Chronic heart failure (CHF) has a high morbidity and mortality. Chronic kidney disease (CKD) has consistently been found to be an independent risk factor for unfavorable cardiovascular (CV) outcomes. Early intervention on CKD reduces the progression of CHF, hospitalizations and mortality, yet there are very few studies about CKD as a risk factor in the early stages of CHF. The aims of our study were to assess the prevalence and the prognostic importance of CKD in patients with systolic CHF stages B and C.This is a prospective cohort study, dealing with prognostic markers for CV endpoints in patients with systolic CHF (ejection fraction ≤ 45%).2 and CV endpoints as death or hospitalization due to CHF, in 12 months follow-up. Eighty three patients were studied, the mean age was 62.7 ± 12 years, and 56.6% were female. CKD was diagnosed in 49.4% of the patients, 33% of patients with CHF stage B and 67% in the stage C. Cardiovascular endpoints were observed in 26.5% of the patients. When the sample was stratified into stages B and C of CHF, the occurrence of CKD was associated with 100% and 64.7%, respectively, of unfavorable CV outcomes. After adjustments for all other prognostic factors at baseline, it was observed that the diagnosis of CKD increased in 3.6 times the possibility of CV outcomes , whereas higher ejection fraction  and serum sodium  were protective.CKD was defined as estimated glomerular filtration rate <60 mL/min/1.73 mIn this cohort of patients with CHF stages B and C, CKD was prevalent and independently associated with increased risk of hospitalization and death secondary to cardiac decompensation, especially in asymptomatic patients. Sistema Único de Saúde (SUS), is responsible for more than 75% of the hospitalization for CHF, which generates a large social and financial burden [per se, predicts cardiovascular mortality [Chronic heart failure (CHF) is considered a public health problem, in view of its high costs and increasing number of hospital admissions -4. In Brl burden ,2,5-7. Sortality .Chronic kidney disease (CKD) is associated with a high risk of cardiovascular events -12. It iThe prevalence of CHF among CKD patients is elevated and equally predicts mortality -16. CHF Most studies which assess the negative impact of CKD and other factors in the curse of CHF have been done in patients with most severe form of the disease (NYHA Class IV of CHF), usually in a hospital setting ,14-16,18Despite the incentives, the prognostic classification of CHF has rarely been applied in practice. This may be one of the explanations for the scarcity of studies evaluating risk factors and adverse outcomes in outpatients with CHF -3. In thEighty-three patients treated at the Center for Control of Hypertension, Diabetes and Obesity - SCHDO, in the city of Juiz de Fora- MG, were observed from the period of January through December of 2006.rd degree obese patients with associated morbidities, and those referred from other municipal basic health care units.SCHDO is a municipal unit of secondary outpatient clinic that offers free treatment to hypertensive patients in stage 3, group C, complications of type 2 diabetics, type 1 diabetics with difficult clinical control, 3This was an observational study during which the patients were prospectively followed for 12 months, for surveillance of cardiovascular outcomes. Data were collected at the study baseline and after 12 months. All patients confirmed participation by signing the informed consent form, and the study was approved by the Ethics Committee of the Federal University of Juiz de Fora.The patients were selected among those with CHF who were attended bimonthly at the SCHDO. The patients were taking medications that optimize CHF treatment, including angiotensin-converting enzyme inhibitors and/or angiotensin receptor blocker, beta-blocker (carvedilol), furosemide, and digital when indicated. Patients over the age of 18 years, regularly attending the Clinic in the last six months, with CHF stages B and C, and ejection fraction by bi-dimensional Doppler echocardiogram of less than or equal to 45% were included . Patient2; sedentariness was considered when the regular physical activity was less than 30 minutes per day and less than 3 times per week; smokers were identified as those who smoke at least one cigarette per day for a period of more than six months; arterial hypertension was considered when blood pressure levels were above 140 × 90 mmHg, or when on antihypertensive treatment; diabetes mellitus was diagnoses when the fasting blood glucose levels were over 100 mg/dL, or when using an oral hypoglycemic medication or insulin [The patients were classified according to the chronological staging of CHF, in stages B and C. Stage B was characterized when there was a structural heart disease and no symptoms (NYHA class I symptoms), and stage C when the structural disease was associated with previous or current symptoms (NYHA class II or III symptoms) ,3. Demog insulin -22.The diagnosis of ischemic cardiopathy (IC) was based on previous history and/or documented upon hospitalization by angina, acute myocardial infarction, myocardial revascularization, percutaneous transcoronary angioplasty, or coronary angiography with injuries consistent with coronary artery disease . Pulse pThe echocardiographic parameters studied were left ventricular ejection fraction (including those patients with percentage ≤ 45%), measures of left atrium diameter, and of left ventricular diastolic diameter, due to their importance as prognostic parameters in CHF ,3.2, measured at least 3 months apart, were diagnosed with CKD [The glomerular filtration rate (GFR) was estimated by the determination of serum creatinine using the equation of the study Modification of Diet in Renal Disease (MDRD) . The diawith CKD . The outThe Kolmogorov-Smirnov study was used for evaluation of the presence or not of normal distribution of the variables. The data were expressed as mean and standard deviation and percentages. The population was divided into stages B and C of CHF. To compare the qualitative variables among the two groups, we utilized the chi-squared test or the Fisher's test, and for numerical variables the Student's t test or the Mann-Whitney test.The univariate analysis was used to evaluate the association between the stages of CHF and the occurrence of outcomes. The multivariate analysis was employed by the backward logistic regression method in order to evaluate the relationship between outcomes, stages of CHF, and the covariates that presented p-valor ≤ 0.1 in the univariate analysis. In the first stage of regression, we utilized variables for which the p-value in the univariate analysis was less that 0.1. The level of significance was set at 5%. The analyses were performed using the SPSS program for Windows 11.0 .2, and 33 patients (39.8%) were obese. The mean systolic blood pressures were 134.5 ± 20.3 mmHg and the mean PP was 52.2 ± 16.2 mmHg. The mean values of hemoglobin, blood glucose, total cholesterol, LDL-cholesterol, and triglycerides, were not different after stratification of patients in stages B and C of CHF  in stage B of CHF, and 50 (60.2%) in stage C. The mean age of the patients was 62.6 ± 12 years, and 47 were (56.6%) females. Sedentarism and smoking were presented in 57 (68.7%) and 12 (14.5%) patients, respectively. Of the total patients, 79 (95.2%) were hypertensive, and 41 (49.4%) were type 2 diabetics. Stage C was diagnosed in 50 (60.2%) of the patients, representing the major cause of CHF. With the exception of sedentarism, more frequent in patients with CHF stage C compared to stage B (p = 0.02), there were no statistical differences in the remaining demographic parameters between the two groups.  was diagnosed in 41 (49.4%) patients, 14 (42.4%) in the stage B of CHF and 27 (54%) in the stage C (p = 0.05) (Table 2 (stage 3 of CKD).The evaluation of the renal function by creatinine and GFR did not differ statistically between the two stages of CHF. CKD  , that CKD is a frequent complication with an unfavorable impact in the course of the disease ,23,28,29Estimation of the GFR used to define glomerular filtration rate (GFR) and CKD stages according to the criteria of the US National Kidney Foundation is considered the new standard of evaluation and severity of renal diseases ,27. So fThe greater occurrence of CV outcomes in patients with CHF and CKD can be explained by the overlap of risk factors common in both diseases separately -32. PrevThe natural course of CHF in its initial stages associated with CKD is still unknown, since, thus far, most studies have evaluated primarily hospitalized patients with severe form of the disease (NYHA class IV), mainly in cross-sectional analyses, and improperly using serum creatinine as a diagnosis of CKD and sometimes excluding patients with CKD from the analysis .2) present in stages B and C of CHF was associated with 100% and 64.7% of the CV outcomes, respectively. These results provide new information regarding the "natural" course of systolic CHF in its early stages, and if confirmed in studies with greater number of patients, they can define renal function staging as a major tool to identify risk factors for adverse outcomes in patients with less severe CHF.In our study, it was observed that CKD , is an important determinant of the observed increase in CV outcomes [The unfavorable impact of CKD in the evolution of CHF stages B and C imposes a better understanding of the reasons for such an adverse association. In CHF, low cardiac output, neurohumoral stimulation, aggressive use of diuretics, treatment with renin-angiotensin-aldosterone system blockers, anemia, and comorbidities, such as hypertension and diabetes mellitus, can contribute to the reduction of GFR, and the observed functional deficit merely reflects the severity of CHF in the baseline period -37. Howe2; however, previous studies have demonstrated that it is below this level of renal function that the risk of mortality increases for all causes of CHF [2, and was not determined in this study since its occurrence could be mitigated by the use of optimized angiotensin-converting enzyme inhibitors, AT1 blockers, and aldosterone antagonists, thereby inducing false negative diagnoses [It is important to recognize the limitations of our study. Renal function was evaluated by the GRF estimated from creatinine, and not by the use of methods considered to be the gold standard, such as inulin clearance . In addis of CHF ,34. Albuiagnoses . Additio2, as a strong prognostic risk factor for adverse CV outcomes in CHF, also in patients with less advanced heart failure. These findings suggest that clinical physicians, particularly cardiologists, should incorporate the serial estimation of GFR in order to optimize the results of treatment in CHF. Future studies could elucidate the determinants of the decrease in GFR in CHF stages B and C, and whether or not preservation of renal function will associate with an improved outcome of the cardiac disease.CKD, a recognizable common risk factor for adverse outcomes in more severe forms of CHF, is also frequent in patients in the early stages of the disease. Our results corroborate with the proposal for using GFR, mainly when it is <60 mL/min/1.73 mIn the cohort studied, composed predominantly of hypertensive, diabetic, and obese patients, CKD was common and associated with an increased frequency of cardiovascular outcomes. These findings should be confirmed in studies with larger number of patients and greater diversity of causes of left ventricular dysfunction, in order to better understand the impact of renal function in the course of CHF, and to stimulate the development of new therapeutic strategies, aiming to reduce the rates of hospitalization and mortality, secondary to cardiovascular diseases.The authors declare that they have no competing interests.HS have been involved in drafting the manuscript and revising with important intellectual content. AC participated in the design of the study and performed the statistical analysis and contributions to interpretation of data. DM has been involved in drafting the manuscript and revising. MG conceived of the study, and participated in its design, contributions to interpretation of data and coordination. All authors read and approved the final manuscript.The pre-publication history for this paper can be accessed here:http://www.biomedcentral.com/1471-2369/10/31/prepub


