21916120
Treated hypertension and the white coat phenomenon: Office readings are inadequate measures of efficacy.
To better define the prevalence of white coat hypertension (WCH) among patients with type 2 diabetes mellitus and to estimate the magnitude of white coat effect (WCE), before and after antihypertensive therapy, we gathered data from an open-label forced-titration study of a combination of antihypertensive drugs that was titrated sequentially, in the order amlodipine, olmesartan, and hydrochlorothiazide, over an 18-week period among 187 patients with type 2 diabetes mellitus. WCH was defined as daytime ambulatory blood pressure (BP) of 135/85 mm Hg or less, but clinic BP of 140/90 mm Hg or more. WCE was obtained as the mean difference between clinic and daytime ambulatory BP. At baseline, the prevalence of WCH was 12%; all but one subject had WCE of >10/5 mm Hg. After treatment, the prevalence of WCH had increased to 39% (P < .001). In the overall population, at baseline, the mean (±SD) WCE for systolic BP was 10.4 ± 10.9 mm Hg and 3.7 ± 8.6 mm Hg for diastolic BP. After treatment, the reduction in systolic WCE was 3.01 ± 0.93 (SE; P < .0001); no reduction was seen for diastolic WCE. Among patients treated with amlodipine-olmesartan combination, WCE at baseline was 11 mm Hg systolic and was attenuated to -0.9 mm Hg. Among patients treated with amlodipine-olmesartan-hydrochlorothiazide combination, systolic WCE was similar at baseline (10.1 mm Hg) and at end of therapy (8.1 mm Hg). Mean systolic difference between dual and triple therapy of 9.9 mm Hg, SE 2.98 was significant (P < .001). The drop in diastolic WCE from 6.4 with dual therapy to -1.2 with triple therapy was also significant (mean difference 7.6, SE 2.2; P < .001). In conclusion, the prevalence of WCH increases three-fold with treatment as a result of fewer patients having sustained hypertension. Thus, out-of-office BP monitoring especially among treated hypertensive patients with type 2 diabetes is necessary to provide better assessment of overall BP and response to treatment.
24249726
Regulation of circadian blood pressure: from mice to astronauts.
PURPOSE OF REVIEW
Circadian variation is commonly seen in healthy people; aberration in these biological rhythms is an early sign of disease. Impaired circadian variation of blood pressure (BP) has been shown to be associated with greater target organ damage and with an elevated risk of cardiovascular events independent of the BP load. The purpose of this review is to examine the physiology of circadian BP variation and propose a tripartite model that explains the regulation of circadian BP.


RECENT FINDINGS
The time-keeper in mammals resides centrally in the suprachiasmatic nucleus. Apart from this central clock, molecular clocks exist in most peripheral tissues including vascular tissue and the kidney. These molecular clocks regulate sodium balance, sympathetic function and vascular tone. A physiological model is proposed that integrates our understanding of molecular clocks in mice with the circadian BP variation among humans. The master regulator in this proposed model is the sleep-activity cycle. The equivalents of peripheral clocks are endothelial and adrenergic functions. Thus, in the proposed model, the variation in circadian BP is dependent upon three major factors: physical activity, autonomic function, and sodium sensitivity.


SUMMARY
The integrated consideration of physical activity, autonomic function, and sodium sensitivity appears to explain the physiology of circadian BP variation and the pathophysiology of disrupted BP rhythms in various conditions and disease states. Our understanding of molecular clocks in mice may help to explain the provenance of blunted circadian BP variation even among astronauts.
191311
Assessment of iothalamate plasma clearance: duration of study affects quality of GFR.
BACKGROUND AND OBJECTIVES
Measurement of GFR is important for the management of chronic kidney disease (CKD). Although bolus administration of radiocontrast agents is commonly used to measure GFR, the optimal duration of sampling to assess their plasma clearance is unknown. The purpose of this study was to evaluate whether the duration of plasma sampling influences precision and estimation of GFR.


DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS
GFR was measured by sampling plasma 12 times over 5 h in 56 patients with CKD (mean age 64 yr, 98% men, 79% Caucasian, 34% diabetics, estimated GFR 31.8 +/- 14.2 ml/min/1.73 m(2)). In a subset of 12 patients we measured GFR by sampling plasma 17 times over 10 h.


RESULTS
Short sampling intervals considerably overestimated GFR measured using total plasma iothalamate clearance, especially in larger patients. In the higher estimated GFR group (>30 ml/min/1.73 m(2)), the 5-h GFR was 17% higher and 2-h GFR 54% higher compared with the 10-h GFR, which averaged 40.3 ml/min/1.73 m(2). In the lower estimated GFR group (<30 ml/min/1.73 m(2)), the 5-h GFR was 36% higher and 2-h GFR 126% higher compared with the 10-h GFR, which averaged 22.2 ml/min/1.73 m(2). Short sampling duration also reduced the precision of the estimated GFR from 1.67% for 10-h GFR, to 3.48% for 5-h GFR, and to 7.07% for 2-h GFR.


