Flavanol-rich chocolate and lycopene-rich tomato extract have attracted interest as potential alternative treatment options for hypertension, a known risk factor for cardiovascular morbidity and mortality. Treatment of prehypertension (SBP 120–139/DBP 80–89 mmHg) may forestall progression to hypertension. However, there has been only limited research into non-pharmacological treatment options for prehypertension. We investigated the effect of dark chocolate or tomato extract on blood pressure, and their acceptability as an ongoing treatment option in a prehypertensive population.Our trial consisted of two phases: a randomised controlled three-group-parallel trial over 12 weeks (phase 1) followed by a crossover of the two active treatment arms over an additional 12-week period (phase 2). Group 1 received a 50 g daily dose of dark chocolate with 70% cocoa containing 750 mg polyphenols, group 2 were allocated one tomato extract capsule containing 15 mg lycopene per day, and group 3 received one placebo capsule daily over 8 weeks followed by a 4-week washout period. In phase 2 the active treatment groups were crossed over to receive the alternative treatment. Median blood pressure, weight, and abdominal circumference were measured 4-weekly, and other characteristics including physical activity, general health, energy, mood, and acceptability of treatment were assessed by questionnaire at 0, 8 and 20 weeks. We analysed changes over time using a linear mixed model, and one time point differences using Kruskal-Wallis, Fisher's-Exact, or t-tests.Thirty-six prehypertensive healthy adult volunteers completed the 6-month trial. Blood pressure changes over time within groups and between groups were not significant and independent of treatment. Weight and other characteristics did not change significantly during the trial. However, a marked difference in acceptability between the two treatment forms (chocolate or capsule) was revealed (p < 0.0001). Half of the participants allocated to the chocolate treatment found it hard to eat 50 g of dark chocolate every day and 20% considered it an unacceptable long-term treatment option, whereas all participants found it easy and acceptable to take a capsule each day for blood pressure.Our study did not find a blood pressure lowering effect of dark chocolate or tomato extract in a prehypertensive population. Practicability of chocolate as a long-term treatment option may be limited. Identifier: ACTRN12609000047291 Prehypertension (systolic blood pressure (SBP) 120–139 mm Hg, diastolic blood pressure (DBP) 80–89 mm Hg) is considered a precursor of hypertension and has been associated with an increased risk of up to 3.5 times in cardiovascular morbidity and mortality later in life . TreatmeLifestyle modifications including dietary approaches have been recommended for the management of prehypertension ,7. BecauPolyphenols, in particular flavanols, in chocolate have been associated with the formation of endothelial nitric oxide leading to vasodilation and lowering of blood pressure -12, wherChocolate has recently been a popular target in studies investigating dietary effects on blood pressure -27. HoweThe trial was conducted between June and December 2007 in Adelaide, South Australia. Recruitment started in February 2007 by advertising in local newspapers, the University websites, flyers around University noticeboards, a public hospital's health promotion unit, and items on local radio and evening television news programs. We received about 200 enquiries regarding the study, with 87 individuals filling in a screening questionnaire assessing eligibility criteria including recent blood pressure readings and availability for the 6-month study. Inclusion criteria were: 1. Two of either four systolic or diastolic blood pressure readings in the prehypertensive range (SBP 120–139 or DBP 80–89 mm Hg), as measured by our research nurse; 2. Not taking any antihypertensive prescription medication. Exclusion criteria were: 1. Diabetes mellitus; 2. Allergy to or intolerance of tomato or chocolate products. Forty-eight individuals did not meet inclusion criteria (n = 31) or decided not to participate (n = 17) including some who did not want to take the chance of not being randomised to the chocolate group. The remaining 39 healthy volunteers, aged between 22 and 73 years, provided written consent and were allocated to one of three treatment arms , followed by a crossover of the two active treatment arms (phase 2). The duration of each study arm was 12 weeks, consisting of an 8-week intervention period followed by a 4-week washout period. Participants were randomly allocated to the chocolate (group 1), tomato extract (group 2), or placebo control (group 3) group by permuted block randomisation using the SAS 9.1 software package . Partici, followe® Tomato Lycopene Complex capsules, LycoRed Ltd, Beer Sheva, Israel, equivalent to four to five medium size tomatoes) [Over an 8-week period, group 1 participants were allocated a 50 g daily dose  of commercially available dark chocolate with 70% cocoa, containing 750 mg of polyphenols ; group omatoes) ; and groTo conceal allocation from investigators, trained staff not involved in trial design and analysis handed out intervention packs to participants. Blinding of participants to chocolate was impractical, however blinding of participants in the capsule groups was achieved by identical packaging of active tomato extract and placebo capsules.Blood pressure, weight and abdominal circumference were measured every 4 weeks by a trained research nurse, and questionnaires assessing physical activity, smoking status, alcohol intake, general health, mood and energy levels, habitual chocolate and tomato product intake, ease and acceptability of treatment, were administered at baseline and after each intervention period . The questionnaire consisted of 5-point Likert-scales, and closed and open ended questions, and can be obtained from the corresponding author.Habitual lycopene intake at baseline was estimated using summary values of lycopene content in tomato products based on five databases by Porrini M and Riso P . ParticiBlood pressure was assessed by a trained research nurse using a digital calibrated sphygmomanometer with appropriately sized cuffs . Participants rested for 5 minutes before four blood pressure readings were taken in intervals of 3 minutes in alternate upper arms in a seated position. Median SBP and DBP at one time point were used for analysis to minimise the effect of blood pressure variability.On a population level a reduction of 4 to 5 mm Hg in SBP and 2 to 3 mm Hg in DBP has been estimated to reduce the risk of cardiovascular morbidity and mortality by up to 20 per cent . We calcAs random number generation was based on a sample size of 60, which we were unable to match in practice, numbers allocated to each of the three groups were slightly disproportionate. Smaller group sizes between n = 10 and 15 in study 1  reduced the power to 0.5 for detecting a difference of 4.5 mm SBP and 2.5 mm DBP, while reductions of 5–6 mm SBP and 3–4 mm DBP would retain the power at 0.8. However, larger group sizes in the crossover analysis  assessing acceptability of the two treatment forms led to a reasonable effect size > 0.9.Analyses were performed using SPSS version 15.0 and SAS version 9.1 ,34. BetwWe collected baseline characteristics of all 39 randomised prehypertensive individuals. However, three participants withdrew before the second time point for data collection scheduled at week 4. All comparisons were subsequently based on the thirty-six remaining participants. At baseline, groups did not differ in anthropometric measures, habitual chocolate or tomato product intake, physical activity, alcohol intake, general health, energy and mood levels. None of the participants smoked. A significantly higher proportion of participants in the chocolate and tomato extract groups took daily fish oil and/or garlic supplements than in the control group Table . As therAs mentioned above three individuals withdrew after baseline assessment but before the 4-week assessment. In addition, one individual withdrew after crossover to study 2 (after 12 wks but before the 16 wk assessment). Two individuals withdrew when allocated to a chocolate group , both indicating that they found the dark chocolate unpalatable , abdominal circumference, physical activity, general health, energy and mood levels were assessed at three time points at 0, 8 and 20 weeks . No significant changes over time within the three groups were observed Table . DiffereAt the end of the intervention periods of phases 1 and 2 we assessed acceptability and willingness to continue with treatment long-term with daily consumption of chocolate or a capsule. The two chocolate groups of phase 1 and crossover phase 2 were analysed together, as well as all capsule groups (tomato extract and placebo groups of phase 1 and tomato extract group after crossover in phase 2). Differences in acceptability between the two treatment forms were highly significant : half of the participants allocated to the chocolate treatment found it hard to eat 50 g of dark chocolate every day and 20% considered it an unacceptable long-term treatment option, whereas all participants found it easy and acceptable to take a capsule each day for blood pressure Table . UnaccepOur trial did not demonstrate an effect of either dark chocolate or tomato extract on blood pressure in prehypertensive individuals over 8 week intervention periods. However, our trial provided clear insights into acceptability and practicability regarding long-term treatment modalities for blood pressure. While half of the participants expressed difficulty in daily consumption of 50 g dark chocolate and 20% did not consider this a long-term treatment option, all trial participants found it acceptable to take a non-prescription capsule a day for their blood pressure.Dosages of active components in our trial treatment arms were comparable to earlier controlled trials investigating the effect on blood pressure of either dark chocolate (~750 mg polyphenols daily) -23,26,27It is likely that blood pressure level at the start of treatment  is associated with a treatment's effectiveness. Taubert et al.  observedOther factors, such as duration of intervention, frequency of blood pressure assessments, and inclusion of washout periods may also influence findings. While most trials investigating the effect of chocolate on blood pressure were of short duration , consumption of a diet rich in fruits and vegetables and low in saturated fat, and engagement in daily moderate physical activity  [It is debateable whether an initial run-in period should have been included. While the majority of similar trials to date on the effect of chocolate on blood