Renal hypertrophy occurs early in diabetic nephropathy, its later value is unknown. Do large kidneys still predict poor outcome in patients with diabetes and Chronic Kidney Disease (CKD)?2 or an Albumin Excretion Rate above 30 mg/24 H, had an ultrasound imaging of the kidneys and were cooperatively followed during five years by the Diabetology and Nephrology departments of the Centre Hospitalier Universitaire de Bordeaux.Seventy-five patients with diabetes and CKD according to a Glomerular Filtration Rate  below 60 mL/min/1.73 m2, AER: 196 (20-2358) mg/24 H. Their mean kidney lenght  was correlated to the GFR . During the follow-up, 9/11 of the patients who had to start dialysis came from the half with the largest kidneys (LogRank: p < 0.05), despite a 40% higher initial isotopic GFR. Serum creatinine were initially lower  μmol/L, Large: 103 (50-371), p < 0.05), but significantly increased in the "large kidneys" group at the end of the follow-up  μmol/L, Large: 140 (50-952), p < 0.005 vs initial). The difference persisted in the patients with severe renal failure .The patients were mainly men (44/75), aged 62 ± 13 yrs, with long-standing diabetes , and CKD: initial GFR: 56.5 (8.5-209) mL/min/1.73 mLarge kidneys still predict progression in advanced CKD complicating diabetes. In these patients, ultrasound imaging not only excludes obstructive renal disease, but also provides information on the progression of the renal disease. The scr2) ,4, renal2) , and ren2) , but the2) ,8.Ultrasound allows non-invasive renal imaging at moderate expense, and it is recommended for the first line evaluation of CKD , althougIn 75 patients with diabetes and CKD, we measured the AER, the GFR by 51Cr-EDTA clearance, and kidney length by ultrasound. The patients were then enrolled in a structured collaborative care program involving diabetologists and nephrologists, and followed up for 5 years, to determine whether their outcome  differed according to initial kidney size.Seventy-five patients  were recruited from the Nutrition-Diabetology and Nephrology departments of the Centre Hospitalier Universitaire de Bordeaux. The inclusion criteria were:1-Diabetes. Twenty patients had type 1 diabetes, 55 type 2,2-CKD according to an AER above 30 mg/24 H or a GFR below 60 mL/min/1.73 m2, not requiring renal replacement therapy at inclusion,3-An ultrasound imaging with measurement of the length of the kidneys (Two other patients were excluded because they only had one kidney).The patients gave written informed consent to participate to the study, which was approved by the ethical committee of our institution. This study was supported by a clinical research program in the Bordeaux University Hospital.The AER was determined on two 24 H urine collections during a short hospitalization, with an immunonephelometric analyzer (Behring Nephelometer 2) using an appropriate kit . Serum creatinine was determined on a multiparameter analyzer  using the Jaffé method with bichromatic measurements according to the manufacturer's specifications, and daily calibration of the analyzer. This procedure did not change in our laboratory during the study. The GFR was estimated from serum creatinine by the Mayo clinic quadratic equation . ClearanThis prospective study began on June 2001, untill December 2008. It was based on a cooperative follow-up between diabetologists and nephrologists with the establishment of a joint medical file for each patient. This cooperative follow-up was complementary and included one visit with the diabetologist every four months, and visits with the nephrologist with intervals proportional to the e-GFR. Mean duration of the follow-up was 61 ± 19  months.The care program objectives included glycemic control according to the French 1999 recommendations , but also control of associated factors such as hypertension (objective: < 130/80 mmHg) and dyslipidemia (objective: LDL-cholesterol < 1.3 g/L). We have previously reported  that we The primary outcome was requirement for dialysis. The secondary outcomes were the AER, serum creatinine and e-GFR at the end of the follow-up.The results are expressed as mean ± SD, and median (range) for the GFR, creatinine and AER which were not normally distributed. The association between kidney length and other variables was tested by regression analysis for continuous variables and by ANOVA and unpaired Student's t tests for dichotomous variables. The subjects were then categorized as having large (mean length > median mean length of the group) vs small kidneys, and these two groups were compared by ANOVA for the continuous variables, and by Chi2 for the categorical variables. Non-parametric tests  were used for the GFR, creatinine and AER. For the primary outcome , prognostic curves were obtained using the Kaplan-Meier estimation method and compared by log-rank test, the patients who did not present any event  were censored at the end of the follow-up. A survival analysis using the Cox proportional hazards model was also performed to distinguish the effects of kidney length and GFR on the risk of requiring dialysis. For the secondary outcome, the baseline and final characteristics of the patients were compared by paired Student t tests. Similar analysis were performed after categorizing the subjects as KDOQI stage 1-2,3 and 4-5 . All the2. Their MCQ e-GFR (63.8 (11-143) mL/min/1.73 m2) was slightly higher (p < 0.05), and was well correlated with isotopic GFR .Seventy five patients were included. Their mean diabetes duration was 17 ± 9 yrs, Body Mass Index: 28.2 ± 5.3, arterial pressure 145 ± 21/80 ± 12 mmHg, and HbA1C: 8.6 ± 1.5%. Their AER was 196 (20-2358) mg/24 H, serum creatinine 126 (50-371) μmol/L, and isotopic GFR was 56.5 (8.5-209) mL/min/1.73 mThe lengths of the right (108 ± 13 mm) and left kidney (108 ± 16 mm) did not differ, and were correlated . The analysis was therefore conducted on the mean kidney length , which did not differ for gender or type of diabetes. The mean kidney length was correlated with isotopic GFR  or "small" kidneys. The initial characteristics of the two groups did not differ, as shown in table The eleven subjects who required dialysis during the follow-up had lower isotopic GFR (20.4 (8.5-80) vs 59.2 (12-209) mL/min/1.73 m2 for others, p = 0.001) and larger kidneys  on inclusion. The multivariate survival analysis using the Cox proportional hazards model showed that both initial GFR  and mean kidney length  were predictors of dialysis onset. The influence of the kidney lenght did not remain significant after adjustment for the AER.There was no significant difference between the subjects with type 1 and type 2 diabetes , except for the age and the BMI as expected. Although the different outcomes only reached significance for dialysis onset for type 2, according to the restricted number of patients, the results seemed homogenous in both types of diabetes, as shown in the table 22; none of them required dialysis during the follow-up. Although the difference was not significant, the MCQ-eGFR declined faster for the eleven subjects with the largest (> 109 mm) kidneys: -4.2 mL/min/1.73 m2 (-14-+16), vs -2.3 (-6-+5) for the 10 subjects with the smaller kidneys.As shown in table Renal hypertrophy with ~30% higher than normal kidney size has been noted in type 1 diabetics , in someOur inclusion criterion was CKD: most of our patients had an isotopically determined GFR below 60 mL/min/1.73 m2, and the others had an AER above 30 mg/24 H. The half with the largest kidneys did not differ from the others in age, gender, diabetes duration, BMI, and the conventional progression factors  were not significantly higher. They had 40% higher GFR than the "small kidney" group, as expected. High GFR has been associated with faster rates of decline in renal function in other cohorts ,32. The Renal hypertrophy is an early phenomenon in diabetic patients: clinical observations show that it precedes microalbuminuria , which iTwo limitations of our study should be born in mind. Apart from the "hard" endpoint of dialysis onset, we used an estimation of GFR to measure the decline in renal function; creatinine-based estimations  are known to underestimate GFR decline in diabetes , especiaLarge kidneys still predict progression in advanced CKD complicating diabetes. In these patients, ultrasound imaging not only excludes obstructive renal disease, but also provides information on the progression of the renal disease,The authors declare that they have no competing interests.VR conceived of the study, and participated in its design and coordination and wrote the manuscript. MG collected data and performed the statistical analysis. CL, CR, BV, PC collected data and participated in the study design. FL and MM performed the ultrasound imaging, NB performed the isotopic GFR measurements, MCB performed the biochemical analysis. CC and HG conceived of the study, and participated in its design and coordination. All authors read and approved the final manuscript.The pre-publication history for this paper can be accessed here:http://www.biomedcentral.com/1471-2369/11/3/prepub


