Fine mapping of the Darier's disease locus on chromosome 12q

Darier's disease (DD) is an autosomal dominant genodermatosis characterized by epidermal acantholysis and dyskeratosis. We have performed genetic linkage studies in 10 families with DD (34 affected) by analyzing 14 polymorphic microsatellite markers. Our results confirm recent reports mapping the DD gene to chromosome 12q23-q24.1. Haplotype analysis of recombinant chromosomes in our families, along with previously reported data, narrow the location of the DD gene to a 5 cM interval flanked by the loci D12S354 and D12S84/D12S105. This localization allowed exclusion of two known genes, PLA2A and PAH, as candidate loci for DD. Three other gene loci (PPP1C, PMCH, PMCA1), mapping in 12q21-q24, remain potential candidates.     

Chronic venous insufficiency: mechanisms and management

CVI is a common disease with significant morbidity that results from venous hypertension of the extremities. Increased perfusion pressure probably traps excessive numbers of white blood cells in the capillaries. Activated leukocytes subsequently damage capillary endothelium, increase capillary permeability, and cause ischemia of the overlying skin as a result of leakage of fibrinogen and formation of a fibrin cuff. Diagnosis of CVI is not difficult because its clinical manifestations are usually evident. Vascular compression therapy remains the foundation of medical management for CVI. Refractory cases may require a combined medical and operative approach.     

Activating and dominant inactivating c-KIT catalytic domain mutations in distinct clinical forms of human mastocytosis

Human mastocytosis is characterized by increased mast cells. It usually occurs as a sporadic disease that is often transient and limited in children and persistent or progressive in adults. The c-KIT protooncogene encodes KIT, a tyrosine kinase that is the receptor for mast cell growth factor. Because mutated KIT can transform cells, we examined c-KIT in skin lesions of 22 patients with sporadic mastocytosis and 3 patients with familial mastocytosis. All patients with adult sporadic mastocytosis had somatic c-KIT mutations in codon 816 causing substitution of valine for aspartate and spontaneous activation of mast cell growth factor receptor (P = 0.0001). A subset of four pediatric onset cases with clinically unusual disease also had codon 816 activating mutations substituting valine, tyrosine, or phenylalanine for aspartate. Typical pediatric patients lacked 816 mutations, but limited sequencing showed three of six had a novel dominant inactivating mutation substituting lysine for glutamic acid in position 839, the site of a potential salt bridge that is highly conserved in receptor tyrosine kinases. No c-KIT mutations were found in the entire coding region of three patients with familial mastocytosis. We conclude that c-KIT somatic mutations substituting valine in position 816 of KIT are characteristic of sporadic adult mastocytosis and may cause this disease. Similar mutations causing activation of the mast cell growth factor receptor are found in children apparently at risk for extensive or persistent disease. In contrast, typical pediatric mastocytosis patients lack these mutations and may express inactivating c-KIT mutations. Familial mastocytosis, however, may occur in the absence of c-KIT coding mutations.     

Differential north to south gastric cancer-duodenal ulcer gradient in China. China Ulcer Study Group

There are suggestions that duodenal ulcer protects individuals from gastric cancer and that rice is ulcerogenic while wheat is gastro-protective. We aimed to examine the relationship of gastric cancer, duodenal and gastric ulcers in different geographical regions in China and identified dietary risk factors for duodenal ulcer and gastric cancer. The prevalence of peptic ulcer and gastric cancer among symptomatic patients in eight major cities, four each from the north and the south representing all the six defined regions of China were studied. Endoscopy and case records over a 10 year period were reviewed and cases of confirmed duodenal and gastric ulcer and gastric cancer, together with the total number of endoscopies performed per year, were recorded. Rates were expressed as cases/1000 endoscopies. Results were compared to another epidemiological study on diet and mortality in the same regions in China conducted at the same time. Duodenal ulcer rates were 2.4-fold higher in southern China than northern China, whereas gastric cancer rates were 1.6-fold higher in the north than in the south. Correlation studies showed for the first time an inverse linear relationship between the gastric cancer rates and the duodenal ulcer rates (r=-0.8076, P=0.015), as well as the duodenal ulcer: gastric ulcer ratios (r=-0.9133, P=0.002). Gastric ulcer rates were higher in southern China but did not correlate with the gastric cancer rates (r=0.1455, P=0.731). Duodenal ulcer rates were found to be related to daily rice intake (r=0.8554, P=0.029) and inversely related to daily wheat flour intake (r=-0.8472, P=0.033). Gastric cancer rates were not related to any dietary risk factors tested. We concluded there was an inverse relationship between gastric cancer rates and duodenal ulcer rates. Although duodenal ulceration and gastric cancer are both linked to Helicobacter pylori infection, the findings of this study indicate independent additional aetiological factors for the pathogenesis of these conditions. Dietary factors such as rice or wheat intake may play a role.     

Long-term propofol infusion and airway management in a patient with Goldenhar''s syndrome

SAPHO syndrome is characterized by osteoarticular involvement of ventral chest wall in the form of sternocostoclavicular osteoarthritis and hyperostosis and skin changes such as palmoplantar pustulosis and acne. Occasionally, psoriatic lesions and sacroiliitis are observed. However, despite the higher frequency of psoriasis in this syndrome, its inclusion in psoriatic arthropathy spectrum is not clearly established. The authors report three cases of SAPHO syndrome in psoriatic patients commenting on the difficulty in differentiating this entity from psoriatic arthritis as well as its relationship with seronegative spondyloarthropathies. This disease has been described mainly in Japan and only a few cases of this disease have been reported in the European or American literature.     

Helicobacter pylori induces interleukin-8 expression in endothelial cells and the signal pathway is protein tyrosine kinase dependent

Helicobacter pylori (HP) infection has been shown to increase gastric mucosal interleukin 8 (IL-8) expression, and whether HP or its toxin induces endothelial cell IL-8 expression is unknown. We aimed to compare the IL-8 expression in endothelial cells after stimulation with HP toxin, tumor necrosis factor alpha (TNF-alpha), and lipopolysaccharide (LPS) and to study their signal pathways. HP or its toxin induced significant IL-8 expression in endothelial cells. HP toxin, TNF-alpha, and LPS also showed a time- and dose-dependent increase in IL-8 expression over the control. Both protein kinase C (PKC) and protein kinase A (PKA) inhibitors had no effect on IL-8 response to these stimuli. Protein tyrosine kinase (PTK) inhibitor genistein at concentrations of 150, 300, and 450 microM dose-dependently reduced LPS- and TNF-alpha-induced IL-8 expression by 29.43, 43.8, and 47.3% and 20.5, 49.9, and 61.8% respectively, whereas HP toxin-induced IL-8 secretion could only be reduced at 450 microM by 35.7%. Geldanamycin, a more potent PTK inhibitor, at doses of 0.5, 1, and 2 microM dose-dependently reduced HP toxin induced endothelial cell IL-8 expression by 24.8, 26, and 44.3% respectively. It is concluded that HP and its toxin can increase IL-8 expression in endothelial cells, and the expression of IL-8 elicited by HP toxin, TNF-alpha, and LPS is partially dependent on PTK but not PKA or PKC activation.