Patients' perceptions versus medical testing of function in women with lymphangioleiomyomatosis (LAM).
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Lymphangioleiomyomatosis (LAM), a rare pulmonary disease that occurs primarily in women is characterized by progressive cystic lung lesions causing respiratory failure, which may require lung transplantation. It has been observed that in diseases of the lungs, objective medical tests frequently do not translate to subjective functional status. However, patient's perceptions of functional status directly impact quality of life. In order to evaluate this relationship in LAM, a cross sectional study of 31 lung transplant candidates and 43 lung transplant recipients with LAM was conducted to evaluate functional status. Objective tests (Pulmonary function tests, PFTs, 6 min walk) were obtained in 19 candidates and 23 recipients, and subjective function was assessed in all women using the Functional Performance Inventory. For both groups statistically significant relationships emerged between forced vital capacity with subjective measures of function including total, social and recreational function (P < 0.05). As well diffusing capacity related significantly to total function, ability to maintain household chores, body care, and social function (P < 0.05), where higher scores were associated with better subjective function. Forced expiratory volume in one second was not found to significantly relate to subjective function in these groups, except the physical exercise domain in transplant recipients. However, despite better PFT results in double lung transplant recipients, no differences were found in subjective measures of function between single and double lung recipients. Results suggest that clinicians need to better recognize that certain aspects of spirometry/6 min walk tests do not necessarily correlate well with patient's perceptions of their function. This has implications for the assessment and follow-up of women living with LAM; considering subjective aspects of function may help focus interventions and improve quality of life. (+info)
Aberrant beta-catenin signaling in tuberous sclerosis.
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The pathology associated with tuberous sclerosis complex (TSC) shows diverse phenotypes that suggest abnormal signaling of multiple pathways. Besides the negative regulatory role of the TSC1/TSC2 proteins on mTOR, we have reported an effect on beta-catenin signaling at the level of the degradation complex in vitro. The TSC1/TSC2 complex associates with GSK3 and Axin and promotes beta-catenin degradation to inhibit Wnt-stimulated TCF/LEF-dependent transcription. Here, we show that beta-catenin and its effectors, cyclin D1 and connexin 43, were up-regulated in TSC-related angiomyolipomas and lymphangioleiomyomatosis. This was supported by the failure of three disease-causing TSC2 missense mutants to inhibit Wnt signaling. Further, the interaction between TSC1/TSC2 and components of the beta-catenin degradation complex was dependent on Wnt stimulation such that binding of tuberin to GSK3 and Axin was reduced in the presence of Wnt whereas the tuberin-Dishevelled interaction was increased. GSK3 activity played a role in regulating the assembly/stability of the degradation complex. Inhibition of GSK3 by lithium chloride reduced its association with TSC1 whereas disruption of GSK3-phosphorylation sites in TSC1 reduced interaction between TSC2 and TSC1. Collectively, our data provide further evidence that beta-catenin signaling plays a role in TSC pathogenesis in vivo and suggest a novel role of GSK3 in modulating the TSC1/TSC2 complex through TSC1 phosphorylation. (+info)
The association of pulmonary lymphangioleiomyomatosis with renal and hepatic angiomyolipomas in a prepubertal girl: a previously unreported entity.
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Pulmonary lymphangioleiomyomatosis (PLAM) is a rare, diffuse progressive interstitial lung disease that affects females of childbearing age and is characterized by diffuse proliferation of abnormal smooth muscle fibers predominantly developing in the lung and leading to cystic destruction. A prepubertal 13-year-old girl with PLAM associated with renal and hepatic angiomyolipomas who was treated by nephroureterectomy and thoracoscopic pleurodesis is presented. To the best of our knowledge, this is the first reported case of PLAM associated with renal and hepatic angiomyolipomas at the prepubertal age. After evaluating the clinicopathologic features of this rare entity, the authors conclude that PLAM should be considered in the differential diagnosis of cystic pulmonary pathologies in children, particularly teenagers. The most important clinical aid is to bear this rare entity in mind when a child presents with renal and/or hepatic angiomyolipomas. Thoracoscopic pleurodesis is the most effective treatment modality for recurrent pneumothoraces. (+info)
Interferon-gamma-Jak-Stat signaling in pulmonary lymphangioleiomyomatosis and renal angiomyolipoma: a potential therapeutic target.
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Pulmonary lymphangioleiomyomatosis (LAM) and renal angiomyolipoma (AML) are proliferative lesions that occur in sporadic patients, and at much higher frequency in patients with tuberous sclerosis (TSC). The TSC1 and TSC2 genes play a critical role in their pathogenesis. Here we report a marked decrease in interferon (IFN)-gamma expression in both sporadic and TSC-associated AML and LAM. A marked increase in Stat1 expression and phosphorylation at Ser 727, and in phospho-Tyr705-Stat3 levels, was also seen in both AML and LAM tissues. Our results demonstrate that the IFN-gamma-Jak-Stat pathway is perturbed in TSC-related and sporadic LAM and AML, and suggest that IFN-gamma has potential therapeutic benefit for treatment of those lesions. (+info)
Rounded atelectasis associated with pulmonary lymphangioleiomyomatosis.