Dynamic retinal vessel analysis represents a well-established method for the assessment of vascular reactivity during both normal conditions and after various provocations. We present a case where the subject showed abnormal retinal vessel reactivity after fasting voluntarily for 20 hours.A healthy, 21-year-old man who fasted voluntarily for 20 hours exhibited abnormal retinal vascular reactivity (dilation and constriction) after flicker provocation as measured using the Dynamic Retinal Vessel Analyser .The abnormal vascular reactivity induced by fasting was significant; abnormal levels of important nutrients due to fasting and dehydration could play a role through altering the concentration of vasoactive substances such as nitric oxide. This hypothesis needs further investigation. The assessment of retinal vessel diameters during both normal conditions and after various provocations could represent an important tool in investigating ocular diseases as well as for the initial diagnosis and subsequent followup of systemic disorders such as hypertension, cardiovascular disease and diabetes . Since rA 21-year-old healthy man presented voluntarily for a routine research appointment involving the assessment of retinal vessel reactivity using the Dynamic Retinal Vessel Analyser (DVA) at the Aston Academy of Life Sciences, Aston University, Birmingham. This device consists of a digital fundus camera combined with a CCD camera for electronic online image acquisition coupled to a video recorder for archiving . During After 20 minutes of room acclimatization to obtain stabile haemodynamic conditions, systemic blood pressure (BP) was measured three times (1 minute apart) using a manual sphygmomanometer. Systolic BP (SBP) and diastolic BP (DBP) values were obtained; the average readings for SBP and DBP were then used to calculate the mean arterial BP (MABP) using the formula: MABP = 2/3 × DBP+1/3 × SBP. After instilling one drop of oxybuprocaine hydrochloride 0.4% in the right eye, intraocular pressure (IOP) was also measured by means of a handheld contact tonometer. The IOP and MBP measurements were used to calculate the mean ocular perfusion pressure (MOPP) according to the formula: MOPP = 2/3 × MABP-IOP.After full pupil dilation was reached by using tropicamide 1.0% retinal diameters of the superior temporal retinal artery and vein, measured approximately 1.5 disc diameters away from the optic nerve head, were assessed continuously over 350 seconds by using the DVA machine according to a previously established protocol . BrieflyThe results of the initial measurements under fasting conditions and after a meal are shown in Table The results of the second set of measurements are shown in Table With the subject's consent, the experiment was repeated on three additional occasions, each one month apart. During these subsequent tests, the subject was in a similar physiological condition to the initial experiment. Results of all observations are shown in Table Although SBP was statistically different when measured in the fasting versus non-fasting state  the MABP, IOP and OPP were not statistically different in the fasting versus non-fasting state .This case demonstrates for the first time that despite having comparable intraocular and systemic 'pressure' conditions, the retinal vascular reactivity was blunted during voluntary fasting in a healthy, young individual. This observation was repeatable on four separate occasions.The ocular circulation has a very complex regulating system able to maintain constant blood flow and oxygen supply to the tissue despite variations in systemic BP ,7. AutonThe vascular response to flickering light has been widely studied in both animals and humans ,6. This Although the data obtained in this case study is limited and needs further investigation to demonstrate the exact mechanism behind our observation, it clearly shows the clinical significance of detailed medical history before conducting and interpreting any test results. Knowledge of medical and/or family history and ethnic background at the time of examination is of great importance. In addition, since fluid and/or nutrient intake plays an important role in the physiology of important variables such as BP, vessel dynamics and blood composition, which are commonly used in diagnosing various systemic vascular disorders, fasting and dehydration could act as confounding factors and the clinical and/or laboratory results could be misleading.We present a case of decreased retinal vascular reactivity due to fasting and dehydration in a young and healthy man. This scenario could represent a potential case of vasoactive substance imbalance resulting in vasodilatory inhibition at the level of retinal vessels. The importance of this finding should be investigated in further studies and additional tests should be included to verify our hypothesis.BP: blood pressure; DBP: diastolic blood pressure; DVA: dynamic retinal vessel analyser; IOP: intraocular pressure; MABP: mean arterial blood pressure; MOPP: mean ocular perfusion pressure; NO: nitric oxide; RVO: retinal vein occlusion; SBP: systolic blood pressure.The authors declare that they have no competing interests.RH collected the data, was involved in data analysis and interpretation and drafting of the manuscript. DG revised the manuscript and was involved in the data analysis and interpretation. RA was involved in the statistical analysis and interpretation. RC made substantial contributions to the design and collection. SH made substantial contributions to the design and collection. All authors read and approved the final manuscript.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.


Patients face increasing insurance restrictions on prescription drugs, including generic-only coverage. There are no generic inhaled corticosteroids (ICS), which are a mainstay of asthma therapy, and patients pay the full price for these drugs under generic-only policies. We examined changes in ICS use following the introduction of generic-only coverage in a Medicare Advantage population from 2003–2004.Subjects were age 65+, with asthma, prior ICS use, and no chronic obstructive pulmonary disorder . In 2004, 74.0% switched from having a $30 brand-copayment plan to a generic-only coverage plan (restricted coverage); 26% had $15–25 brand copayments in 2003–2004 (unrestricted coverage). Using linear difference-in-difference models, we examined annual changes in ICS use (measured by days-of-supply dispensed). There was a lower-cost ICS available within the study setting and we also examined changes in drug choice (higher- vs. lower-cost ICS). In multivariable models we adjusted for socio-demographic, clinical, and asthma characteristics.In 2003 subjects had an average of 188 days of ICS supply. Restricted compared with unrestricted coverage was associated with reductions in ICS use from 2003–2004 : -25.0 to -6.0). Among patients using higher-cost ICS drugs in 2003 (n = 662), more restricted versus unrestricted coverage subjects switched to the lower-cost ICS in 2004 (39.8% vs. 10.3%). Restricted coverage was not associated with decreased ICS use (2003–2004) among patients who switched to the lower-cost ICS , but was among patients who did not switch . In addition, restricted coverage was associated with decreases in ICS use among patients with both higher- and lower-risk asthma .In this elderly population, patients reduced their already low ICS use in response to losing drug coverage. Switching to the lower-cost ICS mitigated reductions in use among patients who previously used higher-cost drugs. Additional work is needed to assess barriers to switching ICS drugs and the clinical effects of these drug use changes. As prescription drug costs continue to rise, public and private payers are increasing insurance restrictions and patient cost-sharing for prescription drugs. Cost-sharing aims to promote cost-effective drug consumption, such as greater use of generic drugs or reduced use of clinically unnecessary drugs, by exposing patients to a greater share of the costs of treatment. For example, in the United States, Medicare Part D drug benefits, which were offered starting in 2006 through a number of private plans, include high levels of cost-sharing. In 2007, about 70% of Part D drug plans included a coverage gap (often referred to as a "doughnut hole") wherein patients lose coverage for all drugs after their total drug spending exceeds $2,400 and until their out-of-pocket costs reach $3,850. About 27% of plans supplement this coverage gap with generic-only coverage, under which patients have coverage for generic drugs, but no coverage for brand-name drugs .Under Medicare Part D cost-sharing arrangements, many beneficiaries may be at risk for losing drug coverage for inhaled corticosteroids (ICS) during the coverage gap, even if they have generic-only coverage supplements, because no generic ICS formulations are available in the U.S. Inhaled corticosteroids are the mainstay of treatment for all forms of asthma, except mild-intermittent  and asthTo gain insight about the impact of brand name drug coverage loss, we examined changes in ICS use among Medicare Advantage (MA) beneficiaries whose plans switched from generic and brand coverage with an annual cap in 2003 to generic-only coverage  in 2004. We compared them with MA enrollees with brand-name coverage in both 2003 and 2004.We used automated data from Kaiser Permanente-Northern California (KPNC), an integrated delivery system that provides comprehensive medical care to over three million members, which included about 280,000 MA beneficiaries. Members could join the KPNC MA plan either by purchasing individual insurance or through plans supplemented by their current or former employers. There was only one MA plan  for individual subscribers, while employers determined KPNC cost-sharing levels for patients with employer-supplemented plans.In 2003 individual MA beneficiaries had $10 generic and $30 brand copayments, and a $1,000 benefit cap . In 2004, the cap was replaced with generic-only coverage – i.e., patients paid full member price for brand drugs, and $10 copayments for generics throughout the year ("restricted coverage"). By contrast, employer-supplemented MA beneficiaries paid $10 generic and $15–25 brand copayments 2003–2004, with no other limits ("unrestricted coverage"). Patients' coverage type was determined by their employment history and enrollees could not switch between the coverage types , at a significantly lower member price compared with other inhaled corticosteroids. Beclomethasone dipropionate was the most frequently prescribed ICS within the health system, comprising 75% of all ICS prescriptions in our study, and was followed by fluticasone propionate (Flovent), which comprised 23% of ICS prescriptions . The average cost increase due to loss of coverage for a canister of beclomethasone dipropionate was about $15, compared with $65 or $110 for fluticasone propionate 110 mcg or 220 mcg, respectively. The KPNC Institutional Review Board approved the study.All subjects included in this study  were continuous MA enrollees , 65+ years old, who met at least one of the following criteria as of January 1, 2003: (1) ≥ 1 inpatient admissions with a primary asthma diagnosis in the previous three years; (2) ≥ 1 ED visits with an asthma diagnosis in the previous two years; or (3) ≥ 2 outpatient visits with an asthma diagnosis in the previous two years. Further, all subjects were dispensed ≥ 30 days-of-supply of an ICS in both 2002 and 2003. We excluded patients with inpatient or outpatient chronic obstructive pulmonary disorder (COPD) diagnoses: ICD-9-CM codes 491 (chronic bronchitis), 492 (emphysema), 493.20 (asthma with COPD), or 496 (COPD) in 2003–2004. We also excluded patients who were dispensed ipratropium bromide (Atrovent), the primary pharmacologic therapy for COPD within KPNC in 2003 or 2004, and patients with Medicaid because they had substantially lower cost-sharing.We measured ICS use based on days-of-supply dispensed. Days-of-supply were calculated for each prescription by multiplying the number of actuations per canister by the number of canisters dispensed and dividing by the prescribed dose (actuations) and frequency of administration. We carried over remaining supply from month-to-month and calculated patients' ICS supply in each month (standardized to a 30-day month) and year. We considered beclomethasone dipropionate as "lower-cost", and all other ICS brands as "higher-cost". We calculated monthly and annual days-of-supply for lower- and higher-cost ICS drugs separately. We