Six pregnant Ripollesa sheep, weighing 47.1 ± 4.4 kg, were used. Twenty-four hours after instrumentation, sheep were anaesthetized with intravenous alfaxalone in cyclodextrin. Time to standing from anaesthesia was 30.0 ± 10.81 min. Foetal heart rate increased significantly during the first 5 min after alfaxalone administration. Significant differences were observed in maternal diastolic arterial blood pressure between minute 10 and minutes 90, 120, 150, 180, 210, and 240. Significant differences were observed for foetal systolic arterial blood pressure between 5 and 30 min after alfaxalone administration. Significant differences in foetal pH were detected during the entire study period, whereas maternal pH returned to baseline values by 60 min after alfaxalone administration. The present study indicated that alfaxalone in 2-hydroxypropyl-β-cyclodextrin administered as an intravenous bolus at 2 mg/kg body weight produced minimal adverse effects and an uneventful recovery from anaesthesia in pregnant sheep and their foetus.The objective of this study was to determine the pharmacodynamics effects of the anaesthetic alfaxalone in 2-hydroxypropyl- General anaesthesia is often indicated for surgery during pregnancy or for caesarean section. Nevertheless, drugs given to the mother during pregnancy or for caesarean section can affect the ability of the neonate to survive in and adapt to its new environment. Neonatal drug elimination is usually slow, and many drugs have prolonged effects in the neonatal period . Use of PaCO2 in the mother and the foetus, inducing a foetal acidosis [Pregnant ewes have been popularly used as animal models for placental transfer research as well as for the determination of the anaesthetic effects in the foetus. Although extrapolation of results from animals to humans should be done with caution because of anatomical and physiological differences, sheep have been shown to be the most appropriate experimental model for studies of placental transfer of drugs, especially the soluble ones, such as general anaesthetics , 3. It hacidosis , 8. Injeacidosis . Recent acidosis , 11.β-cyclodextrin (HPCD)  is the new formulation of this neurosteroid anaesthetic characterized by not producing histamine release. In veterinary medicine, it is used to induce and maintain general anaesthesia [Alfaxalone  in 2-hydroxypropyl-esthesia –15. Follesthesia . Experimesthesia , 17, 18,esthesia , 19, 20,esthesia , and sheesthesia  have shoesthesia , so it cThe aim of the present study was to determine the cardiovascular effects and the changes in acid-base balance both for ewes that were 4 months pregnant and their foetuses after the administration of a single IV bolus of alfaxalone. All procedures were approved by the Ethical Commission of Animal and Human Experimentation (Spanish Government) under the auspices of the Ethical Commission of the Universitat Autònoma de Barcelona (Authorization nos. DARP 4544 and CEEAH 791).Six pregnant Ripollesa breed sheep weighing (mean ± SD) 47.1 ± 4.4 kg were included in the study. Mean gestational age was 120 ± 3.8 days (term 147–150 days).The anaesthetic and surgical techniques used in our study were similar to those described by Andaluz et al.  with somEach sheep was positioned in dorsal recumbency. The neck and the abdomen were prepared aseptically. Firstly, a small incision was made in the skin over the neck. The carotid artery was dissected for a 32 cm, 14G plain polyurethane catheter  placement. The maternal carotid artery catheter was used for blood gases determination and for heart rate and blood pressure measurement. Then, a midline laparotomy was performed, and through a small hysterotomy, the foetus was delivered partially to permit adequate exposure for insertion of a 71 cm, 14G plain polyurethane catheter  into the carotid artery. This catheter was used for blood gas determination and for heart rate and foetal blood pressure measurement. The skin of the foetus was incised over the carotid artery. Fine dissection of the vessels and placement of the catheter were performed and the catheter was immediately heparinised and the blood pressure was measured to ensure the functionality of the catheter. The skin incision was sutured and the foetus returned to the uterus. Care was taken during surgery to minimize loss of amniotic fluid. The placenta and the uterus were closed as previously described . The foeThroughout the surgical process, temperature, cardiac frequency, respiratory frequency, capnography, arterial pressure, pulse, and electrocardiography were monitored using a multifunction patient VetCare monitor (B. Braun).Following recovery from anaesthesia, sheep were returned to their pen and allowed to recover for 24 h before the experimental phase began. During this period, ewe and foetal arterial catheters were heparinised every 8 h to avoid occlusion. Animals were treated with SC buprenorphine (0.02 mg/kg every 6 h) and meloxicam (0.1 mg/kg every 24 hours) for pain control after surgery. During the study period, maternal and foetal heart rate, arterial blood pressure , and maternal respiratory rate were determined at different times using a multifunction patient VetCare monitor (B. Braun). Foetal and maternal arterial blood samples were also taken at different times for acid-base variables evaluation using an i-STAT Portable Clinical Analyzer. Blood samples for acid-base determination were collected into a 1 mL heparinised insulin syringe and processed within 5 min. All efforts were made to keep the sheep in sternal recumbency during the anaesthetic periods. The appearance of adverse effects  was recorded if present. Time to recovery from anaesthesia (standing) was also recorded.EtCO2 represent the means of four determinations taken at 15 min intervals, while baseline values for blood gases were measured only once at minute 30.Before starting the study, a control period of 60 min was established. Baseline values for heart rate, blood pressure, respiratory rate, and After the 60 min control period, a single IV bolus of 2 mg/kg alfaxalone was administered through the cephalic vein catheter and both maternal and foetal cardiovascular variables were measured at 2, 5, 10, 15, 20, 30, 45, 60, 90, 120, 150, 180, 210, and 240 min after alfaxalone injection. Blood samples for acid-base status evaluation were taken simultaneously from mother and foetus at 5, 15, 30, 60, 120, and 240 min after alfaxalone injection.All animals were monitored and received a lactated Ringer's solution therapy at 60 mL/kg/day for the entire study period. If episodes of apnoea occurred, artificial ventilation was initiated until spontaneous respiration was regained.P < 0.05 was considered to be significant. To evaluate time of anaesthesia and time to standing, one-sample t-test was used.Data were analyzed using a statistical computer software program . Normality was tested using the Shapiro-Wilk statistic. The results were analyzed by analysis of variance using a mixed model, including time as fixed effect and sheep as the random effect. When significant differences were found, a Bonferroni post hoc analysis for pairwise comparisons was performed. A value of Time to standing from anaesthesia, after a single IV bolus of 2 mg/kg body weight of alfaxalone in ewes, was 30.0 ± 10.81 min (mean ± SD). No adverse effects were observed after alfaxalone injection. Maternal cardiovascular and acid-base variables are shown in Tables No significant differences were observed in maternal heart rate (HR) and systolic (SAP) and mean (MAP) arterial blood pressure during the entire study period. Significant differences were observed in diastolic arterial blood pressure (DAP) between minute 10 and the minutes 90, 120, 150, 180, 210, and 240. P < 0.05); this returned to baseline at 30 min. This alteration was accompanied by a significant increase in PaCO2 5 min after alfaxalone administration from the baseline value and a significant decrease in PaO2 during min 5 and 15 compared with the entire study period (P < 0.05). A significant decrease from baseline values was observed in maternal pH 5 minutes after alfaxalone administration . Foetal arterial blood pressure remained constant during the entire study period compared to the control period. Only significant differences in SAP between minutes 5 and 30 were observed.Foetal heart rate was significantly increased during minutes 2 and 5 after alfaxalone administration  from the baseline value remained during the entire study period only for pH. No significant differences were observed for PaCO2 and PaO2.Foetal pH decreased and To the authors' knowledge, this is the first published study in which alfaxalone in HPCD has been evaluated in pregnant ewes.The alfaxalone dosages used and the times chosen for recording all the variables were those described previously for alfaxalone in nonpregnant sheep by Andaluz et al. . Time to standing was longer in the present study (30.0 ± 10.81 min) than that described in nonpregnant sheep (22.0 ± 10.6 min) , the resPaCO2. However, pH remained within the clinically acceptable range for sheep (7.48–7.58) [As described for nonpregnant sheep, apnoea or other adverse effects did not occur in any of the animals of this study. However, apnoea is one of the most frequently reported side effects after alfaxalone use. The slow administration rate, as postulated by Andaluz et al.  in nonpr48–7.58)  througho48–7.58)  and are 48–7.58)  for etomPaO2 may also have contributed to the increase in heart rate. Oxygen supplementation prior to alfaxalone administration as well as during early recovery may have diminished this effect. For this reason, although sheep used in the present study did not receive oxygen supplementation, the authors strongly recommend to oxygenate patients before and during induction of anaesthesia.Moreover, as observed in nonpregnant sheep , alfaxalAlthough inhalant anaesthetic agents may be used for anaesthesia induction, this technique is not the most recommended in many patients as it can be slow, delaying the time of endotracheal intubation and increasing the probability of vomiting and aspiration pneumonia. Moreover, induction with inhalant anaesthetic agents may cause agitation when no sedative agents have been used, which often happens with pregnant patients. Because etomidate may result in the suppression of foetal serum cortisol concentrations  and propIt can be concluded that the administration of a single bolus of alfaxalone in HPCD has no apparent major adverse effects on the pregnant ewe when compared to those described in nonpregnant animals or those described in pregnant ewes undergoing inhalant or propofol anaesthesia. However, as respiratory effects on the foetuses could be important, the authors recommend to provide 100% oxygen to ewes in order to prevent hypoxia and foetal respiratory acidosis during alfaxalone anaesthesia.


