Maternal low-protein diet during mouse pre-implantation development induces vascular dysfunction and altered renin-angiotensin-system homeostasis in the offspring

Environmental perturbations during early mammalian development can affect aspects of offspring growth and cardiovascular health. We have demonstrated previously that maternal gestational dietary protein restriction in mice significantly elevated adult offspring systolic blood pressure. Therefore, the present study investigates the key mechanisms of blood pressure regulation in these mice. Following mating, female MF-1 mice were assigned to either a normal-protein diet (NPD; 18% casein) or an isocaloric low-protein diet throughout gestation (LPD; 9% casein), or fed the LPD exclusively during the pre-implantation period (3.5d) before returning to the NPD for the remainder of gestation (Emb-LPD). All offspring received standard chow. At 22 weeks, isolated mesenteric arteries from LPD and Emb-LPD males displayed significantly attenuated vasodilatation to isoprenaline (P=0.04 and P=0.025, respectively), when compared with NPD arteries. At 28 weeks, stereological analysis of glomerular number in female left kidneys revealed no significant difference between the groups. Real-time RT-PCR analysis of type 1a angiotensin II receptor, Na /K ATPase transporter subunits and glucocorticoid receptor expression in male and female left kidneys revealed no significant differences between the groups. LPD females displayed elevated serum angiotensin-converting enzyme (ACE) activity (P=0.044), whilst Emb-LPD males had elevated lung ACE activity (P=0.001), when compared with NPD offspring. These data demonstrate that elevated offspring systolic blood pressure following maternal gestational protein undernutrition is associated with impaired arterial vasodilatation in male offspring, elevated serum and lung ACE activity in female and male offspring, respectively, but kidney glomerular number in females and kidney gene expression in male and female offspring appear unaffected. © 2010 The Authors.

Randomised masked clinical trial of the MGDRx eyebag for the treatment of meibomian gland dysfunction-related evaporative dry eye

Background/aims To investigate the efficacy and safety of the MGDRx EyeBag (The Eyebag Company, Halifax, UK) eyelid warming device. Methods Twenty-five patients with confirmed meibomian gland dysfunction (MGD)-related evaporative dry eye were enrolled into a randomised, single masked, contralateral clinical trial. Test eyes received a heated device; control eyes a non-heated device for 5 min twice a day for 2 weeks. Efficacy (ocular symptomology, noninvasive break-up time, lipid layer thickness, osmolarity, meibomian gland dropout and function) and safety (visual acuity, corneal topography, conjunctival hyperaemia and staining) measurements were taken at baseline and follow-up. Subsequent patient device usage and ocular comfort was ascertained at 6 months. Results Differences between test and control eyes at baseline were not statistically signi ficant for all measurements ( p>0.05). After 2 weeks, statistically significant improvements occurred in all efficacy measurements in test eyes ( p<0.05). Visual acuity and corneal topography were unaffected (p>0.05). All patients maintained higher ocular comfort after 6 months ( p<0.05), although the bene fit was greater in those who continued usage 1-8 times a month (p<0.001). Conclusions The MGDRx EyeBag is a safe and effective device for the treatment of MGD-related evaporative dry eye. Subjective benefit lasts at least 6 months, aided by occasional retreatment. Trial registration number NCT01870180.

Cardiac dysfunction and cell damage across clinical stages of severity in growth-restricted fetuses

Objective - The purpose of this study was to assess cardiac function and cell damage in intrauterine growth-restricted (IUGR) fetuses across clinical Doppler stages of deterioration. Study Design - One hundred twenty appropriate-for-gestational-age and 81 IUGR fetuses were classified in stages 1/2/3 according umbilical artery present/absent/reversed end-diastolic blood flow, respectively. Cardiac function was assessed by modified-myocardial performance index, early-to-late diastolic filling ratios, cardiac output, and cord blood B-type natriuretic peptide; myocardial cell damage was assessed by heart fatty acid–binding protein, troponin-I, and high-sensitivity C-reactive protein. Results - Modified-myocardial performance index, blood B-type natriuretic peptide, and early-to-late diastolic filling ratios were increased in a stage-dependent manner in IUGR fetuses, compared with appropriate-for-gestational-age fetuses. Heart fatty acid–binding protein levels were higher in IUGR fetuses at stage 3, compared with control fetuses. Cardiac output, troponin-I, and high-sensitivity C-reactive protein did not increase in IUGR fetuses at any stage. Conclusion - IUGR fetuses showed signs of cardiac dysfunction from early stages. Cardiac dysfunction deteriorates further with the progression of fetal compromise, together with the appearance of biochemical signs of cell damage.