also classified patients as either lower- or higher-cost ICS users in each year by the type with the greater days-of-supply.Comparisons between the restricted and unrestricted coverage groups were adjusted for a number of potential confounders including age, gender, and race/ethnicity. Race/ethnicity was determined based on routine member surveys and inpatient records (we included an unknown category with 7.5% of subjects). We constructed a neighborhood socioeconomic status (SES) indicator using patients' residential addresses and information from the 2000 US Census. Neighborhoods were considered low SES if ≥ 20 percent of residents had average household incomes below the federal poverty level, or ≥ 25 percent of residents ≥ 25 years old had less than a high school education ,9. We adTo adjust for asthma severity, we used a number of medication- and diagnosis-related variables in 2002: number of rescue medication canisters dispensed, having a high-dose ICS, any oral steroid dispensed, a high-risk asthma registry flag  approach. The models included indicators for propensity score quintile (2–5), month (2–24), restricted coverage, and interactions between restricted coverage and month. The coefficients of the interactions test the hypothesis that coverage type was associated with different patterns of ICS use over months.To examine annual ICS use associated with restricted coverage we calculated the change in days-of-supply (2004 minus 2003) for each subject and used this difference as the outcome in linear models, adjusted for propensity score quintile. We examined annual changes among all subjects, among users of higher- and lower-cost ICSs in 2003, separately, and by type of ICS use in 2004, separately. We also examined changes in ICS use among patients identified as having high-risk asthma in the health system's disease registry, and those with lower-risk asthma .To examine changes in Lastly, we examined the patient characteristics associated with having no ICS use in 2004 using multivariable logistic regression, and included the covariates described above.Table Figure Figure Table For higher-cost ICS users in 2003, the effect of restricted coverage on ICS use differed by the type of medication used in 2004. Restricted coverage was not associated with decreased ICS use (2003–2004) among patients who switched to the lower-cost ICS in 2004 , but was among patients who did not switch .We also examined changes in ICS use associated with restricted coverage, stratified by asthma disease severity, as defined by having a high-risk asthma flag in the disease registry Table . Table 5In separate analyses (more details available upon request), among all subjects and among higher-cost ICS users in 2003, restricted coverage was not significantly associated with having no ICS use in 2004 . Among all subjects, having a high-dose ICS in 2002 and greater ICS use (days-of-supply) in 2003 were associated with lower odds of no ICS use in 2004 .Inhaled corticosteroids are a critical component of therapy for persistent asthma. In this population of Medicare beneficiaries with asthma, levels of ICS use were low , and switching appeared to mitigate reductions in 2004 ICS use due to loss of drug coverage. However, many patients did not switch to the lower-cost ICS and those with restricted coverage reduced their ICS use by over one month of supply compared with patients with unrestricted coverage.Patients who were taking higher-cost ICS drugs at baseline exhibited greater asthma severity compared with lower-cost ICS users, as indicated by several medication and diagnoses measures shown in Table Encouraging greater substitution of higher-cost with lower-cost ICS drugs could mitigate potential adverse effects of restricted drug coverage policies. In this setting, switching to the lower-cost ICS would not be likely to result in adverse clinical effects as head-to-head trials have not produced definitive conclusions on the comparative efficacy of different inhaled corticosteroids . There iPoor adherence to ICS therapy has been demonstrated in other studies ,23-28. TBecause ours was a non-randomized study it is possible that differential changes in ICS use between the restricted and unrestricted groups are due to unmeasured differences. We were able to adjust for a large a number of socio-demographic and clinical characteristics, including a number of asthma severity measures. Identifying patients with persistent asthma based on administrative data is challenging; we examined other cohort definitions of varying restrictiveness  and found similar results across these definitions. ICS use was measured using pharmacy data. These data do not capture whether patients actually took dispensed medications or took them correctly; we also did not assess the clinical effects of changes in ICS use. The pharmacy data do not include drugs dispensed outside of KPNC; however, patients had a financial incentive to purchase their medications within KPNC because of favorable in-system prices throughout the study period. As a result, in telephone interviews, members report rarely going outside of the system to obtain medications or other services . Lastly,This study highlights the importance of offering a low-cost option within the ICS drug class, particularly during uncovered periods, such as during the Medicare Part D coverage gap. Insurers may also consider maintaining coverage for ICS drugs during otherwise uncovered periods for patients with a clinical need for these drugs. Additional work is needed to understand patient responses to drug cost-sharing, especially for patients who did not switch to the lower-cost option yet reduced ICS use, as well as the clinical effects of restricted drug coverage policies.CI: confidence interval; COPD: chronic obstructive pulmonary disorder; ED: emergency department; ICS: inhaled corticosteroids; KPNC: Kaiser Permanente-Northern California; MA: Medicare Advantage; OR: odds ratio.The authors declare that they have no competing interests.VF made substantial contributions to the study's conception and design, acquisition of data, analysis and interpretation of data, drafted the manuscript, and revised the manuscript critically for important intellectual content. IBT made substantial contributions to the study's design, analysis and interpretation of the data, and revised the manuscript critically for important intellectual content. RB made substantial contributions to the study's design, analysis and interpretation of the data, and revised the manuscript critically for important intellectual content. JPN made substantial contributions to the study's design, analysis and interpretation of the data, and revised the manuscript critically for important intellectual content. JH made substantial contributions to the study's conception and design, acquisition of data, analysis and interpretation of the data, and revised the manuscript critically for important intellectual content. All authors read and approved the final manuscript.The pre-publication history for this paper can be accessed here:


Various structural and functional factors of foot function have been associated with high local plantar pressures. The therapist focuses on these features which are thought to be responsible for plantar ulceration in patients with diabetes. Risk assessment of the diabetic foot would be made easier if locally elevated plantar pressure could be indicated with a minimum set of clinical measures.Ninety three patients were evaluated through vascular, orthopaedic, neurological and radiological assessment. A pressure platform was used to quantify the barefoot peak pressure for six forefoot regions: big toe (BT) and metatarsals one (MT-1) to five (MT-5). Stepwise regression modelling was performed to determine which set of the clinical and radiological measures explained most variability in local barefoot plantar peak pressure in each of the six forefoot regions. Comprehensive models were computed with independent variables from the clinical and radiological measurements. The difference between the actual plantar pressure and the predicted value was examined through Bland-Altman analysis.Forefoot pressures were significant higher in patients with neuropathy, compared to patients without neuropathy for the whole forefoot, the MT-1 region and the MT-5 region . The clinical models explained up to 39 percent of the variance in local peak pressures. Callus formation and toe deformity were identified as relevant clinical predictors for all forefoot regions. Regression models with radiological variables explained about 26 percent of the variance in local peak pressures. For most regions the combination of clinical and radiological variables resulted in a higher explained variance. The Bland and Altman analysis showed a major discrepancy between the predicted and the actual peak pressure values.At best, clinical and radiological measurements could only explain about 34 percent of the variance in local barefoot peak pressure in this population of diabetic patients. The prediction models constructed with linear regression are not useful in clinical practice because of considerable underestimation of high plantar pressure values. Identification of elevated plantar pressure without equipment for quantification of plantar pressure is inadequate. The use of quantitative plantar pressure measurement for diabetic foot screening is therefore advocated. Clinical examination is considered important in the evaluation of the diabetic foot. Physicians and foot care specialists should be able to identify patients at risk of adverse outcomes such as ulceration. A structured clinical assessment that incorporates diagnostic tests alongside a thorough history and examination is thought to be essential for preventive strategies. High plVarious structural and functional factors of foot function have been associated with high local plantar pressures such as limited joint mobility -4, plantAn alternative diagnostic screening method for abnormal physical stress on the foot sole is direct quantitative measurement of plantar pressure. In the last few decades electronic devices such as pressure sensitive platforms have become commercially available for this purpose. This equipment is relatively expensive and there is no reimbursement by health insurers of the costs for the provision of this screening procedure. Consequently, this diagnostic facility is seldom provided as standard care in clinical settings.The primary objective of this study was to assess the relationship between clinical measurements, radiological data and barefoot plantar pressure in order to find clinical measures that predict local peak pressure in patients with diabetes. In addition, we also evaluated previously proposed regression models by various authors with the same and/or similar variables as those obtained in our current study. To evaluate the effect of peripheral neuropathy as a predictor in this study, we included both patients with – and without peripheral neuropathy. The secondary objective of this study was to assess the differences in clinical measurements, radiological data and barefoot peak pressure between patients with – and without peripheral neuropathy.Diabetic patients were selected from the outpatient clinic of the University Hospital Maastricht. Inclusion criteria were diabetes mellitus type 1 (longer than 