For decades, symptoms of anxiety and depression have been included among psychological factors associated with development of hypertension. Although this has been questioned in recent studies, most findings have been based on a single assessment of mental distress at baseline. We examined these associations using repeated assessments of anxiety, depression and blood pressure.Data on 17,410 men and women aged 20 to 67 participating in the Nord-Trøndelag Health Study (HUNT) in Norway in 1984-86 were re-examined 11 and 22 years later. The main outcome was change in mean blood pressure (mm Hg) during follow-up.th percentile) of combined anxiety and depression at baseline, as compared to a lower symptom level, was associated with lower mean systolic  and diastolic  blood pressure at year 22. A high symptom level present at all three examinations was associated with a stronger decrease in mean systolic  and diastolic  blood pressure and with a 20% (p = 0.001) lower risk of developing hypertension (BP ≥140/90 mm Hg) at year 22. The associations were only slightly attenuated in multivariate analyses, with no evidence of a mediating effect of alteration in heart rate.We found that a high symptom level score (≥80This study do not support previous hypothesis that emotional stress may be a cause of hypertension. Our findings indicate that symptoms of anxiety and depression are associated with decrease in blood pressure, particularly when a high symptom level can be detected over decades. The origin of the hypothesis that emotional stress might be a cause of hypertension goes back to 1919 when Moschcowitz described features of a stressed personality type in hypertensive patients . In receOverall, previous studies in this area differ in their findings. With a few exceptions ,17, howehttp://www.hunt.no), Norway. All inhabitants in the county aged ≥20 years were invited to a general health study that was conducted three times with 11-year intervals: in 1984-86 (HUNT 1 = baseline) [This study is part of the Nord-Trøndelag Health Study  , 1995-97In the present 22-year longitudinal study we included individuals aged 20-67 years at baseline (HUNT 1) who participated in all three surveys with valid data on anxiety/depression, blood pressure, heart rate and waist circumference. Of the 48,907 HUNT 1 participants with valid data, 5,990 died or moved out of the county during the first 11 years of follow-up. Among the remaining 42,917 individuals, 34,263 (79.8%) participated with valid data in HUNT 2. Of these individuals, 4,725 died or moved out of the county during the next 11 years of follow up. Of the remaining 29,538 individuals, 58.9% participated in HUNT-3 with valid data, giving a study population of 17,410 participants  aged 20-67 years at baseline (42-89 years at year 22). Compared with participants , those who did not complete the study  among eligible individuals at year 22 were older (53 versus 51 years) and were less often women (52.5 versus 54.7%), had slightly higher mean blood pressure (140.5/82.3 versus 136.5/81.5 mm Hg) and higher symptom scores of anxiety (4.33 versus 4.20) and depression (3.76 versus 3.50); p ≤ 0.001 for all comparisons. However, we found no interaction between age or sex and the association between anxiety/depression and blood pressure [Twelve questions on anxiety and depression were included in the baseline questionnaire, constituting a one-dimensional anxiety and depression symptom index (the ADI-12 Index) which was found to correlate strongly (r = 0.82) with the Hopkins Symptoms Checklist-25 . The Hoscombined anxiety-depression score and blood pressure were almost identical at baseline and at 11-year follow-up, despite use of different measurements of anxiety and depression and of blood pressure [th percentile on the ADI-12 Index at baseline and as combined HADS-A and HADS-D scores ≥12  at 11-year and at 22-year follow-up. Finally, we used continuous measures of anxiety (HADS-A) and of depression (HADS-D), respectively, at 11-year follow-up in analyses of their individual effects on change in blood pressure from 11-year to 22-year follow-up. Supplementary analyses were performed using well-established anxiety/depression cut-offs  [We previously reported that the cross-sectional associations between a pressure . ConsequS-D ≥ 8) .Specially trained nurses measured blood pressure in seated participants, after four minutes (baseline) or two minutes (years 11 and 22), with the cuff placed on the right upper arm, and with the arm rested on a table at heart-level. Cuff size was adjusted after measuring the arm circumference. At baseline, blood pressure was measured using calibrated mercury manometers with standard cuff size. The first pulse sound (Korotkoff's phase I) was registered as systolic blood pressure and the level at which the pulse disappeared (phase V) as diastolic blood pressure. The measurements were repeated after two minutes, and the second reading was used in this study. At years 11 and 22, blood pressure was measured with a Dinamap 845XT  based on oscillometry. Blood pressure was measured automatically three times at one-minute intervals. The mean of the second and third reading was used in this study. At HUNT 1, resting heart rate at the wrist was counted for 15 seconds or for 30 seconds if the heart was irregular. At HUNT 2 and 3, heart rate was measured by the Dinamap. Heart rate was expressed as beats/min.The main outcome measures were change in mean systolic or diastolic blood pressure (mm Hg) from baseline to year 22, and from year 11 to year 22. In logistic regression analyses we used blood pressure ≥ 140/90 mm Hg or < 120/75 mm Hg at year 22 as the outcome measures.combined anxiety and depression with change in blood pressure from baseline to year 22. Symptoms of anxiety and depression were first included as a continuous measure at baseline, and then categorically as a high symptom level at baseline, at both baseline and year 11, and at all three measurements, respectively. Effects were reported as unstandardised regression coefficients (b = mm Hg change in blood pressure during follow-up). We repeated analyses after excluding those taking antihypertensive or antidepressant medication, respectively.Characteristics of the participants were calculated as means (± standard deviation) or percentages. We used linear regression models to analyse the association of We used three regression models. First, we analysed the association with adjustment for demographic factors  and systolic or diastolic blood pressure at baseline. Second, we further adjusted for angina pectoris, myocardial infarction, stroke, diabetes mellitus, smoking status, low physical activity, antihypertensive medication ; hypertension among siblings (baseline and change from baseline to year 11); and waist circumference . Third, after examining separately the associations of heart rate with anxiety and depression and with blood pressure, we included adjustment for heart rate  in the analyses of the association of anxiety and depression with blood pressure.anxiety and of depression, respectively, at year 11 on change in blood pressure from year 11 to year 22. In a second model, we examined the effects of pure anxiety and of pure depression by adjusting for each other.We also analysed the individual effects of In additional logistic regression analyses we examined the effect of a high symptom level of anxiety/depression at all three measurements on blood pressure at year 22 dichotomised into hypertension (≥ 140/90 mm Hg) or not, and then with blood pressure dichotomised into "hypotension" (< 120/75 mm Hg)  or not, Data were analysed using SPSS version 18.0 for Windows .r = 0.61) but more weakly with that of year 22 (r = 0.38). For diastolic blood pressure, the corresponding figures were r = 0.52 and r = 0.26. The correlations between the combined anxiety and depression score at baseline (the ADI-12 Index) and the HADS at years 11 and 22 were r = 0.45 and r = 0.42, respectively. The correlation between HADS-A at years 11 and 22 was r = 0.59. For HADS-D, the correlation was r = 0.55. . There were only minor variations in the levels of HADS-A and HADS-D scores at years 11 and 22.Characteristics of the sample are listed in Table We found symptoms of anxiety and depression to predict a relative decrease in blood pressure during 22-year follow-up. Baseline level of anxiety and depression was positively associated with a decrease in systolic blood pressure in linear regression analyses adjusted for age, sex, educational level and baseline blood pressure. For diastolic blood pressure, we found a similar non-significant trend. A high symptom level at both baseline and at year 11 was more strongly associated with a decrease in blood pressure during 22-year follow up. In individuals with a high symptom level at all three examinations, we found an even stronger decrease for both systolic and diastolic blood pressure  compared with individuals with a lower symptom level. Additional adjustment for other health factors and for antihypertensive medication did not change the overall pattern of results, but the effect of combined anxiety and depression on blood pressure was slightly attenuated  did not change the results essentially: a high symptom level at all three examinations was associated with a slightly lower decrease in systolic  and diastolic  blood pressure. However, after excluding those using antihypertensive medication at baseline or at year 22 , we found a stronger effect on systolic  and diastolic  blood pressure.In analyses using symptoms of anxiety and depression as continuous scores separately at year 11, we found that both anxiety and depression predicted lower blood pressure at year 22. In analyses where anxiety and depression were further adjusted for each other, the remaining (pure) effects of anxiety and of depression on blood pressure were attenuated or became non-significant Table . FurtherAt baseline, an increase in symptoms of combined anxiety and depression (per standard deviation) was associated with a dose-response increase in heart rate, as shown by regression coefficient (b) = 0.36, p < 0.001, in cross-sectional analyses adjusted for age, sex and educational level. Prospectively, a high symptom level at all three examinations was non-significantly associated with an increased heart rate at year 22  compared with individuals with a lower symptom level. Similarly, at baseline, an increase in heart rate was associated with an increase in systolic  and diastolic  blood pressure. Prospectively, an increase in heart rate from baseline to year 22 was associated with an increase in systolic  and diastolic  blood pressure.2). In all analyses, we found that additional adjustment for heart rate attenuated the adjusting effect of the other covariates  and, conversely, with higher odds for blood pressure < 120/75 mm Hg . Thus, the probability for development of hypertension among individuals with a high symptom level of anxiety/depression at all three examinations was 20% lower compared to those with a lower symptom level.Recently, we reported that symptoms of combined anxiety and depression predicted a decrease in blood pressure 11 years later in both sexes and in all adult age groups [Although one might question the clinical value of a modest reduction in mean blood pressure, studies have suggested that this might translate into significant public health benefits . In our The study confirms and extends findings from other large population-based studies indicating that symptoms of anxiety and depression predict lower blood pressure -11. TogeOur findings also contrast with a recent study based on data from the British Whitehall