pressure chose a one-week cocoa/flavanol-free run-in period ,19-24,26Despite some limitations, our trial, for the first time, compared the practicability of using two different treatment modalities (chocolate or capsule) for people with blood pressures in the prehypertensive range. Acceptability and projected long-term compliance of chocolate as a treatment option for blood pressure might be limited, suggesting that chocolate may be a less practical treatment option than capsules or pills. This finding was somewhat unexpected, as recruitment was mainly driven by the interest of the public in a study using chocolate.While our trial was not designed to assess the effect of chocolate or tomato extract on other cardiovascular factors such as lipid levels or endothelial function, other studies in prehypertensive and normotensive populations have associated chocolate consumption with improved coronary circulation , improveOur study did not find a blood pressure reducing effect of 50 g dark chocolate daily or 15 mg lycopene containing tomato extract daily in a small prehypertensive population over a period of 8 weeks. While we cannot rule out cardiovascular health benefits of these dietary treatment options, our study suggests that chocolate may not be an acceptable long-term treatment option for some individuals.Abdom. circ.: abdominal circumference; BP: blood pressure; BMI: body mass index; CI: confidence interval; d: day; DBP: diastolic blood pressure; g: gram; mg: milligram; min: minutes; mm Hg: millimetre mercury; n: number; RCT: randomised controlled trial; RR: relative risk; SBP: systolic blood pressure; SD: standard deviation; SE: standard error; LDL: low density lipoprotein that transports cholesterol and triglycerides; Wk: week.The study was conceived and initiated by the authors. Haigh's Chocolates, Adelaide, LycoRed Ltd, Beer Sheva, Israel, and JA Davey Pty Ltd, Melbourne donated their products at the authors' request. They did not provide funding and were not involved in study design, data collection, analysis or preparation of the manuscript. The authors declare that they have no competing interests.All authors conceptualised the study and obtained funding. KR managed data acquisition, analysis and interpretation in discussion with the statistician NB and authors ORF and NPS. KR prepared the manuscript with contributions from co:authors. All authors approved the final version.The pre-publication history for this paper can be accessed here:


It is well know that arterial stiffness, oxidative stress and inflammation are features of chronic kidney disease. The arterial changes have a multitude of potential interconnected causes including endothelial dysfunction, oxidative stress, inflammation, atherosclerosis and vascular calcification. There is evidence that arterial stiffness becomes progressively worse as CKD progresses. The contribution of the biochemical changes of uremic toxicity to arterial stiffness is less clear. The aim of this study is to elucidate the vascular changes in acute kidney injury. We hypothesise that arterial stiffness will be increased during acute kidney injury and this will return to normal after kidney function recovers.One hundred and forty four patients with acute kidney injury defined as an acute increase in serum creatinine to > 133 μmol/l or urea > 14.3 mmol/l or urine output < 410 ml/day will be recruited. Baseline measures of aortic pulse wave velocity, augmentation index, and brachial and central blood pressure will be recorded along with blood measures for oxidative stress and inflammation. Repeat measures will be taken at six and 12 months after the onset of the acute kidney injury.The role and contribution of the biochemical changes to arterial stiffness in the acute phase of kidney disease is not known. This study will primarily assess the time course changes in pulse wave velocity from the onset of acute kidney injury and after recovery. In addition it will assess augmentation index, central blood pressure and oxidative stress and inflammation. This may shed light on the contribution of biochemical kidney toxins on arterial stiffness in both acute kidney injury and chronic kidney disease.ACTRN 12609000285257 Vascular disease, characterised by premature atherosclerosis and large artery stiffness, is a feature of advanced chronic kidney disease (CKD) ,2. CentrThis is a longitudinal observational clinical study. Patients from the Royal Brisbane and Women's Hospital and the Launceston General Hospital will be recruited into this study. These hospitals service populations of approximately 1.2 million and 250,000 respectively.The Tasmanian Statewide Scientific and Ethics Committees and the Human Research and Ethics Committee of the Royal Brisbane and Women's Hospital have approved this study.One hundred and forty four patients with acute kidney injury and 45 matched controls.Acute kidney injury participants will be recruited from two settings at each hospital.1. The Intensive care unit: The distinguishing features of intensive care research are the requirements to recruit and obtain informed consent rapidly when it may be difficult to communicate with the patient. As the patient requirements for this study are minimal and non-invasive it is not expected that these requirements will be problematic. All attempts will be made to gain informed written consent directly from the patient. The patients will be approached by one of the investigators who will explain the study, provide them with the information sheet and request they consider entering the study and therefore sign the consent form. If patients are unable to provide written informed consent themselves (e.g. they are unconscious or too unwell) the next of kin will be approached by one of the investigators who will explain the study, provide them with the information sheet and request that they consider the patient enters the study and sign the consent form on their behalf.2. The Renal medicine service: This will include the renal inpatients and referrals from General Internal Medicine, Surgery and other departments in the Royal Brisbane and Women's Hospital. For these patients the recruitment will be based on the standard informed consent process as described above for the conscious intensive care unit patient.Two yearsInclusion criteria: Male and female patients > 18 years of age presenting to the Royal Brisbane and Women's Hospital and the Launceston General Hospital with acute kidney injury but not having started dialysis or continuous venovenous hemofiltration will be eligible for recruitment  due to pre-existing malignancy or other disease will be excluded. Finally, patients that are pregnant or have a planned pregnancy will also be excluded.To determine the effects of acute kidney injury on arterial stiffnessPatients with acute kidney injury will have increased arterial stiffness compared to matched controls.Patients who recover kidney function following acute kidney injury will have a concomitant reduction in arterial stiffness.Carotid to femoral PWV will be derived by electrocardiography-gated sequential applanation tonometry  using the foot-to-foot method  [To determine the associations between oxidative stress and inflammation with changes in arterial stiffness and central blood pressure in patients with acute kidney injury.There will be significant relationships between oxidative stress and inflammation and changes in arterial stiffness and central blood pressure in patients with acute kidney injury.The outcome measure for oxidative stress will be plasma isoprostanes measured using gas chromatography mass spectrometry . In addiThe outcome measure for inflammation will be pentraxin 3 measured using an ELISA assay . In addiThe SphygmoCor device will be used to determine central blood pressure and AIx as additional markers of arterial stiffness. A central (ascending aortic) pressure waveform will be derived by radial tonometry as previously described . This meRoutine measures including full blood count, electrolytes, coagulation profile, liver function test and lipid profile will be carried out at the Hospitals' Pathology Laboratories. Other data collected at the time will include demographic details, medical history and medication profile.Upon collection, blood samples will be placed on ice and then centrifuged (500 g) at 4°C for five minutes. One ml aliquots of plasma will be stored in eppendorf tubes immediately at -80°C for future biochemical analyses of oxidative stress and inflammation.After patients provide informed consent they will undergo baseline testing to measure resting peripheral and central blood pressure, arterial stiffness and have blood taken for standard biochemistry and measures of oxidative stress and inflammation. Control data will be obtained from a database of one of the authors that contains arterial stiffness measures on healthy individuals with normal kidney function. Subjects from this database will be selected to match with patients included in the analyses.All measures taken at baseline will be repeated at six and twelve months after the onset of the acute kidney injury.2) or, where data is available, a return to the level of kidney function within 5% assessed by eGFR present within three months prior to the acute kidney injury.This will be defined as return of kidney function to normal (eGFR > 60 ml/min/1.73 mIf requested, subjects will be withdrawn from the study without prejudice, as documented and explained at the time of consenting.Sample sizes of 144 acute kidney injury patients and 45 matched controls have been determined as follows. The primary outcome measure is aortic PWV. To our knowledge, there is no published aortic PWV data available for acute kidney injury patients. We therefore used haemodialysis patient aortic PWV data from one of our other investigations, the PEDAL study. We founGeneral linear modelling will be used to test the hypotheses. Bi-variate and multivariate techniques will be used to assess the secondary aims of the relative independent effects of variables on the outcomes measures. Significance will be assumed if P < 0.05.The objective of this study is to assess whether the biochemical changes seen in acute kidney injury can affect arterial stiffness. Although arterial stiffness is a feature of vascular dysfunction in chronic kidney disease it is not clear how much, if at all the biochemical abnormalities seen in the circulation account for such changes. In addition, the study will assess augmentation index, central blood pressure and oxidative stress and inflammation. Data from this study may lead to a better understanding of the vascular dysfunction seen in kidney disease.The authors declare that they have no competing interests.RGF and JSC designed the study and wrote the protocol. JG provided advice and input and will be involved with the intensive care component of the study. VD and HH provided advice and input and will be involved with the renal medicine department component of the study. J-S G will perform arterial stiffness measures and contributed to manuscript review. JS provide advice and input into the arterial stiffness measures and reviewed the manuscript. All authors read and approved the final manuscript.The pre-publication history for this paper can be accessed here:http://www.biomedcentral.com/1471-2369/10/15/prepub


