In addition we tested for an influence of PAR-2 on salt-sensitivity  and angiotensin II-induced hypertension (1 μg IleP < 0.001) during periods of nocturnal activity. The diurnal pattern and intensity of locomotor activity were not found to differ between strains. A high salt diet led to increased blood pressures, decreased heart rates, increased time spent active and decreased intensity levels of locomotor activity. Salt-induced changes in systolic and pulse pressures in PAR-2 -/- were less than in C57B/6J. Angiotensin II treatment increased pressures, decreased heart rates, decreased time spent active and decreased intensity levels of activity of PAR-2 -/-, all to the same extent as C57BL/6J. A trend of lower blood pressures during the middle period of angiotensin II treatment period was observed in individual PAR-2 -/-.Systolic arterial pressures of PAR-2 -/-  were statistically higher than those of C57BL/6J  throughout the 24 h period under baseline conditions. Pulse pressures in PAR-2 -/- were also significantly elevated , whereas diastolic arterial pressures were not. Heart rates in PAR-2 -/- were not significantly different than controls, with the exception that heart rate of PAR-2 -/- was 23 beats per min higher than controls (The data indicated gene knockout of PAR-2 was associated with a modest change in blood pressure phenotype. PAR-2 -/- mice exhibited moderate elevation of systolic arterial and pulse pressures, yet no increased diastolic arterial pressure, no increased blood pressure responses to high salt diet and a subtle difference in the time course of the blood pressure responses to angiotensin II infusion. High salt diet feeding [2 [2 with regulation of blood pressure during altered hemodynamic states particularly with the development of acquired hypertension.Protease-activated receptor 2  and PAR2-deficient mice  were purchased from the Jackson Laboratories . Except during high-salt (HS) diet feeding, mice were fed a standard regular-salt (RS) feed containing 0.28% sodium (0.5% NaCl), 1% calcium, 0.59% potassium and 0.93% phosphorus . High-salt diet containing 8% NaCl was comprised otherwise as above . Mice were provided water ad libitum. Mice were housed individually in air filter-topped cages in a room of the Animal Care Facility of the Health Sciences Center dedicated to recording radiotelemetry data. The room lighting was set to a 12 h light and 12 h dark cycle and room temperature was 20–22°C.Control mice  were implanted with a telemeter  via the right carotid artery [2 +/+ and 5 PAR2 -/-). For the protocol comparing the effect of high Ang II in each strain, baseline recordings were made for a 4–7 day period. On Day 0 of the Ang II infusion protocol, mice were removed from their rooms shortly after the start of the light period and a micro-osmotic pump (ALZET model 1002) containing either isotonic saline (13 PAR2 +/+ and 7 PAR2 -/-) or Ang II  was implanted dorsally s.c. Pump implantation (~10–15 min) was performed using isoflurane/oxygen anaesthesia, followed by monitoring their recovery for 4–6 h before being returned to their home cages. BP data sampling was then restarted ~18 h later at the start of the next light period (day 1). According to the manufacturer's literature provided with the product, steady state rate of infusion was expected to be reached 12 h after implant of micro-osmotic pumps. BP data in saline-treated and Ang II-treated mice were recorded for 12–13 days before being sacrificed. The proper placement of the catheter tips of telemeters in the aortic arch were confirmed at autopsy.Mice , diastolic arterial pressure (DAP), heart rate (HR)) and locomotor activity data were sampled for 3 s at 30 s intervals . The 24 P < 0.05 was considered significant.Values reported and symbols on graphs are the means ± standard error of the mean. For overall characterization of phenotype, the data obtained at baseline preceding both experimental protocols  were combined for each strain. Linear regression analysis indicated that age did not have an effect on baseline blood pressures or the effects of the experimental protocols in our study. The calculations of difference in telemetry variables during the experimental treatments are paired to the average value of the individual mouse's baseline recordings. There are 6 parts to the presentation of statistical analyses: 1) Comparison of the effect of strain on 12 h light and 12 h dark telemetry variables at baseline (2 way ANOVA). 2) Comparison of the effect of strain on 12 h light and 12 h dark variables at baseline with matching of variables to activity level . 3) Comparison of the effect of strain on change in variables during HS diet (2 way repeated measures ANOVA). 4) Comparison of the effect of treatment  on variables with time (2 way repeated measures ANOVA). 5) Comparison of the effect of strain on change in variables during micro-osmotic pump treatments (2 way ANOVA). 6) Comparison of the effect of micro-osmotic pump treatment on variables (2 way ANOVA). Bonferroni post-hoc testing was used to identify differences between specific groups in the multiple comparisons. P < 0.05) higher in PAR2 -/- than PAR2 +/+ mice . Differences in diastolic pressures and HR between PAR2 -/- and PAR2 +/+ were generally slight and, with one exception  multiple comparisons between strains were not statistically significant  irrespective of night or day during the HS diet, but differences for specific time points were not resolved by Bonferroni post-hoc tests. However, in contrast to our initial hypothesis, the elevation of SAP by HS was less in PAR2 -/- than in PAR2 +/+. The elevation of DAP by HS diet was not different between the strains. 12 h dark period pressures remained elevated throughout the treatment period  difference between strains was resolved by Bonferroni post-hoc for the 12 h light PP difference on day 12 . In both strains, the rise in BP tended to be biphasic, with an initial peak on days 1–4 being followed by a dip in BP before it again rose during the final days of the infusion. The intensity of the BP dip tended to be greater in PAR2 -/- mice, and this effect reached significance for all indices of BP recorded on the 7th day of infusion. However, the initial and final BP levels produced by Ang II infusion did not differ between strains. Ang II infusion also led to a progressive increase in PP which tended to be greater in PAR2 -/- mice, an effect that reached statistical significance for data obtained during the 12 h dark period  provide the first description of blood pressures and heart rates in conscious PAR2 -/-. Previously it was reported that the acute hemodynamics  of PAR2 -/- were not different than controls based on intracarotid catheter recordings under anaesthesia [2 -/- mice, we resolved a very small difference in hemodynamic variables. The magnitude of these differences were so small that the physiological impact may at first glance be considered inconsequential under baseline conditions and further dissection of its nature would appear to be unfeasible. Nevertheless the use of telemetry methodology allows us to conclude with a high degree of confidence that these subtle differences are in fact real effects of PAR2 -/-, being observed consistently in freely behaving conscious mice without the limitations that may be imposed by other methods . Telemetry has been shown to be the most accurate of current techniques available for assessing BP in rodents and has received recommendation as the gold standard method for quantifying the BP phenotype in experimental animals [2 -/- while active at night.We found small yet significant increases in blood pressures of PAResthesia . Using a animals . We also animals ,32. No o2 -/- were relatively the same as PAR2 +/+ except during activity episodes at night. Differences in HR of PAR2 -/- and PAR2 +/+ during activity of the dark period coincided with similarly raised intensity levels of activity in the dark period  and/or increased cardiac stroke volumes in PAR2 -/-. Activation of PAR2 has numerous effects including endothelium-dependent vasodilation [2 in modulating vascular tone. Endothelial NO synthase (eNOS) is considered a major modulator of peripheral resistance and the 24 h mean blood pressures of eNOS -/- mice were found to increase by ~15% relative to controls when measured by radiotelemetry [2 -/- mice in the present study amounts to approximately one fourth of this level. Such differences in BP may be reduced by compensations from the time of conception so could explain the small size of effect of PAR2 -/- on baseline hemodynamics in mice even if PAR2 was a critical enzyme in blood pressure regulation. Theoretically, the small impact on BP could also underestimate the role played by PAR2 in modulating peripheral resistance (if cardiac output decreased in knockouts as part of compensation) or regulating local blood flow distribution.Slightly higher PP in PARdilation ,35-38, selemetry . The BP 2 to interact pathophysiologically with blood pressure control during high salt diet loading, there should be enzymes that mediate its activation that are linked to blood pressure regulation. The human kallikreins family of serine proteinases consists of several isoforms that have been found to activate PAR2 [2 was one such substrate. As a possible contributor to the mechanism of residual blood pressure lowering activity by kallikreins during salt loading, we had expected that PAR2 -/- would have been more salt-sensitive relative to controls, but these mice were in fact less salt sensitive than controls. Even so, the impact of such small absolute differences in the salt-sensitivity of BP between PAR2 -/- and PAR2 +/+ would likely to be physiologically trivial, and suggests that PAR2 is unlikely to play a significant role in the regulation of salt balance. In both strains HR was lowered during HS diet, an observation that has been reported in humans [2 interaction with non-blood pressure actions of HS diet that remain to be investigated.For PARate PAR2 . It was ate PAR2 ,21,40,41ate PAR2 . In the n humans . The dat2 on high Ang II acquired hypertension. At the end of 2 weeks, the effects of Ang II on BP were similar in PAR2 -/- and PAR2 +/+ mice. Collating the findings of classic physiology studies in multiple model systems, we expect that the immediate effects of elevating Ang II involve central nervous system and sympathetic nervous system activations and increases in peripheral resistance that are then followed later by mechanisms involving the resetting of kidney function and remodeling of the vasculature. Increasingly often there have been studies that have sought out links between inflammation and hypertension development involving angiotensin II. Studies to induce inflammatory responses in PAR2 -/- have resulted in mixed findings about pathological outcomes and our data support a main finding of a null effect on Ang II-acquired hypertension. Chronic high dose Ang II infusions over the period used in this study were shown to result in production of signs of vascular inflammation and endothelial dysfunction by the end-point, but have not been studied at the early time point (~7 day) at which we observed consistent differences in the trend for hemodynamic changes of PAR2 -/- [2 appears inconsequential to BP in the long term, other pathological effects of high Ang II that arise independent of BP such as endothelial dysfunction or the effects of threshold BP changes by a lower dose of Ang II could be manifested differently in PAR2 -/-. Other characteristics of endothelium-dependent inflammatory responses which have been shown to be different have included the time to onset which was delayed in PAR2 -/- [2 -/-[In addition to HS diet, a condition where the renin-Ang II system would be downregulated, we also treated mice with Ang II infusion in order to investigate possible interaction with PARPAR2 -/- ,19. We d/- [2 -/-.2 -/- mice exhibited a BP phenotype which was characterized by modest increases of systolic arterial and pulse pressures. The BP of PAR2 -/- is not more salt-sensitive than that of wild type mice, but differences in the time course of the BP responses to Ang II in PAR2 -/- and PAR2 +/+ may indicate the presence of a subtle influence of PAR2 on Ang II modulation of BP.In conclusion, PARJJM conceived and designed the study, supervised the planning and execution of experiments, acquisition of data, conducted data analysis and prepared the manuscript. SJH carried out the surgical and telemetry protocols and managed data collection. BVV provided guidance to study design, execution of technical protocols, data analyses and preparation of the manuscript. All authors have read and approved the final draft of the manuscript. Granting agencies did not contribute to study design, data collection, analyses, interpretation, manuscript writing or decision to submit the manuscript for publication.


