Perceptual Expectations Are Reflected by Early Alpha Power Reduction.

The predictability of a stimulus can be characterized by its transitional probability. Perceptual expectations derived from the transitional probability of the stimulus were found to modulate the early alpha oscillations in the sensory regions of the brain when neural responses to expected versus unexpected stimuli were compared. The objective of our study was to find out the extent to which this low-frequency oscillation reflects stimulus predictability. We aimed to detect the alpha-power difference with smaller differences in transitional probabilities by comparing expected stimuli with neutral ones. We studied the effect of expectation on perception by applying an unsupervised visual statistical learning paradigm with expected and neutral stimuli embedded in an image sequence while recording EEG. Time-frequency analysis showed that expected stimuli elicit lower alpha power in the window of 8-12 Hz and 0-400 msec after stimulus presentation, appearing in the centroparietal region. Comparing previous findings of expectancy-based alpha-band modulation with our results suggests that early alpha oscillation shows an inverse relationship with stimulus predictability. Although current data are insufficient to determine the origin of the alpha power reduction, this could be a potential sign of expectation suppression in cortical oscillatory activity.

Geroscience and pathology: a new frontier in understanding age-related diseases.

Geroscience, a burgeoning discipline at the intersection of aging and disease, aims to unravel the intricate relationship between the aging process and pathogenesis of age-related diseases. This paper explores the pivotal role played by geroscience in reshaping our understanding of pathology, with a particular focus on age-related diseases. These diseases, spanning cardiovascular and cerebrovascular disorders, malignancies, and neurodegenerative conditions, significantly contribute to the morbidity and mortality of older individuals. We delve into the fundamental cellular and molecular mechanisms underpinning aging, including mitochondrial dysfunction and cellular senescence, and elucidate their profound implications for the pathogenesis of various age-related diseases. Emphasis is placed on the importance of assessing key biomarkers of aging and biological age within the realm of pathology. We also scrutinize the interplay between cellular senescence and cancer biology as a central area of focus, underscoring its paramount significance in contemporary pathological research. Moreover, we shed light on the integration of anti-aging interventions that target fundamental aging processes, such as senolytics, mitochondria-targeted treatments, and interventions that influence epigenetic regulation within the domain of pathology research. In conclusion, the integration of geroscience concepts into pathological research heralds a transformative paradigm shift in our understanding of disease pathogenesis and promises breakthroughs in disease prevention and treatment.

Gamma oscillations in visual statistical learning correlate with individual behavioral differences.

Statistical learning is assumed to be a fundamentally general sensory process across modalities, age, other cognitive functions, and even species. Despite this general role, behavioral testing on regularity acquisition shows great variance among individuals. The current study aimed to find neural correlates of visual statistical learning showing a correlation with behavioral results. Based on a pilot study, we conducted an EEG study where participants were exposed to associated stimulus pairs; the acquisition was tested through a familiarity test. We identified an oscillation in the gamma range (40-70 Hz, 0.5-0.75 s post-stimulus), which showed a positive correlation with the behavioral results. This change in activity was located in a left frontoparietal cluster. Based on its latency and location, this difference was identified as a late gamma activity, a correlate of model-based learning. Such learning is a summary of several top-down mechanisms that modulate the recollection of statistical relationships such as the capacity of working memory or attention. These results suggest that, during acquisition, individual behavioral variance is influenced by dominant learning processes which affect the recall of previously gained information.

The Effectiveness of Supplementation with Key Vitamins, Minerals, Antioxidants and Specific Nutritional Supplements in COPD-A Review.