Differences could exist in the likelihood of asthma attacks in patients treated with inhaled corticosteroid (ICS), long-acting beta-agonist (LABA), and montelukast (MON) (ICS/LABA/MON) and patients treated with an inhaled corticosteroid (ICS) and montelukast (MON) (ICS/MON).This was a post-hoc analysis of a pretest-posttest retrospective cohort study. Patients with mild persistent asthma and allergic rhinitis, who were taking an ICS either alone or in combination with a LABA, started concomitant MON treatment as part of their routine care. Rates of asthma- and allergic rhinitis-related medical resource use in the 12-months after the initial (index) MON prescription were compared in the ICS/MON and ICS/LABA/MON groups. An asthma attack was defined as an asthma-related hospitalization, ER visit, or use of an oral corticosteroid.Of the total of 344 patients, 181 (53%) received ICS/MON and 163 (47%) received ICS/LABA/MON in the post-index period for means of 10.5 and 11.4 months, respectively, (P < 0.05). Short-acting beta-agonists were used by 74.6% in the ICS/MON and 71.8% in the ICS/LABA/MON groups (P > 0.05). An asthma attack occurred in 4.4% of the ICS/MON group and 6.8% of the ICS/LABA/MON group (P > 0.05). The adjusted odds of an asthma attack in the post-index period in the ICS/LABA/MON group relative to the ICS/MON group was 1.24, 95% confidence interval 0.35–4.44.In this observational study of combination drug treatment of mild persistent asthma and allergic rhinitis, no difference was observed between LABA/ICS/MON combination therapy and the ICS/MON combination without LABA use, for the rate of asthma attacks over one year. The precise roles of drug combinations in the management of asthma and allergic rhinitis remain uncertain . The recAlthough current asthma treatment guidelines recommend ICS + LABA as the first line therapy for patients with severe asthma, there are a lot of controversies ,7 over tThe PRAACTICAL (Patient-level Review of Asthma and Allergy Care Therapy Including Current Asthma treatment and Leukotrienes) study was a two-year retrospective pre-posttest study designed to assess the role of MON when added to an ICS in the treatment of patients with persistent asthma and allergic rhinitis . The addIn PRAACTICAL, patient groups diagnosed with mild and moderate asthma differed significantly in certain characteristics: mean age (31.6 versus 34.0 years); proportion with intermittent versus persistent allergic rhinitis (58.6% versus 41.1%); and the proportion being treated with LABAs on the index date (48.0% versus 84.2%). We analyzed the subgroup of patients having a physician's diagnosed with mild persistent asthma and concomitant allergic rhinitis. The objective was to determine differences in the likelihood of asthma attacks in patients treated with inhaled corticosteroid (ICS), long-acting beta-agonist (LABA), and montelukast (MON) (ICS/LABA/MON) and patients treated with an inhaled corticosteroid (ICS) and montelukast (MON) (ICS/MON).This was a post-hoc analysis of a cohort study of adults 15–55 years of age, with mild persistent asthma and concomitant allergic rhinitis, in three European countries  from January 1, 1998 to December 31, 2003. Data were extracted from medical records with the collaboration of patients' health care providers. Patients already being treated with ICSs were included in the study if they began co-therapy with MON as part of their routine care during an index period between January 1, 1999 and December 31, 2002. Pre-index and post-index periods of 12 months were defined prior to and following the initial, index prescription for MON. Patient characteristics in the 12-month pre-index period were recorded and study outcomes were determined for the 12-month post-index period. Further details of the study were described elsewhere . Here, wPatients in this analysis: had physician-diagnosed mild persistent asthma on the index date; had physician-diagnosed intermittent or persistent allergic rhinitis ; had prescription(s) for an ICS for at least 3 months during the 12-month post-index period, with or without a concomitant prescription(s) for a LABA for at least 3 months in the post-index period; started MON therapy as part of their routine care; and completed 12 months of MON therapy in the post-index period. The severities of asthma and seasonal allergic rhinitis on the index date were determined by physician diagnosis based on the GINA and ARIA guidelines that were provided to ensure that all patients had a diagnosis of mild persistent asthma on the index date. This is an ad hoc retrospective analysis of data from a cohort study, in which patients were asked to provide informed consent that authorized investigators to review their charts when the original cohort study was conducted.The study outcome variables were the numbers of prescriptions for asthma-and allergic rhinitis-related medications  and numbers of asthma-related hospitalizations and ER visits in the post-index period. A composite endpoint, an 'asthma attack', was defined as either use of an oral corticosteroid for asthma, or an asthma-related ER visit or hospitalization.Two parallel groups, ICS/LABA/MON and ICS/MON, were defined on the basis of their treatment in the post-index period. Uni-variable analyses were used to compare the two treatment groups. T-test was used for continuous data and the chi-square test for discrete data in the comparisons of patient characteristics in the pre-index period and unadjusted study outcomes in the post-index period. Multiple logistic regression was used to compute the adjusted likelihood of asthma-and allergic rhinitis-related health care use in the post-index period in the ICS/LABA/MON group relative to ICS/MON group. Adjustments were made for age, years of diagnosed allergic rhinitis, severity of allergic rhinitis, number of allergist visits, days on ICS or ICS/LABA treatment during the pre-index period, and days of ICS or ICS/LABA treatment during the post-index period. The analysis considered patients treated for at least three months with an ICS or an ICS/LABA combination in the post-index period . A p value of 0.05 was considered to be statistically significant. All statistical analyses were performed using SAS v8.2 .A total of 344 patients were included: 181 treated with ICS/MON and 163 with ICS/LABA/MON. Most patients had mild intermittent (36.1%) or mild persistent (46.8%) allergic rhinitis (Table 2 test). The likelihood of an ER visit or of occurrence of an asthma attack was similar in the ICS/MON and ICS/LABA/MON groups .Rates of medical resource use for asthma and allergic rhinitis in the 12-month post-index period were not significantly different in the ICS/MON and ICS/LABA/MON groups Table . The likMeta-analyses of clinical trials indicate that the anti-asthmatic effects of both leukotriene modifiers and LABAs are additive to those of ICSs ,18. ClinThe results of this study should be interpreted in the light of the following. The absence of an incremental effect of LABAs was inferred from the comparison of two parallel treatment groups. This study compared differences in the asthma-related outcomes of various combinations of asthma therapy . Patients in the two groups differed in certain respects: patients in the ICS/MON/LABA group had slightly longer durations of ICS therapy in the pre-index and post-index periods, and appeared to have a lesser burden of allergic rhinitis . We adjusted for differences between the two patient groups by multivariate regression modeling. Patients in the ICS/MON/LABA group had a greater adjusted odds of using antibiotics in the post-index period, presumably reflecting inappropriate prescribing and a perceived need for additional therapies in these patients. Although small, the proportion of asthma attacks differed in the two groups with the ICS/LABA/MON group experiencing more as compared to ICS/MON group. Data from this study provided evidence of differences between the two therapy groups. Due to the rare occurrence of asthma attacks, studies with larger sample sizes are needed to confirm our findings.Based on this observational study, patients with comorbid asthma and allergic rhinitis receiving ICS/MON combination therapy, and those receiving ICS/MON/LABA combination therapy had similar rates of asthma attacks.Dr. Dal Negro and Dr. Borderias were consulting for Merck & Co., Inc. Drs. Zhang, Sazonov, Fan and Taylor are employees and stock holders of Merck & Co., Inc., a manufacturer of respiratory drugs.RWDN, LB, MG, SV and ST contributed to the study design and conceptualization. RWDN, LB acquired data. QZ conducted statistical analysis. TF, SV, QZ, and ST interpreted the study results. And QZ, TF and ST prepared the manuscript.A preliminary version of this material was presented at the American Thoracic Society's Annual International Conference, May 19-24, 2006, San Diego, CA, USAThe pre-publication history for this paper can be accessed here:


The aim of the study was to investigate inflammation during the birch pollen season in patients with rhinitis or asthma.Subjects with birch pollen asthma (n = 7) or rhinitis (n = 9) and controls (n = 5) were studied before and during pollen seasons. Eosinophils (Eos), eosinophil cationic protein (ECP) and human neutrophil lipocalin were analysed.Allergic asthmatics had a larger decline in FEV1 after inhaling hypertonic saline than patients with rhinitis (median) . The asthmatics had a lower sesonal PEFR than the rhinitis group. The seasonal increase in B-Eos was higher among patients with asthma (+0.17 × 109/L) and rhinitis (+0.27 × 109/L) than among controls . Allergic asthmatics and patients with rhinitis had a larger increase in sputum ECP (+2180 and +310 μg/L) than the controls . No significant differences in inflammatory parameters were found between the two groups of allergic patients.Patients with allergic asthma and rhinitis have the same degree of eosinophil inflammation. Despite this, only the asthmatic group experienced an impairment in lung function during the pollen season. For many years, it has been known that allergic rhinitis and bronchial asthma co-exist . The majet al. have demonstrated a reduction in airway function and an airway inflammatory response after local antigen challenge in atopic patients with or without asthma [et al. [1 in patients with perennial allergic rhinitis has been reported [This link between the upper and lower airways is also supported by experimental data from allergen challenges. Becky Kelly t asthma . Braunstt asthma ,10. Murit asthma ,12. Trea [et al.  demonstrreported .It is well established that the allergic inflammation in the nasal and bronchial mucosa is characterised by tissue eosinophilia. The allergic cascade and eosinophil migration is dependent on the expression of cytokines, chemokines and adhesion molecules. The eosinophils release their cytotoxic granule proteins as eosinophil cationic protein (ECP), myeloperoxidase, eosinophil protein X and eosinophil peroxides, causing airway damage and the remodelling of the airway ,16. The There are still many questions to be resolved. Previous studies have mainly been performed with high-dose allergen challenge, which is not consistent with natural allergen exposure, although a few studies have used very-low-dose allergen challenge . The aim1) out of season was more than 75% of predicted and FEV1/forced vital capacity (FVC) more than 70% in all patients. All the patients had doctors diagnosed seasonal allergic rhinitis or allergic asthma, diagnosed by a lung physician and allergologist at the allergy out-patient clinic. The patients with birch pollen induced asthma had a positive history of wheezing and dyspnea during pollen season, whereas patients whith allergic rhinitis all denied symptoms from the airways.Sixteen birch-pollen-allergic patients were selected for the study. All these patients were skin prick test positive to birch pollen. None of the patients had symptoms during the winter and/or were on regular treatment for rhinitis or asthma outside the birch pollen season. Inhaled steroids or nasal steroids were not allowed out of season nor during the birch pollen season and none of the patients was on any other regular medication during season. None of the patients had smoked for the past ten years. Forced expiratory volume in one second . Nine patients with a diagnosis of allergic rhinitis but not allergic asthma and having mainly eye and nose symptoms were categorised as having rhinitis as the predominant symptom .1 of more than 80% of predicted.The control group consisted of five healthy, non-atopic, never-smoking hospital employees and their relatives. These persons had no allergic symptoms either outside or during the birch pollen season. They were skin prick test negative to nine standard allergens, including birch pollen, had no IgE antibodies to birch and had normal lung function with an FEV3 of air, the patients were told to start recording their diary and, two to three weeks later, the season visit was made. The study was performed during the birch pollen seasons in 2000 and 2002, due to the low pollen count in 2001. Patients were included consecutively, thus all patients were studied pre-season and during season in the same year. The subjects were told to avoid short-acting bronchodilators and anti-histamines for 24 hours before the visit and nasal decongestants for four hours before the visit.The study included three visits to our out-patient clinic and all the subjects were tested according to the procedure presented in Table The number of airborne pollen particles was counted by the Palynological Laboratory, Swedish Museum of Natural History, Stockholm, between 1 April and 31 May 2000 and 2002. Pollen recordings were made using a Burkhard seven-day recording volumetric spore trap [Dermatophagoides pteronyssinus, Cladosporium herbarum and Alternaria), using Soluprick SQ ALK . The results were read after 15 minutes, measuring the largest diameter of the weal and its perpendicular diameter, and the product was expressed in mm2. Skin reactions were considered positive when larger than 9 mm2.were performed with nine standard aeroallergen extracts  and recorded in the diary.Lung function tests were performed with a Vitalograph-Compact spirometer, . FEVnd Steel . Peak flet al. [g for five minutes. The supernatant was then centrifuged at 1,400 g for five minutes and immediately frozen in small aliquots to -70°C for analyses of eosinophilic cationic protein (ECP) and human neutrophil lipocalin (HNL). The cell suspension was concentrated in object glasses using cytospin centrifugation for differential counting.Lavage of the nasal mucosa was performed according to Wåhlinder et al.  with a 2et al. [1 was measured before and after the inhalation of physiological saline and induction was then started with hypertonic saline solution. An ultrasonic nebuliser  was used for the inhalations. FEV1 was measured before and 90 seconds after inhalation of physiologic saline. Then hypertonic (4.5%) saline solution was administered for 0.5, 1, 4, 8 and 16 minutes. FEV1 was recorded 90 seconds after each inhalation. The subjects were asked to rinse their mouths with water and then to cough sputum into a sterile container. The test was stopped if FEV1 fell with 20% or more compared with the value obtained after inhaling isotonic saline. After completing the inhalation, the subjects were instructed to "huff" and cough into the container. The mucus clods were aspirated with a 2-ml syringe and collected. The entire sputum clod was weighed and immediately transported to the laboratory. The sputum sample was kept on ice and an equal amount of 0.2% dithiothreitol in phosphate buffer, sputolysin , was added before incubation at 22°C for 15 minutes. The sample was then centrifuged and the supernatant frozen at -70°C for the subsequent analysis of ECP and HNL. The cell suspension was concentrated on object glasses using cytospin centrifugation for differential cell counting.Sputum samples were obtained by hypertonic saline inhalation modified after Pizzichini et al. ,24, exceFour ml of EDTA blood was collected for routine laboratory tests of eosinophil counts . Serum for analyses of ECP and HNL was collected from the four ml of blood in SST tubes (Becton Dickinson AB), kept for 60 minutes in room temperature and centrifuged for 10 minutes at 3600 rpm. The serum was frozen to -70°C.9/l) were determined using routine methods at the Department of Clinical Chemistry, Uppsala University Hospital. Differential cell counts were obtained using a cytospin preparation  stained with May Grünewald and Giemsa, and examined under light microscope. ECP was analysed by Unicap, Pharmacia. HNL was assayed by a double-antibody RIA described in detail elsewhere [Blood eosinophil counts (B-Eos)  for each symptom: rhinitis, conjunctivitis and respiratory symptoms  during the day and night. A symptom score was constructed for rhinoconjunctivitis by adding the nose and eye score each day divided by two. The daytime and nocturnal respiratory score was combined in the same way. A total score for the four symptoms was also calculated. A mean symptom score for each subject was calculated from the sum of symptoms, divided by the number of registered days.Medication was recorded in the diary. The following medication categories were used: oral anti-histamine, topical treatment in the nose and eyes (anti-histamines and/or cromones) and inhaled short-acting beta-agonists during the day and night. The number of drugs in each category was calculated for each day and divided by the number of registered days and a total medication score was generated by combining all the categories.The study was performed with the approval of the ethics committee at the Medical Faculty at Uppsala University and informed consent was obtained from each subject.The Kruskal-Wallis, ANOVA and Mann-Whitney U test were used to evaluate statistical differences between patient groups. For paired analyses, we used Friedman's ANOVA and Wilcoxon's matched pairs test. A p-value of < 0.05 was considered significant. All the calculations were performed using the Statistica statistical software package .No significant differences concerning sex, age or smoking were found between the three groups of test persons. There were no differences in allergy variables between the two groups of allergic patients. Table .1 after inhaling hypertonic saline solution (median (IQ range): -7.0 %) than patients with allergic rhinitis %) or controls %)   could be seen during the pollen season in any of the allergic groups  -ECP in the rhinitis group compared with the control group p = 0.045) (Table 5 (Table During the birch pollen seasons there were significant increases in B-Eos and sputum (Sp) ECP in the rhinitis and asthma groups but not in the control group Table . The ΔNLet al. showed that both nasal provocation and segmental bronchial allergen challenge induce inflammation in both bronchial and nasal mucosa, i.e. the link is bi-directional [The main finding in our study is that birch pollen allergic patients with either rhinitis or asthma as predominant expression of their disease have comparable levels of eosinophil inflammation in the blood, nose and lower airways both before and during the pollen season. Our results highlight the close relationship between the upper and lower airways in both allergic diseases and support the concept of "one airway – one disease" ,27. The ectional ,10. Nasaectional , and othectional .2-agonists than patients with predominant rhinitis. On the other hand, both groups had the same degree of rhinoconjunctivitis and used the same amounts of oral antihistamines and local treatment in eyes and nose. Our data partly disagrees with that of Ciprandi et al. [In spite of the fact that both groups of allergic patients had a similar inflammation pattern, distinct differences were found between the groups. The patients with predominant asthma had a higher bronchial responsiveness when measured with hypertonic saline challenge, a lower PEFR during the season and were much more likely to use βi et al. , who fouet al. also demonstrated an increase in eosinophils in induced sputum after repeated very-low-dose allergen challenge in allergic rhinitis, without any changes in FEV1 or response to metacholine challenge [The eosinophil inflammation in different compartments, measured as the number of eosinophils as well as the concentration of ECP, was comparable between the two allergic groups. In both groups, a significant increase was found in B-Eos and Sp-ECP compared with the non-allergic controls, whereas no distinct pattern was found when it came to neutrophil inflammation. The role of neutrophils in mild asthma and allergic rhinitis is uncertain, whereas in severe asthma neutrophils play an important role in the pathogenesis of airway inflammation . Our dathallenge .The strength of our study is that we have evaluated the nasal and bronchial inflammation in the same patients simultaneously. Another advantage is that we have used natural exposure to allergens. Allergen exposure during the pollen season is a low-dose challenge over a long period and is more like the natural course of allergy development than high-dose allergen challenge. It is known from both experimental studies and real life that very high doses of allergen can elicit asthma symptoms in non-asthmatics, if the doses are high enough . The SweIn conclusion allergic asthma and allergic rhinitis have the same degree of eosinophil inflammation in blood, nasal mucosa and bronchial mucosa during the pollen season. In spite of this, only the asthmatic group present with significant BHR and impairment of lung function during the pollen season. This indicates that eosinophil inflammation in the bronchial mucosa alone is not enough to cause asthma and that factors other than eosinophil inflammation determine whether or not an allergic patient develops asthma.• B-Eos: blood eosinophil count• ECP: eosinophil cationic protein• FEV1: forced expiratory volume in 1 second• FVC: forced vital capacity• HNL: human neutrophil lipocalin• NL: nasal lavage• PEFR: peak expiratory flow rate• RAST: radio-allergo-sorbent test• Sp: sputum