CONCLUSIONS
GFR measured over a longer duration with multiple plasma samples spanning the distribution and elimination phases may improve precision and provide a better measure of renal function.
22176722
Alar web in cleft lip nose deformity: study in adult unilateral clefts.
BACKGROUND
The correction of alar webbing in unilateral cleft lip nose deformity is challenging because of progressive distortions in the alar web region during the period of growth. Alar webbing is a persistent universal deformity in both the primary and secondary cleft lip noses. The purpose of this article is to study the alar web deformity in adult patients with unilateral cleft lip noses.


METHODS
Twenty-five patients aged 13 years and older presenting with unilateral cleft nasal deformity were included. Preoperative and postoperative measurements of the nose, along with detailed intraoperative recording of the deformed anatomy, were done. Preoperative magnetic resonance imaging was also done in selected cases. Transcolumellar open rhinoplasty was performed in all the cases, and nasal septal straightening with centralization was done. Cleft alar base augmentation was done using bone graft to restore symmetry of the nasal tripod. Both the cleft and noncleft alar cartilages were extensively mobilized from the skin and mucosal sides. The overgrown and caudally slumped cleft-side alar cartilage was resected caudally and was then resuspended in a symmetrical position with the noncleft alar cartilage. A midline-strut septal cartilage extension graft was used to restore the tip aesthetics. The skin overlying the alar web was in-rolled after semilunar cartilage resection, and skin excision was also done to restore symmetry with the opposite vestibule. The remaining secondary cleft nasal and lip deformities were corrected depending upon the specific presenting pathologic abnormality.


RESULTS
The cleft alar cartilage was found to be caudally displaced in all the cases. The caudal border of the lateral crus was prolapsing in the cavity of the vestibule on the superomedial aspect and was tenting the skin in the area of the weak triangle, producing the characteristic alar web deformity. In the study group, the maximum width of the cleft alar cartilage at the level of the lateral crus was increased by approximately 4 mm when compared with the noncleft alar cartilage. The before- and after-rhinoplasty surgery results were objectively assessed using a patient, surgeon, and independent observer survey. The cosmetic result of the nasal tip complex was found to be very good and good (90%), satisfactory (5%), and poor (5%) in patients.


