Regulation of neuronal bioenergetics as a therapeutic strategy in neurodegenerative diseases

Neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease, Huntington's disease, and amyotrophic lateral sclerosis are a heterogeneous group of debilitating disorders with multifactorial etiologies and pathogeneses that manifest distinct molecular mechanisms and clinical manifestations with abnormal protein dynamics and impaired bioenergetics. Mitochondrial dysfunction is emerging as an important feature in the etiopathogenesis of these age-related neurodegenerative diseases. The prevalence and incidence of these diseases is on the rise with the increasing global population and average lifespan. Although many therapeutic approaches have been tested, there are currently no effective treatment routes for the prevention or cure of these diseases. We present the current status of our knowledge and understanding of the involvement of mitochondrial dysfunction in these diseases and highlight recent advances in novel therapeutic strategies targeting neuronal bioenergetics as potential approach for treating these diseases.

Single balloon enteroscopy for endoscopic retrograde cholangiography in patients with Roux-en-Y hepaticojejuno anastomosis

AIM:To evaluate single balloon enteroscopy in diagnostic and therapeutic endoscopic retrograde cholangiography(ERC)in patients with Roux-en-Y hepaticojejunoanastomosis(HJA).METHODS:The study took place from January 2009to December 2011 and we retrospectively assessed 15patients with Roux-en-Y HJA who had signs of biliary obstruction.In total,23 ERC procedures were performed in these patients and a single balloon videoen-teroscope(Olympus SIF Q 180)was used in all of the cases.A transparent overtube was drawn over the videoenteroscope and it freely moved on the working part of the enteroscope.Its distal end was equipped with a silicone balloon that was inflated by air from an external pump at a pressure of≤5.4 kPa.The technical limitations or rather the parameters of the single balloon enteroscope(working length-200 cm,diameter of the working channel-2.8 mm,absence of Albarran bridge)showed the need for special endoscopic instrumentation.RESULTS:Cannulation success was reached in diagnostic ERC in 12 of 15 patients.ERC findings were normal in 1 of 12 patients.ERC in the remaining 11 patients showed some pathological changes.One of these(cystic bile duct dilation)was subsequently resolved surgically.Endoscopic treatment was initialized in the remaining 10 patients(5 with HJA stenosis,2 with choledocholithiasis,and 3 with both).This treatment was successful in 9 of 10 patients.The endoscopic therapeutic procedures included:balloon dilatation of HJA stenosis-11 times(7 patients);choledocholitiasis extraction-five times(5 patients);biliary plastic stent placement-six times(4 patients);and removal of biliary stents placed by us-six times(4 patients).The mean time of performing a single ERC was 72 min.The longest procedure took 110 min and the shortest took34 min.This shows that it is necessary to allow for more time in individual procedures.Furthermore,these procedures require the presence of an anesthesiologist.We did not observe any complications in these 15 patients.CONCLUSION:This method is more demanding than standard endoscopic retrograde cholangiopancreatography due to altered postsurgical anatomy.However,it is effective,safe,and widens the possibilities of resolving biliary pathology.

Administration of pre/probiotics with conventional drug treatment in Alzheimer’s disease

Alzheimer’s disease(AD)is a neurodegenerative disease with long preclinical phase,typically followed by a slow decline in memory,thinking and reasoning abilities.The underlying pathological processes are not yet fully elucidated,although two main disease hallmarks have been associated with AD pathology:amyloid beta species and neurofibrillary tangles.The plaques are deposits of a protein fragment called beta-amyloid(Aβ),which accumulates in the spaces between neurons.Tangles are twisted fibers of the tau protein,which accumulates inside the cells.

Test of incremental respiratory endurance as home-based, standalone therapy in chronic obstructive pulmonary disease: A case report

BACKGROUND The prevalence of chronic obstructive pulmonary disease(COPD)is increasing worldwide,and at the same time it is associated with increased mortality and reduced quality of life.Efforts to build sustainable rehabilitation approaches to COPD treatment and prevention are crucial.The system of long-term pulmonary rehabilitation care is insufficient.The main reasons for the absence of these outpatient programs are the lack of experience,the lack of interest of insurance companies in secondary prevention programs,and the lack of healthcare facilities in large geographical areas.The possibility of at-home pulmonary rehabilitation models(telemonitoring and telecoaching)could solve this problem.CASE SUMMARY A 71-year-old man with severe COPD,Global Initiative for Obstructive Lung Diseases stage 3 underwent an 8-wk remotely monitored inspiratory muscle training with a device based on the test of incremental respiratory endurance method.Spirometry,body plethysmography,test of incremental respiratory endurance examination,6-min walking test,body mass index,airflow obstruction,dyspnea,exercise capacity index,and subjective perception of dyspnea were performed as part of the initial and final examination.The patient performed training at home,and the physiotherapist monitored the patient remotely through a web application that allowed the physiotherapist to evaluate all training parameters in real-time and respond to any problems.After 8 wk of home training,there was a significant increase in all monitored values:maximal inspiratory pressure,a novel parameter sustained maximal inspiratory pressure,forced expiratory volume in 1 s,total lung capacity,forced vital capacity,peak expiratory flow,and inspiratory capacity.There was also an improvement in the perception of dyspnea according to the COPD Assessment Test and a modified Medical Research Council Breathlessness Scale,an increase in exercise tolerance according to the 6-min walking test,and a decrease in the exercise capacity index as a predictor of prognosis.CONCLUSION Respiratory telerehabilitation was greatly beneficial in a cooperative patient with COPD and may represent an alternative therapeutic approach to the increasing incidence of all lung diseases.

