Spatial memory deficits are a common hallmark of psychiatric conditions, possibly due to a genetic predisposition. Thus, unravelling the relationship between genes and memory might suggest novel ...therapeutic targets and pathogenetic pathways. Genetic deletions are known to lead to memory deficits (post-deletion “forgetfulness” genes, PDF), or, in few instances to improve spatial memory (post-deletion “hypermnesic” genes, PDH). To assess this topic, we performed a meta-analytic approach on memory behavior in knock-out mice. We screened 300 studies from PubMed and retrieved 87 genes tested for possible effects on spatial memory. This database was crossed with the Allen Brain Atlas (brain distribution) and the Enrichr (gene function) databases. The results show that PDF genes have higher expression level in several ventral brain structures, particularly the encephalic trunk and in the hypothalamus. Moreover, part of these genes are implicated in synaptic functions. Conversely, the PDH genes are associated to G-protein coupled receptors downstream signalling. Some candidate drugs were also found to interfere with some of the PDH genes, further suggesting that this approach might help in identifying drugs to improve memory performance in psychiatric conditions.
•Few genes improve memory performance when deleted (post-deletion ‘hypermnesic’ genes, PDH).•The PDH genes are largely distributed in the brain and in part belong to the family of G-protein coupled receptors.•A larger number of genes lead to memory defects when deleted (post-deletion ‘forgetfulness’ genes).•The PDF genes are mostly enriched in the hypothalamus and encephalic trunk, which might play a role in genetic forms of memory derangements.
Abstract Introduction Few data exist regarding the outcome and survivorship of medial UKA in patients with minor varus alignment. The purpose of this study was therefore to analyse the clinical ...results of medial UKA implanted with no more than 7° of varus, and to verify whether there was a relationship between limb alignment and overall outcomes. Material and methods One hundred and twenty five medial fixed-bearing UKAs with no more than 7° of varus were retrospectively analysed. The varus/valgus inclination and thickness of the bone cuts were performed relating to the proximal tibial epiphyseal axis. Patients were assessed with the IKS scores and range of knee motion. The subjects were classified into three groups according to the postoperative femoro-tibial mechanical alignment angle (group A: − 2° to 1°; group B: 2° to 4°; group C: 5° to 7°). Results The mean follow-up was 7.6 years (range, 3.5–9.3). IKS knee scores increased proportionally with increasing varus according to a linear relationship ( p ≪ 0.01). Additionally, IKS knee scores were significantly higher in group B and still higher in group C if compared to those in group A ( p = 0.003). Finally, a significantly higher frequency of IKS function scores > 90 points in subjects with femoro-tibial mechanical alignment angle ≥ 4° was found ( p = 0.009). Conclusions Minor varus alignment does not compromise the mid- to long-term outcome of a medial UKA, and gives better results compared to neutral or close-to-neutral alignment. Level of evidence IV — Retrospective case series study.
Abstract Background and Aims Gliflozins are a class drugs widely used in diabetes as they act as sodium-glucose co-transporter type 2 inhibitors (SGLT2i). Irrespective from glycaemic control, SGLT2i ...are known to possess kidney and heart protective effects. The kidney- and heart-protective effects of gliflozins (SGLT2i) have received different explanations because of their efficacy in non-diabetic patients. Indeed, the non-glycemic effects of SGLT2i are puzzling because SGLT2, the molecular target of gliflozins, is mainly expressed in proximal tubule cells, with very low expression levels in other cell types. Though SGLT2 inhibitors might be nephroprotective because of a reduction of eGFR, this mechanism seems insufficient to explain heart protection. Emerging evidence suggests that SGLT2i have off-target effects in endothelial cells. In this study, we analyze this assumption by testing the effects of gliflozins on endothelial cells in vitro and verifying a differential effect of gliflozins on glomerular diseases involving primarily the endothelial compartment vs those involving podocytes or both. Methods In vitro studies have been conducted on EA.hy926 cells. A dose-response curve of gliflozins