Currently, an increasing amount of evidence supports the notion that vitamins C, D and E, carotenoids, and omega-3 fatty acids may protect against the progression of chronic respiratory diseases. Although chronic obstructive pulmonary disease (COPD) primarily affects the lung, it is often accompanied by extrapulmonary manifestations such as weight loss and malnutrition, skeletal muscle dysfunction, and an excess of harmful oxidants, which can lead to a decline in quality of life and possible death. Recently, the role of various vitamins, minerals, and antioxidants in mitigating the effects of environmental pollution and smoking has received significant attention. Therefore, this review evaluates the most relevant and up-to-date evidence on this topic. We conducted a literature review between 15 May 2018 and 15 May 2023, using the electronic database PubMed. Our search keywords included COPD, chronic obstructive pulmonary disease, FEV1, supplementation: vitamin A, vitamin D, vitamin E, vitamin C, vitamin B, omega-3, minerals, antioxidants, specific nutrient supplementations, clinical trials, and randomized controlled trials (RCTs). We focused on studies that measured the serum levels of vitamins, as these are a more objective measure than patient self-reports. Our findings suggest that the role of appropriate dietary supplements needs to be reconsidered for individuals who are predisposed to or at risk of these conditions.

Comorbidities and increased mortality of COVID-19 among the elderly: A systematic review.

Purpose: The purpose of current review is to conduct a systematic overview of articles published between 2019 and 2021 on the relationship of comorbidities and mortality due to Coronavirus Disease 2019 (COVID-19) among the elderly population. Methods: We conducted a systematic search on PubMed for articles published between 2019 and 2021 to identify any cohort and case-control studies that investigated the relationship of comorbidities and COVID-19 mortality among the elderly, defined as 60 years of age and above. Databases were searched independently by two authors. Disagreements were resolved by the inclusion of a third investigator. Reviews, systematic reviews, and meta-analyses were excluded from our systematic review. Results: A total of 15 studies were selected for our systematic review. Of the included studies, 3 were case-control, 3 were prospective cohort studies and 9 were retrospective cohort studies. As for size, 10 studies were conducted on populations of <1000 participants, 3 ranging from 1001 to 10,000, and 2 on populations of >10,000 individuals. The included studies found that the presence of certain conditions, such as cardiovascular, respiratory, renal diseases, malignancies, diseases of the nervous system and diabetes are associated to increased mortality in populations that consisted of elderly patients. Conclusion: Results of our systematic review suggest that comorbidities contribute to increased COVID-19 mortality among the elderly. The detrimental effect of comorbidities and advanced age on the immune response could lead to a more frequent occurrence of symptomatic and severe infections with COVID-19.

Online measurement of learning temporal statistical structure in categorization tasks.

The ability to grasp relevant patterns from a continuous stream of environmental information is called statistical learning. Although the representations that emerge during visual statistical learning (VSL) are well characterized, little is known about how they are formed. We developed a sensitive behavioral design to characterize the VSL trajectory during ongoing task performance. In sequential categorization tasks, we assessed two previously identified VSL markers: priming of the second predictable image in a pair manifested by a reduced reaction time (RT) and greater accuracy, and the anticipatory effect on the first image revealed by a longer RT. First, in Experiment 1A, we used an adapted paradigm and replicated these VSL markers; however, they appeared to be confounded by motor learning. Next, in Experiment 1B, we confirmed the confounding influence of motor learning. To assess VSL without motor learning, in Experiment 2 we (1) simplified the categorization task, (2) raised the number of subjects and image repetitions, and (3) increased the number of single unpaired images. Using linear mixed-effect modeling and estimated marginal means of linear trends, we found that the RT curves differed significantly between predictable paired and control single images. Further, the VSL curve fitted a logarithmic model, suggesting a rapid learning process. These results suggest that our paradigm in Experiment 2 seems to be a viable online tool to monitor the behavioral correlates of unsupervised implicit VSL.

COVID-19 infection in patients with chronic obstructive pulmonary disease: From pathophysiology to therapy. Mini-review.

INTRODUCTION: Patients with chronic obstructive pulmonary disease (COPD) are a vulnerable group in terms of the outcome of coronavirus infection in relation to their disease or its treatment, with a higher risk of developing serious complications compared to the healthy population. AIM: The aim of our summary study is to review the background and health outcomes of chronic obstructive pulmonary disease and COVID-19 infection in the presence of both diseases. METHODS: Review of national and international medical databases (PubMed, MEDLINE, and MOB) with keywords COPD, COVID-19, disease risk, cause, prevention, complications, and prognosis. RESULTS: Meta-analyses show that COPD is one of the most common underlying conditions in patients hospitalized for COVID-19. Such patients are five times more likely to develop a serious complication due to oxygen supply problems therefore they are more likely to be admitted to intensive care units, where they may require mechanical ventilation. In the case of underlying COPD, the usual care plan for COVID-19 infection should be followed, as well as all public health recommendations to minimize the risk of developing and transmitting COVID-19. CONCLUSION: Coronavirus infection is especially dangerous for COPD patients, who are much more likely to become seriously ill, so increased surveillance, prevention, early detection, adequate treatment and rehabilitation of the disease group are of paramount importance.