II Study suggesting that the risk of hypertension increased with repeated experience of depressive symptoms over time . HoweverWith a few exceptions ,17, prevBlood pressure, heart rate, and depression are all related to cardiovascular mortality, whereas the literature on anxiety is more conflicting . RegardiThis study provides the first data suggesting that the pathophysiological mechanisms underlying the observed association do not involve alteration in heart rate. In recent years, authors of other epidemiological studies have proposed various mechanisms, including the use of antihypertensive medication, but no explanation for the association has been found . NeitherA recent review deals with other possible mechanisms between chronic psychological states like anxiety and depression and the cardiovascular system . These mLimitations of the present study include that different methods of measuring blood pressure, anxiety and depression were used at baseline compared to at years 11 and 22. We have previously examined and discussed this potential limitation ,11. HoweSecond, it might be argued that measurement of blood pressure and mental symptoms at three single time points gives only snapshots of the participants' situation during 22 year of follow-up. However, the procedures at each wave were standardised and all participants underwent similar examinations. Moreover, in large epidemiological studies like the HUNT study, screening instruments are the standard. Certainly there have been fluctuations in mental symptoms and blood pressure between the three assessments, but it is unlikely that this would bias the association in any particular direction. Statistically, reduced validity of measuring blood pressure or anxiety/depression would weaken rather than strengthen any association between them. It is also of note that the association between a high anxiety/depression symptom level and decrease in blood pressure from baseline to year 22, and from year 11 to 22, was similar to the association we previously found from baseline to year 11 in the same individuals. Given our large data-set based on standardised procedures, we regard that our findings indicate a true association between anxiety/depression and decrease in blood pressure.Third, we had data only on resting heart rate but not on heart rate variability which is a more precise index of autonomic nervous function than heart rate alone. Low heart rate variability reflects excessive sympathetic and/or inadequate parasympathetic modulation of heart rate and is found associated with depression  and anxiThis study benefits from being a large general population-based study covering a wide age range, using repeated assessments of anxiety, depression and blood pressure over 22 years. We found that anxiety and depression were associated with decrease in blood pressure, particularly in individuals with a persistent high symptom level. Heart rate did not mediate the association. The significance of our findings lies partially in stimulating further research on the underlying biological pathways between mental symptoms and blood pressure regulation. Our findings should also have consequences for clinical studies on pharmacological treatment of blood pressure which should take common mental symptoms of participants into account.HUNT: the Nord-Trøndelag Health study; ADI-12 Index: a one-dimensional anxiety and depression symptom index used at HUNT 1; HADS: the Hospital Anxiety and Depression Scale.The authors declare that they have no competing interests.JH is principal investigator of the HUNT study, and was in charge of the data collection. All authors participated in the study design, evaluation of data and contributed later with text revisions and table revisions. BH planned the study, performed the analyses and drafted the manuscript. UR supervised the statistical analyses. All authors read and approved the final manuscript.The pre-publication history for this paper can be accessed here:http://www.biomedcentral.com/1471-2458/11/601/prepub


Multiple myeloma (MM) has a high incidence rate in the elderly. Responsiveness to treatments differs considerably among patients because of high heterogeneity of MM. Chronic kidney disease (CKD) is a common clinical feature in MM patients, and treatment-related mortality and morbidity are higher in MM patients with CKD than in patients with normal renal function. Recent advances in diagnostic tests, chemotherapy agents, and dialysis techniques are providing clinicians with novel approaches for the management of MM patients with CKD. Once reversible factors, such as hypercalcemia, have been corrected, the most common cause of severe acute kidney injury (AKI) in MM patients is tubulointerstitial nephropathy, which results from very high circulating concentrations of monoclonal immunoglobulin free light chains (FLC). In the setting of AKI, an early reduction of serum FLC concentration is related to kidney function recovery. The combination of extended high cutoff hemodialysis and chemotherapy results in sustained reductions in serum FLC concentration in the majority of patients and a high rate of independence from dialysis. Kidney dysfunction is a worldwide public health problem with an increasing incidence and prevalence, and it is associated with high costs and relatively poor outcomes . MultiplAlong with other clinical features including hypercalcemia, anemia, and lytic bone lesions, kidney dysfunction is a common complication in active MM  9, 11]., 11.9, 1P = 0.06) has been reported as associated with marginally better long-term outcome in MM patients . AK. AK19]. patients . In 2012patients . Recentlpatients , 26. In patients with suspected MM, monoclonal heavy or light chains, known as Bence-Jones protein, should be analyzed in concentrated urine using electrophoresis with immunofixation of any identified protein bands in accordance with current myelomas guidelines . CoincidCast nephropathy is nearly always observed in advanced MM, when production of large amounts of LC overwhelms the capacity of catabolism in proximal tubules . This ne2 and an albumin-creatinine ratio (ACR) of 30 mg/g or greater were retained. The exact frequency of GFR and ACR monitoring will depend on the severity of CKD There is an even higher prevalence of the earlier stages of CKD, with adverse outcomes, including loss of kidney function, cardiovascular disease (CVD), and premature death. The KDIGO organization developed clinical practice guidelines in 2012 to provide guidance on the evaluation, management, and treatment of CKD  33]. Di. Di33]. Factors associated with progression include cause of CKD, level of GFR, level of albuminuria, AKI, age, gender, race or ethnicity, elevated BP, hyperglycemia, dyslipidemia, smoking, obesity, history of cardiovascular disease, and ongoing exposure to nephrotoxic agents. The cause of CKD has been traditionally assigned based on presence or absence of underlying systemic diseases and location of known or presumed pathological abnormalities. The distinction between systemic diseases affecting the kidney and primary kidney diseases is based on the origin and locus of the disease process. In primary kidney disease the process arises and is confined to the kidney, whereas in systemic diseases the kidney is only one victim of a specific process, for example, diabetes. Certain genetic diseases cross this boundary by affecting different tissues, for example, adult polycystic kidney disease. The location of pathological and anatomical findings is based on the magnitude of proteinuria and findings from the urine sediment examination, imaging, and renal biopsy. In MM patients, CKD occurs mainly as a result of damage caused to renal tubules by FLCs (cast nephropathy). A variety of other nephrotoxic processes may also contribute to this damage including dehydration, hypercalcemia, nephrotoxic drugs, and infection. In the era of conventional chemotherapy, several studies have confirmed that CKD is associated with poor prognosis in MM, with a median survival of <2 years –38. EffeSince 2005, the treatment strategy for MM has significantly changed because of the successful introduction of new therapeutic agents. Three drugs, a proteasome inhibitor (bortezomib) and two immunomodulatory drugs , are referred to as novel agents, and each drug has a characteristic efficacy. Notably, there are reports of hyperkalemia occurring with the use of thalidomide in patients with severe CKD (including those on RRT); thus, at present, its usage requires caution , 43. ThaWhile these agents can be expected to restore kidney function by improvement in the primary disease, bortezomib, with a strong antitumor effect, is reported to rapidly improve kidney function . Bortezoμm and membrane area of 0.1–0.8 m [There are several types of apheresis therapy that are applicable in MM patients. Plasma exchange (PE) or plasmapheresis involves the separation and removal of the blood cells and other substances from the plasma by centrifugation (based on cell density) or ultrafiltration using large-pore hemofilters (based on molecular size) . This me.1–0.8 m . Homogen.1–0.8 m . Cryofil.1–0.8 m . The gelκ, 25 kDa; λ, 50 kDa) that they equilibrate between the intravascular and extra vascular compartments; thus, the intravascular compartment may only contain 20% of the total capacity. Namely, a standard series of single PE session might remove only 65% of intravascular FLCs [2, compared with chemotherapy alone. In this study, FLC levels were not measured, and histologic evidence of cast nephropathy was insufficient. Recently, Leung et al. have suggested that histological confirmation of cast nephropathy should be considered to analyze the effects of PE. In a retrospective series of 40 patients with MM-associated CKD, 18 cases had cast nephropathy that was biopsy proven. In their study including patients with cast nephropathy, the combination of PE with high-dose dexamethasone-based chemotherapy induced an attenuation of kidney dysfunction in 45% and in 75% of patients in whom serum FLC levels decreased by >50% with treatment. In contrast, no correlation between renal response and reduction in serum FLC levels was observed in another study including patients without biopsy-proven cast nephropathy [FLC removal by apheresis therapies has been investigated as a means of preserving kidney function. The initial treatment investigated was PE, which has been tested in three trials –55, and lar FLCs . Howeverlar FLCs . In thishropathy . The rephropathy , 60.P < 0.01) [CKD is a common clinical feature of MM. Even with aggressive treatment, progression to ESRD occurs in up to 65% patients with cast nephropathy within 3 months of diagnosis . Treatme < 0.01) . MM pati < 0.01) , 65. If  < 0.01) , 67. Sim < 0.01) . The inc < 0.01) . Some st < 0.01) , 13, 68. < 0.01) . Accordi < 0.01) . Patient < 0.01) . Patient < 0.01) . We prev < 0.01) . Erythro < 0.01) , 72.Besides the theoretical limitations of PE –60, highKidney dysfunction is a common feature of symptomatic MM and may cause major problems in clinical management. Its management remains challenging. Cast nephropathy is the most common cause of severe kidney dysfunction in MM. Serum FLC concentrations should be considered in MM patients with AKI. The successful introduction of new therapeutic agents and novel techniques for serum FLC removal has profoundly altered the therapeutic approach toward patients with cast nephropathy. Long-term dialysis is an efficacious treatment for patients with MM and ESRD. FLC removal with a combination of HCO-HD and chemotherapy may lead to early decrease in serum FLC concentrations and ameliorate AKI complicating MM.


