Obstructive sleep apnea syndrome is a common disorder with significant health consequences and is on the rise in consonance with the obesity pandemic. In view of the association between sleep-disordered breathing and pulmonary hypertension as depicted by multiple studies, current clinical practice guidelines categorize obstructive sleep apnea as a risk factor for pulmonary hypertension and recommend an assessment for sleep disordered breathing in evaluating patients with pulmonary hypertension. The dysregulatory mechanisms associated with hypoxemic episodes observed in sleep related breathing disorders contribute to the onset of pulmonary hypertension and identification of these potentially treatable factors might help in the reduction of overall cardiovascular mortality. In consonance with the obesity pandemic, there is an increasing awareness of sleep-related breathing disorders (SRBDs) as a potentially treatable factor in reducing overall cardiovascular mortality. The spectrum of SRBD ranges from habitual snoring to obstructive sleep apnea (OSA) and increasing evidence shows that improved cardiovascular function may be obtained by early recognition and treatment of these disorders .Over the past three decades, the pathophysiology of sleep-related breathing disorders (SRBDs) has been better understood and though the exact contributory pathways are still not clearly defined several studies allude to multi-factorial mechanisms being involved in the development of pulmonary hypertension in relation to SRBD .Sleep apnea occurs in about 12 million US adults in their 4th to 6th decades of life and about a quarter of all those are over the age of 65 yrs. Nearly half of all nursing home residents have sleep apnea and 38,000 deaths annually are directly attributed to SRBD. With the prevalence of SRBD currently exceeding that of asthma in adults, the cardiovascular consequences of its associated comorbidities especially pulmonary hypertension (PH) have been of significant interest in recent years [l is PH due to pulmonary veno-occlusive diseases and/or pulmonary capillary haemangiomatosis. Group 2 includes PH due to left heart disease. Group 3 comprises PH due to lung diseases and hypoxia. Group 4 refers to chronic thromboembolic PH. Group 5 encompasses PH due to unclear or multifactorial mechanisms [The most recent classification system of pulmonary hypertension was published in the 2009 European Society of Cardiology Guidelines where the definition of PH was based on an increased mean pulmonary arterial pressure >−25 mmHg at rest. This broadly encompasses all clinical subgroups of PH as outlined by the 4th World Symposium on Pulmonary Hypertension in Dana Point, California, in 2008. This update classifies Group 1 as pulmonary arterial hypertension (PAH) due to idiopathic, heritable, or drug- and toxin-induced causes; it also includes PAH associated with specific disease conditions or persistent pulmonary hypertension of the newborn. Group 12, BMI, and AHI are significantly associated with both [Pulmonary arterial hypertension though comparatively rare can be very devastating as it progresses rapidly to right heart failure and subsequent occurrence of death within three years of diagnosis. Peak age of incidence is in the 4th and 5th decades of life with a female preponderance. Multiple studies have shown a higher prevalence of SRBD in patients with pulmonary hypertension  as well ith both .This paper presents a review of the current literature on dysregulatory mechanisms in sleep-related breathing disorders which result in pulmonary hypertension. Emphasis will be placed on Group 3 PH where the broad principles which underlie etiopathogenesis have been elucidated.Accurate diagnosis of PH is based on the acquisition and precise analysis of invasive hemodynamic data as this ultimately determines appropriate treatment options. Current recommendations are for transthoracic echocardiography in the initial screening process with possible subsequent evaluation by right heart catheterization for diagnostic confirmation. Though PH refers broadly to a mean pulmonary artery pressure >25 mmHg from any cause, these invasive studies are crucial to excluding left heart causes of PH where vasodilator therapies should be avoided. For patients with a PCWP <15 mmHg, vasodilator challenge is a crucial diagnostic step for evaluation of vasoreactivity and this is commonly done with inhaled nitric oxide or intravenous agents such as adenosine, epoprostenol, or nitroprusside. All patients with PAH should also undergo routine biochemical, hematologic, immunologic, and thyroid function tests as well as high resolution CT to identify the specific associated condition .In view of the association between sleep disordered breathing (SDB) and pulmonary hypertension as depicted by multiple studies –17, the The pathological changes observed in PH due to hypoxia and SRBD include medial hypertrophy and obstructive proliferation of the tunica intima within the distal pulmonary arteries. The severity of intimal and medial thickening is highly variable and results in near total occlusion of these vessels. This results in major increments in the pulmonary vascular resistance and considerably impedes blood flow through the lungs. Regions of the lungs with significant emphysematous changes or fibrosis may exhibit substantial destruction of the pulmonary vascular bed. The disordered mechanisms resulting in the observed pathophysiological manifestations are multifactorial . CrucialCompensatory changes occur in the right ventricle to overcome the maladaptive responses of these resistance vessels and improve pulmonary blood flow particularly in situations of increased oxygen demand. Eventually, the right ventricle becomes unable to maintain adequate blood flow and this heralds the onset of dyspnea on exertion. This progresses to overt right ventricular failure and poor cardiac output. Finally, severe debilitation sets in and significant dyspnea occurs at rest; ultimately death occurs in most untreated patients in less than 3 years after initial diagnosis , 25. ThiUnder healthy conditions cardiovascular regulatory changes occur in specific stages of normal sleep. Nonrapid eye movement (NREM) sleep is associated with a generalized decrease in sympathetic drive; and deeper stages are associated with bradycardia, reduction in blood pressure, stroke volume, cardiac output, vasomotor tone, and systemic vascular resistance. Conversely, REM sleep is characterized by remarkable increases in sympathetic activity and thus labile heart rate and blood pressure values analogous to those observed while in the wakeful state . DysreguSRBD encompasses several overlapping disorders with varying degrees of severity. These include habitual snoring, increased upper airway resistance syndrome, hypoventilation syndromes, obstructive sleep apnea (OSA), and central sleep apnea (CSA). The most prevalent of the SRBD is OSA which occurs in 4% of all US adult males and 2% of the female population, thus it is the most studied of all SRBD . Poor coSleep apnea can be defined as repetitive, prolonged airflow cessation with associated sleep arousal and occasional oxygen desaturation. Variants of sleep apnea include obstructive sleep apnea, with persistent respiratory effort in spite of oropharyngeal airway occlusion; central sleep apnea, involving cessation of both airflow and all respiratory effort; and a mixed pattern of both . The terObstructive sleep apnea is a common chronic SRBD that is characterized by complete or partial airway obstruction with resultant episodes of apnea or hypopnea, respectively. One-fifth of all adults in Western nations have mild OSA, while 1 in 15 adults has moderate to severe OSA. The prevalence is highest in older males with a high body-mass index and features of the metabolic syndrome; yet this disorder is seldom diagnosed and undiagnosed cases are as high as 85% in certain communities. These values are expected to rise in parallel with the current rising trend in obesity worldwide, leading to a resultant increase in the associated cardiovascular comorbidities, depression, and reduced quality of life of affected individuals –34.2, as well as a concurrent rise in pCO2 [An abrupt withdrawal of the nonchemical respiratory drive accompanies the transition from the wakeful state to NREM sleep resulting in a sudden decline in minute ventilation and pO in pCO2 . The dec in pCO2 . In cont in pCO2 . In REM  in pCO2 .Recent studies have shown that individuals with OSA are at significant risk of developing systemic hypertension, cerebrovascular events, and ischemic heart disease. These result from acute cardiovascular changes which gradually become chronic and lead to cardiac remodeling and altered cardiovascular hemodynamics , 39. KeyA physiologic reduction in systemic blood pressure of up to 15% occurs during stages 3 and 4 of NREM sleep accompanied by a 10% reduction in cardiac output; this results in an overall decline in systemic vascular resistance. More complex hemodynamic responses occur in response to apneic stimuli which causes pulmonary and systemic hypertension, increased afterload, and reduction in cardiac output . These a2O. The altered cardiac configuration and chamber filling pressures may consequently increase left ventricular transmural pressure and afterload, while LV relaxation is impaired by the exaggerated negative intrathoracic pressure thus worsening LV filling. This reduces stroke volume and cardiac output while the negative intrathoracic pressure stretches the aortic wall and activates intramural baroreceptors with episodic inhibition of sympathetic outflow with each Mueller maneuver. Increased venous return which occurs as the individual resumes breathing causes right ventricular distention and a leftward interventricular septal shift (ventricular interdependence) compromising LV diastolic filling and compliance [A hallmark of sleep apnea is the Mueller maneuver (inspiration against a closed upper airway) which could generate negative intrathoracic pressures with values as low as −80 cm Hmpliance –51. Transient rises in sympathetic activity with vasoconstriction and hypertension accompany episodes of apnea with the lowest blood pressure values recorded at the midpoint of these episodes. Blood pressure then rises gradually with a sudden elevation at onset of breathing. Apneic episodes that exceed 35 seconds are characterized by decline in cardiac output of about 33%; however cardiac output rises by up to 15% above baseline at resumption of breathing –55. ElevActivation of carotid chemoreceptors by hypoxemia triggers arteriolar vasoconstriction and systemic catecholamine secretion. This response is most marked in the systemic vascular bed at oxyhemoglobin saturation levels lower than 65% and leads to transient hypertension [Conversely, pulmonary vasoconstriction is a direct response to alveolar hypoxia in a physiologic attempt to minimize ventilation perfusion mismatch. The recurrence of hypoxemic episodes in sleep apnea result in repetitive increases in pulmonary artery pressures; however, about 1 in 5 patients develops sustained pulmonary hypertension during the daytime –70. MoreRepetitive bouts of nocturnal hypoxemia and intermittent reperfusion which accompany apneic episodes may generate highly reactive superoxide radicals as well as reperfusion-mediated endothelial damage, thus increasing susceptibility to atherosclerosis. Several polymorphonuclear leukocytes respond to hypoxemia with the release of free oxygen radicals; the cumulative effect of repetitive cycles of hypoxia followed by