Co-infections in COVID-19 patients and correlation with mortality rate. Minireview.

PURPOSE: The goal of our review was to gather information on the most important community-acquired and hospital-acquired co-infections among coronavirus disease 2019 (COVID-19) patients, and to examine not only the effect of these co-infections on disease outcomes but also to identify the possible risk factors that predispose COVID-19 patients to co-infections. METHODS: Medline (PubMed) and Google Scholar were searched for relevant articles published between January 1st, 2020, and September 31st, 2021, on the topic of co-infections among COVID-19 patients. RESULTS: Among community-acquired and hospital-acquired co-infections, bacterial and fungal co-infections are equally frequent, followed by viral co-infections that affected a relatively smaller portion of patients. Overall, co-infections were more frequent in the hospital than at the community level. Risk factors for acquiring co-infections include male gender, longer length of hospital stay, presence of supportive treatment, such as ventilation, the admission to intensive care units, the administration of medications, such as steroids or antibiotics, and certain blood parameters, such as high C-reactive protein or lymphopenia. The presence of co-infections could aggravate the COVID-19 disease severity, prolong the healing time of patients, and lead to worse disease outcomes overall. CONCLUSION: Co-infections may increase the mortality of COVID-19 patients, especially in the hospital setting. Paying closer attention to hygiene, adhering to diagnostic and therapeutic protocols, implementing antimicrobial stewardship programs could decrease the occurrence of co-infections and lead to improved outcomes for COVID-19 patients.

Nutrition Strategies Promoting Healthy Aging: From Improvement of Cardiovascular and Brain Health to Prevention of Age-Associated Diseases.

BACKGROUND: An increasing number of studies suggest that diet plays an important role in regulating aging processes and modulates the development of the most important age-related diseases. OBJECTIVE: The aim of this review is to provide an overview of the relationship between nutrition and critical age-associated diseases. METHODS: A literature review was conducted to survey recent pre-clinical and clinical findings related to the role of nutritional factors in modulation of fundamental cellular and molecular mechanisms of aging and their role in prevention of the genesis of the diseases of aging. RESULTS: Studies show that the development of cardiovascular and cerebrovascular diseases, neurodegenerative diseases, cognitive impairment and dementia can be slowed down or prevented by certain diets with anti-aging action. The protective effects of diets, at least in part, may be mediated by their beneficial macro- (protein, fat, carbohydrate) and micronutrient (vitamins, minerals) composition. CONCLUSIONS: Certain diets, such as the Mediterranean diet, may play a significant role in healthy aging by preventing the onset of certain diseases and by improving the aging process itself. This latter can be strengthened by incorporating fasting elements into the diet. As dietary recommendations change with age, this should be taken into consideration as well, when developing a diet tailored to the needs of elderly individuals. Future and ongoing clinical studies on complex anti-aging dietary interventions translating the results of preclinical investigations are expected to lead to novel nutritional guidelines for older adults in the near future.

Management of antiplatelet therapy in acute coronary syndrome patients with thrombocytopenia / Akut coronaria szindrómán átesett thrombocytopeniás betegek thrombocytaaggregáció-gátló gyógyszeres kezelése.