We investigated 1) the frequency of hypertension in patients with type 2 diabetes graded by the new classification of chronic kidney disease (CKD) reported by the Kidney Disease: Improving Global Outcomes (KDIGO) and 2) the number of antihypertensive agents needed to achieve treatment goals using a prospective observational study.A population of 2018 patients with type 2 diabetes mellitus was recruited for the study. The CKD stage was classified according to the eGFR and the urinary albumin excretion levels.Hypertension was found in 1420 (70%) of the patients, and the proportion of subjects showing a blood pressure < 130/80 mmHg was 31% at the baseline. Although the mean blood pressure was approximately 130/75 mmHg, the rate of patients with a blood pressure of < 130/80 mmHg became limited to 41-50% during the observation period. The number of antihypertensive agents required for treatment was significantly higher at the endpoint (2.0 ± 1.3) than at the baseline (1.6 ± 1.2). Furthermore, it increased with the progression of the CKD stage at both the baseline and the endpoint of the observation. However, the frequency of subjects who did not achieve the blood pressure target was found to increase in the group demonstrating the later stage of CKD.Hypertension resistant to antihypertensive agents was common in the patients with type 2 diabetes mellitus and increased with the progression of CKD. Although powerful combination therapy using antihypertensive agents is considered necessary for the strict control of blood pressure, this became difficult in individuals who were in advanced stages as graded based on the eGFR and the urinary albumin excretion levels. It is well-known that hypertension is common in the patients with type 2 diabetes mellitus ,2. HyperThe frequency of hypertension is elevated with the progression of renal damage in both diabetic and non-diabetic patients. In the present prospective observational study, we investigated 1) the frequency of hypertension in the patients with type 2 diabetes as graded by the new classification of chronic kidney disease (CKD) reported by the Kidney Disease: Improving Global Outcomes (KDIGO)  and 2) tThis study was conducted according to the principles expressed in the Declaration of Helsinki. The Ethics Committees of Edogawa Hospital approved the protocol of this study and waived the need for written informed consent because the data were analyzed anonymously for this observation study based on the data stored in the hospital database.A population of 2018 patients diagnosed with type 2 diabetes mellitus who underwent consecutive evaluations, including blood pressure, urinalysis and determination of the serum creatinine levels in the Department of Diabetes, Metabolism and Kidney Disease of Edogawa Hospital, Tokyo, Japan between April 2008 and March 2011 was recruited for the study. Antihypertensive agents were essentially initiated when a systolic blood pressure (SBP) ≥ 130 mmHg and/or a diastolic blood pressure (DBP) ≥ 80 mmHg persisted after the lifestyle modification. The selection of antihypertensive agents was determined by each patient’s physician during the prospective observation period.The blood pressure was measured twice with the subjects in the sitting position after a 5 minute rest. The lower value of the two measurements was used for the study. Hypertension was defined as a SBP ≥ 140 mmHg and/or a DBP ≥ 90 mmHg. The participants currently using antihypertensive medications were also classified as positive for hypertension. The target blood pressure is less than 130/80 mmHg according to the JNC7  and the The patients were divided into four groups according to their blood pressure status. Categories 1, 2, 3 and 4 were defined to be the subjects showing 1) SBP < 130 mmHg and DBP < 80 mmHg, 2) SBP < 130 mmHg and DBP ≥ 80 mmHg, 3) SBP ≥ 130 mmHg and DBP < 80 mmHg, and 4) SBP ≥ 130 and DBP ≥ 80 mmHg, respectively. The doses and specific drug classes of antihypertensive agents for blood pressure control were dependent on the judgment of each patient’s physician.The number of antihypertensive agents used was expressed as the sum of antihypertensive agents such as thiazide diuretics, loop diuretics, aldosterone antagonists, alpha blockers, beta blockers, calcium channel blockers (CCBs), ACEIs, ARBs, renin inhibitors, and centrally-acting adrenergic drugs being used.et al.[2) = 194 × Scr-1.094 × Age-0.287 × 0.739 .The estimated glomerular filtration rate (eGFR) was calculated using the formula reported by Matsuo et al.. This eqet al. arranged2; G2, 90 mL/min/1.73 m2 > eGFR ≥ 60 mL/min/1.73 m2; G3a, 60 mL/min/1.73 m2 > eGFR ≥ 45 mL/min/1.73 m2; G3b, 45 mL/min/1.73 m2 > eGFR ≥ 30 mL/min/1.73 m2; G4, 30 mL/min/1.73 m2 > eGFR ≥ 15 mL/min/1.73 m2; and G5, 15 mL/min/1.73 m2 > eGFR [The CKD stage was classified according to the eGFR and the urinary albumin excretion (UAE). The GFR stage was graded as: G1, eGFR ≥ 90 mL/min/1.73 mThe HbA1c levels were determined by a high performance liquid chromatography method using an automated HLC-723 G7 analyzer  and calibrated by the Japan Diabetes Society (JDS) standard calibrators. The value for HbA1c (%) was estimated as a National Glycohemoglobin Standardization Program (NGSP) equivalent value (%) calculated by the formula: HbA1c = HbA1c (JDS) + 0.4, considering the relational expression of HbA1c (JDS) measured by the previous Japanese standard substance and the measurement methods and HbA1c (NGSP) .χ2 test were used for between-group comparisons of the continuous and categorical variables, respectively. A paired-t test was performed to determine the significance of the change in the number of antihypertensive agents. Differences of P < 0.05 (two-tailed) were considered to be statistically significant. The statistical software package JMP, version 8.0 , was used to perform all of the analyses.All data are shown as the means ± SD. An analysis of variance (ANOVA) and the Table P < 0.01) and the GFR stage (P < 0.01)  and the GFR (P < 0.01) at the endpoint of the observation  and at the endpoint of the observation for more than 12 months (n = 990). The number of antihypertensive agents was significantly higher at the endpoint than at the baseline. Furthermore, it increased with the progression of CKD stage at both the baseline and the endpoint of the observation period.Table CCBs, ACEIs, ARBs and thiazide diuretics were used by 52%, 15%, 55% and 13% of the patients at the baseline, and by 64%, 23%, 65% and 7% at the endpoint of the observation period.In the present study, a much higher frequency of hypertension was found in the patients with type 2 diabetes mellitus. It could be argued that this is because our study included a number of CKD patients, although our results were consist with previous reports that showed hypertension to be frequently complicated with diabetes ,2. Our iBakris et al. reviewed the various clinical trials for either diabetes or renal impairment. An average of 3.2 different antihypertensive medications was taken daily in the UKPDS , MDRD 2, HOT 2121 and AAThe target value of blood pressure has continued to decline after the JNC I  was publTherapeutic resistance to antihypertensive agents in the late stage of CKD with diabetes mellitus is considered to be caused some defective mechanisms of vascular homeostasis and impaired nitric oxide production . VasculaThe present study has several important limitations. First, the follow-up period was relatively short, and the number of patients decreased to nearly one-half at 24 months and to one-fourth at 36 months. This might have led us to incorrectly estimate the blood pressure control and the number of antihypertensive agents required for control. Second, we did not determine the dose of antihypertensive agents required. The doses administered were dependent on the judgment of each patient’s physician, as was the decision to add another antihypertensive agent or increase the dose of a drug that was already being used. When the dose increases, the enhanced antihypertensive therapy is not reflected in the number of antihypertensive agents. Third, the blood pressure measured at home was not evaluated in this study. If self-monitoring of blood pressure shows good control for hypertension, then physicians will not increase the therapy, even if the office blood pressure does not meet the target goal levels. This is considered to be one of the reasons why more than half of the patients remained within categories 2–4 in the present study. Fourth, the lower value of two measurements of blood pressure was used for this study, not the average value, which is recommended by the National Institutes of Health . This miIn conclusion, hypertension was common in patient with type 2 diabetes mellitus and increased with the progression of CKD. Although powerful combination therapy using antihypertensive agents is considered to be necessary for the strict control of blood pressure, it becomes more difficult for individuals in the progressive stages of CKD as determined based on the albuminuria and GFR levels.The author(s) declare that they have no competing interests.HI contributed to the conception and design of the study, research, analysis and interpretation of data, and the drafting of the manuscript. MM, MA, KO, SA, YT, MT, SA and ET contributed to the research and interpretation of the data, and to the critical revision of the manuscript. All authors have given their final approval of the submitted version of the manuscript. All authors read and approved the final manuscript.The pre-publication history for this paper can be accessed here:http://www.biomedcentral.com/1471-2369/13/48/prepub


Elevated levels of calcium and parathyroid hormone (PTH), characteristics of primary hyperparathyroidism (PHPT), may be associated with cardiovascular morbidity and mortality in the general population. We evaluated the possible vascular effects of these risk factors in patients with mild PHPT by using standard methods and new imaging techniques.A prospective case-control study.ao), radial (IMTrad) and common carotid artery (IMTcca) intima media thicknesses, and the grayscale median (IM-GSM) of the latter.Forty-eight patients with mild PHPT without any known cardiovascular risk factors were studied at baseline and at one year after parathyroidectomy (PTX) in comparison with 48 healthy age- and gender-matched controls. We measured biochemical variables, augmentation index (AIx), aortic pulse wave velocity (PWVrad (0.271±0.060 vs. 0.255±0.053 mm), IMTcca (0.688±0.113 vs. 0.680±0.135 mm), or IM-GSM (82.3±17.2 vs. 86.5±15.3), while PWVao was slightly higher in patients . Systolic blood pressure (SBP), calcium, and PTH were higher in patients compared with controls, and decreased after PTX, while vitamin D was lower in patients and increased after PTX. While AIx, PWVao, IMTrad, and IMTcca were related to SBP, neither correlated to vitamin D levels. Only PWVao correlated weakly to plasma PTH  and ionized calcium  but showed no relation when age and SBP were adjusted for.No significant differences were observed between PHPT patients and controls at baseline for AIx (28.6±12.2 vs. 27.7±12.8%), IMTWe found normal arterial function despite high calcium, PTH, and low vitamin D levels, in patients with mild PHPT without cardiovascular risk factors. The cardiovascular risk associated with low vitamin D and/or high PTH and calcium levels may be explained by their coupling to blood pressure and other risk factors rather than direct effects on arterial structure. Associations between high calcium and parathyroid hormone (PTH) as well as low 25-OH-D levels and cardiovascular risk have been reported in the general population Primary hyperparathyroidism (PHPT) is characterized by elevated calcium levels, inappropriately increased PTH levels, and is often associated with vitamin D deficiency Thus, PHPT is a good model to determine the influence of these alterations on the vasculature.An increased mortality rate has been noted in both unselected PHPT ao) has been found in PHPT patients with hypertension cca) measured by ultrasound is associated with a risk of myocardial infarction and stroke cca have been reported in patients with mild PHPT cca was found to be increased only in the group with risk factors rad) has been shown to be increased in hypertension Endothelial function and vasodilatation regulated by nitride oxide (NO) release is of importance in the early atherosclerotic process. Endothelial vasodilatory dysfunction has been described in patients with PHPT With mild PHPT without concomitant disease or known cardiovascular risk factors as a model, our aim was to determine the potential effects of PTH, calcium, and vitamin D on arterial structure and function. Thus, applying the as mentioned novel diagnostic techniques, we compared patients with age- and gender matched healthy controls, and evaluated the vascular effects of normalizing PTH, calcium, and vitamin D by parathyroidectomy (PTX).In a prospective, previously described A healthy control group, age- and gender-matched, was randomly selected from the population registry of the city of Stockholm. They were informed by mail and asked to participate in the study. If they fulfilled the inclusion criteria, described above, they were included in the study. If anyone declined, a new randomly chosen control from the population registry was contacted. Two controls were replaced before entering the study: one because of hypertension and the other because of a high PTH level. The median  time from baseline to