reoxygenation occurring multiple times in each hour of sleep over decades in patients who remain untreated may further worsen this preexisting vascular oxidative stress. The use of CPAP in patients with sleep apnea has been shown to reduce superoxide production –79.A high level of sympathetic tone has been observed in patients with sleep apnea and administration of 100% oxygen results in deactivation of the chemoreceptor reflex response and significant reduction in sympathetic activity –82. ThisThe release of vasoactive substances and vascular endothelial dysfunction may follow recurrent bouts of hypercapnia, hypoxia, and changes in vasomotor tone. Surges in plasma endothelin levels may help sustain vasoconstriction and endothelial dysfunction as observed in hypertension, dyslipidemia, and smoking, and diabetes has also been demonstrated in persons with OSA in the absence of other overt cardiovascular co-morbidity –90.Dysregulation of metabolic pathways associated with OSA may heighten cardiovascular risk and increase the predilection for weight gain. Leptin, a hormone derived from adipocytes and primarily responsible for appetite suppression, demonstrates increased levels in obesity possibly from resistance to its metabolic effects. This hormone, which has been identified as an independent cardiovascular risk marker and might induce platelet aggregation, has been observed to occur at much higher levels in OSA than in obesity. Moreover, patients with OSA have been observed to develop significant weight gain in the year immediately preceding diagnosis, and treatment of OSA with CPAP decreases leptin levels and accumulation of visceral fat, further implicating leptin resistance in the predisposition to weight gain –97.1c have been observed in these individuals with a direct correlation between severity of insulin resistance and OSA; patients with severe OSA are five times more likely to develop overt diabetes mellitus than the general population [Impaired glucose tolerance may also result from OSA. Elevated fasting blood glucose, serum insulin, and HbApulation , 98–101.α may be increased in response to hypoxia and sleep deprivation, both of which are present to varying degrees in patients with OSA. Patients with OSA have also shown elevated levels of these cytokines. The inhibition of nitric oxide synthase mediated by CRP which also increases the expression of certain cell adhesion molecules may worsen endothelial dysfunction and further aggravate preexisting vascular disease [Serum levels of C-reactive protein (CRP) and inflammatory cytokines such as interleukin-6 and tumor necrosis factor- disease –111. TheIncreased nocturnal catecholamine levels in conjunction with other factors increase the tendency for platelet aggregation in OSA; a condition almost completely reversed by the use of CPAP. Similarly, an increase in fibrinogen level, hematocrit and hyperviscosity of blood result in a predilection for thromboembolism and atherosclerosis. The reversal of these hypercoagulable phenomena with CPAP therapy suggests a causal relationship to OSA , 112–1182, reduced waking pO2, coexisting obstructive pulmonary disease, and body mass index, particularly in severe cases [OSA is frequently regarded as an independent risk factor in the development of pulmonary hypertension and subsequent cor pulmonale. However, studies show a stronger association between PH and obstructive ventilatory patterns observed on pulmonary function testing as well as daytime hypercapnia and hypoxemia; where most of this association is attributed to coexisting obstructive airway disease. PH correlates highly with elevated waking pCOre cases –121. Patre cases , 14, 123re cases , 127. Pulmonary vascular response to hypoxia has been shown to reduce with significant drop in the mean pulmonary artery pressures after the therapeutic use of nasal CPAP, suggesting potential reversibility of pulmonary hypertension upon treatment of OSA –130. OthSRBD encompasses conditions which range from habitual snoring to obstructive sleep apnea and may be associated with considerable morbidity and mortality. Increasing evidence points to the significant association between SRBD and PH. Though the majority of research endeavors in recent times have focused on left heart hemodynamics, few studies have attempted to outline the effects of SRBD on the pulmonary vascular system and multiple studies are ongoing to further elucidate the specific pathways underlying these mechanisms. Available evidence indicates that the development of pulmonary hypertension in patients with SRBD involves the complex interplay of multiple factors and correlates strongly with the severity and duration of nocturnal desaturations as well as associated risk factors. Early recognition and treatment may effectively reduce these complications.


The primary aim of the study was to determine the effects of massage therapy, delivered to post-surgery cardiothoracic patients, on pain, anxiety, relaxation and muscular tension at two different time points and compare it to an equivalent period of rest time. The secondary aims were to explore the effects of massage on heart rate, respiratory rate and blood pressure, feasibility of treatment delivery in a busy ward and staff acceptance of the new therapy and therapists.A randomised study conducted at the Alfred hospital compared massage therapy to an equivalent period of rest time. Visual analogue scales measured pain, anxiety, relaxation, muscular tension and satisfaction. Heart rate, respiratory rate and blood pressure were measured pre- and post-treatment by a cardiac nurse. Focus groups, staff and therapist feedback were utilised to collect qualitative data about clinical significance and feasibility of delivering the treatment.One hundred and fifty-two (99% response rate) patients participated. Compared to rest time, massage therapy produced a significantly greater reduction in pain (p=0.001), anxiety (p<0.0001), muscular tension (p=0.002) and increases in relaxation (p<0.0001) and satisfaction (p=0.016). No significant differences were seen for heart rate, respiratory rate and blood pressure. The effects at different time points were also compared between the groups. Pain significantly reduced after massage on day 3/4 (p<0.0001) and day 5/6 (p=0.003) whereas controls experienced no significant change at either time point. At both time points, massage significantly reduced anxiety (p<0.0001) and muscular tension (p<0.0001). Relaxation significantly improved on day 3/4 for both groups  but only massage was effective on day 5/6 (p<0.0001). Nurses and physiotherapists confirmed patient improvements and helped facilitate delivery of the treatment.Post-surgery massage therapy significantly improved pain, anxiety, muscular tension and relaxation amongst cardiothoracic surgery patients, was well accepted and feasible to deliver.


VDR gene maps to chromosome 12q, region q13-23 near a region commonly linked to asthma. The VDR hence is good candidate to be investigated for association with asthma. In this study, we analyzed the association between SPNs VDR and asthma susceptibility in a sample of asthmatic patients living in a Colombian Caribbean area.http://www.ncbi.nlm.nih.gov/SNP/. Nine VDR polymorphisms were genotyped : FokI (rs2228570), Apal (rs7975232), BsmI (rs1544410) , TaqI (rs731236), rs703842, rs4516035, rs 2248098, rs 71139166, rs7975232.Blood samples were collected from 37 asthmatics patients and 60 unrelated normal individuals with informed consent. The DNA was isolated from PBL by using a salting out technique. SNPs were selected from dbSNP: Total IgE was determined with a commercial ELISA kit .The allergens tested on patients by Prick Test were D Pteronyssinus, D Farine B Tropicalis and P Americana, Genotyping was performed using MALDI-TOF mass spectrometry of allele-specific primer extension products generated from amplified DNA sequences .There was no statistically significance difference in allelic frequencies of TaqI (rs731236), and rs2248098.The patients rs7975232 BSMI  and rs1544410  polymorphism demonstrated significant association as a susceptibility markers. The alleles rs4516035 (OR 0.4 p= 0.090) and rs7139166 Apa I ( OR 0.41 p=0.064) was observed to be significantly associated as a protective markers .The FokI rs2228570 marker was excluded from the analysis (Hardy-Weinberg disequilibrium failed).There was no difference in the serum levels of 25 hydroxyvitaminD3 between patients and controls. (mean=51.95ng/ml); p= 0,15 .Levels of IgE was higher in the patients ( mean=262.9UI/ml) compared with controls( mean=162.03UI/ml); p= 0.002. It wasn´t significant difference between levels of vitamin D and total IgE .Although a association of the VDR variants to patients with asthma could not be asserted, our results raise the possibility of a susceptibility association in rs7975232 BSMI and rs1544410 in this group of Caribbean patient’s population. This is the first work set up in the Colombian population. More data from family studies on this admixed population should be done to validate this possible association.


According to the National Health survey only 3% of the population has controlled hypertension. This study was designed to elucidate the knowledge about hypertension in hypertensive patients at three tertiary care centers in Karachi. Secondly we sought to compare the knowledge of those with uncontrolled hypertension and controlled hypertension.It was a cross-sectional study conducted at The Aga Khan University hospital (AKUH), Ziauddin Hospital (ZH) and Civil hospital, Karachi (CHK. All diagnosed Hypertensive patients (both inpatients and outpatients) coming to a tertiary care hospital in Pakistan aged > 18 years were included. Patients were categorized into 2 groups: controlled and uncontrolled hypertension based on their initial BP readings on presentation Uncontrolled Hypertension was defined as average BP ≥ 140/90 mm Hg in patients on treatment. Controlled Hypertension (HTN) was defined as average BP <140/90 mm Hg in patients on treatment. Standardized methods were used to record BP in the sitting position. Knowledge was recorded as a15 item question. Primary outcome was knowledge about hypertension.A total of 650 participants were approached and consented 447 were found eligible. 