Összefoglaló. Az akut coronaria szindrómán (ACS) átesett betegek kezelésének alappillére a kettos (aszpirin + klopidogrél ) thrombocytaaggregáció-gátló kezelés. Az immunthrombocytopeniás purpurás (ITP-s) betegek - és különösen azok, akik refrakter ITP miatt thrombopoetinanalóg kezelésben részesülnek - külön elbírálást igényelnek. 50-100 G/l thrombocytaszám közötti és vérzéses szövodménnyel nem rendelkezo ACS-s betegeken a gyógyszerkibocsátó stent beültetését követoen kettos thrombocytaaggregáció-gátló kezelést csak 1 hónapig kell alkalmazni (ez az idotartam átlagos vérzéses rizikójú betegeken 1 év), majd klopidogrél-monoterápia javasolt. Munkánk során a 2015. január 1. és 2020. október 1. között a Semmelweis Egyetem I. Belgyógyászati Klinikáján kezelt ITP-s betegek körében vizsgáltuk az ACS elofordulását és lefolyását. Klinikánkon az elmúlt 5 évben gondozott, 168 ITP-s beteg közül 3 beteg esetében alakult ki ACS. A refrakter ITP kezelésének részeként mind a 3 beteg thrombopoetinanalóg - (2 beteg romiplosztim-, 1 beteg eltrombopág-) kezelésben részesült. A 3 ITP-s betegünk egyikénél sem alakult ki vérzéses szövodmény a thrombopoetinanalóg-kezelés és a thrombocytaaggregáció-gátlás mellett. Elso betegünk esetében 5 év alatt három alkalommal alakult ki ACS (egy ízben fémstentet és két alkalommal gyógyszerkibocsátó stentet kapott). A második betegnél két alkalommal (1 év különbséggel), a harmadik betegnél egy esetben történt gyógyszerkibocsátó stent beültetése. ITP és ACS együttes fennállása esetén az akut és a hosszú távú gyógyszeres kezelés egyéni mérlegelést igényel. Ezen speciális betegcsoport számára a kezelési irányelv kidolgozása megfontolandó. Orv Hetil. 2021; 162(33): 1335-1340. Summary. Dual antiplatelet therapy (DAPT) consisting of aspirin and clopidogrel is essential in the treatment of acute coronary syndrome (ACS). Immune thrombocytopenic purpura (ITP) patients - and especially those receiving thrombopoietin analog (TPO) treatment - deserve special attention. In ACS patients with platelet counts between 50 G/L and 100 G/L and no bleeding symptoms, DAPT is indicated for 1 month after the placement of new generation drug-eluting stents (the length of treatment is 1 year in the case of patients with average bleeding risk) followed by clopidogrel monotherapy. In patients with average bleeding risk, DAPT is recommended for 1 year after the ACS. Our aim was to investigate the incidence and outcome of ACS in ITP patients, who were treated in our clinic between 1st January 2015 and 1st October 2020. Out of 168 patients treated for ITP, 3 patients suffered from ACS in the last 5 years. These patients received TPO treatment (2 patients subcutan romiplostim, 1 patient oral eltrombopag). None of these ITP patients treated with DAPT and with TPO analog suffered from bleeding complications. 1 patient developed ACS three times within the last 5 years (he received bare-metal stent once and drug-eluting stent twice). Drug-eluting stent was placed once in the third, and twice (with 1 year difference) in the second patient. Acute and long-term medication of patients suffering from both ITP and ACS is a challenging task and needs individual evaluation. Establishment of treatment guidelines for this special group is warranted. Orv Hetil. 2021; 162(33): 1335-1340.

Fatal outcome of cervical myelopathy caused by fibrocartilaginous embolism. Rare cause of spinal vascular damage.

BACKGROUND AND PURPOSE: Fibrocartilaginous embolism is a rare cause of ischemic myelopathy. Authors report a case of a 39-year-old woman with progressive tetraparesis and severe autonomic dysfunction. Despite of the detailed examinations, the definite diagnosis was verified by autopsy. METHODS: The patient was admitted because of progressive pain and numbness of the upper extremities and tetraparesis. Hypotonic muscles of the lower extremities with mild tetraparesis were observed. Magnetic resonance imaging showed an intramedullary lesion at the level of the cervical V-VII vertebral. Patient's tetraparesis worsened gradually to plegia with urinary retention. Expansive, rapidly progressing multiple decubiti developed, which were resistant to therapy. In spite of the complex therapy, the patient died. RESULTS: No internal disease was found to explain the death by autopsy. Multiple subacute infarctions of the cervical myelon (involving the lateral columns as well) in the territory of the anterior spinal artery were verified by neuropathological examination. The occluded vessels were filled by a material containing cartilaginous cells, while signs of atherosclerosis or thrombosis were not present. CONCLUSION: Cartilaginous embolism of spinal arteries was diagnosed.