Overt hypothyroidism has been associated with arterial hypertension and increased arterial stiffness. Results in euthyroid individuals have been conflicting. We investigated associations of thyroid function with systolic (SAP) and diastolic (DAP) arterial pressure in euthyroid subjects.311 euthyroid individuals  without a history of diabetes attending a preventive medicine program were examined. Subjects receiving thyroxine (10.6%) were excluded; 19.3% had hypertension, 43% had a family history for hypertension. TSH, fT4, thyroid autoantibodies, insulin, glucose were measured. The "fT4.TSH product", which has been suggested as a T4 resistance-index, was calculated.TSH range was 0.1–8, median 1.4 mU/L, fT4 range was 11.5–25.2 pmol/L, median 17.4. TSH and the "fT4.TSH product" were positively associated with DAP . In the subgroup of individuals with TSH levels 0.36–2.5 mU/L, both TSH and the "fT4.TSH product" were positively correlated with SAP  and DAP ; in multivariate analysis the "fT4.TSH product" was a significant predictor of DAP independently of HOMA-IR and BMI (p < 0.001). Similar associations were found when only the non-hypertensive subjects were analysed (p = 0.004). Hypertensive patients had higher TSH levels (p = 0.02) and belonged more frequently to the subgroup with TSH > 2 mU/L .In euthyroid individuals the association of thyroid function with diastolic arterial pressure remains significant even when a stricter "normal range" for TSH levels is considered. The "freeT4.TSH" product appears to be an even stronger predictor of DAP, independently of HOMA insulin resistance index and obesity. Thyroid hormones influence cardiovascular function ,2 and moSubclinical hypothyroidism has also been associated with arterial hypertension, mostly diastolic -12, as wIt is interesting that such associations have also been reported for euthyroid individuals. TSH variation within the normal range has been associated with alterations in various cardiovascular parameters including arterial pressure ,22,23 anThe mechanism through which slightly impaired thyroid function might influence arterial blood pressure is not clear; increased systemic vascular resistance, premature atherosclerosis and increased arterial stiffness may all be involved ,30. It hThe purpose of our study was to investigate associations of thyroid function parameters with systolic (SAP) and diastolic (DAP) arterial pressure in clinically euthyroid subjects.We studied 311 euthyroid individuals  who visited the cardiovascular laboratory in response to an announcement for free examination for unrecognized features of the metabolic syndrome in the outpatients' clinic of our hospital over a period of 12 months. Thyroid function tests were included in the protocol.Exclusion criteria were a history of diabetes mellitus (previously diagnosed according to the American Diabetes Association criteria), overt coronary heart disease or a previous history of stroke. The presence of hypertension was defined as systolic and/or diastolic blood pressure higher than 139 mmHg and/or 89 mmHg, respectively and/or current use of antihypertensive drugs.Patients receiving thyroxine as well as those who were on drugs possibly affecting thyroid function such as lithium, amiodarone or γ-interferon were excluded from the analysis (10.6%). Of the studied individuals included in the analysis  19.3% had hypertension and 43% had a family history for hypertension. The study was approved by the institutional Ethics Committee and all subjects gave their informed consent.2). Waist and hip perimeter (cm) measurements were performed and waist to hip ratio (W/H R) was used to evaluate fat distribution. Current drug therapy and clinical history were also recorded. Ninety one (55.1%) of the women participating in the study were premenopausal.Using a standard mercury sphygmomanometer and after 5 minutes of rest, three consecutive measurements of arterial pressure were obtained while all subjects were in a sitting position and the mean was calculated. Height and weight were also measured with subjects wearing indoor clothes without shoes. Body mass index (BMI) was calculated according to the formula weight (kg)/height (mFasting blood samples were obtained by venipuncture between 08:00–09:00 h. Serum TSH and free thyroxine were measured using chemiluminescent immunometric assays with the DPC Immulite 200 (Siemens). Serum anti-thyroid antibodies  analysis was performed by RIA using the reagents Brahms DINOtest . Reference range was: TSH 0.36–4 mU/L, fT4 9–25 pmol/L, antiTPO < 60 IU/ml, antiTG < 60 IU/ml. Data were also analysed using a TSH cutoff of either 2 or 2.5 mU/L. Glucose levels  and insulin levels  were also estimated. Basal insulin resistance index  was calculated according to the formula: Insulin resistance = FI × G/22.5, where FI = fasting insulin (μU/ml) and G = fasting glucose (mmol/L).The "fT4.TSH product", derived by multiplying TSH by fT4, was calculated. Previous studies have suggested that this index, referred to as T4 resistance-index, may determine the fT4-TSH set-point for each person. TSH appears to contribute by 85% to the fT4.TSH variance ,36.Statistical analysis was done using the SPSS statistical package. All descriptive data are presented as mean ± SD. Linear regression analysis was used to investigate correlations between continuous variables. In the multivariate analysis we included as possible confounders all the variables for which there was some correlation which was statistically significant or which showed a tendency to be significant in the univariate analysis. Student's t – test was used to compare mean values between groups where the distribution was normal. Chi – square test with Yates' continuity correction was used, or chi – square for linear association as appropriate.TSH range was 0.1–8, median 1.4 mU/L; fT4 range was 11.5–25.2, median 17.4 pmol/L. The clinical and biochemical characteristics of the population are shown in table TSH and the "fT4.TSH product" were positively associated with diastolic arterial pressure (DAP) . In the subgroup of individuals with TSH levels 0.36–2.5 mU/L (n = 238), TSH levels were positively correlated with systolic  and diastolic arterial pressure . Normotensive subjects with a family history for hypertension belonged more frequently to the subgroup with TSH > 2 mU/L although this finding was not significant .Hypertensive patients had higher TSH levels  and belonged more frequently to the subgroup with TSH > 2 mU/L compared to normotensive ones .In the subgroup with subclinical hyperthyroidism  there were no associations between TSH levels and systolic and/or diastolic blood pressure.Our study has demonstrated that in euthyroid individuals with TSH levels in the narrow "normal range" (0.36–2.5 mU/L), diastolic as well as systolic arterial blood pressure is positively associated with TSH levels. These associations remained significant even when only normotensive subjects were considered. Similar positive associations have also been reported by other investigators ,12. AsvoWe have further demonstrated that the "fT4.TSH product" is also positively associated with diastolic as well as with systolic blood pressure. This association was independent of age, sex, insulin resistance and obesity. The same result was found even when only normotensive subjects were considered for the analysis. This marker has been rarely used in the literature and may reflect an individually determined fT4-TSH relationship ,36; it mAnother finding in our study concerns the subjects with a history of hypertension. Higher TSH levels were associated with a history of hypertension. Moreover, hypertensive subjects belonged more frequently to the subgroup with TSH > 2 mU/L. As we have previously shown, TSH values above these levels, may be associated with endothelial dysfunction  and incrFinally, normotensive individuals with a family history of hypertension belonged more frequently to the subgroup with TSH > 2 mU/L although this association just missed statistical significance. A similar finding has been reported by Gumieniac et al in a study of hypertensive families . In thisWe did not find associations between arterial pressure and TSH at the lower levels of the normal range or with the presence of subclinical hyperthyroidism. This could be due to the small sample of subjects with subclinical hyperthyroidism. In the literature there are reports for such associations ,22 althoA limitation of our results was the relatively small number of studied individuals. However, several of our findings point to the same direction.In conclusion, in euthyroid individuals the associations of thyroid function with arterial blood pressure remain significant even when a stricter "normal range" for TSH levels is considered. The "freeT4.TSH" product appears to be an even stronger predictor of diastolic arterial blood pressure, independently of HOMA insulin resistance index and obesity.BMI: Body Mass Index; DAP: Diastolic Arterial Pressure; fT4: free Thyroxine; HOMA-IR: Homeostasis Model Assessment-Insulin Resistance Index; SAP: Systolic Arterial Pressure; T3: Triiodothyronine; T4: Thyroxine; TSH: Thyroid Stimulating Hormone; W/H R: Waist-to-Hip Ratio.The authors declare that they have no competing interests.KS drafted the manuscript and performed the statistical analysis. PV participated in the design of the study and collected the data. KS performed the statistical analysis. EM carried out the immunoassays. CP conceived the study. MA performed the statistical analysis, conceived the study and participated in its design and coordination. All authors read and approved the final manuscript.