284(63.5%) were from Aga Khan University, 101(22.6) from Dow University of health sciences and 62(13.9) were from Ziauddin University. Mean (SD) age of participants was 57.7(12) years, 50.1(224) were men. Controlled hypertension was present in 323(72.3) and uncontrolled hypertension was present in 124(27.4). The total mean (SD) Knowledge score was 20.97(4.93) out of a maximum score of 38. On comparison of questions related to knowledge between uncontrolled and controlled hypertension, there was statistically significant different in; meaning of hypertension (p <0.001), target SBP(p0.001), target DBP(p 0.001), importance of SBP versus DBP, improvement of health with lowering of blood pressure (p 0.002), high blood pressure being asymptomatic (p <0.001), changing lifestyle improves blood pressure(p 0.003),hypertension being a lifelong disease (<0.001), lifelong treatment with antihypertensives(<0.001) and high blood pressure being part of aging(<0.001). On comparison of knowledge as a composite score between uncontrolled and controlled hypertensive; Mean (SD) score was 21.85(4.74) v18.67 (4.70) . On multivariate analysis; gender β (95% CI) 1.67 p <0.001, uncontrolled blood pressure; -2.70 p <0.001, Sindhi ethnicity; -1.79 p 0.01 and pukhtoon ethnicity; -2.72 p <0.001 were significantly associated with knowledge score.Knowledge about hypertension in hypertensive patients is not adequate and is alarmingly poor in patients with uncontrolled hypertension. More emphasis needs to be made on target blood pressure and need for taking antihypertensives for life to patients by physicians. Hypertension (HTN) is one of the most common medical disorders, associated with an increased incidence of all-cause and cardiovascular disease (CVD) mortality. Fifty-fAccording to the National Health Survey of Pakistan (NHSP) the prevalence of HTN amongst adults >15 yrs was 17.9% and amongst them only 3% had their BP under control as opposed to a prevalence of 28.7% and control of around 31% being reported from US. Hence tThe NHSP showed that 70% of all hypertensive in Pakistan are unaware if their condition. KnowledIt was a crossectional study conducted at three tertiary care hospitals in Karachi; Aga Khan Hospital, Ziauddin Hospital and Civil Hospital Karachi. The Aga Khan Hospital is a 577 bedded facility, which provides high quality of patient care in a broad range of secondary and tertiary services to over 50,000 hospitalised patients and to approximately 600,000 outpatients annually. It is located in the center of Karachi. The Ziauddin hospital is a 300 bedded hospital and is located in north of Karachi. The Civil hospital is a 1900 bedded public sector hospital located in center of Karachi. Population of different socioeconomic strata caters to these hospitals. The study was conducted in 2009–2010. All hypertensive patients (an average BP of ≥140/90 mm Hg or if the participant is taking antihypertensive medications) > 18 years of age presenting to the outpatient clinics were included. DiagnosPrimary outcome was knowledge score which was based on 15 item questions. Knowledge was also computed as a composite measure of sum of all the 15 item questions. These questions were developed by brainstorming with experts managing hypertension and who suggested that correct response of these questions can be counted towards having sound knowledge on hypertension (in patients). Questions regarding knowledge were asked and were marked on a scale of 1–5. . Data was also stratified on basis of control of hypertension. Uncontrolled hypertension was defined as average BP ≥140/90 mm Hg in no diabetic patients on treatment . ControlA total of 650 participants were approached; 350 in AKU, 150 in DUHS and 150 in ZMU.Of the total participants who were approached and who consented, 447 were found eligible%(n); 63.5(284) from Aga Khan University, 22.6(101) from Dow University of health sciences and 13.9(62) from Ziauddin University. Overall response rate was 71.52%; 81% in AKU, 80% in DUHS and 49.6% in ZMU.Mean (SD) age of participants was 57.712) years, 224(50.1) were men and 223(49.8) were women. In ethnicity 108(24.3) were of Muhajir ethinicity. In education, 208(46.5) had > 10 years formal education. Comorbid conditions are shown in Table 2 years, Outcome of knowledge is reported as percentage(n) and mean(SD) scores have also been computed. Table On comparison of individual item question in men and women%(n); 57.7(128) men and 35.5(78) women agreed that hypertension means high blood pressure , 93.5(203) man and 92.5(205) women agreed that hypertension can be dangerous , 79.4(177) men and 60.5(135) women said that systolic blood pressure (SBP) should be <140 mm hg , 78.6(176) men and 58.3(130) women said that diastolic blood pressure (DBP) should be < 90 mm hg , 26.7(58) men and 11.8(26) women said that both SBP and DBP are important to control  men and 91.2(197) agreed that lowering blood pressure improves health , 45.8(99) men and 33(71) women agreed that high blood pressure can be asymptomatic , 82.8(184)men and 84(186) agreed that changing lifestyle improves blood pressure , 76(166) men and 73.3(162) women agreed that hypertension is a lifelong disease , 77(174) men and 72.8(161) women agreed that antihypertensives have to be taken for life , 57.3(126) men and 50.4(112) said that high blood pressure is a part of aging  The mean (SD) knowledge score in men was 21.8(4.9) and in women was 20.07(4.8) .On comparison of demographics of patients with controlled and uncontrolled hypertension, there was statistically significant difference in; Mean (SD) age (59.05 years 11.2) v 54.33 years (13.4)p <0.001), gender ,> 10 years of formal education (38.7% v8.1% p <0.001). Comorbids and history of hospitalization is shown in Table 1.2 v 54.On comparison of questions related to knowledge, there was statistically significant different in; meaning of hypertension (p <0.001), target SBP (p0.001), target DBP (p 0.001), importance of SBP versus DBP, improvement of health with lowering of blood pressure p 0.002), high blood pressure being asymptomatic (p <0.001), changing lifestyle improves blood pressure (p 0.003), hypertension being a lifelong disease (<0.001), lifelong treatment with antihypertensives (<0.001) and high blood pressure being part of aging (<0.001)  was 21.85(4.74) v18.67 (4.70)  Knowledge score on most of individual item questions between the two group was significantly different Table .On univariate linear regression for outcome of knowledge score; β(95% CI) was 0.064 for age, 1.79 for gender,-1.93 for sindhi ethinicity, -1.66 for Punjabi ethinicity, -2.22 for balochi ethnicity, -2.84 for pukhtoon ethinicity, -0.95 for Muhajir ethinicity, -0.99 for education up to <5 years,-1.14 for < 10 years of education, 0.75 for >10 years of education, 0.47 for history of hospitalization for uncontrolled hypertension, -3.17 for having uncontrolled hypertension. However on multivariate analysis gender β(95% CI) 1.67 p <0.001,uncontrolled blood pressure; -2.70p <0.001,sindhi ethnicity; -1.79 p 0.01 and pukhtoon ethnicity; -2.72 p <0.001 were significantly associated with knowledge score (Table We are first to report a knowledge score in patients with hypertension belonging to three different tertiary care hospitals in Karachi, Pakistan. We found that overall knowledge scores in hypertensive patients was not up to the mark. Furthermore scores in patients with uncontrolled hypertension were significantly low. The lowest scores were obtained to questions related to importance of systolic blood pressure versus diastolic blood pressure, high blood pressure being asymptomatic and high blood pressure being an unavoidable part of aging. Factors associated with knowledge scores were male gender, having uncontrolled hypertension and ethnicity. Interestingly formal education did not show any relation with high knowledge scores in these hypertensive patients. This suggests that specific knowledge about disease is needed and just education alone may not suffice.Sufficient knowledge about hypertension in patients has been associated with greater medication adherence and better blood pressure control. SeveralGaps in knowledge have been reported with regard to risk factors associated with hypertension in 110 university students in a crossectional study conducted in Gulf region. Nationality, course of study, raised blood pressure, and history of diabetes showed significant association with good knowledge, however their net effect was not significant by the Adjusted Odds Ratio. We repoSimilar results have been reported from Karachi, Pakistan on hypertensive and normotensives,14. The Less than 75% of people prescribed drugs for hypertension continue using them after 6 months after initiation, and this is associated with an increased risk of hospitalization for cardiovascular problems. KnowledThe strength of this study is that it is multi centered study focusing on in depth analysis of knowledge regarding hypertension. It points out specific aspects on knowledge about hypertension, by taking care of which the hypertensives may have better blood pressure control. There are several limitations to this study. Firstly the results from this study cannot be generalized to the rural population in Pakistan. Hence similar studies need to me conducted in rural areas as well. Secondly the questionnaire used for knowledge assessment was not validated; however it was pretested before using. Thirdly blood pressure reading at a single occasion was used for classifying patients into controlled and uncontrolled hypertension. Fourthly we did not account for white coat effect while making this classification. Although the research staff was trained in recording the responses of the item questions, the possibility of a small percentage of interviewer bias cannot be completely ruled out. Additionally we did not measure compliance to antihypertensive therapy in this patient population. However adherence related questions were asked and will be reported elsewhere.Knowledge about hypertension in hypertensive patients is not adequate and is alarmingly poor in patients with uncontrolled hypertension. More emphasis needs to be made on target blood pressure and need for taking antihypertensives for life to patients by physicians. Alternatively group education of such patients needs to be tested as an intervention to improve knowledge on these aspects in addition to the risk factors of hypertension.The authors’ declare that they have no competing interests.AA was responsible for conceiving the idea, drafting the protocol and getting approvals, SSG, SL and ZAH were responsible for implementation data collection and entry of the study, AA and AAH were responsible in drafting, revising and proof reading of the study. All authors read and approved the final manuscript.Appendix A.Click here for file


We examined the relationship between central blood pressure (BP), brachial BP with carotid atherosclerosis and microvascular complications in type 2 diabetes mellitus (T2DM).We recruited 201 patients who were evaluated for central BP, brachial BP, carotid ultrasonography, brachial-ankle pulse wave velocity (baPWV), ankle-brachial index (ABI) and microvascular complications. Central BP were calculated using a radial automated tonometric system.Agreement between central BP and brachial BP was very strong . Central pulse pressure (PP) was correlated with mean carotid intima-media thickness (CIMT), baPWV and ABI, whereas brachial PP was borderline significantly correlated with CIMT. The prevalence of nephropathy(DN) and retinopathy(DR) according to the brachial PP tertiles increased, the prevalences of microvascular complications were not different across central PP tertiles. In multivariate analysis, the relative risks (RRs) for the presence of DR were 1.2 and 4.6 for the brachial PP tertiles 2 and 3 when compared with the first tertile. Also, the RRs for the presence of DN were 1.02 and 3 for the brachial PP tertiles 2 and 3 when compared with the first tertile.Agreement of central BP and brachial BP was very strong. Nonetheless, this study showed that higher brachial PP levels are associated with increased probability for the presence of microvascular complications such as DR/DN. However, there are no associations with central SBP and central PP with microvascular complications. Central BP levels than brachial BP are correlated with surrogate marker of macrovascular complications. Blood pressure (BP) management is important for the prevention and management of cardiovascular disease (CVD) and microvascular complications in T2DM . BrachiaPulse pressure (PP) is traditionally thought of as a marker of arterial stiffness and has been suggested as an independent CV risk factor ,9. RecenCentral BP is most accurately measured by an invasive method. It has been evaluated noninvasively by mathematically transforming the radial artery pulse waveform to the aortic pulse