Objective. To investigate changes in serum pituitary-gonadal hormones and restoration of sexual and reproductive functions after successful kidney transplantation. Patients and Methods. Serum pituitary-gonadal hormones before and after kidney transplantation were measured in 78 patients with end-stage renal disease (ESRD) and in 30 healthy adults. Pre- and postoperative semen specimens of 46 male recipients and 15 male controls were collected and compared. Additional 100 married kidney transplant recipients without children were followed up for 3 years to observe their sexual function and fertility. Results. Serum PRL, LH, and T or E2 levels gradually restored to the normal ranges in all kidney transplant recipients, and sperm density, motility, viability, and morphology significantly improved in the male recipients 4 months after successful kidney transplantation (P < .05). Thirty-three male recipients (55.93%) reobtained normal erectile function, and 49 kidney transplant recipients (61.25%) had children within the 3-year follow-up period. Conclusion. Successful kidney transplantation could effectively improve pituitary-gonadal hormone disturbance and sexual and reproductive dysfunctions of ESRD patients.  End-stage renal disease (ESRD) is usually associated with pituitary-gonadal hormone disturbance, and most ESRD patients are often perplexed by moderate or severe sexual dysfunction . AlthougSexual dysfunction and infertility are not uncommon in ESRD patients, and the occurrence of sexual dysfunction is about 50% to 70% in both male and female patients during dialysis . AccordiIncluded in this study were 78 married patients with ESRD  who ranged in age from 25 to 45 years with a mean of 33 years. The course of disease ranged from 2 to 6 years (mean 3.6 years), and the preoperative course of dialysis ranged from 3 to 34 months (mean 7.5 months). ABO and Rh blood types of the recipients and the donors were comparable, and the proportion of dead cells in lymphocytotoxicity test was <10%. Immunosuppressive therapy (Cyclosporine A (CsA) + Azathioprine (AZA) + Prednisone) was initiated from postoperative day 1. Additional 30 healthy adults  with normal erectile function or menstrual cycles were selected from the family members (SCr <2.0 mg/dl) of the 78 patients as controls, who ranged in age from 26 to 45 years (mean 33 years). There was no significant difference in age, habits, and living environments between the study and control groups. Additional 100 married kidney transplant recipients  without children who ranged from 26 to 45 years (mean 34 years) were followed up for 3 years. Exclusion criteria were (1) recipients who were unmarried, widowed, or divorced, (2) recipients who suffered from diabetes, hypertension, or other diseases that might significantly impair sexual or reproductive functions, and (3) recipients who had children before kidney transplantation. These recipients received the same immunosuppressive therapy.All selected recipients in this study were from Shanghai Tenth People's Hospital, 117th Hospital of PLA and Changzheng Hospital. no organs were used from prisoners and no subjects were prisoners in this study. Written informed consents were obtained from all subjects involved. This study was approved by the local ethics committee and conducted in accordance with the Declaration of Helsinki (1964).2 were measured immediately by electrochemiluminescence immunoassay  according to the manufacturer's instructions. All blood samples were measured in duplicate. Semen specimens of the 46 male ESRD patients were collected before kidney transplantation and 4 months after transplantation when their renal function was nearly restored to the normal range, and semen specimens of the 15 male healthy adults were used as the control. All semen specimens were analyzed and compared between the two groups. Serum pituitary-gonadal hormones were measured as follows: Venous blood samples of the 78 ESRD patients were collected during dialysis and at 1-2 and 3-4 months postoperatively, respectively. Blood samples of the 32 female recipients were collected 4-5 days after the menstrual period. Venous blood samples of the 30 healthy adults served as controls. Serum prolactin (PRL), follicle stimulating hormone (FSH), LH, and T or EThe investigation items of the additional 100 married kidney transplant recipients during the 3-year follow-up period include recording and analyzing the day of first nocturnal erection and sexual activity after transplantation, sexual desire, degree of erection, satisfaction with sexual activities, frequency of sexual activities, and international index of erectile function-5 (IIEF-5) score for the 68 male patients and the day of first menstruation and sexual activity after transplantation, satisfaction with sexual activities, frequency of sexual activities, pregnancy, and reproductive function for the 32 female patients.t test for independent samples. P < .05 was considered statistically significant.Statistical analyses were performed with SPSS version 13.0 statistical software. Pre- and post-operative serum pituitary-gonadal hormone levels, the volume of semen, and sperm viability, density, and morphology were compared between the study and control groups, using P < .01). Serum PRL, LH, and T levels of the 46 male ESRD patients gradually restored to the normal range after transplantation, and 3-4 months after transplantation no significant difference in serum PRL, LH and T was observed between the two groups . Serum PRL, LH, FSH, and E2 levels of the 32 female patients gradually restored to the normal range after transplantation, and 3-4 months after transplantation no significant difference in serum PRL, LH, FSH, and E2 levels was observed between the two groups  had severe oligospermia (sperm density was <5 × 106/ml), 29 patients (63.04%) had mild or moderate oligospermia (sperm density was 5–30 × 106/ml), and only 5 patients (10.87%) had normal sperm density before transplantation, and the proportion of sperms in normal morphology was only 2%–12%. Four months after transplantation, sperm density, motility, and viability as well as the proportion of sperms in normal morphology were significantly higher than those before transplantation (P < .05)  .Of the 100 married kidney transplant recipients without children, 59 male and 21 female recipients were followed up for more than 3 years, and the remaining 20 recipients lost followup by the end of this study.n = 21, 26.25%), workers , farmers , and freelancers .Researchers and civil servants , senior middle school , junior middle school , and primary school .University or above (1–18 years (mean 7.65 years).49 (61.25%) had children, and the remaining 31 (38.75%) had no children.(1)The day of first postoperative nocturnal erection in 59 male recipients was averagely 45 days (2–180 days) after transplantation, and the first postoperative sexual activity occurred averagely 252 days (80–560 days) after transplantation. Pre- and post-operative IIEF-5 scores of the 59 male recipients are listed in (2)The first postoperative menstruation of the 21 female recipients occurred averagely 38 days (5–90 days) after transplantation, and the first postoperative sexual activity occurred averagely 324 days (110–690 days) after transplantation. The mean frequency of postoperative sexual activities was 1.6 times (1–4 times) monthly.Of the 80 recipients who were followed up for 3 years, 49 (61.25%) had children and the remaining 31 (38.75%) had no children. Of the 21 female recipients who were followed up for 3 years, 8 patients (38.10%) had children, 4 patients (19.05%) experienced spontaneous abortion during the first trimenon of pregnancy, 5 patients (23.81%) terminated their pregnancy because of edema-hypertension-proteinuria syndrome or gradual worsening of their renal function, and the remaining 4 patients (19.05%) had never conceived.P < .05). Our 3-year follow-up showed that 72 recipients (90.00%) believed that sexual activities were unsafe within one year after kidney transplantation.All recipients felt anxious about or even afraid of sexual activities after transplantation, and therefore the frequency of sexual activities was very low or even naught in the first year after transplantation. Of the 59 male recipients, 46 patients (77.97%) felt anxious about sexual activities, 28 patients (47.46%) were afraid of sexual activities, and 19 patients (32.20%) deemed that sexual activities were harmful to the kidney grafts, even though most of them tried their first