Intae Lee

Migraine, headache, and the risk of stroke in women A prospective study

Background: Migraine and headache in general have been associated with subsequent risk of stroke, primarily in retrospective case-control studies. Prospective data evaluating the association between specific headache forms and stroke are sparse. Methods: A prospective cohort study was conducted among 39,754 US health professionals age 45 and older participating in the Women’s Health Study with an average follow-up of 9 years. Incident stroke was self-reported and confirmed by medical record review. Results: A total of 385 strokes (309 ischemic, 72 hemorrhagic, and 4 undefined) occurred. Compared with nonmigraineurs, participants who reported migraine overall or migraine without aura had no increased risk of any stroke type. Participants who reported migraine with aura had increased adjusted hazards ratios (HRs) of 1.53 (95% CI 1.02 to 2.31) for total stroke and 1.71 (95% CI 1.11 to 2.66) for ischemic stroke but no increased risk for hemorrhagic stroke. Participants with migraine with aura who were <55 years old had a greater increase in risk of total (HR 1.75; 95% CI 1.02 to 3.00) and ischemic (HR 2.25; 95% CI 1.30 to 3.91) stroke. Compared with participants without headache, headache in general and nonmigraine headache were not associated with total, ischemic, or hemorrhagic stroke. Conclusions: In these prospective data, migraine was not associated with total, ischemic, or hemorrhagic stroke. In subgroup analyses, we found increased risks of total and ischemic stroke for migraineurs with aura. The absolute risk increase was, however, low, with 3.8 additional cases per year per 10,000 women.

Physical activity, physical fitness and longevity.

Numerous studies consistently have shown that higher levels of physical activity are associated with decreased risks of coronary heart disease, cerebrovascular disease, hypertension, non-insulin-dependent diabetes mellitus, colon and, possibly, breast cancer, as well as osteoporosis. The biological processes proposed to explain these inverse associations are highly plausible. If physical activity does reduce the risk of developing these chronic diseases, we also would expect physical activity to delay mortality and enhance longevity. In this article, we review the major epidemiological studies worldwide that have examined the association between physical activity or physical fitness and all-cause mortality. The data from these studies indicate that physical activity is effective in postponing mortality and enhancing longevity. Public health professionals worldwide should emphasize the need to increase activity levels during leisure time, as well as the need to incorporate physical activity into the daily activities of life.

REDOX CYCLING BY MOTEXAFIN GADOLINIUM ENHANCES CELLULAR RESPONSE TO IONIZING RADIATION BY FORMING REACTIVE OXYGEN SPECIES

PURPOSE To examine the mechanism of radiation enhancement by motexafin gadolinium (Gd-Tex) in vitro. METHODS AND MATERIALS Oxidation of ascorbate and NADPH by Gd-Tex was evaluated in a neutral buffer. Growth inhibition of human uterine cancer cell line MES-SA was measured using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) dye. Clonogenic assays were used to measure radiation response in MES-SA, A549 human lung carcinoma, E89, a CHO cell line variant deficient in glucose-6-phosphate dehydrogenase activity, and murine lymphoma cell lines LYAR and LYAS. RESULTS Gd-Tex catalyzed the oxidation of NADPH and ascorbate under aerobic conditions, forming hydrogen peroxide. Decreased viability was observed in MES-SA cells incubated with Gd-Tex in media containing NADPH or ascorbate. Gd-Tex and ascorbate increased fluorescence in dichlorofluorescin acetate-treated cultures. Synergistic effects on the aerobic radiation response in MES-SA and A549 were seen using Gd-Tex in combination with L-buthionine-(S,R)-sulfoximine (BSO). Incubation with Gd-Tex in the presence of ascorbate increased the aerobic radiation response of E89 and the apoptosis-sensitive B-cell line (LYAS). CONCLUSIONS Gd-Tex sensitizes cells to ionizing radiation by increasing oxidative stress as a consequence of futile redox cycling. Optimization of the concentration of ascorbate (or other reducing species) may be required when evaluating Gd-Tex activity in vitro.

Physical activity, body weight, and pancreatic cancer mortality

In a study of 32 687 subjects with data on physical activity and body mass index (BMI) collected serially over time, we examined associations with pancreatic cancer mortality (n=212). Despite plausible biologic mechanisms, neither physical activity (multivariate relative risks for increasing levels: 1.00, 0.98, 0.92, and 1.31, respectively) nor BMI (corresponding findings: 1.00, 0.84, 1.08, and 0.99, respectively) significantly predicted pancreatic cancer mortality.

Changes in tumour blood flow, oxygenation and interstitial fluid pressure induced by pentoxifylline.

