The efficacy of protective ventilation in acute lung injury has validated its use in the operating room for patients undergoing thoracic surgery with one-lung ventilation (OLV). The purpose of this study was to investigate the effects of two different modes of ventilation using low tidal volumes: pressure controlled ventilation (PCV) vs. volume controlled ventilation (VCV) on oxygenation and airway pressures during OLV.We studied 41 patients scheduled for thoracoscopy surgery. After initial two-lung ventilation with VCV patients were randomly assigned to one of two groups. In one group OLV was started with VCV  and after 30 minutes ventilation was switched to PCV  for the same time period. In the second group, ventilation modes were performed in reverse order. Airway pressures and blood gases were obtained at the end of each ventilatory mode.2, PaCO2 and alveolar-arterial oxygen difference did not differ between PCV and VCV. Peak airway pressure was significantly lower in PCV compared with VCV  without any significant differences in mean and plateau pressures.PaOIn patients with good preoperative pulmonary function undergoing thoracoscopy surgery, the use of a protective lung ventilation strategy with VCV or PCV does not affect the oxygenation. PCV was associated with lower peak airway pressures. Anesthesia for thoracic surgery routinely involves one lung ventilation (OLV) to provide optimum surgical operating conditions and to isolate and protect the lungs during the procedure. Unfortunately, this practice may associate with an important impairment in gas exchange, particularly in patients with previous lung disease .T) that are equal to those being used on two lung ventilation (TLV) , somatic  or autonomic  responses were treated with boluses of remifentanil 0.5 μg/kg followed by 50% increments in the infusion rate. A minimum time of 1 minute was required between infusion rate increases. Excessive depth of anesthesia judged by hypotension (MAP < 20% of the preinduction baseline) and/or bradycardia (HR < 40 bpm) was treated by a 50% decrement in the remifentanil infusion rate. If this treatment proved inadequate, IV etilefrine (for hypotension) or atropine (for bradycardia) was administered. The propofol infusion was unchanged. No volatile anesthetics were used. The trachea was intubated with a double lumen tube  no. 37 for male and no. 35 for female patients. Left double-lumen tubes were chosen as long as there was no contraindication. The position of the tube was confirmed by auscultation and fiberoptic bronchoscopy before and after turning the patient to the lateral decubitus position.Upon arrival to the operating room, patients were monitored with electrocardiogram and SpO2 of 1.0, a VT of 9 mL/kg, and a ventilator rate of 12/min, then adjusted to maintain end-tidal carbon dioxide tension (ETCO2) of 25 to 30 mmHg  [Normal arterial oxygen and carbon dioxide tension in Bogota are 60 ± 3 and 30 ± 3 mm Hg respectively (8700 ft or 2600 m above sea level)]. The inspiratory time and the end-inspiratory pause time were adjusted as 25% and 10% respectively, and it was unchanged during all the study. No external positive end expiratory pressure (PEEP) was applied during this period. Prior initiation of OLV, patients were randomly assigned, according to a computer-generated random number table, to one of two groups. Group A: OLV was started by VCV (OLV-VCV) using a VT of 6 mL/kg, PEEP of 5 cm H2O, and the ventilator rate adjusted to maintain a ETCO2 of 25 to 30 mmHg. After 30 min PCV (decelerating inspiratory flow) was started with a FIO2 of 1.0, PEEP of 5 cm H2O, a peak airway pressure adjusted to obtain the same VT as during VCV, and a ventilator frequency adjusted to keep ETCO2 of 25 to 30 mmHg. Group B: PCV was initiated with a peak airway pressure that provided a VT of 6 mL/kg, PEEP of 5 cm H2O, and a ventilator rate adjusted to maintain ETCO2 of 25 to 30 mmHg. After 30 min the ventilator was changed to VCV with a VT 6 mL/kg, PEEP of 5 cm H2O, and the ventilator frequency adjusted to maintain a ETCO2 of 25 to 30 mmHg.Initially, TLV with VCV was performed in all patients using a FIOT were measured and recorded at four stages: (1) During TLV using VCV prior the beginning of OLV; (2) During OLV 30 min after initiation of the first ventilation mode; (3) During OLV 30 min after the second ventilator mode; and (4) End of surgery: 30 min after reestablishing TLV with VCV. During the measurement period surgical manipulation of the lung was not allowed.Blood gas analysis, hemodynamic measurements, peak inspiratory pressure (Ppeak), mean inpiratory (Pmean), plateau inspiratory pressure (Pplateau), and expired V2 value. Student's t test and ANOVA were used to determine the significance of normally distributed parametric values. Categorical variables were tested using χ2 test or, when appropriate, Fisher's exact test. Statistical significance was accepted at p < 0.05.A power analysis based on a previous study  revealedForty-one patients were enrolled into the study. There were no significant differences between the two groups in demographic characteristics, type of surgical procedure performed or pre-operative lung function test table . No pati2 with any mode of OLV was significantly lower compared to TLV (p < 0.001) and increased to a similar level after switching again to TLV. Comparison of the OLV-VCV and OLV-PCV showed a significant difference in Ppeak (p = 0.003) without differences in Pmean, Pplateau PaO2, and PaCO2, (Table The beginning of OLV with either VCV or PCV produced a significant increase in mean (p < 0.001), and plateau (p < 0.01) airway pressures; the Ppeak was significantly higher in VCV patients (p = 0.001) but not in PCV patients (p = 0.53) compared with the initial TLV. As expected, the PaO2O) [The ventilator strategy recommended to reduce the incidence of ALI in patients undergoing thoracic surgery is to use lower Vt (5-7 mL/kg) with moderate amounts of PEEP (5-6 cmH2O) ,16. The VCV has been considered the traditional or conventional approach to mechanical ventilation of patients undergoing thoracic surgery and OLV. However, in recent years PCV has gained renew interest due to its potential advantages ,17,18. Vet al found a statistically significant decrease in Ppeak and Pplateau and improved oxygenation and intrapulmonary shunt with PVC compared to VCV in patients undergoing thoracotomy using a Vt of 10 mL/kg during TLV and OLV. The findings were more relevant in subjects who had poor preoperative lung function [et al showed that PCV with a PEEP of 4 cmH2O was associated with an improvement in oxygenation compared to VCV and zero PEEP [et al reported reduced alveolar concentrations of TNF-α in patients undergoing thoracotomy ventilated with small vs. large Vt (5 vs. 10 mL/kg) [et al reported a decreased proinflammatory response, improved oxygenation index and earlier extubation in patients undergoing esophagectomy who received low Vt (5 mL/kg) with a PEEP level of 5 cmH2O compared with subjects receiving Vt of 10 mL/kg and zero PEEP [The literature concerning the comparative effects of PCV and VCV on intraoperative arterial oxygenation during OLV has produced inconsistent results. Tugrul function . In a suero PEEP . Howeverero PEEP ,20,21. I0 mL/kg) . Consistero PEEP .2O- was likely to contribute to the development of ALI on patients undergoing major surgery  [2O- were likely to have contributed to the development of ALI in these patients  [Exposure to an elevated inspiratory pressure during OLV has been identified as strong predictor of ALI in patients undergoing thoracic surgery and during TLV in high-risk elective surgeries -24. Howe1.7-8.4) .2O and Pplateau less than 25 cm H2O [et al who compared airway pressure in the breathing circuit with that in the dependent lung bronchus during VCV followed by PCV. These authors observed that PCV reduced both circuit pressure and bronchial pressure but the decrease in Ppeak was significantly higher in the circuit. They found a small reduction in bronchial airway pressure that is probably not clinically significant [In our study we found differences in Ppeak, while the Pplateau were similar in both groups. However, the pressure values in PCV and VCV groups were below those currently recommended in this type of surgery: Ppeak less than 35 cm H5 cm H2O ,26. Our nificant . A limitnificant .In conclusion, in patients without severe lung disease undergoing thoracic surgery with OLV, lung-protective strategies using "low Vt" combined with PEEP is safe and effective. The pressure-controlled mode of ventilation (vs. volume-controlled mode) decreases peak airway pressure maintaining similar blood oxygenation indices.The authors declare that they have no competing interest.FRM: Study design, development of methodology, collection and analysis of data, writing the manuscript. DFP: Study design, collection, analysis and interpretation of data. HC: Study design, development of methodology, supervision. LJT: Study design, collection and analysis of data. JCG: Study design, collection and analysis of data. CO: Study design, collection and analysis of data. All authors have read and approved the final manuscript.