follow-up was 1.06 and 1.48 years. One woman did not participate in the vascular examinations at follow-up. The blood pressure and all examinations were performed the morning after an over-night fast, with a resting period of 30–60 minutes in supine position. The same investigator performed the ultrasound examinations and pulse wave analysis. Each participant provided written consent to participate in the study, which was approved by the Local Ethics Committee, Regional Ethical Review Board, EPN, of Stockholm, Sweden.2). Body surface area (BSA) was calculated by the formula: BSA (m2) = 0.007184 × 0.425 × 0.725.Blood pressure (BP) was measured in both arms using a digital automatic blood pressure monitor Omron M7 . The mean values of systolic and diastolic blood pressure (SBP and DBP) in both arms were calculated. Mean arterial blood pressure (MAP) was calculated as DBP + (SBP-DPB)/3. Body mass index (BMI) was calculated by dividing weight (kg) by the square of height (mao) were noninvasively measured using SphygmoCor equipment connected to a computer with SphygmoCor 2000 software . Recordings were performed using a single high-fidelity tonometer gently pressed to the radial, carotid, and femoral arteries . To measure AIx, the radial artery waves were recorded and processed by the system software. The corresponding aortic pressure waveform was generated from an averaged radial artery waveform using a validated transfer factor ao, the pulse waveform was collected sequentially from femoral and carotid artery sites, and by using the R- wave  as a reference, the mean difference in time (ΔT) between sites A (carotid) and B  was calculated. The surface distance (xsubtracted) was measured as (carotid-jugulum distance) subtracted from . The direct distance over the body surface (xdirect) was obtained by a standardized formula: xdirect = 0.45xsubtracted +0.21* height +0.08 (m) direct leads to an overestimation of the real PWVao, and a scaling factor was used to convert PWVao distance to “real” PWVao. The real PWVao was calculated as: 0.8* xdirect/ΔT, m/s, ao are presented as mean values from two recordings.Augmentation index (AIx) and aortic pulse wave velocity  www.wlab.gu.se), Gothenburg University, Gothenburg, Sweden. A region of interest (ROI) of a 10 mm long segment was manually placed proximal to the carotid bulb, , upper panel. The boarders of the IMTcca of the far wall and the inner lumen diameter (LDcca) were identified automatically by the program and the analysis could be manually corrected if necessary. IMTcca was defined as the distance from the leading edge of the lumen-intima interface to the leading edge of the media-adventitia of the far wall. LDcca was defined as the distance from the leading edge of the intima-lumen interface of the near wall and the leading edge of the lumen-intima interface of the far wall Two-dimensional images of the common carotid artery (CCA) were acquired using an 8 MHz transducer, 7L, Vivid 7 . The CCA was evaluated 1–2 cm proximal to the carotid bulb. Diastolic images at the time of the electrocardiographic R-wave were stored digitally on EchoPAC . For detection of IMTcca, and from analysis of pixels on a scale from 0 (black) to 255 (white). The adventitia was used as the reference for white and the blood as the reference for black. IMTcca, IM-GSM, and LDcca are presented as mean values of six images from both the right and left CCA. Lumen diameter and IMTcca values are shown in mm, while IM-GSM is shown as median gray. At the end of the study, the same investigator performed the image analyses and calculations in random order. Intra- and interobserver variability was measured in 30 randomly selected participants, and the calculations in terms of coefficients of variation (CV) were: 2.90% and 3.80% for IMTcca, 0.40% and 0.70% for LDcca, and 2.74% and 3.81% for IM-GSM. Bland-Altman plots for IMTcca and IM-GSM are shown in The IM-GSM was calculated in the same intima-media segment of the far wall that was evaluated for IMTrad) and lumen diameter (LDrad) were measured according to the leading edge principle rad of the far wall is presented as a mean value from nine measurements corresponding to the end-diastole, the smallest lumen diameter. The IMTrad was defined as the distance from the lumen-intima interface to the media-adventitia interface, , lower panel. Diastolic LDrad was measured from the M-mode image, defined by the distance between the intima-lumen interface of the near wall and the lumen-intima interface of the far wall. LDrad is presented as a mean value taken from three representative beats. Intra- and interobserver variability in terms of CV were 5.78 and 10.94% for IMTrad, and 3.16 and 3.56% for LDrad.A high-resolution ultrasound investigation of the radial artery was performed in 43 patients. The images of the intima media of the radial artery were obtained by high-resolution ultrasound using a 55 MHz transducer . B-mode images were recorded from the right radial artery in a longitudinal projection, 1–2 cm proximal to the fold separating the palm of the hand from the forearm. All cine-loops were stored on an external disk and measured offline using VisualSonics software. The thickness of the radial artery intima media (IMT++) was analyzed on ABL 800 , and plasma concentration of intact parathyroid hormone (PTH) was measured with electro-chemiluminescence immunoassay on the Modular E system . Total serum IGF-1 was analyzed by chemiluminescence immunoassay on DPC Immulite 2000 . Serum concentrations of 25-OH-D were measured by chemiluminiscence on Liason® . The plasma concentrations of VWF antigen were determined with latex immunoassay on the BCS XP system . The plasma activity of PAI-1 was measured by a functional enzymatic ELISA assay (Chromolyze PAI-1) from Medinor . The samples of 25 hydroxyvitamin D (25-OH-D), von Willebrand factor (VWF) antigen, and PAI-1 were frozen at −70°C and analyzed in the same series in order to minimize inter-assay variation. Renal function was estimated by calculating the glomerular filtration rate (GFR) according to Cockroft-Gault’s formula: GFR = (140-age in yr) x (weight in kg/creatinine) x (1.23 in men or 1.04 in women).Plasma concentrations of total calcium, creatinine, glucose, high sensitivity C-reactive protein (hsCRP), phosphate, serum concentration of total cholesterol, triglycerides (TG), apolipoprotein A-1 (Apo-A1), and apolipoprotein B (Apo-B) were estimated using Synchron LX® 20 system . Serum-ionized calcium . Data are expressed as mean ± SD. Comparisons between the patients at baseline and the control group were performed with the Mann-Whitney U test for unpaired data, and for intra-individual analyses, Wilcoxon signed rank sum test was used. Spearmańs rank correlation coefficients were computed to assess relationships between variables. Univariate and stepwise multiple linear regression analyses were used to evaluate relationships and adjust for confounders. Results from the multiple regression analyses were presented as standardized beta and adjusted RThe coefficient of variation (CV), defined as the standard deviation of the absolute differences between the measurements, divided by the mean of two measurements was used to evaluate the intra- and interobserver variability. The reproducibility was illustrated according to Bland-Altman Clinical data of healthy controls as well as PHPT patients at baseline and follow-up are presented in ao, IMTcca, IMTrad, IM-GSM, S-Ca, ionized Ca, or PTH levels. Further, these measures did not differ between those with 25-OH-D levels below or above the median (39 nmol/L).Biochemical data are presented in cca, IM-GSM values, or lumen of the CCA and no changes were observed during follow-up. PWVao was slightly higher in patients 8.68±1.50 (mean±SD) compared to controls 8.13±1.55 (mean±SD), p<0.05, (range 6.6–13.2 for patients and 5.3–13.3 for controls), and did not change during follow-up. The IMTrad did not differ between the groups and remained unchanged at follow-up, while the LDrad was similar to that of controls; however, a marginal increase was noted after one year (p<0.05).Vascular structural and functional results are presented in ao, IMTrad, IMTcca, and IM-GSM to baseline data in the complete study cohort of patients and controls in order to verify expected patterns, ao, IMTcca, IMTrad, and IM-GSM with biochemical variables are also presented in ao were weakly related to cholesterol, PWVao, and IM-GSM also to PTH, and PWVao to ionized Ca and triglycerides. None of AIx, PWVao, IMTrad, IMTcca, or IM-GSM correlated to P- Phosphate, hsCRP, Apo-B/Apo-A1, Ca*P product, or homocysteine levels.We evaluated the univariate relations of vascular measures in terms of AIx, PWVao, IMTcca, IMTrad and IM-GSM, one at a time) as dependent variables and demographic data  as independent variables are presented in ao, and IMTcca, were explained by age and SBP, in AIx also by gender.Multiple stepwise regression analyses with indices of vascular function  on the five indices of vascular function, one at a time, considering also demographic data, ao) were weakly related to PTH and the latter also to ionized calcium levels in univariate analysis, but not when adjusting for confounders like blood pressure. Furthermore, the PTX did not cause any change in indices of vascular function or arterial wall thickness. Our conclusions were substantiated by adding new variables, such as echogenicity of the carotid artery and intima media thickness of the radial artery to the established measures AIx, PWVao, and IMTcca.In this prospective case-control study of mild PHPT without any known cardiovascular risk factors or medications affecting the cardiovascular system, we found no indication that circulating levels of vitamin D influenced arterial structure or function. Wall composition (IM-GSM) and aortic stiffness 2 D and common carotid IMT or internal carotid IMT, apart from a weak association to internal carotid IMT among patients with hypertension in one of several subgroup analyses Thus, although vitamin D deficiency is common in patients with PHPT ao in patients. However, data are not unanimous. While Rosa et al. noted PHPT patients to have increased arterial stiffness with and without hypertension Kosch et al. showed no difference in PWV between PHPT patients and controls, and found no correlations between PWV and increased PTH levels Interestingly, it was recently demonstrated that PHPT causes up- regulation of the matrix metallopeptidase 9 (MMP9) gene and a number of other inflammatory and metabolic genes in fat tissue, with possible impacts on blood pressure and atherosclerosis et al.et al.et al.et al.et al.et al.Our PHPT patients and healthy controls showed no difference in AIx. This is in contrast to the results of Smith et al.et al.et al.et al.et al.ao in patients with a significant reduction in blood pressure one year after PTX. All our vascular measurements, apart from IM-GSM, were related to age and blood pressure. Adjusting for age and blood pressure, PWVao was not related to circulating levels of PTH, Ca++, phosphate, or 25-OH-D.Probably, cardiovascular diseases combined with PHPT are more likely to affect the arterial wall and IMT than PHPT alone. This is supported by Fallo rad in the PHPT patients compared with controls. By measurement of the grayscale in the intima media images of carotid artery, we tried to obtain information regarding the wall composition, with the assumption that fibrotic infiltration should be more echogenic and lipidous transformation should be more echolucent. Earlier studies have shown that IM-GSM in CCA is closely related to the echogenicity in overt carotid plaques; moreover, the same group further reported a relationship between echolucency in the intima-media complex and cardiovascular risk factors in elderly subjects In order to investigate the vascular structure more thoroughly, we have used new validated techniques in our study, such as grayscale median for the evaluation of echogenicity of the carotid intima media, and a high- resolution ultrasound for measurement of IMT in the radial artery. We have demonstrated that high- resolution ultrasound allows measurement of very thin structures such as IMT of the rat carotid artery wall rad and the echogenicity in the intima media of the CCA in patients with mild PHPT. The strict design, excluding cardiovascular risk factors, is the strength of our study, which should favorably influence the reliability of our results. The material is comparatively large for this type of study; however, it is too small for any prognostic evaluations.To our knowledge, this is the first study to describe IMTWe measured the IMT of the common carotid artery in the far wall only, as we assumed relatively symmetrical wall thickness in our patients and controls. Since most patients with PHPT today do not express typical signs and since calcium- and PTH-levels are not examined routinely, it is rarely possible to estimate the duration of the disease.We found normal arterial function, despite high PTH and Ca as well as low vitamin D levels, in patients with mild PHPT without cardiovascular risk factors. The cardiovascular risk associated with low vitamin D and/or high PTH and Ca levels may be explained by their coupling to blood pressure and other risk factors rather than direct effects on the arterial structure. Our findings support the importance of adequate blood pressure control in PHPT if PTX is not performed, but do not indicate vascular abnormalities motivating extended follow-up after PTX.


