Combined high-grade basal cell carcinoma and malignant melanoma of the skin ("malignant basomelanocytic tumor"): report of two cases and review of the literature

We describe two cases of a malignant cutaneous neoplasm with combined phenotypical features of high-grade basal cell carcinoma and malignant melanoma. Some tumor cells showed a keratinocytic phenotype (cytokeratins, p63) and others a melanocytic phenotype (HMB-45, MART-1, Melan-A, S100-protein). We favor the hypothesis of a tumor with bidirectional keratinocytic and melanocytic differentiation, an exceptionally rare event.     

Influence of rifampin on serum markers of cholesterol and bile acid synthesis in men

OBJECTIVE: It has been demonstrated in preliminary studies that rifampin, a semisynthetic antibiotic and known inducer of hepatic cytochrome P450 3A4, reduces serum concentrations of total bile acids only in individuals with liver disease and elevated serum bile acid levels. METHODS: We studied the effect of rifampin on concentrations of surrogate serum markers of cholesterol and bile acid synthesis as well as of cholesterol absorption in 10 male subjects before and after administration of rifampin (600 mg/day) for 6 days. Cholesterol and its precursors were analyzed by gas-liquid chromatography (GLC), bile acid intermediates and individual bile acids by isotope-dilution methods using GLC-mass spectrometry (MS) or by high-performance liquid chromatography (HPLC). RESULTS: Treatment with rifampin resulted in a 70% increase (p = 0.008) of the serum concentration of the bile acid precursor 7alpha-hydroxy-4-cholesten-3-one, which is a marker for bile acid production. Serum total cholesterol was not altered, however, treatment with rifampin elevated the ratio of lathosterol to cholesterol, an indicator of cholesterol synthesis, by 23% (p = 0.037). Interestingly, serum concentration of total bile acids decreased slightly by 29% (p = 0.022), mainly due to a lowering of the secondary bile acid, deoxycholic acid (-60%; p = 0.005). CONCLUSION: A 6-day treatment with rifampin induces a reduction of deoxycholic serum concentrations in healthy men associated with a moderate increase of serum markers of bile acid and endogenous cholesterol synthesis.     

Interaction of nucleoside analogues with nucleoside transporters in rat brain endothelial cells

A number of nucleoside analogues, consisting of antiviral compounds and agents designed as adenosine A1 receptor agonists, were examined for nucleoside transporter affinity using an in vitro model of the blood-brain barrier (BBB), the rat brain endothelial cell line, RBE4. Structure-activity relationships (SAR) were also performed to identify the key structural requirements for transporter recognition and the suitability of these systems for carrier-mediated strategies to deliver therapeutics across the BBB. Adenosine receptor agonists did not show transport affinity for concentrative nucleoside carriers, but exhibited affinity for equilibrative systems (Ki=10.8-97.9 microM) within the range of Kms for natural substrates. However, none of the antiviral compounds tested in this study showed affinity for either class of nucleoside transporter. SAR studies suggest that the hydroxyl group located at the 3'-position of the ribose moiety is an essential requirement for transporter recognition. This may explain the inability of nucleoside derived anti-viral compounds to use these systems despite the significant structural homology with naturally occurring nucleosides. Sites have also been identified which accommodate structural additions with retention of carrier affinity, suggesting that compounds which fail to penetrate the BBB could be attached to these sites for carrier-mediated delivery using a prodrug strategy.     

Clinical findings in macular hole surgery with indocyanine green-assisted peeling of the internal limiting membrane

PURPOSE: Indocyanine green (ICG) staining of the internal limiting membrane has facilitated ILM peeling in macular hole surgery. However, it has been reported that ICG-assisted peeling of the ILM may result in retinal damage and unfavorable functional outcome. Therefore, we analyzed our visual and anatomical results of ICG assisted macular hole surgery. METHODS: In a retrospective study the records of a consecutive series of 37 patients with full-thickness idiopathic macular holes operated with ICG-assisted ILM peeling by a single surgeon were analyzed. All patients underwent a standard three-port vitrectomy with surgically induced posterior vitreous detachment, staining of the ILM with ICG, peeling of the ILM in a circular manner around the fovea, and SF6 20% endotamponade. RESULTS: A total of 37 patients (37 eyes) were included in the study. The mean age was 69+/-7 years (range 52-81 years), and there were 26 women and 11 men. The follow-up ranged from 6 to 30 months (mean 18+/-6 months). At baseline visual acuity ranged from 20/400 to 20/40. Anatomically, 13 eyes had stage 2 holes, 21 eyes (57%) stage 3 holes, and three eyes stage 4 holes. At the postoperative visit (8-12 weeks after surgery) anatomical closure of the macular hole was achieved in 36 eyes. Visual acuity ranged between 20/400 and 20/20. At the last follow-up after initial surgery the macular hole was closed in all eyes. Visual acuity ranged from 20/200 to 20/20. CONCLUSION: In our retrospective series anatomical and functional results of macular hole surgery with ICG-assisted peeling of the ILM are satisfactory. Primary hole closure was achieved in 97% of eyes and visual acuity increased in 62% of eyes in our series.     