The purpose of the study is to estimate the prevalence and risk factors for diabetic peripheral neuropathy (DPN) in type 2 diabetic outpatients at the BIRDEM hospital, Bangladesh.Type 2 diabetic outpatients, diagnosed 5-11 years prior to the investigation were randomly selected for the study. DPN was assessed using the Neuropathy Symptom Score (NSS) and Neuropathy Disability Score (NDS). Data about demographics, blood pressure, height, weight, waist and hip circumference, and random blood and urine samples were collected.Two hundred and ninety four  type 2 diabetic outpatients were studied. The overall DPN prevalence was 19.7 %; male (20.9%), female (18.7 %). The prevalence increased with age (from 11.1% in the 23-40 year-old group to 32.3% in the 60-80 year-old group) and duration of diabetes (from 14.1% in patients with five years to 29.2% in patients with 9-11 years duration). Age > 60 years , low/normal WHR , income < 800 TK  and insulin treatment  were independent, significant risk factors. Longer duration of diabetes (OR1.2 95% CI 1.0-1.4), and higher HbA1c  were marginally independent, significant risk factors for DPN.We observed a DPN prevalence of 19.7%. Higher age, low socioeconomic status, treatment with insulin, longer duration of diabetes and poor glycemic control were risk factors for DPN. Chronic peripheral sensorimotor symmetrical neuropathy (DPN) accounts for approximately 75% of the diabetic neuropathies. It is deIt has been reported that the risk of diabetes related amputations and the prevalence of diabetic foot ulcers is significantly lower in Asians compared to Europeans in the U.K.–8 The re12 deficiency, alcoholism, drug-abuse, hypothyroidism, paraneoplastic disorders, cerebral vascular disease, Parkinsonism, uremia and acute or chronic musculoskeletal disorders. The rationale behind selecting subjects with long duration was to include sufficient number of patients with DPN so that determinants of DPN can be identified.We carried out a cross-sectional study in the outpatient department (OPD) of BIRDEM hospital, Dhaka, Bangladesh from July 2006 to September 2006. BIRDEM is a 550-bed general tertiary level hospital with the most modern disciplines. The OPD is mainly dedicated to diabetic patients, the turnover is approximately 3000 patients, including 60 to 70 new patients, per day. All the The patient list for the OPD was made three days prior to the doctor appointment. The list was then distributed among 10 investigation rooms with two to six doctors in each room. In order to match the investigating team members' (the researcher and two assistants) credentials, one, two or three examination room(s), depending on the number of doctors attending, was randomly drawn every day. The doctors were well informed of the research objectives, procedures and the inclusion, exclusion criteria. The doctors informed and requested the appropriate patients to stay in contact with the research department after the initial examination. The patients were informed about their right to withdraw and restrict their data from analysis at any stage. Informed consent was secured prior to inclusion in the study, which was carried out according to the Helsinki declaration. The Ethical Committee of Medical Research in Norway and the BIRDEM hospital approved the protocol.A total of 303 patients were examined. One patient withdrew from the study and seven patients were excluded due to complications related to stroke, ankle and low back operations. One patient was excluded due to diabetes duration of less than four years. Subsequently, a total of 294 patients remained for analyses.The laboratory analyses were done at the BIRDEM hospital. Eight ml whole blood was drawn from each patient, and urine was collected in a glass test tube (6ml). Glycosylated hemoglobin (HbA1c) was analyzed by high-performance liquid chromatography (HPLC). Good glucose control was defined as HbA1c th ≤ 7.0. The tota132 (kg/m2). Waist and hip circumference were measured with a non-stretchable measuring tape. Waist girth was measured through the midway between the lower border of the ribs and the iliac crest on the mid-axillary line. Hip circumference was measured to the nearest centimeter at the greatest protrusion of the buttocks just below the iliac crest. Both measurements were done with the patient standing and breathing normal. A WHR > 0.90 in men and > 0.80 in women was defined as abdominal obesity.[Information regarding diagnosis, registration date, medication, height and the present day's blood pressure (BP) and weight was collected from the patients' medical record book. High BP was defined as systolic blood pressure ≥ l40 mmHg or diastolic pressure ≥ 90 mmHg. The body obesity.A structured questionnaire with clear and simple questions was made for this study. An academic in the field of community medicine translated the questionnaire into Bengali. It was used to prevent any language misinterpretation between the researcher and the participants. The Bengali version was pilot tested on five patients fulfilling the inclusion criteria. There were no remarks or misunderstandings, and no changes were made.Information regarding demographic and socioeconomic factors  and lifestyle characteristics  was obtained by interview. The Neuropathy Symptom Score (NSS) was recorded by interview following the standard guidelines. The NSS Burning/numbness/tingling (2p) or Fatigue/ Cramping /Aching feelings (1 p) in the lower extremitySymptoms present in the feet(2p) or in the calf (1p)Nocturnal exacerbation of the symptoms (2p) or present equally at day and night (1p)The symptoms awake the patient from sleep (1p)Walking (2p) or standing (1p) maneuvers reduce the symptomsThe Neuropathy Disability Score (NDS) consists of four clinical tests on both feet. The procAchilles tendon reflex: The broad end of the reflex hammer (Babinski) was applied at the Achilles tendon. Jerk with reinforcement (1p), no jerk (2p).Vibration perception: A 128-Hz vibrating fork (Hartmann C128) was applied longitudinally on the first toe three times with at least one false application (not-vibrating fork). The patient was required to tell which application that was vibrating or not. Two of three right responds were set to be a correct answer (0p), two of three wrong responds were an incorrect answer (1p).Thermal sensation (cold sponge): One cold and one room temperature sponge was applied on the dorsum of the foot. The patients were required to tell which application was cold or normal, correct answer (0p), incorrect answer (1p).Tactile sensation (pin-prick): The reverse end of the turning fork and tendon hammer, sharp and dull respectively, was applied at the cuticle of the 1st toe. The patients were required to tell which application was sharp or dull, correct answer (0p), incorrect answer (1p).A total symptom score of 3-4 points was considered as mild symptoms, 5-6 points as moderate symptoms and 7-9 points as severe symptoms. A total disability score 3-5 points was considered mild disability, 6-8 points as moderate disability and 9-10 points as severe disability. The minimum acceptable criteria for diagnosis of DPN were moderate disability, with or without symptoms, or mild disability with moderate symptoms. Mild disability alone or with mild symptoms was not considered adequate to make a diagnosis of DPN.2) or Fisher's exact test was preformed for categorical data, the t-test for normally distributed continuous data and the Mann-Whitney test for non-normally distributed continuous data. Spearman correlation was used to assess the relationship between variables of interest.The data was entered in the SPSS 14.0 for Windows software. The variables age, diabetes duration and income were categorized. Descriptive statistics were used to identify DPN prevalence, determined in simple percentages. For comparison of baseline variables between the groups, the Chi-Square  with 95 % confidence interval (CI) were provided. Statistical significance was set at p < 0.05. All tests performed were two tailed.There were 155 (52.7%) female and 139 (47.3%) male subjects . The meaAn increasing trend in prevalence of DPN with increasing age was observed from 11.1% in those aged 23-40 years to 32.3% in those aged 60-80 years  . The preThere was no significant correlation between the treatment procedure and age, or between the treatment procedure and duration of diabetes. A significant correlation was detected between the treatment procedure and income . The prevalence increased with decreasing income from 9.4% in the group earning ≥ 3000 TK per month to 25.3% in the group earning ≤ 800 TK per month , and with decreasing protein intake from 13.8 % in the group having a high protein intake compared to 32.8% the group having a low protein intake  . There wAge ≥ 60 years , treated with insulin , low/normal WHR , and income ≤ 800 TK , remained as statistically significant risk factors, whereas duration of diabetes , and HbA1c , remained as borderline, statistically significant risk factors for DPN after controlling for potential confounding factors included in the multivariate logistic regression model .The overall prevalence of DPN in this study was 19.7 %. It is lower compared to European studies using similar diagnostic criteria,1718 whic17We used similar diagnostic criteria as studies from the U.K. showing a lower DPN prevalence among type 2 diabetic South-Asian patients compared with European patients living in the U.K. even after adjusting for age.7 However10The results from the multiple logistic regression analysis revealed that age and duration of diabetes117–1921221921181916162123We found a significant correlation between the treatment modality and income, and between the treatment modality and DPN. This is in agreement with other studies showing that subjects treated with insulin are at increased risk for DPN.1925 The 19Possible explanations for the phenomenon could be that poor people are less likely to use health services, which miOur data suggest that the prevalence of DPN increases with age, poverty and type of treatment provided and subtly by the duration of diabetes and poor glycemic control. Our results were generated from a relatively small study in diabetic population with duration of 5-11 years prior to investigation, and the DPN prevalence rate should therefore be interpreted with some caution. However, the findings of early age for the onset of diabetes and its complication in Bangladesh, and correlation insulin treatment with increased risk for DPN deserve further attention. The data of DPN from the South Asian population, where the prevalence of type 2 diabetes is likely to increase substantially in the near future, is scarce. Therefore, the data on DPN from this population is vital to improve the preventive measures and the quality of care related to foot complication among type 2 diabetic patients.Duality of interest The authors declare that there is no duality of interest for this study.


