Iron status and oxidative stress in the aged rabbit heart.

Altered iron status may be relevant to the pathophysiology of aging. We have assessed redox-active catalytic low molecular weight iron (LMWI), non-heme iron (NHI), heme iron (HI), and total iron (TI) in the aerobically perfused hearts of aged rabbits (AR, about 4.5years old) and young adult control rabbits (YACR, 3-4months old); myocardial lipid and protein oxidations were also assessed as oxidative stress biomarkers. The levels of LMWI and NHI, as well as of lipid and protein oxidation, were higher, while HI content was lower, in the hearts of AR than in those of YACR; TI did not differ significantly between the two groups. Together with these findings, hemodynamic dysfunction, namely heightened end-diastolic pressure (EDP) and lowered coronary flow (CF), occurred in the AR hearts. Notably, such pattern of hemodynamic dysfunction associated with myocardial oxidant damage occurred in the hearts of other YACR perfused in the presence of a cell-permeable form of iron, i.e., the iron/hydroxyquinoline complex, pointing to the involvement of catalytic iron in the aged heart damage. Moreover, as shown in other AR, heart perfusion in the presence of the iron chelator deferoxamine (0.6mM or 3.6mM) reduced the myocardial levels of LMWI, without significantly affecting those of NHI, HI, and TI; concomitantly, in AR deferoxamine lowered myocardial lipid and protein oxidation, and reduced EDP with a tendency to augment CF. Instead, deferoxamine, even at high concentration of 3.6mM, had no significant effects in the YACR. In conclusion, altered iron status with catalytic LMWI burden occurs in the aged rabbit heart, eventually resulting in iron-dependent cardiac oxidative stress and hemodynamic dysfunction.

Effects of topical vs injection treatment of cervical myofascial trigger points on headache symptoms in migraine patients: a retrospective analysis.

BACKGROUND: In migraine patients with cervical myofascial trigger points whose target areas coincide with migraine sites (M + cTrPs), TrP anesthetic injection reduces migraine symptoms, but the procedure often causes discomfort. This study evaluated if a topical TrP treatment with 3% nimesulide gel has similar efficacy as the injection but produces lesser discomfort with higher acceptability by the patients. METHODS: Retrospective analysis of medical charts of M + cTrPs patients in the period January 2012-December 2016 at a single Headache Center. Three groups of 25 patients each were included, all receiving migraine prophylaxis (flunarizine 5 mg/day) for 3 months and symptomatic treatment on demand. Group 1 received no TrP treatment, group 2 received TrP injections (bupivacaine 5 mg/ml at basis, 3rd, 10th, 30th and 60th day), group 3 received daily TrP topical treatment with 1.5 g of 3% nimesulide gel for 15 consecutive days, 15 days interruption and again 15 consecutive days. The following were evaluated: monthly number of migraine attacks and rescue medications, migraine intensity; pain thresholds to skin electrical stimulation (EPTs) and muscle pressure stimulation (PPTs) in TrP and target (basis, 30th, 60th and 180th days); discomfort from, acceptability of and willingness to repeat treatment (end of study). ANOVA for repeated measures and 1-way ANOVA were used to assess temporal trends in each group and comparisons among groups, respectively. Significance level was set at p < 0.05. RESULTS: Migraine improved over time in all groups, but significantly more and earlier in those receiving TrP treatment vs no TrP treatment (0.02 < p < 0.0001, 30-180 days for intensity and rescue medication, 60-180 days for number). All thresholds in the non-TrP-treated group did not change over time, while significantly improving in both the injection and nimesulide gel groups (0.01 < p < 0.0001, 30-180 days). Improvement of migraine and thresholds did not differ in the two TrP-treated groups. Discomfort was significantly lower, acceptability and willingness to repeat treatment significantly higher (0.05 < p < 0.0001) with gel than injection. CONCLUSION: In migraine patients, topical treatment of cervical TrPs with 5% nimesulide gel proves equally effective as TrP injection with local anesthetics but more acceptable by the patients. This treatment could be effectively associated to standard migraine prophylaxis to improve therapeutic outcomes.

Use of Nonsteroidal Anti-Inflammatory Drugs for Symptomatic Treatment of Episodic Headache.

