Metabolism and anticancer activity of the curcumin analogue, dimethoxycurcumin.

PURPOSE: The plant-derived compound curcumin has shown promising abilities as a cancer chemoprevention and chemotherapy agent in vitro and in vivo but exhibits poor bioavailability. Therefore, there is a need to investigate modified curcumin congeners for improved anticancer activity and pharmacokinetic properties. EXPERIMENTAL DESIGN: The synthetic curcumin analogue dimethoxycurcumin was compared with curcumin for ability to inhibit proliferation and apoptosis of human HCT116 colon cancer cells in vitro by estimating the GI(50) and LC(50) values and detecting the extent of apoptosis by flow cytometry analysis of the cell cycle. Metabolic stability and/or identification of metabolites were evaluated by recently developed mass spectrometric approaches after incubation with mouse and human liver microsomes and cancer cells in vitro. Additionally, circulating levels of dimethoxycurcumin and curcumin were determined in mice following i.p. administration. RESULTS: Dimethoxycurcumin is significantly more potent than curcumin in inhibiting proliferation and inducing apoptosis in HCT116 cells treated for 48 h. Nearly 100% of curcumin but <30% of dimethoxycurcumin was degraded in cells treated for 48 h, and incubation with liver microsomes confirmed the limited metabolism of dimethoxycurcumin. Both compounds were rapidly degraded in vivo but dimethoxycurcumin was more stable. CONCLUSIONS: Compared with curcumin, dimethoxycurcumin is (a) more stable in cultured cells, (b) more potent in the ability to kill cancer cells by apoptosis, (c) less extensively metabolized in microsomal systems, and (d) more stable in vivo. It is likely that the differential extent of apoptosis induced by curcumin and dimethoxycurcumin in vitro is associated with the metabolite profiling and/or the extent of stability.     

Survey of german clinical prescribing philosophies for hyperopia.

PURPOSE: We surveyed a group of German ophthalmologists to evaluate their prescribing philosophies for hyperopic refractive error in symptom-free children and to compare them with the two groups of U.S. pediatric ophthalmologists and U.S. pediatric optometrists as surveyed by Lyons et al. METHODS: Practitioners were selected from a list of ophthalmologists on the Internet. They were either in general practice in three cities in northern Bavaria or affiliated with large ophthalmology teaching hospitals in Wuerzburg and Erlangen. The survey questions of Lyons et al. were translated into German and mailed to 103 ophthalmologists. The data received from the German ophthalmologists were compared with those of the U.S. optometrists and ophthalmologists. RESULTS: A total of 45 surveys (44%) were returned to us and analyzed. In cases of asymptomatic bilateral hyperopia, German ophthalmologists did not prescribe significantly differently from U.S. optometrists at all patient age groups (p > or = 0.05), but they did differ significantly from U.S. ophthalmologists (p < 0.001). Prescribing fractional amounts of hyperopia or astigmatism was not a popular rule of thumb among the German ophthalmologists, and there was no statistical difference between the German and U.S. practitioners. German ophthalmologists would prescribe for anisometropia for all patient age groups in the same way as both U.S. optometrists and U.S. ophthalmologists. CONCLUSION: The prescribing philosophies of German ophthalmologists for pediatric patients did not differ from those of U.S. ophthalmologists and U.S. optometrists when prescribing for anisometropia; they did differ from those of U.S. ophthalmologists but not of those of the U.S. optometrists when prescribing for asymptomatic bilateral hyperopia.     

Caspase‐related apoptosis in chronic ischaemic microangiopathy following experimental vein occlusion in mini‐pigs

Purpose: Acute brain ischaemia (stroke) causes a central area of coagulation necrosis. Peripheral to it and after a few hours, apoptosis causes neurons throughout the entire area to die progressively. However, this sequence of events is related to the reperfusion of regenerated capillaries or collateral circulation, and is considered to be potentially salvageable. Similar findings have been reported in the retina after ischaemia?reperfusion injury in rats. In the present study, we intended to investigate whether delayed cell death is involved in neuronal injuries to the inner retina during chronic retinal ischaemia. Methods: Experimental branch retinal vein occlusion (BRVO) was induced in miniature pigs using indirect argon laser. The eyes were prelevated at 4, 24 and 48 hours and at 1 and 3 weeks following BRVO. The caspase inhibitor Z‐VAD was injected intravitreally 24 hours after BRVO. Affected retinas were examined 24 hours later for any protective effect from apoptotic cell death. Histological examination with cresyl violet staining and TUNEL (TdT‐mediated dUTP?biotin nick‐end labelling) was performed on the samples. Results: A progressive oedema of the nerve fibre, ganglion cell and inner plexiform layers, related to a widely diffused cell necrosis, was observed in the affected territory within 4–24 hours after BRVO. This was followed by a wave of apoptosis localized at the periphery of the affected territory, which peaked approximately 48 hours after BRVO and was associated with a diffuse oedema of the inner nuclear layer. A progressive atrophy of the inner retina was observed 1–3 weeks after BRVO. Injection of the caspase inhibitor Z‐VAD (24 hours after BRVO) decreased the amount of apoptotic cell bodies 48 hours after BRVO. Conclusions: This study shows that although necrosis is the predominant form of neuronal death in the early phase, massive delayed neuronal cell death caused by apoptosis occurs on a widespread basis as a result of chronic ischaemia after BRVO in the retina. Further studies are needed to evaluate the possibility of rescuing retinal neurons from death by neuroprotective treatments.     