10 years after date of diagnosis) or type 2 (at least one year after date of diagnosis); age between 30 and 75 years and able to perform daily-life activities without supporting devices. Exclusion criteria were a history of rheumatoid arthritis, severe foot trauma, severe deformity i.e. which require orthopaedic shoes and/or surgery of the foot.Before the start of the study, patients were informed about all study procedures and their possible risks. The Research Ethical Committee of the University Hospital Maastricht approved the study. One hundred and twenty five eligible patients were screened for peripheral neuropathy through determination of the vibration perception threshold (VPT) at the apex of the hallux with a biothesiometer ,30. A VP® pressure sensitive platform  was used to quantify the barefoot plantar pressures of the patients' feet and was performed according to a one-step protocol[®' software[An EMED SF-4 protocol,32. Bare software.Prior to data collection the grade of callus formation under the plantar aspect of the hallux and the metatarsals' heads was scored according to the method described by Colagiuri et al (1995). The 'Valk' scoring system for clinThe passive ankle joint dorsal flexion range of motion was measured through use of a plastic goniometer with the patient in prone position and the knee flexed. The ranThe presence of claw toe, mallet toe, curly toe or hammer toe deformity was scored according to the definitions described by Myerson and Shereff. These dFrom a dorsal view, a crude judgement of the resting calcaneal stance position was made through visual inspection while the patient was in standing at rest position. The resting calcaneal stance position was recorded as neutral, varus or valgus alignment. In addition, the medial arch height was subjectively classified into: no arch (pes planus); lowered arch; normal arch; elevated arch and excessively elevated arch.For vascular tests, the patient lay supine and rested for at least 15 minutes prior to testing. A standard examination protocol for each lower extremity was performed. Resting ankle-brachial index (ABI) was obtained through continuous wave Doppler technique and performed at a 45 degree angle to the skin. Ankle-brachial index was calculated with the highest Doppler derived systolic pressure at the ankle , indexed to the highest Doppler derived brachial artery pressure.A Hokanson CE-4 strain gauge and photoplethysmograph was used to obtain toe pressure. A suitably sized cuff was wrapped around the proximal phalanx of the hallux. Once the best signal was acquired, the cuff was inflated until the signal disappeared, after which the cuff was slowly deflated until the signal reappeared . This was taken as the toe systolic pressure. Settings of equipment for all vascular assessment procedures were standardized. All measurements were carried out by the same experimenter. Each measurement was done three times, with the mean used for analysis.Measurements from standardized static weight-bearing foot radiographs have been shown to be an objective and reliable way of assessing both bony structure and soft tissue dimensions -42. WeigAll radiographs were taken by the same radiographer, using the same equipment and settings. Measurements were taken through line drawing and a protractor was used to measure the angles. Nine angular and six linear measurements were determined from the lateral radiographs. Five angular and thirteen linear measurements were determined from the anterior-posterior radiographs. All measurements were taken by the same experimenter.To meet assumptions of normality of statistical distributions peak plantar pressure scores were natural log transformed. At first, data from 186 feet were used for analysis. Repeated measures ANOVA showed no statistical significant differences between left and right feet as a general effect in the repeated measures model, nor specified for the peak pressures scores (i.e. the interactions of peak pressure with left or right side), nor specified for regional peak pressure . Therefore it was legitimate in the eventual data analysis to average scores over left and right sides.Next, stepwise regression analysis modelling was performed to determine which of the clinical or radiological measures will explain how much of the variance in averaged local barefoot plantar peak pressure, in each of the six forefoot regions and the whole forefoot separately. At first, all potential predictors of each subsets  were entered into the regression model through 'forward selection' and the resulting model with predictors having only statistical significant effects were noted. In the second step, all potential predictors are entered simultaneously and 'backward elimination' was applied until a model was found with predictors having statistical significant effects only. Finally, a cross-section of both resulting models was made using predictors having statistically significant effects in both models and this cross-section of predictors is 'force-entered' into the final regression model,45. Comp® .To evaluate the prediction models for each individual patient the difference between the predicted value and the actual value was plotted against their mean. This method is also known as residual analysis. In the clinical literature this method is recognized as Bland-Altman analysis, which allows one to judge the agreement between two different measurement techniques. CategorForefoot pressures were significant higher in patients with neuropathy, compared to patients without neuropathy for the whole forefoot, the MT-1 region and the MT-5 region , table There were no were statistically significant differences between extremities with and without neuropathy with respect to the ankle-brachial index, toe pressure and passive dorsal flexion range of the ankle joint .The range of dorsal flexion motion of the MT-1 joint was statistically significantly greater in feet without neuropathy compared to neuropathic feet: 15 degrees. The hallux valgus angle measured with a goniometer was statistically significantly greater in diabetic feet: 5.3 degrees .For both groups the grade of toe deformity increased from the first to the fifth toe. No statistically significant differences for callus formation and toe deformity were found , except that neuropathic feet had a slightly higher grade of deformity of the 4versus 51.2 percent; 'valgus' 46.2 percent versus 47.5 percent and 'varus' 6.6 percent versus 1.3 percent, respectively.The proportions for classification of the calcaneal resting position for feet with and without neuropathy was: 'neutral' 47.2 percent versus 13.8 percent; 'lowered arch' 42.5 percent versus 31.3 percent; 'normal arch' 17.9 percent versus 21.1 percent; 'elevated arch' 26.4 percent versus 32.5 percent and 'excessively elevated arch' 6.6 percent versus 1.3 percent.The proportions of arch height classification for patients with and without neuropathy were: 'no arch' 6.6 percent No statistically significant differences between neuropathic feet and feet without neuropathy for both calcaneal resting position and arch height were found (p > .062).The statistically significant differences for patients with neuropathy compared to patients without neuropathy listed as radiographic measures in millimetres (mm) and degrees (deg) were: MT-5 base height -0.6 mm, navicular height -3.7 mm, inferior calcaneal inclination -2.9 deg, Chopart's joint angle -1.4 deg, Lisfranc's joint angle +2.0 deg, MT-5 inclination -1.5 deg, MT-1 inclination -1.6 deg, Talar inclination +3.0 deg, 1st PIP joint inclination -2.1 deg, hallux valgus +2.4 deg, MT-2 thickness +0.4 mm and MT-3 thickness +0.4 mm , 34% (MT-1 region), 25% (MT-2 region), 16% (MT-3 region), 13% (MT-4 region) and 29% (MT-5 region), table r of .061 and an r2 of .004, SE 0.71 .We used the same radiological measures in the present study as in previous studies by Morag and Cavanagh (1999). The modr .27, r2 .075, SE 0.51 (p = .007) and Morag and Cavanagh (1999)[r .31, r2 .10, SE 0.51 (p = .002). The only statistically significant beta, also known as beta weight or standardized regression coefficient, in the MT-1 model was 'sesamoid height', i.e. soft tissue thickness under the first metatarsalphalangeal joint.The models for the MT-1 region proposed by Cavanagh et al (1997), resultegh (1999), r .31, We also evaluated proposed regression models by Mueller et al.(2003), Ahroni r .32, r2 .105 SE 0.50 (p = .001); MT-2 region r .32, r2 .103, SE 0.43 (p = .001); MT-3 region r .22, r2 .046, SE 0.38, (p = .013) and MT-5 region R .29, r2 .072, SE 0.61 (p = .004). This was also true for the model for prediction of plantar pressure under the forefoot by Ahroni et al.  and the model for the MT-1 region suggested by Payne et al. : r .46, r2 .212, SE 0.19 (p = .001) and r .36, r2 .131, SE 0.49 (p = .001), respectively.The models proposed by Mueller et al. for MT-1  to MT-3  and MT-5  were statistically significant: MT-1 region Figures The dotted lines in figures We explored new and previously suggested relationships between clinical measurements, data from radiographs and barefoot plantar pressure in patients with diabetes. The primary aim of the present study was to find a minimal combination of measures which could indicate locations with elevated plantar pressure as an alternative for quantitative plantar measurement.Consistent with what is reported in the literature, higher peak pressures were measured under the neuropathic forefoot than those under the forefoot without neuropathy. The greth and 5th toe. Results from the regression analysis showed that toe deformities were weakly associated with peak pressures in their pertaining forefoot regions. There were no statistically significant differences in calcaneal resting position and arch height between feet with and without neuropathy. Callosities, toe deformity, calcaneal alignment and arch height were previously identified as distinct features in high risk diabetic patients with neuropathy[The distributions of callus formation and toe deformity grades were similar for feet with and without neuropathy. Neuropathic feet had a slightly higher grade of deformity of the 4europathy,49,54,55Relatively many differences were found for measurements on lateral radiographs compared to anterior-posterior radiographs. The soft tissue thickness under the head of MT-5 is greater in patients without neuropathy, which could be an explanation for the lower peak pressure in this region compared to patients with neuropathy. A similar relationship between soft tissue thickness and peak pressure exists for MT-1 and was reported in previous studies,56.Various radiological parameters indicate that neuropathic feet have a lower arch structure than feet without neuropathy. Some parameters obtained from lateral and anterior-posterior radiographs indicate similar classifications found through clinical examination, such as arch height and hallux alignment, although no statistically significant differences were found.In general, the regression models with selected clinical variables explained more variance in plantar pressure data than the models with only radiological measures, suggesting that clinical examination tells us more about plantar pressure than information from radiographs.For most regions, the prediction of plantar pressure improved with the combination of radiological and clinical data. The