waveform recently ,16. AlthTherefore, the aim of this study was to evaluate the value of central BP and brachial BP components in relation to microvascular complications and surrogate markers of macrovascular diseases , in patients with T2DM.We recruited 201 patients with T2DM who were evaluated for central BP, carotid ultrasonography and standard brachial BP measurement at the diabetes clinic of Soonchunhyang University Bucheon Hospital, from June 2012 to July 2012. We reviewed detailed demographic data, biochemical data and clinical history using medical records. Participants provided written informed consent for the use of their data for research. This study was reviewed and approved by the Institutional Review Board of Soonchunhyang University College Medicine, Bucheon Hospital.Central BP was evaluated noninvasively by mathematically transforming the radial artery pulse waveform to the aortic pulse waveform with an automated tonometric system, HEM-9000AI  in a sitting position after at least 5 min of rest. The radial artery pressure waveform was recorded for 10 sec with the HEM-9000AI system. The radial pulse wave was calibrated to brachial BP, measured with an automated oscillometric device. From the average radial pulse wave form, the corresponding ascending aortic pulse wave form was derived, using a validated generalized transfer function incorporated in the software , which also provided the calculated central BP and the calculated central Aix. The measurements of blood pressure were performed twice by the same trained observer in same day at intervals of at least one minute.Carotid atherosclerosis was assessed by the use of a model SSA-660A high-resolution B-mode ultrasonograph device  performed with an ultrasound scanner equipped with a 12-MHz linear-array transducer. IMT measurements were performed on the right and left common carotid arteries 1.0 cm proximal to the origin of the bulb and the mean IMT values were calculated. Carotid IMT thickening was defined as mean CIMT ≥ 1.0 mm ,18.Diabetic nephropathy (DN) was defined using albuminuria, which was measured by radioimmunoassay . Albumin excretion rate (AER) in the range of 20-200 μg/min or urine albumin 30-300 mg/g creatinine was defined as microalbuminuria, and AER > 200 μg/min or urine albumin ≥ 300 mg/g creatinine as overt proteinuria. Patients were considered to have nephropathy if they displayed microalbuminuria or overt proteinuria.Diabetic retinopathy (DR) was evaluated by experienced ophthalmologists while the patients’ pupils were dilated. If needed, fluorescein angiography was performed. DR was classified as normal, nonproliferative and proliferative retinopathy . PatientDiabetic peripheral neuropathy (DPN) was diagnosed with recommendation by the Expert Committee of Korean Diabetes Neuropathy Study Group, as: the presence of typical symptoms using the Michigan Neuropathy Screening Instrument (MNSI) and compatible findings on neurologic screening examinations or electrophysiologic studies ,21. AlthCardiac autonomic neuropathy (CAN) was assessed by autonominc function test (AFT). CAN was assessed by the five standard cardiovascular reflex tests according to the Ewing’s protocol . The sevAn automated device  was used to measure arterial baPWV and ABI. The insulin resistance status was evaluated by the HOMA-IR index, which was calculated by the formula: [fasting insulin (uIU/mL) × fasting blood glucose (mmol/L)]/22.5. The HOMA-IR score was available only in 164 patients not receiving exogenous insulin.Data are presented as mean ± standard deviation (SD) for variables normally distributed or as median (interquartile range) for variables not normally distributed or as number of participants (percentages). Non-normally distributed variables of, triglyceride, high-sensitivity C-reactive proein (hsCRP) and HOMA-IR were transformed as natural logarithm before analysis. The concordance correlation coefficient between central BP and brachial BP was measured to evaluate the agreement between two variables. The categorical variables of the groups were compared by Chi-square test. Correlation between BP and other clinical parameters were analyzed by Spearman’s correlation analysis. The significance of the mean differences including several parameters of BP between patients with and those without microvascular complications was evaluated with Student’s t-test. Patients were divided into theree groups by the tertiles of central or brachial PP levels, respectively. One-way ANOVA was used to evaluate differences of means among tertiles of central or brachial PP groups. The prevalence of microvascular complications and carotid atherosclerosis according to the tertile of brachial PP, central SBP and central PP were analyzed using Chi-square test. Relationships of central BP and brachial BP with microvascular complications were determined in multivariate logistic regression analyses. Two-tailed p < 0.05 was considered significant. Statistical analyses were performed with SPSS, version 18 .A total of 201 patients with T2DM  participated in this cross-sectional study. Clinical and biochemical characteristics of the study subjects are presented in Table The concordance correlation coefficient between central SBP and brachial SBP was 0.889 and between central PP and brachial PP was 0.816  and brachial BP components  to carotid atherosclerosis, vascular stiffness and other clinical variables are presented in Table Comparison of carotid atherosclerosis, vascular stiffness and clinical variables among tertile groups of central PP or brachial PP is shown in Tables Comparisons of the prevalence of diabetic microvascular complications according to the tertile levels of central PP or brachial PP are shown in Figure Differences of several parameters of BP according to the presence or absence of microvascular complications are presented in Table C, duration of DM and mean baPWV levels were significantly different according to the presence or absence of DR. After adjustment for these variables, age and gender, multivariate logistic regression analysis was done to examine the relationship of central or brachial BP with the presence of DR/DN . Total cholesterol, LDL-cholesterol, eGFR and mean baPWV levels were significantly different according to the presence or absence of DN. HbA1DN Table . In multDR Table .To the best of our knowledge, our study is the first to report associations between central versus brachial BP with all diabetic microvascular complications as well as carotid atherosclerosis.The main finding of this study is that central BP and brachial BP show very strong agreement. Nevertheless, the higher brachial PP levels are associated with increased probability for the presence of diabetic microvascular complications and are more powerful than central BP in relation to DR and DN. But, to the contrary, central BP levels rather than brachial BP are correlated with surrogate marker of macrovascular complications.Peripheral  BP is an essential parameter for the evaluation and management of BP and remains the standard reference. On the other hand, there is increasing evidence that measurement of central BP, reflecting ascending aortic BP, is more strongly correlated to CVD or TOD than brachial BP levels ,25. AlthFew studies have evaluated whether central and brachial BP are associated differently with carotid atherosclerosis and microvascular complications in patients with T2DM. The Strong Heart Study revealed that central PP was more strongly related to CIMT and plaque score than was brachial PP in 3520 population (including diabetes in 46.5% of women and 38.1% of men) . To the The present study revealed that central PP is significantly correlated with CIMT and brachial PP values also showed positive, but weaker, correlation than central PP. The levels of mean CIMT demonstrated an increasing trend as the levels of central PP or brachial PP increased. However, measures of central or brachial SBP/DBP were not correlated with carotid atherosclerosis. In contrast to this our study, Westerbacka et al. reported measures of central SBP correlate with CIMT . One repPP, the arithmetic difference between systolic and diastolic BP, has been reported as a potent predictor for CVD . SeveralCentral BP can be directly measured only using a pressure sensor or catheter inserted into the aorta. This procedure is invasive and can lead to complications. Recently, central BP has been evaluated noninvasively by mathematically transforming the radial artery pulse waveform to the aortic pulse waveform ,16. HoweTo our knowledge, no study has examined the relative importance of central and brachial BP in their relations to microvascular complications in patients with T2DM. This present study examined the relationship between central BP, brachial BP and all microvascular complications. We established good association higher brachial PP levels and increased probability for the presence of diabetic nephropathy and retinopathy. However, our study showed that no associations of any central BP components or brachial BP components with CAN and DPN. In agreement of our study, Knudsen et al. reported that in 80 patients with T2DM, brachial PP is associated with DR and DN . Also, iSeveral limitations of our study should be addressed. First, due to the cross-sectional design, we cannot determine the causative relationship between brachial PP and diabetic microvascular complications, DN or DR. Prospective studies are required to address this important question. Second, because our study population included individuals who received the examination for diabetic complications, some characteristics of the present study population may be substantially different from other populations that did not perform complication study. Therefore, the generalizability of our study may be limited. Third, the present study included a small numbers of subjects. A larger number of patients should be analyzed for the confirmation of our results. Fourth, information for central BP is that derived from automated radial artery tonometry. Although the clinical significance of central BP by automated applanation tonometry, has not been fully elucidated, many studies revealed that central BP from radial artery automated tonometry showed excellent correlation with direct measured central BP . HoweverIn conclusion, this study showed that agreement of central BP and brachial BP was very strong. Brachial BP are associated with presence of microvascular complications such as DR/DN than central BP. On the other hand, central BP levels rather than brachial BP are correlated with surrogate marker of macrovascular complication. However, further prospective studies are needed to evaluate the superiority or difference of central BP versus brachial BP in respective of associations with development of micro-and macrovascular complications in T2DM.The authors declare that they have no competing interests.Study design: CHJ, JOM. Data collection: CHJ, SHJ, BYK. Data analysis: CHJ, SHJ, JOM. Writing the first draft: CHJ, KJK, BYK, JOM. Data interpretation, discussion and preparation of the final manuscript: CHJ, SHJ, KJK, BYK, CHK, SKK, JOM. All authors read and approved the final manuscript.Chan-Hee Jung and Sang-Hee Jung both should be considered as first authors.The pre-publication history for this paper can be accessed here:http://www.biomedcentral.com/1471-2261/14/23/prepub


