Age‐related macular degeneration and functional promoter and coding variants of the apolipoprotein E gene

Age‐related macular degeneration (AMD) is a frequent, multifactorial disease of the central retina and a major cause of irreversible vision loss in industrialized countries. Apolipoprotein E (APOE) has been consistently associated with AMD, particularly its two functional isoforms E2 (predisposing) and E4 (protective). The biological correlate of this association, however, is still unclear. In this study, we have defined an extended haplotype block encompassing the entire APOE gene locus, including known coding as well as cis‐regulatory promoter variants. Of the five extended APOE haplotypes common in the general population, two were found to be significantly associated with AMD, namely G‐G‐G‐G‐ε2 (odds ratio [OR], 1.59; 95% confidence interval [CI], 1.19–2.12) and T‐G‐A‐G‐ε4 (OR, 0.76; 95% CI, 0.58–0.99). When analyzing common extended haplotype combinations, T‐C‐G‐G‐ε3/T‐G‐A‐G‐ε4 exhibited the most prominent effect (OR, 0.32; 95% CI, 0.20–0.51). Intriguingly, we also found one extended ε3‐haplotype, G‐G‐G‐A‐ε3, to be protective in the homozygous state (OR, 0.65; 95% CI, 0.49–0.87). Since single nucleotide polymorphism (SNP) rs405509:G>T is a constituent of the extended ε‐haplotype block and is known to significantly influence APOE promoter activity, we hypothesize that both the relative rate of APOE isoform expression in conjunction with established functional differences of the respective isoforms may be crucial in mediating AMD pathology. This would also imply that genotyping of the core ε‐haplotypes alone is not sufficient to estimate AMD risk, but that determination of extended haplotype combinations, including the functional promoter SNP rs405509, is required instead. Hum Mutat 0:1–6, 2009. © 2009 Wiley‐Liss, Inc.     

Kidney fusion anomalies revisited: clinical and radiological analysis of 209 cases of crossed fused ectopia and horseshoe kidney

OBJECTIVE

To analyse the morphological appearance of horseshoe kidneys (HKs) and crossed fused ectopia (CFE) and to assess the frequency and clinical significance of associated anomalies and diseases.

PATIENTS AND METHODS

The findings and images of 209 patients with fused kidneys (FKs) were reviewed; in all, 244 scans from computed tomography (CT), 233 ultrasonograms and 89 micturition cysto‐urethrograms, urograms, magnetic resonance images and angiograms were taken.

RESULTS

HKs (found in one of 474 abdominal CT scans) and CFEs (found in one of 3078 CT scans) showed a high variability of vasculature that could not be classified. However, some generalized conclusions were possible about the renal vasculature (430 arteries in 103 kidneys). Variants of the most cephalad artery of both sides were rare. The second artery on the right had a pre‐caval course. The origins of vessels located further caudal were more ventral. CFEs were anatomically different from HKs with respect to lower position, greater axial rotation, smaller pelvic width, more caudal origin, and fewer vessels, but not in accompanying anomalies. Severe anomalies or malformations were found in 23% of patients, with half of them in the urogenital system. Malformations were found considerably more often in children than in adults. There was no increased incidence of diseases such as stones or inflammation of the renal pelvis.

CONCLUSION

Concomitant anomalies and diseases were equally frequent for HK and CFE, but less frequent than generally assumed. Individual cases of complex anatomical situations require special examination strategies, and CT appears to be the most reliable imaging method.     

Inhibition of prolyl 4-hydroxylase prevents left ventricular remodelling in rats with thoracic aortic banding

BACKGROUND: Pressure overload leads to myocardial remodelling with collagen accumulation, left ventricular hypertrophy (LVH), neurohormonal activation and myocardial dysfunction. Prolyl 4-hydroxylases (P4H) are involved in collagen maturation. Inhibition of P4H has been shown to prevent LV remodelling and improve survival post-myocardial infarction. AIM: To evaluate the role of P4H in pressure overload-induced myocardial remodelling. METHODS: Male Wistar rats underwent thoracic aortic banding (AoB) and were treated with a P4H inhibitor (P4HI) or vehicle (control). Echocardiography and haemodynamic measurements were performed after 4 weeks. Collagens, matrix metalloproteinases (MMP), tissue inhibitors of MMPs (TIMP), growth factors and neurohormonal markers were quantitated in LV samples. RESULTS: AoB led to LVH, increased LV enddiastolic pressure (LVEDP) and decreased contractility compared to sham. P4HI reversed these effects. AoB increased collagen I and III expression, which was normalized by P4HI. AoB led to deregulation of matrix remodelling enzymes, enhanced expression of growth factors and activation of the endothelin system. P4HI partially prevented deregulation of the MMP/TIMP system, inhibited upregulation of growth factors and normalized AoB-induced ECE-1 and ETB expression. CONCLUSIONS: P4HI leads to an improvement of AoB-associated LV dysfunction and reduces imbalance of extracellular matrix turnover and hypertrophy-associated gene expression. P4H inhibition could therefore be of value in treatment of myocardial remodelling accompanying pressure overload hypertrophy.     

Activation-flow coupling differentiates between vascular and Alzheimer type of dementia

The activation-flow coupling describes a mechanism, which adapts local cerebral blood flow in accordance with the underlying neuronal activity. It was suggested that the mechanism helps in differentiation between Alzheimer and vascular type of dementia. We combined EEG and Doppler techniques and assessed integrity of the activation-flow coupling in the occipital cortex utilizing a visual stimulation task. Alzheimer patients (MMSE: 18+/-8 points, DemTect 5+/-4 points) without signs of vascular lesions on a MRI scan and vascular demented patients (MMSE: 20+/-6 points, DemTect 6+/-3 points; MRI Fazekas score 7+/-3 points) were compared with data from an age-matched control group. Evoked flow velocity responses in the posterior cerebral artery were analysed according to a control system model specifying the parameters gain, attenuation, natural frequency and rate time. Evoked potentials were analysed for the N(75)-P(100) amplitude difference. Vascular demented patients exhibited a significant decreased gain parameter and increased attenuation parameter indicating severe cerebrovascular dysfunction. Also, the potential amplitudes were significantly decreased indicating neuronal damage due to the vascular disease process. Alzheimer patients did not differ in parameters as compared to the control group supporting other reports of intact occipital function at this stage of disease. Simultaneous assessment of electrical as well as vascular integrity might help in differentiating the most frequent forms of dementia.     

Spontaneous eyeblink rate predicts the strength of visuomotor binding

The primate cortex represents the external world in a distributed way, which requires for a mechanism that integrates the features of a processed event. Animal and patients studies suggest that feature binding in the visual cortex is under muscarinic-cholinergic control, whereas visuomotor integration is driven by the dopaminergic system. Consistent with this picture, we present evidence that the binding of visual and action features is modulated by spontaneous eyeblink rate (EBR), which is a functional marker of central dopaminergic function. Remarkably, the impact of EBR was restricted to the task-relevant visuomotor binding, suggesting that dopamine increased the maintenance of task-relevant information.