on mitochondrial activity and cell viability has been obtained using MTT staining. Morphological parameters were obtained using phase contrast microscopy, and the details of the plasma membranes were studied using Atomic Force microscopy. Patients with IgA nephropathy, minimal change disease or Focal Segmental Glomerulo Sclerosis FSGS, and with diabetic nephropathy (n = 12 per group). were studied for the percent change in albuminuria and creatinine four months after gliflozin treatment (empagliflozin or dapagliflozin). Three additional control groups (IgA, podocytopathies, diabetes) without gliflozin treatment (n = 12 per group) were also included. Results Gliflozin treatment induced a dose-response improvement in EA.hy926 cells' survival and restoration of cell-cell borders in AFM images. In patients, the albuminuria was reduced by a similar extent (−38 ± 6%) in all groups when treated with gliflozins. However, in diabetic patients and podocytopathies, this was associated with decreased eGFR (−6% and −8%), whereas in IgA nephropathy, the eGFR levels were increased after treatment (+3.8%). Conclusion In vitro, gliflozins show a direct endothelial protection effect. In vivo, part of the effects on proteinuria may be explained by a hemodynamic effect on the glomerular filtration rate in diseases affecting podocytes (diabetes, MCD, FSGS), as shown by the increase in creatinine. However, for diseases involving the endothelium (IgA nephropathy), the endothelial protection effect of gliflozins is demonstrated by the reduction in proteinuria and the protective effect on creatinine levels.
Abstract
Background and Aims
Chronic kidney disease (CKD) is a systemic condition because it modifies all organs' function due to an imbalance in plasma volume, electrolytes, hormones, and proteins.
...Indeed, at the nervous system level, mild cognitive impairment (MCI), sleep disorders and depression often accompany CKD. MCI partially explains the low quality of life of CKD patients, comparable to that of metastatic cancer patients.
Mild Cognitive Impairment (MCI) has a high prevalence in this cohort (27-62%). Nevertheless, scattered literature data suggest that CKD patients can also have poor motor control, evidenced by a higher risk of falls, postural instability, reduced gait speed. In this cohort, few data are available regarding the motor circuits called central pattern generators, which control physiological tremor. Specifically, uraemic encephalopathy accentuates physiological tremor, which is regulated by central and peripheral oscillators. Overall, subtle changes in motor control often accompany other forms of MCI.
Therefore, this study aimed at evaluating the effects of chronic kidney disease on cognitive and motor functions using up-to-date technologies to record physiological tremor and innovative data analysis.
Method
This retrospective case-control study enrolled 313 patients (139 controls, 79 CKD patients stage III-IV, 35 kidney transplant (Tx), 60 dialysis (HD) patients). These groups were comparable for age and weight. Creatininemia, azotemia, LDL, HDL, hemoglobin, and proteinuria were used for correlative analyses. We evaluated the chronotype using the Morningness-Eveningness Questionnaire (MEQ) and the degree of sleepiness using the Epworth Sleepiness Scale (ESS). Cognitive impairment was assessed by the Montreal Cognitive Assessment test (MoCA). Cognitive domains of the MoCA score were projected onto brain regions using CerebroViz library in R and a new transformation matrix derived from fMRI literature data. UMAP algorithm was used to identify patients' subgroups. The physiological tremor was recorded on patients maintaining the dominant arm extended using the smartphone App Phyphox. The tremor frequency spectrum was extracted by Fourier analysis.
Results
The sleepiness score (ESS) was significantly increased in HD (ESS = 5±0.4) compared to the healthy controls (ESS= 4±0.41) whereas was not significantly modified in CKD patients (3.24± 0.32). The chronotype was also not significantly different among the various groups.
The mean score of the MoCA test was significantly lower in CKD, Tx, and HD groups (CKD MoCA =24.5±0.3; Tx MoCA =25.4±0.6; HD MoCA =24.6±0.7) than controls (MoCA score=28±0.1). A different pattern of impairment in the cognitive domains of MoCA was evidenced in the various groups using the CerebroViz projection and UMAP tools.
MoCA score was inversely correlated with proteinuria (Pearson coefficient=-0.47; p<0.05).