Hypercalcemia and renal insufficiency ­ where can we start? / Hypercalcaemia és veseelégtelenség - merre induljunk?

Összefoglaló. Közleményünkben egy 63 éves férfi esetét ismertetjük, aki fáradékonyság, fogyás miatt végzett laboratóriumi vizsgálatokon igazolódó veseelégtelenség és hypercalcaemia miatt került felvételre Klinikánkra. A területen végzett röntgenvizsgálaton a koponyán frontalisan és a sacrumon csonteltérések (temporofrontalisan 13 mm-es, körülírtabb, mérsékelten intenzív árnyék és az S1-es rés sclerosisa) ábrázolódtak, ultrahangvizsgálat során lépmegnagyobbodás volt látható. Tünetei hátterében endokrin vagy malignus betegség nem igazolódott. A háttérben elsosorban myeloma multiplex merült fel, ugyanakkor azt célzott vizsgálatokkal sem megerosíteni, sem kizárni nem lehetett, így csontvelo-biopszia történt. A vesefunkció-romlás okának tisztázása végett vesebiopsziát végeztünk, melynek elozetes eredménye interstitialis nephritist véleményezett óriássejtekkel. Az angiotenzinkonvertáló enzim szérumszintjének ez okból történo vizsgálata emelkedett szintet mutatott, így esetünket Boeck-sarcoidosis extrapulmonalis manifesztációjának tartottuk. Per os szteroidkezelésre a beteg tünetei egyértelmu regressziót mutattak. A csontvelo- és vesebiopszia eredménye megerosítette a Boeck-sarcoidosis diagnózisát. A sarcoidosis ezen extrapulmonalis formája hypercalcaemiával és veseérintettséggel - de tüdoérintettség nélkül - rendkívül ritka, különös tekintettel a vesét érinto formára. Hypercalcaemia nagyjából 7,9%-ban, veseelégtelenség 1,4%-ban fordul elo. Ezen eset alapján fontos hangsúlyozni, hogy a hypercalcaemia és a veseelégtelenség hátterében a gyakoribb endokrin, malignus, hematológiai okok mellett a Boeck-sarcoidosisnak is fel kell merülnie a differenciáldiagnosztika során. Orv Hetil. 2021; 162(13): 514-518. Summary. We present the case of a 63-year-old male patient who was admitted to our Clinic with fatigue, weight loss, hypercalcemia, renal insufficiency and anemia. X-ray showed lesions on the frontal skull and sacral region. On abdominal ultrasound, splenomegaly was detected. Based on these, myeloma multiplex was the most likely initial diagnosis; this, however, could not be confirmed with targeted serum tests, therefore bone marrow biopsy was performed. To clarify the underlying cause of decreased kidney function, renal biopsy was performed, the preliminary results of which revealed interstitial nephritis accompanied by giant cells. Serum angiotensin converting enzyme level was elevated, which led to the diagnosis of Boeck sarcoidosis with extrapulmonary manifestations. Oral corticosteroid therapy was commenced that was followed by regression of the patient's symptoms and laboratory abnormalities. Both the bone marrow and the kidney biopsies supported the diagnosis of Boeck sarcoidosis. Presentation of sarcoidosis with hypercalcemia and renal insufficiency but without the involvement of the lungs is extremely rare. Hypercalcemia occurs in about 7.9% and renal insufficiency in 1.4% of the cases. Based on this case, it is important to highlight that in the background of hypercalcemia and renal failure - beside the more frequent causes such as endocrine and hematological diseases, malignancy - one is to consider the possibility of Boeck sarcoidosis as well. Orv Hetil. 2021; 162(13): 514-518.