The GOOD  survey showed that blood pressure control was significantly worse in hypertensive patients with metabolic syndrome and/or diabetes mellitus than in those with essential hypertension only. This analysis aimed to investigate which components of the metabolic syndrome are primarily associated with poor blood pressure control.The GOOD survey was designed as an observational cross-sectional survey in 12 European countries to assess the cardiometabolic risk profile in patients with essential hypertension. Investigators were randomly selected from a list of general practitioners (70% of investigators) and a list of specialists such as internists, cardiologists and hypertension specialists (30% of investigators). Data from 3,280 outpatients with hypertension, aged at least 30 years who were receiving antihypertensive treatment or had newly diagnosed hypertension according to the European Society of Hypertension and the European Society of Cardiology criteria, were included in the analyses. Blood pressure control, body mass index (BMI), waist circumference, serum triglycerides, total and high density lipoprotein (HDL) cholesterol measurements were compared in patients with diabetes mellitus and metabolic syndrome, with diabetes mellitus only, with metabolic syndrome only, and with neither metabolic syndrome nor diabetes mellitus.The highest blood pressure values were found in patients with metabolic syndrome with or without diabetes mellitus. Blood pressure was significantly lower in patients with diabetes mellitus only. The highest BMI, waist circumference and serum triglycerides, and the lowest HDL cholesterol levels among the groups studied occurred in patients with metabolic syndrome, either with or without diabetes mellitus.Among the components of the metabolic syndrome, it is not impaired glucose tolerance which is associated with the poor response to antihypertensive treatment. Instead, visceral obesity and dyslipidemia components of the metabolic syndrome, i.e. hypertriglyceridemia and low HDL cholesterol levels, are associated with resistance to antihypertensive treatment. In a previous paper, in which the principal results of the Global Cardiometabolic Risk Profile in Patients with Hypertension Disease (GOOD) survey were reported, the main finding was that blood pressure control was significantly worse in hypertensive patients with diabetes mellitus and/or metabolic syndrome . The preThe GOOD survey was designed as an observational cross-sectional survey in 12 European countries to assess the cardiometabolic risk profile in patients with essential hypertension [The first patient to be seen by physicians each working day who fulfilled the inclusion criteria were asked to participate. In the case of decline the next patient was asked to participate. Maximally two patients per day were recruited. Further details of the selection procedure have been published earlier .Patients included in the survey were outpatients with hypertension, aged at least 30 years, who were receiving antihypertensive treatment or had newly diagnosed hypertension according to the European Society of Hypertension and European Society of Cardiology (ESH/ESC) criteria ,3, whichExclusion criteria were pregnancy, menstruation, hospitalization, secondary hypertension, fever, known renal disease (serum creatinine > 177 μmol/l) and current drug treatment and/or concomitant conditions that could affect microalbuminuria measurements.The following data were collected during the patients' visits: weight, height, waist circumference, seated blood pressure (two measurements taken after at least 3 minutes' rest), heart rate at rest, urinary albumin excretion, cardiometabolic risk factors, including duration of hypertension, history of diabetes, cardiovascular disease or stroke, lifestyle factors including alcohol consumption, physical exercise and smoking habits, and laboratory measurements of fasting blood glucose, fasting lipid profile and serum creatinine. Furthermore, data on current antihypertensive medications, other cardiovascular, antithrombotic, lipid, glucose and uric acid-lowering drugs were collected. Patients with incomplete records were not excluded. Metabolic syndrome was diagnosed according to the National Cholesterol Education Program Adult Treatment Panel III (ATP III) criteria , i.e. atThe study was conducted in accordance with the principles laid down by the 18th World Medical Assembly  and all subsequent amendments. The study was also conducted in accordance with the European guidelines for Good Epidemiology Practice (GEP), and Proper Conduct in Epidemiologic Research . Each participating country ensured that all necessary regulatory submissions  were performed in accordance with local regulations including local data protection regulations.Among the hypertensive patients studied, four groups were compared: patients with metabolic syndrome and diabetes mellitus, with metabolic syndrome but no diabetes mellitus, with diabetes mellitus but no metabolic syndrome, and with neither diabetes mellitus nor metabolic syndrome. The haemodynamic, clinical and metabolic parameters were tested for significance using analysis of variance with Tukey's test as a post-hoc test.n = 1033), with diabetes mellitus (n = 206), with both (n = 864), and with none of these (n = 1177). Systolic blood pressure was highest in patients with metabolic syndrome with or without diabetes mellitus. Furthermore, systolic blood pressure was significantly higher in patients with metabolic syndrome only, than in patients with diabetes mellitus only.In total, 3,464 outpatients were recruited in the survey and of these 3,280 were included in these analyses. The regional distribution of the patients has been described earlier [Similar findings were obtained with diastolic blood pressure Figure , Table 1The number of different antihypertensive therapies the patients were receiving is shown in Table The next question to arise was which component of the metabolic syndrome, except blood glucose, may be associated with blood pressure. Figure Waist circumference was highest in patients with metabolic syndrome whether or not they had concomitant diabetes mellitus. Patients with diabetes mellitus alone showed significantly lower waist circumference than those with metabolic syndrome alone Figure , Table 1Next, we examined the lipid parameters obtained for their association with diabetes mellitus and the metabolic syndrome. Figure The findings show that blood pressure is influenced by the metabolic syndrome, irrespective of the presence or absence of diabetes mellitus. This finding was not a reflection of the antihypertensive treatments received by the patients, as those with metabolic syndrome alone and those with diabetes alone were receiving a similar number of treatments. Other factors may be more important for conferring resistance to antihypertensive treatment, since patients with diabetes mellitus alone, without accompanying metabolic syndrome, showed much lower blood pressure than patients with metabolic syndrome with or without diabetes mellitus. In addition, resistance to antihypertensive treatment may also reflect some doubts about target blood pressure values and low physician compliance in prescribing further therapy for patients with metabolic syndrome.As disturbed glucose metabolism is present in both metabolic syndrome and diabetes mellitus, other factors of the metabolic syndrome are likely to be responsible for the tendency towards higher blood pressure in patients with metabolic syndrome. Indeed, when we evaluated the other components of the metabolic syndrome with respect to their impact on blood pressure, it was BMI and waist circumference which showed the closest association with blood pressure, both systolic and diastolic. On the other hand, the presence or absence of diabetes mellitus was not a major determinant of blood pressure. The above analyses were based on blood pressure values instead of blood pressure control rates. This seemed appropriate since blood pressure control rates were much lower in patients with diabetes mellitus than in patients with metabolic syndrome due to the fact that in patients with metabolic syndrome without diabetes mellitus the blood pressure target was < 140/90 mm Hg, but in patients with diabetes mellitus with or without metabolic syndrome the blood pressure target was < 130/80 mm Hg. Due to the different blood pressure targets, blood pressure control rates differed markedly depending on the presence or absence of diabetes mellitus.These findings suggest that among the components of the metabolic syndrome, it is central obesity which affects blood pressure most. These findings are in line with the newer concepts on the pathophysiology of hypertension. The role of adipocytokines in the pathogenesis of hypertension has been of increasing interest in the last decade, and has markedly extended our view on the humoral mechanisms of hypertension -6. AmongAdiponectin, besides its effects on insulin sensitivity, may also act on the vasculature directly. Hypoadiponectinemia was found to be associated with an impaired endothelium-dependent vasodilation in humans and mice -10. ConvThere is also ample epidemiological evidence that obesity is one of the major causes of essential hypertension. Excess weight gain has been repeatedly shown to be one of the best predictors for the development of hypertension -19. MoreRecent results from the National Health and Nutrition Examination Survey (NHANES) support the eminent role of obesity in the development of hypertension : betweenThe relative contributions of subcutaneous and visceral fat to the development of hypertension have been elucidated in further studies. It is visceral fat which has been identified as the more prominent factor inducing hypertension : quantifBlood pressure is also associated with humoral components of the metabolic syndrome. Low HDL levels are known to confer an increased cardiovascular risk. Moreover, a direct association between low serum HDL levels and blood pressure has been shown in elderly hypertensive patients . The mecAs in the present survey we studied patients receiving antihypertensive treatment, the results do not imply a higher prevalence of hypertension with increasing BMI, but show less effective blood pressure control in obese patients. This finding infers that in obesity-related hypertension other pathogenetic mechanisms may be involved than occur in other forms of essential hypertension.The data in this survey show that metabolic syndrome is not only associated with higher blood pressure but also with the poor response to treatment. Interestingly, among the components of the metabolic syndrome, it is not impaired glucose tolerance which is associated with the response to antihypertensive treatment. Instead, both visceral obesity and the dyslipidemia of the metabolic syndrome, i.e. hypertriglyceridemia and low HDL cholesterol levels, are associated with resistance to antihypertensive treatment.There have been few studies addressing the relative contributions of single components of the metabolic syndrome to the development of hypertension and vascular disease . The GOOAmong the components of the metabolic syndrome, impaired glucose tolerance is not associated with the poor response to antihypertensive treatment. Instead, other components of the metabolic syndrome, viz. visceral obesity and dyslipidemia, hypertriglyceridemia and low HDL cholesterol levels, are associated with resistance to antihypertensive treatment.Dr Naditch-Brûlé declares to be an employee of Sanofi-Aventis. All other authors have attended advisory boards and have held lectures for a number of pharmaceutical companies including the sponsor.WZ prepared the manuscript, LN-B provided statistical expertise, SP created the database, CF developed the hypotheses tested, SEK significantly contributed to the design of the GOOD trial. All authors read and approved the final manuscript.