The higher frequencies of the physiological tremor (11-13 Hz) were significantly more represented in Tx patients compared to controls (p<0.05). Conversely, the lower frequencies (1-4 Hz) were significantly less represented in the HD group compared to controls (p<0.05). The peak frequency was inversely correlated with age in all patients (Pearson coefficient= -0.45; p<0.05) and inversely associated with azotemia levels, particularly in HD patients (Pearson coefficient=0.43; p<0.05).
Conclusion
Our results suggest that CKD patients present altered cognitive and motor control patterns, linked in part to the proteinuria level, suggesting a pathogenetic role of endothelial dysfunction.
The characteristic motor, sleepiness and cognitive patterns of HD patients might be due to the arteriovenous fistula or the other peculiarities of these patients.
These results might help identify new early markers of brain dysfunction in these patients, with the possibility of delaying or reversing cognitive decay.
The purpose of this study was to study the incidence and factors influencing retinal displacement in eyes treated for rhegmatogenous retinal detachment (RRD) with pars plana vitrectomy (PPV) and gas ...or silicone oil.
This was a prospective observational case series. One hundred twenty-five eyes with macula-off RRD from 125 patients underwent 25-gauge PPV at two vitreoretinal institutional practices. Eyes without proliferative vitreoretinopathy (PVR) or PVR grade A were tamponated with sulfur hexafluoride (SF6) gas, whereas eyes with PVR grade B received 1000 centistokes silicone oil (SO). The patients postured face-down immediately after surgery. Blue-fundus autofluorescence (B-FAF) pictures were obtained at each follow-up examination. Main outcome measures were incidence and direction of retinal displacement.
Ninety-seven eyes (77.6%) were tamponated with SF6 and 28 eyes (22.4%) with SO. After retinal reattachment, displacement was observed in 44 of 125 (35.2%) eyes (40 eyes in the SF6 group and 4 eyes in the SO group, respectively). The type of tamponade, specifically gas, was the only significant predictor of retinal displacement (P = 0.007). The displacement was downward in 39 (88.6%) eyes (36 tamponated with SF6 and 3 with SO) and upward in 5 (11.4%) eyes (4 tamponated with SF6 and 1 with SO).
Displacement of the retina after repair of macula-off RRD with PPV is observed using either SF6 gas or SO. Downward and upward displacements may occur with both tamponades, but downward dislocation is more common. Of the factors potentially implicated in favoring displacement that were studied, only the type of tamponade, specifically the gas, was significant.
Abstract The relationship between genes and behavior, and particularly the hyperactive behavior, is clearly not linear nor monotonic. To address this problem, a database of the locomotor behavior ...obtained from thousands of mutant mice has been previously retrieved from the literature. Data showed that the percent of genes in the genome related to locomotor hyperactivity is probably more than 1.56%. These genes do not belong to a single neurotransmitter system or biochemical pathway. Indeed, they are probably required for the correct development of a specific neuronal network necessary to decrease locomotor activity. The present paper analyzes the brain expression pattern of the genes whose deletion is accompanied by changes in locomotor behavior. Using literature data concerning knockout mice, 46 genes whose deletion was accompanied by increased locomotor behavior, 24 genes related to decreased locomotor behavior and 23 genes not involved in locomotor behavior (but important for other brain functions) have been identified. These three groups of genes belonged to overlapping neurotransmitter systems or cellular functions. Therefore, we postulated that a better predictor of the locomotor behavior resulting from gene deletion might be the brain expression pattern. To this aim we correlated the brain expression of the genes and the locomotor activity resulting from the deletion of the same genes, using two databases (Allen Brain Atlas and SymAtlas). The results showed that the deletion of genes with higher expression level in the brain had higher probability to be accompanied by increased behavioral activity. Moreover the genes that were accompanied by locomotor hyperactivity when deleted, were more expressed in the cerebral cortex, amygdala and hippocampus compared to the genes unrelated to locomotor activity. Therefore, the prediction of the behavioral effect of a gene should take into consideration its brain distribution. Moreover, data confirmed that genes highly expressed in the brain are more likely to induce hyperactivity when deleted. Finally, it is suggested that gene mutations linked to specific behavioral abnormalities (e.g. inattention) might probably be associated to hyperactivity if the same gene has elevated brain expression.
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