Functional characterisation of nucleoside transport in rat brain endothelial cells

Multiple nucleoside transport systems exist in the body yet the subtypes functional at the blood-brain barrier (BBB) have not been fully investigated. We have employed RBE4 immortalised rat brain endothelial cells to functionally identify the carrier subtypes involved in nucleoside transfer between blood and brain. Uptake in RBE4 cells was partially sodium dependent, indicating the presence of both equilibrative and concentrative systems. Uptake of adenosine via equilibrative transporters was sensitive to nitro-benzylmercaptopurine riboside, which showed biphasic inhibition. Uptake of [3H]-adenosine via concentrative transporters was studied using the subtype-specific inhibitors thymidine (cit), formycin-B (cif) and tubercidin (cib) and was significantly reduced by thymidine and formycin-B but not by tubercidin. This study suggests that nucleoside transport at the in situ BBB may be mediated by ei and es equilibrative transporters and by cit and cif concentrative transporters.     

An immune response after intraocular administration of an adenoviral vector containing a beta galactosidase reporter gene slows retinal degeneration in the rd mouse

BACKGROUND/AIMS: Retinal degenerations are a leading cause of blindness for which there are currently no effective treatments. This has stimulated interest in the investigation of gene therapy strategies for these diseases in a variety of animal models. A number of attempts have been made to prevent photoreceptor loss in the rd mouse model of retinal degeneration using adenoviral vectors containing either a copy of the missing functional gene or a gene encoding either a neurotrophic factor or an antiapoptotic factor. The authors have previously demonstrated that intraocular administration of an adenoviral vector containing a beta galactosidase gene (AV.LacZ) results in an immune response to viral gene products and beta galactosidase. Here the effect of the immune response on retinal degeneration is examined. METHODS: Juvenile rd mice were injected intravitreally with AV.LacZ and a proportion were depleted of either CD4+ or CD8+ T cells or both. Control animals were injected with PBS. The mice were sacrificed 10 and 20 days post-injection and their eyes embedded in paraffin wax and sectioned. RESULTS: 10 days after intravitreal injection of AV.LacZ, the outer nuclear layer contains an average of 2.5 rows compared with 1.5 in PBS injected animals (p<0.005). The protective effect of AV.LacZ is negated by immune suppression and does not extend beyond 20 days. CONCLUSION: An immune response to vector and transgene products is able to slow degeneration in the rd mouse. This phenomenon should be taken into account when analysing the degeneration in the rd mouse following gene transfer.     

Angiotensin-converting enzyme (ACE) gene polymorphisms and familial occurrence of sarcoidosis

OBJECTIVES: The aim of this study was to test for genetic linkage and association between polymorphisms of the angiotensin-converting enzyme (ACE) gene and familial occurrence of sarcoidosis. DESIGN, SETTING AND SUBJECTS: German families with more than one member suffering from sarcoidosis were contacted and a DNA bank was established. Sixty-two families (140 patients, 77 females and 63 males, and 104 unaffected relatives) were genotyped for the ACE gene insertion/deletion (I/D) polymorphism and for two flanking variable sites (ACE A-5466C and ACE 4656(CT)2/3). As controls, 100 DNAs from unrelated resident Caucasians (50 females, 50 males) were analysed. ACE allele and genotype frequencies were determined, and parametric linkage and affected sib pair analyses and transmission disequilibrium tests were performed. RESULTS: There was a striking over-representation of the ACE I/D genotype DD in patients with sarcoidosis and their families as compared with controls of the study and well founded genotype frequencies from the literature. The same was evident for the accompanying genotypes CC and 2,2 of the flanking polymorphisms. Linkage between the segregation of ACE alleles and the disorder within families was clearly excluded for simple models of inheritance. However, there was a suggestive but not significant (P = 0.06) excess of allele sharing amongst affected siblings. There was no transmission disequilibrium for any ACE allele or haplotype. CONCLUSIONS: ACE is involved in the pathogenesis of sarcoidosis, but the ACE polymorphisms are not an inherited main cause of the disease. They are more likely to modify the development of the disorder, and the ACE I/D genotype DD might be a promoter to clinical manifestation.