Microwave decontamination of eyelid warming devices for the treatment of meibomian gland dysfunction

PURPOSE: The role of bacteria in meibomian gland dysfunction is unclear, yet contamination of compresses used as treatment may exacerbate this condition. This study therefore determined the effect of heating on bacteria on two forms of compress. METHODS: Cotton flannels and MGDRx EyeBags (eyebags) were inoculated by adding experimental inoculum (Staphylococcus aureus, Streptococcus pyogenes, Pseudomonas aeruginosa; one species for each set of 3 eyebags and flannels). One of each were then randomised in to 3 groups: no heating (control); therapeutic (47.4±0.7°C); or sanitisation (68±1.1°C). After treatment, bacteria cell numbers were calculated. The experiment was repeated in triplicate. RESULTS: There was a statistically significant difference between each treatment with the eyebag for S. aureus (control=7.15±0.11logC/ml, therapeutic heating=5.24±0.59logC/ml, sanitisation heating=3.48±1.43logC/ml; P<0.001) and S. pyogenes (7.36±0.13, 5.73±0.26, 4.75±0.54; P<0.001). P. aeruginosa also showed a significant reduction (P<0.001) from control (6.39±0.34) to therapeutic (0.33±0.26) and sanitisation (0.33±0.21), but the latter were similar (P=1.000). For the flannels, there was significant difference between each treatment for S. aureus (6.89±0.46, 3.96±1.76, 0.42±0.90; P<0.001). For S. pyogenes, there was a significant reduction (P<0.001) from control (7.51±0.10) to therapeutic (5.91±0.62) and sanitisation (5.18±0.8), but the latter were similar (P=0.07). For P. aeruginosa, there was a significant difference (P<0.001) from control (7.15±0.36) to sanitisation (5.83±0.44); but not to therapeutic (6.84±0.31) temperatures (P=0.07). CONCLUSIONS: Therapeutic heating produces a significant reduction in bacteria on the eyebags, but only sanitisation heating appears effective for flannels. However, patients should be advised to heat the eyebag to sanitisation temperatures on initial use.

Endothelial NADPH oxidase-2 promotes interstitial cardiac fibrosis and diastolic dysfunction through proinflammatory effects and endothelial-mesenchymal transition

OBJECTIVES: This study sought to investigate the effect of endothelial dysfunction on the development of cardiac hypertrophy and fibrosis. BACKGROUND: Endothelial dysfunction accompanies cardiac hypertrophy and fibrosis, but its contribution to these conditions is unclear. Increased nicotinamide adenine dinucleotide phosphate oxidase-2 (NOX2) activation causes endothelial dysfunction. METHODS: Transgenic mice with endothelial-specific NOX2 overexpression (TG mice) and wild-type littermates received long-term angiotensin II (AngII) infusion (1.1 mg/kg/day, 2 weeks) to induce hypertrophy and fibrosis. RESULTS: TG mice had systolic hypertension and hypertrophy similar to those seen in wild-type mice but developed greater cardiac fibrosis and evidence of isolated left ventricular diastolic dysfunction (p < 0.05). TG myocardium had more inflammatory cells and VCAM-1-positive vessels than did wild-type myocardium after AngII treatment (both p < 0.05). TG microvascular endothelial cells (ECs) treated with AngII recruited 2-fold more leukocytes than did wild-type ECs in an in vitro adhesion assay (p < 0.05). However, inflammatory cell NOX2 per se was not essential for the profibrotic effects of AngII. TG showed a higher level of endothelial-mesenchymal transition (EMT) than did wild-type mice after AngII infusion. In cultured ECs treated with AngII, NOX2 enhanced EMT as assessed by the relative expression of fibroblast versus endothelial-specific markers. CONCLUSIONS: AngII-induced endothelial NOX2 activation has profound profibrotic effects in the heart in vivo that lead to a diastolic dysfunction phenotype. Endothelial NOX2 enhances EMT and has proinflammatory effects. This may be an important mechanism underlying cardiac fibrosis and diastolic dysfunction during increased renin-angiotensin activation.

