Optic nerve oxygenation

The oxygen tension of the optic nerve is regulated by the intraocular pressure and systemic blood pressure, the resistance in the blood vessels and oxygen consumption of the tissue. The oxygen tension is autoregulated and moderate changes in intraocular pressure or blood pressure do not affect the optic nerve oxygen tension. If the intraocular pressure is increased above 40 mmHg or the ocular perfusion pressure decreased below 50 mmHg the autoregulation is overwhelmed and the optic nerve becomes hypoxic. A disturbance in oxidative metabolism in the cytochromes of the optic nerve can be seen at similar levels of perfusion pressure. The levels of perfusion pressure that lead to optic nerve hypoxia in the laboratory correspond remarkably well to the levels that increase the risk of glaucomatous optic nerve atrophy in human glaucoma patients. The risk for progressive optic nerve atrophy in human glaucoma patients is six times higher at a perfusion pressure of 30 mmHg, which corresponds to a level where the optic nerve is hypoxic in experimental animals, as compared to perfusion pressure levels above 50 mmHg where the optic nerve is normoxic. Medical intervention can affect optic nerve oxygen tension. Lowering the intraocular pressure tends to increase the optic nerve oxygen tension, even though this effect may be masked by the autoregulation when the optic nerve oxygen tension and perfusion pressure is in the normal range. Carbonic anhydrase inhibitors increase the optic nerve oxygen tension through a mechanism of vasodilatation and lowering of the intraocular pressure. Carbonic anhydrase inhibition reduces the removal of CO2 from the tissue and the CO2 accumulation induces vasodilatation resulting in increased blood flow and improved oxygen supply. This effect is inhibited by the cyclo-oxygenase inhibitor, indomethacin, which indicates that prostaglandin metabolism plays a role. Laboratory studies suggest that carbonic anhydrase inhibitors might be useful for medical treatment of optic nerve and retinal ischemia, potentially in diseases such as glaucoma and diabetic retinopathy. However, clinical trials and needed to test this hypotheses.     

Pharmacokinetics of intravitreal 5-fluorouracil prodrugs in silicone oil: experimental studies in pigs

PURPOSE: To examine the in vivo pharmacokinetics of intravitreal 5-Fluorouracil (5-FU) following tamponade with 5-FU prodrug silicone oil formulations. METHOD: Two different alkoxycarbonyl 5-FU prodrugs denoted C12 and C18 were synthesized and formulated as silicone oil suspensions. A total of 26 pigs underwent conventional three-port lens-sparing pars plana vitrectomy. Approximately 1.6 ml of the prodrug-silicone oil formulation was placed in the vitreous cavity. Operated eyes were enucleated between 20 min and 168 hours postoperatively, and analysed for their content of free 5-FU by high performance liquid chromatography. RESULTS: With the C12 prodrug silicone oil formulation, the concentration of free 5-FU in the vitreous water phase 1 hour after surgery was 3.30 +/- 1.62 microg/ml. After 4 hours this concentration had declined to 1 microg/ml. With the C18 prodrug, the concentration of free vitreal 5-FU never reached 1 microg/ml during the 7 days these experiments lasted. A mathematical model is presented that can explain the measured data if the clearance of 5-FU from the vitreous water phase follows first order kinetics with a half-life of 20 min. CONCLUSION: These experiments, and the model analysis, suggest that the elimination half-life of 5-FU in the vitreous cavity of a vitrectomized, silicone oil-filled eye is very fast. The model analysis indicates that an alkoxycarbonyl 5-FU prodrug with a specific release rate constant of 10.7 microg/square root h cm(2) can maintain an intravitreal 5-FU concentration above 1 microg/ml for 5 days in the porcine eye.     

