Recently occluded intracranial and extracranial carotid arteries. Relevance of the unstable atherosclerotic plaque.
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BACKGROUND AND PURPOSE: It is now widely accepted that thrombotic coronary artery occlusion usually follows rupture of an unstable atherosclerotic plaque. The significance of such instability in arteries supplying the brain is less well appreciated. We therefore describe the clinical and pathological features of recent, symptomatic internal carotid artery occlusion to examine the pathogenetic role of plaque instability at both extracranial and intracranial sites. METHODS: Cases were selected from a consecutive series of 188 adult neuropathology autopsies. In 90 of these, the principal neuropathological abnormality was cerebral infarction, in 14 cases due to recent occlusion of 1 or more segments of the internal carotid artery. In each case, a full systemic, cardiovascular, and neuropathological autopsy was performed. Plaque instability was assessed by the presence or absence of a large, necrotic, lipid core; a thin, fibrous cap; and superficial inflammation. RESULTS: Of the 14 cases, 3 showed extracranial (carotid sinus), 7 intracranial, and 4 both extracranial and intracranial carotid artery occlusion. In 6 of the 7 occluded carotid sinuses, thrombus overlay an ulcerated, unstable, atherosclerotic plaque. In 1 extracranial and all 11 intracranial occlusions, there was either no atheroma or a mildly stenotic, stable, fibrous plaque, and in these cases, the cause of occlusion was embolism (8 cases), giant-cell arteritis (1 case), and unknown (3 cases). CONCLUSIONS: Coronary-type rupture of an unstable atherosclerotic plaque is the usual cause of fatal occlusion of the carotid sinus, but other causes usually underlie intracranial carotid occlusion. The nature and consequences of intracranial atherosclerosis require further study. (+info)
CFEOM3: a new extraocular congenital fibrosis syndrome that maps to 16q24.2-q24.3.
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PURPOSE: To define the clinical characteristics and determine the gene localization for a previously undescribed form of congenital fibrosis of the extraocular muscles (CFEOM), referred to as CFEOM type 3 (CFEOM3). METHODS: A large family with CFEOM was identified, and participating individuals underwent ophthalmologic examination and donated blood for genetic analysis. The family's disorder was tested for linkage to the known CFEOM loci, followed by a genome-wide search and linkage refinement using polymorphic DNA markers. RESULTS: Thirty-eight members of this Canadian family participated in the study. Affected individuals are born with a nonprogressive eye movement disorder characterized by variable expression of ptosis and restrictive external ophthalmoplegia. Severely affected individuals have ptosis, primary gaze fixed in a hypo- and exotropic position, and marked restriction of eye movement bilaterally. Mildly affected individuals have normally positioned globes with a limitation of vertical gaze. Moderately affected individuals have asymmetrical involvement with one eye severely and one eye mildly affected. The disorder is autosomal dominant with variable expression and probable incomplete penetrance. Genetic analysis reveals linkage to markers on 16q24.2q24.3. A maximum lod score of 5.8 occurs at markers D16S3063 and D16S689, and the CFEOM3 disease gene is located within a 5.6-cM region flanked by D16S486 and D16S671. CONCLUSIONS: These data establish that CFEOM3 is a phenotypically variant and genotypically distinct form of CFEOM with linkage to chromosome 16qter. The authors have previously demonstrated that CFEOM1 results from a developmental absence of the superior division of the oculomotor nerve. The authors hypothesize that CFEOM3 results from a defect analogous to, but distinct from CFEOM1. (+info)
Promotion of atrial fibrillation by heart failure in dogs: atrial remodeling of a different sort.
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BACKGROUND: Studies of atrial fibrillation (AF) due to atrial tachycardia have provided insights into the remodeling mechanisms by which "AF begets AF" but have not elucidated the substrate that initially supports AF before remodeling occurs. We studied the effects of congestive heart failure (CHF), an entity strongly associated with clinical AF, on atrial electrophysiology in the dog and compared the results with those in dogs subjected to rapid atrial pacing (RAP; 400 bpm) with a controlled ventricular rate (AV block plus ventricular pacemaker at 80 bpm). METHODS AND RESULTS: CHF induced by 5 weeks of rapid ventricular pacing (220 to 240 bpm) increased the duration of AF induced by burst pacing (from 8+/-4 seconds in control dogs to 535+/-82 seconds; P<0.01), similar to the effect of 1 week of RAP (713+/-300 seconds). In contrast to RAP, CHF did not alter atrial refractory period, refractoriness heterogeneity, or conduction velocity at a cycle length of 360 ms; however, CHF dogs had a substantial increase in the heterogeneity of conduction during atrial pacing (heterogeneity index in CHF dogs, 2. 76+/-0.16 versus 1.46+/-0.10 for control and 1.51+/-0.06 for RAP dogs; P<0.01) owing to discrete regions of slow conduction. Histological examination revealed extensive interstitial fibrosis (connective tissue occupying 12.8+/-1.9% of the cross-sectional area) in CHF dogs compared with control (0.8+/-0.3%) and RAP (0. 9+/-0.2%) dogs. CONCLUSIONS: Experimental CHF strongly promotes the induction of sustained AF by causing interstitial fibrosis that interferes with local conduction. The substrates of AF in CHF are very different from those of atrial tachycardia-related AF, with important potential implications for understanding, treating, and preventing AF related to CHF. (+info)
Phlebosclerosis of the colon with positive anti-centromere antibody.
