Identification and use of biomarkers in Gaucher disease and other lysosomal storage diseases

The value of biomarkers in the clinical management of lysosomal storage diseases is best illustrated by the present use of plasma chitotriosidase levels in the diagnosis and monitoring of Gaucher disease. The enzyme chitotriosidase is specifically produced and secreted by the pathological storage macrophages (Gaucher cells). Plasma chitotriosidase levels are elevated on average 1000-fold in symptomatic patients with Gaucher disease and reflect the body burden on storage cells. Changes in plasma chitotriosidase reflect changes in clinical symptoms. Monitoring of plasma chitotriosidase levels is nowadays commonly used in decision making regarding initiation and optimization of costly therapeutic interventions (enzyme replacement therapy or substrate reduction therapy). A novel substrate has been developed that further facilitates the measurement of chitotriosidase in plasma samples. Moreover, an alternative Gaucher-cell marker, CCL18, has been very recently identified and can also be employed to monitor the disease, particularly in those patients lacking chitotriosidase due to a genetic mutation. There is a need for comparable surrogate markers for other lysosomal storage diseases and the search for such molecules is an area of intense investigation.
Conclusion: The use of biomarkers can provide valuable insight into the molecular pathogenesis of LSDs, such as Gaucher disease and Fabry disease.     

Therapeutic dilemma: the use of anticonvulsants in HIV-positive individuals

ARTICLE ABSTRACT: The concurrent use of anticonvulsants and antiretrovirals is a poorly studied area that poses a therapeutic dilemma for the clinician caring for HIV-positive patients requiring both classes of medications. Anticonvulsants and antiretrovirals may interact through multiple mechanisms including competition for protein binding, enhanced or reduced liver metabolism, and increased viral replication. The authors present many of the challenges faced by clinicians caring for HIV-positive patients who may require anticonvulsant therapy.     

Complications of tracheal sleeve pneumonectomy: personal experience and overview of the literature

OBJECTIVES: Tracheal sleeve pneumonectomy, although technically demanding, is considered the choice for tracheobronchial angle cancers. Complications in our 49 tracheal sleeve pneumonectomies are reviewed. Results, complications, and technical aspects are critically discussed. Although series in the literature differ in selection of patients and surgical techniques and extend over long periods, we attempt to compare our experience with results from the literature. METHODS: From 1983 to September 1999, 60 patients eligible for tracheal sleeve pneumonectomy after conventional staging underwent operation. A Sybilla Fome-Cuf ventilation tube (Bivona, Inc, Gary, Ind) was used starting in 1987 to facilitate anastomosis. Since 1993, all patients have undergone video-assisted thoracoscopy immediately before the operation. RESULTS: There were 11 (18.3%) exploratory thoracotomies, 48 right tracheal sleeve pneumonectomies, and 1 left tracheal sleeve pneumonectomy. Among the tracheal sleeve pneumonectomies, we recorded 4 (8.2%) perioperative deaths (myocardial infarction, n = 1; heart failure, n = 1; pulmonary edema, n = 1; gastric ulcer hemorrhage, n = 1; and anastomotic fistula in a patient who received high-dose radiation before the operation, n = 1). We observed 5 (10.2%) complications (lung edema, n = 1; transitory recurrent nerve palsy, n = 2; empyema without fistula cured conservatively, n = 1; and pneumonia, n = 1). Anastomotic stenosis did not occur. Twenty-six (53%) patients are alive 14 to 87 months postoperatively, 12 (24.5%) of these more than 5 years postoperatively. Five (10.2%) died of mediastinal recurrence at 6 and 54 months. Two others (4.1%) died in road accidents. CONCLUSIONS: Tracheal sleeve pneumonectomy is a demanding operation with a high risk of complications. Analysis of literature and personal experience shows that complications can be greatly reduced through accurate selection of patients, precise technique, and optimal postoperative care. Long-term survival equals that obtained after standard pneumonectomy.     

Antibodies to tumor necrosis factor alpha prevent increases in cell replication in liver due to the potent peroxisome proliferator, WY- 14,643

Several structurally dissimilar hypolipidemic drugs, plasticizers and halogenated hydrocarbons induce peroxisomes in hepatocytes, and cause hepatocellular adenoma and carcinoma in rats and mice. The mechanism by which these agents act is unknown, although recent studies have suggested a link between increased cell proliferation and hepatic cancer caused by peroxisome proliferators. Here, we demonstrate that neutralizing antibodies to tumor necrosis factor alpha (TNF alpha) block increases in protein kinase C and cell proliferation due to [4- chloro-6-(2,3-xylidino)-2-pyrimidinylthio]acetic acid (WY-14,643), a hypolipidemic drug and potent peroxisome proliferator that causes tumors. WY-14,643 moderately elevated the level of TNF alpha mRNA in the liver. TNF alpha was detected immunohistochemically exclusively in Kupffer cells. These results demonstrate that WY-14,643 acts as an indirect mitogen on hepatocytes via TNF alpha. We propose that the Kupffer cell, a major source of TNF alpha in the liver, is involved in the mechanism of the mitogenic effect of WY-14,643.      

Evaluation of attempted prevention of unexpected infant death in very high-risk infants by planned health care

Three hundred and ninety-six babies born in Sheffield between 1982 and 1990 identified as being at "very high risk" of unexpected infant death by means of a scoring system, received an intensive programme of health care including a case discussion between a paediatrician, the GP and the health visitor held in the family doctor's surgery, weekly visits from the health visitor and informal hospital admission. Significantly fewer sudden unexpected infant deaths occurred in this group than were expected by logistic regression anlysis or occurred in the best available control group with comparable scores ( p = 0.024). Problems in evaluation include identification of an adequate control population, ethical difficulties in introducing a controlled study when the programme is already perceived as effective, and the calculation of "expected death rates". The results of this study indicate that very energetic programmes of intervention may prevent some deaths in vulnerable infants.     

Serum profiles of insulin-like growth factors and their binding proteins in adults with growth hormone receptor deficiency treated with insulin like growth factor I

Six adult patients with growth hormone receptor deficiency (GHRD) (2 men, 4 women) with an identical defect in the growth hormone receptor (GHR) gene, were treated with recombinant human insulin-like growth factor I (IGF-I), 40 μgikg S.C. twice daily, for 7 days. Serum concentrations of IGF peptide and IGF binding protein-3 (IGFBP-3) were measured by specific radioimmunoassays; serum IGFBPs were also measured by Western ligand blotting. The size distribution of both IGF-I and IGF-II was measured in serum following size-exclusion fast-performance liquid chromatography. IGF-I treatment resulted in a normalization of serum IGF-I levels on days 1–7 of treatment and a decrease in serum IGF-II levels. The fall in IGF-II levels and the simultaneous rise in IGF-I levels, however, resulted in an unchanged total serum IGF level. The low IGFBP-3 values did not significantly change during treatment, whereas there was a slight increase in IGFBP-2 levels. Preliminary analysis of size-fractionated sera suggested an increase in IGF-I levels in the 40 and 150 kDa regions at the expense of IGF-II levels. The results suggest that despite the failure of IGF-I treatment to increase IGFBPs significantly, serum IGFBP concentrations were sufficient to maintain normal levels of IGF-I. 0 Laron syndrome, growth hormone receptor deficiency, insulin-like growth factors, insulin-like growth factor binding protein