Related Pathomechanism Research Articles

More extensive white matter disruptions present in untreated obstructive sleep apnea than we thought: A large sample diffusion imaging study.

Obstructive sleep apnea (OSA) may lead to white mater (WM) disruptions and cognitive deficits. However, no studies have investigated the full extent of the brain WM, and its associations with cognitive deficits in OSA remain unclear. We thus applied diffusion tensor imaging (DTI) tractography with multi-fiber models and used atlas-based bundle-specific approach to investigate the WM abnormalities for various tracts of the cerebral cortex, thalamus, brainstem, and cerebellum in patients with untreated OSA. We enrolled 100 OSA patients and 63 healthy controls. Fractional anisotropy (FA) and mean diffusivity (MD) values mapped on 33 regions of interest including WM tracts of cortex, thalamus, brainstem, and cerebellum were obtained from tractography-based reconstructions. We compared FA/MD values between groups and correlated FA/MD with clinical data in the OSA group after controlling for age and body mass index. OSA patients showed significantly lower FA values in multiple WM fibers including corpus callosum, inferior fronto-occipital fasciculus, middle/superior longitudinal fasciculi, thalamic radiations, and uncinate (FDR <0.05). Higher FA values were found in medial lemniscus of patients compared to controls (FDR <0.05). Lower FA values of rostrum of corpus callosum correlated with lower visual memory performance in OSA group (p < .005). Our quantitative DTI analysis demonstrated that untreated OSA could negatively impact the integrity of pathways more broadly, including brainstem structures such as medial lemniscus, in comparison to previous findings. Fiber tract abnormalities of the rostral corpus callosum were associated with impaired visual memory in untreated OSA may provide insights into the related pathomechanism.

Interaction Mechanism Between the HSV-1 Glycoprotein B and the Antimicrobial Peptide Amyloid-β.

Background:Unravelling the mystery of Alzheimer’s disease (AD) requires urgent resolution given the worldwide increase of the aging population. There is a growing concern that the current leading AD hypothesis, the amyloid cascade hypothesis, does not stand up to validation with respect to emerging new data. Indeed, several paradoxes are being discussed in the literature, for instance, both the deposition of the amyloid-β peptide (Aβ) and the intracellular neurofibrillary tangles could occur within the brain without any cognitive pathology. Thus, these paradoxes suggest that something more fundamental is at play in the onset of the disease and other key and related pathomechanisms must be investigated.Objective:The present study follows our previous investigations on the infectious hypothesis, which posits that some pathogens are linked to late onset AD. Our studies also build upon the finding that Aβ is a powerful antimicrobial agent, produced by neurons in response to viral infection, capable of inhibiting pathogens as observed in in vitro experiments. Herein, we ask what are the molecular mechanisms in play when Aβ neutralizes infectious pathogens?Methods:To answer this question, we probed at nanoscale lengths with FRET (Förster Resonance Energy Transfer), the interaction between Aβ peptides and glycoprotein B (responsible of virus-cell binding) within the HSV-1 virionResults:The experiments show an energy transfer between Aβ peptides and glycoprotein B when membrane is intact. No energy transfer occurs after membrane disruption or treatment with blocking antibody.Conclusion:We concluded that Aβ insert into viral membrane, close to glycoprotein B, and participate in virus neutralization.

Pruritus in autoimmune connective tissue diseases.

Pruritus is one of the most common and bothersome symptoms of skin disorders, and its clinical characteristics and related pathomechanisms have been well described in certain dermatologic conditions, such as atopic dermatitis and urticaria. Although pruritus is believed to be as common in cutaneous autoimmune connective tissue diseases (ACTDs) as in other inflammatory skin disorders, its true characteristics have not been elucidated either qualitatively or quantitatively. Pruritus is present in ACTDs with various prevalence rates, characteristics, and mechanisms depending on the disease types. Pruritus most frequently and severely affects the patients with dermatomyositis, in which itch is strongly correlated with disease activity and severity, thus increased itch could also indicate a disease flare. Patients with other ACTDs, including lupus erythematosus (LE), Sjögren syndrome (SS), morphea, and systemic sclerosis (SSc), also suffer from their fair share of pruritus. Unfortunately, the currently available treatments for ACTDs seem to have only limited and unsatisfactory effects to control pruritus. The extensive impact of pruritus on the patients’ quality of life (QOL) and functioning warrants more targeted and individualized approaches against pruritus in ACTDs. This review will address the prevalence, suggested pathogenesis based on currently available evidences, and potential treatment options of pruritus in various ACTDs of the skin.

Advanced glycation end products in musculoskeletal system and disorders.

