Abstract:The p38 mitogen-activated protein kinase is a stress-activated enzyme responsible for transducing inflammatory signals and initiating apoptosis. In the Alzheimer's disease (AD) brain, increased levels of phosphorylated (active) p38 were detected relative to age-matched normal brain. Intense phospho-p38 immunoreactivity was associated with neuritic plaques, neuropil threads, and neurofibrillary tangle-bearing neurons. The antibody against phosphorylated p38 recognized many of the same structures as an antibody against aberrantly phosphorylated, paired helical filament (PHF) tau, although PHF-positive tau did not cross-react with the phosphop38 antibody. These findings suggest a neuroinflammatory mechanism in the AD brain, in which aberrant protein phosphorylation affects signal transduction elements, including the p38 kinase cascade, as well as cytoskeletal Alzheimer's disease (AD) is a progressive dementing disorder characterized by selective neuron loss in the limbic system and association regions of the neocortex. The characteristic histopathologic alterations in AD are neuritic or senile plaques (SPs) composed largely of amyloid P-peptides (AP) and neuronal aggregates of abnormally phosphorylated cytoskeletal proteins [neurofibrillary tangles (NFTs)] (GrundkeIqbal et al., 1986). Brain regions affected by AD also demonstrate hallmarks of inflammation, including elevated levels of proinflammatory cytokines (particularly interleukin-1 and -6), complement, and acutephase reactants (Rogers et a]., 1996); higher than normal levels of lipid, protein, and DNA oxidation (Smith et al., 1991;Mecocci et al., 1993;Smith et al., 1997;Hensley et al., 1998); and proliferation of microglial cells, which are functionally similar to monocytes (Itagaki et al., 1989). Epidemiological data indicate that long-term use of nonsteroidal antiinflammatory drugs (NSAIDs) diminishes risk for AD (Carpenter et al., 1993), and clinical studies indicate that the antioxidant a-tocopherol as well as NSAIDs may slow the progression of the disease (Rich et al., 1995;Sano et al., 1997). Recent models for AD pathogenesis therefore propose that atypical forms of inflammation, perhaps initiated by an immune response to plaque deposition, engender oxidative stress and neuronal damage in sensitive brain regions. The principal weakness of the neuroinflammatory model is that specific biochemical mechanisms have not been discovered that might explain precisely how an inflammatory process can propagate chronically in the AD brain.Because inflammation is fundamentally an autocrine or paracrine process involving cytokine-mediated activation of gene expression in target cells, we reasoned that dysfunction of specific signal transduction pathways responsible for cytokine-, AP-, or oxidant-stimulated gene induction might engender chronic inflammatory and oxidative processes in AD. We now report evidence that the p38 mitogen-activated protein (MAP) kinase pathway, a major proinflammatory signal transduction pathway activated by oxidants, cytokines, and ...

Purposes We tested the hypotheses that women have greater impairment in calf muscle hemoglobin oxygen saturation (StO2) in response to exercise than men, and that the sex-related difference in calf muscle StO2 would partially explain the shorter claudication distances of women. Methods Twenty-seven men and 24 women with peripheral arterial disease limited by intermittent claudication were studied. Patients were characterized on calf muscle StO2 before, during, and after a graded treadmill test, as well as on demographic and cardiovascular risk factors, ankle/brachial index (ABI), ischemic window, initial claudication distance (ICD), and absolute claudication distance (ACD). Results Women had a 45% lower ACD than men (296 ± 268 meters vs. 539 ± 288 meters; p = 0.001) during the treadmill test. Calf muscle StO2 declined more rapidly during exercise in women than in men, as the time to reach minimum StO2 occurred 54% sooner in women (226 ± 241 sec vs. 491 ± 426 sec; p = 0.010). Additionally, the recovery time for calf muscle StO2 to reach the resting value after treadmill exercise was prolonged in women (383 ± 365 sec vs. 201 ± 206 sec; p = 0.036). Predictors of ACD included the time from start of exercise to minimum calf muscle StO2, the average rate of decline in StO2 from rest to minimum StO2 value, the recovery half-time of StO2, and ABI (R2 = 0.70; p < 0.001). The ACD of women remained lower after adjusting for ABI (mean difference = 209 meters; p = 0.003), but was no longer significantly lower (mean difference = 72 meters; p = 0.132) after further adjustment for the three calf muscle StO2 variables. Conclusion In patients limited by intermittent claudication, women have lower ACD and greater impairment in calf muscle StO2 during and following exercise than men, the exercise-mediated changes in calf muscle StO2 are predictive of ACD, and women have similar ACD as men after adjusting for calf StO2 and ABI measures.