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Rounded atelectasis is an unusual form of lung collapse that develops as a consequence of pleural diseases. Among a variety of conditions, asbestos inhalation has been attributed in most cases, but many other causes have also been implicated. Here, we describe the first case of rounded atelectasis and pneumothorax associated with pulmonary lymphagioleiomyomatosis. (+info)
Emerging clinical picture of lymphangioleiomyomatosis.
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OBJECTIVE: To provide a comprehensive update of the clinical picture of lymphangioleiomyomatosis (LAM) using two large patient registries. METHODS: A cross sectional questionnaire survey which included questions on 14 LAM symptoms, pneumothorax, tuberous sclerosis complex (TSC), date of diagnosis, and pulmonary function tests (PFTs). RESULTS: The response rate was 70.5% (n = 328). The mean age at the time of the survey was 46.7 years. The mean age at diagnosis was 42.7 years for women diagnosed 1 year before the survey and 35.8 years for women diagnosed 10 years previously. The main symptoms were dyspnoea (74%), fatigue (72%), cough (47%) and chest pain (44%); younger patients (<40 years) were less likely to report dyspnoea (p = 0.02). Patients with TSC (n = 51) were less likely to report dyspnoea (p = 0.05) and 76.5% reported angiomyolipoma (p < 0.0001) compared with patients with sporadic LAM. Patients with pneumothorax (63.0%) were less likely to report dyspnoea or fatigue (p < or = 0.05) than patients without pneumothorax. PFT results showed that low forced expiratory volume in 1 second and carbon monoxide transfer factor were highly associated with dyspnoea (p < 0.0001), but not with fatigue or history of pneumothorax. CONCLUSION: Previously considered a condition of women of childbearing age, more older women (50% without pneumothorax) are now being diagnosed with LAM. LAM should be considered in women over 40 with unexplained dyspnoea. LAM patients with pneumothorax have less fatigue and less dyspnoea than those without pneumothorax. Fatigue has been overlooked as a symptom of LAM and appears across the spectrum of pulmonary function. (+info)
In vitro studies of lymphangioleiomyomatosis.
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Lymphangioleiomyomatosis (LAM) is associated with abnormal airway smooth muscle that leads to the characteristic pathology of lung nodule formation and destruction of lung tissue. The current authors have previously identified abnormal behaviour of airway smooth muscle cells from patients with asthma. In this study, cells and tissue sections derived from patients with LAM (n=7), asthma (n=8), and nonasthmatic controls (n=9) were compared. The presence of the antigen human melanosome (HM)B-45 was investigated, along with the proliferation and release of extracellular matrix proteins, release of endogenous prostaglandin E2 (PGE2), vascular endothelial growth factor and connective tissue growth factor, and the expression of integrins. Positive HMB-45 staining was found in all LAM patients and no controls. Proliferation of LAM cells was not different from control cells nor was its inhibition by beta-agonists, corticosteroids, rapamycin or PGE2. However, endogenous PGE2 levels were markedly decreased in LAM cells, and this was associated with decreased expression of the inducible form of cyclooxygenase (COX-2). The increased levels of connective tissue growth factor seen in asthma cells were not observed in LAM. Elastin mRNA in response to transforming growth factor-beta stimulation was markedly lower in LAM cells than either asthma or control cells. In conclusion, lymphangioleiomyomatosis cells exhibit abnormal properties in vitro that may contribute to pathophysiology and symptomatology in patients with lymphangioleiomyomatosis. (+info)
The NHLBI lymphangioleiomyomatosis registry: characteristics of 230 patients at enrollment.
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RATIONALE: Pulmonary lymphangioleiomyomatosis is a progressive cystic lung disease that is associated with infiltration of atypical smooth muscle-like cells. Previous descriptions of clinical characteristics of subjects with lymphangioleiomyomatosis have been based on a limited number of patients. OBJECTIVES: To describe the clinical characteristics of subjects with pulmonary lymphangioleiomyomatosis, both sporadic and tuberous sclerosis-related forms. METHODS: Over a 3-yr period, from 1998 to 2001, 243 subjects with pulmonary lymphangioleiomyomatosis were enrolled into a national registry; 13 subjects who had already undergone lung transplantation were excluded for the purposes of this report. MEASUREMENTS AND MAIN RESULTS: All 230 subjects were women, aged 18 to 76 yr (mean +/- SE, 44.5 +/- 0.65 yr). The average age at onset of symptoms was 38.9 +/- 0.73 yr and at diagnosis was 41.0 +/- 0.65 yr. Tuberous sclerosis complex was present in 14.8% of subjects. Pulmonary manifestations, most commonly spontaneous pneumothorax, were the primary events leading to the diagnosis in 86.5% of cases. Nearly 55% of the subjects were being treated with a progesterone derivative. An obstructive pattern on pulmonary function testing was observed in 57.3% of the subjects, whereas 33.9% had normal spirometric results. Women with tuberous sclerosis-related lymphangioleiomyomatosis were younger and had less impaired lung function compared with those with the sporadic form. CONCLUSIONS: The age range of women afflicted with pulmonary lymphangioleiomyomatosis is broader than previously appreciated and the degree of pulmonary function can be quite variable, with one-third of subjects having normal spirometry at enrollment into this registry. (+info)