The human population is ageing globally, and the number of old people is increasing yearly. Diabetes is common in the elderly, and the number of diabetic patients is also increasing. Elderly and diabetic patients often have musculoskeletal disorder, which are associated with advanced glycation end products (AGEs). AGEs are heterogeneous molecules derived from non-enzymatic products of the reaction of glucose or other sugar derivatives with proteins or lipids, and many different types of AGEs have been identified. AGEs are a biomarker for ageing and for evaluating disease conditions. Fluorescence, spectroscopy, mass spectrometry, chromatography, and immunological methods are commonly used to measure AGEs, but there is no standardized evaluation method because of the heterogeneity of AGEs. The formation of AGEs is irreversible, and they accumulate in tissue, eventually causing damage. AGE accumulation has been confirmed in neuromusculoskeletal tissues, including bones, cartilage, muscles, tendons, ligaments, and nerves, where they adversely affect biomechanical properties by causing charge changes and forming cross-linkages. AGEs also bind to receptors, such as the receptor for AGEs (RAGE), and induce inflammation by intracellular signal transduction. These mechanisms cause many varied aging and diabetes-related pathological conditions, such as osteoporosis, osteoarthritis, sarcopenia, tendinopathy, and neuropathy. Understanding of AGEs related pathomechanism may lead to develop novel methods for the prevention and therapy of such disorders which affect patients' quality of life. Herein, we critically review the current methodology used for detecting AGEs, and present potential mechanisms by which AGEs cause or exacerbate musculoskeletal disorders.

Dopamine receptors and BDNF-haplotypes predict dyskinesia in Parkinson's disease

ObjectiveDyskinesia is a known side-effect of the treatment of Parkinson's Disease (PD). We examined the influence of haplotypes in three dopamine receptors (DRD1, DRD2 and DRD3) and the Brain Derived Neurotrophic Factor (BDNF) on dyskinesia. MethodsPatient data were drawn from a population-based case-control study. We included 418 patients with confirmed diagnoses by movement disorder specialists, using levodopa and a minimum three years disease duration at the time of assessment. Applying Haploview and Phase, we created haploblocks for DRD1-3 and BDNF. Risk scores for DRD2 and DRD3 were generated. We calculated risk ratios using Poisson regression with robust error variance. ResultsThere was no difference in dyskinesia prevalence among carriers of various haplotypes in DRD1. However, one haplotype in each DRD2 haploblocks was associated with a 29 to 50% increase in dyskinesia risk. For each unit increase in risk score, we observed a 16% increase in dyskinesia risk for DRD2 (95%CI: 1.05–1.29) and a 17% (95%CI: 0.99–1.40) increase for DRD3. The BDNF haploblock was not associated, but the minor allele of the rs6265 SNP was associated with dyskinesia (adjusted RR 1.31 (95%CI: 1.01–1.70)). ConclusionCarriers of DRD2 risk haplotypes and possibly the BDNF variants rs6265 and DRD3 haplotypes, were at increased risk of dyskinesia, suggesting that these genes may be involved in dyskinesia related pathomechanisms. PD patients with these genetic variants might be prime candidates for treatments aiming to prevent or delay the onset of dyskinesia.

Imaging of impingement syndromes around the hip joint.

Impingement syndromes are increasingly recognised as significant causes of hip pain and dysfunction. A broad spectrum of intraarticular and extraarticular conditions has been implicated in their pathophysiology. Physical examination is often inconclusive as clinical findings may be unclear or misleading, often simulating other disorders. With current improvements in imaging techniques and better understanding of hip impingement related pathomechanisms, these entities can be accurately diagnosed. In addition, preoperative imaging has allowed for targeted treatment planning. This article provides an overview of the various types of hip impingement, including femoroacetabular impingement, ischiofemoral impingement, snapping hip syndrome, greater trochanteric-pelvic and subspine impingement. Current literature data regarding their pathogenesis, clinical manifestation and imaging work-up are discussed.

Identification of Blood Let-7e-5p as a Biomarker for Ischemic Stroke.

Circulating microRNAs (miRNAs) are emerging as novel disease biomarkers. Using a miRNA microarray, we previously showed that the whole blood level of let-7e-5p was significantly higher in ischemic stroke patients than in control subjects. However, the association between let-7e-5p expression and the occurrence of ischemic stroke remains unknown. In this study, we validated the expression levels of let-7e-5p in two case-control populations using miRNA TaqMan assays and further investigated the potential targets of let-7e-5p. The results suggest that the blood level of let-7e-5p was significantly higher in patients with ischemic stroke than in controls (p<0.05). Higher levels of let-7e-5p were associated with increased occurrence of ischemic stroke (adjusted OR, 1.89; 95% CI, 1.61~2.21, p<0.001) in the combined population. The addition of let-7e-5p to traditional risk factors led to an improvement in the area under the curve, which increased from 0.74 (95% CI, 0.70~0.78) to 0.82 (95% CI, 0.78~0.85), with a net reclassification improvement of 16.76% (p<0.0001) and an integrated discrimination improvement of 0.10 (p<0.0001) for patients with ischemic stroke. Bioinformatics prediction and cell experiments suggested that the expression levels of four genes enriched in the MAPK signaling pathway were down-regulated by let-7e-5p transfection. Specifically, the expression levels of the genes CASP3 and NLK were significantly lower in ischemic stroke patients than in controls and were negatively correlated with let-7e-5p expression. In summary, our study suggests the potential use of blood let-7e-5p as a biomarker for ischemic stroke and indicates its involvement in the related pathomechanism.