results show that clinical and radiological measurements, either independently or in combination, could explain only about 34 percent of the variance in local bare foot peak pressure. In other words, with the models constructed we have only 34 percent of useful information from the clinical and radiological measurements to make an prediction about the actual bare foot peak pressure.The Bland-Altman method was used for a visual impression of the individual difference between the predicted and the actual pressure values. We evaluated the comprehensive regression model for the MT-1 region. The scattered data along the wide interval of the horizontal axis in figure In general, the previously reported regression models with independent variables from clinical examination showed similar results to our study. Ahroni et al. (1999) claimed that high in-shoe plantar pressure in diabetic subjects  could be predicted through the use of clinical variables, such as body mass, insulin use, Caucasian race, male sex, plantar callus and diabetes duration. Only 12Various predictive models relating plantar peak pressure and structural variables obtained through imaging techniques have been suggested)-49,58-62Various regression models with demographically, clinically and radiologically independent variables have been suggested in the literature to estimate local plantar pressure in patients with diabetes. Comparison of these models is difficult. Various methodological aspects are different such as the population characteristics, the choice of the plantar pressure parameters and how the data of the independent variables were obtained. Despite these differences, we constructed regression models with the same or similar parameters and applied these models to our data set.We used radiological measures identical to those used by Morag and Cavanagh (1999) for the This study was directed from a practical and ecological research perspective, which means that the patients were mostly screened according through common practice procedures: e.g. goniometry, blood pressure measurements, etc. According to scientific criteria, these common practice procedures often have inferior clinimetric qualities and are likely to contribute to inherent variability. Maybe other clinical or radiological measurements are less prone to inherent variability and may be stronger predictors for local peak pressure. We studied diabetic patients without foot complications such as severe deformities and gait abnormalities. Some of the results might well be different in patients with these complications of diabetes. Nevertheless, we think it is important to identify patients with elevated plantar pressures in their early stage of disease in order to take appropriate preventive measures. The screening of these kind of patients is typically done in peripheral care centres where there is no radiological facility or plantar pressures equipment are available.Clinical signs are potentially more cost-effective than sophisticated diagnostic tests which are less feasible in community settings. However, the results form this study confirm the conclusions of a previous study which showed that identification of locations with elevated plantar pressure is not possible through physical examination. The usePeak pressures were higher in patients with neuropathy than in patients without neuropathy, although feet were quite similar as far as clinical and radiological evaluations is concerned. At best, clinical and radiological measurements could explain about 34 percent of the variance in local barefoot peak pressure in this population of diabetic patients. The prediction models constructed with regression modeling were not useful in clinical practice, because of considerable discrepancies between the predicted and the actual peak pressure values. Identification of elevated plantar pressure without equipment for quantification of plantar pressure is inadequate. This points toward the merit of quantitative plantar pressure measurement for diabetic foot screening.The pre-publication history for this paper can be accessed here:


Although magnesium is used through intravenous and inhalation route in the management of asthma, actual prevalence of hypomagnesemia in asthma is not known. We conducted this study: 1) to detect the prevalence of hypomagnesemia in stable asthma and 2) to assess the significance of hypomagnesemia in these patients.Prospective clinical study.Department of Respiratory Medicine, Calcutta National Medical College, Kolkata.Four months from January, 2007, to April, 2007.Fifty patients attending outpatients department of respiratory medicine with stable asthma were randomly selected. They were assessed clinically and their serum magnesium levels were measured. This was compared with the serum magnesium values of 45 nonasthmatic healthy controls.Out of 50 patients, 14 had hypomagnesemia. Possible relationship of hypomagnesemia with tachycardia, tachypnoea, severity of asthma, medication use, and previous and future exacerbations were analyzed.2 -agonist or montelukast.There was statistically significant association of hypomagnesemia with tachypnoea, severe asthma, use of long-acting β-agonist, inhaled corticosteroids, theophylline, use of ≥ 3 medications, previous and future exacerbations but not with tachycardia or use of short-acting β Mg++ in extracellular fluid is crucial for normal neuromuscular activities; intracellular Mg++ forms a key complex with ATP and is an important cofactor for a wide range of enzymes, transporters, and nucleic acids needed for normal cellular function, replication, and energy metabolism.[++ is about 25 g (1000 mmol). About 50% of it is in the bones, only 1% is in the extracellular fluid, and the rest is within the cells. About 30% of the serum Mg++ is bound to albumin. Mg++ has several actions on rabbit bronchial airways including relaxation of airway smooth muscle, bronchodilation, anticholinergic effects, and stabilization of mast cells.[++ is proved to be useful in the management of acute coronary syndrome,[Magnesium .Age more than 12 years.Nonsmoker.The exclusion criteria were as follows:Medical disorders like chronic kidney disease, diabetes mellitus, alcoholism, diarrhea.Patients on diuretic therapy.Pregnancy.Intermittent asthma.Cardiac disease.All the patients were evaluated with detailed history, general survey, and examination of the respiratory system. The diagnosis of asthma was confirmed by the presence of any of the following:Previous document of spirometric evidence of asthma.Spirometric evidence of asthma at the time of presentation.1 < 80% of predicted, FVC < 80% of predicted, FEV1/FVC < 70%, and improvement of FEV1 by >200 ml and 12% after 400 μg of salbutamol inhalation through metered dose inhaler with spacer was considered spirometric evidence of asthma.FEVSeverity of asthma was assessed on the basis of GINA guidelines.2 autoanalyzer machine . Serum albumin level was also estimated in all patients to exclude hypoalbuminemia as a cause of hypomagnesemia. Each patient was also questioned regarding their inhaled and oral medications and the presence of any history of acute exacerbation in the previous 3 months. Acute exacerbation of asthma was defined as per GINA guideline,[1. They were also followed up for the next 3 months for the development of any acute exacerbation. The relationship of hypomagnesemia with tachycardia (heart rate > 100 beats/min), tachypnoea (respiratory rate>20 breaths/min), severity of asthma, types of medication use, total number of medications used, occurrence of acute exacerbation in past 3 months, and in the next 3 months follow up were assessed and their statistical significance was calculated using Chi-square test and Fisher’s test.Two milliliter of fasting venous blood was drawn from each patient for estimation of serum magnesium with autoanalyzer method using Erba CHEM-5 Plus Vuideline, i.e., epTotal 50 patients of stable asthma who attended our outpatients department and satisfied the inclusion criteria were enrolled for the study. There were 18 (36%) males and 32 (64%) females. The age and sex distribution of the patients are shown in Age ranged from 13 years to 71 years (mean 42.7 years). Asthma in this study is found to be more common in female and mostly affects the younger age group (<30 years) in both sexes.Assessment of severity of asthma in them revealed that 28 (56%) had mild persistent asthma, 12 (24%) had moderate persistent asthma, and 10 (20%) had severe persistent asthma.2 -agonist (SABA) daily, 34 patients (68%) were using inhaled corticosteroid (ICS), 22 (44%) patients were using long-acting β2 -agonist (LABA), 11 patients (22%) were using montelukast (MTK), and 13 patients (26%) were using theophylline (THP). Out of 50 patients, 17 (34%) patients were using ≥ 3 medications for the control of asthma.Total 35 patients (70%) were using short-acting βTotal 10 patients (20%) gave history of acute exacerbation in past 3 months and 5 patients (10%) developed acute exacerbation in the 3 months follow up.In this study, serum magnesium value between 1.8 and 3.0 mg/dl was considered normal and any value below 1.8 mg/dl was considered as hypomagnesemia. Using this cut-off value, 14 (28%) patients were found to have hypomagnesemia and their serum magnesium value ranged between 0.91 and 1.6 mg/dl. Rest 36 patients (72%) had normal serum magnesium level. Serum albumin level was measured in all patients and none of them had hypoalbuminemia.Here 45 nonasthmatic healthy control persons were selected. The controls were subject to similar inclusion (except being nonasthmatics) and exclusion criteria. The age and sex distributions of the control are depicted in Serum magnesium and serum albumin level were measured to look for hypomagnesemia and hypoalbuminemia in them. All of them had serum magnesium values between 1.8 and 3 mg/dl, and serum albumin level between 3.5 and 5.5 g/dl.The relationship of serum magnesium values with tachycardia, tachypnoea, severity of asthma, types of medications used, total number of medication use, and episode of exacerbation in previous 3 months and future 3 months were assessed. The results are presented in From this Table, it is evident that hypomagnesemia is related to tachypnoea, moderate to severe asthma, use of ICS, LABA and THP, use of ≥3 medications, past history of asthma exacerbation in previous 3 months, and also occurrence of future exacerbation in the 3 months follow-up. However, this study did not reveal any statistically significant relationship of hypomagnesemia with tachycardia, use of SABA, and montelukast.++ levels correlate poorly with the total body store and serum Mg++ may appear normal in spite of depletion of body store. The estimation of Mg++ level in RBC, WBC, or muscle cell will be more representative of the body store but it is expensive, not easily available and not clinically applicable. Serum Mg++ level, therefore, is often used to assess the change in the Mg++ status despite its limitation. We also have measured serum Mg++ level is our study as these expensive tests are not available in our institution.Magnesium is an intracellular ion. Serum Mg1 is between 25–30% of predicted at presentation, or if there is poor response with SABA.