consistent with the presence of multiple different deleted mtDNA species demonstrated by single fiber PCR. There was no consistent correlation between the mitochondrial abnormalities and markers of muscle regeneration, inflammation, or microscopically detectable pathological alterations of myonuclei in the same fibers. Thus, early molecular abnormalities in IBM may simply accelerate the accumulation of mtDNA abnormalities that occurs with natural aging.     

Venous hemangioma. An immunohistochemical and ultrastructural study

OBJECTIVE: To elucidate the roles of integrins in tumorigenesis, progression, differentiation, invasiveness and metastasis, and the role of the integrin alpha 5 subunit in hepatocellular carcinoma (HCC). METHODS: 79 formalin-fixed sections of hepatocellular carcinoma (HCC) were obtained. The integrin alpha 5 subunit was measured by immunohistochemistry assay (ABC method). RESULTS: In 79 cases of HCC, cancerous tissues had lower expression than their adjacent non-tumor tissues (32.9% vs 81.0%, P < 0.01). The alpha 5 positive rate in small HCC (= < 5 cm in diameter) was higher than large HCC > 10 cm in diameter), being 55.6% and 10.0% respectively. Well-differentiated HCC expressed higher alpha 5 than poorly differentiated ones. The alpha 5 positive rates were lower in highly invasive HCC than those to low invasive ones. CONCLUSION: Our study indicated that expression of the integrin alpha 5 subunit is correlated with growth, differentiation, invasiveness and metastasis of HCC. It is possible that alpha 5 subunit is a negative regulator to these biological parameters of HCC.     

An intimal sarcoma of the pulmonary artery. An immunohistochemical study

Pulmonary artery intimal sarcomas tend to be presented with symptoms of pulmonary thromboembolism and grow regionally, with little capacity to metastasize. They probably originate from subendothelial cells, that become myofibroblasts. Knowledge of it is important to establish a presurgery diagnosis, with the possibility of a total resection, the only useful treatment until now. We report a case of a pulmonary artery primary sarcoma, in a 73 year old woman, admitted with hemoptysis and pleuritic chest pain, who died ten days after. Autopsy revealed an intraluminal mass at the pulmonary artery trunk, without regional nor distance involvement. Microscopic study showed a pleomorphic tumor with spindle and epithelioid cells, positive for actin, desmin and vimentin. All these data support the diagnosis of primary intimal sarcoma of the pulmonary artery. We want to emphasize the myogenic differentiation of the tumor, uncommon in previously reported cases.     

Innervation of developing human taste buds. An immunohistochemical study

1. Vinorelbine produced a dominant metabolite (M1) after incubation with rat liver microsomes. 2. Several major metabolites other than M1 were identified by HPLC in bile and faeces of rat after intravenous administration. 3. The structures of the major metabolites were identified as 15,16-epoxyvinorelbine (M1), 11'-hydroxyvinorelbine (M2), 19'-hydroxyvinorelbine (M3a), 15,16-epoxy-10'-hydroxyvinorelbine (M3b) and 10'-hydroxyvinorelbine (M4) by comparison of HPLC retention times and by extensive analyses of two-dimensional NMR and hybrid MS/MS spectra.     

The treatment of inclusion body myositis: a retrospective review and a randomized, prospective trial of immunosuppressive therapy

We have sought to examine the response to immunosuppressive therapeutic intervention in inclusion body myositis (IBM) in a retrospective review of prior responses to therapy and in an open, randomized crossover trial. We collected information on the response to prior therapy on 25 patients, and for prospective therapy on 11 of these patients. All met criteria for a definite idiopathic inflammatory myopathy and had biopsy-proven IBM. Clinical and laboratory results were assessed by interviews of patients and by chart review in the retrospective trial. Manual muscle strength was assessed by a single trained observer; the patients' activities of daily living were assessed by questionnaire; and serum tests of muscle-associated enzymes were measured in the prospective trial. In the retrospective review, prednisone appeared to have been of some, albeit modest, clinical benefit in 10 of 25 (40%) patients. Other therapies, primarily azathioprine and methotrexate, also appeared to have halted the progression of weakness in 8 of 35 trials (23%). In the prospective study, combination therapy of oral azathioprine and methotrexate and a biweekly infusion of high-dose intravenous methotrexate with leucovorin rescue were given for 3 to 6 months in an open, crossover design. Both the oral and the intravenous regimens were clinically effective in some patients. There was clinical improvement in 3 trials, stabilization in 11 trials, and worsening in 5 trials, out of a total of 19 completed (22 intended) trials. The presence of active inflammation at entry into the prospective therapeutic protocol, either directly observed on muscle biopsy or indirectly indicated by serum creatine kinase level, may have been associated with clinical improvement. A complete laboratory response with normalization of creatine kinase and other muscle-associated enzymes did not, however, significantly predict clinical responsiveness in the prospective trial. In this first report, to our knowledge, of a prospective trial of immunosuppressive therapy for this disease, stabilization and even slight improvement of strength and functional abilities appeared to be achieved in some patients. We believe that prednisone and other immunosuppressive therapies were of modest benefit in about half of patients with inclusion body myositis, especially those with some evidence of active inflammation. Stabilization of an otherwise inexorably deteriorating course appears, therefore, to be an attainable goal in some patients with IBM.     