Cardiovascular morbidity and mortality remains excessive in patients with chronic kidney disease. The association of vascular changes with regulators of extraosseous calcification in this patient population is still under investigation. The aim of the present study was to investigate the associations of the calcification inhibitor fetuin-A, and the anti-osteoclastic factor osteoprotegerin (OPG) with vascular pathology in chronic hemodialysis patients.In this cross-sectional study including 81 stable chronic hemodialysis patients, we measured carotid-to-femoral pulse wave velocity (cfPWV) with applanation tonometry, reflecting arterial stiffness, and common carotid intima-media thickness (ccIMT), a surrogate of early atherosclerosis, as well as serum levels of fetuin-A and OPG. Co-morbidities, traditional cardiovascular risk factors, inflammatory markers and mineral-bone disease serology parameters were also recorded.cfPWV correlated inversely with fetuin-A  and positively with OPG . In multilinear regression analysis including age, gender, diabetes, cardiovascular disease, hypertension, pulse pressure, LDL, logCRP, both fetuin-A and OPG were independently associated with cfPWV (p=0.024 and p=0.041 respectively). ccIMT was negatively associated with fetuin-A  and positively with OPG ; however these associations lost statistical significance after adjustment for age.In chronic hemodialysis patients both fetuin-A and OPG levels are independently associated with arterial stiffness but not with early atherosclerotic vascular changes. Cardiovascular pathology remains the leading cause of morbidity and mortality in patients with chronic kidney disease (CKD) . Two typThe pathogenesis of vasculopathy in end-stage renal disease (ESRD) involves traditional risk factors of atherosclerosis , which are highly prevalent in this patient population, but also several uremia-related risk factors , which are still under investigation .Recent evidence suggests that vascular calcification is a highly regulated active process, and that the phenotypic trans-differentiation of vascular smooth muscle cells (VSMCs) into osteoblast-like cells is a key pathogenetic event . A varieFetuin-A is a liver-derived potent systemic inhibitor of calcification and a negative acute phase reactant . Apart fOsteoprotegerin (OPG) is a soluble member of the tumor necrosis factor (TNF) receptor superfamily, produced by osteoblasts and vascular endothelial and smooth muscle cells . It has The precise roles of fetuin-A and OPG in the development of uremic vasculopathy are not fully elucidated . The aimEighty one adult patients  on chronic maintenance HD for at least three months  were included in the study. All patients were from the Dialysis Unit of the University Department of Nephrology at “Hippokration” General Hospital who consented to the protocol and entered the study consecutively. Chronic renal failure was attributed to glomerulonephritis in 21 cases (25.9%), diabetes mellitus in 17 (21%), tubulointerstitial nephritis in 10 (12.3%), polycystic kidney disease in 8 (10.0%), renovascular hypertension in 7 (8.6%), and was undetermined in 18 cases (22.2%). Patients were clinically stable without active malignancy, infection, or liver disease. None of the patients was receiving antibiotics or immunosuppressive agents and none had a history of parathyroidectomy at the time of the study. All patients were receiving conventional 3.5 to 4.5-h HD, three times weekly, with synthetic (polysulphone or helixone) dialyzers, bicarbonate dialysate and tinzaparin as standard anticoagulation. Dialysis prescription was guided by a goal of achieving a value of Kt/V ≥1.2, as calculated by the second-generation Daugirdas equation. The achieved Kt/V was 1.46 ±0.21 (range 0.92 – 2.0).The protocol conformed to the ethical guidelines of our institution and it was approved by the Institutional Review Board of “Hippokration” General Hospital. All patients signed an informed consent prior to the study entry.Blood samples were drawn from a peripheral vein under fasting conditions in the morning of a midweek routine dialysis session. Serum samples were separated from clotted blood by immediate centrifugation (1500g for 10 min), aliquoted and stored at −70°C until assay. Serum levels of fetuin-A and OPG were measured by an enzyme-linked immunosorbent assay (ELISA) using commercially available standard kits . Serum albumin, total cholesterol, triglycerides, HDL cholesterol, LDL cholesterol, calcium, phosphorus and alkaline phosphatase were determined by routine techniques using an automated analyser . Levels of albumin were time averaged for the last six months before inclusion in the study. Intact parathormone (iPTH) levels were measured by radioimmunoassay (RIA). Serum CRP levels were measured by nephelometry. The detection limit was 3.75 mg/L and in the statistical evaluation all values <3.75 mg/L were treated as 3 mg/L.cfPWV measurements were performed with the SphygmoCor® , by a trained operator unaware of the patient’s clinical and laboratory parameters. The device uses a high-fidelity applanation tonometer for transdermal pulse wave recording. Each subject was examined in the supine position during a mid-week non-dialysis day and within one month from blood sampling. cfPWV measurements were done in two steps. The first step involved recording the carotid pulse wave, and the second recording the femoral pulse wave, both with simultaneous ECG, for synchronization of carotid and femoral pulse wave times. Transit time between carotid and femoral pressure waves was calculated using the foot-to-foot method. Wave “foots” were identified using the intersecting tangents algorithm. Two distances on the body surface were measured, that is, from sternal notch to the femoral location and from sternal notch to the carotid location of the respective pulse wave recording sites. On entering the data into the computer, travelled distance was calculated automatically as the difference between the two distances, that is, femoral location-sternal notch minus sternal notch-carotid location. cfPWV results were expressed in meters per second (m/s) ± SD . MeasureUltrasonographic studies were performed with an Aloka® Prosound A6 instrument , using a 10 MHz high-resolution probe. Each subject was examined in the supine position in a semi-dark room during a mid-week non-dialysis day within one month from blood sampling. The common carotid artery was investigated bilaterally by the same trained operator, who was unaware of the patients’ clinical and laboratory parameters. Longitudinal 2D images of the vessel were acquired, frozen in diastole and analysed offline. ccIMT was calculated as the distance between the leading edge of the lumen–intima interface and the media–adventitia interface on the far wall of the artery . MeasureBlood pressure was recorded with an upper arm mercury sphygmomanometer according to the recommendations of the American Heart Association , before < 0.1 on bivariate analyses or the independent samples t-test were entered into the multiple regression models. Despite the significant bivariate correlation of SAP and PP with cfPWV, and DP and MAP with ccIMT, only PP and MAP respectively were entered in the relevant multiple regression models, in order to avoid co-linearity. The calculations were performed using SPSS for Windows® version 13.0 statistical software . A two-tailed p value <0.05 was considered statistically significant.Data are expressed as mean ± SD, median with range, or number of patients with percentage as appropriate. The associations between fetuin-A, OPG, cfPWV, ccIMT, and demographic, clinical and laboratory parameters were assessed. Normality of distribution of continuous variables was tested by the one sample Kolmogorov-Smirnov test. Non-normally distributed variables were log-transformed before entering the analysis. The significance of differences between groups was assessed by the independent samples t-test. Associations between continuous variables were tested by Pearson’s bivariate and partial correlation analyses. Multiple linear regression analysis, with simultaneous inclusion of values into the model, was used to assess the adjusted combined influence of variables on the dependent variables (cfPWV or ccIMT). Variables with p The patients’ epidemiological and clinical characteristics and laboratory parameters are summarized in Tables Fetuin-A correlated negatively with age , and logCRP , and positively with albumin  and smoking habit .OPG correlated positively with age , dialysis duration , SAP  and PP , and negatively with BMI  and albumin .There was a non-significant negative association between fetuin-A and OPG levels .Arterial stiffness was associated with history of cardiovascular disease (CVD) , hypertension  and diabetes mellitus , and correlated positively with age , SAP , PP , and LDL levels    the correlations of cfPWV with both fetuin-A and OPG did not reach statistical significance (p=0.173 and p=0.177 respectively) , along with age, PP and LDL  and history of CVD , and correlated significantly with age , DAP , MAP , serum albumin  and logCRP    the correlations of ccIMT with fetuin-A and OPG did not reach statistical significance (p=0.144 and p=0.989 respectively) Figure a and 3b 2=0.305, p<0.001), OPG was the only variable significantly correlated with ccIMT .In multiple regression analysis only age, gender, diabetes mellitus and history of CVD were independently associated with ccIMT Table . In a muFetuin-A is a potent systemic inhibitor of calcium phosphate precipitation, that binds hydroxyapatite structures, thus protecting VSMCs from the effects of calcium overload and calcification . Recent Fetuin-A mediated prevention of VSMC calcification could potentially attenuate hemodynamic consequences of vascular calcification, such as arterial stiffening and increased PWV . In the In the present study, fetuin-A also showed a significant negative association with ccIMT, which however, lost significance after adjustment for age. Studies investigating the above association are limited and the results are inconsistent. A recent study in patients with essential hypertension and normal renal function showed an independent negative correlation of fetuin-A with carotid IMT . HoweverFetuin-A is a negative acute phase reactant and its associations with cardiovascular morbidity and mortality might be influenced by the presence of inflammation, a well recognised risk factor for atherosclerosis and cardiovascular events . In our OPG is produced by osteoblasts as well as by endothelial cells and VSMCs . Its antIn the present study an independent association was observed between cfPWV and OPG. There are few relevant published studies in dialysis patients and their results appear again inconsistent. A previous study in adult HD patients failed to document any association , and in We also documented a positive association of ccIMT with OPG, even though it was not independent of age, which appeared, as expected, the strongest predictor of ccIMT. Previous studies have shown an independent positive association between OPG and carotid IMT in non-renal patients, such as healthy post-menopausal women , women wThere are some limitations of the present study that should be considered. It is cross-sectional, which precludes validation of causative associations, and from a single centre, which affects generalizability of the results.Although in the present study, a clear distinction between arterial stiffness and atherosclerosis cannot be made, our results suggest that in stable chronic hemodialysis patients serum levels of the calcification inhibitor fetuin-A and the osteoclast inhibitor osteoprotegerin are independently associated with pulse wave velocity, a marker of arterial stiffness but not with carotid intima-media thickness, a marker of early atherosclerosis.ccIMT: Common carotid intima-media thickness; cfPWV: Carotid to femoral pulse wave velocity; CKD: Chronic kidney disease; CRP: C-reactive protein; CT: Computed tomography; CVD: Cardiovascular disease; DAP: Diastolic arterial pressure; ELISA: Enzyme linked immunosorbent assay; FMD: Flow mediated dilatation; HD: Hemodialysis; iPTH: Intact parathormone; MAP: Mean arterial pressure; OPG: Osteoprotegerin; PP: Pulse pressure; RANKL: Receptor activator of nuclear factor κΒ; RIA: Radioimmunoassay; SAP: Systolic arterial pressure; VSMC: Vascular smooth muscle cells.The authors declare that they have no competing interestsPP was responsible for recruiting, data acquisition, vascular measurements, statistical analysis and drafting of the manuscript, AP conceived and supervised the study, the execution of the immunoassays, and reviewed/edited the manuscript. SD contributed to the study design and to the discussion GE contributed to the discussion and reviewed/edited the manuscript. DM supervised the study, contributed to the discussion and reviewed/edited the manuscript. All authors have read and approved the final manuscriptThe pre-publication history for this paper can be accessed here:http://www.biomedcentral.com/1471-2369/14/122/prepub