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A 56-year-old woman with symptoms of chronic bowel disease presented a peculiar calcification of the mesenteric vein of the ascending to transverse colon on barium enema study. The resected colon was hard and black. Histo-pathologic examinations demonstrated fibrous change of the colon with a calcified and hyaline-deposited mesenteric vein. No cell infiltration was observed. These findings were compatible with phlebosclerosis and also with systemic sclerosis. Positive anti-centromere antibody and Raynaud's phenomenon, hallmarks of a variant systemic sclerosis, the CREST syndrome were observed. We therefore speculated that the pathogenesis of the phlebosclerosis of the colon is related to the CREST syndrome. (+info)
Whole-body positron emission tomography using 18F-fluorodeoxyglucose for posttreatment evaluation in Hodgkin's disease and non-Hodgkin's lymphoma has higher diagnostic and prognostic value than classical computed tomography scan imaging.
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A residual mass after treatment of lymphoma is a clinical challenge, because it may represent vital tumor as well as tissue fibrosis. Metabolic imaging by 18F-fluorodeoxyglucose (18F-FDG) positron emission tomography (PET) offers the advantage of functional tissue characterization that is largely independent of morphologic criteria. We compared 18F-FDG PET to computed tomography (CT) in the posttreatment evaluation of 54 patients with Hodgkin's disease (HD) or intermediate/high-grade non-Hodgkin's lymphoma (NHL). Residual masses on CT were observed in 13 of 19 patients with HD and 11 of 35 patients with NHL. Five of 24 patients with residual masses on CT versus 1 of 30 patients without residual masses presented a positive 18F-FDG PET study. Relapse occurred in all 6 patients (100%) with a positive 18F-FDG PET, 5 of 19 patients (26%) with residual masses on CT but negative 18F-FDG PET, and 3 of 29 patients (10%) with negative CT scan and 18F-FDG PET studies (P +info)
Connective tissue growth factor is a regulator for fibrosis in human chronic pancreatitis.
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OBJECTIVE: To evaluate the parameters that mediate fibrogenesis in chronic pancreatitis (CP). BACKGROUND: Connective tissue growth factor (CTGF), which is regulated by transforming growth factor beta (TGF-beta), has recently been implicated in skin fibrosis and atherosclerosis. In the present study, the authors analyzed the concomitant presence of TGF-beta1 and its signaling receptors-TGF-beta receptor I, subtype ALK5 (TbetaR-I(ALK5)), and TGF-beta receptor II (TbetaR-II)-as well as CTGF and collagen type I in the pancreatic tissue of patients undergoing surgery for chronic pancreatitis. PATIENTS AND METHODS: CP tissue samples were obtained from 40 patients (8 women, 32 men) undergoing pancreatic resection. Tissue samples of 25 previously healthy organ donors (12 women, 13 men) served as controls. The expression of TGF-beta1, TbetaR-I(ALK5), TbetaR-II, CTGF, and collagen type I was studied by Northern blot analysis. By in situ hybridization and immunohistochemistry, the respective mRNA moieties and proteins were localized in the tissue samples. RESULTS: Northern blot analysis showed that CP tissue samples exhibited concomitant enhanced mRNA expression of TGF-beta1 (38-fold), TbetaR-II (5-fold), CTGF (25-fold), and collagen type I (24-fold) compared with normal controls. In addition, TbetaR-I(ALK5) mRNA was increased in 50% of CP tissue samples (1.8-fold). By in situ hybridization, TGF-beta1, TbetaR-I(ALK5), and TbetaR-II mRNA were often seen to be colocalized, especially in the ductal cells and in metaplastic areas where atrophic acinar cells appeared to dedifferentiate into ductal structures. In contrast, CTGF was located in degenerating acinar cells and principally in fibroblasts surrounding these areas. Moreover, CTGF mRNA expression levels correlated positively with the degree of fibrosis in CP tissues. CONCLUSION: The concomitant overexpression of CTGF, collagen type I, TGF-beta1, and its signaling receptors in CP suggests that these proteins contribute to enhanced extracellular matrix synthesis and accumulation, resulting finally in the fibrogenesis observed in CP. (+info)
Myofibroblast proliferation, fibrosis, and defective pancreatic repair induced by cyclosporin in rats.