Papillary cystadenoma of the epididymis. An ultrastructural and immunohistochemical study

Papillary cystadenoma of the epididymis is a rare neoplasm that is sometimes associated with von Hippel-Lindau's syndrome. Electron microscopic study of the present case revealed that neoplastic cells contained abundant glycogen granules and large lipid droplets, but a few organelles. On the apical surface there were numerous microvilli and a few single cilia, but no ciliated cells. Subepithelial basal lamina was noted, but it was occasionally disrupted. Furthermore, microvilli sprang from the circumference of the small tumor-cell nest and became associated with matrix components (microvillus-matrix associations). On immunohistochemical study, neoplastic cells showed epithelial characteristics, but positive reactivity for S-100 protein. These findings resembled those of the epithelial cells of the efferent ductules of the epididymis. In the stroma, prominent vasculature was characteristic and fenestrated-type capillaries were found in the peripheral portion of the tumor. Papillary cystadenoma of the epididymis may originate from non-ciliated epithelial cells of the efferent ductules.     

Neurotrophins and their receptors in the pigeon caecal tonsil. An immunohistochemical study

Neurotrophins are growth factors which bind to signal-transducing receptors called Trk proteins. The neurotrophins and their receptor proteins are present in the mammalian and avian lymphoid organs, thus suggesting that these factors could act upon cells of the immune system. Nevertheless, little is known about the cellular distribution of neurotrophins and their receptor proteins in avian lymphoid tissues. In this study we use immunohistochemistry to detect the cellular localisation of neurotrophins and their receptor proteins in the pigeon caecal tonsil, used as a model for avian secondary lymphoid organs. Rabbit polyclonal antibodies against neurotrophins (nerve growth factor -NGF-, brain-derived neurotrophic factor -BDNF- and neurotrophin -3 NT-3-) and against specific epitopes of TrkA, TrkB and TrkC proteins were used. Cytokeratins, vimentin, S-100 protein and chromogranin A were studied in parallel to identify cells which seemed to express neurotrophins and Trk proteins. TrkA-like protein was seen in the intestinal epithelium, whereas TrkB-like and TrkC-like proteins was found in cells which we identified as dendritic cells and macrophages. BDNF-like and NT-3-like reactivity was localised in intestinal epithelial cells, especially endocrine cells. Present results add further evidence to the presumptive immune role of neurotrophins and their receptors and the possible functions of these peptides in the caecal tonsil are discussed.     

Intracellular phosphates in inclusion body myositis--a 31P magnetic resonance spectroscopy study

Muscle phosphorus magnetic resonance spectroscopy was used to study oxidative metabolism at rest and during recovery from exercise in 7 patients with sporadic inclusion body myositis (s-IBM), compared with normal controls (n=8) and mitochondrial myopathies (n=20). At rest, 6/7 patients had elevated inorganic phosphates. Recovery parameters were not different from controls, in contrast with mitochondrial myopathies, who showed abnormal rest and recovery. The normal recovery suggests that mitochondrial oxidative capacity is not impaired in s-IBM.     

Quantitative analysis of proliferating sinusoidal cells in dimethylnitrosamine-induced cirrhosis. An immunohistochemical study

Proliferating lipocytes (fat-storing cells or perisinusoidal stellate cells of the liver) were detected by in vivo incorporation of bromodeoxyuridine (BrdU) in an experimental model of cirrhosis in the rat by dimethylnitrosamine. Lipocytes were identified by sequential double immunohistochemical staining on frozen sections using anti-desmin antibodies as a marker of cytoplasmic intermediate filaments followed by anti-BrdU antibodies to identify S-phase nuclei in animals treated for 7, 14 or 21 days. The number of desmin-positive (lipocytes) and desmin-negative (Kupffer and endothelial cells) sinusoidal cells incorporating BrdU was recorded. The labelling index of lipocytes was calculated as the percentage of BrdU-labelled desmin-positive cells with respect to total number of lipocytes. In control animals, when the total number of lipocytes was 153.9 +/- 11/mm2 (mean +/- 1 S.E.) the number of desmin-positive S-phase sinusoidal cells never exceeded 6.8 +/- 1.2/mm2 with a maximum labelling index of 4.3 +/- 0.5%. At 7 days of treatment, the values were respectively 236 +/- 26.5/mm2, 53.2 +/- 5.9/mm2 and 22.6 +/- 0.5% (p less than 0.001 vs. controls), while, at 21 days they were 272.5 +/- 21.2/mm2, 23.3 +/- 4.0/mm2 and 8.5 +/- 1.1% respectively (p less than 0.01). These results show that hyperplasia of lipocytes represents an early reaction to dimethylnitrosamine-induced liver injury. The local accumulation of lipocytes appears to occur in areas where fibrous septa develop later on.     