Circulating matrix metalloproteinase (MMP)-2, -3 and -9 are well recognized in predicting cardiovascular outcome in coronary artery disease (CAD), but their risks for chronic kidney disease (CKD) are lacking. Therefore, the present study aimed to investigate whether circulating MMP levels could independently predict future kidney disease progression in non-diabetic CAD patients.The prospective study enrolled 251 non-diabetic subjects referred for coronary angiography, containing normal coronary artery (n = 30) and CAD with insignificant (n = 95) and significant (n = 126) stenosis. Estimated glomerular filtration rate (eGFR) was calculated using the CKD-EPI formula. eGFR decline rate was calculated and the primary endpoint was a decline in eGFR over 25% from baseline.2 per year) in patients with CAD  was greater than that in those with normal coronary artery . The circulating MMP-2, -3 and -9 were independently associated with faster eGFR decline among CAD patients. The mean follow-up period was 8.5±2.4 years, and 39 patients reached the primary endpoint. In multivariate Cox regression model, the adjusted hazard ratios of MMP-2 ≥861 ng/mL, MMP-3 ≥227 ng/mL and MMP-9 ≥49 ng/mL for predicting CKD progression were 2.47 , 2.15 (1.12 to 4.18), and 4.71 (2.14 to 10.4), respectively. While added to a model of conventional risk factors and baseline eGFR, MMP-2, -3 and -9 further significantly improved the model predictability for CKD progression . In the sensitivity analyses, the results were similar no matter if we changed the endpoints of a decline of >20% in eGFR from baseline or final eGFR < 60 mL/min/1.73 m2.The eGFR decline rate (ml/min/1.73 mCirculating MMP-2, -3 and -9 are independently associated with kidney disease progression in non-diabetic CAD patients and add incremental predictive power to conventional risk factors. Matrix metalloproteinases (MMPs) form a family of zinc-dependent enzymes with proteolytic activity against connective tissue proteins The nexus between CAD and CKD is extremely complex and partially attributable to some risk factors in CAD. Diabetes mellitus and proteinuria have been known as important factors for CKD progression. Therefore, we focus on a CAD cohort without diabetes and proteinuria to appraise whether the estimated glomerular filtration rate (eGFR) decline rate in CAD is greater than that of subjects with normal coronary artery, and to assess whether circulating MMP-2, -3, and -9 levels at baseline could independently predict future progression of kidney disease and overall mortality.The study complied with the Declaration of Helsinki and was approved by the institutional review board of Taipei Veterans General Hospital. All participants gave their written informed consent before inclusion.Between March 1999 and June 2003, 601 consecutive non-diabetic patients who were referred to the Catheterization Center of Taipei Veterans General Hospital for coronary angiography by reason of angina and/or suspected CAD. Patients were excluded if they had acute coronary syndrome including acute myocardial infarction or unstable angina during hospitalization, uncontrolled congestive heart failure, unstable hemodynamic status, chronic liver disease, renal insufficiency , proteinuria by dipstick, chronic systemic inflammatory disease, and malignancy with expected life span less than 1 year. Initially, 346 consecutive patients were enrolled in the study. Two expert angiographers, who were unaware of the patient’s clinical and laboratory data, independently reviewed the coronary angiography. Accordingly, 174 patients had significant CAD (the presence of ≥50% stenosis in at least one major coronary artery), 125 had insignificant CAD (the presence of <50% but ≥20% stenosis in at least one major coronary artery), and 47 had normal coronary artery . Baseline demographic data were recorded at the time of recruitment. All patients were enrolled by one physician to minimize interobserver variations. The protocol was approved by the Committee on Human Research at Taipei Veterans General Hospital, and informed consent was obtained from each participant.A 20-mL venous blood was drawn in the early morning after overnight fasting in each patient before coronary angiogram. The plasma and serum samples were stored at −80°C until use. Biochemical parameters including total cholesterol, triglyceride, low-density lipoprotein (LDL) and high-density lipoprotein (HDL) cholesterol, glucose, albumin, creatinine, calcium, phosphate, and uric acid were determined using commercial kits by a Hitachi 7600 autoanalyzer . Serum high-sensitivity CRP (hs-CRP) was measured by an immunoturbidimetric assay, using rate nephrelometry .Total form of MMP-2, -3, and -9 levels in plasma were determined using commercially available kits by enzyme-linked immunosorbent assay  according to the manufacturer’s instructions. Within- and between-assay coefficients of variation determined in our laboratory were 5.4% and 8.2% for MMP-2, 2.4% and 9.8% for MMP-3, and 5.3% and 9.1% for MMP-9, respectively. The methodology in our study has been published before 2 per year.The eGFR was calculated using the CKD Epidemiology Collaboration (CKD-EPI) study equation 2 per year over the age of 40 is suggested by classic inulin clearance study 2 at baseline. During a follow-up period of 8.5 years, a 25% decline of eGFR from baseline was 18 ml/min/1.73 m2 and exceeded the decline rate attributed to the aging process in the present study. The secondary endpoint was all-cause death. The cause of death was obtained according to the Taiwan National Death Registry. Among all participants, 95 patients were lost to follow-up with the observation time of <12 months and/or less than 3 outpatient eGFR measurements during the follow-up. They were further excluded from the study to avoid an incomplete observation in renal function change. Before starting the study, a sample size calculation was performed in which the statistical power was 80% and the 10-year kidney disease progression rate was estimated as 20% to 30% for the entire population. Inter-group difference would be reflected by a hazard ratio of at least 2.0. The required sample size was estimated between 70 and 100 patients. Therefore, a total of 221 CAD patients recruited in this study fulfilled the minimal requirement of case number.After the baseline investigation, patients were followed prospectively until the study endpoints or the observation period was reached. The study was ended on December 31, 2009. There are two endpoints in this study. The primary endpoint was two consequent outpatient eGFR values that were more than 25% decline from baseline. The time reaching renal endpoint was the time to the first occurrence of a >25% decline in eGFR since enrollment. GFR decline rate of 1 ml/min/1.73 m2.To assess the reliability of our findings and minimize misclassification bias, we conducted the secondary analyses using different study endpoints of a decline of >20% in eGFR from baseline or final eGFR <60 mL/min/1.73 mt test for normally distributed data, the Mann-Whitney U test for non-normally distributed data, or the Pearson x2 test for categorical variables. Linear regression analysis was used to identify the MMPs and other factors associated with eGFR slope. Because adjustment of baseline eGFR may disregard the notion that individuals with a rapid decline in eGFR in the past may have lower levels of eGFR at enrollment than those without P>0.05 to remove any identified independent predictors for kidney disease progression or death. To assess discrimination ability, c statistic for model of conventional risk factors, including age, sex, smoking status, BMI, systolic blood pressure, fasting glucose, total cholesterol, and eGFR (base model), then with stepwise addition of MMP-2, -3 and -9 values (newer biomarker model) was calculated for prediction of progression of CKD at 8 years of the study P-value less than 0.05 was considered statistically significant. All statistical analyses were performed using the computer software Statistical Package of Social Science, version 16.0 .Descriptive statistics included means ± SD for continuous data and percentages for categorical data. The values of serum hs-CRP, MMP-2, -3, -9 and eGFR slope were not normally distributed and were reported as median with interquartile range (IQR). Potential differences between the two patient groups were assessed by the student’s Ninety five (27.5%) patients were excluded due to incomplete follow-up. Finally, a total of 251 (72.5%) patients from the baseline cohort could be assessed during the follow-up. Both groups did not differ significantly with respect to the demographic data and baseline laboratory parameters  in patients with significant CAD  was greater than that in those with normal coronary artery . In multivariate regression analysis among CAD patients, the independent determinants of annual eGFR decline rate were age , serum levels of albumin  and hs-CRP , and plasma levels of MMP-2 , MMP-3 , and MMP-9 . Furthermore, using baseline MMP-2, MMP-3 or MMP-9 levels above versus below the respective medians as categorical variables .Mean decline rate of eGFR  along with age (P = 0.03) and basal eGFR (P = 0.04) were the significantly risk factors for mortality during the follow-up. In contrast, the adjusted hazard ratios of MMP-2≥861 ng/mL, MMP-3≥227 ng/mL and MMP-9≥49 ng/mL for predicting CKD progression were 2.47 , 2.15 , and 4.71 . In the sensitivity analyses, the results were similar no matter if we changed the study endpoints  further improved the model predictability with increment in the c statistic of 0.069 and 0.102 (P<0.05), respectively. To assess the clinical implications of MMPs in CAD patients, we further developed a risk score with a range of zero to three by using the baseline MMP levels. A score of zero was defined when the plasma levels of three MMPs were all below the medians. Scores of one, two and three were defined as one, two or all of the three MMPs being above the corresponding median values, respectively. As shown in P<0.001), the higher the incidence of kidney disease progression (P<0.001), and the higher the mortality rate (P = 0.01).To test discrimination ability, plasma MMP-2, -3 and -9 levels at baseline were incorporated into the conventional risk factors (base model) for predicting CKD progression . The c sThis study prospectively demonstrated that baseline MMP-2, -3 and -9 levels were the independent predictors for faster eGFR decline and subsequent kidney disease progression . Moreoveet al.et al.2 per year.Long-term outcomes of CAD, such as major adverse cardiovascular events and all-cause mortality, are well documented. However, the impact of CAD on renal outcomes like progression of kidney disease is still largely undefined. Elsayed 12 have shown that plasma