Tibolone is a synthetic steroid, used with increasing frequency to treat symptoms of menopause, including patients with solid-organ transplants who are taking concurrent immune suppression. To the best of our knowledge, there are no reported drug interactions between tibolone and tacrolimus, one of the principal immune suppressants used in kidney transplantation.We report the case of a 49-year-old Caucasian woman who had received a kidney transplant and who developed acute kidney injury secondary to tacrolimus toxicity 10 days after starting tibolone therapy. No alternative causes were found. Tibolone is known to be a weak competitive inhibitor of CYP3A4, which is involved in tacrolimus metabolism.Despite a careful evaluation, no alternative reason was found for the acute kidney injury, and her kidney function returned to the previous baseline within several days of cessation of the medication, and with no other specific treatment. Using the Drug Interaction Probability Scale we conclude that she experienced a probable drug interaction. We believe that transplant clinicians should utilise frequent therapeutic drug monitoring of tacrolimus in patients starting or stopping tibolone therapy. Tibolone is a synthetic steroid with estrogenic, androgenic and progestagenic properties. It is indicated for relief of the symptoms of menopause in many countries and has been used in Europe for nearly 20 years , but is A 49-year-old Caucasian woman presented with an acute deterioration in her allograft function seven years after she underwent a deceased-donor kidney transplant for end-stage kidney disease, secondary to autosomal dominant polycystic kidney disease. Her transplant was a three human leukocyte antigen (HLA) mismatch to an unsensitised recipient. The initial therapy was standard immunosuppression at that time . The transplantation was complicated by acute rejection after one year due to steroid withdrawal, which was treated with reinstitution of steroids and conversion to tacrolimus therapy one year later. This was some five years prior to her current presentation. Her serum creatinine concentration then stabilized at 125 μmol/L. She subsequently developed osteoporosis and was commenced on calcitriol and alendronate. She was prescribed HRT in the form of estradiol and norethisterone for both the symptoms of menopause and for protection of her bones. In 2002 after the publication of the WHI study [3 at our institution), with a quantitative polymerase chain reaction (PCR) level of 1.7 × 102, which had been noted for several months previously and had not changed.In early 2007, she presented to our transplant centre with lethargy, difficulty sleeping and anxiety over a period of one week. She had no recent illness. Her medications at this time included: tacrolimus 1.5 mg in the morning and 2 mg at night, prednisolone 4 mg daily, mycophenolate mofetil 500 mg twice daily, atorvastatin 20 mg daily, alendronate 70 mg weekly, omeprazole 20 mg daily, citalopram 20 mg daily, calcium carbonate 600 mg daily, calcitriol 0.25 μg daily and folic acid 5 mg daily. The only change to her medications had been the addition of tibolone therapy (2.5 mg per day) for the symptoms of menopause 10 days prior to presentation. On examination she was apyrexial, but was noted to be extremely tremulous and was newly hypertensive with a blood pressure of 144/96 mmHg (previous blood pressure: 118/74 mmHg). She was hyperglycemic with a blood sugar of 12.1 mmol/L, having not been diabetic previously (fasting glucose: 4.5 mmol/L). There was no abnormality found on examination of her cardiovascular, respiratory or gastrointestinal systems. She was found to have worsening graft function with a serum creatinine level of 177 μmol/L (previously 120 μmol/L) and to have tacrolimus toxicity with a level of 17.9 μg/L (liquid chromatography with tandem mass spectrometry (LC-MS/MS) performed at the transplant centre, see Figure Management included ceasing tibolone and reducing the tacrolimus dose to 0.5 mg in the morning and 1 mg at night until the concentration reduced to target level, which occurred over the next six days. Her creatinine level slowly returned to baseline over a period of three months, at which time her tacrolimus level was 4 μg/L at a dose of 2.5 mg per day; a similar dosage and drug level to where she had started.The differential diagnosis of acute kidney injury included tacrolimus toxicity, BK nephropathy, acute rejection and chronic allograft nephropathy. Tacrolimus toxicity was consistent with the acute nature of the presentation, explained all of her symptoms and signs and was borne out by the resolution of her kidney injury as her tacrolimus level and allograft function returned to the previous baseline. It was noted that the baseline and recovery tacrolimus concentrations were measured by MEIA, compared to LC-MS/MS in our centre. However, previous studies have shown that MEIA overestimates tacrolimus concentration in the blood of kidney transplant recipients by 16 to 20 percent [The differential diagnosis of tacrolimus toxicity included interaction with new medications, overdose of tacrolimus tablets (either inadvertent or deliberate) and diarrhea. She had no history of a diarrheal illness or loose bowel motions. It was considered unlikely that she accidentally overdosed on the tablets as she was known to be adherent with very consistent blood levels of both tacrolimus and cyclosporin before that. There had been no recent dose changes to cause confusion. The only recent medication had been the tibolone, and although there are no reported drug interactions with tacrolimus and tibolone, we considered it possible that the initiation of tibolone had precipitated the tacrolimus toxicity by some unrecognised mechanism.Tacrolimus is a calcineurin inhibitor immunosuppressive agent which is metabolized in the liver and the gut by CYP3A4 and CYP3A5 isoenzymes to several metabolites. Tibolone is rapidly metabolized to its three metabolites in the gastrointestinal tract and the liver by 3α/β hydroxysteroid dehydrogenase. Pharmacokinetic studies in three healthy volunteers showed that tibolone was a weak competitive inhibitor of CYP3A4 and CYP2C9, but the authors concluded that tibolone would be unlikely to have a clinically significant effect . DespiteDIPS has recently been developed to provide a guide to evaluating drug interaction causation in a specific patient . Our casGiven the polymorphisms in the cytochrome P450 metabolic pathway and the potential for a wide variation in the metabolism of these two drugs, there is a strong likelihood that other patients may experience a similar interaction. However, given pharmacogenetic variability, not all patients would be expected to be affected. Primary care physicians may not seek the advice of transplant specialists for treatment not directly related to the transplant, and given that there are no reports in the literature, would not expect a complication such as this. We believe that all clinicians (transplant and primary care) should be aware of this probable drug interaction and should ensure monitoring of tacrolimus concentration within three days of commencement of tibolone. Prophylactic dose reduction of tacrolimus is not advised, as it is not likely that all patients will be affected.Written informed consent was obtained from the patient for publication of this case report and any accompanying images. A copy of the written consent is available for review by the Editor-in-Chief of this journal.The authors declare that they have no competing interests.CC wrote the manuscript. CH reviewed our case report and provided her data. DM edited the manuscript and provided overall direction. All authors read and approved the final manuscript.


Several studies have examined the association of biomarkers of iron metabolism with measures of carotid artery atherosclerosis, with inconsistent results. Few studies, however, have evaluated the association between biomarkers of iron metabolism and peripheral arterial disease (PAD). The purpose of this study is to examine the association of ferritin and transferrin saturation with PAD.Serum ferritin, transferrin saturation, and PAD, defined as having an ankle-brachial blood pressure index <0.9, were measured in 1,631 men and 1,031 postmenopausal women participating in the 1999-2002 National Health and Nutrition Examination Survey (NHANES).The multivariable adjusted odds ratios  for PAD associated with a two-fold increase in serum ferritin and transferrin saturation were 1.18 (1.00-1.41) and 1.45 (0.83-2.51), respectively, for men and 1.04 (0.87-1.25) and 1.55 (0.98-2.45), respectively, for women. After stratifying by cholesterol levels, the multivariable adjusted odds ratios  for PAD associated with a two-fold increase in ferritin and transferrin saturation was 1.04 (0.78-1.39) and 0.73 (0.35-1.50), respectively, for men with total cholesterol <200 mg/dL and 1.30 (0.99-1.72) and 2.59 (0.99-6.78), respectively, for men with total cholesterol ≥ 200 mg/dL . After stratifying by cholesterol levels, the multivariable adjusted odds ratios  for PAD associated with a two-fold increase in ferritin and transferrin saturation was 0.66 (0.41-1.05) and 0.75 (0.44-1.28), respectively, for women with total cholesterol <200 mg/dL, and 1.20 (0.95-1.51) and 2.07 (1.01-4.22), respectively, for women with total cholesterol ≥ 200 mg/dL .In this large nationally representative sample of men and postmenopausal women, we found a modest association of ferritin and transferrin saturation with PAD, particularly among those with high cholesterol levels. Peripheral arterial disease (PAD), a condition characterized by advanced atherosclerosis in the lower extremities , affectsThe purpose of the current analysis was to evaluate the association of serum ferritin and transferrin saturation with the prevalence of PAD, assessed through the ankle-brachial blood pressure index (ABI), using data from the 1999-2002 National Health and Nutrition Examination Survey (NHANES 1999-2002).NHANES 1999-2002 was a stratified, multistage probability survey designed to select a representative sample of the civilian non-institutionalized US population . NHANES Data were collected during an in-home interview and a subsequent visit to a mobile examination center. During the in-home interview, information on demographic, household income, education, smoking status, alcohol consumption, and medication use was collected using a standardized questionnaire.2. We