Incidence and progression of cataract in the Melbourne Visual Impairment Project

PURPOSE: To determine the 5-year incidence and progression of cataract and cataract surgery in the Melbourne Visual Impairment Project. DESIGN: Prospective cohort study. methods: Demographic information including race, sex, age, and education level was collected at baseline. Cortical cataract was defined as 4/16 or greater opacity; progression was defined as a more than 2/16 increase. Nuclear cataract was defined as Wilmer standard grade 2 or higher; progression was defined as more than 0.5 increase. Posterior subcapsular (PSC) cataract was defined as opacity 1 mm(2) or greater; progression was defined as greater than 1 mm(2) increase. results: Of the 3040 participants eligible to attend follow-up examinations, 2594 (85% of those eligible) participated. The mean age of participants at follow-up was 62.5 years, and 55% were female. The percentage of patients who had at least one lens extracted over 5 years increased from 0.5% of those aged 40 to 49 years at baseline to 35.7% of those aged 80 years or more at baseline. The overall incidence of the three types of cataract was as follows: cortical 7.7% (95% confidence limits [CL] = 5.8-9.8), nuclear 16.4% (95% CL = 12.1-20.8), and PSC 7% (95% CL = 5.3-8.7). The overall progression of cataract was cortical 14.3% (95% CL = 10.2-18.3), nuclear 19.3% (95% CL = 15.9-22.7), and PSC 20% (95% CL = 8.7-31.1). The incidence and progression rates increased significantly by age, but the rates were not significantly different by sex. CONCLUSION: These cataract incidence data confirm the public health importance of cataract in Australia. The data also support the need to plan both primary prevention program and adequate surgical services to meet the anticipated increase in demand with the aging population.     

Primary perineal alveolar rhabdomyosarcoma metastatic to an extraocular muscle

A 17-year-old boy diagnosed with an alveolar rhabdomyosarcoma involving the perineum and with extensive lymphadenopathy was treated with chemotherapy yet developed metastases to the head and neck 6 months into therapy. Ten months after initial diagnosis, while receiving salvage chemotherapy and radiotherapy, he returned with pain on movement of his left eye, proptosis, and ptosis of the left upper eyelid. Computed tomography (CT) revealed a mass within the left lateral rectus muscle that biopsy confirmed to be metastatic alveolar rhabdomyosarcoma. Despite continued chemotherapy and radiotherapy, he ultimately died of the disease. Alveolar rhabdomyosarcoma from distant sites rarely metastasizes to the extraocular muscles. However, our case shows that alveolar rhabdomyosarcoma may metastasize to the orbit and involve a single muscle.     

In vivo effects of fluoroquinolones on rabbit corneas

Purpose: The use of topical fluoroquinolones to treat microbial keratitis is associated with an increased incidence of corneal perforation compared to other standard treatments. This study examined the effects of topical fluoro­quinolones on corneal collagen and keratocytes in intact rabbit corneas and corneas with an epithelial defect. Methods: Studies consisted of one group of intact corneas and one group of corneas where a 6‐mm epithelial defect was created with a surgical scrape. Within each group, eyes were randomly assigned to one of four topical medications (0.3% ciprofloxacin, 0.3% ofloxacin, fortified antibiotics (1.36% tobramycin, 5% cefrazolin) or Tears Naturale (Alcon Laboratories, Frenchs Forest, NSW, Australia). Two drops were instilled hourly for 48 h and then 2‐hourly for an additional 48 h. At 96 h the corneas were removed and processed for light microscopy, immunohistology for collagen IV, V and VI, and apoptosis staining. Results: In intact rabbit corneas there was no demonstrable difference between treatment groups. In corneas with an epithelial defect, both fluoroquinolones delayed epithelial healing when compared to fortified antibiotics or tears. Keratocyte loss was seen in all groups and was greatest in the ofloxacin group. Median stromal thickness with keratocyte loss were: ofloxacin 30%; ciprofloxacin 10%; fortified antibiotics 7.5%; and tears 15% (ofloxacin vs tears, Mann?Whitney = 16.0, P = 0.09). Keratocyte loss did not correlate with the amount of demonstrable apoptosis. Collagens IV, V and VI showed no differences between treatments. Conclusions: These results suggest that ofloxacin is potentially cytotoxic to corneal keratocytes. Such an effect could lead to the observed increased incidence of corneal per­foration in microbial keratitis.     