CONCLUSIONS
The alar web in unilateral cleft lip nose deformity is the result of caudal overgrowth and migration of the alar cartilage. The caudal edge of the prolapsed lateral crus overhangs the cleft-side nasal aperture on its superomedial aspect, producing this deformity. Satisfactory correction of this deformity should envisage caudal resection and repositioning of the dislocated alar cartilage along with caudal resection of the lateral crus with in-rolling of the skin after resection to achieve symmetric results in unilateral cleft lip rhinoplasty.
36005104
Volume Overload in Dialysis: The Elephant in the Room, No One Can See
interests of the authors. However, considering the totality of the evidence, I am less convinced that this marker is superior to other volume markers. First, there are few head-to-head studies comparing BIA to other established markers of volume. Second, there is no range that defines ‘normal’. Unlike blood pressure (BP) or cholesterol, there is no target that has been established. The normal values are obtained from healthy subjects whose body composition differs substantially from those on dialysis. Extrapolating from healthy subjects to those with ESRD on hemodialysis does not appear scientifically valid. Third, there is no study to my knowledge that demonstrates convincingly that compared to probing dry weight without BIA, BIA-guided dry weight reduction results in improved outcomes. Most data provided to support the use of BIA are associative and observational. A large amount of observational data does not prove causation. We therefore have to be cautious in interpreting these data as ‘strongly indicative of fluid overload’. Nearly all markers of volemia suffer from the same shortcomings. These shortcomings include lack of normative data, and data being largely observational and associative in nature. As an example, several observational studies suggest that B-type natriuretic peptide (BNP), NT-proBNP or other natriuretic peptides are associated with volume state among people with ESRD on dialysis [2–10] . However, only one study has been reported to date that relates the change in BNP to an intervention of probing dry weight [11] . In this study, a direct relationship existed at baseline between BNP and interdialytic ambulatory BP. Since interdialytic ambulatory BP is reVolume overload is the invisible threat to the health of dialysis patients. Currently, Medicare incentivizes the measurement of the dose of dialysis (urea reduction ratio) but has no measure of volume. Perhaps this is because the few who can recognize the epidemic nature of volume excess cannot agree on how to define it. Whereas, some have proposed interdialytic weight gain (IDWG) as a marker of volume, the in-depth review of Hecking et al. [1] quite clearly and importantly makes the distinction that IDWG should not be confused with hypervolemia. One has to wonder how IDWG got confused with dry weight in the first place. It appears that epidemiologists decided to use IDWG as a proxy of dry weight because of its ready availability in large databases. IDWG is a marker that is convenient; it can be measured easily and it can be related to outcomes such as all-cause mortality. This analysis was performed and a relationship emerged between IDWG and all-cause mortality. But establishing a relationship between IDWG and mortality does not establish causality. It could be numerous other factors, measured and unmeasured, associated with IDWG which may be causally related to mortality. Factors such as missing or cutting short dialysis, not taking medications as prescribed, and consuming a diet rich in phosphorus and potassium are some confounding factors that may also be associated with IDWG but may be more plausibly related to mortality. The authors discuss several markers of volume excess. Although several exist, one marker, bioimpedance analysis (BIA), is discussed in great detail. This is understandable given both the academic and intellectual property Published online: July 6, 2013 Nephrology American Journal of
11453581
Proinflammatory effects of oxidative stress in chronic kidney disease: role of additional angiotensin II blockade.
Oxidative stress plays an important role in causing progressive chronic kidney disease (CKD). We examined the influence of add-on ANG II receptor blockade administered as losartan (50 mg/day for 1 mo) on oxidative stress and proinflammatory state of the kidney in patients with CKD. All subjects were taking an angiotensin-converting enzyme inhibitor plus other antihypertensive agents. Oxidative stress to lipids and proteins was measured by an HPLC assay for malondialdehyde (MDA) and carbonyl concentration, respectively. Urinary inflammation was measured by monocyte chemotactic protein-1 (MCP-1) excretion rate. The etiology of CKD was type 2 diabetes mellitus in 12 and glomerulonephritis in 4 patients. There was no change in proteinuria or 24-h ambulatory blood pressure (BP) with add-on ANG II receptor blockade with losartan therapy. Before losartan therapy, urinary protein and albumin oxidation were 99 and 71% higher, respectively, compared with in plasma (P < 0.05). There was a 35% reduction in urinary oxidized albumin with add-on losartan therapy (P = 0.036). Urinary and plasma MDA were elevated compared with age-matched controls. Urinary MDA was significantly reduced from 4.75 +/- 3.23 to 3.39 +/- 2.17 micromol/g creatinine with add-on losartan therapy. However, plasma MDA or oxidized proteins did not change in response to additional ANG II blockade. A good correlation was seen between the change in urinary oxidized albumin and MCP-1 levels (r = 0.61, P = 0.012). These data demonstrate that oxidative damage to urinary protein and lipids can be reduced with additional ANG II receptor blockade, independently of reductions in proteinuria or BP. Urinary measurements of markers of oxidative damage to lipids and proteins appear to be more sensitive than plasma measurements in patients with CKD. The significant association of the change in urinary MCP-1 with a reduction in oxidative stress supports the role of the redox state in the kidney with renal fibrosis and progressive kidney damage.
30834959
Kava, a Tonic for Relieving the Irrational Development of Natural Preventive Agents
The last two decades have witnessed explosive growth in the study of natural and other cancer chemopreventive agents ([1][1], [2][2]). Extensive preclinical data have been generated for natural agents, and many (such as green tea, curcumin, phenyl isothiocyanate, indole-3-carbinol, silibinin,
18999099
Pathogenetic role of magnesium deficiency in ophthalmic diseases
Magnesium is one of the most important regulatory cation involved in several biological processes. It is important for maintaining the structural and functional integrity of several vital ocular tissues such as cornea, lens and retina. The magnesium content of lens, especially in its peripheral part, is higher than that in aqueous and vitreous humor. Magnesium has also been shown to play critically important role in retinal functions. Magnesium plays significant role as a cofactor for more than 350 enzymes in the body and regulates neuroexcitability and several ion channels. Membrane associated ATPase functions that are crucial in regulating the intracellular ionic environment, are magnesium-dependent. Moreover, the enzymes involved in ATP production and hydrolysis are also magnesium-dependent. Magnesium deficiency by interfering with ATPase functions causes increased intracellular calcium and sodium and decreases intracellular potassium concentration. Such ionic imbalances in turn alter the other cellular enzymatic reactions and form the basis of the association of magnesium deficiency with ophthalmic diseases such as cataract. In presence of magnesium deficiency, an imbalance between mediators of vasoconstriction and vasorelaxation may underlie the vasospasm, which is one of the pathogenic factors in primary open angle glaucoma. Furthermore, magnesium deficiency is also a contributing factor in increased oxidative stress and inducible NOS stimulation that can further contribute in the initiation and progression of ocular pathologies such as cataract, glaucoma and diabetic retinopathy. In this paper we review the association of disturbances of magnesium homeostasis with several ophthalmic diseases.
24077597
Allergic bronchopulmonary aspergillosis: review of literature and proposal of new diagnostic and classification criteria.
Allergic bronchopulmonary aspergillosis (ABPA) is an immunological pulmonary disorder caused by hypersensitivity to Aspergillus fumigatus, manifesting with poorly controlled asthma, recurrent pulmonary infiltrates and bronchiectasis. There are estimated to be in excess of four million patients affected world-wide. The importance of recognizing ABPA relates to the improvement of patient symptoms, and delay in development or prevention of bronchiectasis, one manifestation of permanent lung damage in ABPA. Environmental factors may not be the only pathogenetic factors because not all asthmatics develop ABPA despite being exposed to the same environment. Allergic bronchopulmonary aspergillosis is probably a polygenic disorder, which does not remit completely once expressed, although long-term remissions do occur. In a genetically predisposed individual, inhaled conidia of A. fumigatus germinate into hyphae with release of antigens that activate the innate and adaptive immune responses (Th2 CD4(+) T cell responses) of the lung. The International Society for Human and Animal Mycology (ISHAM) has constituted a working group on ABPA complicating asthma (www.abpaworkinggroup.org), which convened an international conference to summarize the current state of knowledge, and formulate consensus-based guidelines for diagnosis and therapy. New diagnosis and staging criteria for ABPA are proposed. Although a small number of randomized controlled trials have been conducted, long-term management remains poorly studied. Primary therapy consists of oral corticosteroids to control exacerbations, itraconazole as a steroid-sparing agent and optimized asthma therapy. Uncertainties surround the prevention and management of bronchiectasis, chronic pulmonary aspergillosis and aspergilloma as complications, concurrent rhinosinusitis and environmental control. There is need for new oral antifungal agents and immunomodulatory therapy.
25550116
Noninvasive estimation of clinically asymptomatic pulmonary hypertension in idiopathic pulmonary fibrosis.
OBJECTIVES
To determine the prevalence of pulmonary hypertension in patients with idiopathic pulmonary fibrosis (IPF) by noninvasive methods.