[2Both intravenous and inhaled magnesium have been used for decades in the treatment of asthma during acute and chronic stable state.8 Internaith SABA. The possth SABA.2The prevalence of hypomagnesemia in asthma is variable. Although there are reports of significantly high prevalence of hypomagnesemia both in acute asthma and chronic stable asthma when compared with general nonasthmatic population,12 these 13P <0.01); serum magnesium level also correlated significantly with severity of asthma (P<0.04). These findings are similar to our study which has shown high prevalence of hypomagnesemia (28%) and the significant association of hypomagnesaemia with severe asthma and previous and future exacerbations. Therapeutic and dietary supplementation of magnesium have been shown to either reduce the BHR[8++ flux into airway smooth muscle cell,[Several studies have proved beyond doubt that hypomagnesemia in asthma is associated with increased incidence of wheeze, impairment of lung function, and more significantly, increased bronchial hyper-reactivity (BHR).18 In ano the BHR8 It is pr the BHR8 increase the BHR8 increasecle cell, or increcle cell,2 -agonist, corticosteroid, and theophylline.[2419Causes of magnesium deficiency in asthma may be multifactorial. It may be genetically determined. It is alphylline.2425 But ylline.241920 In oIt can be concluded from the present study that hypomagnesemia is more prevalent in stable asthmatics than nonasthmatic control. There is statistically significant correlation of hypomagnesemia with tachypnoea, severe asthma, use of LABA, ICS and THP, requirement of multiple medications (≥3), and the presence of exacerbation in past 3 months and in next 3 months follow-up. This study could not find any significant correlation between hypomagnesemia and the presence of tachycardia or use of SABA and MTK.++ level in RBC, WBC, or muscle cell in addition to serum Mg++ will give better insight in this field. The cause of hypomagnesemia in asthmatics and whether magnesium supplementation has a role in asthmatic population are important fields of further research.There are few pitfalls in our study. We measured serum concentration of magnesium which may not be representative of actual body store. We did not consider the amount of dietary magnesium in the patients. So, further studies using large number of patients, and measuring Mg


Dark chocolate and flavanol-rich cocoa products have attracted interest as an alternative treatment option for hypertension, a known risk factor for cardiovascular disease. Previous meta-analyses concluded that cocoa-rich foods may reduce blood pressure. Recently, several additional trials have been conducted with conflicting results. Our study summarises current evidence on the effect of flavanol-rich cocoa products on blood pressure in hypertensive and normotensive individuals.P < 0.05.We searched Medline, Cochrane and international trial registries between 1955 and 2009 for randomised controlled trials investigating the effect of cocoa as food or drink compared with placebo on systolic and diastolic blood pressure (SBP/DBP) for a minimum duration of 2 weeks. We conducted random effects meta-analysis of all studies fitting the inclusion criteria, as well as subgroup analysis by baseline blood pressure (hypertensive/normotensive). Meta-regression analysis explored the association between type of treatment, dosage, duration or baseline blood pressure and blood pressure outcome. Statistical significance was set at P = 0.001; DBP: -2.0 ± 1.3 mmHg, P = 0.003). However, subgroup meta-analysis was significant only for the hypertensive or prehypertensive subgroups , while BP was not significantly reduced in the normotensive subgroups . Nine trials used chocolate containing 50% to 70% cocoa compared with white chocolate or other cocoa-free controls, while six trials compared high- with low-flavanol cocoa products. Daily flavanol dosages ranged from 30 mg to 1000 mg in the active treatment groups, and interventions ran for 2 to 18 weeks. Meta-regression analysis found study design and type of control to be borderline significant but possibly indirect predictors for blood pressure outcome.Fifteen trial arms of 13 assessed studies met the inclusion criteria. Pooled meta-analysis of all trials revealed a significant blood pressure-reducing effect of cocoa-chocolate compared with control (mean BP change ± SE: SBP: -3.2 ± 1.9 mmHg, Our meta-analysis suggests that dark chocolate is superior to placebo in reducing systolic hypertension or diastolic prehypertension. Flavanol-rich chocolate did not significantly reduce mean blood pressure below 140 mmHg systolic or 80 mmHg diastolic. Flavanol-rich chocolate and cocoa products have attracted interest as nonpharmacological treatment options for high blood pressure, a known risk factor for cardiovascular disease ,2. Even et al. (2007)  mmHg, P = 0.01; I 2 = 79%; Figure normo: -1.28  mmHg, P = 0.12; I 2 = 24%; Figure Results of DBP subgroup analyses were similar to the results of SBP subgroup analyses. While the DBP pre-/hypertensive subgroup analysis remained significant ; and type of control (flavanol-free control versus low-flavanol product as control) was borderline significant for DBP (P = 0.052).Five variables tested  did not show any significant association with blood pressure outcomes in the meta-regression analysis, while study design  was borderline significantly associated with BP outcome . These effect sizes were smaller than in previous meta-analyses including fewer trials , 5 trials, SBP: -4.7 ± 2.9 mmHg, P = 0.002; DBP: -2.8 ± 2.0 mmHg, P = 0.006, [et al. (2010), 10 trials, SBP: -4.5 ± 1.4 mmHg, P = 0.001, DBP: -2.5 ± 1.4 mmHg, P = 0.001, [Our meta-analysis including 15 trial arms demonstrated a small but significant blood pressure-reducing effect of flavanol-rich cocoa products compared with control .P = 0.0009; DBP: -2.7 ± 2.2 mmHg, P = 0.01), analyses of normotensive subgroups did not demonstrate a significant reduction in blood pressure of flavanol-rich cocoa products . These findings are in line with meta-analyses of other nutritional supplements on blood pressure, which similarly found that blood pressure was significantly reduced in hypertensive subgroups but not in the normotensive subgroups [In contrast to previous meta-analyses ,14, subgubgroups ,45.Heterogeneity was reduced satisfactorily in the normotensive subgroups, indicating that trials in these subgroup analyses are highly comparable and the meta-analyses results can be interpreted with confidence. In contrast, heterogeneity remained high in the hypertensive subgroups, influenced greatly by one relatively small study arm , which dThe relatively modest but significant blood pressure-lowering effect of cocoa in the hypertensive subgroup is clinically relevant: a decline of 5 mmHg in systolic blood pressure may reduce the risk of a cardiovascular event by about 20% over 5 years . FurtherMeta-regression analyses suggested study design  and type of control (flavanol-free versus low-flavanol) to be significant predictors of blood pressure outcome but failed to show any statistically significant associations in the other variables tested. However, study design as well as type of control might be indirect predictors, as about half the trials using a crossover design and white chocolate as flavanol-free control were conducted by the same two teams and within similar study populations ,13,16,18Furthermore, results of trials using flavanol-free controls, including white chocolate or milk, might overestimate the effect of the active treatment, owing to potential bias of unblinded participants. Therefore, related subgroup analyses need to be interpreted cautiously.Meta-regression analysis did not suggest an association between dosage, duration, quality of trials, age, BMI and blood pressure outcome. However, inclusion of future trials in meta-regression analysis might provide further insight into predicting factors.While regular consumption of flavanol-rich cocoa products may have a beneficial short-term effect in reducing blood pressure in hypertensive individuals, the practicability of chocolate or cocoa drinks as long-term treatment is questionable. A recent small study by our team investigating the acceptability of commercially available chocolate bars as an alternative treatment to capsules concluded that daily chocolate consumption for blood pressure may not be an acceptable and practical treatment option .Our meta-analysis of 15 trial arms suggests that dark chocolate and flavanol-rich cocoa products are superior to placebo in reducing systolic hypertension and diastolic prehypertension. However, flavanol-rich cocoa products did not significantly reduce mean blood pressure below 140 mmHg systolic or 80 mmHg diastolic. Additional trials of hypertensive populations are needed to elucidate whether local dietary habits or genetic factors influence the blood pressure-lowering effect of cocoa.BP: blood pressure; BMI: body mass index; CI: confidence interval; DBP: diastolic blood pressure; mg: milligrams; mm Hg: millimetre mercury; RCT: randomised controlled trial; SBP: systolic blood pressure; SD: standard deviation.The authors declare that they have no competing interests.KR, ORF and NPS conceptualised the study and obtained funding. Data was acquired independently by KR and PF. KR and TS undertook data analysis and interpretation. KR prepared the manuscript with contributions from all co-authors. All authors approved the final version.The pre-publication history for this paper can be accessed here:http://www.biomedcentral.com/1741-7015/8/39/prepub


Ktrans following CA4P, and one a statistically significant fall in IAUGC60. No statistically significant correlations were seen between the continuous or categorical variables and the DCE-MRI kinetic parameters other than between ang-2 and Ktrans (P=0.044). In conclusion, we found no strong relationships between changes in DCE-MRI kinetic variables following CA4P and the immunohistochemical angiogenic profile.Combretastatin-A4-phosphate (CA4P) acts most effectively against immature tumour vasculature. We investigated whether histological angiogenic profile can explain the differential sensitivity of human tumours to CA4P, by correlating the kinetic changes demonstrated by dynamic MRI (DCE-MRI) in response to CA4P, with tumour immunohistochemical angiogenic markers. Tissue was received from 24 patients . An angiogenic profile was performed using standard immunohistochemical techniques. Dynamic MRI data were obtained for the same patients before and 4 h after CA4P. Three patients showed a statistically significant fall in  Combretastatin-A4-phosphate (CA4P) is a tubulin-binding, selective vascular disruptive agent (VDA) that causes rapid shutdown of blood flow to tumours with minimal effects on normal vasculature. Tumour endothelial cells are often immunohistochemically immature, lacking smooth muscle and pericyte coverage, and more sensitive to the effects of VDAs probably because the intracellular cytoskeleton is less developed (β3-integrin), a pericyte marker α-smooth muscle actin (αSMA), a marker of hypoxia (Glut-1), proliferation marker (Ki-67), and markers associated with the angiogenic switch .We selected antibodies to differentiate immature vascular endothelium – CD105 (endoglin), CD61 (μm) were cut onto slides, and stained with the panel of antibodies at concentrations and with control samples illustrated in Following ethics approval, patients enrolled in Mount