Physical activity in leisure-time and risk of cancer: 14-year follow-up of 28,000 Danish men and women

AIM: The preventive effect of physical activity on risk of cancer in general remains controversial. This study aimed at assessment of the associations between leisure- time physical activity and incidence of cancer in the general population of adult men and women. METHODS: 13,216 women and 18,718 men aged 20-93 years selected from the general population participated in a health examination including a questionnaire with information on physical activity, smoking, alcohol intake, postmenopausal hormones, and socioeconomic status. Incident cases of cancers where recorded during a follow-up period of 14 years. The six most frequent cancer cases in both sexes were included in this analysis. RESULTS: A highly significant inverse association was seen between vigorous physical activity in leisure time and cancer of the ovary, adjusted rate ratio being 0.33 (95% CI 0.16-0.67; p = 0.001) for the most physical active women. In men there was a highly significant increase for non-melanoma skin cancer, with adjusted rate ratio of 1.72 (95% CI 1.23-2.40; p = 0.001), for the most active men and vigorous activity was associated with a non-significant lower risk of colon cancer, the adjusted rate ratio being 0.72 (95% CI 0.47-1.11; p = 0.06). CONCLUSION: Generally, there were no, or only weakly, inverse associations between physical activity in leisure time and incidence of cancer, except for cancer of the ovary.     

Clinical characteristics of subretinal deposits in central serous chorioretinopathy

PURPOSE: To describe abnormal subretinal material in central serous chorioretinopathy (CSC). DESIGN: Retrospective observational case series. PARTICIPANTS: 168 consecutive patients (336 eyes) with a definite diagnosis of serous foveal detachment attributable to CSC in one or both eyes, on one or more occasions. METHODS: Review of all cases seen during a six-year period. Grading of the amount of subretinal material at presentation as absent, questionable, mild, moderate or severe. RESULTS: Of 168 patients with CSC, 133 (79%) were men and 35 (21%) women. The median age was 45.2 years (range 22-70 yrs). The median duration of symptoms was 2 months (range 0.1-144 months). Subretinal material was found in the symptomatic eye or, in bilateral cases, in the eye that had most recently become symptomatic in 138 patients and in increasing amounts with increasing duration of symptoms (p < 0.001) but unrelated to age or sex. A substantial fraction of the material was shown by optical coherence tomography to be attached to the photoreceptor outer segments of the detached retina. CONCLUSIONS: Increasing amounts of subretinal material are found with increasing duration of symptoms in eyes with CSC. This suggests that early granular deposits may be composed of fragments of photoreceptor outer segments that accumulate when the phagocytosis photoreceptor outer segment material is disrupted by the serous detachment of the retina. Other possible origins that cannot be excluded include plasma proteins excluding from the choriocapillaris, inflammatory debris, and lipid exudate originating from occult choroidal neovascularization secondary to CSC.     

Vital exhaustion and risk for cancer: a prospective cohort study on the association between depressive feelings, fatigue, and risk of cancer

BACKGROUND: Vital exhaustion, defined as feelings of depression and fatigue, has previously been investigated mainly as a risk factor for cardiovascular disease. The authors investigated the association between depressive feelings and fatigue as covered by the concept of vital exhaustion and the risk for cancer. METHODS: The sample consisted of 8527 persons aged 21-94 who had been examined in 1991-1994 within the Copenhagen City Heart Study. For the analysis, the sample was divided into quartiles on the basis of vital exhaustion scores. Cancer cases were ascertained by linkage to the Danish Cancer Registry. The mean length of follow-up was 8.6 years. Regression analyses for etiology-based groups of cancer sites were conducted on the basis of the Cox proportional hazards model, with adjustment for a number of confounding variables. RESULTS: Cancer was diagnosed in 976 persons (12%) during follow-up. In comparison to those with the lowest scores, persons with the highest vital exhaustion scores had a significantly decreased risk for developing cancer at all sites (hazard ratio [HR], 0.80; 95% confidence interval [CI}, 0.66-0.96), smoking-related cancers (HR, 0.64; 95% CI, 0.46-0.90), and virus and immune-related cancers (HR, 0.51; 95% CI, 0.26-0.99). No significant change in risk was found for cancers related to alcohol consumption or hormones. CONCLUSIONS: The results did not support the hypothesis that symptoms of fatigue and depression, as ascertained in the vital exhaustion index, increased the risk for cancer.     

