Cognition, ocular accommodation, and cardiovascular function in emmetropes and late-onset myopes

PURPOSE. To investigate objectively and noninvasively the role of cognitive demand on autonomic control of systemic cardiovascular and ocular accommodative responses in emmetropes and myopes of late-onset. METHODS. Sixteen subjects (10 men, 6 women) aged between 18 and 34 years (mean ± SD: 22.6 ± 4.4 years), eight emmetropes (EMMs; mean spherical equivalent [MSE] refractive error ± SD: 0.05 ± 0.24 D) and eight with late-onset myopia (LOMs; MSE ± SD: -3.66 ± 2.31 D) participated in the study. Subjects viewed stationary numerical digits monocularly within a Badal optical system (at both 0.0 and -3.0 D) while performing a two-alternative, forced-choice paradigm that matched cognitive loading across subjects. Five individually matched cognitive levels of increasing difficulty were used in random order for each subject. Five 20-second, continuous-objective recordings of the accommodative response measured with an open-view infrared autorefractor were obtained for each cognitive level, whereas simultaneous measurement of heart rate was continuously recorded with a finger-mounted piezoelectric pulse transducer for 5 minutes. Fast Fourier transformation of cardiovascular function allowed the relative power of the autonomic components to be assessed in the frequency domain, whereas heart period gave an indication of the time-domain response. RESULTS. Increasing the cognitive demand led to a significant reduction in the accommodative response in all subjects (0.0 D: by -0.35 ± 0.33 D; -3.0 D: by -0.31 ± 0.40 D, P < 0.001). The greater lag of LOMs compared with EMMs was not significant (P = 0.07) at both distance (0.38 ± 0.35 D) and near (0.14 ± 0.42 D). Mean heart period reduced with increasing levels of workload (P < 0.0005). LOMs exhibited a relative elevation in sympathetic system activity compared to EMMs. Within refractive groups, however, accommodative shifts with increasing cognition correlated with parasympathetic activity (r = 0.99, P < 0.001), more than with sympathetic activity (r = 0.62, P > 0.05). CONCLUSIONS. In an equivalent workload paradigm, increasing cognitive demand caused a reduction in accommodative response that was attributable principally to a concurrent reduction in the relative power of the parasympathetic component of the autonomic nervous system (ANS). The disparity in accommodative response between EMMs and LOMs, however, appears to be augmented by changes in the sympathetic nervous component of the systemic ANS. Copyright © Association for Research in Vision and Ophthalmology.

Low protein diet fed exclusively during mouse oocyte maturation leads to behavioural and cardiovascular abnormalities in offspring

Early embryonic development is known to be susceptible to maternal undernutrition, leading to a disease-related postnatal phenotype. To determine whether this sensitivity extended into oocyte development, we examined the effect of maternal normal protein diet (18% casein; NPD) or isocaloric low protein diet (9% casein; LPD) restricted to one ovulatory cycle (3.5 days) prior to natural mating in female MF-1 mice. After mating, all females received NPD for the remainder of gestation and all offspring were litter size adjusted and fed standard chow. No difference in gestation length, litter size, sex ratio or postnatal growth was observed between treatments. Maternal LPD did, however, induce abnormal anxiety-related behaviour in open field activities in male and female offspring (P <0.05). Maternal LPD offspring also exhibited elevated systolic blood pressure (SBP) in males at 9 and 15 weeks and in both sexes at 21 weeks (P <0.05). Male LPD offspring hypertension was accompanied by attenuated arterial responsiveness in vitro to vasodilators acetylcholine and isoprenaline (P <0.05). LPD female offspring adult kidneys were also smaller, but had increased nephron numbers (P <0.05). Moreover, the relationship between SBP and kidney or heart size or nephron number was altered by diet treatment (P <0.05). These data demonstrate the sensitivity of mouse maturing oocytes in vivo to maternal protein undernutrition and identify both behavioural and cardiovascular postnatal outcomes, indicative of adult disease. These outcomes probably derive from a direct effect of protein restriction, although indirect stress mechanisms may also be contributory. Similar and distinct postnatal outcomes were observed here compared with maternal LPD treatment during post-fertilization preimplantation development which may reflect the relative contribution of the paternal genome. © Journal compilation © 2008 The Physiological Society.

Elevated serum free light chains predict cardiovascular events in type 2 diabetes

OBJECTIVE: Elevated polyclonal serum immunoglobulin free light chains (FLCs; combined FLCκ+FLCλ [cFLC]) are associated with adverse clinical outcomes and increased mortality; we investigated cFLC and cardiovascular disease (CVD) events in type 2 diabetes. RESEARCH DESIGN AND METHODS: In a cohort study of 352 south Asian patients with type 2 diabetes, serum cFLC, high-sensitivity C-reactive protein (hsCRP), and standard biochemistry were measured. CVD events over 2 years were recorded and assessed usingmultiple logistic regression. RESULTS: cFLC levels were elevated significantly in 29 of 352 (8%) patients with CVD events during 2 years of follow-up (50.7 vs. 42.8mg/L; P = 0.004). Inmultivariate analysis, elevated cFLC (>57.2 mg/L) was associated with CVD outcomes (odds ratio 3.3 [95% CI 1.3-8.2]; P = 0.012) and remained significant after adjusting for age, albumin-to-creatinine ratio, diabetes duration, or treatment. CONCLUSIONS: cFLC elevation is a novel marker for CVD outcomes in type 2 diabetes that warrants further investigation. © 2014 by the American Diabetes Association.