postoperative sexual intercourse within the first year after operation. Of the 21 female recipients, 17 patients (80.95%) deemed that sexual activities were harmful to the grafts. This figure was significantly higher than that in the male recipients  were willing to take care of the recipients lifetime, 25 spouses (31.25%) were willing for a take care of the recipients for the time being, and the remaining 8 spouses (10.00%) were unwilling to take care of the recipients at all. Fifty-seven spouses (71.25%) believed that the recipients could be cured. Twenty-five patients (31.25%) had marital relationships as that before kidney transplantation; the marital relationship became worse in 43 patients (53.75%) after operation; 12 patients (15.00%) got divorced. Twenty-six recipient spouses (32.50%) had extramarital affairs, 23 spouses (28.75%) could tolerate no sexual activities with the recipients, and 7 spouses (8.75%) felt disgusted about sexual activities with the recipients and eventually left them.Serum T, FSH, LH, and PRL levels were abnormal in ESRD patients even during hemodialysis or peritoneal dialysis –5. Previ2 level in the female recipients restored to the normal range 3-4 months after kidney transplantation. However, some immunosuppressive regimens such as sirolimus seemed to impair the improvement of gonadal function in kidney transplant recipients [The pre- and post-operative hormone changes of the 78 ESRD patients in our study indicated that the pituitary-gonadal function was significantly improved after kidney transplantation. Serum T level in the male recipients and Ecipients  conductecipients  reportedSexual disorders are common in ESRD patients, and about 50% of them had erectile dysfunction during dialysis , 12, whiThere is no recognized appropriate time for recipients to have the first sexual activity after kidney transplantation, although it mainly depends on the normal function of the renal grafts and the overall situation of the recipients. It was found in our study that the pituitary-gonadal function nearly restored to the normal range in most recipients four months after operation, suggesting that the first postoperative sexual activity could be attempted from four months postoperatively. However, most recipients in our series did not dare to have the first postoperative sexual activity until six months later; the frequency of sexual activity in the female recipients was less than that in the male recipients; the first day of postoperative sexual activity in the female recipients was also two months later than that in the male recipients, probably due to the misunderstanding that sexual activity was harmful to the grafts, especially in female recipients. It is therefore important to provide kidney recipients with timely psychological consultation, support, and treatment.Male ESRD patients are usually associated with spermatogenesis dysfunction, eventually leading to infertility. Semen analysis showed that the volume of semen, sperm count and motility were decreased in these patients. Histological examination of the testes further confirmed that spermatogenesis was inactive in such patients . We founμmol/L, no hyperlipemia, no hypertension or well-controlled hypertension, no proteinuria, good general conditions, no dilated renal calices as detected by B-ultrasound, and good tolerance with immunosuppressive therapy. With the development of kidney transplantation technique and the application of new immunosuppressants, pregnancy after kidney transplantation is no longer impossible –19. In tIn summary, with the development of social civilization, a new biopsychosocial medical model has been gradually recognized. Our study showed that serum pituitary-gonadal hormone levels were gradually restored to the normal range, and sexual and reproductive functions were also significantly improved after kidney transplantation, indicating that successful kidney transplantation could effectively improve pituitary-gonadal hormone disturbance and sexual and reproductive dysfunction in ESRD patients. Nevertheless, some recipients had a misunderstanding or psychologic barriers about postoperative sexual activity and fertility, and some other recipients were unable to get appropriate health care and psychological support from their spouses. It is therefore important and necessary to provide kidney graft recipients with timely medical education and psychological support after successful kidney transplantation.


Takayasu's arteritis is described to be the single most important cause of renovascular hypertension. Anaesthetising a child with Takayasu's arteritis for auto renal transplantation is a challenge as it is complicated by severe uncontrolled hypertension, end-organ dysfunction resulting from hypertension, stenosis of major blood vessels affecting regional circulation, and difficulties encountered in monitoring arterial blood pressure. A balanced anaesthetic technique, maintenance of stable haemodynamics with monitoring is required for a successful outcome. We describe the anaesthetic management of a child with Takayasu's arteritis and severe hypertension refractory to medical treatment requiring auto renal transplantation. Severe persistent hypertension in childhood is mainly due to renalparenchymal disease with renovascular lesions being the second most common cause. Takayasu's arteritis is the single most important cause of renovascular hypertension in non white childrenA 4-year-old male child weighing 13 kg, presented with history of dyspnoea on exertion for 3 month duration. On examination, all peripheral pulses were palpable except on the right upper limb. His blood pressure was 140/100 mm Hg in the left upper limb and was not recordable on the right upper limb. He was evaluated for secondary hypertension and found to have Type III Takayasu's arteritis with aortography revealing 99% stenosis of left main renal artery and 60% stenosis of the right main renal artery as well as occlusion of the right subclavian artery . He had −1. Under standard monitoring , anaesthesia was induced with air, oxygen and sevoflurane. The trachea was intubated following atracurium administration and the patient mechanically ventilated. Under ultrasound guidance, a 5F triple lumen catheter was sited in the right internal jugular vein. The left femoral artery was selected for direct arterial pressure monitoring. Anaesthesia was maintained with 50% mixture of air and oxygen, end-tidal isoflurane concentration of 1% with morphine, fentanyl and atracurium boluses as needed. Normocarbia was maintained to preserve cerebral perfusion. Surgery was done in supine position. A good perfusion pressure of the transplanted kidney was ensured by maintaining a systolic blood pressure of 130 mm Hg, CVP of 13-15 mmHg. Mannito 10.5g.kg−1 was infused 20 minutes before clamp release. Blood loss was replaced with fresh whole blood. Urine output was more than 0.5 ml.kg−1.hr−1 after the anastamosis. The intraoperative period was uneventful. Arterialblood gas analysis was within normallimits and trachea extubated at the end of the procedure. Post operatively, the child was monitored in the high dependency unit and had an unremarkable stay. Outpatient visit at 8 weeks revealed improved sensorium and blood pressure of 130/85mmHg in left upperlimb. Diethylene Tetramine Penta Acetate(DTPA) scan done at 8 weeks showed functioning of auto transplanted kidney (The patient was fasted and premedicated with Syp.Triclofos 75mg.kgd kidney  and antid kidney Patients with Takayasu's arteritis (TA) present for surgery either incidentally or more frequently for correction of the consequences of vascular occlusive disease. Anaesthetising such a child for auto renal transplantation is a challenge as it is complicated by severe uncontrolled hypertension, end-organ dysfunction resulting from hypertension, stenosis of major blood vessels affecting regional circulation, and difficulties encountered in monitoring arterial blood pressure59. Routine use of inotropes is not warranted and vasopressors should be given as the last resortSudden hypertensive or hypotensive episodes are avoided intraoperatively so as to prevent possible cerebrovascular or cardiovascular crises1Anaesthetising a child with Takayasu's arteritis for an auto renal transplantation is a challenge due to the various pathological and hemodynamic changes involved. Successful outcome depends on preoperative optimisation, intra operative maintenance of stable hemodynamics and invasive monitoring during perioperative period.