Expression of urokinase plasminogen activator, its receptor and type-1 inhibitor in malignant and benign prostate tissue

The plasminogen activation (PA) cascade participates in degradation of extracellular matrix during cancer invasion. We have studied the expression of urokinase-type plasminogen activator (uPA) mRNA, uPA receptor (uPAR) mRNA and immunoreactivity, and type-1 plasminogen activator inhibitor (PAI-1) mRNA and immunoreactivity in 16 prostate adenocarcinomas and 9 benign prostate hyperplasias. uPA mRNA and uPAR mRNA expression were found in 9 and 8 of the adenocarcinomas, respectively, and in 7 and 6 of the benign hyperplasias, respectively. In both malignant and benign lesions, expression of these 2 mRNAs was predominantly seen in cells identified as macrophages, which in most of the carcinomas (approximately 90%) were located in the interstitial tissue between the tumor cell islands, while in most of the benign hyperplasias they were located in the lumen of the glands and were in only a few cases (approximately 30%) found in the interstitial tissue. uPAR immunoreactivity correlated with the mRNA expression and was, in addition, found in neutrophils. PAI-1 mRNA was detected in 13 of the 16 carcinomas and in 8 of the 9 benign hyperplasias, located in scattered fibroblast-like cells in both groups, in some vascular structures and in a few macrophages located in the interstitial tissue of both malignant and benign lesions. A similar expression pattern was found for PAI-1 immunoreactivity. In 8 of the 16 carcinomas, all 3 components were present, and in several areas colocalization was observed in stromal cells in close proximity to cancer cell islands. No immunoreactivity and/or mRNA expression of uPA, uPAR or PAI-1 was observed in cancer cells or in other epithelial cells in any of the cases.     

Diet and risk of rheumatoid arthritis in a prospective cohort

OBJECTIVE: To assess the association between dietary factors and risk of rheumatoid arthritis (RA) in a large prospective cohort. METHODS: Information about dietary intake was obtained from a detailed self-administered food frequency questionnaire completed by 57,053 individuals who participated in a prospective cohort. Linking the cohort to the Danish National Patient Registry we identified patients who developed RA. A rheumatologist scrutinized original medical records for these individuals in order to confirm the diagnosis of RA. Cox proportional hazards regression analyses were performed for dietary and lifestyle factors. RESULTS: The average time of followup in the cohort was 5.3 years (range < 1 mo to 7.7 yrs). Sixty-nine individuals were identified with confirmed incident RA. In multivariate models each increase in intake of 30 g fat fish (> or = 8 g fat/100 g fish) per day was associated with 49% reduction in the risk of RA (p = 0.06), whereas medium fat fish (3-7 g fat/100 g fish) was associated with significantly increased risk of RA. Intake of fruit and coffee was not associated with risk of RA. Furthermore, no associations were found between risk of RA and intake of a range of other dietary factors including long chain fatty acids, olive oil, vitamins A, E, C, D, zinc, selenium, iron, and meat. CONCLUSION: The limited number of patients who developed RA during followup of our large cohort prevented us from concluding that dietary factors are unimportant as risk factors for RA. It appears, however, that if dietary factors are important modifiers of RA risk, they must play a role more than a few years before clinical diagnosis.     

Fuel utilization in subjects with carnitine palmitoyltransferase 2 gene mutations

Patients with the myopathic form of carnitine palmitoyltransferase II (CPT II) deficiency typically experience muscle pain, cramps, and myoglobinuria during prolonged exercise. It has been suggested that carriers of CPT2 gene mutations also may have milder clinical symptoms, but fatty acid oxidation (FAO) has never been investigated in vivo in this group. We studied fuel utilization by indirect calorimetry and stable isotope methodology in four patients with CPT II deficiency, three subjects who carried one CPT2 gene mutation, and five healthy control subjects. Cycle exercise at a constant workload of 50% of maximal oxygen uptake capacity was used to facilitate FAO. We found that in vivo oxidation of long-chain fatty acids was normal at rest but severely impaired during prolonged, low-intensity exercise in patients with CPT II deficiency, and that two of the single CPT2 gene mutation carriers, who displayed symptoms of CPT II deficiency, had an FAO comparable with the patients. These results indicate that residual CPT II activity is sufficient to maintain long-chain FAO at rest in CPT II deficiency but not to increase FAO during exercise. The findings also suggest that single CPT2 gene mutations may exert a dominant-negative effect on the tetrameric CPT II protein.