INTRODUCTION: Primary headaches have high epidemiologic impact but their symptomatic treatment often remains problematic. Nonsteroidal anti-inflammatory drugs (NSAIDs) are frequently used, but their modality of employment and efficacy/differential efficacy are highly variable. This study investigated current NSAID use for episodic headache at an Italian headache center (January 2000 to February 2013). METHODS: A retrospective evaluation was performed on 6,443 patient records: migraine (n = 2,330), tension-type headache (TTH; n = 807), and migraine plus TTH (n = 3,306). RESULTS: Among migraine patients, 80% had used NSAIDs in the past year. Preferences were: nimesulide (57%), ketoprofen (25%), and ibuprofen (24%); complete efficacy was significantly higher than incomplete/absent efficacy (P < 0.0001). NSAIDs were replaced with triptans in 53% of patients at first visit; after 1 year there was a spontaneous significant return to NSAIDs (56%; P < 0.0005). Among TTH patients, 90% were NSAID users; preferences were: nimesulide (48%), ketoprofen (47%), and diclofenac (19%), with significantly higher complete vs. incomplete/absent efficacy (nimesulide and ketoprofen, P < 0.02). Replacement with analgesics was performed in 24% of patients; after 1 year, there was a 29% return to NSAIDs. Among migraine plus TTH patients, 89% were NSAID users. Preferences were: nimesulide (44%), ibuprofen (42%), and ketoprofen (38%), with significantly higher complete vs. incomplete/absent efficacy (0.001 < P < 0.0001). Replacement with analgesics was performed in 31% of patients; after 1 year, there was a 37% return to NSAIDs. CONCLUSIONS: Nonsteroidal anti-inflammatory drug use in headache was higher than could be hypothesized based on guidelines, with NSAID preferences not entirely coinciding with international recommendations. This outcome suggests the need for greater awareness of all treatment options in headache by both patients and physicians.

Impact of migraine on fibromyalgia symptoms.

BACKGROUND: Fibromyalgia (FMS) and high frequency episodic/chronic migraine (M) very frequently co-occur, suggesting common pathophysiological mechanisms; both conditions display generalized somatic hyperalgesia. In FMS-M comorbidity we assessed if: a different level of hyperalgesia is present compared to one condition only; hyperalgesia is a function of migraine frequency; migraine attacks trigger FMS symptoms. METHODS: Female patients with fibromyalgia (FMS)(n.40), high frequency episodic migraine (M1)(n.41), chronic migraine (M2)(n.40), FMS + M1 (n.42) and FMS + M2 (n.40) underwent recording of: -electrical pain thresholds in skin, subcutis and muscle and pressure pain thresholds in control sites, -pressure pain thresholds in tender points (TePs), -number of monthly migraine attacks and fibromyalgia flares (3-month diary). Migraine and FMS parameters were evaluated before and after migraine prophylaxis, or no prophylaxis, for 3 months with calcium-channel blockers, in two further FMS + H1 groups (n.49, n.39). 1-way ANOVA was applied to test trends among groups, Student's t-test for paired samples was used to compare pre and post-treatment values. RESULTS: The lowest electrical and pressure thresholds at all sites and tissues were found in FMS + M2, followed by FMS + H1, FMS, M2 and M1 (trend: p < 0.0001). FMS monthly flares were progressively higher in FMS, FMS + M1 and FMS + M2 (p < 0.0001); most flares (86-87 %) occurred within 12 h from a migraine attack in co-morbid patients (p < 0.0001). Effective migraine prophylaxis vs no prophylaxis also produced a significant improvement of FMS symptoms (decreased monthly flares, increased pain thresholds)(0.0001 < p < 0.003). CONCLUSIONS: Co-morbidity between fibromyalgia and migraine involves heightened somatic hyperalgesia compared to one condition only. Increased migraine frequency - with shift towards chronicity - enhances both hyperalgesia and spontaneous FMS pain, which is reversed by effective migraine prophylaxis. These results suggest different levels of central sensitization in patients with migraine, fibromyalgia or both conditions and a role for migraine as a triggering factor for FMS.

Effects of topical diclofenac plus heparin (DHEP+H plaster) on somatic pain sensitivity in healthy subjects with a latent algogenic condition of the lower limb.

