23113580
Future Target Molecules in Antiglaucoma Therapy: TGF-β May Have a Role to Play
Glaucoma, a leading cause of irreversible blindness, is often associated with increased resistance to aqueous outflow in trabecular tissue. Increased outflow resistance has been attributed to increased extracellular matrix (ECM) deposition in trabecular tissue. A critical balance between the synthesis and breakdown of the components of extracellular tissue is important in keeping the intraocular pressure within the normal range. Multiple mechanisms have been shown to affect ECM turnover in trabecular tissue. In this review, we examine the related literature to understand the role of TGF-β in ECM turnover, in the development and progression of glaucoma, and in possible therapeutic strategies that can be devised by targeting the TGF-β signaling pathways.
15667066
Oculohypotensive effects of foeniculum vulgare in experimental models of glaucoma.
PURPOSE
Evaluation of oculohypotensive activity of single drop application of aqueous extract of Foeniculum vulgare in experimental models of glaucoma.


METHODS
The evaluation of oculohypotensive activity of Foeniculum vulgare was done in rabbits with normal intraocular pressure (IOP) and with experimentally elevated IOP. The experimental increase in IOP was achieved using water loading and steroid induced glaucoma models.


RESULTS
The aqueous seed extract of Foeniculum vulgare exhibited 17.49, 21.16 and 22.03% reduction of intraocular pressure (IOP) in normotensive rabbits at 0.3%, 0.6% and 1.2% (w/v) concentrations respectively. The 0.6% concentration was further evaluated in acute and chronic models of glaucoma. A maximum mean difference of 31.20% was observed between vehicle treated and extract treated eyes in water loading model while a maximum mean IOP lowering of 31.29% was observed in steroid induced model of glaucoma.


CONCLUSIONS
The aqueous extract of Foeniculum vulgare possesses significant oculohypotensive activity, which was found to be comparable to that of timolol. Further investigations into the mechanism of action, possible toxicity and human clinical trials are warranted before the Foeniculum vulgare finds place in the arsenal of antiglaucoma drugs prescribed by physicians.
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.
11594402
Intraocular Pressure-Lowering Activity of Topical Application of Aegle Marmelos Fruit Extract in Experimental Animal Models
Aim: The present study was designed to evaluate the intraocular pressure (IOP)-lowering activity of topical application of the aqueous extract of Aegle marmelos fruit in experimental animal models. Materials and Methods: New Zealand white rabbits with normal and experimentally elevated IOP using water loading and steroid-induced models were included in this study. The IOP-lowering effect of A. marmelos fruit extract in rabbits with experimentally elevated IOP was also compared with that of timolol 0.25%. Results: In rabbits with normal IOP, the A. marmelos fruit extract at a concentration of 1% showed the maximum IOP-lowering effect with 22.81% reduction from baseline IOP. The maximum IOP reduction achieved in water loading and steroid-induced models with the same concentration of A. marmelos was 27.57 and 28.41% from baseline, respectively. The efficacy was comparable to that of timolol after 45 min of water loading in the water loading model, and during the first 2 h of treatment in the steroid-induced model. Conclusion: A. marmelos fruit extract showed significant IOP-lowering activity in experimental animal models.
7910812
Hypertension, hypokalemia, and thiazide-induced diabetes: a 3-way connection.
Reduction in the dose of diuretics to treat essential hypertension occurred with the recognition that higher doses of thiazides cause hypokalemia, glucose intolerance, and hyperuricemia but little additional reduction in blood pressure.1 Subsequently, large randomized, controlled trials have demonstrated a higher incidence of diabetes mellitus with thiazide diuretics compared with other antihypertensive drugs.2 A meta-analysis done with 143153 participants without diabetes mellitus in 22 clinical trials showed that thiazide diuretics and β-blockers had similarly high risks of developing new-onset diabetes mellitus, followed by placebo and calcium channel blockers; the most protective were angiotensin II receptor blockers and angiotensin-converting enzyme inhibitors.3 This detrimental effect on glucose tolerance together with the growing epidemic of diabetes and obesity has reined in the wider use of thiazides despite being effective and inexpensive antihypertensive drugs with strong cardiovascular benefits.

