bluuebunny/crossref_metadata_2025_split huggingface dataset:
Comparison of different techniques for evaluation of cellular immunity to SARS-CoV-2 virus
Authors: Afridonova Z. E. , Toptygina A. P. , Bogolyubova A. V. , Semikina E. L. 
Published: January 2024

Most techniques for evaluation of T-cell immunity are laborious and unsuitable for routine laboratory diagnostics, thus encouraging researchers to look for accessible and reproducible tests. The purpose of our study is to compare three methods aimed for evaluation of cellular immune response levels to the SARS-CoV-2 viral antigens in patients who have been ill and vaccinated against a new coronavirus infection. We have examined 26 persons who experienced mild or moderate COVID-19 (group 1); 19 people vaccinated twice with Sputnik V, who did not have clinical COVID-19 (group 2); 21 subjects who had COVID-19 and were twice vaccinated with Sputnik V (group 3), and 14 persons who had COVID-19 twice (group 4). Peripheral blood mononuclear cells were isolated by gradient centrifugation. The first tested technique was performed as follows: the mononuclear cells were incubated with the S-protein of the SARS-CoV-2 virus, and stained with fluorescently labeled antibodies. The percentage of CD8highCD107a was counted by means of BD FACS Canto II flow cytometer. When assessed by the ELISpot method with “Human IFN-γ ELISpot” kit, IFNγ production was stimulated by SARS-CoV-2 S-protein, or a mixture of SARS-CoV-2 protein peptides in the “Corona-T-test” kit. There were no significant differences in the levels of CD107a expression on CD8high cells between the groups 1, 2, 3, and 4, as well as in amounts of IFNγ producers against SARS-CoV-2 S-protein when using “Human IFN-γ ELISpot” kit. Production of IFN was significantly lower in group 3 (hybrid immunity), i.e., 317.29±19.04 pg/ml compared to groups 1 and 2 (post-infection and post-vaccination immunity), i.e., 454.95±20.32 and 470.77±26.24 pg /ml, respectively. The relative level of IFNγ -producing cells in group 2 was higher (22.34±3.77) versus 16.83±2.35 in group 1, and 15.46±1.83 in group 3, whereas the relative levels of IFNγ did not differ in these groups. Stimulation with full-length S-protein showed a significant reduction in the number of spots in group 4 (breakthrough immunity), i.e., 30.59±2.29 vs 58.97±4.47 in group 3. Stimulation with a mixture of SARS-CoV-2 peptides in group 4 vs group 3 revealed a significantly increased number of IFNγ -producing cells (86.72±7.20 versus 69.38±5.53) and higher IFNγ production (991.25±65.18 pg/ml versus 760.76±50.70 pg/ml). Appropriate relative values were as follows: 10.30±2.77 versus 8.61±2.66, and 68.10±9.41 versus 48.35±8.15, respectively. The results of three methods for evaluation of cellular immune response correlate positively with each other, but at different significance levels.
γδT cells in patients with tumors of the nasal cavity and paranasal sinuses
Authors: Nizheharodava D. B. , Kolyadich J. V. , Marozava N. A. , Zafranskaya M. M. 
Published: January 2024

The immunological factors can play an important role as predictive and prognostic biomarkers in oncopathology. Recently, non-conventional innate-like γδT-lymphocytes have received a lot of attention as a promising effector cell population for cancer immunotherapy. This study describes structural and functional subpopulations of γδT lymphocytes involved in antitumor immunity in patients with malignant and benign tumors of the nasal cavity and paranasal sinuses. The aim of the study was to estimate γδT cell subsets composition and functions in patients with neoplasms of nasal cavity and paranasal sinuses in order to characterize cellular immunity in tumor-associated pathological process.The peripheral venous blood was obtained from 21 patients (13 men and 8 women, average age of 63.0 (56.0-69.0) y. o.) with neoplasms of nasal cavity and paranasal sinuses, and 10 healthy donors. Lymphoid cells phenotype and production of intracellular cytokines were investigated using monoclonal antibodies and flow cytometry, production of extracellular cytokines was measured using enzyme-linked immunosorbent assay kits.The increase of total γδT cells number in patients with squamous cell carcinoma accompanied by changes in Vγ2+/Vγ1+T cells ratio in peripheral blood of both patients’ groups with malignant and benign nasal cavity and paranasal sinuses tumors were revealed as compared to healthy donors. The upregulated γδT cell response to phosphoantigen induction in combination with reduced indices of stimulations were shown in the both patients groups but cytokine profile was different, i.e., the elevated IFNγ production has been determined in patients with squamous cell carcinoma. However, in patients with inverted papilloma, redistribution of γδT cell subsets has been associated with IL-17-producing γδT cells. Moreover, the percent of IFNγ+γδT lymphocytes did correlate with IFNγ concentration in cell culture supernatants of patients with malignant nasal cavity and paranasal sinuses neoplasms (R = 0.61; p < 0.05).The revealed data suggest an involvement of γδT lymphocytes in malignant and benign tumor pathogenesis and may provide a fundamental basis for further detection of possible tumor-associated inflammation and malignization predictors.
Some reflections on immunosuppressants and their delivery to the lungs by aerosol in the treatment of COVID-19
Authors: Kobylyansky V. I. 
Published: January 2024