Visually guided associative learning in pediatric and adult migraine without aura.

INTRODUCTION: The Rutgers Acquired Equivalence Test is a visually guided equivalence learning paradigm that involves rule acquisition and generalization. Earlier we found impaired performance in this paradigm among adult migraine patients without aura. The aim of the study was to investigate if similar impairments can be found already in the pediatric form of the disease and to compare the performance of the pediatric study population with that of an adult study population. We hypothesized that the deficits observed in adults would be observable already in the pediatric population. METHODS: Twenty-seven children and adolescents newly diagnosed with migraine without aura and 27 age- and sex-matched healthy controls were tested with the Rutgers Acquired Equivalence Test. Their performance data were compared to each other and those of an earlier adult study population involving 22 patients and 22 age- and sex-matched healthy controls. Four parameters characterizing performance in the two main phases of the paradigm were calculated for each of the four groups. Performance parameters were compared with Mann-Whitney U test. RESULTS: In contrast to the decreased performance of the adult patients in the Rutgers Acquired Equivalence Test, no significant difference was found between pediatric patients and controls in any phase of the paradigm. CONCLUSION: Children living with migraine without aura do not exhibit the same cognitive deficits in the Rutgers Acquired Equivalence Test as their adult counterparts. It can be hypothesized that the deficit of equivalence learning is not an inherent feature of the migrainous cognitive profile, rather the result of the interference of the disease with normal development.

[Medical students' knowledge on vaccinology]. / Az orvostanhallgatók vakcinológiai tájékozottsága.

Introduction: The mistrust of vaccinations is already experienced among physicians. It is important for physicians to be well informed, able to convince their patients of the usefulness of vaccinations and set good example for them in this field. Aim: The aim of the study was to assess the vaccine knowledge and attitudes of the general medical students of Semmelweis University and their attitudes towards vaccinations before and after the education of 'Public Health and Preventive Medicine'. Emphasis was placed on the students' opinion on the vaccines against influenza, measles and hepatitis B virus and their effectiveness. Method: Data collection was done with volunteer participants, using anonymous self-administered questionnaires. The relationship between education and vaccination coverage was proved by calculating Pearson's correlation and one-way analysis of variance. Results: The knowledge of medical students is incomplete, with negative attitudes towards vaccination against influenza. Generally, respondents found the vaccines useful, but only two-thirds of them considered the influenza vaccine to be important. Students had 6.5% flu vaccination coverage before education, and 24% after education. Two-thirds (67.8%) of the students were aware that the flu vaccine could be given during an epidemic. Surprisingly, the importance of hand washing has been given a greater role in the primary prevention of influenza than flu vaccine. Conclusions: Education plays an important role in shaping the attitudes and responsible behaviour of future physicians. They need to acquire reliable knowledge to persuade their patients as practitioners to use the most effective means of primary prevention of infectious diseases. A change of attitude is needed to stop the route of infection through vaccination, to protect not only their own health but also that of their environment and thus of their patients. Orv Hetil. 2019; 160(30): 1193-1199.

[Relationship of chronic obstructive pulmonary disease and nutritional status - clinical observations]. / Krónikus légzoszervi betegek tápláltsági állapotának vizsgálata ­ klinikai megfigyelések.

Introduction: The increased metabolism of nutrients and the low energy intake may lead to malnutrition among chronic obstructive pulmonary disease (COPD) patients. Aim: The goal of our study was to examine the nutritional status of our population aged over 40, and its relationship with the severity of the disease. Method: We conducted a retrospective study at the National Korányi Institute of Pulmonology in 2017. Pulmonary function and anthropometric data were obtained from the electronic health record system. Inclusion criteria were age over 40 and the diagnosis of COPD. Severity of disease was assessed by forced expiration volume and categorized according to GOLD stages. We used SPSS Statistics V22.0 for data analysis. Results: The mean age of participants was 66; 49.3% were men, 50.7% were women. Average BMI was 27.14 kg/m², with values comprising cachexia and severe obesity. According to the FEV1%pred results of the 3236 patients, 30% fell in the GOLD I, 40% in the GOLD II, 23% in the GOLD III, and 7% in the GOLD IV categories. Pearson coefficient found positive correlation between FEV1 and nutritional status (H = 0.2297, r = 0.1401), specifically between severity of cachexia and severity of disease. The analysis of variance showed significant correlation between severity of disease and nutritional status; patients with higher BMI had better pulmonary function. Conclusion: Malnutrition had an adverse effect on pulmonary functions and performance of respiratory muscles, whereas higher BMI had a positive effect on FEV1. Our results suggest that BMI could be used as a lung function prognostic indicator for COPD patients. Orv Hetil. 2019; 160(23): 908-913.