Vimentin expression in different types of breast carcinoma immunohistochemical study

Vimentin was preferentially expressed in medullary and high grade ductal not otherwise specified (NOS) carcinomas. It was not expressed in lobular carcinoma whether of the classical or the variant types. In the present study, 58 cases of invasive breast carcinomas were tested for vimentin on formaldehyde fixed paraffin embedded sections. Vimentin was expressed in 14/ 44 (32%) of infiltrating duct carcinoma NOS. It was expressed in less than 10% of tumour cells in 5/44 (11.4%) and in > or = 10% of tumour cells in 4/7 (57%). However, none of the lobular carcinoma expressed vimentin. Vimentin was expressed in 9 of 18 (50%) of grade III infiltrating duct NOS carcinoma versus 5 of 21 (24%) of grade II and 0 of 5 (0%) of grade I carcinoma. It was preferentially expressed in tumour growing in broad anastomosing bands or sheets with numerous mitoses, high nuclear grade, scanty supportive stroma and extensive necrosis.     

Histogenetical investigations on adenocarcinomas of the esophagogastric junction. An immunohistochemical study

The presence of Pepsinogen II (PG II), gastral mucin (2B5), CA 19-9, BW 494 and Cytokeratin 20 (CK 20) was investigated in 69 adenocarcinomas of the esophagogastric junction (15 carcinomas in Barrett's esophagus, 9 distal esophageal carcinomas, 31 carcinomas of the cardia and 14 subcardial carcinomas). Evidence of gastric differentiation (expression of Pepsinogen II and/or gastric mucin) was found in more than 50% of the Barrett's carcinomas and the carcinomas of the cardia, but only in 20% of the subcardial carcinomas. High rates of antigen expression were found for the "intestinal" markers CA 19-9 (between 55.5% and 100%) and BW 494 (between 42.9 and 86.7%). CK-20 expression was detected to a significantly higher degree in Barrett's carcinomas (73.3%) than in the other groups (between 29% and 44.4%). These data indicate that the distribution of adenocarcinomas with gastric and/or intestinal differentiation at the esophagogastric junction forms a continuum without clear-cut borders.     

p53 expression in neurofibroma and malignant peripheral nerve sheath tumor. An immunohistochemical study of sporadic and NF1-associated tumors

OBJECTIVES--(1) to evaluate regional cerebral blood flow (rCBF) with single photon emission computed tomography and 99mTc-hexamethylpropyleneamine oxime in patients with the idiopathic adult hydrocephalus syndrome (IAHS); (2) to examine regional cerebral blood flow (rCBF), gait, and psychometric functions before and after CSF removal (CSF tap test); (3) to assess abnormalities in subcortical white matter by MRI. METHODS--Thirty one patients fulfilling the criteria for IAHS (according to history and clinical and neuroradiological examination) were studied. Quantified gait measurements, psychometric testing, and rCBF before and after removal of CSF were obtained. Pressure of CSF and CSF outflow conductance were investigated with a constant pressure infusion method. Brain MRI was used to quantify the severity of white matter lesions and periventricular hyperintensities. In IAHS a widespread rCBF hypoperfusion pattern was depicted, with a caudal frontal and temporal grey matter and subcortical white matter reduction of rCBF as the dominant feature. Removal of CSF was not accompanied by a concomitant increase in rCBF. Significant white matter lesions were detected only in a minority of patients by MRI. An altered CSF hydrodynamic state with a higher CSF pressure and lower conductance was confirmed. IAHS is characterised by an abnormal CSF hydrodynamic state, associated with a widespread rCBF reduction with preference for subcortical white matter and frontal-temporal cortical regions. Furthermore in most patients MRI did not show white matter changes suggestive of a coexistent subcortical arteriosclerotic encephalopathy. At least in the idiopathic group of patients with AHS, measurements of rCBF before and after temporary relief of the CSF hydrodynamic disturbance will not provide additional information that would be helpful in the preoperative evaluation but is suggestive of a preserved autoregulation of rCBF.