Stress is a risk factor for musculoskeletal pain. We wanted to explore stress related physiology in healthy subjects in order to gain insight into mechanisms of pain development which may relate to the pathophysiology of musculoskeletal pain disorders.Continuous blood pressure, heart rate, finger skin blood flow, respiration, surface electromyography together with perception of pain, fatigue and tension were recorded on 35 healthy women and 9 healthy men before, during a 60 minute period with task-related low-grade mental stress, and in the following 30 minute rest period.Subjects responded physiologically to the stressful task with an increase in trapezius and frontalis muscle activity, increased blood pressure, respiration frequency and heart rate together with reduced finger skin blood flow. The blood pressure response and the finger skin blood flow response did not recover to baseline values during the 30-minute rest period, whereas respiration frequency, heart rate, and surface electromyography of the trapezius and frontalis muscles recovered to baseline within 10 minutes after the stressful task. Sixty-eight percent responded subjectively with pain development and 64% reported at least 30% increase in pain. Reduced recovery of the blood pressure was weakly correlated to fatigue development during stress, but was not correlated to pain or tension.Based on a lack of recovery of the blood pressure and the acral finger skin blood flow response to mental stress we conclude that these responses are more protracted than other physiological stress responses. A substantial epidemiological literature has shown that mental and social stress is a risk factor for development of musculoskeletal pain, especially for pain in the shoulder and neck -4. DiffeIn order to explore further the physiological basis for the link between stress and muscle pain, which again may relate to chronic pain development, we performed this study on healthy subjects performing a long-lasting stressful task (1 hour) with a 30 minute recovery period. We used a stressful task of sufficient duration to mimic real-world (e.g. work-related) stress, adding external validity to the methodology . The strFirstly, we wanted to describe the autonomic and muscular response and recovery profiles after low-grade mental stress of long duration in healthy subjects. Secondly, we hypothesized that development of subjective complaints during a long lasting low-grade stressful task were related to the physiological response to the task. Lastly, we hypothesized that those variables with the slowest recovery profile would be related to the subjective complaints induced by the stressful task.Forty-four healthy subjects participated in the study Table . The parAll subjects answered a questionnaire on biographical data , exercise habits, and the neuroticism index of the Eysenck Personality Questionnaire (EPQ-N). The queAll potential participants went through a short telephone interview to exclude those not fulfilling inclusion criteria. Subjects not excluded by the initial screening received the questionnaire by post within two weeks of the test day. On the morning of the test day the subjects first went through a short interview controlling the answers from the questionnaire. Afterwards venous blood was sampled from the right cubital fossa. Subjects were instructed to empty their bladder before starting the test. Brassieres were removed and subjects wore only a light shirt on the upper part of the body. The laboratory temperature was regulated to 24.5 ± 1.0°C and was recorded every ten minutes during the experiment.The subject was seated in an office chair with the lower arms resting on the table top before, during and after the test. Subjects got acquainted to the work-task by performing a mini-trial with instructions before the test started. The mini-trial was performed without introducing stress-imposing feedback on reaction time and was used to determine the subjects' habitual, non-stressed reaction time. Short maximal voluntary contractions were performed on each pair of muscles twice . The maximal contractions were carried out in order to normalize the muscle activity during test to a percent of maximal force. However, the variability between the two maximal muscle contractions in the frontalis muscle was too large to make a reliable estimate of the maximal muscle force and thus none of the muscle activity measurements were normalized. In order to measure the subjects habitual level of physiological activation, the laboratory experiment started with a five minute period which served as a baseline period for the physiological variables. The subjects were alone in the room and were not given any instructions other than to find a comfortable position with their arms resting on the table in front of them. To ensure that all subjects had the same low level of muscle activity before the test started a five minute feedback period with muscle activity visualized on a screen followed. The subject experienced how it was possible to influence the level of muscle activity by adopting different postures and thereafter concentrated on minimising any muscle activity. The stressful task  was thenA second blood sample was drawn during 5 min immediately after the test, before the 30 minute recovery period. Blood analysis was not a major aim of the study and these results are reported elsewhere .Muscle activity was quantified by bilateral bipolar recording of surface electromyography (SEMG) . The system noise level was less than 1.5 μV root mean square (RMS). The signals were bandpass-filtered (10–1250 Hz) and stored on a digitizing recorder (Earth Data 128). Data were subsequently fed into an A/D converter  for calculation of the RMS values (100 ms running time window). Sharp transients and electrical activity from the heart in the SEMG signals were removed with a median filter .The following electrode sites were used: (1) Frontalis muscle; both electrodes placed on a vertical line crossing the pupil, 10 mm and 30 mm above the upper border of the eyebrow. (2) Temporal muscle; the lower electrode 10 mm posterior to the lateral canthus of the orbit, and the second electrode 20 mm above. (3) Splenius muscle; upper electrode 35 mm lateral to the spinous process of C2, and the second electrode 20 mm below. (4) Trapezius muscle; medial electrode 10 mm lateral to the midpoint of a line connecting the acromion and the spinous process of C7, and the second electrode 20 mm lateral to the first electrode. The ground electrode was placed on the spinous process of C7.Activity in the autonomic nervous system was assessed by measurements of continuous non-invasive finger blood pressure (Portapres), measureRespiration frequency was calculated by the Chart 4.2 software . Heart rate and blood pressure were calculated with the Beatscope 1.0 software . One blood pressure recording could not be analyzed due to technical difficulties.Technical difficulties resulted in exclusion of seven subjects from analysis of respiration frequency and exclusion of two subjects from analysis of heart rate and blood pressure responses.Mean values for each 10-minute period were calculated for all physiological recordings. Muscular activity and finger blood flow values are reported as the average of the left and right side for each region because ANOVA repeated measures analysis (rANOVA) revealed no side differences for the finger skin blood flow and muscle activity except for the frontalis muscle SEMG (left side (10.9 μV) > right side (9.2 μV); F(43) = 8.0, p = 0.007). However, performing all subsequent tests separately for right and left frontalis muscles did not give deviant results from those reported. Pain scores are reported from the side with the highest response (there were no side differences in neither pain level (side effect) nor pain development (side × time effect) for any of the four regions .ANOVA with repeated measurements was used for evaluation of subgroup effects  with ten time intervals. For subgroup analysis of the recovery period we calculated a recovery variable (the difference between the mean of the last 10 minutes of rest 85–95 min) and the baseline period mean), a measure considered to be more meaningful than the absolute level when comparing groups [5 min andFor evaluation of the total response to the test we first performed repeated measures ANOVA tests  with the same time intervals as in the subgroup analysis. For further post-hoc exploration of the response and recovery time-course we performed a series of paired-sample tests  and Wilcoxon signed rank test for subjective variables (not Gauss-distributed)): We first evaluated the early response to the stressful task by comparing the first part (0–10 min) of the stressful task to baseline (immediately before the stressful task for the subjective variables). Secondly, changes during the stressful task (adaptation/summation effects) were investigated by a comparison of the first (0–10 min) and the last (50–60 min) part of the stressful task. Thirdly, we evaluated the recovery by comparing the change from the end of the stressful task (50–60 min) with the first part of the recovery period (65–75 min) and the first (65–75 min) and last (85–95 min) part of the recovery period with baseline.Physiological responses (the difference between the average of the whole stressful task (0–60 min) and the average of the baseline period) and subjective responses to the stressful task  were calculated as summary-variables for correlation analysis. Subjects with a pain response larger than zero were defined as pain responders. For each subject the location with the highest pain response during the task was identified (i.e. only one location for each subject). The pain response in this location  was treated as a separate summary variable in the analysis .p) for physiological variables (Gauss-distributed) and Spearman's rank order correlation (rs) when subjective data were involved (not Gauss-distributed).Possible associations between variables were investigated by correlating the muscular responses  with the autonomic responses , and by correlating physiological responses (as above) with subjective responses , and finally by correlating the subjective responses with each other . The correlation coefficients between pain and muscular responses were calculated separately for each localisation . Furthermore, as post-hoc analysis we searched for possible correlations between blood pressure/finger skin blood flow recovery variables and physiological responses, subjective responses and other recovery variables. We used Pearson correlation  participants received NOK 500 (USD 75). The Regional Committee for Medical Ethics approved the protocol, and all participants gave written informed consent before volunteering. Experiments were performed according to the Helsinki Declaration.All variables are listed in Table The development of all physiological variables is illustrated in Figure The stressful task induced a clear response evident in all physiological variables  and height correlated negatively with the average systolic