MMP-9 concentration predicted the development of microalbuminuria in type 2 diabetes by an observation period of 4 years.Guidelines for the assessment of the risk of a faster eGFR decline or kidney disease progression remain focused largely on conventional risk factors in vivoThe role of MMPs in renal fibrosis is probably dual during the different phases of the pathology evolution in vivo. Most MMPs are secreted as proMMPs and activation usually requires cleavage of the prodomain by plasmin or other MMPs. MMP-2 and MMP-3 activate pro-MMP-9 by cleaving their prodomains Individual MMP modestly provided incremental benefit in risk prediction of kidney disease progression when added separately to a base model, but combining the three MMPs offered the greatest improvement in risk prediction beyond conventional risk factors in our study . This noIn our statistical analysis, older age, low basal eGFR and higher MMP-9 levels at baseline were the independent predictors of mortality in CAD patients over a mean follow up of 8.5 years. These findings are in general agreement with our previous study Some limitations of this study should be acknowledged. First, the number of serum creatinine measurements for measuring the eGFR slope varied in each patient, and thus, the calculation of eGFR slope was not uniform in every subject. However, to avoid an unreliable estimation of eGFR slope, we excluded 95 patients with either fewer than three eGFR measurements or a follow-up period of <12 months from the study. Second, the predominant sources of MMPs detected in the circulation are unknown. Circulating levels of MMPs presumably reflect their expression in the whole body as well as in the kidney. Elevation of MMPs could also result from impaired filtration in the damaged kidneys, but this seems unlikely since the relatively large size of MMPs (∼60 kDa) would apparently preclude their excretion from the kidneys. Finally, some medications have been shown to alter the expression of MMPs in CAD patients In summary, circulating MMP-2, -3 and -9 are independently associated with subsequent progression of kidney disease in non-diabetic CAD patients. Plasma MMP-2,-3 and -9 provide information that is complementary to conventional risk factors and baseline eGFR for kidney disease progression. The potential impact of these results, if confirmed and expanded upon in future studies, includes providing new insight into mechanisms of CKD and the possibility of improving screening, intervention, and prevention.File S1Includes Table S1 and S2. Table S1. Baseline demographic characteristics and laboratory data of the study cases with completed follow-up and those withdrawn from the study. Table S2. Multivariate Cox proportional hazard models for the prediction of kidney disease progression by different end-points among patients with coronary artery disease.(RTF)Click here for additional data file.


Purpose. To determine the presence and type of glaucoma in a cohort of adult Chinese subjects with systemic hypertension. Methods. This prospective cohort study included 200 hypertensive Chinese adults aged >40 years old who underwent screening via frequency doubling technology (FDT) perimetry and intraocular pressure (IOP) measurement by noncontact tonometry (NCT) in a general outpatient clinic. Those with IOP > 21 mmHg and/or visual field (VF) defects on FDT were referred for complete ophthalmological examination. The diagnosis of glaucoma was based on an abnormal VF on Humphrey Field Analyzer (HFA) by Hodapp-Parrish-Anderson's criteria and an increased vertical cup-disc ratio (VCDR). Results. The mean age of the subjects was 64.66 ± 9.47 years, and the male:female ratio was 92 : 108. All patients were hypertensive with a mean blood pressure (BP) of 131.1 ± 15.1/76.6 ± 11.1 mmHg whilst on systemic antihypertensive medication. Of the 111 patients that had an abnormal initial screening, 14 (7.9%) were confirmed to have glaucoma with the highest prevalence of normal tension glaucoma (NTG) (6.2%), followed by primary angle closure glaucoma (PACG) (1.1%) and primary open angle glaucoma (POAG) (0.5%). The positive predictive value of FDT perimetry was 71%. Conclusion. Nearly 8% of the adults with systemic hypertension had glaucoma, and NTG was the most prevalent type. Glaucoma is a progressive optic neuropathy with characteristic changes in the optic nerve head and corresponding visual field loss. Currently, glaucoma accounts for 12% of all global blindness with 4.5 million people affected worldwide [Raised intraocular pressure (IOP) remains the most common and clinically modifiable risk factor. However, glaucomatous optic neuropathy can occur despite normal IOP as in NTG . The rolSpeculations about the association of glaucoma and systemic hypertension still exist. Systemic hypertension has been found to be associated with glaucoma but hypoperfusion has been associated with the development and progression of NTG , 11. ThePatients with systemic hypertension and older than 40 years of age attending a regional general outpatient clinic were recruited in the study. Ethics committee approval and informed consent from subjects were obtained for this study.Hypertension was defined as a presenting systolic BP ≥ 140 mmHg and/or diastolic BP ≥ 90 mmHg without medication. Patients were allowed to rest for 15 minutes before checking BP via an automated digital machine . Patients with BP > 160/100 mmHg were rechecked. The exclusion criteria consisted of those with central nervous system disease that might affect the perimetry result. Patients underwent measurement of IOP with a noncontact tonometry  and visual field assessment using the FDT perimetry C-20-5 program . Patients with IOP > 21 mmHg and/or visual field defects on FDT were referred to an Ophthalmology Specialty Clinic where they underwent a complete ophthalmic examination including measurements of best corrected Snellen visual acuity, IOP measurement with Goldman applanation tonometry, gonioscopy, anterior segment examination with slit lamp biomicroscopy, detailed fundus examination including the evaluation of vertical cup disc ratio (VCDR), visual field examination with Humphrey Field Analyzer (HFA) using the 24-2 Swedish Interactive Threshold Algorithm (SITA) , and central corneal thickness measurement with a pachymeter echograph . The presence of glaucomatous optic neuropathy (GON) was established for those with abnormal visual field defects on the HFA according to Hodapp-Parrish-Anderson's criteria together with a corresponding enlarged VCDR . An elevnormal tension glaucoma (NTG): GON plus IOP < 21 mmHg and open angle,primary angle closure glaucoma (PACG): GON  plus ≥ 270° peripheral anterior synechiae or appositional closure less than grade 2 on gonioscopy according to the Shaffer grading system,primary open angle glaucoma (POAG): GON  with ≥270° grade 2 or above on gonioscopy according to the Shaffer grading system,Ocular hypertension (OHT): IOP > 21 mmHg without evidence of GON clinically and on HFA.The types of glaucoma were defined asTwo hundred patients were included in this study. The mean age was 64.66 ± 9.47 years (range 44–88 years). The male-to-female ratio was 92 : 108. All patients were previously diagnosed with hypertension and were started on antihypertensive therapy; they had a mean BP of 131.1 ± 15.1/76.6 ± 11.1 mmHg whilst on antihypertensive medication at the time of the study. Eighty-nine (44.5%) patients had normal IOP and FDT on initial screening. Of the remaining 111 patients that had an abnormal initial screening, 3 (1.5%) patients had an elevated IOP > 21 mmHg, 3 (1.5%) had both an elevated IOP and abnormal FDT perimetry, and 105 patients (52.5%) had an abnormal FDT perimetry only. All 111 patients were referred to an Ophthalmology Specialist Clinic for further assessment. Of these, 2 had coexisting central nervous system disease and therefore were excluded. Twenty patients were lost to followup during the referral process. Of the remaining 89 patients, 14 patients had glaucomatous visual field defects on HFA. Thirty-two subjects had nonspecific visual field defects, and 16 had unreliable visual fields despite repeated investigations. In all, 14 (7.9%) patients were confirmed to have glaucoma. Of these, there was highest prevalence of NTG (6.2%), followed by PACG (1.1%) and POAG (0.5%). OHT (not requiring treatment) was found in 0.5%. Those with nonspecific visual field defects were labeled as glaucoma suspects and on subsequent examinations were diagnosed to be normal (no glaucoma). A summary of participant inclusion and results is shown in The positive predictive value of FDT perimetry was 70% whist the false positive rate was 22.2% with 7.8% of patients unable to produce reliable visual field results. There are controversies regarding the role of blood pressure in glaucoma –21. WhilOur study has shown that a substantial proportion (7.9%) of systemic hypertensive Chinese subjects over 40 had glaucoma, with NTG being the most common (6.2%) followed by PACG (1%) and POAG (0.5%). Thirty-two percent of the hypertensive subjects had suspicious HFA results and were followed up as glaucoma suspects for the development of glaucoma. The presence of glaucoma in our systemic hypertensive population in Hong Kong (7.9%) is almost double the prevalence of glaucoma (3.8%)  in a genThe possible relationship between systemic hypertension and NTG can be explained by the postulation that the glaucomatous damage in NTG is caused by unstable perfusion of the optic nerve. Autoregulation is a physiological phenomenon whereby the vascular resistance changes dynamically to keep the blood flow at a constant level to uphold local metabolic demands. Systemic hypertension exerts an oxidative stress to the arterial wall which in addition to atherosclerosis can then impair autoregulation such that an elevation of IOP above a criteria level will comprise the ocular blood flow and induce optic nerve damage even though IOP may still be within normal range . AdditioFDT perimetry has been effective for rapid detection of early, moderate and advanced glaucomatous visual field loss , 24. It There were certain limitations of our study. First, there was no local control group for the presence of glaucoma in nonhypertensive subjects. This was because the clinic at which the patients underwent initial screening was a general outpatient clinic which examined the patients with systemic diseases, of which hypertension was one of the most common systemic diseases. Nevertheless we used published data by He et al. from a nearby locality as a basis of comparison to determine the prevalence of glaucoma in the general population . SecondlIn conclusion, nearly 8% of the systemic hypertensive Chinese adults over 40 were found to have glaucoma with NTG being the most prevalent, followed by PACG and POAG.