Retinal vascular dysfunction relates to cognitive impairment in Alzheimer's disease

Cerebral vascular dysregulation has been increasingly implicated as a risk factor in the development of Alzheimer disease (AD)1; however, because of the difficulties associated with assessing and visualizing the cerebral vasculature directly, the ability to detect such dysregulation, noninvasively, is currently limited.2 Consequently, one concept that is being increasingly explored is the possibility of using the eye as a "window to the brain"; this approach has reasonable scientific validity as the retinal and brain vessels share a large number of embryological, anatomic, and functional similarities.2 Indeed, previous research has demonstrated a correlation between cognition and the geometry of the retinal vessels in elderly people.3 The aim of this pilot study, therefore, was to explore whether microvascular functional anomalies are evident at the retinal level in mild AD patients and to determine whether these anomalies relate to the degree of concurrent cognitive deficit..

The role of H2S bioavailability in endothelial dysfunction

Endothelial dysfunction (EDF) reflects pathophysiologicalchanges in the phenotype and functions of endothelial cells that result fromand/or contribute to a plethora of cardiovascular diseases. We review the roleof hydrogen sulfide (H2S) in the pathogenesis of EDF, one of thefastest advancing research topics. Conventionally treated as an environmentpollutant, H2S is also produced in endothelial cells and participatesin the fine regulation of endothelial integrity and functions. Disturbed H2Sbioavailability has been suggested to be a novel indicator of EDF progress andprognosis. EDF manifests in different forms in multiple pathologies, buttherapeutics aimed at remedying altered H2S bioavailability maybenefit all.

Retinal microvascular dysfunction occurs similarly in Alzheimer's disease and primary open angle glaucoma patients

Purpose: The exact nature of the relationship between Alzheimer’s disease (AD) and primary open angle glaucoma (POAG) is still the subject of debate. One factor attributed to the aetiology of both conditions is vascular dysfunction. This study aimed to investigate the similarities and differences in retinal microvascular function between mild AD patients, early stage POAG patients and healthy controls Methods: Retinal vessel reactivity to flickering light was assessed in 10 AD, 19 POAG and 22 healthy age matched control patients by means of dynamic retinal vessel analysis (DVA, IMEDOS, GmbH, Jena, Germany) according to an established protocol. All patients additionally underwent BP measurements and blood analysis for glucose and lipid metabolism markers Results: AD and POAG patients demonstrated comparable alterations in retinal artery reactivity, in the form of an increased arterial reaction time (RT) to flicker light on the final flicker cycle (p=0.014), which was not replicated in the healthy age and cardiovascular risk matched controls (p>0.05). Furthermore, the sequential changes in RT on progressing from flicker one to flicker three were found to differ between healthy controls and the two disease groups (p=0.001) Conclusions: AD and POAG patients demonstrate comparable signs of vascular dysfunction in their retinal arteries at the early stages of their disease process. These comparable signs may reflect similarities in the pathophysiological processes that occur in the development of both conditions

Overweight status is associated with extensive signs of microvascular dysfunction and cardiovascular risk

The aim of this present study was to investigate if overweight individuals exhibit signs of vascular dysfunction associated with a high risk for cardiovascular disease (CVD). One hundred lean and 100 overweight participants were recruited for the present study. Retinal microvascular function was assessed using the Dynamic Retinal Vessel Analyser (DVA), and systemic macrovascular function by means of flow-mediated dilation (FMD). Investigations also included body composition, carotid intimal-media thickness (c-IMT), ambulatory blood pressure monitoring (BP), fasting plasma glucose, triglycerides (TG), cholesterol levels (HDL-C and LDL-C), and plasma von Willebrand factor (vWF). Overweight individuals presented with higher right and left c-IMT (p = 0.005 and p = 0.002, respectively), average 24-h BP values (all p <0.001), plasma glucose (p = 0.008), TG (p = 0.003), TG: HDL-C ratio (p = 0.010), and vWF levels (p = 0.004). Moreover, overweight individuals showed lower retinal arterial microvascular dilation (p = 0.039) and baseline-corrected flicker (bFR) responses (p = 0.022), as well as, prolonged dilation reaction time (RT, p = 0.047). These observations emphasise the importance of vascular screening and consideration of preventive interventions to decrease vascular risk in all individuals with adiposity above normal range.