Angiotensin II induces soluble fms-Like tyrosine kinase-1 release via calcineurin signaling pathway in pregnancy

Maternal endothelial dysfunction in preeclampsia is associated with increased soluble fms-like tyrosine kinase-1 (sFlt-1), a circulating antagonist of vascular endothelial growth factor and placental growth factor. Angiotensin II (Ang II) is a potent vasoconstrictor that increases concomitant with sFlt-1 during pregnancy. Therefore, we speculated that Ang II may promote the expression of sFlt-1 in pregnancy. Here we report that infusion of Ang II significantly increases circulating levels of sFlt-1 in pregnant mice, thereby demonstrating that Ang II is a regulator of sFlt-1 secretion in vivo. Furthermore, Ang II stimulated sFlt-1 production in a dose- and time-dependent manner from human villous explants and cultured trophoblasts but not from endothelial cells, suggesting that trophoblasts are the primary source of sFlt-1 during pregnancy. As expected, Ang II-induced sFlt-1 secretion resulted in the inhibition of endothelial cell migration and in vitro tube formation. In vitro and in vivo studies with losartan, small interfering RNA specific for calcineurin and FK506 demonstrated that Ang II-mediated sFlt-1 release was via Ang II type 1 receptor activation and calcineurin signaling, respectively. These findings reveal a previously unrecognized regulatory role for Ang II on sFlt-1 expression in murine and human pregnancy and suggest that elevated sFlt-1 levels in preeclampsia may be caused by a dysregulation of the local renin/angiotensin system.

Moderate-intensity statin therapy seems ineffective in primary cardiovascular prevention in patients with type 2 diabetes complicated by nephropathy:a multicenter prospective 8 years follow up study

Background: Although numerous studies and metanalysis have shown the beneficial effect of statin therapy in CVD secondary prevention, there is still controversy such the use of statins for primary CVD prevention in patients with DM. The purpose of this study was to evaluate the occurrence of total major adverse cardio-vascular events (MACE) in a cohort of patients with type 2 diabetes complicated by nephropathy treated with statins, in order to verify real life effect of statin on CVD primary prevention. Methods: We conducted an observational prospective multicenter study on 564 patients with type 2 diabetic nephropathy free of cardiovascular disease attending 21 national outpatient diabetes clinics and followed them up for 8 years. 169 of them were treated with statins (group A) while 395 were not on statins (group B). Results: Notably, none of the patients was treated with a high-intensity statin therapy according to last ADA position statement. Total MACE occurred in 32 patients from group A and in 68 patients from group B. Fatal MACE occurred in 13 patients from group A and in 30 from group B; nonfatal MACE occurred in 19 patients from group A and in 38 patients from group B. The analysis of the Kaplan-Meier survival curves showed a not statistically significant difference in the incidence of total (p 0.758), fatal (p 0.474) and nonfatal (p 0.812) MACE between the two groups. HbA1c only showed a significant difference in the incidence of MACE between the two groups (HR 1.201, CI 1.041-1.387, p 0.012). Conclusions: These findings suggest that, in a real clinical setting, moderate-intensity statin treatment is ineffective in cardiovascular primary prevention for patients with diabetic nephropathy.

Ocular and systemic markers for vascular function in those at risk of type 2 diabetes mellitus and cardiovascular disease