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BACKGROUND: Full recovery is always achieved after caerulein induced pancreatitis. Cyclosporin stimulates transforming growth factor beta (TGF-beta) and may interfere with pancreatic regeneration. AIM: To investigate the effects of cyclosporin after caerulein induced pancreatitis or after caerulein injury. METHODS: Protocol A: rats received cyclosporin daily (20 mg/kg) and caerulein pancreatitis was induced on days 2 and 8. Protocol B: six courses of caerulein pancreatitis were induced at weekly intervals. Cyclosporin was administered on induction and the day before. Rats recovered for two weeks before being killed. Control groups received saline, cyclosporin, or caerulein alone. RESULTS: Protocol A: plasma TGF-beta1 and tissue collagenase rose after pancreatitis but decreased towards baseline values on day 15, matching a low collagen content. Morphology disclosed minimal inflammatory infiltration and some interstitial cells immunoreactive for smooth muscle alpha-actin (SMA). TGF-beta1 increased, and remained high in cyclosporin treated groups (cyclosporin alone and cyclosporin plus caerulein). Rats treated with cyclosporin and caerulein showed severe pancreatic weight reduction, abundant inflammatory infiltrates, increased SMA immunoreactive interstitial cells, high collagen content, and delayed collagenase response. No SMA immunoreactive cells were detected in normal rats. Cyclosporin alone also increased SMA immunoreactive cells, despite the absence of inflammatory infiltration and fairly conserved pancreatic structure. Protocol B: the combined pulse treatment induced appreciable collagen deposition and resulted in a smaller pancreas than controls. Morphological examination showed atrophy, fibrosis, fibroblast proliferation, and mononuclear infiltrates. CONCLUSION: Cyclosporin greatly distorts pancreatic repair, transforming caerulein induced pancreatitis into a fibrotic chronic-like disease. The mechanism involves TGF-beta, myofibroblasts, and defective collagenase activation. (+info)
Detection of meningeal fibrosis after subarachnoid haemorrhage by assaying procollagen propeptides in cerebrospinal fluid.
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OBJECTIVE: To study whether meningeal collagen synthesis under normal conditions is reflected in the CSF and whether a meningeal fibroproliferative reaction or fibrosis after subarachnoid haemorrhage can be detected by measuring markers of collagen synthesis in the CSF. METHODS: Serum samples and CSF were collected from 56 patients with various neurological symptoms and from nine patients with a recent subarachnoid haemorrhage. The concentrations of the carboxyterminal propeptide of type I procollagen (PICP) and the aminoterminal propeptide of type III procollagen (PIIINP) were measured using radioimmunoassays. RESULTS: The mean(SD) concentration of PICP was 75.2 (SD 13.6) microgram/l and that of PIIINP 3.56 (SD 0.91) microgram/l in the CSF of the controls, and the CSF/serum ratios were 0.74 (SD 0.24) for PICP and 1.34 (SD 0.48) for PIIINP. A 1.4-fold increase in both the PICP (p=0.001) and the PIIINP (p=0.001) concentration was found in patients with a neurological disease and with an abnormal CSF leucocyte count or protein concentration. In eight patients with a recent subarachnoid haemorrhage the PICP was 5.9-fold higher (p<0.001) and the PIIINP concentration 7.7-fold higher (p<0.001) than that in the controls, whereas no difference was found in the serum values. Similar high concentrations were also found in a patient from whom the CSF sample was obtained before operation for aneurysm. CONCLUSIONS: The intrathecal compartment is a site for active collagen synthesis under normal conditions. The synthesis rate is markedly increased in patients with a recent subarachnoid haemorrhage, suggesting a fibroproliferative reaction or fibrosis. Assays of procollagen propeptides may be useful in the clinical diagnosis of meningeal fibrosis and their use may enable the identification of diseases and symptoms aetiologically related to meningeal fibrosis. (+info)