Comparative analysis of clinicopathological correlations of cyclooxygenase-2 expression in resectable pancreatic cancer

AIM:To perform a comparative analysis of clinicopathological correlations of cyclooxygenase2 (COX2) expression in pancreatic cancer, examined by monoclonal and polyclonal antibodies.METHODS: The COX2 expression in 85 resection specimens of pancreatic ductal adenocarcinoma was immunohistochemically examined using both monoclonal and polyclonal antibodies. The final immunoscores were obtained by multiplying the percentage of positive cells with the numeric score reflecting the staining intensity.COX2 expression levels were classified into three categories (0, 1+, and 2+) and the clinicopathological correlations were statistically evaluated and analyzed.RESULTS: The positive tumor expression rates of COX2 were 80.5% using monoclonal antibody and 69.4% using polyclonal antibody. In the KaplanMeier analysis, no significant correlations were found between levels of COX2 expression and overall survival (OS), but trends to longer OS were found in COX2 negative cases using monoclonal antibody. Significantly longer disease free survival was revealed in COX2 negative cases using monoclonal antibody (P = 0.019). No correlations between COX2 expression levels and grade (G), tumor (T) status and nodal (N) status were demonstrated. Low histological grade showed a strong association with a longer OS (P < 0.001). Correlation of survival and T status revealed a shorter OS in T3 tumors, but the results reached only marginal statistical significance (P = 0.070). In the multivariate Cox proportional hazards regression model, histological grade, T and N status remained valuable predictors of a worse survival with borderline significance for T [hazards ratio (HR) = 4.18 for G (if G = 3, P < 0.001); HR = 1.64 for T (if T = 3, P = 0.065); HR = 2.53 for N (if N = 1, P = 0.006)]. Higher grade, T or N status was associated with a worse OS. CONCLUSION: The immunohistochemically assessed level of COX2 expression does not seem to represent a valuable independent prognostic factor and is not superior to the conventional prognostic factors.

Intervertebral disc degeneration is rescued by TGFβ/BMP signaling modulation in an ex vivo flamin B mouse model

Spondylocarpotarsal syndrome(SCT) is a rare musculoskeletal disorder characterized by short stature and vertebral, carpal, and tarsal fusions resulting from biallelic nonsense mutations in the gene encoding filamin B(FLNB). Utilizing a FLNB knockout mouse,we showed that the vertebral fusions in SCT evolved from intervertebral disc(IVD) degeneration and ossification of the annulus fibrosus(AF), eventually leading to full trabecular bone formation. This resulted from alterations in the TGFβ/BMP signaling pathway that included increased canonical TGFβ and noncanonical BMP signaling. In this study, the role of FLNB in the TGFβ/BMP pathway was elucidated using in vitro, in vivo, and ex vivo treatment methodologies. The data demonstrated that FLNB interacts with inhibitory Smads 6 and 7(i-Smads) to regulate TGFβ/BMP signaling and that loss of FLNB produces increased TGFβ receptor activity and decreased Smad 1 ubiquitination. Through the use of small molecule inhibitors in an ex vivo spine model, TGFβ/BMP signaling was modulated to design a targeted treatment for SCT and disc degeneration. Inhibition of canonical and noncanonical TGFβ/BMP pathway activity restored Flnb-/-IVD morphology. These most effective improvements resulted from specific inhibition of TGFβand p38 signaling activation. FLNB acts as a bridge for TGFβ/BMP signaling crosstalk through i-Smads and is key for the critical balance in TGFβ/BMP signaling that maintains the IVD. These findings further our understanding of IVD biology and reveal new molecular targets for disc degeneration as well as congenital vertebral fusion disorders.

Non-Linear EEG Measures in Meditation

In this study, the performance of Sevcik’s algorithm that calculates the fractal dimension and permutation entropy as discriminants to detect calming and insight meditation in electroencephalo-graphic (EEG) signals was assessed. The proposed methods were applied to EEG recordings from meditators practicing insight meditation and calming meditation before as well as during both types of meditation. Analysis was conducted using statistical hypothesis testing to determine the validity of the proposed meditation-identifying techniques. For both types of meditation, there was a statistically significant reduction in the permutation entropy. This result can be explained by the increased EEG synchronization, which is repeatedly observed in the course of meditation. In contrast, the fractal dimension (FD) was significantly increased during calming meditation, but during insight meditation, no statistically significant change was detected. Increased FD during meditation can be interpreted as an increase in self-similarity of EEG signals during self-organisation of hierarchical structure oscillators in the brain. Our results indicate that fractal dimension and permutation entropy could be used as parameters to detect both types of meditation. The permutation entropy is advantageous compared with the fractal dimension because it does not require a stationary signal.

Mechanisms behind elevated serum levels of plasminogen activator inhibitor-1 in frontotemporal lobar degeneration

Frontotemporal lobar degeneration(FTLD)is a form of progressive dementia characterized by degeneration of the frontal and temporal lobes of the brain.This pathology involves a series of cognitive,behavioral,and neurological symptoms that influence personality,decision-making ability,and language.