Cervical Cancer in South Australia: Trends in Incidence, Mortality and Case Survival

Summary: Approximately 90% of cervical cancers are considered preventable through regular screening and the treatment of precursor lesions, but fewer than 20% of South Australian women were found to have been screened in 1984.
Data from the State Cancer Registry have shown an increase in cervical cancer incidence of approximately 80% in women under 50 years of age in the 9-year period to 1986, but a decrease of about 25% in older women. Mortality data have shown similar patterns by age, although the increase in younger women tended to extend to an older age.
Case survival was unchanged between the diagnostic periods 1977–1981 and 1982–1987 and there was little change in the proportion of cases that were adeno-carcinomas.     

Brain cancer incidence,mortality and case survival: Observations from two australian cancer registries

Data from 2 Australian cancer registries covering a population of 1.7 million people were combined for the purposes of analysing brain cancer incidence, mortality and survival patterns for the time period 1978 through 1992. A total of 1,752 cases of primary brain cancer were registered, representing age-standardised incidence rates of 6.7 per 100,000 in men and 4.6 in women. Histological confirmation was available for 94% of cases. The incidence rate among persons aged 75 or over was higher during 1986–1992 than during 1978–1985, the rate for men increasing from 16.3 to 26.2 and that for women increasing from 9.7 to 18.0. The largest increases in this age group occurred for cases of glioblastoma multiforme. During the study period, 1,411 brain cancer deaths were notified to the 2 registries at age-standardised rates of 5.3 in men and 3.4 in women. Mortality rates among persons aged 75 years or older were higher during 1986–1992 than 1978–1985, increasing from 15.7 to 28.4 in men and from 10.1 to 15.3 in women. Only among men aged 15–49 years was a decline in mortality rates observed, from 3.3 to 2.4. Survival analyses indicated that age and histological type were the most powerful prognostic indicators. There was no improvement in 5-year survival for any of the age groups or histological types. An improvement in 36-month survival was noted for the 15–49 year age group diagnosed with gliomas other than glioblastoma multiforme.     

Changes to visual acuity and the visual field in a case of meningioma operated at the anterior level

It's presented a midline meningioma of anterior level case which preoperative has an importance affectation of the visual acuity and visual field, and postoperative in dynamic is founded the important improvement of visual acuity and visual field. It's discussed visual field topography and atrophy optic pathophysiology. It's a neuro-ophthalmology case example, where the cooperation neurosurgery-ophthalmology permit medical solution and restored in social life of the patient.     

Central serous chorioretinopathy and glucocorticoids

Central serous chorioretinopathy is a relatively common retinal disease characterized by the accumulation of subretinal fluid at the posterior pole of the fundus, creating a circumscribed area of serous retinal detachment. It typically affects young and middle-aged men with no previous medical and family history, and no systemic symptoms or signs. However, it has been noted that central serous chorioretinopathy is associated with different conditions, characterized by exposure to increased levels of endogenous or exogenous glucocorticoids. In fact, central serous chorioretinopathy has been described in patients with endogenous Cushing's syndrome. It is also prevalent in patients with type-A behavior, and following stressful events, and pregnancy probably represents a risk factor for central serous chorioretinopathy; these conditions are characterized by endogenous hypercortisolism. In addition, many cases of central serous chorioretinopathy have been described during or following treatment with glucocorticoids, administrated by any route, for various systemic or ocular conditions. Central serous chorioretinopathy, when related to the exposure to exogenous glucocorticoids, has a less prominent male predilection, presents more often with a chronic or atypical form, and is frequently bilateral. Furthermore, treatment of central serous chorioretinopathy with glucocorticoids was found to exacerbate the clinical picture. Based on these observations it could be suggested that glucocorticoids may be involved in the development of central serous chorioretinopathy, even though the exact pathogenic mechanism remains unclear. Glucocorticoids should not be used in the treatment of central serous chorioretinopathy and central serous chorioretinopathy should be added to the list of ocular complications of glucocorticoids.     

Design and pharmacology of N-[(3R)-1,2,3,4-tetrahydroisoquinolinium- 3-ylcarbonyl]-(1R)-1-(4-chlorobenzyl)- 2-[4-cyclohexyl-4-(1H-1,2,4-triazol- 1-ylmethyl)piperidin-1-yl]-2-oxoethylamine (1), a potent,selective, melanocortin subtype-4 receptor agonist

Synthetic and natural peptides that act as nonselective melanocortin receptor agonists have been found to be anorexigenic and to stimulate erectile activity. We report the design and development of 1, a potent, selective (1184-fold vs MC3R, 350-fold vs MC5R), small-molecule agonist of the MC4 receptor. Pharmacological testing confirms the food intake lowering effects of MC4R agonism and suggests another role for the receptor in the stimulation of erectile activity.