Whether thiazide-induced diabetes mellitus has the same adverse prognostic significance as spontaneously occurring diabetes mellitus is not known with certainty.2 If thiazide diuretics unmask the presence of underlying diabetes mellitus, then the earlier detection of diabetes with more aggressive hypertension, lipid, and metabolic control may in fact, instead of being harmful, be protective. There is also some evidence that, although new-onset diabetes mellitus is associated with cardiovascular mortality, treatment of such patients with diuretics has survival benefits. In a long-term analysis of the Systolic Hypertension in Elderly Program with a mean follow-up of 14.3 years, the long-term fatality rate was higher in those with had diabetes mellitus at baseline, followed by patients who developed diabetes during follow-up.4 However, diabetes mellitus …
3038618
Is the mortality higher in the pulmonary vs the extrapulmonary ARDS? A meta analysis.
BACKGROUND AND AIM
ARDS can occur from the following two pathogenetic pathways: a direct pulmonary injury (ARDSp); and an indirect injury (ARDSexp). The predisposing clinical factor can influence the pathogenesis and clinical outcome of ARDS. This metaanalysis was aimed at evaluating whether there is any difference in mortality between the two groups.


METHODS
We searched the MEDLINE, EMBASE, and CINAHL databases for relevant studies published from 1987 to 2007, and included studies that have reported mortality in the two groups of ARDS. We calculated the odds ratio (OR) and 95% confidence interval (CI) to assess mortality in patients with ARDSp vs patients with ARDSexp and pooled the results using three different statistical models.


RESULTS
Our search yielded 34 studies. In all, the studies involved 4,311 patients with 2,330 patients in the ARDSp group and 1,981 patients in the ARDSexp group. The OR of mortality in ARDSp group compared to the ARDSexp group was 1.11 (95% CI, 0.88 to 1.39), as determined by the random-effects model; 1.04 (95% CI, 0.92 to 1.18), as determined by the fixed-effects model; and 1.04 (95% CI, 0.92 to 1.18), as determined by the exact method, indicating that mortality is similar in the two groups. The mortality was no different whether the studies were classified as prospective (OR, 1.15; 95% CI, 0.87 to 1.51) or retrospective (OR, 1.01; 95% CI, 0.61 to 1.69); small (OR, 1.11; 95% CI, 0.77 to 1.60) or large (OR, 1.1; 95% CI, 0.82 to 1.49); or observational (OR, 1.10; 95% CI, 0.82 to 1.49) or interventional (OR, 0.97; 95% CI, 0.79 to 1.19). There was methodological and statistical heterogeneity (I(2), 50.9%; 95% CI, 21.3 to 66.2%; chi(2) statistic, 67.22; p = 0.0004).


CONCLUSIONS
The results of this study suggest that there is no difference in mortality between these two groups. Further studies should focus on specific etiologies within the subgroups rather than focusing on the broader division of ARDSp and ARDSexp.
25760349
Antihypertensive agents and arterial stiffness: relevance to reducing cardiovascular risk in the chronic kidney disease patient.
PURPOSE OF REVIEW
Arterial stiffness is a sign of diffuse adventitial macrovascular disease. The purpose of the present review is to discuss, in patients with chronic kidney disease, the pathophysiology of increased arterial stiffness, the role of antihypertensive therapy on reduction of arterial stiffness, and the clinical ways by which the prognostication of cardiovascular disease in patients with chronic kidney disease can be refined using arterial stiffness monitoring.


RECENT FINDINGS
Arterial stiffness is increased with increasing prevalence of traditional cardiovascular risk factors. In patients with chronic kidney disease some unique factors further increase the risk of arterial stiffness, and include volume overload, activation of the renin-angiotensin system, anemia, and dysregulated mineral metabolism. Arterial stiffness is increased even in patients with early-stage chronic kidney disease. Blood pressure reduction when accompanied by a reduction in arterial stiffness is associated with improved prognosis. Angiotensin-converting enzyme inhibitors and angiotensin receptor blockers can preferentially improve arterial stiffness, which may be an additional mechanism of cardiovascular protection with these agents.