Association study of the ABCA7 rs3752246 polymorphism in Alzheimer's disease.

The ATP-binding cassette, sub-family A, member 7 (ABCA7) gene has been identified as a strong genetic risk locus for Alzheimer's disease (AD). Our case-control study (416 AD patients and 302 controls) provides further data on the rs3752246 polymorphism in AD in the Hungarian population that has not been investigated so far regarding the ABCA7 gene variants. A modest, marginally significant association of the G allele containing genotypes with AD was observed (p = 0.054). In line with the previous results in other populations, the G allele carriers had an increased risk for developing AD considering C/C genotype as reference category.

Electroporation-enhanced transdermal diclofenac sodium delivery into the knee joint in a rat model of acute arthritis.

PURPOSE: Since electroporation (EP) can increase the permeability of biological membranes, we hypothesized that it offers an opportunity to enhance the transdermal delivery of drugs for intra-articular indications. Our aim was to compare the anti-inflammatory and analgesic efficacy of EP-combined topical administration of diclofenac sodium hydrogel (50 mg mL-1 in 230 µL volume) with that of an equivalent dose of oral (75 mg kg-1) and simple topical administration. METHODS: Arthritis was induced with the injection of 2% λ-carrageenan and 4% kaolin into the right knee joints of male Sprague Dawley rats. EP was applied for 8 min with 900 V high-voltage pulses for 5 ms followed by a 20 ms break. Drug penetration into the synovial fluid and plasma was detected by high-performance liquid chromatography. Leukocyte-endothelial interactions were visualized by intravital videomicroscopy on the internal surface of the synovium. Inflammation-induced thermal and mechanical hyperalgesia reactions, knee joint edema, and inflammatory enzyme activities were assessed at 24 and 48 h after arthritis induction. RESULTS: EP significantly increased the plasma level of diclofenac as compared with the topical controls 10 min after the 2% λ-carrageenan and 4% kaolin injection. Increased leukocyte-endothelial interactions were accompanied by joint inflammation, which was significantly reduced by oral and EP diclofenac (by 45% and by 30%, respectively) and only slightly ameliorated by simple topical diclofenac treatment (by 18%). The arthritis-related secondary hyperalgesic reactions were significantly ameliorated by oral and EP-enhanced topical diclofenac treatments. The knee cross-section area (which increased by 35%) was also reduced with both approaches. However, simple topical application did not influence the development of joint edema and secondary hyperalgesia. CONCLUSION: The study provides evidence for the first time of the potent anti-inflammatory and analgesic effects of EP-enhanced topical diclofenac during arthritis. The therapeutic benefit provided by EP is comparable with that of oral diclofenac; EP is a useful alternative to conventional routes of administration.

ABCA1 rs2230805 and rs2230806 common gene variants are associated with Alzheimer's disease.

The ATP-binding cassette, sub-family A, member 1 gene (ABCA1) is a relevant positional and functional candidate gene for Alzheimer's disease (AD). A case-control association study of genetic variations covering the ABCA1 locus was performed in relation to AD risk in a Hungarian sample. Five single nucleotide polymorphisms (rs2422493: C-477T, rs2740483: G-17C, rs2230805: G474A/L158L, rs2230806: G656A/R219K and rs2066718: G2311A/V771M) were genotyped in 431 AD patients and 302 cognitively healthy, elderly controls. In single marker analysis, significant associations were found in the case of rs2230805 and rs2230806 polymorphisms: the minor A allele containing genotypes for both polymorphisms were more frequent in the control compared to the AD group. Haplotype analysis revealed that rs2230805, rs2230806 and rs2066718 polymorphisms created a linkage disequilibrium (LD) block with a strong LD between rs2230805 and rs2230806 polymorphisms. In the haplotype risk association tests, A-A-G haplotype of the rs2230805-rs2230806-rs2066718 polymorphisms was found to be nominally significantly more frequent in the control group. After correcting p values for multiple testing, only the effects of the rs2230805 and rs2230806 polymorphisms remained significant in the recessive model suggesting a modest protective effect of their minor alleles in AD, which should be interpreted with considerable caution, until further studies elucidate their role in AD pathology.