The devastating impact of Type 2 Diabetes Mellitus (T2DM) -related morbidity and mortality on global healthcare is escalating with higher prevalences of obesity, poor diet, and sedentary lifestyles. Therefore, the clinical need for early diagnosis and prevention in groups of high-risk individuals is necessary. The purpose of this thesis was to investigate the use of surrogate markers, namely retinal vascular function, to determine future vascular endothelial dysfunction, atherosclerosis, large vessel disease and cardiovascular risk in certain groups. This namely covered normoglycaemic and normotensive South Asians (SAs), those with Impaired-Glucose Tolerance (IGT) and individuals with a familial history (FH) of T2DM. Additionally the effect of overweight and obesity was studied. The techniques and modified protocols adopted for this thesis involved the investigation of endothelial function by means of vascular reactivity at the ocular and systemic level. Furthermore, the relationships between retinal and systemic function with circulating markers for endothelial cell function and cardiovascular risk markers were explored. The principal studies and findings of the research were: Vascular Function in Normoglycaemic Individuals with and without a FH of T2DM WE FH individuals exhibited higher levels of total cholesterol levels that correlated well with the retinal arterial dilation amplitude to flicker light stimulus. However this did not extend to noticeable differences in markers for endothelial cell damage and impaired retinal and systemic function. Vascular Function in Normoglycaemic South-Asians vs. White-Europeans without a FH and Vascular Disturbances Compared to healthy WEs (normo -glycaemic and -tensive), SA participants exhibited levels of dyslipidaemia and a state of oxidative stress that extended to impaired vascular function as detected by reduced brachial artery flow-mediated dilation, slower retinal arterial vessel dilation reaction times (Appendix 3) and steeper constriction profiles. Furthermore, gender sub-group analysis presented in a sub-chapter shows that SA males demonstrated 24-hour systemic blood pressure (BP) and heart rate variability (HRV) abnormalities and heightened cardiovascular disease (CVD) risk. Vascular Function in Individuals Newly Diagnosed with IGT as compared to Normoglycaemic Healthy Controls Newly-diagnosed WE and SA IGT patients showed a greater risk for CVD and T2DM progression by means of 24-hour BP abnormalities, dyslipidaemia, increased carotid artery intimal-media thickness (c-IMT), Framingham scores and cholesterol ratios. Additionally, pre-clinical markers for oxidative stress and endothelial dysfunction, as evident by significantly lower levels of plasma glutathione and increased levels of von-Willebrand factor in IGT individuals, extended to impaired vascular systemic and retinal function compared to normal controls. This originally shows retinal, systemic and biochemical disturbances in newly-diagnosed IGT not previously reported before. Vascular Function in Normal, Overweight and Obese Individuals of SA and WE Ethnicity In addition to the intended study chapters, the thesis also investigated the influence of obesity and overweight on vascular function. Most importantly, it was found for the first time that compared to lean individuals it was overweight and not obese individuals that exhibited signs of vascular systemic and ocular dysfunction that was evident alongside markers of atherosclerosis, CVD risk and endothelial damage.

Individualized glycaemic targets and pharmacotherapy in type 2 diabetes

The Global Partnership for Effective Diabetes Management, established to provide practical guidance to improve patient outcomes in diabetes, has developed and modified recommendations to improve glycaemic control in type 2 diabetes. The Global Partnership advocates an individualized therapeutic approach and, as part of the process to customize therapy, has previously identified specific type 2 diabetes patient subgroups that require special consideration. This article builds on earlier publications, expanding the scope of practical guidance to include newly diagnosed individuals with complications and women with diabetes in pregnancy. Good glycaemic control remains the cornerstone of managing type 2 diabetes, and plays a vital role in preventing or delaying the onset and progression of diabetic complications. Individualizing therapeutic goals and treatments to meet glycaemic targets safely and without delay remains paramount, in addition to a wider programme of care to reduce cardiovascular risk factors and improve patient outcomes. © The Author(s) 2013.

Pregnancy complications in hyperemesis-affected pregnancy:a large hospital database study

Objective: Vomiting in pregnancy is a common condition affecting 80% of pregnant women. Hyperemesis is at one end of the spectrum, seen in 0.5–2% of the pregnant population. Known factors such as nulliparity, younger age and high body mass indexare associated with an increased risk of this condition in the first trimester. Late pregnancy complications attributable to hyperemesis, the pathogenesis of which is poorly understood, have not been studied in large population-based studies in the United Kingdom. The objective of this study was to determine a plausible association between hyperemesis and pregnancy complications,such as pregnancy-related hypertension, gestational diabetes and liver problems in pregnancy, and the rates of elective (ElCS) and emergency caesarean section (EmCS). Methods: Using a database based on ICD-10 classification, anonymised data of admissions to a large multi-ethnic hospital in Manchester, UK between 2000 and 2012 were examined.Notwithstanding the obvious limitations with hospital database-based research, this large volume of datasets allows powerful studies of disease trends and complications.Results Between 2000 and 2012, 156 507 women aged 45 or under were admitted to hospital. Of these, 1111 women were coded for hyperemesis (0.4%). A greater proportion of women with hyperemesis than without hyperemesis were coded forhypertensive disorders in pregnancy such as pregnancy-induced hypertension, pre-eclampsia and eclampsia (2.7% vs 1.5%;P=0.001). The proportion of gestational diabetes and liver disorders in pregnancy was similar for both groups (diabetes:0.5% vs. 0.4%; P=0.945, liver disorders: 0.2% vs. 0.1%;P=0.662). Hyperemesis patients had a higher proportion of elective and emergency caesarean sections compared with the non-hyperemesis group (ElCS: 3.3% vs. 2%; P=0.002, EmCS: 5% vs.3%; P=0.00). Conclusions: There was a higher rate of emergency and elective caesarean section in women with hyperemesis, which could reflect the higher prevalence of pregnancy-related hypertensive disorders(but not diabetes or liver disorders) in this group. The factors contributing to the higher prevalence of hypertensive disorders arenot known, but these findings lead us to question whether there is a similar pathogenesis in the development of both the conditions and hence whether further study in this area is warranted.