Purpose To determine the association between daily ambulatory activity patterns and exercise performance in patients with intermittent claudication. Methods One hundred thirty-three patients limited by intermittent claudication participated in this study. Patients were assessed on their ambulatory activity patterns for one week with a small, lightweight step activity monitor attached to the ankle using elastic velcro straps above the lateral malleolus of the right leg. The step activity monitor recorded the number of strides taken on a minute-to-minute basis, and the time spent ambulating. Patients also were characterized on ankle/brachial index (ABI), ischemic window (IW) after a treadmill test, as well as initial claudication distance (ICD), and absolute claudication distance (ACD) during treadmill exercise. Results The patient characteristics (mean ± SD) were as follows: ABI = 0.71 ± 0.23, IW = 0.54 ± 0.72 mmHg.min.meter−1, ICD = 236 ± 198 meters, and ACD = 424 ± 285 meters. The patients took 3366 ± 1694 strides/day, and were active for 272 ± 103 minutes/day. The cadence for the 30 highest, consecutive minutes of each day (15.1 ± 7.2 strides/minute) was correlated with ICD (r = 0.316, p < 0.001) and ACD (r = 0.471, p < 0.001), and the cadence for the 60 highest, consecutive minutes of each day (11.1 ± 5.4 strides/minute) was correlated with ICD (r = 0.290, p < 0.01) and ACD (r = 0.453, p < 0.001). Similarly, the cadences for the highest 1, 5, and 20 consecutive minutes, and the cadence for the 30 highest, non-consecutive minutes all were correlated with ICD and ACD (p < 0.05). None of the ambulatory cadences were correlated with ABI (p > 0.05) or with ischemic window (p > 0.05). Conclusion Daily ambulatory cadences are associated with severity of intermittent claudication, as measured by ACD and ICD, but not with peripheral hemodynamic measures.

Varicose veins (VVs) are the most common manifestation of chronic venous insufficiency, affecting 25% of women and 15% of men. Reticular veins and telangiectasias (spider veins) are found in more than 80% of the general population. VVs produce symptoms of pain, swelling, heaviness, fatigue, and pruritus and predispose patients to complications including bleeding, superficial thrombophlebitis, and ulcerations that interfere with activities of daily living and result in lost time from work. Current treatments for VVs include conservative measures, and when these are unsuccessful, more invasive surgical and endovenous interventions primarily aimed at reducing venous hypertension and preventing progression to chronic inflammation and ulcerations. Surgical procedures including saphenous vein stripping, ligation of the saphenofemoral junction, and ambulatory phlebectomy are effective in the treatment of VVs but are associated with a high complication rate and recovery time. Emerging endovenous therapies, including endovenous laser therapy, radiofrequency ablation, and endovenous foam sclerotherapy, have shown similar efficacy in the treatment of VVs compared with more invasive surgical procedures, with lower complication rates and less time lost from work.

Varicose veins (VVs) are associated with lifestyle-limiting symptoms and complications. Patients who fail compression therapy are candidates for more invasive treatments. This study evaluates the efficacy and safety of endovenous foam sclerotherapy (EFS) for the treatment of VVs in a US academic center. We reviewed medical records of a consecutive cohort of patients who underwent EFS over a 2-year period. The primary outcome measure was obliteration of VVs. The secondary outcome measures were symptomatic improvement, ulcer healing, recurrence, and adverse events. A total of 166 patients (217 legs) underwent EFS for pain (81%), pruritis (41%), swelling (17%), ulcerations (17%), thrombophlebitis (14%), and varix rupture (3%). Complete (65%) or near-complete (34%) obliteration was achieved in 215 (99%) legs after one injection. Additional injections achieved complete obliteration in 39 of 53 legs. Ninety-three percent (27/29) of active ulcers healed or were decreasing in size. Five ulcers and 11 VVs recurred. Common adverse events included pain and hyperpigmentation. Thrombosis, hematoma, skin necrosis, and neurologic events were rare. In conclusion, EFS appears to be a safe and effective outpatient therapy for the treatment of symptomatic and complicated VVs.