Cardiovascular risk is increased in patients with systemic lupus erythematosus (SLE). Drugs used to treat SLE can modify traditional cardiovascular risk factors. We examined the effect of selected drugs used in the treatment of SLE on cardiovascular risk factors.2-isoprostane concentrations in 99 patients with lupus who were either current users or non-users of systemic corticosteroids, antimalarials, non-steroidal anti-inflammatory drugs (NSAIDs), COX-2 selective NSAIDs, azathioprine, and methotrexate. Multivariable adjustment was done with linear regression modeling using sex, age and disease activity (SLEDAI) as controlling variables.We compared systolic and diastolic blood pressure, serum lipid concentrations, glucose, homocysteine, and urinary FP = 0.003) in patients receiving corticosteroids. Homocysteine concentrations were marginally higher in patients receiving methotrexate (adjusted P = 0.08). Current use of either NSAIDs or COX-2 inhibitors was not associated with increased cardiovascular risk factors. Current hydroxychloroquine use was not associated with significant alterations in lipid profiles.Serum triglyceride concentrations were higher (135.1 ± 61.4 vs. 95.3 ± 47.5 mg/dL, adjusted In a non-random sample of patients with SLE, current corticosteroid use was associated with increased triglyceride concentrations, but other drugs had little effect on traditional cardiovascular risk factors. Patients with systemic lupus erythematosus (SLE) have accelerated atherosclerosis and increased cardiovascular morbidity and mortality . We have2-isoprostane concentrations, a measure of oxidative stress [This study enrolled 99 patients with SLE from the Vanderbilt Lupus Cohort. This cohort had an increased prevalence of coronary atherosclerosis detected by electron-beam computed tomography (EBCT). The methods have been reported in detail elsewhere ,7–9. Alle stress , were me2-isoprostane concentrations were logarithmic-transformed for regression analysis. These analyses were exploratory, therefore no adjustment for multiple statistical comparisons were performed. Statistical analysis was conducted using SPSS 15.0 for Windows . Descriptive values are presented as mean ± standard deviation (SD). Statistical significance was determined as P < 0.05.Cardiovascular risk factors were compared in patients receiving or not receiving a drug of interest  using Mann-Whitney U tests. Additional multivariable adjustment was performed by linear regression using age, sex and SLEDAI (Systemic Lupus Erythematosus Disease Activity Index)  as contrP = 0.003). Antimalarial use was not associated with altered cardiovascular risk factors. Neither NSAIDs nor COX-2 inhibitors were associated with increased blood pressure or other risk factors. When patients taking  or not taking antihypertensive drugs were analyzed separately, blood pressure did not differ between non-NSAID and NSAID users . COX-2 inhibitors were weakly associated with lower serum triglyceride concentrations and F2-isoprostane excretion after statistical adjustment  but this was attenuated after statistical adjustment . There is some experimental [2-isoprostane excretion, indicative of lower oxidative stress. Other studies have suggested that COX-2 selective drugs can decrease oxidative stress [Traditional NSAIDs, and particularly COX-2 inhibitors, increase cardiovascular risk ,5. One mrimental ,19 and crimental  that COXe stress ,22.Methotrexate is widely used to treat rheumatoid arthritis and there are several reports indicating that it increases serum homocysteine concentrations due to folate antagonism ,24. ConcThis study has several limitations. First, it was cross-sectional, and the pattern of drug use may have been affected by indication bias. Thus, patients with hypertension, for example, would be less likely to continue to receive drugs such as NSAIDs. However, despite this limitation, the study provides valuable information about the relationship between current use of drugs and cardiovascular risk factors. For example, in this same cohort of patients, blood pressure was significantly higher than that of controls , however


Compartment syndrome is a potentially devastating condition. Increased intracompartmental pressure has been incriminated as the primary pathogenic factor in compartment syndrome. The purpose of this prospective study was to monitor the anterior compartmental pressure and differential pressure to minimize the incidence of acute compartment syndrome.Seventy-five consecutive cases of closed fractures of leg presenting within six hours of injury were taken for measurement of anterior compartment pressure at the level of fracture and at 5 cm and 10 cm away from the fracture site, using the Whitesides' infusion technique. A differential pressure of less than 30 mm Hg was taken as the criterion for diagnosis of compartment syndrome.P < 0.001).Two patients (2.67%) developed acute compartment syndrome. The mean anterior compartment pressures were highest at the level of the fracture and went on decreasing as we went away from the fracture site, which was found to be statistically significant (Compartment pressure measurement is the most reliable and objective method for early diagnosis of compartment syndrome. Whitesides' infusion technique is a relatively easy and inexpensive method to come to a diagnosis of compartment syndrome in a developing country like India. Differential pressure is more reliable than absolute pressure in predicting the development of an impending compartment syndrome. Early diagnosis is important for the prevention of disability. Approximately 40% of all compartment syndromes occur after fractures of the tibial shaft.2We studied 75 consecutive patients with closed fractures of leg between July 2004 and December 2006. Only those patients presenting within six hours of injury were included in the study. Patients with compound fractures and who presented after six hours of injury were excluded from the study. Informed consent was taken from each individual. There were 63 male and 12 female patients with the majority in the age group of 21-40 years (65.33%), the mean age being 30.44 years. Only 20% patients had isolated fracture of tibia, the remaining 80% had an associated fracture of the ipsilateral fibula. Right-sided involvement was seen in 46 patients (61.33%). Middle third was fractured in 44 patients (58.67%) and comminution was present in 21 patients (42%). The fractures were classified according to Oestern and Tscherne (1984) classification for closed fractures of tibia into four grades - C0 (n = 5), C1 (n = 47), C2 (n = 19) and C3 (n = 4). This classification is based on the extent of soft tissue abrasions and contusions, the radiological features of the fracture, the presence of closed degloving, the rupture of major blood vessels and the presence of a compartment syndrome.All the patients were evaluated for the presence of any associated life-threatening emergency and as such resuscitation was carried out for these patients (n = 9). A careful physical examination was carried out to look for the clinical features of compartment syndrome including pain out of proportion with firmness of the compartment, pain on passive stretching of the involved muscles as well as paralysis, paraesthesia and pulselessness. Proper radiographs of the involved extremities were taken. Anterior compartment pressures of the injured extremities were measured using the Whitesides' infusion technique.6Whitesides' technique employs the following materials - i) One mercury manometer, ii) Two plastic intravenous extension tubes, iii) Two 18-gauge needles, iv) One 20-cc syringe, v) one three-way stopcock, vi) One bottle of bacteriostatic normal saline . The extPressure measurements were taken at the level of fracture and at 5 cm and 10 cm away from the fracture site proximally and distally. Differential pressures were calculated by subtracting the absolute tissue pressure from the patients' diastolic blood pressure.Patients with high absolute tissue pressure (>50 mm Hg) were subjected to repeat measurements after one or two hours. The diagnosis of impending compartment syndrome was made when the differential pressure was less than 30 mm Hg.p-values of < 0.001, which is statistically significant. Statistical analysis was done using Fisher's exact test.Road traffic accident was the commonest mode of injury and accounted for 62.67% of the cases in our series. Other modes of injury included domestic falls (16%), fall from height (13.33%), sports injury (6.67%) and assault (1.33%). The compartment pressure was found to be highest at the level of the fracture. A pressure gradient was established as we moved away from the fracture site. The mean anterior compartment pressures at the level of fracture and at 5 cm and 10 cm away from the fracture site were found to be 31.47 mm Hg, 17.07 mm Hg and 3.41 mm Hg respectively. The mean difference in pressure at 5 cm from the highest level recorded was 14.4 mm Hg and at 10 cm was 28.05 mm Hg. On comparing the mean anterior compartment pressure in different modes of injury, it was found to be more in patients sustaining injuries following road traffic accidents.Based on the results of the absolute anterior compartment pressures (ACP), differential pressures (DFP) and the presence or absence of clinical features, the patients were divided into four groups.Group I: patients with ACP < 30 mm Hg and DFP > 30 mm Hg. There were 33 patients in this group.Group II: patients with ACP > 30 mm Hg and DFP > 30 mm Hg with no clinical signs of raised pressure. There were 21 patients in this group.The patients in Group I and Group II were diagnosed as having no compartment syndrome. The fractures in these groups were treated with immobilization in plaster cast or internal fixation as appropriate.Group III: patients with ACP > 30 mm Hg and DFP > 30 mm Hg with clinical signs of raised pressure. There were 19 patients in this Group. All these patients were kept under observation and treated with splitting of the casts and paddings. The limb was elevated to the level of the heart and hyperbaric oxygen inhalation administered. Repeat pressure measurements were performed at every one or two-hourly intervals until the pressure fell down to the safe range.Group IV: patients with ACP > 30 mm Hg and DFP < 30 mm Hg. These patients were diagnosed as having acute compartment syndrome and were treated with four-compartment decompression using the double incision fasciotomy technique. In our series only two out of 75 patients developed acute compartment syndrome (incidence 2.67%). Fasciotomies were performed in both the patients within eight hours of injury and the fractures were stabilized with tibial interlocking nails.A 26-year-old male riding a motorbike was struck by a truck and sustained closed fracture of right tibia and ipsilateral fibula. The patient had associated exhaust pipe thermal burn over the anterolateral aspect of the leg. The fracture was in the middle third of the leg. Clinically, there was only swelling of the compartment with mild pain at the fracture site. The absolute anterior compartment pressure was 54 mm Hg at the level of the fracture and the differential pressure was 16 mm Hg. A double incision fasciotomy of all the four compartments was carried out within six hours of injury. There was no evidence of muscle necrosis. The fracture was stabilized with interlocking nail. Primary wound closure was not attempted. The wounds were covered with split skin graft after five days. The fracture united in 15 weeks time. The patient did not have any sequelae of acute compartment syndrome at the latest follow-up at 22 months after injury, except for the presence of a scar over the lateral wound.A 29-year-old male sustained closed fracture involving the middle third of both bones of the right leg following injury by a speeding vehicle. The fracture was non-comminuted. The patient had stretch pain and swelling of the compartment. The absolute anterior compartment pressure was 48 mm Hg and the differential pressure was 22 mm Hg. Four-compartment decompression was performed using double incision fasciotomy within eight hours of injury. The fracture was stabilized with interlocking nail. Medial wound was closed primarily and the lateral wound was covered with a split skin graft after seven days. The fracture united in 18 weeks time. He did not have any neuromuscular deficit at the latest follow-up (16 months) after injury, except for a scar over the lateral wound.Acute compartment syndrome is an acute surgical emergency.1516It is evident from our study that young patients, especially men and those sustaining road traffic accidents are at increased risk of developing compartment syndrome.et al., introduced the concept of relative or differential pressure, stating that ischemia begins when pressure rises to within 10 to 30 mm Hg of the diastolic blood pressure.et al., absolute compartment pressure is an unreliable indication of the need for fasciotomy.22The critical level of absolute tissue pressure above which decompression should be performed has always been variably reported as 30 mm Hg,We have also taken the differential pressure of less than 30 mm Hg as the criterion for diagnosis of acute compartment syndrome.6et al., reported a relationship between compartmental tissue pressures and the distance from the site of the fracture.P < 0.001). Pressure measurements, therefore, should be carried out as close to the fracture site as possible. Our findings are consistent with those of Heckman et al.23Heckmann From our study, we conclude that intracompartmental pressure monitoring is a reliable and objective method for early and accurate diagnosis of compartment syndrome. Early diagnosis can minimize the soft tissue damage and therefore improve the long-term results. We therefore believe that all patients with closed fractures of leg should have routine anterior compartmental monitoring. Whitesides' technique, though not much widely favored, is a safe, inexpensive, easily assembled and reliable method for measurement of intracompartmental pressure in a peripheral setup in developing countries.