defined diabetes mellitus as a self-reported history of diabetes with concurrent use of anti-diabetes medication.Height and weight were measured and body mass index (BMI) was calculated as weight in kilograms divided by height in meters squared. Systolic blood pressure was determined based on the average of 3 blood pressure measurements. Participants had a blood specimen drawn from their antecubital vein by a trained phlebotomist according to a standardized protocol. Serum C-reactive protein (CRP) was quantified using latex-enhanced nephelometry, a high sensitivity assay. Alanine aminotransferase (ALT) and total serum cholesterol was measured enzymatically. High-density lipoprotein (HDL) cholesterol was measured using a heparin-manganese precipitation method. Serum creatinine was measured by a kinetic rate Jaffe method. We calculated estimated glomerular filtration rate (eGFR) using the Modification of Diet and Renal Disease equation after aligning the serum creatinine concentrations with the assay employed in the development of the equation ,16. IndiA detailed description of the measurement of ferritin and transferrin saturation is available elsewhere . FerritiSystolic blood pressure measurements for ABI determination were taken via blood pressure cuff on the right brachial artery and both posterior tibial arteries with the participant lying supine on the exam table. These measurements were taken separately from the measurements to determine blood pressure. Participants with conditions preventing measurement in the right arm had the left brachial artery systolic blood pressure measured instead (n = 8). ABI measurements were taken twice for participants aged 40-59 years and once for participants aged ≥ 60 years. Right and left ABI were calculated as the ratio of the mean systolic blood pressure in the respective ankle to the mean brachial systolic blood pressure in the arm. Participants with an ABI <0.9 in either leg were considered to have PAD. The 0.9 cutoff value for ABI has 95% sensitivity for detecting angiogram positive disease and almost 100% specificity in excluding healthy individuals .All analyses were conducted separately for men and postmenopausal women. Participants were categorized into gender-specific tertiles of ferritin and transferrin saturation based on the weighted population distribution. Age and race-ethnicity adjusted means and percentages were calculated by linear regression for continuous covariates and logistic regression for dichotomous covariates.2). Additional models further adjusted for systolic blood pressure (continuous), high sensitivity C-reactive protein , ALT , total cholesterol (continuous), high-density lipoprotein-cholesterol (continuous), estimated glomerular filtration rate , diabetes mellitus, use of blood pressure medication, diabetes medication, aspirin, and hormone replacement therapy (among women). Tests for linear trend across tertiles of ferritin and transferrin saturation were computed by including an ordinal variable with the median of each tertile of ferritin or transferrin in the regression models. Further analyses included ferritin and transferrin saturation as continuous, log-transformed variables. For these analyses, we present odds ratios for PAD associated with a two-fold increase in ferritin or transferrin saturation. The analysis of ferritin and transferrin saturation as continuous, log-transformed variables was repeated after stratifying by total cholesterol levels above and below 200 mg/dL to investigate the potential interaction with cholesterol levels as has been reported in previous studies [We calculated the odds ratios of PAD associated with tertile of ferritin and transferrin saturation after multivariable adjustment using logistic regression. Initial models adjusted for age (continuous) and race-ethnicity . Subsequent models further adjusted for household income , high school education, smoking status , alcohol consumption (<1 and ≥ 1 drink per week), and body mass index  to account for the complex NHANES sampling design, including unequal probabilities of selection, over-sampling, and non-response.2  for PAD comparing the highest to the lowest tertiles of ferritin and transferrin saturation were 1.87 (0.96-3.63) and 1.48 0.82-2.64), respectively  for PAD comparing the highest to the lowest tertiles of ferritin and transferrin saturation were 0.77 (0.46-1.30) and 1.29 (0.79-2.10), respectively (Table In this representative sample of US adult men and postmenopausal women, ferritin and transferrin saturation were not statistically significantly associated with PAD. After stratifying the analysis by cholesterol levels, the observed associations were consistent with a synergistic interaction between ferritin and transferrin saturation with cholesterol levels among men and women. Our findings were consistent with a modest association of ferritin and transferrin saturation with PAD, particularly among those with high cholesterol levels, but we cannot exclude a chance association.In 1981 Sullivan  introducWhile there is limited information in the literature on the association of iron with PAD, several studies have evaluated the association of iron with carotid artery atherosclerosis. In the Bruneck Study of 826 men and women, high ferritin levels were associated with greater progression of carotid artery atherosclerosis after 5 years . In the The association of biomarkers of iron metabolism with coronary heart disease or stroke has been a source of substantial controversy -20,22-28The findings from the present study need to be considered in the context of its limitations. Ferritin and transferrin saturation are acute-phase reactants and may not accurately reflect body iron stores. To minimize this potential source of confounding we adjusted for CRP. NHANES 1999-2002 is a cross-sectional study susceptible to reverse causation and selection bias and, therefore, we cannot determine causality in any observed associations. There were relatively few cases of PAD, limiting our ability to detect modest associations and subjecting our findings to substantial random variability. Also, when investigating a possible interaction between ferritin and cholesterol levels, the use of LDL cholesterol would have been preferable to total cholesterol, but fasting LDL cholesterol was only available in 47% of our study participants. Despite these limitations, the present study maintains a number of strengths. NHANES data were collected using a rigorous study protocol with extensive quality control procedures and with technicians trained and certified in all data collection procedures. Additionally, the results are representative of the US noninstitutionalized civilian population.In a large nationally representative sample of US adults, we found a modest association of ferritin and transferrin saturation with PAD, particularly among those with high cholesterol levels, but we cannot exclude a chance association. After stratifying the analysis by cholesterol levels, the associations were also consistent with a synergistic interaction of cholesterol levels with ferritin and transferrin saturation. Prospective cohort studies with adequate power to investigate ferritin-cholesterol interaction are needed to fully characterize the relationship between biomarkers of iron status, cholesterol, and measures of atherosclerosis.PAD: peripheral arterial disease; ABI: ankle-brachial blood pressure index; NHANES: National Health and Nutrition Examination Survey; BMI: body mass index; CRP: C-reactive protein; HDL: high-density lipoprotein; eGFR: estimate glomerular filtration rate; LDL: low-density lipoprotein; ARIC: Atherosclerosis Risk in Communities.The authors declare that they have no competing interests.AM participated in the analysis and interpretation of the data and drafted the manuscript. JMFR and PM participated in interpretation of the data and revised the manuscript. EG conceived the study, participated in the analysis and interpretation of the data, and revised the manuscript. All authors read and approved the final manuscript.The pre-publication history for this paper can be accessed here:


The pathophysiology of sepsis-associated encephalopathy (SAE) is not entirely clear. One of the possible underlying mechanisms is the alteration of the cerebral microvascular function induced by the systemic inflammation. The aim of the present work was to test whether cerebral vasomotor-reactivity is impaired in patients with SAE.Patients fulfilling the criteria of clinical sepsis and showing disturbance of consciousness of any severity were included (n = 14). Non-septic persons whithout previous diseases affecting cerebral vasoreactivity served as controls (n = 20). Transcranial Doppler blood flow velocities were measured at rest and at 5, 10, 15 and 20 minutes after intravenous administration of 15 mg/kgBW acetazolamide. The time course of the acetazolamide effect on cerebral blood flow velocity  and the maximal vasodilatory effect of acetazolemide  were compared among the groups.P < 0.01).Absolute blood flow velocities after adminsitration of the vasodilator drug were higher among control subjects than in SAE. Assessment of the time-course of the vasomotor reaction showed that patients with SAE reacted slower to the vasodilatory stimulus than control persons. When assessing the maximal vasodilatory ability of the cerebral arterioles to acetazolamide during vasomotor testing, we found that patients with SAE reacted to a lesser extent to the drug than did control subjects (CRC controls:46.2 ± 15.9%, CRC SAE: 31,5 ± 15.8%, We conclude that cerebrovascular reactivity is impaired in patients with SAE. The clinical significance of this pathophysiological finding has to be assessed in further studies. Sepsis-associated encephalopathy is defined as a diffuse cerebral dysfunction induced by the systemic response to the infection without clinical or laboratory evidence of direct infectious involvement of the central nervous system . Previou2) either by inhalation of carbon dioxide or by changing respiratory rate (carbon dioxide reactivity), breath holding test (carbon dioxide reactivity), decreasing systemic blood pressure and therewith cerebral perfusion pressure  and intravenous injection of acetazolamide. Acetazolamide, the reversible inhibitor of the enzyme carbonic anhydrase, has been used to test cerebral VMR in various diseases and conditions [When assessing cerebral microvascular contributing factors, in previous human investigations