Sitagliptin is a DPP-4 inhibitor that became available for use in Japan three years ago. This study was conducted to identify the pleiotropic effects of sitagliptin other than blood glucose lowering in Japanese type 2 diabetes mellitus patients.A retrospective, observational study of 940 type 2 diabetes mellitus patients was conducted. The primary outcome measures were HbA1c, blood pressure, and lipid profiles measured at 0, 4, and 12 weeks of sitagliptin therapy.After 12 weeks of sitagliptin treatment, compared with baseline, HbA1c decreased 0.64% ± 0.86%; systolic blood pressure (SBP) and diastolic blood pressure (DBP) decreased significantly; and serum creatinine (Cr) and uric acid (UA) levels were mildly but significantly elevated. A correlation analysis of the changes in systolic blood pressure, diastolic blood pressure, creatinine, and uric acid  from baseline to 12 weeks showed significant negative correlations between ΔSBP and ΔCr, ΔSBP and ΔUA, and ΔDBP and ΔCr. Total cholesterol and postprandial triglycerides were significantly decreased at both 4 and 12 weeks. Alkaline phosphatase (ALP) decreased significantly, and there was a significant positive correlation between changes in ALP and HbA1c.Sitagliptin seems to be effective not only in lowering blood glucose but also in lowering blood pressure, lipid, and ALP levels. Sitagliptin appears to contribute to a Na-diuretic action due to GLP-1. Sitagliptin is a DPP-4 inhibitor that became available for use in Japan three years ago. It has been shown to be effective in Japanese diabetes mellitus patients , 2, who DPP-4 inhibitors administered from the early stage of diabetes help to protect pancreatic β cells and normalize glucagon secretion control, combining reliable hypoglycemic action and safety, inhibiting the progression of diabetes and maintaining glycemic control, along with the potential for cardiovascular protection and anti-arteriosclerotic action . IncretiThe present study was a retrospective cohort study of type 2 diabetes mellitus patients who were given sitagliptin continuously for 12 weeks in actual clinical practice, to determine not only the hypoglycemic effect of sitagliptin but also its other pleiotropic effects.The survey subjects were type 2 diabetes mellitus patients receiving outpatient treatment at 28 hospitals or clinics specializing in diabetes belonging to the Diabetes Committee of the Kanagawa Physicians Association from December 2009 to August 2010.Oral informed consent for participation in this study was obtained from type 2 diabetes mellitus patients who were using diet and exercise therapy and from patients with insufficient glycemic control despite the use of hypoglycemic agents. Sitagliptin monotherapy or sitagliptin in combination with other drugs was then given, starting at a dose of 25 mg or 50 mg. If good glycemic control was not obtained after this, the sitagliptin dose could be increased to 100 mg. To evaluate the effects of sitagliptin on blood pressure and lipids, the use of hypoglycemic agents and dyslipidemia medications was examined, excluding patients whose antihypertensive and lipid medications had been changed during the observation period. A total of 940 patients were registered. This study was an observational study that aimed to evaluate the efficacy of sitagliptin, and approval was obtained from the Ethics Review Board of the Kanagawa Physicians Association.2. The primary outcome measures, HbA1c, blood pressure, and lipid profiles, were measured at the start and after 4 and 12 weeks of sitagliptin therapy. HbA1c, expressed in National Glycohemoglobin Standardization Program (NGSP) units-equivalent value [The patients’ baseline characteristics were as follows: 538 men, 402 women; mean age 63.3 ± 11.5 years; duration of diabetes 12.2 ± 8.0 years; and body mass index (BMI) 24.5 ± 4.3 kg/mnt value , was meaThe 940 patients included 178 patients who received sitagliptin monotherapy and 762 patients who received combination therapy that included other oral medications. Co-administered drugs in the combination therapy group were analyzed, and the numbers of patients taking sulfonylureas, biguanides, pioglitazone, αGI, and glinides were 620, 420, 210, 84 and 13, respectively. HbA1c was analyzed at baseline and after 4 and 12 weeks, and body weight was analyzed at baseline and after 12 weeks.All analyses were performed using SPSS version 19 for Windows. For parameters during sitagliptin treatment, data were analyzed by one-way ANOVA. The correlations between variables were assessed by Pearson’s correlation coefficient. In correlation analysis, Δ was used as the difference in each variable between the start of sitagliptin and after 12 weeks. Data are presented as means ± SD. A P value < 0.05 was considered significant.Blood pressure was analyzed after the start of sitagliptin in 940 patients, including 619 in whom antihypertensive agents were not administered from before the start of sitagliptin until 12 weeks afterward, and 321 in whom antihypertensive agents were administered but the agent was not changed during the same observation period. With the administration of sitagliptin, HbA1c decreased significantly from 8.02% ± 1.12% at baseline to 7.71 ± 0.98% at 4 weeks (P < 0.01) and 7.38% ± 0.89% at 12 weeks (P < 0.01). Systolic blood pressure (SBP) decreased significantly from 128.8 ± 14.3 mmHg at baseline to 127.6 ± 13.7 mmHg at 4 weeks (P < 0.05) and 127.4 ± 13.4 mmHg at 12 weeks (P < 0.01). During the 12 weeks, significant changes were seen in diastolic blood pressure (DBP), which went from 74.7 ± 9.8 mmHg at baseline to 74.0 ± 9.6 mmHg at 4 weeks and 74.0 ± 9.3 mmHg at 12 weeks (P < 0.01).Of the lipids, total cholesterol (TCHOL) decreased significantly from 198.2 ± 34.3 mg/dL at baseline to 192.6 ± 34.3 mg/dL at 4 weeks (P < 0.01) and 191.7 ± 32.5 mg/dL at 12 weeks (P < 0.01). HDL did not change significantly after sitagliptin administration. Triglycerides were analyzed with patients divided into a postprandial measurement group and a fasting measurement group. No significant change was seen in fasting triglycerides (fTGs), but postprandial triglycerides (ppTGs) decreased significantly from 157.4 ± 99.4 mg/dL before the start of sitagliptin administration to 144.9 ± 87.2 mg/dL at 4 weeks (P < 0.05) and 146.3 ± 86.8 mg/dL at 12 weeks (P < 0.05).Although the changes in serum creatinine (Cr) and uric acid (UA) after sitagliptin administration were within the normal range, they rose significantly from 0.75 ± 0.22 mg/dL at baseline to 0.78 ± 0.24 mg/dL at 12 weeks and 5.07 ± 1.21 mg/dL at baseline to 5.40 ± 1.45 mg/dL at 12 weeks, respectively. Correlations among changes in systolic blood pressure, diastolic blood pressure, creatinine, and uric acid  between baseline and 12 weeks were analyzed . The resSerum alkaline phosphatase (ALP) was also found to decrease significantly after sitagliptin administration, from 255.3 ± 93.0 IU/L at baseline to 240.3 ± 86.1 IU/L at 4 weeks (P < 0.01) and 231.8 ± 78.2 IU/L at 12 weeks (P < 0.01) . No signThe results of a survey of 940 Japanese type 2 diabetes mellitus patients treated with sitagliptin showed that not only blood glucose but also blood pressure decreased significantly with sitagliptin therapy. Compared with the start of treatment, significant decreases of 1.4 mmHg in systolic pressure and 0.78 mmHg in diastolic pressure were seen at 12 weeks. There are still few reports on the effects of sitagliptin on blood pressure. Mistry  and OgawIt was also shown that both TCHOL and ppTGs decreased significantly with sitagliptin treatment. In a meta-analysis of the effects of DPP-4 inhibitors on lipids, Monami et al showed that TCHOL decreased with DPP-4 inhibitor treatment . A decreIt was also interesting that, in this observational study, ALP was significantly decreased after sitagliptin therapy. In fact, there is a past report of decreased ALP with sitagliptin therapy . The sigSince the present study was an observational study without controls, there are limits to the interpretation of results. However, unlike prospective studies, it is thought that the findings reflect the effects of sitagliptin in actual clinical practice. The large number of subjects in the analysis is another feature of this study, and the results were also statistically significant. The present retrospective cohort study showed that sitagliptin in actual clinical practice has pleiotropic effects other than lowering blood glucose.


Postoperative visual loss is a devastating perioperative complication. The commonest aetiologies are anterior ischaemic optic neuropathy (AION), posterior ischaemic optic neuropathy (PION), and central retinal artery occlusion (CRAO). These appear to be related to certain types of operation, most commonly spinal and cardiac bypass procedures; with the rest divided between: major trauma causing excessive blood loss; head/neck and nasal or sinus surgery; major vascular procedures ; general surgery; urology; gynaecology; liposuction; liver transplantation and duration of surgery. The non-surgical risk factors are multifactorial: advanced age, prolonged postoperative anaemia, positioning (supine v prone), alteration of venous drainage of the retina, hypertension, smoking, atherosclerosis, hyperlipidaemia, diabetes, hypercoagulability, hypotension, blood loss and large volume resuscitation. Other important cardiac causes are septic emboli from bacterial endocarditis and emboli caused by atrial myxomata. The majority of AION cases occur during CPB followed by head/neck surgery and prone spine surgery. CPB is used to allow coronary artery bypass grafting on a motionless heart. It has many side-effects and complications associated with its use and we report here a case of bilateral retinal infarction during routine coronary artery bypass grafting in a young male patient with multiple risk factors for developing this complication despite steps to minimise its occurrence. He had episodic chest pain for 1 year increasing in frequency over six weeks prior to admission. On admission to hospital he was commenced on medication including acetylsalicylic acid, Clopidogrel, Elantan LA, Bisoprolol, Ramipril, Ezetimibe and Enoxaparin and he remained as an inpatient until his scheduled surgical procedure without requiring heparin, GTN infusion or inotropes. Urgent coronary