blood pressure response . None of the other physiological responses  and the temporalis muscle response . The other correlations in the SEMG vs autonomic response matrix were non-significant (p > 0.06).The heart rate response correlated with the trapezius muscle response , respiration frequency (p < 0.001) and muscle activity in the trapezius (p < 0.003) and the frontalis (p < 0.002) decreased significantly (50–60 min vs. 65–75 min). Trapezius and frontalis SEMG recovered to the baseline level  while heart rate and respiration frequency recovered to a level lower than baseline . However, systolic and diastolic blood pressure, finger skin blood flow and muscle activity in the splenius and temporalis muscles did not change significantly upon cessation of the stressful task . The systolic and diastolic blood pressure level remained elevated and finger skin blood flow was reduced during the whole recovery period (baseline vs. 85–95 min p ≤ 0.001).p = -0.52, p = 0.001 and rp = -0.40, p = 0.01 respectively). This means that a high blood pressure at the end of the recovery period was associated with a small finger skin blood flow at the same time. The finger skin blood flow and blood pressure recovery variables did not correlate with other physiological  response or recovery variables .The finger skin blood flow recovery variable Table  correlatDevelopment of tension, fatigue and pain scores in the maximal pain location is illustrated in Figure Thirty subjects (68.2%) reported an increase in pain in at least one location during the test and twenty-eight subjects (63.6%) had an increase in pain VAS score of more than 30 mm during the test Table . The pais ≤ 0.19, p ≥ 0.20), however, fatigue and tension responses were correlated .Pain responses did not correlate with tension and fatigue responses . However, the fatigue response correlated with systolic  indicating a larger fatigue response during the stressful task for those subjects who recovered less during the rest period. However, no significant correlations were found between the blood pressure recovery and the pain and tension response variables  and finger skin blood flow recovery was not correlated to subjective responses .Pain, tension and fatigue responses did not correlate significantly with physiological responses , the physiological responses were not correlated to the Nevroticism index or the "autonomic symptom index". The Nevroticism index .Except for a correlation between the autonomic symptom index Table  and the Subgroup analyses with the dichotomized variables in Table Major findings in the present study on stress responses in healthy subjects can be summarized as: 1) A significant proportion of healthy subjects (64%) respond with a pain increase of more than 30 mm (VAS 0–100) in at least one of the four muscle groups investigated. 2) Pain develops gradually as a response to a stressful task. 3) The trapezius and frontalis muscles are activated in response to the task with fast recovery after a stressful task. 4) The HR-response habituates gradually during a long-lasting stressful task and recovers fully afterwards. 5) There is a lack of skin blood flow and blood pressure recovery after a stressful task of long duration. 6) Physiological responses (and recovery) are not correlated with pain responses, but 7) lack of blood pressure recovery is correlated to the fatigue response to the preceding stressful task.The most important finding is that blood pressure and finger skin blood flow did not recover to baseline during the 30-min rest period, contrasting the recovery pattern of the other autonomic and muscular responses. The finger skin blood flow apparently had biphasic response pattern with a fast reduction during the first ten minutes of the stressful task and a further monotonic reduction (trend) during the stressful task, while the blood pressure increased during the first ten minutes of the stressful task and stayed elevated both during and after the stressful task.Slow recovery of blood pressure following experimental stress has previously been reported by Steptoe and co-workers ,21. TheyThe present study of healthy controls shows that slow vascular recovery after mental stress is a normal phenomenon and is not related to simultaneous pain development. The theoretical models linking stress and subjective health complaints emphasize lack of recovery after stress as an important factor for development of subjective complaints -7. AccorA long-lasting, presumably sympathetically mediated vasoconstriction is evident in the present study. Environmental temperature was monitored throughout the experiment and was stable and not related to skin blood flow (data not shown). The slightly different time course of blood pressure and the finger skin blood flow response indicate differential control of vascular beds. This is interpreted as an example of the specificity of different neuroanatomical circuits within the autonomic nervous system  and corrAlthough the reduction of finger skin blood flow was not related to subjective complaints in the present study, it is potentially relevant that some patients with musculoskeletal complaints report a cold feeling in wrist/hand ,27. A reA previous study on pain-free subjects using a similar protocol, but without measurements of blood pressure, heart rate and respiration frequency, found a correlation between pain development and muscle activity in the right trapezius muscle  during the stressful task . In the In the present study most cardiovascular vs. EMG correlations were not significant. However, we found correlations between the heart rate response and trapezius and temporalis muscle responses. The correlations were strong (p < 0.005), and we cannot exclude that it is relevant. The electrical activity from the heart was filtered out of the electromyographic signals, and a correlation with heart rate was not observed for the splenius muscles, hence it is probably not related to an ECG-artefact. Increased muscular activity in a rather large muscle like trapezius is reasonably paralleled by increased HR if the increased muscular activity demands a higher cardiac output to satisfy the metabolic needs.The low-grade stress response in the present experiments is shown by the heart rate only being elevated by 4 beats per minute (bpm) on average, and 5 bpm the first 10 min. Other studies of stress responses have exposed subjects to stress for a shorter period of time and report elevated heart rate responses of 10–20 bpm indicating a higher level of stress -31. The The subject's perception of the stressor was not considered in terms of stress level in the present study, but evaluated using the term "tension". Holte et al.  investigThe feedback period was necessary in order to ensure that all subjects had the same low level of muscle activity before the stressful task. The feedback was given solely on muscular activity. The feedback was introduced after the baseline period in order to get a true baseline period without influence from the feedback procedure. It is possible that the feedback procedure influenced the measured muscle activity during the stressful task by teaching the subjects how to relax their muscles. However, this effect was supposedly similar for all subjects. Furthermore, subjects did not receive any feedback on the measured variables during the stressful task.In the correlation analysis we have used summary variables in order to minimize the number of calculated correlations. While the subjective variables were steadily increasing through the task, most physiological responses were more stable . The physiological variables were measured continuously and we did not want to place emphasis on any (possible random) peak value. Instead, the average value was considered a summary variable reflecting the total physiological "burden" of the stressful task. However, the average pain score will in our opinion not reflect the subjective "burden" of the stressful task. An average pain score would underestimate the pain-inducing effect of the stressful task in case the subject's pain pathways would have been sensitised in any way, thus potentially neglecting the effect of any temporal summation of pain. We have chosen to use the maximal value during the task as an approximation of this "burden", and this is in line with others -39.Our subgroup analysis did not reveal any differences between groups regarding the recovery variables, and the present study thus confirms the findings of Steptoe  who repoWe are not aware of other studies investigating the relation between development of fatigue during stress and degree of physiological recovery and thus our finding of a correlation between lack of blood pressure recovery and fatigue development during stress should be further investigated. It must be emphasized that the correlation was weak and may be a chance finding because of the large number of correlations performed. Nevertheless, the correlation may indicate that psychological mechanisms are important when considering the mechanisms for the protracted vascular response. Moreover, the correlation between the blood pressure and finger skin blood flow recovery variables may point to a common mechanism responsible for the lack of recovery in these two variables.Steptoe (2003) proposed sustained changes in centrally mediated neurogenic vasoconstriction, or disturbance of nitric-oxide-dependent endothelial function, as explanations for lack of recovery of blood pressure after mental stress . HoweverIn the present study of healthy subjects exposed to mental stress in 60 minutes the blood pressure and acral finger skin blood flow response did not recover to baseline even after 30 minutes rest. This was in clear contrast to other physiological stress response variables  which recovered to baseline values early in the rest period. The protracted blood pressure response was correlated to fatigue development, but not to pain development, possibly implicating psychological mechanisms. However, because of the large number of correlations performed in the present study, one must keep in mind that this correlation may be a chance finding. The results imply that a long recovery period is necessary when the physiological recovery to mental stress is studied. Moreover, a thorough exploration of different aspects of the subjective complaints that develops during and after low-grade stress of long duration is needed. Examplewise, a valid and reliable way to distinguish between mild fatigue and unpleasantness in contrast to pain should be established in later studies of the relation between stress and development of subjective complaints. Furthermore, the duration of stress period may be of importance and should be addressed in future studies of physiological recovery after mental stress. Finally, further studies should in a prospective design investigate whether healthy subjects with a slow vascular recovery after mental stress is at risk for developing chronic stress-related disorders later in life.The authors declare that they have no competing interests.KBN participated in study design, in collecting the data, carried out the analysis and drafted the manuscript. TS participated in the design, advised and assisted in the statistical analysis and in the progress and drafting of the manuscript. LJS participated in the study design and in the progress of the manuscript. RBL participated in the statistical analysis and in the progress of the manuscript. RHW participated in the design, and in the progress and drafting of the manuscript. All authors read and approved the final manuscriptThe pre-publication history for this paper can be accessed here:


Blood pressure lowering drugs are usually evaluated in short term trials determining the absolute blood pressure reduction during trough and the duration of the antihypertensive effect after single or multiple dosing. A lack of persistence with treatment has however been shown to be linked to a worse cardiovascular prognosis. This review explores the blood pressure reduction and persistence with treatment of antihypertensive drugs and the cost consequences of poor persistence with pharmaceutical interventions in arterial hypertension.We have searched the literature for data on blood pressure lowering effects of different antihypertensive drug classes and agents, on persistence with treatment, and on related costs. Persistence was measured as patients' medication possession rate. Results are presented in the form of a systematic review.Angiotensin II receptor blocker (ARBs) have a competitive blood pressure lowering efficacy compared with ACE-inhibitors (ACEi) and calcium channel blockers (CCBs), beta-blockers (BBs) and diuretics. 8 studies describing the persistence with treatment were identified. Patients were more persistent on ARBs than on ACEi and CCBs, BBs and diuretics. Thus the product of blood pressure lowering and persistence was higher on ARBs than on any other drug class. Although the price per tablet of more recently developed drugs  is higher than that of older ones (diuretics and BBs), the newer drugs result in a more favourable cost to effect ratio when direct drug costs and indirect costs are also considered.To evaluate drugs for the treatment of hypertension several key variables including the blood pressure lowering effect, side effects, compliance/persistence with treatment, as well as drug costs and direct and indirect costs of medical care have to be considered. ARBs, while nominally more expensive when drug costs are considered only, provide substantial cost savings and may prevent cardiovascular morbidity and mortality based on the more complete antihypertensive coverage. This makes ARBs an attractive choice for long term treatment of hypertension. Blood pressure lowering drugs are approved based on short term trials determining the absolute blood pressure reduction during trough and the duration of the antihypertensive effect after single or multiple dosing. The absolute amount of blood pressure reduction in mmHg over the short term can however not be extrapolated to the degree of protection against hypertensive end organ damage because low patient's compliance and poor persistence with treatment may lead to early discontinuation of treatment in clinical practice -3.To be effective treatment must continue, sometimes for a patient's life, despite an absence of symptoms or any perceived benefit to the patient -6. UnforTherefore this review explores the cost consequences of poor persistence with pharmaceutical interventions in arterial hypertension. The aim is 1) evaluating the antihypertensive effects of drugs, 2) reviewing persistence with different pharmacotherapies and 3) exploring the related expenditure, such as drug costs, overall healthcare expenditure and productivity costs, and investigating the effect it has on the cost-effectiveness of pharmaceutical interventions for hypertension.In this review, the definitions of the International Society for Pharmacoeconomics and Outcomes Research (ISPOR) were used, which define compliance as taking medication as prescribed, on time and at the correct dose, and persistence as the continuing use in time of the prescribed therapy . DefinedWe have identified studies describing compliance/persistence with treatment using different antihypertensive classes and their related costs. The following search term was entered into pubmed: "hypertens* AND (complia* OR adhere* OR persiste*) AND (cost* OR econo*)" with the limits: "Publication Date from 1995/01/01, Humans, English." A manual search of the reference lists from retrieved publications was also performed to identify further relevant studies.Studies were regarded relevant if they were in English language, involved human studies published before November 2008, involved patients with hypertension, examined compliance (adherence) and/or persistence to pharmaceutical interventions (even if the primary objective was not to measure compliance/persistence), provided an economic evaluation or cost analysis and quantified the cost consequences of compliance/persistence. Studies published before 1995 were excluded as results from those earlier studies could not be compared with those from more recent studies because of changes in treatment patterns, study methodology and the price of healthcare resources, including drug prices. Studies were also excluded from analysis if the economic consequence of compliance/persistence was not quantified.Qualitative data extracted from the studies included the country where the study was performed, the number of patients, the database used, the type of study , the duration of follow-up, definitions used for persistence, compliance, switching and discontinuation as well as the type of patients with mean age, gender and drugs at the onset of the study  or ARBs  was analysed for example for the degree of blood pressure reduction -14. At o,651 pts Table Bloom et al. .,42.WithiThe majority of patients with hypertension receive combination antihypertensive therapy. Current guidelines of the ESH/ESC recommend combination treatment for patients uncontrolled on monotherapy or in patients with blood pressure values on presentation exceeding 20/10 above the respective patient target . Fixed-dTo evaluate drugs for the treatment of hypertension several key variables have to be considered. These variables include the blood pressure lowering effect, side effects, compliance and persistence with treatment, as well as drug costs and direct and indirect costs of medical healthcare. Given that the highest persistence with treatment results in the lowest non-drug costs, substantial cost savings and a reduction of morbidity might be expected making these drugs an attractive choice for long term treatment of hypertension.All authors have attended advisory boards and have held lectures for a number of pharmaceutical companies including sanofi-aventis and BMS.All authors have made substantial contributions to conception and design, or acquisition of data, or analysis and interpretation of data. PB has drafted the manuscript. JH revised the manuscript for important intellectual content. All authors have given final approval of the version to be published.


Home Blood Pressure Measurement, HBPM) has positive effects on treatment adherence and is helpful in achieving the target blood pressure. Only a few studies have investigated whether adherence to HBPM can be improved through simple measures resulting also in better blood pressure control.Insufficient blood pressure control is a frequent problem despite the existence of effective treatment. Insufficient adherence to self-monitoring as well as to therapy is a common reason. Blood pressure self-measurement at home (Improvement of self-monitoring and improved blood pressure control by using a new colour-coded blood pressure diary.Primary outcome: Change in systolic and/or diastolic blood pressure 6 months after using the new colour-coded blood pressure diary.Secondary outcome: Adherence to blood pressure self-measurement (number of measurements/entries).Randomised controlled study.Population: 138 adult patients in primary care with uncontrolled hypertension despite therapy. The control group uses a conventional blood pressure diary; the intervention group uses the new colour-coded blood pressure diary .The visual separation and entries in three colour-coded areas reflecting risk  lead to better self-monitoring compared with the conventional (non-colour-coded) blood pressure booklet. The colour-coded, visualised information supports improved perception (awareness and interpretation) of blood pressure and triggers correct behaviour, in the means of improved adherence to the recommended treatment as well as better communication between patients and doctors resulting in improved blood pressure control.ClinicalTrials.gov ID NCT01013467 Arterial hypertension is the most common cardiovascular risk factor throughout the world and guidelines for the management of hypertension underscore the need for strict blood pressure (BP) control to decrease the risk of morbidity and mortality in hypertensive patients ,2. DespiIn Switzerland every seventh adult is affected, only half of them receive treatment. Of those patients treated, which cost the health system in Switzerland over CHF 435 million in 2005 [An important factor in achieving targets in the management of hypertension is patient adherence to treatment . A plethA review on how to reach targets in the treatment of diabetes patients in primary care showed that interventions with the greatest positive effect were complex and should include activities which change the behaviour of doctors, changes to practice organisation, expansion and provision of information and educational programmes for patients . The meaWith a chronic illness as hypertension the role of the patient changes. The patient is central to efforts to monitor and control the illness to the best possible extent. Knowledge about illness and treatment is the basis, but in particular behaviour strategies are necessary to achieve the best possible long-term control. Our study focuses on patient-related factors as the central condition for improved treatment adherence .Blood-pressure self-measurement at home (HBPM) is an established and evidence-based behaviour measure, which is recommended in guidelines on the treatment of hypertension and which has been shown to improve knowledge about treatment and also adherence to treatment with medication by about 20% -19. UntiThe colour-coded blood pressure booklet improves adherence to self-monitoring (higher number of HBPM) and leads to improved blood pressure control.We are assuming that the colour-coded tool supports adequate patient behaviours by improving awareness and interpretation of blood pressure control. It also might support better patient-doctor communication which is a central aspect for treatment adherence and improved blood pressure control.A two-armed study randomised and controlled at patient level. The intervention group will receive a new colour-coded blood pressure booklet, the control group a standard blood pressure record booklet without colour coding. The measuring period for both groups is 6 months figure .General practitioners will be invited to join the study via letters sent by post and information sessions. Any general practitioners who provide basic medial care with a workload of at least 20 hours per week are entitled to participate in the study.