Patterns of recurrence after sentinel lymph node biopsy for cutaneous melanoma

BACKGROUND: Previous sentinel lymph node (SLN) studies for cutaneous melanoma have shown that the SLN accurately reflects the nodal status of the corresponding nodal basin. However, there are few long-term studies that describe recurrence site patterns, predictors for recurrence, and overall survival and disease-free survival after SLN biopsy. METHODS: A retrospective review of patients over a 6-year period was performed to determine patient outcomes and the patterns of recurrence. In all cases, Tc-99 sulfur colloid along with isosulfan blue dye was injected at the primary melanoma site. After resection, the SLN was serially sectioned and evaluated by hematoxylin and eosin staining and immunohistochemistry. RESULTS: One hundred ninety-eight patients were identified who underwent SLN biopsy for cutaneous melanoma including T1 (n = 21), T2 (n = 88), T3 (n = 75), and T4 (n = 14) primary tumors. Of these patients, 38 had a positive SLN. Of the 38 patients with a positive SLN (mean follow-up 38 months), recurrent disease was identified in 10 (26.3%) at a mean interval of 14.2 months. The site of first recurrence was distant (n = 4) and local (n = 6). Regional lymphatic basin recurrence was not identified. Of the 160 patients with a negative SLN (mean follow-up 50 months), recurrent disease was identified in 16 (10.0%) at a mean interval of 31.3 months. The site of first recurrence was systemic (n = 11), local (n = 4), and nodal (n = 1). Overall survival and disease-free survival for patients with a positive SLN at 55 months was 53.3% and 47.7% respectively, while overall survival and disease-free survival for patients with a negative SLN at 53 months was 92.2% and 87.7% respectively (P <0.01). Univariate and multivariate analysis of the entire cohort (n = 198) identified primary tumor depth and positive SLN status as significant predictors of recurrence. CONCLUSIONS: The incidence of nodal basin recurrence after SLN biopsy was found to be 0.6%. Primary tumor depth and pathological status of the SLN are significant predictors of local and systemic recurrence. Long-term follow-up indicates that patients with a positive SLN clearly recur sooner and have decreased overall survival than those with a negative SLN.     

Induction of neuropilin-1 and vascular endothelial growth factor by epidermal growth factor in human gastric cancer cells

The epidermal growth factor receptor (EGF-R) pathway plays a pivotal role in the progression of human gastric cancer. The angiogenic factor vascular endothelial growth factor (VEGF) has been shown to be induced by EGF in various cancer cell lines. Neuropilin-1 (NRP-1) acts as a coreceptor for VEGF-165 and increases its affinity for VEGF receptor 2 (VEGFR-2) in endothelial cells. Furthermore, NRP-1 has been found to be expressed by tumour cells and has been shown to enhance tumour angiogenesis and growth in preclinical models. We examined the expression of NRP-1 mRNA and EGF-R protein in seven human gastric cancer cell lines. NRP-1 expression was expressed in five of seven cell lines, and EGF-R expression closely mirrored NRP-1 expression. Moreover, in EGF-R-positive NCI-N87 and ST-2 cells, EGF induced both NRP-1 and VEGF mRNA expression. C225, a monoclonal antibody to EGF-R, blocked EGF-induced NRP-1 and VEGF expression in NCI-N87 cells in a dose-dependent manner. The treatment of NCI-N87 cells with EGF resulted in increases in phosphorylation of Erk1/2, Akt, and P38. Blockade of the Erk, phosphatidylinositol-3 kinase/Akt, or P38 pathways in this cell line prevented EGF induction of NRP-1 and VEGF. These results suggest that regulation of NRP-1 expression in human gastric cancer is intimately associated with the EGF/EGF-R system. Activation of EGF-R might contribute to gastric cancer angiogenesis by a mechanism that involves upregulation of VEGF and NRP-1 expression via multiple signalling pathways.     

Supplemental creatine may decrease serum homocysteine and abolish the homocysteine 'gender gap' by suppressing endogenous creatine synthesis

Creatine synthesis is responsible for the large majority of the methyl group transfers in normal hepatic metabolism, and is significantly greater in men than in women. Since methyl group depletion impairs the efficiency of homocysteine disposal, it is believed that the comparatively high rate of creatine synthesis in men is primarily responsible for the 'gender gap' in homocysteine levels. Adequate supplemental intakes of creatine can suppress creatine synthesis by inhibiting expression of the enzyme arginine-glycine transamidase. Thus, it is proposed that creatine supplementation may represent a practical strategy for decreasing plasma homocysteine levels.     

Self-complementary recombinant adeno-associated virus (scAAV) vectors promote efficient transduction independently of DNA synthesis

Adeno-associated virus (AAV) vectors package single-stranded genomes and require host-cell synthesis of the complementary strand for transduction. However, when the genome is half wild-type size, AAV can package either two copies, or dimeric inverted repeat DNA molecules. Dimeric, or self-complementary molecules (scAAV) should spontaneously reanneal, alleviating the requirement for host-cell DNA synthesis. We generated and characterized scAAV vectors in order to bypass the rate-limiting step of second-strand synthesis. In vitro, scAAV vectors were five- to 140-fold more efficient transducing agents than conventional rAAV, with a 5.9:1 particle to transducing unit ratio. This efficiency is neither greatly increased by co-infection with Ad, nor inhibited by hydroxyurea, demonstrating that transduction is independent of DNA synthesis. In vivo, scAAV expressing erythropoietin resulted in rapid and higher levels of hematocrit than a conventional single-stranded vector. These novel scAAV vectors represent a biochemical intermediate in rAAV transduction and should provide new insights into the biology of vector transduction.