OBJECTIVE: To evaluate whether a diclofenac epolamine + heparin topical (plaster) is more effective than diclofenac plaster alone in reducing deep somatic hyperalgesia in subjects without spontaneous pain and whether the effect is linked to or independent of the anti-edematous action of heparin. DESIGN: Prospective, double-blind, randomized and controlled, four-arm parallel design trial. SUBJECTS: One hundred and four patients (84 women, 20 men, mean age 42.2 ± 13.3 years), with deep somatic hyperalgesia in one thigh, randomly assigned to one of 4 groups of 26 each. INTERVENTION: Each group underwent one of the following plaster treatments on one thigh: diclofenac+heparin; diclofenac; heparin; placebo, for 7 days, renewing the plaster every 24 hours. OUTCOME MEASURES: Before treatment (day 1), at day 4 and day 8, assessment of (a) pressure and electrical pain thresholds of vastus lateralis and overlying subcutis and skin; and (b) structure/thickness of subcutis and muscle with ultrasounds at the same level. RESULTS: During treatment, in placebo and heparin, no significant threshold changes, except subcutis thresholds which increased slightly (P < 0.02); in diclofenac and diclofenac+heparin, significant increase in all thresholds (0.0001 < P < 0.04). Electrical muscle pain thresholds increased significantly more in diclofenac+heparin than in diclofenac, heparin, and placebo (0.0001 < P < 0.04). In all groups: no edema and thickness changes at ultrasounds in muscle and subcutis. CONCLUSIONS: Topical diclofenac+heparin is significantly more effective than diclofenac alone in reducing muscle hyperalgesia in subjects without spontaneous pain, independently of the anti-edematous action of heparin. The results provide a rationale for the use of diclofenac+heparin also in algogenic conditions without evident signs of injury/edema/hematoma.

Myocardial glutathione metabolic status in fat-fed rabbits.

Short-term fat feeding could exert adverse cardiac effects by altering myocardial glutathione-related antioxidant defenses. We have here assessed total glutathione (TG), the activities of glutathione reductase (GSSG-Red), γ-glutamylcysteine synthetase (γ-GCS), γ-glutamyl transpeptidase (γ-GT) and glutathione peroxidase (GSH-Px), fluorescent damage products of lipid peroxidation (FDPL), thiobarbituric acid-reactive substances (TBARS), H2O2, and ATP in the aerobically perfused hearts of control rabbits and of rabbits fed a fat-enriched diet for 18 days. Such biochemical parameters, myocardial hemodynamics and infarct size were assessed in the perfused hearts of other control and fat-fed rabbits subjected to 60 min global ischemia plus 30 min reperfusion. Compared to controls, a reduced activity of GSSG-Red and γ-GT associated with decreased TG content was detected in the aerobically perfused hearts of fat-fed rabbits, which also showed insignificant γ-GCS activation, GSH-Px depressed activity, FDPL, TBARS and H2O2 burden, and unaltered ATP content. Ischemia-reperfusion decreased the myocardial levels of TG, ATP, and γ-GCS activity and augmented those of FDPL, TBARS, and H2O2 especially in the fat-fed rabbits, without significant changes in myocardial GSSG-Red, γ-GT, and GSH-Px activities. Ischemia-reperfusion induced greater hemodynamic dysfunction and infarct size in the hearts of fat-fed rabbits than in those of controls. Thus, short-term fat feeding and hyperlipidemia alter glutathione metabolic status of the rabbit myocardium, inducing a GSSG-Red- and γ-GT-related decrement of myocardial glutathione content, which, together with GSH-Px dysfunction, may favor tissue oxidative stress and render the myocardium more susceptible to ischemia-reperfusion injury.

Prediction of carotid plaques in hypertensive patients by risk factors, left ventricular hypertrophy, and epicardial adipose tissue thickness.

Hypertension and other risk factors (RFs) predispose to carotid plaques (CPs). An association between left ventricular hypertrophy (LVH) or epicardial adipose tissue (EAT) and CPs has also been reported. The aim of the study was to evaluate whether the assessment of LVH and EAT thickness, beyond RFs, would be of additive value in predicting CPs in hypertensive subjects. We studied 548 hypertensive patients aged ≥ 50 years without carotid bruit. LVH and CPs were evaluated and defined according to standard criteria. EAT was measured by echocardiography above the free wall of the right ventricle at end diastole. The presence of LVH and EAT thickness above the median value (3.9 mm) together significantly increased prevalence of CPs in subjects with 0-1 risk factor, but not in those with ≥ 2 RFs who showed high prevalence of CPs independently of LVH and/or EAT. Receiver operating characteristic curve analysis showed that the addition of LVH and higher EAT thickness together significantly improved prediction of CPs in patients with 0-1 risk factor. Indeed, the area under the curve improved from 0.63 (0.56-0.69) to 0.73 (0.67-0.79), which was significantly higher (p < 0.05). In patients with ≥ 2 RFs, the addition of LVH and EAT did not significantly improve prediction of CPs. This study shows that the presence of LVH and higher EAT thickness together improves prediction of CPs in hypertensive patients with 0-1 risk factor and that those with ≥ 2 RFs show high prevalence of CPs independently of LVH and/or EAT.

Glutathione and glutathione-dependent enzymes: From biochemistry to gerontology and successful aging.