PATIENTS AND METHODS
Twenty seven patients with IPF attending the Chest Clinic over a period of one-and-a-half-years underwent echocardiography for evidence of pulmonary hypertension, which was defined as pulmonary artery systolic pressure > or = 40 mmHg by Doppler echocardiography, or pulmonary acceleration time < or = 100 milliseconds or two-dimensional echocardiographic findings of right ventricular hypertrophy or overload.


RESULTS
Two patients with clinical evidence of pulmonary hypertension were excluded from analysis. Their mean age (n = 25) was 53.8 years. The mean duration of symptoms before presentation was 2.1 years. Pulmonary hypertension was diagnosed by echocardiography in nine of the 25 patients (36%). There was a statistically significant difference between the duration of illness, arterial oxygen tension (PaO2) levels and forced vital capacity in patients with pulmonary hypertension than in those without pulmonary hypertension. Logistic regression analysis showed a significant association between the duration of illness, decreasing forced vital capacity and hypoxemia with the development of pulmonary hypertension.


CONCLUSIONS
Echocardiography detects pulmonary hypertension in clinically asymptomatic individuals, and should be used routinely for the diagnosis of pulmonary hypertension in patients with IPF.
6343189
Mechanisms of angiotensin converting enzyme inhibitor-induced IOP reduction in normotensive rats.
Angiotensin converting enzyme inhibitors (ACEIs) have been shown to lower intraocular pressure (IOP). Since, the ACEIs cause increased tissue prostaglandin levels, we hypothesized that the mechanisms of ACEI-induced IOP reduction have similarity with those of prostaglandin analogs. The present study investigated the involvement of matrix metalloproteinases (MMPs) and cytokine activity modulation as the underlying mechanisms of ACEI-induced ocular hypotension. The IOP lowering effect of single drop of enalaprilat dehydrate 1% was evaluated in rats pretreated with a broad spectrum MMP inhibitor or a cytokine inhibitor. Effect of angiotensin receptor blocker, losartan potassium 2%, was also studied to evaluate involvement of angiotensin II receptor type 1 (AT1) in IOP lowering effect of ACEI. Topical treatment with single drop of enalaprilat resulted in significant IOP reduction in treated eye with mean peak reduction 20.3% at 3h post-instillation. Treatment with losartan resulted in a peak IOP reduction of 13.3%, which was significantly lower than enalaprilat, indicating involvement of mechanisms in addition to AT1 blockade. Pretreatment with a broad spectrum MMP inhibitor or a cytokine inhibitor significantly attenuated the enalprilat-induced IOP reduction with mean peak IOP reduction of 11.2% and 13.6% respectively. The IOP-lowering effect of enalaprilat seems to be attributed to reduced angiotensin II type 1 receptor stimulation and modulation of MMP and cytokines activities.