• Age >18 years• BP > 140/90 mmHgTwo consecutive measurements carried out in the practice.• Insufficient knowledge of the German language for instruction and blood pressure recording with a booklet.All patients will be asked consecutively about participating in the study and they will be handed an information sheet. All patients who have been approached will be included in a list containing the blood pressure booklet code which will be passed on to the study centre. The list remains in the practice so that the study leaders only have anonymous access to the patient data. However, in the practice it is possible to link the blood pressure record book with the medical file of the patient so that all the clinical data is available. Any patients who have been approached and have declined to participate will be included in a list in order to carry out a non-responder analysis of patients with regard to socio-demographic and clinical data.Case number calculation and power analysis were carried out on the basis of the expected effect for systolic blood pressure. With an alpha of 0.05 and a power of 0.9 (one-sided test) this means that 138 patients are required in order to be able to show a clinically relevant blood pressure difference of 7 mm Hg systolic with a standard deviation of 14 mmHg between the groups. Assuming a dropout rate of 20% this means that at least 166 patients are required.The randomisation  will take place at patient-level and will be carried out centrally by the study centre. We will draw up a randomising list by computer . The blood pressure record booklets will be distributed on the basis of this list in consecutively numbered opaque envelopes. The opaque envelopes will be given to the practices in numerical order. They can not be resealed. GPs are asked to notice the number (code) of the booklet  on a list together with the name and birthday of the patient and generate a code out of this data. This list will remain in the practice and is just for the purpose to be able to link the booklets with the patients name and therefore the patients' medical file. The study centre will receive a list with the generated code of the patient and the distributed booklet. So, the linkage to the name and medical file is only possible with the list held by the GP. Opened but not used envelopes have to be noticed in the list as used ones and marked as "not distributed". The practices will each receive four envelopes in which there will either be a colour-coded or a standard record booklet. The patients will be included consecutively and the doctor will open one envelope after the other in the order of the envelope numbers. In practice number one envelopes 1-4 will be opened consecutively, in practice number two envelopes 5-8 etc. This central randomisation means that the concealment of random allocation is ensured.Blinding of the general practitioners regarding group identity is not possible. Patients do only know that different types of blood pressure record booklets are being distributed, but they do not know in detail what the difference between the booklets is.The patients in the intervention group will receive a colour-coded blood pressure record booklet. The corresponding colour coded areas are divided into three areas of green, yellow and red following a traffic light system. The green area covers blood pressure readings up to a maximum of 140/90 mmHg, the yellow area includes systolic readings over 140 to 180 mmHg and diastolic readings over 90 to10 mmHg. The red area covers systolic readings over 180 mmHg and diastolic readings over 110 mmHg. All patients will be trained in the standardised use of the blood pressure record booklet including home blood pressure measurement additional they receive an instruction leaflet. They will be asked to measure their blood pressure in the morning while they are sitting and before they take their blood pressure medicaments. The readings will be recorded in the relevant blood pressure booklet for six months. All patients will be trained in the same way for one of the two study BP booklets by the general practitioner or the practice assistant for the duration of the study. The general practitioners and practice assistants will receive the same instruction and training for this as well as an instruction leaflet. Validated electronically blood pressure meters (MioStar Cardioplus 500) will be provided to all practices and patients to assure a standardization of the measurement. All measurements have to be performed with these meters.There will be blood pressure measurements by the general practitioner at the start (t0) as well as after 3 months (t1) and at the end of the study after 6 months (t2). To rule out blood pressure differences BP will be measured at both arms at t0. Each subsequent measurement in the practice of the general practitioner will involve two blood pressure measurements in each case in the left arm if the initial measurement did not differ between both arms by more than 5 mm Hg. If the measurement differed by more than 5 mm Hg at t0, BP will be measured at the arm with the higher reading subsequently. All the readings will be recorded, but for inclusion (as stated above) as ell as for analysis, the second measurement will be used. The difference (t2-t0) between the systolic blood pressure readings at the practice measurement represents the primary end point.All patient contacts will be collected over the entire period. At time t2 (after the end of the study) the number of times there was contact with the general practitioner since the inclusion of the patient will be recorded.- Number of patients, who achieve blood pressure control under 140/90 mm Hg.- Adherence: the absolute number of blood pressure measurements (entries in the BP record booklet) by the patients will be assessed as correlative of adherence during the period of observation.The first supply of data takes place at randomisation and subsequent at the specific measuring points t1 and t2.At the end of the study the list with the booklet codes as well as the code, generated out of the patients' name and his birthday will be send to the study centre. In the study centre, all received questionnaires and lists will be scanned electronically and a TIF-file will be generated to avoid data manipulation. The data will be directly exported in the statistic program .2 test. For continuous variables, comparisons between treatment groups were done with t tests.Descriptive statistics: average value with +/- 1 SD and median values of the average blood pressure readings for both groups. In accordance with the normal distribution test it will be decided whether parametric or non-parametric tests are to be applied. Treatment group comparisons for categorical data will be done with the χPrimary outcome: difference (t2-t0) between the systolic blood pressure average readings from the practice measurement. All patients will be analysed in accordance with the „intention-to-treat” approach and the latest available measurement will be used (last- observation carried forward). When interventions are provided via GPs, one should be aware of a cluster effect. We decided to perform a randomisation on the patient's level since the effect mediated by the GP on the intervention is assumed to be small. Nevertheless, we will account for that and include the factor "Practice" as a random effect in the analysis.Although there is a large amount of data on non adherence in chronic illnesses such as diabetes, heart failure, chronic lung disease and hypertension, there is relatively little research data on interventions which try to solve the problem of non-adherence. In addition, the conclusions of intervention studies are often based on subjective patient information and not on objective investigations. Data and evidence on a true change in behaviour assessed with hard clinical end points are needed.Our study measures the use of a simple, practicable intervention tool. A new BP record booklet containing and providing a visualised interpretation in colour of blood pressure control that is useful as feedback for the patient and doctor and can help to improve patient-doctor communication as well as triggering appropriate behaviour strategies. A change or adjustment in behaviours is an important precondition to achieve relevant clinical end points in the case of chronic illnesses .If there is evidence of a significant effect with this simple intervention and the new hypertension control tool, then this benefit can be achieved without additional treatment and risk of side-effects, without relevant additional costs and without additional effort for the patient and doctor. Patients, who measure their blood pressure at home generally, record their blood pressure. The documentation in a different record booklet as used previously therefore means no extra effort. The instruction for using the new blood pressure record booklet is also no extra effort for the "health professionals", in this case the general practitioner or practice assistant. No extra work load is an important condition for implementation of evidence based recommendations into practice.A double blind approach is not possible because training has to be given on the blood pressure record booklet. Some sub-groups  are too small to reach significance.The study is being conducted in accordance with medical professional codex and the Helsinki Declaration as of 1996 as well as Data Security Laws.Study participation of patients is voluntary and can be cancelled at any time without provision of reasons and without negative consequences for their future medical care.Previous to study participation patients receive written and spoken information about the content and extent of the planned study; for instance about potential benefits for their health and potential risks. In case of acceptance they sign the informed consent form.In case of study discontinuation all material will be destroyed or the patient will be asked if he/she accepts that existing material can be analyzed in the study.The study protocol is approved by the ethics committee of Zurich  Zürich (EK-1738).The patient names and all other confidential information fall under medical confidentiality rules and are treated according to appropriate Federal Data Security Laws. All study related data and documents are stored on a protected central server of the University of Zurich. Only direct members of the internal study team can access the respective files.Intermediate and final reports are stored at the Department of General Practice at the Zurich University Hospital (USZ).HBPM: Home Blood Pressure Measurement; BP: Blood Pressure; KEK: Kantonales Ethisches Kommitee.The authors declare that they have no competing interests.All five authors made a substantial contribution to this manuscript, i.e. conception, design and drafting.