The tripeptide glutathione (GSH), namely γ-L-glutamyl-L-cysteinyl-glycine, is an ubiquitous low-molecular weight thiol nucleophile and reductant of utmost importance, representing the central redox agent of most aerobic organisms. GSH has vital functions involving also antioxidant protection, detoxification, redox homeostasis, cell signaling, iron metabolism/homeostasis, DNA synthesis, gene expression, cysteine/protein metabolism, and cell proliferation/differentiation or death including apoptosis and ferroptosis. Various functions of GSH are exerted in concert with GSH-dependent enzymes. Indeed, although GSH has direct scavenging antioxidant effects, its antioxidant function is substantially accomplished by glutathione peroxidase-catalyzed reactions with reductive removal of H2O2, organic peroxides such as lipid hydroperoxides, and peroxynitrite; to this antioxidant activity also contribute peroxiredoxins, enzymes further involved in redox signaling and chaperone activity. Moreover, the detoxifying function of GSH is basically exerted in conjunction with glutathione transferases, which have also antioxidant properties. GSH is synthesized in the cytosol by the ATP-dependent enzymes glutamate cysteine ligase (GCL), which catalyzes ligation of cysteine and glutamate forming γ-glutamylcysteine (γ-GC), and glutathione synthase, which adds glycine to γ-GC resulting in GSH formation; GCL is rate-limiting for GSH synthesis, as is the precursor amino acid cysteine, which may be supplemented as N-acetylcysteine (NAC), a therapeutically available compound. After its cell export, GSH is degraded extracellularly by the membrane-anchored ectoenzyme γ-glutamyl transferase, a process occurring, as GSH synthesis and export, in the γ-glutamyl cycle. GSH degradation occurs also intracellularly by the cytoplasmic enzymatic ChaC family of γ-glutamyl cyclotransferase. Synthesis and degradation of GSH, together with its export, translocation to cell organelles, utilization for multiple essential functions, and regeneration from glutathione disulfide by glutathione reductase, are relevant to GSH homeostasis and metabolism. Notably, GSH levels decline during aging, an alteration generally related to impaired GSH biosynthesis and leading to cell dysfunction. However, there is evidence of enhanced GSH levels in elderly subjects with excellent physical and mental health status, suggesting that heightened GSH may be a marker and even a causative factor of increased healthspan and lifespan. Such aspects, and much more including GSH-boosting substances administrable to humans, are considered in this state-of-the-art review, which deals with GSH and GSH-dependent enzymes from biochemistry to gerontology, focusing attention also on lifespan/healthspan extension and successful aging; the significance of GSH levels in aging is considered also in relation to therapeutic possibilities and supplementation strategies, based on the use of various compounds including NAC-glycine, aimed at increasing GSH and related defenses to improve health status and counteract aging processes in humans.

A prospective evaluation of iron deficiency anemia in the GI endoscopy setting: role of standard endoscopy, videocapsule endoscopy, and CT-enteroclysis.

BACKGROUND: Iron deficiency anemia (IDA) is a frequently encountered condition in clinical practice. After conventional endoscopy, the cause of anemia remains unknown in up to 40% of patients. OBJECTIVE: To evaluate prospectively the diagnostic efficacy of a systematic endoscopic approach to IDA and to compare the diagnostic yield of videocapsule endoscopy (VCE) and CT-enteroclysis in endoscopy-negative patients. DESIGN: Consecutive patients with IDA were enrolled prospectively. SETTING: Open-access endoscopy within an academic hospital. PATIENTS: This study involved 189 patients with IDA, including 98 women and 91 men; mean (±standard deviation) age 68 years±16.6 years. INTERVENTION: Patients with IDA underwent gastroscopy and colonoscopy plus ileoscopy. Endoscopy-negative patients were further blindly evaluated by both CT-enteroclysis and VCE. MAIN OUTCOME MEASUREMENTS: Diagnostic yield of conventional endoscopy; diagnostic yield of VCE versus CT-enteroclysis. RESULTS: Endoscopy results were positive in 144 of 189 patients (76.2%). CT-enteroclysis and VCE allowed a diagnosis in 37 of 45 endoscopy-negative patients (82.2%). Overall, VCE was superior to CT-enteroclysis (77.8% vs 22.2%; P<.001), in particular when flat lesions were found. LIMITATIONS: Single-center study. CONCLUSION: A systematic approach to IDA, which includes standard endoscopy, VCE, and CT-enteroclysis allows an overall diagnostic rate of 95.7%; however, CT-enteroclysis should be limited to cases of nondiagnostic VCE.

Inhibitory activity of salicylic acid on lipoxygenase-dependent lipid peroxidation.

