The press as a vehicle for the introduction of a fashionable disease

Two journalists wrote a book on HPU (haemopyrrol-lactamuria), a hitherto unknown metabolic disease that was alleged to cause a whole range of complaints. The book is based on the ideas of a biochemist who is also the director of a commercial organisation that offers a diagnostic test as well as a therapy (nutrition supplement) for HPU. The release of the book was accompanied by a press release that provoked various publications in both biomedical journals and the lay press. In response to these reports, the director sometimes registered a complaint with the Dutch Council for Journalism, but on other occasions he did not. The content of this book is in no way based on scientific research. In retrospect, it is obvious that the authors, the biochemist and the publishing company have joint commercial ties. All professional standards of scientific research and journalistic decency are thus being violated. In this way, they are doing harm to the independence and integrity of researchers and journalists in the public image. All the activities of the press seem to have been an essential part of a deliberate marketing strategy for the introduction of a non-disease.     

Gene therapy for lipoprotein lipase deficiency: working toward clinical application

Lipoprotein lipase (LPL) deficiency causes hypertriglyceridemia and recurrent, potentially life-threatening pancreatitis. There currently is no adequate treatment for this disease. Previously, we showed that intramuscular administration of an adeno-associated virus serotype 1 (AAV1) vector encoding the human LPL(S447X) variant cDNA (AAV1-LPL(S447X)) normalized the dyslipidemia of LPL-/- mice for more than 1 year. In preparation for a clinical trial, we evaluated the safety and biodistribution of AAV1-LPL(S447X) in wild-type mice and fully characterized six LPL-deficient patients. Toxicological analysis in mice showed that intramuscular administration was well tolerated. Acute inflammatory response markers were transiently increased, and anti- AAV1 antibodies were generated. Histological analyses indicated a dose-dependent reversible spleen hyperplasia, and myositis at the injection sites. Biodistribution data showed short-term vector leakage from injection sites into the circulation, followed by liver-mediated clearance. Persistence of vector DNA was limited to the injected muscle and draining lymph nodes, and spread to reproductive organs was limited. Characterization of LPL-deficient patients showed that all patients presented with hypertriglyceridemia and recurrent pancreatitis. LPL catalytic activity was absent, but LPL protein levels were 20-100% of normal. Myoblasts derived from skeletal muscle biopsies of these patients were efficiently transduced by AAV1-LPL(S447X) and secreted active LPL. These data support the initiation of a clinical trial in LPL-deficient patients, for which regulatory approval has been granted.     

Mutations causing achondroplasia and thanatophoric dysplasia alter bFGF- induced calcium signals in human diploid fibroblasts

Mutations in the fibroblast growth factor receptor (FGFR) gene family recently have been shown to underlie several hereditary disorders of bone development, with specific FGFR3 mutations causing achondroplasia (Ach) and thanatophoric dysplasia (TD). However, for none of these mutations has the defect in receptor function been demonstrated directly and, therefore, for none has the pathophysiological mechanism of the disease been defined. Using our established techniques for single-cell ratiometric real-time calcium image analysis, we defined the nature of the basic fibroblast growth factor (bFGF)-induced calcium signal in human diploid fibroblasts, and, in blinded studies, have analyzed the bFGF-induced signals from 18 independent fibroblast cell lines, including multiple lines from patients with known mutant alleles of FGFR3 and syndromes of Ach or TD. Control cells responded with transient increases in intracellular calcium, with many cells showing oscillatory calcium waves. Homozygous Ach cell lines failed to signal, whereas heterozygous Ach lines responded nearly normally. We observed heterogeneous signals in TD heterozygotes: the unresponsive lines all turned out to carry TD1 alleles, whereas all responsive lines had TD2 alleles. Since FGFR1, 2 and 3 receptors are known to be expressed in fibroblasts, our results suggest that specific mutant FGFR3 alleles can function in a dosage-dependent dominant-negative fashion to inactivate FGFR signaling.      

Malignant melanoma of the eye: treatment of posterior uveal lesions by Co-60 plaque radiotherapy versus enucleation

Survival rates and visual acuity of 100 patients treated for posterior uveal malignant melanoma by cobalt-60 plaque radiotherapy were compared with 150 patients treated by enucleation for the same disease. Life-table comparisons of the entire group showed significant differences in survival rates, with plaque radiotherapy patients appearing to fare better. However, when patients with small or medium tumors were compared, only slight differences were seen, implying that criteria used to select patients for treatment may affect interpretation. The two groups were also compared using the Cox proportional hazards model, which predicts survival based on the impact of clinical variables. In this analysis, the survival rates of the plaque radiotherapy group were no worse than those of the enucleation group. The advantage of conservative therapy lies in the potential to preserve useful vision over a considerable time. Because patients were specifically selected for treatment modality and because the study size used to calibrate the Cox model was small, the results of this study must be interpreted with caution.     

Arthritis: roles of radiography and other imaging techniques in evaluation

Imaging studies are performed on patients with arthritis for a variety of reasons: to determine whether an arthritic condition is present; to establish the specific diagnosis; to determine the extent of disease; to assess the activity of disease; to detect complications of disease; to evaluate progression of disease; to judge the efficacy of drug treatment; to help in selection of surgical candidates; to aid in the choice of surgical procedures; to size, design, or fabricate prostheses; and to identify complications of surgery. Conventional radiography is still the mainstay of all examinations in arthritic patients. Arthrography is best applied to evaluate complications of disease and of surgery, although it may be useful in disease detection and in determining the specific diagnosis. Nuclear medicine studies are best used to identify complications of surgery and may also be useful to assess disease activity or extent. Ultrasound is useful to detect dissecting synovial cysts and deep venous thrombosis. The most valuable role of computed tomography is in the design and fabrication of prostheses and in evaluating complex anatomy of involved joints. Magnetic resonance imaging may be useful in early detection of articular cartilage damage and may assist in determination of the specific diagnosis; enhancement with contrast material may aid in assessment of disease activity.