P = 0.003) and the duration of diabetes (P = 0.000). No statistically significant correlation was found between microalbuminuria and age, sex, body mass index, levels of fasting blood sugar, glycosylated hemoglobin (HbA1c), serum triglyceride, and serum cholesterol, or systolic blood pressure. For 240 patients for whom the duration of diabetes was known from the answers in their questionnaires, logistic regression was used for analysis. Results showed that two variables including the duration of diabetes and Diastolic Blood Pressure (DBP) play a role in this model and the following Logic association was obtained: g^ (x) = -9.233 ± 0.079 DBP ± 0.114 duration according to this model, both DBP and duration of diabetes were directly correlated with microalbuminuria. Determination of the urine albumin to creatinine ratio is an easy method for screening of microalbuminuria that is suggested for all diabetic patients, especially diabetic patients with hypertension and long-term diabetes.A cross-sectional study was performed from November 2005 to July 2007 to determine the prevalence of microalbuminuria and its risk factors among type 2 diabetic patients.. Two hundred and eighty-eight type 2 diabetic patients  referred to Yazd diabetes research center were randomly recruited for the study. Microalbuminuria was detected by measuring the albumin to creatinine ratio in the early morning urine. Microalbuminuria was diagnosed if this ratio was between 30 and 300 mg/g on two occasions during three months. Prevalence of microalbuminuria was 14.2%. Chi-square analysis revealed that microalbuminuria was correlated with the diastolic blood pressure ( Diabetes is an important metabolic disorder worldwide and is characterized by variable degrees of insulin resistance, impaired insulin secretion, and increased glucose production.46The presence of microalbumin in the urine of persons with type 2 diabetes is perhaps the most important early signal heralding the onset of systemic vasculopathy and associated with target organ damage . Microalbuminuria also identifies patients who need more rigorous cardiovascular risk management, especially more intensive blood pressure control, and strict attention to glycemic control and lipid levels.7One of the central functions of the kidney is the excretion of low molecular weight, water-soluble, plasma waste products into the urine, whereas macromolecules the size of albumin and larger, are retained. The flow of the glomerular filtrate is thought to follow an extracellular route, passing through the endothelial fenestrate, then across the glomerular basement membrane, and finally through the slit diaphragm between the foot processes of podocytes. It has been recently hypothesized that microalbuminuria leading to proteinuria and end-stage renal disease is mainly due to an altered glomerular filtration barrier at the podocyte level. However, arterial hypertension and abnormalities of blood lipid concentrations and structure are also important antecedents of such complications in diabetes mellitus. Interestingly, it has been suggested that hyperglycemia, arterial hypertension, and dyslipidemia cause disorders of the albumin excretion rate by damaging the podocyte and slit diaphragm protein scaffold with overproduction of and extracellular release of oxygen radical species at the glomerular level.8et al. followed 1253 type 2 diabetic patients over seven years and showed the progression of 3.7% of type 2 diabetic patients to overt nephropathy every year and microalbuminuria provided a risk increased by 42% as compared to normoalbuminuria.9Bruno This raises the question as to which of the above statistics shows the importance of early diagnosis, treatment, and prevention of microalbuminuria in type 2 diabetic patients. As there is a high prevalence of diabetes in Yazd (14.2% of the population aged above 30 years are suffering from diabetes),The study group comprised of 300 consecutive type 2 diabetic patients attending the Yazd diabetes research center. The cross-sectional study was performed from November 2005 to July 2007. This study was approved by the Medical Ethics Committee of Shahid Sadoughi University of Medical Sciences and Health Services of Yazd.We completed a questionnaire including demographic data and duration of diabetes for all patients, and measured their heights and weights to estimate the body mass index. Weight was measured using the Secca scale; a body mass index <25 kg/m11The blood pressure was recorded with the aid of a mercury sphygmomanometer in the right upper arm in the sitting position after five minutes rest. Patients were categorized as hypertensive patients if the systolic blood pressure was > 130 mm Hg and / or diastolic blood pressure was >85 mm Hg.4A sample of blood was drawn after overnight fasting of 12 h to measure fasting blood sugar, glycosylated hemoglobin (HbA1c), serum cholesterol, and serum triglyceride levels.Fasting blood sugar, triglyceride, and cholesterol levels were determined by enzymatic methods. HbA1c was measured by using a DS5 device; HbA1c <7% was considered to be normal.45No further investigations were done if the result of the first urine sample indicated normoalbuminuria or macroalbuminuria, however, urine was retested over the following three months if the result indicated microalbuminuria. If the urine albumin to creatinine ratio was between 30 and 300 mg/g on two occasions over a period of three months, a diagnosis of microalbuminuria was made.Medical history was obtained from the patients during recruitment. Treatment consisted of 75% metformin, 72% glibenclamide, 6.8% acarbose, 30% insulin alone, 7% insulin with oral hypoglycemic agents (OHAs), 34% statins, and 22% angiotensine converting enzyme inhibitors (ACEIs).In this study, 12/300 patients were excluded because they had macroalbuminuria. Data analysis was done using the Statistical Package for Social Sciences (SPSS) for Windows version 10. Chi-square test and Logistic Regression were used to determine the correlation between microalbuminuria and its risk factors.2. The mean duration of diabetes (known for 240 patients) was 9.3 ± 6.3 years. The mean fasting blood sugar and HbA1c levels were 167.5 ± 46.5 mg/dL and 9.1 ± 2.15%, respectively. The mean serum triglyceride and cholesterol levels were 211.8 ± 88.5 and 201.7 ± 39.7 mg/dL, respectively. The mean systolic blood pressure and diastolic blood pressure were 127.4 ± 17.6 and 78.0 ± 8.6 mm Hg, respectively [Two hundred and eighty-eight type 2 diabetic patients were studied ; ectively . The oveP = 0.6) [P = 0.754) [P = 0.001) [First, we used the Chi-square test to analyze our results; the prevalence of microalbuminuria was not statistically different between the various age groups (P = 0.6) . The pre= 0.754) . The pre= 0.001) .P = 0.076). The prevalence of microalbuminuria among patients with diastolic blood pressure < and ≥85 mm Hg was 11.7 and 27.5% respectively. There was a significant correlation between microalbuminuria and raised diastolic blood pressure (P = 0.003) [The prevalence of microalbuminuria among patients with systolic blood pressure ≥ and < 130 mm Hg was 17.5 and 10.2% respectively. There was no significant correlation between raised systolic blood pressure and microalbuminuria (= 0.003) .P = 0.926). The prevalence of microalbuminuria among patients with HbA1c ≤ and >7% was 16.7 and 13.7% respectively. There was no significant correlation between HbA1c and microalbuminuria (P = 0.571).The prevalence of microalbuminuria among patients with fasting blood sugar < and > 140 mg/dL was 13.9 and 14.4% respectively. There was no significant correlation between fasting blood sugar and microalbuminuria .The prevalence of microalbuminuria among patients with body mass index < and >25 kg/mP = 0.944).The prevalence of microalbuminuria among patients with triglyceride < and >200 mg/dL was 14.1 and 14.4% respectively. No statistically significant correlation was found between microalbuminuria and serum triglyceride (P = 0.051), although this may not have been the case if we had studied more patientsThe prevalence of microalbuminuria among patients with cholesterol ≤ and >200 mg/dL was 10.5 and 18.5% respectively. No statistically significant correlation was found between microalbuminuria and serum cholesterol  was used for data analysis using a logistic regression model. Results showed that two variables: the duration of diabetes and the diastolic blood pressure (DBP) play a role in this model and the following logic association was obtained: gˆ (x) = -9.233 + 0.079 DBP + 0.114 DurationP=0.001) and diastolic blood pressure (P=0.003) increased the risk of microalbuminuria.According to this model, both the diastolic blood pressure and the duration of diabetes directly correlate with microalbuminuria, although the correlation of duration with microalbuminuria is stronger than with diastolic blood pressure. Duration of diabetes .et al.17Various epidemiological and cross-sectional studies have reported many variations in the prevalence of microalbuminuria.This variation in the prevalence of microalbuminuria can be attributed to several factors such as differences in populations, the definition of microalbuminuria, the methods of measurement of microalbuminuria and urine collection etc.Although both types 1 and 2 diabetic patients were studied in the previous study conducted in Yazd,et al. used an immunoturbidometric method for the assessment of microalbuminuria;et al.et al.Huraib et al.et al. reported a statistically significant correlation between the prevalence of microalbuminuria and the age among 1425 type 2 diabetic patients.No statistically correlation was found between the prevalence of microalbuminuria and the age of patients in the present study which was similar to findings reported by Allawi et al. in European diabetic patients.et al. reported an increased prevalence of microalbuminuria in Indian men compared with Indian women.In the present study, prevalence of microalbuminuria among males and females was 14.9 and 13.6% respectively. Thus, the prevalence of microalbuminuria was not statistically different for the two sexes, which was similar to the findings reported by Mather et al.et al. reported that patients with higher body mass index had higher albumin excretion.In present study, no statistically significant correlation was found between body mass index and the prevalence of microalbuminuria which was similar to the findings reported by Allawi et al. in Saudi Arabia,et al.,et al.In the present study, a good statistically significant correlation was found between the prevalence of microalbuminuria and the duration of diabetes that was consistent with findings of past studies. Huraib et al.et al. reported a correlation of the prevalence of microalbuminuria with the fasting blood sugar and with HbA1c levels.15In the present study, no statistically significant correlation was found between the prevalence of microalbuminuria and the fasting blood sugar or HbA1c, which was similar to findings reported by Huraib et al.et al. reported a good correlation between the prevalence of microalbuminuria and hypertension.et al. showed that high blood pressure increased the risk of developing signs of nephropathy (P = 0.003).In the present study, a good statistically significant correlation was found between the prevalence of microalbuminuria and the diastolic blood pressure which was similar to findings reported by Varghese et al.et al. also reported a statistically significant correlation between the prevalence of microalbuminuria and serum triglyceride levels.et al. reported that diabetic dyslipidemia (high serum triglyceride and low HDL cholesterol levels) is a predictor of rapid progression of microalbuminuria in patients with well-controlled blood pressure.23No statistically significant correlation was found in the present study between the prevalence of microalbuminuria and serum triglyceride and cholesterol levels, which was similar to findings reported by Varghese Considering the high prevalence of diabetes in Iran , we suggest screening for microalbuminuria and vigorous control of blood pressure in diabetic patients to reduce future diabetic kidney disease.In conclusion, the prevalence of microalbuminuria in this study was 14.2%, a finding that was similar to the ones reported in Saudi Arabia and India and the duration of diabetes and hypertension were associated with microalbuminuria, also consistent with past studies.