Genetic targeting of NRXN2 in mice unveils role in excitatory cortical synapse function and social behaviors

Human genetics has identified rare copy number variations and deleterious mutations for all neurexin genes (NRXN1-3) in patients with neurodevelopmental diseases, and electrophysiological recordings in animal brains have shown that Nrxns are important for synaptic transmission. While several mouse models for Nrxn1α inactivation have previously been studied for behavioral changes, very little information is available for other variants. Here, we validate that mice lacking Nrxn2α exhibit behavioral abnormalities, characterized by social interaction deficits and increased anxiety-like behavior, which partially overlap, partially differ from Nrxn1α mutant behaviors. Using patch-clamp recordings in Nrxn2α knockout brains, we observe reduced spontaneous transmitter release at excitatory synapses in the neocortex. We also analyse at this cellular level a novel NRXN2 mouse model that carries a combined deletion of Nrxn2α and Nrxn2β. Electrophysiological analysis of this Nrxn2-mutant mouse shows surprisingly similar defects of excitatory release to Nrxn2α, indicating that the β-variant of Nrxn2 has no strong function in basic transmission at these synapses. Inhibitory transmission as well as synapse densities and ultrastructure remain unchanged in the neocortex of both models. Furthermore, at Nrxn2α and Nrxn2-mutant excitatory synapses we find an altered facilitation and N-methyl-D-aspartate receptor (NMDAR) function because NMDAR-dependent decay time and NMDAR-mediated responses are reduced. As Nrxn can indirectly be linked to NMDAR via neuroligin and PSD-95, the trans-synaptic nature of this complex may help to explain occurrence of presynaptic and postsynaptic effects. Since excitatory/inhibitory imbalances and impairment of NMDAR function are alledged to have a role in autism and schizophrenia, our results support the idea of a related pathomechanism in these disorders.

Does aspirin-induced oxidative stress cause asthma exacerbation?

Aspirin-induced asthma (AIA) is a distinct clinical syndrome characterized by severe asthma exacerbations after ingestion of aspirin or other non-steroidal anti-inflammatory drugs. The exact pathomechanism of AIA remains unknown, though ongoing research has shed some light. Recently, more and more attention has been focused on the role of aspirin in the induction of oxidative stress, especially in cancer cell systems. However, it has not excluded the similar action of aspirin in other inflammatory disorders such as asthma. Moreover, increased levels of 8-isoprostanes, reliable biomarkers of oxidative stress in expired breath condensate in steroid-naïve patients with AIA compared to AIA patients treated with steroids and healthy volunteers, has been observed. This review is an attempt to cover aspirin-induced oxidative stress action in AIA and to suggest a possible related pathomechanism.

Central Retinal Artery Occlusion Following Central Retinal Vein Occlusion- A Case Report

A 73-year-old gentleman with diabetes mellitus was found to have impending central retinal vein occlusion (CRVO), on routine eye check-up. Despite initiation of anti-platelet agent, he developed ischaemic CRVO two months later, with severe macula oedema. His systemic investigations showed good diabetic control, no blood dyscrasia/hypercoagulable state, normal lipid profile and inflammatory markers. Echocardiogram was normal. A month later, arteriolar attenuation was noted with rubeosis irides, and fluorescein angiogram study confirmed central retinal artery occlusion (CRAO). After ruling out the systemic risk factors, we postulate two possible anatomical related patho-mechanism of CRAO following CRVO: 1, CRVO converts the retinal circulation into a closed loop, results in complete hemodynamic block of the retinal circulation, and hence secondary CRAO; 2, swollen retinal nerve fibres at the optic nerve head secondary to CRVO cause compression to the retinal artery at the level of the lamina cribrosa, this compression is further aggravated by the increased in intraocular pressure (IOP), and hence secondary CRAO.

Molecular size and origin do not influence the harmful side effects of hydroxyethyl starch on human proximal tubule cells (HK-2) in vitro.