BACKGROUND: Since iron is essential for lipoxygenase activity and salicylic acid (SA) can interact with the metal, possible lipoxygenase inhibition by SA was investigated. METHODS: Kinetic spectrophotometric evaluation of enzymatic lipid peroxidation catalyzed by soybean lipoxygenase (SLO), rabbit reticulocyte 15-lipoxygenase (RR15-LOX), porcine leukocyte 12-lipoxygenase (PL12-LOX) and human recombinant 5-lipoxygenase (HR5-LOX) with and without SA. RESULTS: SA inhibited linoleic, arachidonic and docosahexaenoic acid or human lipoprotein peroxidation catalyzed by SLO with IC50 of, respectively, 107, 153, 47 and 108 microM. Using the same substrates, SA inhibited RR15-LOX with IC50 of, respectively, 49, 63, 27 and 51 microM. Further, arachidonic acid peroxidation catalyzed by PL12-LOX and HR5-LOX was inhibited by SA with IC50 of 101 and 168 microM, respectively. Enzymatic inhibition was complete, reversible and non-competitive. Conceivably due to its lower hydrophobicity, aspirin was less effective, indicating acetylation-independent enzyme inhibition. SA and aspirin were ineffective peroxyl radical scavengers but readily reduced Fe3+, i.e. FeCl3, to Fe2+, suggesting their capacity to reduce Fe3+ at the enzyme active site. Indeed, similar to the catecholic redox inhibitor nordihydroguaiaretic acid, SA inhibited with the same efficiency both ferric and the native ferrous SLO form, indicating that these compounds reduce the active ferric enzyme leading to its inactivation. GENERAL SIGNIFICANCE: SA can inhibit lipoxygenase-catalyzed lipid peroxidation at therapeutic concentrations, suggesting its possible inhibitory activity against enzymatic lipid peroxidation in the clinical setting.

Chromium and human low-density lipoprotein oxidation.

Chromium is a catalytic metal able to foster oxidant damage, albeit its capacity to induce human LDL oxidation is to date unkown. Thus, we have investigated whether trivalent and hexavalent chromium, namely Cr(III) and Cr(VI), can induce human LDL oxidation. Cr(III) as CrCl3 is incapable of inducing LDL oxidation at pH 7.4 or 4.5. However, Cr(III), specifically at physiological pH of 7.4 and in the presence of phosphates, causes an absorbance increase at 234 resembling a spectrophotometric kinetics of LDL oxidation with a lag- and propagation-like phase. In this regard, it is conceivable that peculiar Cr(III) forms such as Cr(III) hydroxide and, especially, Cr(III) polynuclear hydroxocomplexes formed at pH 7.4 interact with phosphates generating species with an intrinsic absorbance at 234 nm, which increases over time resembling a spectrophotometric kinetics of LDL oxidation. Cr(VI), as K2Cr2O7, can instead induce substantial human LDL oxidation at acidic pH such as 4.5, which is typical of the intracellular lysosomal compartment. LDL oxidation is related to binding of Cr(VI) to LDL particles with quenching of the LDL tryptophan fluorescence, and it is inhibited by the metal chelators EDTA and deferoxamine, as well as by the chain-breaking antioxidants butylated hydroxytoluene and probucol. Moreover, Cr(VI)-induced LDL oxidation is inhibited by mannitol conceivably by binding Cr(V) formed from LDL-dependent Cr(VI) reduction and not by scavenging hydroxyl radicals (OH); indeed, the OH scavengers sodium formate and ethanol are ineffective against Cr(VI)-induced LDL oxidation. Notably, heightened LDL lipid hydroperoxide levels and decreased LDL tryptophan fluorescence occur in Cr plating workers, indicating Cr-induced human LDL oxidation in vivo. The biochemical, pathophysiological and clinical implications of these novel findings on chromium and human LDL oxidation are discussed.

Evidence for oxidative and not reductive stress in the aged rabbit heart.