Pentoxifylline (PTX) has been shown to increase radiation damage to tumours and to decrease late radiation-induced injury to normal tissues. This tumour radiation sensitisation results from increased oxygen supply via improved tumour perfusion. We propose that the improved perfusion results from decreased viscous resistance and/or geometric resistance. The decreased flow resistance may be accompanied by a reduction in microvascular pressure (MVP). Since MVP is approximately equal to the interstitial fluid pressure (IFP), PTX should lead to a decrease in IFP. To test this hypothesis, we measured PO2, laser Doppler flow (RBC flux) and IFP in FSaII murine tumours at two doses (PTX at 25 and 100 mg per kg body weight) which sensitise this tumour to X-irradiation. We found that 25 mg kg-1 PTX was ineffective, but 100 mg kg-1 PTX was effective in increasing the PO2 of this tumour. PTX at 100 mg kg-1 (i.p.) increased median PO2 from 5 to 7 mmHg (P < 0.05) within 2 h, and decreased the fraction of PO2 values < 5 mmHg from 65% to 45% (P < 0.05). In support of our hypothesis, we found that with this dose of PTX, RBC flux in the tumour centre increased significantly (n = 6, P < 0.05) prior to an approximately 40% decrease (n = 13, P < 0.05) in tumour interstitial fluid pressure (TIFP), without changes in mean arterial blood pressure (MABP). In conclusion, a single i.p. administration of PTX at 100 mg kg-1 can increase oxygen availability in the tumour due to ameliorate hypoxia in tumour microregions. Second, PTX can lower the elevated TIFP without lowering the MABP.

Interlaboratory variation in oxygen tension measurement by Eppendorf “Histograph” and comparison with hypoxic marker

The median of pO2 values in tumor measured by Eppendorf “Histograph” with a needle‐type electrode has been used as a prognostic indicator in cancer patients. However, it is not established that a pretreatment measured pO2 value can be used as a universal predictor of local control probability, because the variation in pO2 values, especially in hypoxic tissue, among institutes may not allow comparison of measured “absolute pO2 values.” The purpose of this study was to examine the variation in oxygen tension measurement by Eppendorf “Histograph” among six laboratories using a single batch of mice and tumors and the same detailed protocol. These results were also compared to the immunohistochemical staining of 2‐nitroimidazole adducts.

Low‐dose aspirin for migraine prophylaxis in women

Although migraine is more common among women than men, the only two large, randomized trials of low-dose aspirin for migraine prophylaxis have been conducted in men. As part of the Womens Health Study, an ongoing randomized trial of low-dose aspirin and vitamin E among 39 876 female health professionals aged 45 and older, 1001 women with frequent migraine attacks were assigned to 100 mg of aspirin every other day (n = 525) or aspirin placebo (n = 476). Migraine frequency, as well as severity, duration, and degree of incapacitation, were assessed by self-report on questionnaires 12 months and 36 months after randomization, and also by monthly diaries kept before and after randomization. Women assigned to aspirin reported small and consistent decreases in migraine frequency (59.6% vs. 56.4% assigned to placebo reporting improvement at 36 months; odds ratio 1.13, 95% confidence interval, 0.86–1.48), as well as decreases in severity, duration, and migraine-related incapacitation. These reductions were not, however, statistically significant. These data are compatible with a small treatment effect of low-dose aspirin in the prophylaxis of migraine among middle-aged women.

Lifetime physical activity and risk of breast cancer.

We conducted a case–control study of 394 women with breast cancer and 788 control women (91% response) to investigate the association of lifetime physical activity with mainly menopausal breast cancer risk. After controlling for potential confounders, the odds ratios (95% confidence intervals) for increasing quartiles of lifetime physical activity were 1.00 (referent), 0.91 (0.60–1.37), 0.91 (0.60–1.39), and 1.10 (0.73–1.67), respectively; P, trend = 0.47. We also separately examined physical activity at ages 12–18, 19–34, 35–49 and ≥50 years; no significant trends were observed in any age group. These data do not support a role of physical activity in preventing breast cancer.

Oxygenation in tumors by modified hemoglobins

The effect of systemic injection of modified hemoglobin (Hb) prepared from bovine. human, or mouse Hb on tumor oxygenation was investigated. Hb was modified by (1) diisothiocyanatobenzenesulfonate (DIBS) to yield cross‐linking within a tetramer; (2) glycolaldehyde (Glyal) to yield cross‐linking between and within tetramers; (3) carboxymethylation (Cm) to change oxygen affinity: or (4) poly(ethylene glycol) (PEG) to yield attachment between tetramers. HGL9 (human glioma) in nude mice and FSaII (mice fibrosarcoma) in C3H mice were used as tumor models. Dose and time dependency were detected in the oxygenation effect by bovine‐PEG‐Hb. Internal cross‐linkage prolonged the half‐life in the circulation, and thus showed a significant effect. Compared to bovine‐CmHb, bovine‐DIBS‐Hb and bovine‐DIBS‐CmHb were more effective. Decreasing the oxygen affinity by Cm significantly enhanced tumor oxygenation. Human‐DIBS‐CmHb was more effective than human‐DIBS‐Hb. These effects were caused by oxygen carrying capacity of modified Hbs as well as hemodynamic factors, and the injection seemed to reduce both perfusion‐limited (acute) and diffusion‐limited (chronic) hypoxia.

Tumoricidal effects of onconase on various tumors.

The effects of Onconase (Onc) on the tumor growth in vitro and in vivo were examined. Because elevated tumor interstitial fluid pressure (TIFP) is one of the major causes of inadequate drug delivery into solid tumors, we tested if Onc could lower TIFP in solid tumors.