Peripheral haemodynamic response during adenosine stress CMR perfusion does not vary among those with or without perfusion defects identified during routine clinical practice.Haemodynamic response to adenosine infusion during CMR stress perfusion continues to be used as surrogate to determine adequacy of hyperaemia in clinical setting. Our aim was to determine the proportion of patients who achieve pre-specified adequate response to adenosine (increase in heart rate (HR) by ≥ 10 beats or a drop in systolic blood pressure (SBP) by 10mm Hg from baseline reading) and if this varies in patients identified with and without perfusion defect in a clinical setting.We prospectively identified 94 consecutive patients undergoing A-CMRP, 7 of who were excluded because of missing data. 87 patients underwent first pass CMRP on a Philips Achieva CV 1.5 T MR scanner , with standardised SCMR acquisition protocol infusing adenosine at 140 μg/kg/min for 3 minutes with HR and SBP recorded at baseline, one, two and three minutes. All patients confirmed abstinence from caffeine and chocolate for >24 hours and no patients were on theophylline or dipyridamole. Descriptive statistics and logistic regression were performed.67 (77%) patients achieved the pre-specified adequate haemodynamic response and this was mainly driven by increase in heart rate.The OR (adjusted for age) for predicting perfusion defect by adequate haemodynamic response in patients with and without CAD was 2.5  and 3.26  respectively.Our study shows that in patients undergoing adenosine (140 μg/kg/min) stress perfusion, there is no significant difference in peripheral haemodynamics in patients identified with or without perfusion defect and challenges their use as a marker of hyperaemic response. It remains to be seen whether high dose adenosine will influence these findings and change clinical practice.No funding was obtained for this study.


Air pollution is a growing health problem for urban populations in emerging economies. The present study examines the  relation between blood pressure and particulate air pollution in schoolchildren of Lahore (Pakistan).10 and PM2.5i.e. particles with aerodynamic diameters below 10 μm or 2.5 μm, respectively] was measured at the school sites with a laser operated device (Metone Aerocet 531). Blood pressure was measured, after 5 minutes of sitting rest, using an automated device (average of 5 consecutive measurements). Spot urine samples were also collected and concentrations of Na and K were measured.We recruited a sample of 8–12 year-old children  from two schools in Lahore situated in areas with low (n = 79) and high (n = 100) air pollution, respectively. During the study period (January-April 2009) particulate pollution [PM2.5 were 28.5 μg/m3 (SD: 10.3) and 183 μg/m3 (SD: 30.2), in the low and high pollution areas, respectively. Systolic and diastolic blood pressure were significantly higher in children living in the high pollution area (115.9/70.9 mm Hg) than in the low pollution area (108.3/66.4 mm Hg), independently of age, gender, height, weight, socio-economic status, passive smoking and the urinary concentrations of Na, K, and creatinine.Mean daily values of PMIn 8–12 year-old children, exposure to (traffic-related) air pollution was associated with higher systolic and diastolic blood pressure. These findings, if they persist, might have clinical relevance at older age. Both short-term peaks in pollution and long-term chronic exposure to PM10 or PM2.5 have been consistently associated with increased risks of respiratory and, more importantly, cardiovascular disease and death  than in the low pollution area [mean PM2.5 28.5 μg/m3]. Mean outdoor temperature did not differ between the two schools (15.5°C vs 15.0°C), but relative humidity did differ somewhat (58% vs 67%) due to more rainy days during the first period of study. On the days (n = 4) when humidity was above 80%, the PM data was excluded from analyses. PM values were lower on rainy days. Values of indoor PM were significantly (paired t-test) lower than those measured outdoors in the high pollution area (p < 0.0001), but not in the low pollution area. None of the participants’ families used biomass for cooking or heating. Environmental noise measurements gave mean (SD) values of 44 (0.9) dB(A) and 72 (1.1) dB(A) in the low pollution school versus 52 (10.7) dB(A) and 84 (2.7) dB(A) in the high pollution school.The characteristics of the 166 children and the measured PM levels are listed in Table i.e., gender, age, socio-economic status, weight, height, urinary Na, and K) were forced into all adjusted models.The age, gender, height, weight and BMI distributions did not differ between children from the two schools Table ; howeverValues of systolic and diastolic blood pressure were significantly higher in the children living in the highly polluted area than in those from the less polluted area Figure . These dWhen we applied the criteria of JNC VII blood pressure categories , 59 81%. None ofLogistic regression, with adjustments as before, revealed an odds ratio for not having a normal blood pressure of 2.56  for those living in the area with high PM exposure compared with those living in the area with low PM.In this cross-sectional study we observed that children attending a primary school situated in an area of high air pollution, close to heavy traffic, had a substantially higher arterial blood pressure than children attending a school situated in an area with less air pollution. Our findings are novel on at least two accounts: to our knowledge, our study is the first to investigate the adverse health effects of urban air pollution in children from Pakistan and, moreover, this is one of the first studies to report an association between particulate air pollution and blood pressure in children. With mean differences of 7.6 mmHg for systolic blood pressure and 4.5 mmHg for diastolic blood pressure, the differences between the two groups of children are not only statistically significant, they are also substantial and, therefore, likely to be biologically relevant with regard to the long-term risk of cerebrovascular disease and coronary events.The differences in blood pressure between the two groups are unlikely to be due to technical factors. Blood pressure was measured according to guidelines of the European Society of Hypertension  using a In the absence of technical factors or measurement errors that could explain the differences in blood pressure between the two groups, the following factors can be invoked to explain why the children from the most polluted environment had a higher blood pressure: dietary differences , higher exposure to traffic-related noise and air pollution.The dietary intake of sodium is a well-established determinant of blood pressure in adults and children . The twoIn preschool children from Belgrade, a higher difference in systolic blood pressure (5 mmHg) was found in children from noisy residences compared to those from quiet residences . So, we In view of the established effects of particulate pollution on the cardiovascular system, we must consider traffic-related air pollution by particulate matter as a plausible explanation too. In studies of air pollution, it is important to distinguish short-term temporal effects of peaks of air pollution - which act as triggers of adverse events such as myocardial infarction  - from t2.5, but they did not report on arterial blood pressure in these children. Recently, a large epidemiologic study showed that preschool children exposed to environmental tobacco smoke had on average 1 mmHg higher systolic blood pressure than children not exposed to environmental tobacco smoke [Many epidemiological studies have found a consistent relation between long-term exposure to urban particulate exposure and morbidity or mortality from cardiovascular disease in adults, and experimental studies provide mechanistic plausibility for these associations . Severalco smoke . As withco smoke , therefoth percentile, i.e. not necessarily in hypertensive ranges, were associated with an increased prevalence of elevated blood pressure during adulthood [What are the possible implications of our observations that children living and attending school in an environment with higher levels of air pollution, presumably as a result of traffic, have a higher arterial blood pressure than children living in a less polluted environment? Although no child had hypertension and although the mean systolic blood pressure in the most exposed group was below 140 mmHg, mean differences of about 7 mmHg for systolic blood pressure and about 4 mmHg for diastolic blood pressure are substantial. Thus, in our population, the odds of having a blood pressure above “normal” blood pressure (systolic <120 mmHg and diastolic <80 mm Hg) was 2.56 times higher in those living in the highly polluted area. Admittedly, the criteria used here for defining normal blood pressure and pre-hypertension are those applicable for adults from industrially developed countries  and an idulthood . A follodulthood  showed t10 above 700 μg/m3, average PM2.5 above 180 μg/m3) and still high, by Western standards, even in the “less polluted environment” . These relatively low proportions (15-25%) of PM2.5 to PM10 indicate that in Lahore - as in other locations from developing and emerging countries [i.e. presumably resuspended dust.In the absence of similar studies from other areas, we do not know how representative our findings are for other populations. It has to be noted that in the present study, the outdoor PM levels measured in the high pollution area were extremely high (average PMportions -25% of P2 and O3), nor residential PM. Also, personal exposure to particulate air pollution was not recorded. Due to the aggregation of location and air pollution, we could not control for location in the statistical models. Another limitation is that we only studied a limited number of children from just two schools, so we do not know how representative the results are for the whole city of Lahore, let alone other cities. However, the results of our study justify a larger study on the effect of PM on blood pressure in children.Our study has limitations including the cross-sectional nature. Thus the blood pressure measurements were taken on just one day, which did not account for inter-day variability. We did not measure gases (NOIn conclusion, we discovered that children living and attending school in an area of very high traffic-related air pollution had a substantially higher arterial blood pressure compared to children with less exposure. Although we are aware of the limitations of a cross-sectional study with regard to causality and prognosis, we conclude that traffic-related urban pollution may contribute, even in children, to their later risk of hypertension and cardiovascular complications, if this higher blood pressure persists.We declare that we have no conflict of interests.MS, TSN, and BN designed the study. MS collected data. SI and AA assisted MS in the data collection. MS, TSN, and BN contributed in the discussion of data, drawn conclusions, drafted the manuscript, and approved the final manuscript. All authors read and approved the final manuscript.The pre-publication history for this paper can be accessed here:http://www.biomedcentral.com/1471-2458/12/378/prepub