Recently, clinical trials revealed renal impairment induced by hydroxyethyl starch (HES) in septic patients. In prior studies, we managed to demonstrate that HES accumulated in renal proximal tubule cells (PTCs). The related pathomechanism has not yet been discovered. To validate our hypothesis that the HES molecule itself is harmful, regardless of its molecule size or origin, we conducted a comprehensive study to elucidate the influences of different HES preparations on PTC viability in vitro. Cell viability of human PTC was measured with a cytotoxicity assay, quantifying the reduction of tetrazolium salt to colored formazan. Experiments were performed by assessing the influence of different carrier solutions of HES (balanced, nonbalanced, culture medium), different average molecular weights (70, 130, 200 kDa), different origins (potato or corn derived), and various durations of incubation (2-21 hours). Furthermore, HES 130/0.4 was fractionated by ultrafiltration, and the impact on cell viability of average single-size fractions with <3, 3 to 10, 10 to 30, 30 to 50, 50 to 100, and >100 kDa was investigated. We also tested the possible synergistic effects of inflammation induced by tumor necrosis factor-α. All tested HES solutions, regardless of origin or carrier matrix, decreased cell viability in an equivalent, dose-dependent manner. Coincubation with tumor necrosis factor-α did not reduce HES-induced reduction of cell viability. Minor differences were detected comparing 70, 130, and 200 kDa preparations. Analysis of fractionated HES revealed that each fraction decreased cell viability. Even small HES molecules (10-30 kDa) were significantly deleterious. For the first time, we were able to show that only the total mass of HES molecules applied is responsible for the harmful impact on renal PTC in vitro. Neither molecular size nor their origin showed any relevance.

Cholangiocarcinoma: risk factor and related pathomechanism

Cholangiocarcinoma is rare. It is highly malignant and early diagnosis is difficult. Various risk facts have been linked to the carcinogenesis and development of cholangiocarcinoma. Chronic inflammation and cholestasis are the two common pathways in the malignant transformation of cholangial cells. We reviewed the molecular biological researches of cholangiocarcinoma from two aspects: its risk factors and related pathomechanism. Key words: Cholangiocarcinoma; Risk factor; Pathomechanism

Thrombotic microangiopathies: new insights and new challenges

Thrombotic microangiopathies (TMAs) manifest as a spectrum of related disorders in the form of thrombocytopenic purpura (TTP) and hemolytic uremic syndrome (HUS). New data on both diseases support more and more the relatedness of the disorders and reveal related pathomechanisms, which, however, manifest in different organs. TTP develops primarily at neurological sites, and also in the kidney, and HUS is a kidney disease. In TTP thrombi formation occurs subsequently to the release of multimers of von Willebrand factor (vWF), and in HUS endothelial cell damage is considered the reason for complement and platelet activation leading to thrombus formation. Genetic mutations are associated with both disorders: in TTP the ADAMTS13 gene, the vWF cleaving protease, is affected, and in HUS several complement genes are mutated. In addition autoimmune forms, with acquired, de-novo generated inhibitors in the form of autoantibodies exist for both disorders, affecting ADAMTS13 in TTP or the central complement inhibitor factor H in HUS. In HUS autoantibodies can develop in the context of a specific mostly homozygous chromosomal deletion that represents a new subform of the disease, which is termed DEAP-HUS (deficient for CFHR proteins and autoantibody positive HUS). As the underlying disease mechanisms of TMA are now being better understood new options for a more precise diagnosis, improved therapy and prognosis for kidney transplantation become available for the benefit of patients. Here we summarize the recent developments in this rapidly progressing field.

The future of surgery.

<h3>Abstract</h3> Unravelling the mystery of Alzheimer’s Disease (AD) requires urgent resolution given the worldwide increase of the aging population. There is a growing concern that the current leading AD hypothesis, the amyloid cascade hypothesis, does not stand up to validation with respect to emerging new data. Indeed, several paradoxes are being discussed in the literature, for instance, both the deposition of the Amyloid-Beta peptide (Aβ) and the intracellular neurofibrillary tangles (NFTs) could occur within the brain without any cognitive pathology. Thus, these paradoxes suggest that something more fundamental is at play in the onset of the disease and other key and related pathomechanisms have to be investigated. The present study follows our previous investigations on the infectious hypothesis, which posits that some pathogens are linked to late onset AD. Our studies also build upon the shattering finding that Aβ is a powerful antimicrobial agent capable of inhibiting pathogens as observed in <i>in vitro</i> experiments. Herein, we ask what are the molecular mechanisms in play when Aβ neutralizes infectious pathogens? To answer this question, we probed at nanoscale lengths with FRET (Förster Resonance Energy Transfer), the interaction between Aβ peptides and glycoprotein B (responsible of virus-cell binding) within the HSV-1 virion. We concluded that there is indeed a close interaction, likely nonspecific or semi-specific, between the two types of molecules, which participate in virus neutralization.