Reductive stress, which is due to a paradoxical excess of antioxidants such as reduced glutathione (GSH) and GSH-related enzymes associated with decreased oxidant levels, has emerged as a pathogenetic mechanism of myocardial damage in pathological conditions such as protein aggregation cardiomyopathy. Notably, in the aged heart a cardiomyopathy-like pathology occurs leading to myocardial dysfunction. Whether reductive stress, or instead its counterpart oxidative stress, is operative in the aged mammalian heart needs to be elucidated also for the different therapeutic implications of such redox stress conditions. In the present investigation, we assessed GSH and the specific enzymatic activities of γ-glutamylcysteine synthetase (γ-GCS), glutathione reductase (GSSG-Red) and selenium-dependent glutathione peroxidase (GSH-Px) as endogenous antioxidants, together with oxidized glutathione (GSSG) and the glutathione redox ratio (GSH/GSSG), in the aerobically perfused hearts of aged rabbits (about 4.5 years old) and young adult control rabbits (3-4 months old). We also assessed in the aged and control hearts H2O2 and catalytically active low molecular weight iron (LMWI) as oxidant forces, as well as fluorescent damage products of lipid peroxidation (FDPL) and protein carbonyls (PC) as biomarkers of lipid and protein oxidation. Moreover, the effects of 4.5 mM N-acetylcysteine (NAC) as reducing thiol antioxidant were studied on hemodynamic parameters and lipid peroxidation in the perfused hearts of the aged and control rabbits. The levels of GSH and of the GSH/GSSG ratio were lower, and those of GSSG higher, in the aged than in the control hearts. The aged hearts were also characterized by decreased activities of the antioxidant enzymes γ-GCS, GSSG-Red and GSH-Px, as well as by heightened levels of H2O2, LMWI, FDPL and PC, highlighting the occurrence of aging-dependent oxidative stress. Associated with such biochemical alterations, hemodynamic dysfunction occurred in the aged rabbit hearts, as evidenced by lowered developed pressure (DP) and enhanced end-diastolic pressure (EDP) with decreased coronary flow (CF). Remarkably, NAC administration significantly improved DP and EDP, and lowered lipid peroxidation, electively in the aged hearts. In conclusion, oxidative and not reductive stress is operative in the aged rabbit heart, whose hemodynamic dysfunction is improved by NAC together with reduction in myocardial lipid peroxidation.

A randomized, controlled study comparing a lidocaine patch, a placebo patch, and anesthetic injection for treatment of trigger points in patients with myofascial pain syndrome: evaluation of pain and somatic pain thresholds.

BACKGROUND: Myofascial pain syndrome (MPS), a regional pain condition caused by trigger points in muscle or muscle fascia, produces muscle pain, tenderness, and disability. The gold standard of treatment for MPS-infiltration of trigger points with anesthetic-may provoke discomfort to the patients and require medical intervention. OBJECTIVES: This study was designed to compare the effects of a topical lidocaine patch, a placebo patch, and injection of anesthetic (infiltration) for the symptoms of MPS in terms of pain, disability, and local tissue hypersensitivity, and to determine the acceptability of the lidocaine patch to the patients. METHODS: Patients were randomly allocated to receive 1 of 3 treatments: a lidocaine patch applied to the trigger point for 4 days (replacement every 12 hours; total daily dose, 350 mg), a placebo patch applied to the trigger point for 4 days (replacement every 12 hours), or infiltration of the trigger point with two 1-mL injections of 0.5% bupivacaine hydrochloride given 2 days apart. Treatment with the patches was double-blinded, whereas treatment with infiltration was single-blinded. The number of pain attacks, pain intensity at rest and on movement, and pain-related interference with daily activity, work activity, mood, and quality of life were recorded before, during, and after treatment using a visual analog scale (VAS). Pressure and electrical pain thresholds of the skin, subcutis, and muscle in the trigger point, target area, and a pain-free area were evaluated before starting therapy (day 1) and on days 5 and 9. A VAS was used to measure discomfort from therapy, and a diary was given to each patient to record requests for additional treatment (if needed) and adverse effects. RESULTS: Sixty white patients (46 women and 14 men) 19 to 76 years of age were studied. Mean (SD) age was 46.88 (15.37) years, and mean (SD) weight was 69.58 (13.94) kg. Twenty patients were assigned to each treatment group. Subjective symptoms did not change with placebo, but decreased significantly with the lidocaine patch and infiltration (both, P < 0.001) relative to baseline. Pain thresholds did not vary with the placebo patch, but increased significantly with the lidocaine patch and infiltration (all, P < 0.001); effects at muscle trigger points and target areas were greater with infiltration. Discomfort from therapy was greater with infiltration than with the lidocaine patch. Only patients in the placebo group requested additional treatment (P < 0.001). No adverse events occurred in any group. CONCLUSION: Lidocaine patches were effective in, and highly acceptable to, these patients with MPS and high tissue hypersensitivity.

Impaired enzymatic reactive aldehyde-detoxifying capacity and glutathione peroxidase activity in the aged human arterial tissue.