Matta and Stow  found cenditions . Disturbnditions ,10, artenditions , systeminditions , in subjnditions . With reThe study was approved by the local Medical Ethics Committee of the Debrecen University Health and Medical Science Centre. Patients fulfilling the criteria of clinical sepsis according to the guidelines of the American College of Chest Physicians/Society of Critical Care Medicine (ACCP/SCCM) Consensus Conference Committee  were enrSepsis-related encephalopathy was defined as a combination of the following: patients had to meet the criteria of clinical sepsis and had to show disturbance of consciousness or alertness of any severity. Any other metabolic causes of conscious disturbance were excluded . A certified neurologist (BF) performed a detailed neurological assessment of all the patients in order to exclude direct infectious involvement of the central nervous system . Sedative drugs were not administered before the neurological assessment. Consciousness/alertness disturbance was graded by two scales: the Richmond Agitation-Sedation Scale (RASS) and the Ramsay scores. The different categories of these scoring systems are described elsewhere in detail . As septTranscranial Doppler measurements were performed in the supine position using a Rimed Digilite Transcranial Doppler sonograph . A 2 MHz probe was used for insonation, and sample volume, gain and power were kept constant during the investigation. Temporal window was used for insonation, probes were fixed by LMY-2 probe holder . The device enabled the assessment of the best available signal of the middle cerebral artery between the depths of 45 to 55 mm. Systolic, diastolic and mean blood flow velocities were registered, and pulsatility indices were calculated by the device. After a blood flow velocity measurement was performed at rest, 15 mg/kg acetazolamide  was injected intravenously. As proposed in previous studies , blood fACZ is the middle cerebral artery mean blood flow velocity measured at 5, 10, 15 and 20 minutes after acetazolamide, and MCAVrest is the middle cerebral artery mean blood flow velocity measured at rest. Cerebrovascular reserve capacity , was calculated as follows:where MCAVACZmax is the highest mean blood flow velocity in the middle cerebral artery within 20 minutes after administration of acetazolamide.where MCAVTranscranial Doppler measurements were performed in 20 age- and sex-matched persons, who were free of sepsis, diabetes mellitus, hypertension, significant stenoses of the cerebral arteries or any known diseases which, according to our present knowledge, could have influenced CVR testing. These subjects served as controls for the study. In these subjects arterial sampling for blood gas analysis was only performed at resting state, because inserting a radial artery catheter or serial arterial sampling during the whole study was considered unethical.P value was less than 0.05.Means and standard deviations were reported for all values. Before performing statistical comparisons of the parameters, a normality test was used. Parameters with normal distribution were compared with the appropriate unpaired t-tests. Repeated measure analysis of variance was used to detect differences in MCAV and CVR values after acetazolemide administration. When significant differences were detected, pairwise comparisons were performed between the groups using the Mann-Whitney U test. Differences were accepted as statistically significant if 2 and partial pressure of oxygen slightly increased during the acetazolamide test. The distribution of the Ramsay scales were in the septic groups as follows: Ramsay 1 = 6 cases, Ramsay 3 = 4 cases, Ramsay 4 = 4 cases. There were five cases with RASS +1 and a further eight cases with RASS -1. Thus, in all cases either a sepsis-related delirious state or somnolence was present.Fourteen patients with sepsis-associated encephalopathy and 20 control persons were enrolled. Blood pressure values assessed by arterial blood pressure did not change during the acetazolamide testing. During the study, slight hyperventilation was observed, but any deterioration of the patients' status did not occur during or after acetazolamide. The results of the most important clinical and laboratory data of septic patients and controls are summarized in Table The results of the transcranial Doppler measurements are summarized in Table In the present study we found that cerebral VMR is impaired in patients with sepsis-associated encephalopathy. It is also clear from our results that not only maximal vasodilative capacity (CRC) but also the time-course of the vasodilative effect (CVR) is affected after administration of acetazolamide in septic patients. Thus, the reaction of the cerebral arterioles to the vasodilatory stimulus is not only lower in magnitude, but also occurs slower in patients with sepsis-associated encephalopathy.When analyzing absolute blood flow velocities in the middle cerebral artery, it is clear that they are lower in patients with sepsis-associated encephalopathy compared with non-septic control persons after acetazolemide stimulation. A decrease in the blood flow velocity measured within the middle cerebral artery may theoretically be explained in two ways: either the large and medium-size vessel  is dilated or there is a vasoconstriction at the level of resistance arterioles of its corresponding territory. Although this question cannot be answered based only on the absolute blood flow velocity values, taking the pulsatility indices into account, the higher pulsatility index among patients with sepsis-associated encephalopathy is more likely to indicate vasoconstriction of the cerebral arterioles. It has been shown previously that an increase in resistance distal to the site of insonation results in an increased blood flow pulsatility . Thus, bThere are numerous factors in sepsis that may contribute to the vasoconstriction of the brain resistance arterioles. First, in animal experiments it has been demonstrated that the blood-brain barrier, which normally maintains a homeostatic environment for brain cells, becomes leaky within the first hours of endotoxemia. Disruption of the blood-brain barrier allows high levels of endogenous catecholamines to directly influence cerebrovascular resistance . Second,2 (carbon dioxide reactivity), breath holding test (carbon dioxide reactivity), decreasing systemic blood pressure and therewith cerebral perfusion pressure  and intravenous injection of acetazolamide. Basically, there are two main factors to take into account during VMR tests: the maximal vasodilative capacity (CRC) and the time-course of the reaction (CVR) [The goal of cerebral autoregulation and metabolic vasoreactivity testing is to see whether the brain circulation is able to adopt to sudden and critical changes of blood pressure (autoregulation) or metabolic demands (metabolic regulation). From the previous clinical investigations and animal experiments it is clear that cerebral arterioles of 40 to 200 μm in diameter are common actors of both autoregulatory and metabolic response of the brain circulation. Different stimuli have been used to test cerebral autoregulation and metabolic regulation, such as altering pCOon (CVR) . In the 2 + H2O → H2CO3 → H+ + HCO3). It also induces a slight temporary hypercapnia lasting for approximately 20 minutes, which results in vasodilation of the cerebral arterioles, most probably through inducing nitric oxide synthesis [2 monitoring in the control group.For the sake of clarity we intend to explain the concept of transcranial Doppler acetazolamide tests. Acetazolamide is a reversible inhibitor of the carbonic anhydrase, which is located at the surface of the erythrocytes. The enzyme catalyses the following reaction: COynthesis . As descIn our study, a less intensive CVR was detected in patients with sepsis-associated encephalopathy, that is cerebral arterioles reacted to the vasodilator stimulus slower and to a lesser extent. Besides a slower vasodilation after acetazolamide administration, the maximal dilation of the cerebral arterioles (CRC) was also lower in septic patients. These results are in accordance with those of Terborg and colleagues, who also demonstrated dysfunction in patients with severe sepsis and septic shock . SimilarThe clinical signficance of the present study may be summarized as follows. First, the results of the transcranial Doppler acetazolamide test may help to better understand the pathophysiology of septic encephalopathies. Second, as we mentioned above, cerebral autoregulation and metabolic regulation occur at the same level of the cerebral circulation (resistance arterioles). In our series of septic patients without hemodynamic compromise or need of hemodynamic support, the ability of the brain resistance arterioles to dilate was decreased. If it is considered that sepsis-associated shock situations and sudden decreases of cerebral perfusion pressure evoke a strong autoregulatory response, an already reduced vasodilatory capacity should limit both the static and dynamic autoregulatory response of the cerebral arterioles. One of the most important functions of cerebral autoregulation is to ensure constant cerebral blood flow (and therewith oxygen delivery) during changes in systemic blood pressure. Further studies are needed to clarify the importance of hemodynamic monitoring and proper hemodynamic support in early phases of sepsis , in order to prevent critical blood pressure changes in the cerebral vascular bed and thus the progression of brain damage.• Cerebral arteriolar function is altered in sepsis-associated encephalopathy• Cerebral arterioles of patients with SAE react lesser extent to vasodilatory stimuli• Cerebral hemodynamic changes may be involved in the early pathogenetic phases of SAE2: partial pressure of carbon dioxide; RASS: Richmond Agitation-Sedation Scale; VMR: vasomotor reactivity.CRC: cerebrovascular reserve capacity; CVR: cerebrovascular reactivity; ECG: echocardiogram; EEG: electroencephalogram; MCAV: middle cerebral artery mean blood flow velocity; PCOSS and TV performed the transcranial Doppler tests. ÁC and MC participated in the design of the study. JH and IT drafted the manuscript. BF performed neurological examinations. BF and MC participated in planning the design of the study, performing the statistical analysis, and completing the manuscript. All authors read and approved the final manuscript.The authors declare that they have no competing interests.


