The role of the alternative pathway of complement activation in glomerular diseases

The complement system (CS) has recently been recognized as a bridge between innate and adaptive immunity that constitutes a very complex mechanism controlling the clearance of pathogens, cellular debris, and immune complexes. Out of three known pathways of complement activation, the alternative pathway (AP) plays a critical role in host defense by amplifying the complement response, independently of initiation pathway and continuously maintaining low-level activity in a process called ‘thick-over.’ A key molecule of the CS is C3, in which the AP is constantly activated. To prevent host cell destruction, a group of the AP regulators tightly controls this pathway of the CS activation. Acquired and genetic abnormalities of the CS may alter the delicate balance between enhancing and inhibiting the AP cascade. These can lead to the uncontrolled CS activation, inflammatory response, and subsequent tissue damage. Since complement components are locally produced and activated in the kidney, the abnormalities targeting the AP may cause glomerular injury. C3 glomerulopathy is a new entity, in which the AP dysregulation has been well established. However, recent studies indicate that the AP may also contribute to a wide range of kidney pathologies, including immune-complex-mediated glomerulonephritis (GN), pauci-immune GN, and primary membranous nephropathy (PMN). This article provides insight into current knowledge on the role of the AP in the pathogenesis of glomerular diseases, focusing mainly on various types of primary and secondary GN and PMN.     

Neuropeptide Y and Y2-receptor are involved in development of diabetic retinopathy and retinal neovascularization

BACKGROUND: Neuropeptide Y is a sympathetic neurotransmitter, a potent endothelium-derived angiogenic factor and a vascular mitogen. We have studied the role of the functional leucine7 to proline7 polymorphism of the signal peptide region of preproneuropeptide Y (prepro-NPY) as a genetic susceptibility factor for diabetic retinopathy. In addition, we investigated the role of the NPY Y2-receptor as a putative mediator of angiogenic NPY signaling in the retina. METHODS: Frequencies of proline7 (Pro7) carriers in the prepro-NPY were determined in type 1 and type 2 diabetes patients having retinopathy, in type 2 diabetes patients without retinopathy and in healthy control subjects. The role of Y2-receptor in hyperoxemia-induced retinal neovascularization was investigated in Y2-receptor knockout mice (Y2-/-) and in rats administered Y2-receptor mRNA antisense oligonucleotide. RESULTS: The carriers having Pro7 in the preproNPY are markedly over-represented among type 2 diabetes patients with retinopathy compared to type 2 diabetes patients without retinopathy and to the population control. Neonatal exposure to hyperoxia resulted in development of retinal neovascularization that was prevented in Y2(-1-) -mice, and significantly inhibited in rats treated with the Y2-receptor antisense oligonucleotide. CONCLUSIONS: NPY and Y2-receptor play important roles in diabetic retinopathy and retinal neovascularization and are thus potential new targets for drug molecules for treatment of retinopathy.     

Asymptomatic visual field disturbances in multiple sclerosis patients without a history of optic neuritis

BACKGROUND AND PURPOSE: The aim of our study was to evaluate visual field in patients with multiple sclerosis without a history of optic neuritis. We assessed presence and localisation of visual field defects and evaluated correlation between visual field disturbances and patient's neurological status. MATERIAL AND METHODS: A group of 52 patients with multiple sclerosis and 17 healthy persons who served as the control group were enrolled into the study. The patients went through a routine neurological examination, ophthalmologic check-up and perimetric visual field assessment. Visual fields were examined with static perimetry Medmont M700. In all of the patients, results of perimetry were evaluated according to localisation of lesions. A decibel scale was used to quantitatively assess disturbances in patient's visual field. RESULTS: We found that "asymptomatic" visual field disturbances were present in a large number (38, 73.1%) of multiple sclerosis patients. Among these patients, we diagnosed concentric visual field lesions in 46.2%, and we recognized disturbances in the upper part of the visual field in 26.9%. There was a correlation between the presence of those visual field lesions, duration of multiple sclerosis, and the degree of patients' disability. CONCLUSIONS: Asymptomatic visual field disturbances occur frequently in MS patients (despite no history of retrobulbar optic neuritis). Static perimetry may be a valuable, complementary method in addition to examinations used so far in the diagnosis of multiple sclerosis.     

Visuomotor system uses target features unavailable to conscious awareness

After lesions to primary visual cortex, patients lack conscious awareness of visual stimuli. Interestingly, however, some retain the ability to make accurate judgments about the visual world (i.e., so-called blindsight). Similarly, damage to inferior occipitotemporal regions of cortex (e.g., lateral occipital cortex) can result in an inability to perceive object properties while retaining the ability to act on them (i.e., visual form agnosia). In the present work, we demonstrate that the ability to interact with objects in the absence of conscious awareness is not isolated to those with restricted neuropathologic conditions. Specifically, neurologically intact individuals are able to program and execute goal-directed reaching movements to a target object without awareness of extrinsic target properties; they accurately tune the dynamics of their movement and modulate it online without conscious access to features of the goal object. Thus, the planning and execution of actions are not dependent on conscious awareness of the environment, suggesting that the phenomenon of blindsight (and agnosia) reflect normal conditions of the visual system.     

Dynamic cerebral autoregulation: should intracranial pressure be taken into account?

Summary Background. Although the inclusion of cerebral perfusion pressure (CPP) is a standard feature in static testing of autoregulation after head injury, controversy surrounds the use of CPP versus arterial blood pressure (ABP) in dynamic tests. The aim of our project was to assess the discrepancies between methods of dynamic autoregulation testing based on CPP or ABP, and study possible differences in their prognostic value. Method. Intermittent recordings of intracranial pressure (ICP), ABP and middle cerebral artery blood flow velocity (FV) waveforms were made in 151 anaesthetised and ventilated adult head injured patients as part of their required care. Indices of dynamic autoregulation were calculated as a moving correlation coefficient of 60 samples (total time 3 min) of 6 s mean values of FV and ABP (Mxa) or FV and CPP (Mx). Values of Mx and Mxa were averaged over multiple recordings in each patient and correlated with outcome at 6 months post injury. Findings. Association between Mx and Mxa was moderately strong (r ² = 0.73). However, limit of 95% accordance between both indices was ±0.32. Mxa was significantly greater than Mx (0.22 ± 0.22 versus 0.062 ± 0.28; p < 0.000001). The difference between Mx and Mxa decreased with impairment of autoregulation (r = −0.39; p < 0.000001). Mean value of Mx showed a significant difference between dichotomized outcome groups (better autoregulation in patients with favourable than unfavourable outcome), while Mxa did not. Conclusions. Although relatively similar in a large group of patients, the differences between these two methods of assessment of dynamic autoregulation may be considerable in individual cases. When ICP is monitored, CPP rather than ABP should be included in the calculation of the autoregulatory index.