Although the assessment of cardiovascular risk in individual patients takes into account a range of risk factors, the diagnosis and management of hypertension (high blood pressure) is largely determined by a single numerical value, albeit that often several readings are taken over time. Given the critical impact of a decision to embark on lifelong drug therapy, the importance of ensuring that a blood pressure (BP) record is both accurate and representative is clear. However, there is good evidence that the variability of BP is such that even if measurement is of the highest quality, it can be difficult to say with confidence whether a patient is above or below a treatment threshold. This commentary argues that current BP measurement is inadequate to make the clinical decisions that are necessary and that multiple readings are required to deliver an acceptable degree of accuracy for safe decision-making. This is impractical in a doctor's surgery, and the only realistic long-term strategy is to involve the patient in measuring his or her own BP in their own environment. Evidence is presented that such a strategy is better able to predict risk, is cost-effective for diagnosing hypertension, can improve BP control and is thus better able to protect individuals in the future.In this commentary, I explain why doctors and other healthcare professionals should increase their familiarity with the technology, be aware of its strengths and limitations and work with patients as they become more empowered in the management of their chronic condition, hypertension. Hypertension is the most important risk factor for cardiovascular disease in the world , and eviGiven the vast amount of information relating to hypertension in the world literature, it is interesting to reflect on relatively how little importance has been paid to the measurement of blood pressure itself. A cursory glance at many of the landmark trials over the past 25 years will show that there is no consistency in the documentation of the measurement of blood pressure, nor how many readings are taken to establish BP levels at a given time. Particularly surprisingly, some studies do not even detail how blood pressure was measured.The measurement of blood pressure with a mercury sphygmomanometer is now more than 100 years old and although many primary care doctors in the United Kingdom have moved to the use of aneroid devices, it is the mercury manometer that has been the mainstay of clinical trials. There is no doubt that if properly maintained and used correctly, this device will record an accurate measurement of blood pressure at any point in time.One would hope and believe that in clinical trials, great care is taken to measure blood pressure accurately, but outside the confines of a trial we know that terminal digit preference whereby readings end in either '0' or '5' are commonplace and the impact of the relationship between the measurer and the measured can be considerable, giving rise to what has come to be called 'white coat hypertension' in its most extreme form (see below).One of the difficulties imposed on us in clinical practice is that whilst we use data from clinical trials to inform our decisions, doctors are always considering the management of individual patients who may well behave quite differently from those in trials.Many doctors may be unaware of the enormous variability of blood pressure in an individual subject. This is such that differences in blood pressure between successive visits to a surgery or clinic might simply relate to random variation rather than the impact of treatment. Even in the carefully controlled environment of a clinical trial, where trained nurses measure blood pressure, differences across 2 weeks can be as much as 30 mmHg with no treatment changes , it is not difficult to see that the diagnosis of hypertension may not be robust.Some years ago, our group analysed data from the placebo arm of the Medical Research Council's first treatment trial of mild hypertension (involving many thousands of patients) and demonstrated this lack of consistency . If one It has recently been stated that the variability of blood pressure itself may be important in determining outcome , but conIt is difficult to believe that this is practicable, given the way health care is currently delivered, and we need to consider alternatives if we require many measurements of BP.The development of microelectronics first necessitated by the NASA space programme has resulted in new technologies for measuring blood pressure. Assessment of the waveform produced by blood flowing through arteries can be made oscillometrically, and devices now exist which can convert such waveforms into a single measurement of blood pressure equivalent to that obtained using a stethoscope listening to Korotkov sounds. This has led to two similar but different ways of obtaining multiple blood pressure measurements.While beyond the scope of this commentary, the use of devices that can be worn by patients over  a 24-hour period with multiple measurements has demonstrated a number of points:1. The average of multiple measurements at home tends to be lower that that measured in a surgery or clinic, although this difference is less if the blood pressure is measured by a nurse rather than by a doctor .2. The reproducibility of the average produced is much greater than that of clinic measurements (see ref. [3. Observational data have demonstrated that such measurements are much better predictors of cardiovascular outcome than any clinic or surgery BP. Arguably, this is simply because the figure produced by the average of multiple measurements is a more robust measure of an individual's usual pressure.Ambulatory monitors remain expensive, probably are best utilised in centres of expertise and, whilst cost-effective for the diagnosis of hypertension, are not practicable for the long-term management of individuals who require changes in drug therapy over months and years.There remains variability in the literature as to what to call this technology, and although the term 'home monitoring' is still used extensively, such devices can be used in any environment.The science that led to the development of ambulatory monitors is available in small, simple-to-use self-monitors that use the same oscillometric technology and allow patients to measure blood pressure themselves semiautomatically as often as they wish or as required.Home monitors are generally at least an order of magnitude cheaper than ambulatory devices and can be bought without reference to a health care professional in major pharmacies in the United Kingdom and many other countries.As such electronic devices have developed; national specialist organisations have recommended that they are validated against the so-called 'gold standard' of the mercury manometer and a variety of validation protocols have been published to ensure that retailed machines are indeed accurate.It is salutary to note that there is no obligation on a manufacturer to demonstrate accuracy before selling their devices, and there are examples of inaccurate machines being sold to the public. In Great Britain and Ireland, there are important agencies that have realised this problem and maintain a web-based list of validated devices for both patients and healthcare professionals ,7.The average blood pressure obtained by multiple measurements with a self-monitor approximates to the daytime average of an ambulatory monitor , and theThis is different in different parts of the world, and there are data to suggest that some 85% of patients with hypertension in Japan will have purchased a machine. The figure is around 65% in the USA  but probAnecdotally, it is clear that patients will look at the wide range of blood pressures and learn very quickly that blood pressure does not stay the same. If they are not properly educated, they can assume that the machines are inaccurate, and certainly they receive no consistent response when they attend the general practitioner, who may record a much higher blood pressure in the clinic.Most international hypertension guidelines suggest the use of clinic measurements to guide management and make little mention of the variability of blood pressure outlined above. Where they mention the use of ambulatory or self-blood pressure monitoring, they are careful to emphasise the importance of using such information in conjunction with that obtained by clinic measurements, although how this is to be done is often not defined.As long as we hold to a definition of 140/90 as the threshold for defining hypertension, it is worth emphasising that for both an average daytime ambulatory pressure and the average of a set of home-monitored readings, this equates roughly to around 135/85.There are a number of algorithms and guidelines available as to how one might use self-monitoring of blood pressure to diagnose and manage hypertension, and they all depend upon obtaining a set of readings before making a clinical decision. Once one averages 20-25 readings, the figure derived is at least twice as reproducible as that in the clinic and is practicable for most patients  (see FigNot every patient will benefit from the use of self-monitors. Whilst newer monitors can detect abnormal rhythms and indicate that there is such a clinical situation, their accuracy is questionable in this context. It should be noted, however, that it is difficult to measure blood pressure accurately by any methodology in someone with atrial fibrillation, particularly if there is a fast ventricular response, but it is probably not suitable to use electronic, oscillometric devices in the presence of significant cardiac arrhythmias.It is often cited that patients may be disturbed by measuring their own blood pressure and may become introverted and obsessed by the readings. We have little idea as to what proportion of the patient population might suffer in this way, but any guideline to patients would need to take this into account and consider the impact it would have on them as individuals.There is a natural temptation for patients to measure their blood pressure at times of stress or during any unexpected event, and it is important to emphasise to them that blood pressure will rise under such circumstances but that that should not be considered a problem and should not normally require a change in therapy. It is the average of many measurements rather than the single odd reading that should govern the introduction or a change in drug therapy.Many of the early trials testing whether the use of self-monitoring improved blood pressure control in patients were too small to truly answer the question, and while some were positive, others showed no evidence of benefit. A meta-analysis by Cappuccio some years ago showed that there was evidence of a small but significant improvement in blood pressure control for those patients who were given a self-monitor .If giving a self-monitor is accompanied by input from a healthcare professional such that treatment is affected by the readings obtained more directly, then the evidence of benefit is much more clear-cut ,14, and Within our own group, we are researching the value of telemetry such that patients are given a self-monitor with blood pressure readings instantly transmitted wirelessly to nurses in a healthcare centre who, on the basis of a 'rolling average', will guide treatment along predetermined algorithms of care. A recently published trial has shown positive results .The term 'patient empowerment' is used a lot in modern healthcare literature, and governments are also keen on patients taking responsibility themselves for some of the management of chronic conditions. Hypertension is a classic case in point because it is not an illness, simply a risk factor, and generally speaking treatment changes are based on the figures obtained rather than on any symptoms. If patients can understand their blood pressure more, see their own measurements, and see the impact of treatment, then arguably they may be more likely to comply with medical therapy in the longer term, even if the treatment does not appear to be making them feel better.The evidence for this is scarce currently, and again trials are underway to assess whether this is a reality.Whether one is a convert to the use of self-blood pressure monitoring or not, it is difficult to argue against the fact that such machines are being used extensively by patients themselves in primary care. We can choose to ignore the results that they obtain or we can work with them to improve the information about blood pressure levels and thus perhaps produce more effective drug treatment for the condition of hypertension that is the cause of so much morbidity and mortality.The authors declare that they have no competing interests.The pre-publication history for this paper can be accessed here:http://www.biomedcentral.com/1741-7015/8/55/prepub