Vernon phase I CA4P studies (CR-UK PH1/066 & PH1/092) who underwent DCE-MRI analysis were identified. Records were obtained from 26 identified patients and tissue was available for 24 patients . A full All sections were deparaffinised in xylene and rehydrated through graded alcohols to water.Dako's Cytomation Envision double stain system (K5361) , was used performed according to the manufacturer's instructions. Specimens were counterstained using Gills haematoxylin  for 7 s and washed. The samples were mounted and cover slipped using Dako Faramount aqueous mounting medium (S3025).We used Dako's Catalysed Signal Amplification staining system (K1497) and followed the manufacturer's instructions exactly.M citric acid pH 6. Glut-1 and Ki-67 were microwaved for 3 × 4 min and VEGF for 4 × 4 min. Optimum antigen retrieval times were determined from titration experiments.Dako's Universal autostainer (Dako) was used. Antigen retrieval was performed in 0.01 M citric acid pH 6 for 10 min (ang-1) and 20 min (ang-2). After washing in Tris-buffered saline tween-20 (TBST) primary antibody was applied as shown in Benchside manual staining procedures were used. Endogenous peroxidase activity was quenched with 1.5% hydrogen peroxide in methanol for 10 min. Antigen retrieval was performed by microwaving in 0.01 + endothelial cells that were distinctly separate from other microvessels at high power were considered individual vessels, and recorded as the number of vessels per high power field. αSMA staining was analysed concurrently – any CD34+ vessel also αSMA+ was recorded. Mean microvessel density (MVD per mm2) and pericyte coverage index (PCI) were calculated after analysing at least 20 random fields per slide  image capture software. The random field techniques described by er slide . To deteer slide .The following antigens were analysed using a categorical scale, with the proportion of immunoreactive cells graded as weak, moderate, or strong by direct visual assessment at low ( × 50) and high ( × 400) magnification . The mosRandom results were checked by an experienced immunohistochemist (FD), who had not seen the initial data. In case of disagreement as to the correct result, that slide was analysed by a consultant histopathologist.DCE-MRI involves the rapid acquisition of sets of T1-weighted images through tumour as an intravenous bolus of contrast agent is injected. The change in signal intensity over time can be analysed with mathematical models . QuantitM min) is calculated for the first 60 s following Gd-DTPA injection  and back again (kep) can be calculated using Tofts' mathematical model (Ktrans (and kep) have both blood flow rate and permeability components as Gd-DTPA is not freely diffusible and their biological meaning is dependent on the balance between capillary permeability and blood flow in the tissue of interest. In high permeability tissues, Ktrans is equal to the blood plasma flow per unit volume of tissue. In low permeability tissues such as the brain, it is equal to the permeability surface area product between the blood plasma and the EES per unit volume of tissue (The transfer constants for Gd-DTPA diffusion into the tumour extravascular extracellular space (EES) from blood plasma . The most common histological subtypes . Eighteen patients were taken from the PH1/066 single agent UK CA4P trial  are clinically significant. The 95% confidence interval for Ktrans change  was −62.5 to +166.5%, IAUGC60±80%. There was no obvious visual relationship seen between CA4P dose and fall in kinetic parameters (Ktrans following CA4P (outside 95% CI), and only 1 patient (12) a significant fall in IAUGC60.There was a wide range of DCE-MRI variable change following CA4P . Percentrameters . Three pKtrans (P=0.044). Inspecting No statistically significant correlations were seen between the continuous or categorical variables and the DCE-MRI kinetic variables  and 5b oans P=0.04. InspecWe found no obvious relationships between changes in DCE-MRI variables and the immunohistochemical angiogenic profile. This suggests immunohistochemical analysis of patients' tumours is unlikely to be useful in predicting response to VDA therapy. There was enormous variability seen both in the DCE-MRI kinetic variables and the immunohistochemistry. It is difficult to know whether the variability is related to the MRI and immunohistochemical techniques or is due to specific tumour characteristics that are of interest to us ie vascular maturity.+ vasculature responds better. Tumours with higher CD34 MVD may also have higher CD105+ MVD, however it does not necessarily follow that active angiogenesis takes place.The variability of CD34 and CD105 MVD is consistent with previous studies. Mean microvessel density has been correlated with risk of metastasis, prediction of efficacy of anticancer therapy, and prognosis in a variety of tumour types (There are a number of aspects of this study that undermine the power of our conclusions. We obtained only small numbers of samples with a heterogeneous mix of different tumour types. However, our sample was limited to patients who had received CA4P and undergone DCE-MRI. Within the ANOVA categorical analysis especially, this greatly reduced the statistical power. Our paraffin blocks, up to 21-year old, were taken from the primary surgical procedure, whereas patients received CA4P during phase I trials many years later after metastatic relapse. It is still unclear whether antigenicity within paraffin blocks reduces over time .−2 (Ktrans change was −62.5 to +166.5%, IAUGC60±80%. Conversely, taking the two separate trials individually, in PH1/066 the lower 95% confidence limit for Ktrans was −44% and in PH1/092 it was −76.5%. This wide DCE-MRI parameter variability is in line with previously published data (There were widespread falls in MRI kinetic variables following CA4P, however for most patients these did not achieve statistical significance. For some this was because the CA4P dose received was below the threshold level for DCE-MRI detectable drug activity of 50 mg mhed data . Combini−2 show reductions in MRI variables, and examining those patients' results in −2 exhibiting greater parameter falls has previously been demonstrated (There was no obvious visual relationship between CA4P dose and fall in MRI parameters. Most patients treated with >50 mg mMicrovessel density does not reflect the functional properties of vessels, including permeability, which contribute to DCE-MRI variables. Studies reporting correlation between MRI variables and MVD have therefore found only moderate associations (Ktrans is probably a statistical quirk due to the number of variables investigated. However, it might be explained as: angiopoietins are involved in the angiogenic switch (The significant correlation between ang-2 and c switch . Wang (WIn conclusion, there was wide intrapatient variability in angiogenic profile expression and DCE-MRI kinetic variable changes following CA4P. There was no obvious correlation between falls in MRI variables and vascular markers, however sample numbers were small. Immunohistochemical analysis of patients' tumours is unlikely to be useful in predicting response to VDA therapy. This was an exploratory study, which we hoped would suggest some leads for further analysis. Although one could postulate that this study should be expanded to look at larger patient numbers and use fresh tumour samples from a homogeneous group, such a study is unlikely ever to be performed.


To examine effects of pioglitazone (PIO) on systolic, diastolic, pulse and mean blood pressures  in type 2 diabetes mellitus (T2DM).One hundred and six normotensive patients with T2DM with mean fasting blood glucose  were randomly divided into two groups. Test group was treated with 15 mg of PIO in addition to metformin 500 mg three times per day in both groups. SBP, DBP, PP and MP and fasting insulin, FBS and lipid profiles were measured before and after PIO therapy.vs. 118 ± 2 mmHg, P < 0.05), PP , and MP . Clinical reduction in DBP was observed but not significant . There was a significant correlation between decline in SBP and DBP with respective baseline values . Changes in PP and MP strongly correlated with baseline values . There was a parallel reduction of FBS  but reduction in IR or lipid profiles was not significant in test group. Changes in BP were not significant in control group ( P > 0.05).There was a significant reduction in SBP (123 ± 2 PIO treatment of T2DM showed early reduction of SBP and MP within first 4 weeks. Results suggest that pharmacodynamic effects of PIO mainly affect the systolic component. We hereby suggest that reduction of BP by PIO is independent from mechanisms of changes in IR and dyslipidaemia in normotensive diabetic patients. Correlation between two variables was studied with the Spearman rank order. All statistical analyses were performed using Microcal Origin 4.1 and Microsoft Excel whenever applicable.Power was determined using changes in SBP, DBP, MBP and PP as primary endpoint. For the descriptive statistics after having checked the normality of the variables using the Kolmogorov-Smirnov test, the usual central and dispersion methods were used: average, SD, and 95% CI. All tests were conducted using a probability level of 0.05. The statistical significance of differences between the means were evaluated using the paired Student's P < 0.05). The difference observed in the DBP was not statistically significant . P < 0.001).Baseline demographic data of age, BMI, sex, FI, FBS and values of SBP and DBP of both groups are presented in . Table 2P < 0.05). Further, the reduction of the MP from 95 ± 1 to 91 ± 1 mmHg was statistically significant (P < 0.05).There was a significant reduction of PP from 41 ± 1 (before treatment) to 37 ± 1 mmHg in all patients . In addition, our data show the strong correlation of decline in PP and MP with the baseline values .These results indicate that the changes in BP were mainly due to the decrease in the SBP resulting parallel reduction of PP. Further, we found that there was a significant correlation between decline in SBP and DBP with respective baseline values after the treatment with PIO . Figureet al. demonstrated subjects with salt sensitive essential hypertension are more than low rennin hypertensive group. The discovery may lead to simultaneous treatment options for high blood pressure and diabetes. The newly discovered molecule acts as a neurotransmitter and thus conveys messages throughout different regions of the brain. There was a significant reduction in FBS and SBP, PP and MP in our study group within 4 weeks of therapy and no significant reduction in FI or lipid profiles. This result is supported by above researchers,[28] which shows there is an association of regulating insulin release and control of BP in diabetic patients. Fujishima et al. We suggest mechanism of BP-lowering effect of PIO may be independent from the mechanism-causing IR as well as dyslipidaemia in normotensive diabetic patients. Work has to be expanded to investigate the observed effect of PIO on reducing BP also in type 2 diabetic patients who are complicated with hypertension too.Lowering of blood pressure in diabetic population is particularly important for prevention of progression of DM and complications. The Joint National Commission VI recommends treating high-normal BP in the diabetic population.