angiography revealed a critical lesion of the left main stem artery, 70% stenosis of the proximal circumflex and 70% stenosis of the origin of the posterior descending artery and moderate impairment of left ventricular function with inferoposterior hypokinesis. This impairment in left ventricular was confirmed by transthoracic echocardiography. On arrival in the anaesthetic room his initial blood pressure was recorded as 90/50 mmHg and this had no apparent effect on pre-operative organ function considering all blood tests were within normal range and urine output was >1 ml.kg-1.hr-1. General anaesthesia was induced and was further maintained with propofol target-controlled infusion (1.5μg.ml-1), remifentanil (0.34μg.kg-1.min-1) and isoflurane/oxygen/air mix at FiO2 of 0.4 and end-tidal isoflurane 0.4-0.6%. Peri-operative transoesophageal echocardiography was used as part of monitoring in this case and epi-aortic ultrasound scanning was not utilised. As the left internal mammary artery was being taken down a dose of 250 mg (4.3 mg/kg) of heparin was given with a subsequent ACT of 559s. During CPB mean arterial pressure was maintained between 50-60 mmHg using boluses of phenylephrine and subsequently an infusion of noradrenaline. The lowest recorded mean arterial pressure was 45 mmHg immediately post institution of CPB. The infusion of noradrenaline ran at doses from 0.05-0.075μg.kg-1.min-1 throughout the procedure. Other drugs that were used include glyceryl trinitrate at 0.5 mg.hr-1 as well as an infusion of the synthetic anti-fibrinolytic tranexamic acid initially at 1000 mg.hr-1 reduced to 600 mg.hr-1 (0.2 mg.kg-1.min-1) to reduce perioperative blood loss. He received an infusion of milrinone at a dose 2μg.kg-1.min-1. Mixed venous saturation ranged from 55-70% in the peri-operative period. Pre-operatively the Hb concentration was 11.5 g.dl-1. Intra-operatively the range of Hb was 7.5-10.5 g.dl-1 with the nadir on admission to CSICU. He was cooled and reached a nadir of 30°C. He was successfully weaned from CPB after placement of an intra-aortic balloon pump (IABP) and continuation of vasopressor and inotropic support. On admission to the Cardiac Surgical intensive care unit (CSICU) his mean blood pressure was 60 mmHg with a mean PA pressure of 14 mmHg. The balloon pump counter-pulsation remained on a 1:1 ratio with noradrenaline 0.05μg.kg-1.min-1, dopamine 5μg.kg-1.min-1, adrenaline 0.075μg.kg-1.min-1, and milrinone 1.5μg.kg-1.min-1 to maintain a mean pressure of 75 mmHg, CI> 2.2 and adequate urine output >0.5 ml.kg-1.hr-1. The Hb concentration immediately on admission to CSICU post-operatively was 6.4 g.dl-1, he was transfused with 3 units of packed cells and thereafter it remained between 8-10 g.dl-1. On arrival in CSICU it was noted that his pupils were fixed and dilated at 5 mm. His intraocular pressure (IOP) was measured and found to be 13 mmHg. The measure of intraocular pressure served to rule out glaucoma and was a surrogate for measurement of intracranial pressure (ICP). During a sedation hold he was able to respond to command appropriately. The intra-aortic balloon pump was weaned quickly post-operatively and removed just over 12 hours after admission to CSICU. On the second day post-operatively whilst being turned he suffered a brief asystolic arrest requiring approximately 1 minute of CPR before return of spontaneous circulation, with similar pre-arrest haemodynamics. There was no warning of this from haemodynamic monitoring and on review of the charts the acute nature of the incident would appear to fit with a failure of pacing capture. However, subsequent urgent transesophageal echocardiography showed non-compressive clot and fluid around the right atrium, with CVP of 10-12 and mean PAP 16 mmHg. He returned to theatre for a re-exploration of his pericardium at which time a small amount of clot was removed and no revision of pacing wires was required. Over the next 36 hours he was weaned from all inotropic and vasopressor medications. He was extubated on day 3 post-operatively, had normal vision at this stage and was able to see staff within CSICU despite still having fixed and dilated pupils. He was re-intubated on day 5 after a failed trial of non-invasive therapy for bibasal collapse and worsening oxygenation. 7 days post-operatively, after being extubated for the second time, the patient complained of poor vision. An urgent ophthalmology review was organised and their findings were as follows: visual acuity showed no perception of light bilaterally, both pupils fixed and dilated, unreactive to light or accommodation, no consensual response, normal intraocular pressure, good red reflex, bilateral disc pallor, indistinct disc margins, retinal pallor at posterior pole, cattle-trucking of retinal arterial circulation. He also had bilateral internuclear ophthalmoplegia with up-gaze and down-gaze weakness. The impression was one of bilateral anterior ischaemic optic neuropathy (AION) and impending bilateral central retinal artery occlusion (CRAO) with brain stem involvement. A CT brain showed marked calcification of the falx, tentorium and choroid plexus with a further abnormality in the corpus callosum representing an unusual area of focal ischaemia (most likely in keeping with recent cardiac surgery). Rescue therapy with acetazolamide and topical timolol to reduce IOP and improve intraocular perfusion pressure, despite normal IOP, was attempted, but there was no improvement in vision. During follow up by neurology and ophthalmology services within the hospital he underwent a MRI of his brain with Magnetic Resonance Angiography of his cerebral vessels. No white matter abnormality was identified within cerebral hemispheres and the brainstem, cerebellum and pituitary fossa were unremarkable. He was also referred to a clinical psychologist and the Royal National Institute for the Blind (RNIB) for support and rehabilitation.A 36 year-old Caucasian male  Registry, both eyes were affected, suggesting a systemic event . CompletAION has been primarily associated with CPB procedures but can also occur during prone spine operations and spontaneously. PION is most commonly associated with lengthy prone spine operations and bilateral radical neck operations. Numerous contributory factors for AION and PION have been proposed  but none has been causally linked ,12. OldeBlood flow to the anterior optic nerve is autoregulated by endovascular and metabolic factors similar to cerebral circulation. Autoregulation is effective over a critical range of perfusion pressure - not clearly defined in humans. Diseases of the circulatory system  damage autoregulation and therefore increase the critical perfusion pressure below which autoregulation of the anterior optic nerve fails. PION arises from the suboptimal blood supply from branches of the ophthalmic artery and the central retinal artery. The risk factors for both AION and PION in non-surgical patients include: high serum cholesterol and triglycerides, lipidaemia, fibrinogenaemia, DM and smoking. Risk factors in cardiac surgical patients include: intrinsic small vessel disease (DM), hyperglycaemia, hypertension, prolonged hypotension, vasospasm secondary to inotropes, the inflammatory process induced by CPB, anaemia and lower than normal cup:disc ratio which correlates with small scleral canal and possibly emboli . A combiA large retrospective time-matched, case-control study of 27,915 patients who underwent CPB was undertaken using the Mayo Clinic Surgical and Medical Indexes . ION was2 delivery remained approximately constant as the increased blood flow countered a significant decrease in arterial O2 content. Neely et al found feline retinal tissue oxygen tension increased initially during isovolaemic haemodilution to 50% above baseline at about 2/3 of the original haematocrit level and beyond this a steady decline in tissue oxygen tension [Anaemia is an amenable risk factor to efficient correction. Nevertheless optimum haemoglobin concentration is a controversial subject especially in patients with cardiovascular disease. By contrast Spiess found that a higher haematocrit on intensive care admission was associated with Q wave MI . Brown e tension . Among c tension . 3 patieIncreasing the transfusion threshold in an effort to correct anaemia may minimize the chances of ION. However, transfusion in cardiac surgery has been shown to increase morbidity and mortality. Engoren demonstrated that transfused cardiac surgical patients had a five-year mortality double that of non-transfusion group . Similar-1 [So, with regard to correction of anaemia it would seem that we are "damned if we do and damned if we don't - withholding transfusion may have a cost in terms of increased incidence of ION or renal failure but transfusion itself may increase morbidity and mortality . The Soc-1 .Given the concerns surrounding transfusion as a treatment for perioperative anaemia, it has been proposed that prophylactic measures to minimize bleeding might be the solution to the problem. In a meta-analysis by Laupacis, tranexamic acid administration was associated with lower transfusion requirements in patients undergoing cardiopulmonary bypass . NeverthAnother risk factor for ION, which may be amenable to intervention, is patient positioning. Prone position is known to increase IOP and although prone positioning is not used routinely in cardiac surgical patients, they may develop a lung injury in the post-operative period either from the cardiopulmonary bypass itself, transfusion, or sepsis and I feel it is worth a mention. Ozcan looked at the effect of prone positioning in awake volunteers and found IOPs 50% higher in prone horizontal patients . The risPerfusion pressure of the anterior optic nerve is the difference between the ciliary artery and venous drainage - approximately MAP - IOP. Increased IOP may substantially reduce the perfusion pressure of the anterior optic nerve. Increased IOP may contribute to the higher incidence of ION after operations involving CPB. Sanjay et al showed that intraocular pressure (IOP) increases on commencement of CPB and maximally at 20 minutes to 21 mmHg . MethodsEmbolic phenomena are another possible cause of ION and may be related to aortic cross clamping . In a prThe use of inotropes has also been implicated in cases of ION. Shapira et al found the development of AION in 8 patients out of 602 consecutive cardiac surgery patients (1.3%), an increase from their usual 0.5% rate . AlthougIn conclusion perioperative ION is a rare, devastating event, which may be difficult to detect in a sedated post-operative patient. The signs are subtle and are often late to present. Cardiac surgical procedures involving CPB appear to be at increased risk of causing this condition especially if complicated by hypotension, use of inotropes or anaemia. No effective treatment for ION exists, once established, hence prevention is crucial. Despite this, studies to date have only succeeded in demonstrating that minimizing one risk factor for the development of ION may merely serve to introduce another.Written informed consent was obtained from the patient for publication of this case report and any accompanying images. A copy of the written consent is available for review by the Editor-in Chief of this journal.The authors declare that they have no competing interests.BT, LMcW and AFP wrote the paper. BT and LMcW performed the literature search. HG reviewed all drafts of the manuscript and suggested changes. BV, SAP and RG added important comments to the paper. All authors have read and approved the final manuscript.