Antioxidant supplementations have the potential to alleviate the atherosclerotic damage caused by excessive production of reactive oxygen species (ROS). The present study evaluated the effects of prolonged antioxidant treatment on arterial elasticity, inflammatory and metabolic measures in patients with multiple cardiovascular risk factors.Study participants were randomly assigned to two groups. Group 1 received oral supplementation with 2 capsules per day of Mid Life Guard, SupHerb, Israel. In each capsule vitamin C (500 mg) vitamin E (200 iu), co-enzyme Q10 (60 mg) and selenium (100 mcg), Group 2 received matching placebo(SupHerb) for 6 months.   Patients were evaluated for lipid profile, HbA1C, insulin, C-peptide, hs-CRP, endothelin, aldosterone, plasma renin activity and Homeostasis model assessment-insulin resistance (HOMA-IR). Arterial elasticity was evaluated using pulse wave contour analysis .Antioxidant-treated patients exhibited significant increases in large arterial elasticity index (LAEI) as well as small arterial elasticity index (SAEI). A significant decline HbA1C and a significant increase in HDL-cholesterol were also observed. In the placebo group, significant changes in LAEI, SAEI or metabolic measures were not observed.Antioxidant supplementation significantly increased large and small artery elasticity in patients with multiple cardiovascular risk factors. This beneficial vascular effect was associated with an improvement in glucose and lipid metabolism as well as decrease in blood pressure. The present study was designed to determine the effect of antioxidant supplementation with vitamin C, vitamin E, coenzyme Q10 and selenium on arterial compliance, inflammatory and metabolic parameters in patients with multiple cardiovascular risk factors.Oxidative stress has been considered as a potential pathogenic mechanism for initiation and progression of atherosclerotic disease . ExcessiIn a randomized, placebo-controlled study 70 patients with at least two cardiovascular risk factors were recruited from the hypertension outpatient clinic at E.Wolfson Medical Center for study participation. Screening procedures included physical examination, complete blood chemistry; complete blood count, urinalysis and electrocardiogram.Cardiovascular risk factors were defined using the National Cholesterol Education Program risk factors categories: hypertension (systolic blood pressure > = 140 mm Hg and/or diastolic BP > = 90 mm Hg and/or taking antihypertensive medication); diabetes ; low HDL cholesterol level (< 1.03 mmol/l in men and < 1.3 mmol/l in women); or current cigarette smoking.Patients with a history of unstable angina, MI, CVA or major surgery within the six months preceding entrance to the study were excluded. Patients with unbalanced endocrine disease or any disease that might affect absorption of medications were excluded, as were patients with plasma creatinine > 2 mg/dl, elevation of liver enzymes to more that twice the upper normal limit, and electrolyte abnormalities. Patients included in the study were stabilized on their previous medical treatment in the outpatient clinic for up to three months, and an effort was made not to change treatment during the study. All concomitant medications were kept stable to prevent possible effects on the study parameters.The study was approved by the Institutional Review Board and the patients signed a full informed consent.Study participants were randomly assigned to two groups. Group 1 received oral supplementation with 2 capsules per day of Mid Life Guard, SupHerb, Israel. In each capsule vitamin C (500 mg) vitamin E (200 iu), co-enzyme Q10 (60 mg) and selenium (100 mcg), Group 2 received matching placebo(SupHerb) for 6 months.Blood sampling for full chemistry and metabolic parameters, including fasting glucose, lipid profile, HbA1C, hs-CRP, homocysteine, endothelin, aldosterone, plasma renin activity was performed at baseline and at the end of the study.Arterial compliance measures were performed after an overnight fast and before blood sampling. Measures were performed between 8 and 10 AM, in a quiet, temperature -controlled laboratory. With the subject in a supine position, radial arterial waveforms were recorded for 30 sec. The pressure transducer amplifier system was connected to a specially designed device . The passive transient response of the arterial vasculature to the initial loading conditions was determined by analyzing the diastolic portion of the pressure pulse-wave form. This technique, which has been validated for its reproducibility and used extensively , was perThe primary endpoint in the present study was the paired difference in small artery elasticity (SAEI) within each group. With a sample size of n = 33 in each group, the present study was designed to have not less than 80% power to detect a true, within group difference of at least 1.2 ± 2 mL/mm Hg × 100 in SAEI in each of the two treatment groups assuming a two-tailed alpha of 0.025 .Analysis of data was carried out using SPSS 10.0 statistical analysis software . For continuous variables, such arterial compliance parameters and biochemistry data, descriptive statistics were calculated and reported as mean ± standard deviation. Normalcy of distribution of continuous variables was assessed using the Kolmogorov-Smirnov test (cut off at p = 0.01). Categorical variables such as sex and concomitant illnesses were described using frequency distributions and are presented as frequency (%). The t-test for independent samples was used to compare continuous variables by treatment group. Categorical variables were compared by treatment group using the chi square test (exact as needed). General linear modeling was used to compare post-treatment continuous variables that differed by treatment group at baseline, including treatment group as the fixed factor and the baseline value of the modeled variable as a covariate. All tests are two-sided and considered significant at p < 0.05.10 and selenium. Group 2 included 34 patients who received placebo. As can be seen, both groups were similar with respect to age, sex, BMI, presence of cardiovascular risk factors, baseline blood pressure level and arterial elasticity parameters. Concomitant medications were similarly distributed in both groups at the start and end of the study.Demographic and clinical characteristics of the 70 patients with multiple cardiovascular risk factors are presented in Table Table LAEI increased from 11.0 +/- 4.4 to 12.7 +/- 4.7 ml/mm Hg × 100 after 6 months of treatment (p < 0.006)   in patients received antioxidants. Additionally, significant increase in HDL-cholesterol (p = 0.022) and marginal declines in triglycerides (p = 0.058) as well as total cholesterol levels (p = 0.074) were observed in antioxidant treated patients.As shown in Table 1C, triglycerides, total cholesterol, HDL-cholesterol and CRP did not change in placebo group during the study.Metabolic parameters including HbA10 and selenium significantly increased large and small artery elasticity in patients with multiple cardiovascular risk factors. This beneficial vascular effect was associated with an improvement in glucose and lipid metabolism as well as significant decrease in blood pressure.The present randomized, placebo controlled study demonstrates that antioxidant supplementation with vitamin C, vitamin E, coenzyme QAssessment of arterial function and structure can serve as a surrogate endpoint for prediction of morbid events and for estimation of success of treatment. Pulse wave contour analysis using the modified Windkessel model is one of several noninvasive methods for estimation of arterial properties. Numerous studies performed with the HDI CR-2000 equipment have shown good correlation to age, cardiovascular risk factors and markers of disease . Therapein vitro and in animal models of atherosclerosis [The favorable vascular effect of antioxidants has been observed clerosis -16. Howeclerosis . Additioclerosis ,19. Moreclerosis -22. Neveclerosis ,24. Thesclerosis . The lac2O2 in human lymphocytes, to enhance endogenous plasma and tissue antioxidant defenses and restore endothelium-dependent vasoactivity [10 which plays an essential role as an electron carrier in mitochondrial oxidative phosphorylation, improves endothelial dysfunction in diabetic patients [Although the anti-atherogenic effect of antioxidants has been assessed in several experimental studies, the mechanisms by which these agents inhibit atherosclerosis remain to be clarified. Combined supplementation of vitamin E and C have been shown to inhibit DNA oxidation by Hactivity ,26,27. Cpatients . Finallypatients .The findings of the present study concur with those of previous studies that have shown substantial reduction in blood pressure and improvement in long-term glycaemic control with oral CoQ supplementation, reduction in plasma glucose and insulin resistance with high doses of vitamin E supplementation and significant reduction in blood pressure levels with vitamin E as well as vitamin C in hypertensive patients -33. NeveIn the present study, we did not observe significant changes in humoral factors such as homocystein, endothelin, aldosterone and renin in subjects received antioxidant supplementation. Levels of urine cathecholamines also did not change during the treatment period. These findings emphasize a previously published data which have shown that patophysiologic mechanism of antioxidants action is independent of the changes in plasma concentration of blood pressure modulators, such as renin, aldosterone, endothelin , althougOur study has several limitations. First, the present study contains relatively small number of participants and larger studies are required to establish the beneficial vascular effect of antioxidant supplementation. Second, we did not measure plasma levels of the antioxidants which would have added the information regarding treatment compliance and would have elucidated the pathophysiology for vascular action of antioxidants. Furthermore, since the present study has focused on patients with multiple cardiovascular risk factors, the application of our findings to other patient populations remains uncertain.10 and selenium has beneficial effect on glucose and lipid metabolism, blood pressure and arterial compliance in patients with multiple cardiovascular risk factors. The findings of the present study justify investigating the overall clinical impact of antioxidant treatment in this population.We have demonstrated that combined antioxidant supplementation with vitamin C, vitamin E, coenzyme QCI: confidence interval; NSAIDs: non-steroidal anti-inflammatory drugs; SD: standard deviation.The authors declare that they have no competing interests.MS, OD, ZM and RZ contributed to the study conception and design. MS, OD and RZ were responsible for the data acquisition. RZ and OD performed the analysis and interpretation of data. ZM carried out the immunoassays. MS were responsible for review the existing literature and for writing the first draft of the paper. All authors performed a critical revision of the manuscript for important intellectual content. All authors read and approved the final manuscript.