SUMMARY
The impact of improvement in arterial stiffness with antihypertensive agents on cardiovascular outcomes needs well designed clinical trials.
29270168
Circadian Blood Pressure Classification Scheme and the Health of Patients with Chronic Kidney Disease
Background: In health, a sinusoidal rhythm is observed in systolic blood pressure (BP) that peaks (acrophase) during the waking hours (in-phase), but in those with chronic kidney disease (CKD) the acrophase is often observed during sleeping hours (out-of-phase). Yet in others the amplitude of the variation may be so blunted that acrophase may not be definable (phase-less). Circadian rhythms in systolic BP are often described by the dichotomous dipper classification but may not be adequate to fully characterize derangements in cyclical variation in BP. Methods: To compare classification of circadian BP variation by phase-based classification to dipper-status we examined the cross-sectional relationship of these classification patterns to several markers of health such as health-related quality of life (Kidney Disease Quality of Life Survey, KDQOL) and physical activity (actigraphy over 2 weeks). We also assessed the relationship of circadian BP variation with circadian variation in urine electrolyte and albumin excretion rates. Results: Among 103 veterans with CKD (97% men, age 69, diabetes mellitus 30%, eGFR 38.8 ml/min/1.73 m2) no differences were seen between dippers and non-dippers (n = 77, 75%) in eGFR, urinary Na and Cl excretion rates, or KDQOL. However, non-dippers had lower levels of physical activity and greater albuminuria compared to dippers. The same patients were classified to be in-phase (n = 36, 35%), phase-less (n = 19, 18%) or out-of-phase (n = 48, 47%). Patients in-phase had a higher eGFR and somewhat surprisingly also had the highest Na and Cl excretion rates compared to others. Those with out-of-phase systolic BP had the lowest physical composite score on KDQOL, the lowest level of physical activity, and the greatest amount of albuminuria. Conclusions: Among patients with CKD, circadian BP profile described by either dipper-based or phase-based classification is related to the level of physical activity and the severity of kidney damage. The circadian BP profile is related to overall health and nutritional intake only when using the phase-based classification. The value of these classification schemes to profile circadian BP will require longitudinal studies.
20628925
Chronic kidney disease is associated with oxidative stress independent of hypertension.
BACKGROUND
Oxidative stress is implicated in the pathogenesis of chronic kidney disease (CKD) and essential hypertension (EHTN). However, the role of hypertension in causing increased oxidative stress in patients with CKD is unknown.


METHODS
We performed a case control study in patients with EHTN and those with equal blood pressure assessed by ambulatory blood pressure monitoring but with concomitant CKD. Those with diabetes mellitus and those taking renin angiotensin inhibitors were excluded. Biomarkers of oxidative stress, malondialdehyde (MDA) and protein carbonylation and total glutathione levels were measured.


RESULTS
Average (SD) 24-hour ambulatory blood pressure in 12 patients with CKD was 134 (17)/75 (16) compared to 134 (10)/80 (9) in 11 patients with EHTN (p = NS). Plasma MDA in CKD was 0.89 +/- 0.38 micromol/l compared to 0.68 +/- 0.16 micromol/l in EHTN (p = 0.07). Urinary MDA/creatinine ratio was 1.78 (0.31) in CKD vs 1.43 (0.69) micromol/g in those with EHTN (p = 0.04). Thus, lipid peroxidation was increased in urine of CKD patients. Patients with CKD had higher (1.04 (0.20) nmol) carbonyl/mg protein compared to those with EHTN (0.80 (0.21) nmol carbonyl/mg protein) (p = 0.03). Thus, protein carbonylation was increased in CKD patients. Total glutathione in CKD and EHTN patients was 6.6 (1.8) ng/ml and 7.3 (3.1) ng/ml (p = NS). There was a good correlation between biomarkers of lipid (MDA) and protein oxidation (protein carbonyls) (r = 0.6, p = 0.004).


CONCLUSIONS
Biomarkers of lipid and protein oxidation are higher in patients with CKD compared to EHTN despite similar blood pressure. Thus, nonhemodynamic factors such as inflammation and altered cellular redox state may play a greater role in the generation of oxidative stress in CKD.