Drugs used for the treatment of rheumatoid arthritis (RA) have the potential to affect cardiovascular risk factors. There is concern that corticosteroids, non-steroidal anti-inflammatory drugs (NSAIDs) and COX-2 inhibitors could affect cardiovascular risk adversely, while drugs such as the antimalarial, hydroxychloroquine, may have beneficial effects. However, there is limited information about cardiovascular risk factors in patients with RA receiving different drugs.2-isoprostane excretion in 169 patients with RA. Risk factors were compared according to current use of corticosteroids, methotrexate, antimalarials, NSAIDs, COX-2 inhibitors, leflunomide and TNF-α blockers. Comparisons were adjusted for age, sex, race, disease activity (DAS28 score), current hypertension, diabetes, smoking status and statin use.We measured cardiovascular risk factors including systolic and diastolic blood pressure, serum HDL and LDL cholesterol, glucose and homocysteine concentrations and urinary FP < 0.001). Diastolic blood pressure , serum LDL cholesterol  and triglyceride concentrations  were significantly lower in patients taking antimalarial drugs. Plasma glucose was significantly lower in current lefunomide users .No cardiovascular risk factor differed significantly among current users and non-users of NSAIDs, COX-2 inhibitors, methotrexate and TNF-α blockers. Serum HDL cholesterol concentrations were significantly higher in patients currently receiving corticosteroids (42.2 ± 10.5 vs. 50.2 ± 15.3 mg/dL, adjusted In a cross-sectional setting drugs used to treat RA did not have major adverse effects on cardiovascular risk factors and use of antimalarials was associated with beneficial lipid profiles. Coronary atherosclerosis  and cardThere is some information about the effects of drugs used to treat RA on risk factors. For example, NSAIDs and COX-2 inhibitors increase blood pressure , high doOne hundred and sixty nine 169) patients with RA were recruited as previously described 69 patien–12. The 2-isoprostanes, a measure of oxidative stress that has been associated with cardiovascular risk in other studies [Clinical information and laboratory data were obtained as described . Hyperte studies , were qu studies  and expr2-isoprostane excretion were compared in patients using or not currently using each drug using the Wilcoxon rank-sum test. The difference was further adjusted for age, sex, race, DAS28 score, current hypertension, diabetes, smoking status and statin use by a multiple linear regression model. The inclusion of hypertension and diabetes status as covariates was to account for use of antihypertensive and hypoglycemic agents. Similarly, adjusting for statin use controlled for differences in lipids accounted for by therapy. Our goal was to adjust for confounding as much as possible since cardiovascular risk is affected by the factors considered and inflammation [2-isoprostanes were log-transformed due to their skewed distribution. Statistical significance was determined using 2-sided 5% significance level . Statistical analysis was performed using R 2.7.2 (http://www.r-project.org).Descriptive statistics were calculated as mean with standard deviation (SD) according to distributions of continuous variables. Differences in cardiovascular risk factors such as systolic blood pressure (SBP), diastolic blood pressure (DBP), concentrations of serum HDL, LDL, and triglycerides, plasma glucose and homocysteine, and urinary Fammation ,16. ThusThe characteristics of the patients are shown in P < 0.001). Current use of antimalarial therapy  was associated with lower diastolic blood pressure , serum LDL  and triglyceride concentrations . Plasma glucose was significantly lower in patients taking lefunomide . In a post-hoc analysis, current leflunomide use was associated with a marginally lower body mass index (BMI) . Statistical models that additionally adjusted for the other drugs under consideration yielded very similar results: there was no change in statistical significance for any comparison except that HDL cholesterol concentrations were significantly higher in patients taking antimalarials (P = 0.03).Current corticosteroid use was associated with higher HDL cholesterol concentrations (42.2 ± 10.5 vs. 50.2 ± 15.3 mg/dL, adjusted The major findings of this study are that in a cross-sectional setting drugs used to treat RA did not have major adverse effects on cardiovascular risk factors and antimalarial use was associated with beneficial lipid profiles.Corticosteroids are thought to induce dyslipidemia through impaired catabolism of LDL, and increased lipoprotein lipase activity . They caThe reported association between methotrexate use and increased concentrations of homocysteine, a cardiovascular risk factor, is a concern . We founAntimalarials may have potential benefits on cardiovascular risk since they are associated with lower LDL cholesterol and triglycerides, concordant with other studies ,23. TheyThe lack of a significant association between the use of NSAIDs and COX-2 inhibitors and cardiovascular risk factors in this RA cohort replicates findings in SLE  but needAssociations between leflunomide and cardiovascular risk factors are not well described although there are some reports of leflunomide increasing blood pressure . The finThis study has several limitations. First, it was cross-sectional, and the pattern of drug use may have been affected by indication bias. Also current drug use does not always reflect the true effects of the drug since the duration of drug use needs to be considered, which was not available; we did not analyze information about past use of a drug in patients not currently taking a particular drug. Also, we did not study additional cardiovascular risk markers such as EKG findings or elevated BNP levels.Second, since the study was exploratory, we performed multiple statistical comparisons without statistical adjustment and the findings should be interpreted in that light. Nevertheless, since randomized controlled trials to examine the effects of the drugs of interest on cardiovascular risk factors in RA are not feasible, the study provides useful information, despite its limitations.


Normotensive non-diabetic relatives of type 1 diabetes (T1D) patients have an abnormal blood pressure response to exercise testing that is associated with indices of metabolic syndrome and increased oxidative stress. The primary aim of this study was to investigate the circadian variability of blood pressure and the ambulatory arterial stiffness index (AASI) in healthy siblings of T1D patients vs healthy control subjects who had no first-degree relative with T1D. Secondary aims of the study were to explore the influence of both cardiovascular autonomic function and erythrocyte electron transfer activity as oxidative marker on the ambulatory blood pressure profile.Twenty-four hour ambulatory blood pressure monitoring (ABPM) was undertaken in 25 controls, 20 T1D patients and 20 siblings. In addition to laboratory examination (including homeostasis model assessment of insulin sensitivity) and clinical testing of autonomic function, we measured the rate of oxidant-induced erythrocyte electron transfer to extracellular ferricyanide (RBC vfcy).Systolic blood pressure (SBP) midline-estimating statistic of rhythm and pulse pressure were higher in T1D patients and correlated positively with diabetes duration and RBC vfcy; autonomic dysfunction was associated with diastolic BP ecphasia and increased AASI. Siblings had higher BMI, lower insulin sensitivity, larger SBP amplitude, and higher AASI than controls. Daytime SBP was positively, independently associated with BMI and RBC vfcy. Among non-diabetic people, there was a significant correlation between AASI and fasting plasma glucose.Siblings of T1D patients exhibited a cluster of sub-clinical metabolic abnormalities associated with consensual perturbations in BP variability. Moreover, our findings support, in a clinical setting, the proposed role of transplasma membrane electron transport systems in vascular pathobiology. So far, familial predisposition to arterial hypertension in type 1 diabetes (T1D) families has been related to the development of diabetic nephropathy and systemic hypertension in the proband . The priWe studied the following groups of subjects:1) 20 T1D patients (12 women) with duration of disease ranging from 1 to 47 years (23 ± 15 years). The group included 8 patients with retinopathy  and 1 patient with nephropathy . None received medical treatment except insulin (0.6 ± 0.2 IU/kg) and possibly antihypertensive drugs ;2) 20 normotensive non-diabetic siblings (12 women) of T1D patients. None had clinical evidence of illness or was taking any drugs;3) 25 healthy subjects (16 women) were recruited from the local community to achieve a similar distribution of age and sex to the families. They had no family history of T1D, were taking no drugs, and had no clinical signs or symptoms of illness.All subjects gave informed consent and the ethical committee of the hospital approved the study proposal. The medical examination included standardised family and personal medical history, physical examination, blood chemistry analysis, tests for cardiovascular autonomic functions, resting ECG, and 24-h ambulatory blood pressure monitoring (ABPM).2 (in kg/m2). After 10 minutes rest, sitting systolic and diastolic blood pressure were measured twice. The mean was reported as office SBP and DBP. Individuals not receiving any antihypertensive drug therapy with resting (sitting) SBP/DBP less than 140/90 mmHg were placed in normal blood pressure category.The family and personal medical history and the findings of the clinical examination were recorded . The body mass index (BMI) was calculated as body weight/heightAutonomic function was assessed using four standardised autonomic function tests according to Ewing et al. : deep brThe 24-h ABPM was performed using an automatic oscillometric device (Takeda TM-2430) and data were analysed using SIGMA 2000 software. Patients should keep their habitual routine and present a report with the activities done. SBP, DBP and heart rate (HR) were recorded every 15 minutes throughout the day and every 30 minutes at night. SBP, DBP, and HR measurements were averaged for the day and the night spans according to the patients' reported time of waking up and going to bed. The pulse pressure (PP) was calculated as the difference between the SBP and the DBP. The normal dip was defined as a 10% or greater reduction in BP during sleep compared with the awake period. The circadian characteristics of BP were also estimated: MESOR (midline-estimating statistic of rhythm), amplitude , and acrophase . Ambulatory arterial stiffness index (AASI) was computed from 24-h recordings of each participant as 1 minus the regression slope of DBP on SBP .Fasting venous blood samples and morning urine samples were obtained on the same day just before starting ABPM. Measurements were performed in freshly obtained material immediately after withdrawal. Laboratory evaluation included fasting plasma glucose (FPG), plasma creatinine and uric acid, HbA1c, blood cell count, lipids , bilirubin, liver enzymes, urinary glucose, albumin and creatinine excretion. Urinary albumin-to-creatinine ratio (ACR) was calculated by dividing the urinary albumin concentration in μg by the urinary creatinine mg. Concentrations of fasting plasma insulin (FPI) were measured by commercial radioimmunoassay . Homeostasis model assessment of insulin sensitivity (HOMA-IS) was calculated as the product of the FPI and FPG divided by 22.5.To measure RBC vfcy, 4 ml venous blood were drawn into heparin tubes and immediately centrifuged at 54 g for 9 min at 20°C to remove platelet-rich plasma. After packed erythrocytes were washed three times in 10 volumes of phosphate-buffered saline, 0.5 ml of the packed cells were diluted to 5 ml with phosphate-buffered saline containing l mmol/l ferricyanide and incubated under magnetic stirring in a water bath at 37°C. At 5, 10, 20 and 40 minutes 0.3 ml of cell suspension were removed and centrifuged at 3110 g for 4 min at 4°C. An aliquot of 0.05 ml of the supernatant was sampled, and the ferrocyanide content was measured spectrophotometrically . The initial rate of ferrocyanide generation was expressed relative to the packed cell volume as micromoles per ml packed RBCs per hour [t test or the Mann-Whitney U-test with