New opioid receptor antagonist: Naltrexone-14-O-sulfate synthesis and pharmacology.

Opioid antagonists, naloxone and naltrexone have long been used in clinical practice and research. In addition to their low selectivity, they easily pass through the blood-brain barrier. Quaternization of the amine group in these molecules, (e.g. methylnaltrexone) results in negligible CNS penetration. In addition, zwitterionic compounds have been reported to have limited CNS access. The current study, for the first time gives report on the synthesis and the in vitro [competition binding, G-protein activation, isolated mouse vas deferens (MVD) and mouse colon assay] pharmacology of the zwitterionic compound, naltrexone-14-O-sulfate. Naltrexone, naloxone, and its 14-O-sulfate analogue were used as reference compounds. In competition binding assays, naltrexone-14-O-sulfate showed lower affinity for µ, δ or κ opioid receptor than the parent molecule, naltrexone. However, the µ/κ opioid receptor selectivity ratio significantly improved, indicating better selectivity. Similar tendency was observed for naloxone-14-O-sulfate when compared to naloxone. Naltrexone-14-O-sulfate failed to activate [35S]GTPγS-binding but inhibit the activation evoked by opioid agonists (DAMGO, Ile5,6deltorphin II and U69593), similarly to the reference compounds. Schild plot constructed in MVD revealed that naltrexone-14-O-sulfate acts as a competitive antagonist. In mouse colon, naltrexone-14-O-sulfate antagonized the inhibitory effect of morphine with lower affinity compared to naltrexone and higher affinity when compared to naloxone or naloxone-14-O-sulfate. In vivo (mouse tail-flick test), subcutaneously injected naltrexone-14-O-sulfate antagonized morphine's antinociception in a dose-dependent manner, indicating it's CNS penetration, which was unexpected from such zwitter ionic structure. Future studies are needed to evaluate it's pharmacokinetic profile.

Stress, Neuropeptides and Gastric Mucosa.

Exposure of the organism to a hostile stimulus results in a series of coordinated reactions that aim to avoid the aversive effect and maintain or restore homeostasis of the organism. In response to noxious stimuli corticotropin-releasing factor (CRF), the primary mediator of stress responses is released from the paraventricular nucleus resulting in activation of the hypothalamic-pituitary-adrenocortical axis and coordination of the endocrine, autonomic, behavioral and immune responses to stress. Several other neuropeptides, released in a coordinated way are also involved in the regulation of the stress response. However, besides the development of adaptive physiological, beneficial reactions, pathological, non-desired somatic and psychic responses can also develop, among others: gastric mucosal damage, erosion and ulceration. The mechanism of stress-related gastric mucosal injury is not fully understood; both mucosal injurious and protective mechanisms are activated in response to stress. Decreased mucosal circulation due to redistribution of blood flow from the visceral region toward the vital organs seems to be the primary mechanism of gastric mucosal damage. Mucosal hypoperfusion can result in mucosal ischemia, free radical formation and gastric hypomotiliy. On the other hand, several stressrelated neuropeptides, such as CRF, SP, N/OFQ, opioids, oxytocin and prolactin have been reported to inhibit the stress- and other ulcerogenic stimulus-induced mucosal lesions independently on their effect on other stressrelated symptoms. Consequently, neuropeptides released during stress, besides their numerous physiological and pathophysiological functions, may initiate adaptive mechanisms as well as counteract the stress-induced gastric mucosal injury.