It is not known whether aging alters the enzymatic reactive aldehyde- and lipid hydroperoxide-detoxifying capacity of the human arterial tissue favoring vascular oxidative stress. To address this issue, we studied the specific enzymatic activities of class 1, 2 and 3 aldehyde dehydrogenase (ALDH1, ALDH2 and ALDH3), glutathione S­transferase (isozyme A4-4, GSTA4-4) and aldose reductase (AR), namely the major reactive aldehyde-scavenging enzymes, together with the activity of the lipid hydroperoxide-removing enzyme glutathione peroxidase (GSH-Px), in superior thyroid arteries (STA) specimens obtained in the thyroid surgery setting in aged subjects (age 72.3 ±â€¯3.6 years) and young adult controls (age 31.9 ±â€¯3.5 years). Vascular lipid peroxidation was also studied by assessing in STA fluorescent damage products of lipid peroxidation (FDPL), which reflect oxidant-induced 4­hydroxynonenal and lipid hydroperoxide formation. Remarkably, the activities of ALDH1, ALDH2, ALDH3, GSTA4-4, AR and GSH-Px were significantly lower, and FDPL levels higher, in the arterial tissue of the aged subjects than in that of the young adult controls. Moreover, the enzymatic activities were inversely and significantly correlated with the levels of FDPL in the arterial tissue of both the aged and young subjects, highlighting their vascular antioxidant/antilipoperoxidative role in vivo. Thus, aging impairs the enzymatic reactive aldehyde-detoxifying capacity and GSH-Px activity of the human arterial tissue eventually favoring vascular oxidative stress.

Regression of echocardiographic left ventricular hypertrophy after 2 years of therapy reduces cardiovascular risk in patients with essential hypertension.

BACKGROUND: There is still ambiguity about the prognostic relevance of regression of left ventricular hypertrophy (LVH) (as revealed by echocardiography) in a large population of subjects with hypertension, with and without evidence of LVH in their electrocardiograms (ECGs). This holds true even after adjusting for various confounders including in treatment ambulatory blood pressure (BP). The most suitable time point for a follow-up echocardiography also remains a matter for debate. In this study, we investigated the prognostic relevance of regression of LVH after 2 years of therapy, in a large population of subjects with hypertension, and possessing the aforesaid characteristics. METHODS: The occurrence of adverse cardiovascular events was evaluated in 387 patients with LVH shown by echocardiography at baseline, and these patients were studied again after 2 years of therapy. At the second examination, 245 subjects showed regression of LVH, whereas 142 did not. RESULTS: During the time period before the subsequent follow up (6.2 +/- 3 years, range 1.9-12.9 years), 59 first adverse events (26 cardiac and 33 cerebrovascular) had occurred among these subjects. The event rates per 100 patient-years in patients with and without LVH regression were 1.06 and 4.4, respectively. After adjusting for several covariates at the 2-year visit, including in treatment ambulatory BP, Cox regression analysis showed that cardiovascular risk was significantly lower in patients with LVH regression than in those without (RR 0.36, 95% CI 0.19-0.68, P = 0.002). When left ventricular (LV) mass index reduction was analyzed instead of LVH status, it was found to be significantly associated with reduced risk (RR 0.62 per 1-s.d. decrease, 95% CI 0.44-0.88, P = 0.01). CONCLUSIONS: Regression of LVH, as revealed by echocardiography after 2 years of therapy, is associated with reduced cardiovascular risk in patients with hypertension, whether or not LVH was revealed in their ECGs. This holds true even after adjusting for various confounders including in treatment ambulatory BP.

Prognostic relevance of masked hypertension in subjects with prehypertension.

BACKGROUND: The prognostic impact of masked hypertension is not yet completely clear. The aim of this study was to evaluate the prognostic relevance of masked hypertension in subjects with prehypertension. METHODS: The occurrence of fatal and nonfatal cardiovascular events was evaluated in 591 subjects with prehypertension defined as clinic blood pressure (BP) in the range of 120-139 mm Hg for systolic BP and 80-89 mm Hg for diastolic BP. Among them, 471 were classified as having true prehypertension (clinic BP <140/90 mm Hg and daytime BP <135/85 mm Hg) and 120 as having masked hypertension (clinic BP <140/90 mm Hg and daytime BP > or =135 or 85 mm Hg). RESULTS: During the follow-up (6.6 +/- 4.3 years, range 0.5-15.5 years), 29 cardiovascular events occurred. In subjects with true prehypertension and masked hypertension the event-rates per 100 patient-years were 0.57 and 1.51, respectively. Event-free survival was significantly different between the groups (P < 0.005). After adjustment for other covariates, including clinic BP (forced into the model), Cox regression analysis showed that cardiovascular risk was significantly higher in masked hypertension than in true prehypertension (masked vs. true prehypertension, relative risk 2.65, 95% confidence interval 1.18-5.98, P = 0.018). CONCLUSIONS: Among subjects with prehypertension, those with masked hypertension are at higher cardiovascular risk than those with true prehypertension. Out-of-office BP should be known in individuals with prehypertension, preferably by ambulatory BP monitoring or alternatively by home BP measurement, to obtain a better prognostic stratification.