Bonferroni correction for multiple hypothesis testing. The cut-off level for statistical significance was set at p < 0.05. Pearson's correlation coefficient or Spearman's rho was computed to determine the correlation between variables. Multivariate regression analysis was used to determine independent predictors of the variables of interest; candidate predictors selected in the multivariate model were the variables significantly associated by simple univariate correlation analysis.Analysis was performed using Aabel 3 . Results are given as mean ± SD or median with range . Statistical comparison was by chi-square test, the Student's unpaired The clinical characteristics of the study groups are reported in Table While HR analysis under paced breathing did not evidence any significant difference among groups, HRV in response to standing and Valsalva manoeuvre was abnormal in T1D patients. Five of them had an autonomic neuropathy score ≥2.From the biochemical viewpoint Table , T1D patABPM confirmed the 24-h SBP, 24-h PP, nighttime SBP and SBP MESOR to be significantly higher in T1D patients  than in control subjects and siblings Table . In bivaUnlike office duplicate BP measurements, ABPM records of siblings revealed the daytime SBP, daytime DBP, and SBP amplitude to be higher than controls' values. Among non-diabetic people in the study, daytime SBP was associated positively with BMI , HbA1c , RBC vfcy  accounts for the major part of the non-dipping systolic  and diastolic  profile in the T1D patients.AASI was higher in members of T1D families, probands and siblings, than in control subjects. In T1D patients it was associated negatively with E:I ratio at deep breathing  and positively with age , duration of the disease , and HbA1c . On multivariate regression HRV during deep breathing remained the independent predictor of AASI  even when 24-h SBP was included in the model. In the non-diabetic study groups there was a significant positive relationship between AASI and FPG .Ambulatory BP, particularly the circadian variability of BP, may be a better predictor of cardiovascular disease than office BP in the general population . AbnormaThe acrophase of DBP, i.e. the time of the maximum of the DBP, registered in T1D probands was 3 hours earlier than normal and DBP ecphasia  was more pronounced in patients with lower HR variability during deep breathing. This is a novel finding in type 1 diabetes, which is consistent with previous observations in patients with type 2 diabetes . ChangesAmong previous investigations focused on the relationship between familial predisposition to hypertension and diabetic nephropathy, only one monitored 24-h ambulatory BP in adult T1D relatives (parents aged about 67 years) [Originally, the presence of insulin resistance was highlighted in family members of T1D patients with microalbuminuria . CurrentA circadian hyper-amplitude-tension  has been associated with an increased risk of cardiovascular diseases such as stroke, coronary artery disease, nephropathy, and retinopathy . LongituPresent true novelty lies in that the daytime SBP, as well as PP, is partly explained by RBC vfcy. All eukaryotic cells possess TMET systems that transfer electrons across the plasma membrane; the reduction of extracellular oxidants takes place at expense of intracellular reductants . TMET capacity has been related to various cellular functions: growth, proliferation, differentiation, apoptosis, bioenergetics, cell signal transduction, antioxidation, and iron/copper metabolism . ConsequAASI, recently suggested as a marker of arterial stiffness, resulted to be significantly heritable both before and after adjustment for classical covariates . In our In conclusion, non-diabetic siblings of T1D patients show signs of reduced insulin sensitivity, larger circadian amplitude of SBP and higher ambulatory arterial stiffness index. Their broader range of BMI and FPG  portends nascent or established glucoregulatory perturbations and is associated with consensual perturbations in vascular homeostasis. Moreover, our findings support the proposed role of TPMET systems in vascular pathobiology, which deserves further clinical investigations.We are aware that repeated ABPM recordings could be recommended to correctly estimate the consistency of BP abnormalities and diagnose circadian hyper-amplitude-tension . HoweverAASI: ambulatory arterial stiffness index; ABPM: ambulatory blood pressure monitoring; ACR: albumin creatinine ratio; BMI: body mass index; DBP: diastolic blood pressure; FPG: fasting plasma glucose; FPI: fasting plasma insulin; HOMA-IS: homeostasis model assessment of insulin sensitivity; HRV: heart rate variability; MESOR: midline-estimating statistic of rhythm; PP: pulse pressure; RBC vfcy: erythrocyte velocity of ferricyanide reduction; SBP: systolic blood pressure; T1D: type 1 diabetes; TPMET: transplasma membrane electron transportThe authors declare that they have no competing interests.EM and OG participated in the design, interpretation of the study, analysis of the data, and review of the manuscript. CC and MCM participated in the methodology of the study. All authors read and approved the final manuscript.


Hypertension may lead to irreversible damages in vital organs, such as heart, brain, and kidney, and may cause death in children if treatments are not given despite early diagnosis. This cross-sectional epidemiological study was conducted during 1 January–31 March 2004 to investigate the prevalence of hypertension among high school students. The study cohort included 1,041 students of six high schools, who were selected from among 14,789 students of 26 high schools in Sivas province of Turkey, using the cluster-sampling method. A questionnaire was used for collecting information from students on age, gender, smoking, and whether they or their families have any diseases. Blood pressure, height, and weight of the participitants were determined by the research group. Students whose repeated systolic or diastolic blood pressures were higher than the 95th percentile were considered to be hypertensive patients. Hypertension was prevalent among 4.4% (n=45) of the students. There was a significant correlation between prevalence of hypertension and body mass index. No significant correlation was found between prevalence of hypertension and other variables, such as smoking, age, gender, and family history of diabetes. The results suggest that hypertension is an important public-health problem among high school students. The results also showed that the body mass index was an important parameter in hypertension in such a study group. Researchers should consider overweight a causative risk factor for development of hypertension in early-onset groups. The incidence of hypertension in childhood varies from 1% to 3% . HyperteThe rising prevalence of overweight worldwide has led to an increased prevalence of essential hypertension among younger population. The present study was aimed at detecting the prevalence of hypertension and risk factors for hypertension among high school students in Sivas, Turkey.This cross-sectional epidemiological study was conducted from 1 January to 31 March 2004. Using a multistage sampling method, six high schools, as clusters, were selected systematically from 26 high schools  in Sivas. In total, 1,041 students—from 9th to 11th grades were chosen randomly from those six high schools and examined for hypertension and some other risk factors that could possibly cause hypertension. The study group included 1,020 of targereted 1,041 students. In total, 1,020 students—593 males (58.1%) and 427 females (41.9%)—with the mean age of 15.9±1.0 (range 14–18) years were available for contact in the present study.A questionnaire was used for obtaining information from students by self-reporting on age, gender, smoking, and whether they or their families have had any diseases, such as urinary tract infection and diabetes. The blood pressure, height, and weight of each student were measured by the research group. Other family members were contacted for diabetes or hypertension if the student had hypertension. Based on the present habit, the smoking status was evaluated for each student.th percentile according to the blood pressure percentile curves prepared by the USA Task Force Group. Students whose repeated systolic or diastolic blood pressures were higher than the 95th percentile were considered to be hypertensive patients.Measurements of arterial blood pressure were performed in a quiet room after five minutes of resting in a sitting position. Right arms were kept at the same level of heart during the measurement. Cuff bladder was arranged to cover about 75% of the upper arm, and the measurements were performed using a tool calibrated to cover the upper arm fully . The cuf2). The BMI values that were considered to be underweight, overweight, and obesity were defined as <5th, ≥85th and ≥95th percentile, respectively, of age- and sex-specific National Center for Health Statistics/Centers for Disease Control and Prevention (NHCS/CDC 2000)  sensitive to 0.1 kg and 0.5 cm respectively, and a non-stretch tape was fixed to a flat vertical wall. Body mass index (BMI) was calculated dividing the weight by square of height  . Chi-square, Pearson correlation, and Student's Data of 1,020 students were used; 58.1% (n=593) of them were male, and 41.9% (n=427) were female. Their average age was 15.9±1.0 years. Table th percentile. Hypertension was prevalent among 5.4% of male and 3.0% of female students. Distribution of systolic and diastolic blood pressures by age and gender is given in Table 4.4% (n=45) of the students had blood pressures above the 95The male students had the mean height of 171.5±7.7 cm, the mean weight of 59.4±9.9 kg, and BMI of 20.1±2.6, whereas the female students had the mean height of 160.6±5.7 cm, the mean weight of 53.4±8.4 kg, and BMI of 20.7±2.9. All the three mean values were observed to be significantly (p<0.05) different with respect to gender.Table Hypertension was detected in 5.9% of one or both parents, but could not be detected in 3.8% of parents of the hypertensive students. This difference was not statistically significant.The involvement of some factors/variables in the prevalence of hypertension is shown in Table In Turkish population, the prevalence of hypertension was 5.8% in the age-group of 13–20 years , 7.2% inIn the present study, blood pressure correlated positively with height, weight, and BMI significantly (p=0.00). Furthermore, the BMI was also significantly (p=0.00) associated with hypertension after multivariate regression analysis. This result is consistent with the results of previous studies -22. As ret al. reported the higher mean systolic and diastolic blood pressure values for girls aged 6–11 years when compared with their male peers (et al. stated that the mean systolic and diastolic blood pressure values for boys aged 7–12 years were higher than those of girls (et al. reported the higher mean diastolic blood pressure for girls aged 7–12 years (et al. demonstrated the similar mean systolic blood pressure values for both genders between the ages of 7 and 10 years (et al., the mean systolic blood pressure values for boys at the ages of 6 and 15 years were observed to be higher, while girls had higher values in other age-groups (According to Turkish literature, investigating the association among age-groups, gender, and mean blood pressure values, Kıyak le peers . Tümerdeof girls . Özkan e12 years  and the 10 years . Howevere-groups . On the If any one of the parents is hypertensive, the probability of being hypertensive for their children may be 28%. If both the parents are hypertensive, the probability of being hypertensive for their children may be 41.0% . Our resIt is known that infections in the urinary system, particularly reflu-dependent nephropathy and parenchyma damage, may lead to hypertension ,29. In tHypertension was demonstrated as an important public-health problem among high school students in Sivas. Our results showed that BMI was an important parameter in hypertension in such a study group. Frequent measurement of blood pressure of such cases, especially students with overweight, could be an effective preventive method for the early detection of hypertension and its complications. Effective therapy and continuous health education concerning healthy lifestyle are also essential in this age-group.