Orthostatic hypotension (OH) is a common and disabling symptom affecting Parkinson’s disease (PD) patients. We present the effect of the different therapies commonly used to manage PD on this clinical manifestation. For this purpose, we describe the relationship between OH and the current treatments employed in PD, such as L-DOPA, dopaminergic agonists, and continuous dopaminergic stimulation therapies. Additionally, we review the therapeutic measures that could be used to ameliorate OH. There are different approaches to deal with this manifestation, including pharmacological and non-pharmacological treatments, although none of them is specifically aimed for treating OH in PD. After the first comprehensive description of the cardinal features of Parkinson’s disease (PD) ]  , although many cases go unnoticed  and with all the DA (a slightly greater increase was found with bromocriptine compared with ropinirole)  on autonomous responses of PD subjects , pressure cutoffs, and subsets of patients evaluated. The figures oscillated between 1.9%  to OH .Many of the common prescribed treatments used for PD could increase the frequency of OH. It seems advisable to monitor blood pressure and this side effect when starting any “Other outcomes, like supine nocturnal hypertension   may trigger OH that otherwise may go unnoticed  and α-adrenoreceptor sensitizing activities Hoehn, . The comPyridostigmine acts mainly improving ganglionic cholinergic transmissions through cholinesterase inhibition. It favors normal physiologic responses upon standing, without worsening supine hypertension . Its main action is to augment vascular resistance and therefore blood pressure. In addition to the anti-OH effect, it can also enhance supine hypertension, so close monitoring of recumbent blood pressure and avoiding evening administration are required  do not produce this interference , a dopaminergic antagonist, has also shown beneficial effects on OH  was used in 15 PD patients to increase blood pressure upon standing (mean increase of 4.3%) reporting only headaches as adverse outcomes  was used in a pilot study including 14 PD patients, reducing the drop in blood pressure in 11 mmHg and improving orthostatic symptoms  (Jordan et al., Orthostatic hypotension is a common and challenging symptom affecting PD patients. The neurodegenerative process is responsible for damaging the autonomous nervous system, but anti-parkinsonian treatments could enhance the symptoms derived from it. Current therapeutical strategies include non-pharmacological and pharmacological measures aimed to favor baropressor responses or to increase blood volume. There is insufficient evidence to recommend any specific treatment for the PD-related autonomic failure. Therefore, it should be individualized for the individual patient. Studies addressing the underscored questions related to OH in PD are needed.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


Kidney disease is associated with an increased total mortality and cardiovascular morbimortality in the general population and in patients with Type 2 diabetes. The aim of this study is to determine the prevalence of kidney disease and different types of renal disease in patients with type 2 diabetes (T2DM).2 and/or the presence of albuminuria, 4) Renal impairment (RI): glomerular filtration rate < 60 ml/min/1.73 m2, 5) Nonalbuminuric RI: glomerular filtration rate < 60 ml/min/1.73 m2 without albuminuria and, 5) Diabetic nephropathy (DN): macroalbuminuria or microalbuminuria plus diabetic retinopathy.Cross-sectional study in a random sample of 2,642 T2DM patients cared for in primary care during 2007. Studied variables: demographic and clinical characteristics, pharmacological treatments and T2DM complications . Variables of renal function were defined as follows: 1) Microalbuminuria: albumin excretion rate & 30 mg/g or 3.5 mg/mmol, 2) Macroalbuminuria: albumin excretion rate & 300 mg/g or 35 mg/mmol, 3) Kidney disease (KD): glomerular filtration rate according to Modification of Diet in Renal Disease < 60 ml/min/1.73 mThe prevalence of different types of renal disease in patients was: 34.1% KD, 22.9% RI, 19.5% albuminuria and 16.4% diabetic nephropathy (DN). The prevalence of albuminuria without RI (13.5%) and nonalbuminuric RI (14.7%) was similar. After adjusting per age, BMI, cholesterol, blood pressure and macrovascular disease, RI was significantly associated with the female gender , microvascular disease  and insulin treatment , and inversely associated with HbA1c . Albuminuria without RI was inversely associated with the female gender , duration of diabetes  and directly associated with HbA1c .One-third of the sample population in this study has KD. The presence or absence of albuminuria identifies two subgroups with different characteristics related to gender, the duration of diabetes and metabolic status of the patient. It is important to determine both albuminuria and GFR estimation to diagnose KD. The concept of kidney disease is based on the presence of albuminuria and/or impaired renal function that lasts for more than three months . Kidney During a 15-year follow-up, the United Kingdom Prospective Diabetes (UKPDS) study showed that 5% of the patients with T2DM had a 2-fold increase in creatinine levels, 20% had macroalbuminuria defined as a urinary albumin concentration ≥ 300 mg/l, 40% developed renal impairment, 45% developed microalbuminuria defined as a urinary albumin concentration 50–299 mg/l and 75% experienced a CV event .There have been several reports on the prevalence of kidney disease and forms of renal disease in patients with T2DM of Mediterranean countries -13. OnlyStudy design and organization The Continuous Quality Improvement Gedaps program gathered information from primary care centres on the clinical markers and health outcomes a sample of patients. A detailed description of the evaluation methodology has been previously described [http://www.redgdps.org/index.php?idregistro=259).escribed . During Health providers were instructed to obtain a random sample from the medical records of patients with T2DM with more than six months follow-up from diagnosis. A total sample of 5 patients multiplied by the number of basic care units (physician/nurse) with a minimum of 30 patients per centre was required. The exclusion criteria were as follows: type 1 diabetes mellitus; follow-up exclusively conducted by an endocrinologist; and short life expectancy . Only patients with plasma creatinine available were included for the current study.Due to the retrospective nature of the study, based only on clinical records, patients were not required to give written informed consent. To assure anonymity data were collected and recorded using two different files: one included demographic variables and the other one clinical variables linked by a consecutive record number. The study design and the GCQI program were presented and approved by the Consell Assessor de la Diabetes (Advisory Board on Diabetes) of the Health Departament of the Autonomous Government in Catalunya that acted as Institutional Review Board.Study population The following demographic and clinical characteristics were compared: age, gender, weight, height, BMI, blood pressure, HbA1c, creatinine, total cholesterol, HDL cholesterol, albuminuria, duration of diabetes (in years), estimated cardiovascular risk according to the Framingham equation calibrated to the Spanish population [2. We found 1164 type 2 diabetic patients who had no available albuminuria. Figure pulation  (threshoThe following outcomes were considered: diabetic foot (ulcers and amputations), retinopathy, coronary heart disease , and stroke (including transient ischemic attack). Two composite variables including all microvascular complications  and macrovascular complications (CHD and/or stroke) were separately created. All collected data included the last value recorded in the medical records during 2007.NKF  defines 2 without micro or macroalbuminuria and, 5) Diabetic nephropathy (DN): macroalbuminuria or microalbuminuria plus diabetic retinopathy [The GFR was calculated using the equation previously published by the MDRD study group . Variablinopathy .Patients with available creatinine and UAER were also classified according to the recent proposal of KDIGO workgroup .Statistical analysis Quantitative variables were described using means and standard deviations. Categorical variables were summarised using absolute and relative frequencies . Bivariate relationships between categorical variables were tested using non-parametric chi-squared tests. Bivariate relationships between categorical and quantitative variables were assessed using ANOVA tests (one factor). Descriptive statistics and bivariate inferences were performed using the SPSS (v. 15) statistical program. The multivariate analyses of variables associated with different types of kidney disease in patients with T2DM were assessed by means of logistic regressions. The variables for the adjustment were selected on the basis of significant bivariate relationships. Response variables were assigned a value of 1 when the particular type of kidney disease  occurred, and patients without any type of kidney disease were assigned a value of 0. The estimation of the logistic regressions was performed using the R freeware statistical package (version 2.11.1).From a total sample of 3150 patients with T2DM included in the 2007 Gedaps evaluation, we included 2,642 patients who have a plasma creatinine available. Mean age was 68 years (SD 11.6), and 51.5% of the patients were men. The average duration of diabetes was 7 years (SD 5.6). The mean HbA1c was 6.84% (SD 1.46), and 67.6% of patients had an HbA1c value less than or equal to 7%. The mean blood pressure was 137/76 mmHg. Table The prevalence of different types of renal disease was: 34.1% for kidney disease, 22.9% for renal impairment, 19.5% for albuminuria and 16.4% for diabetic nephropathy. Renal impairment according to the MDRD equation was found in 606 patients (22.9%) of whom 296 (11.2%) showed an elevated serum creatinine value (& 123.76 μmol/dl in women and & 132.6 μmol/dl in men). Moreover, 382 patients (14.5%) showed an estimated GFR between 30 and 59 ml/min/1.73 m2, and 224 patients (8.4%) of the total showed an estimated GFR less than 30 ml/min/1.73 m2. Additional file There were significant differences in gender among the forms of kidney disease. Women had a significantly higher prevalence of kidney disease and renal impairment, and men had a higher prevalence of albuminuria and DN. Significant differences in the forms of kidney disease were also found with the duration of diabetes Table .Figure Among the 1,478 patients with T2DM who had available data for calculating both GFR and albuminuria, patients with albuminuria without renal impairment and nonalbuminuric renal impairment were compared. The prevalence of albuminuria without renal impairment  13.5%) and nonalbuminuric renal impairment (14.7%) was similar. Relative to albuminuric patients without renal impairment, the patients with nonalbuminuric renal impairment were significantly older and with more probability to be women; they had a longer T2DM duration, lower prevalence of obesity, lower diastolic BP and lower HbA1c; and had a lower prevalence of smoking, macrovascular disease and ischemic heart disease , the prevalence of kidney disease, renal impairment, albuminuria and diabetic nephropathy was found to be 34.1%, 22.9%, 19.5% and 16.4%, respectively. The prevalence of albuminuria without renal impairment and nonalbuminuric renal impairment was 13.5% and 14.7%, respectively. In the case of renal impairment, the estimation of GFR identified an additional 13.4% of patients with T2DM with renal impairment who would not have been diagnosed only with the measurement of plasma creatinine. The GFR estimation allowed the detection of 20.6% of patients with kidney disease in addition to the 13.5% of patients with albuminuria alone. When using strict criteria to define DN , the prePrevious studies have shown that renal impairment prevalence is between 10.2 (sample of T2DM patients in China)  and 36% The relationship between the mechanisms responsible for the development of albuminuria and renal impairment are not clear. In keeping with the most relevant studies published to date, our results show that nonalbuminuric RI is associated with female gender ,25,28,29A multivariate analysis showed a clear association between renal impairment and microvascular disease. In contrast, the bivariate analysis showed a clear association between albuminuria and macrovascular disease although the association disappeared in the multivariate analysis. It is possible that small vessels in women are more likely to develop damage than the small vessels in men. If this finding is confirmed in further studies, women with type 2 diabetes should be closely monitored. Another possibility is that the glomerular filtration rate in women estimated by the MDRD equation  underestThis study had several limitations. First, in terms of internal validity, it should be noted that there was a single measurement of GFR. Therefore, it was not possible to distinguish between patients with transient impairment of GFR and those with a persistent alteration. To distinguish between these patients, a reassessment of the GFR at 3 months would be necessary. A previous study has shown that kidney disease detected by a single determination is also associated with increased CV risk although the association contributes to a lesser degree than the two measurements . Second,In summary, our results show that approximately one-third of type 2 diabetic patients in the Mediterranean area have kidney disease and that one-fourth of the patients have renal impairment, but only 10% would have been classified having renal impairment if the estimated glomerular filtration rate was not used. Moreover, one-fifth of the patients had albuminuria. T2DM patients with kidney disease have a different profile depending on the presence or absence of albuminuria or RI. Further studies are needed to identify the etiopathogenesis of these differences and may impact on the prevention and treatment of forms of kidney disease. Thus, it is important to determine AER and to estimate GFR to diagnose kidney disease and to initiate the appropriate treatment.AER: Albumin excretion rate; CV: Cardiovascular; DN: Diabetic Nephropathy; GFR: Glomerular filtration rate; MDRD: Modification of Diet in Renal Disease; RI: Renal impairment; T2DM: Type 2 Diabetes Mellitus.The authors declare that there is no conflict of interest associated with the manuscript.G Coll de Tuero, M Mata-Cases, A Rodriguez-Poncelas and M Saez have participated in the conception and design, interpretation of data, drafting, revising and final approval of the work. JM Pepió, P Roura, B Benito and J Franch have participated in the conception and design, revising and final approval of the work. All authors read and approved the final manuscript.The pre-publication history for this paper can be accessed here:http://www.biomedcentral.com/1471-2369/13/87/prepubTable S2. Classification of patients with creatinine and albumin excretion rateavailable according to KDIGO 2009.Click here for fileList of participating investigators in the GEDAPS 2007 Evaluation.Click here for file