Risk of atrial fibrillation in dipper and nondipper sustained hypertensive patients.

OBJECTIVE: The risk of atrial fibrillation (AF) in sustained hypertensive patients with different circadian blood pressure (BP) patterns is unknown. We investigated the risk of new onset AF in dipper and nondipper sustained hypertensive patients. METHODS: The occurrence of AF was evaluated in 1141 patients aged > or = 40 years with sustained hypertension (clinic BP > or = 140 and/or 90 mmHg and daytime BP > or = 135 and/or 85 mmHg). Among these patients, 783 had night-time systolic BP fall > or = 10% (dippers) and 358 had night-time BP decline <10% (nondippers). RESULTS: During the follow-up (6.1+/-3.2, range 0.5-12.9 years), AF occurred in 43 patients. The AF rate per 100 patient-years in dippers and nondippers was 0.38 and 1.13, respectively. AF free survival was significantly different between the groups (P=0.0002). After adjustment for other covariates, including left atrial enlargement or left ventricular hypertrophy (these variables were analyzed in separate models because of a strong association between them) and 24-h BP, Cox regression analysis showed that the risk of AF was significantly higher in nondippers than in dippers [nondippers vs. dippers, relative risk (RR) 2.02, 95% confidence interval (CI) 1.08-3.79, P=0.028 in the model including left atrial enlargement, and RR 1.97, 95% CI: 1.05-3.69, P=0.035 in the model including left ventricular hypertrophy]. CONCLUSION: This study shows that nondipper sustained hypertensive patients have a two-fold greater risk of developing AF than dipper ones. This aspect could partly contribute to explain the higher cardiovascular risk previously observed in nondipper hypertensive patients.

Impaired glutathione-related antioxidant defenses in the arterial tissue of diabetic patients.

We studied the specific enzymatic activities of selenium-dependent (GSH-Px) and -independent (GST-Px) glutathione peroxidase, glutathione reductase (GSSG-Red), and glutathione S-transferase (GST) in internal mammary arteries (IMArt) specimens obtained during coronary artery bypass surgery in 18 patients with type 2 diabetes mellitus as compared to 18 non-diabetic controls; vascular lipid peroxidation, namely fluorescent damage products of lipid peroxidation (FDPL) as 4-hydroxynonenal-related oxidative stress indicators, was also studied. Moreover, in other 16 diabetic patients and 16 controls, total glutathione (TGlut) was determined in IMArt specimens specifically homogenized in sulfosalycilic acid to prevent vascular GSH depletion. The activities of GSH-Px, GSSG-Red, and GST were significantly lower, and FDPL levels higher, in the arterial tissue of diabetic patients than in that of controls; GST-Px was undetectable. Such enzymatic activities were inversely correlated with vascular lipid peroxidation, highlighting their antioxidant role in the arterial tissue, as were HbA1c and FDPL levels with the enzymatic activities, suggesting that glycation, oxidant species and lipoperoxidation aldehydes may be involved in glutathione-related enzyme inactivation. Further, in the diabetic patients HbA1c was correlated directly with lipid peroxidation but inversely with TGlut of the arterial tissue. In the patients considered for vascular enzymatic activities and FDPL assay, 3/4-vessel coronary artery disease (CAD) as expression of atherosclerosis severity was present in 9 diabetic patients and in 3 controls. Notably, vascular glutathione-related enzymatic activities were significantly lower, and FDPL levels higher, in the 9 diabetic patients with 3/4-vessel CAD than in the 9 without, as well as in the total of 12 patients with 3/4-vessel CAD than in the total of 24 patients without. Moreover, vascular TGlut content was significantly lower in the diabetic than in the control patients. Three/4-vessel CAD was present in 6 diabetic patients and in 2 controls considered for determination of vascular Tglut content, which was significantly lower in the diabetic patients with 3/4-vessel CAD than in those without, as well in the total of 8 patients with 3/4-vessel CAD than in the total of 24 patients without. Thus, weakened glutathione-related antioxidant capacity and oxidative stress of the arterial tissue are associated with the severity of atherosclerosis. In conclusion, impaired glutathione-related antioxidant defenses of the arterial tissue occur in diabetic patients, eventually favoring vascular oxidative stress and the severity of atherosclerosis.