Disorders of immune homeostasis represent the key pathogenetic link of COVID-19, which often manifests as a hyperimmune response to the pathogen, leading to severe uncontrolled inflammation in lungs, followed by complications and death. Accordingly, a certain therapeutic potential is provided by different pharmacological drugs with distinct mechanisms of action, This class of drugs should, however, act in common direction by suppressing the immune response, thus being often classified as immunosuppressants (IS). Of them, the most promising are immunobiological preparations, which include monoclonal antibodies, as well as purinergic regulatory agents. There are several attempts to use the “classical” IS by a certain way, e.g., cytostatics and calcineurin inhibitors which found clinical application in transplantology and oncology. However, their usage for treatment of uncontrolled inflammation of respiratory tract was abandoned by the end of XX century. Meanwhile, the aerosol route of drug administration optimizes treatment, both in terms of their effectiveness, and the reduction of side effects thus promoting usage of IS for treatment of uncontrolled airway inflammation. Previously, the analysis of therapeutic opportunities for some IS delivered as aerosols to the lungs in COVID-19 therapy was not carried out, thus bein the purpose of our work. Methodological analysis was carried out using various databases of biomedical scientific information, including Index Medicus, PubMed, Embase, Cohrane Clinical Trials gov registry and patent databases.The efficiency of the impact of various IS subgroups in COVID-19, including their administration by inhalations into the respiratory ways, was assessed. The role of regulatory T cells considered the central regulator of immune response, in pathogenesis of COVID-19 was considered, and their therapeutic potential was characterized, dependent on phase and severity of the disease as well as drug dose dependence. Methods and approaches to the use of IP, advantages and disadvantages are discussed. The expediency and future prospects of their application are considered.One may conclude that the effectiveness of cytostatics and calcineurin inhibitors in the treatment of airway inflammation in COVID-19 remains unconfirmed and seems to be unpromising. Meanwhile, biological preparations, including monoclonal antibodies and purinergic regulatory agents, offer great promise in this respect.
VALOR-CKD: A Multicenter, Randomized, Double-Blind Placebo-Controlled Trial Evaluating Veverimer in Slowing Progression of CKD in Patients with Metabolic Acidosis
Authors: Tangri Navdeep , Mathur Vandana S. , Bushinsky David A. , Klaerner Gerrit , Li Elizabeth , Parsell Dawn , Stasiv Yuri , Walker Michael , Wesson Donald E. , Wheeler David C. , Perkovic Vlado , Inker Lesley A. 
Published: January 2024

Significance Statement
Metabolic acidosis is a common complication of CKD and is associated with more rapid decline of kidney function, but well-powered controlled randomized trials testing the effect of treating metabolic acidosis on slowing CKD progression have not been conducted. The VALOR-CKD study randomized 1480 individuals with CKD and metabolic acidosis, across 320 sites to placebo or veverimer (a novel hydrochloric acid binder). The findings did not demonstrate the efficacy of veverimer in slowing CKD progression, but the difference in serum bicarbonate between placebo and drug arms was only approximately 1 mEq/L. Veverimer was safe and well tolerated.

Background
Metabolic acidosis is common in CKD, but whether its treatment slows CKD progression is unknown. Veverimer, a novel hydrochloric acid binder that removes acid from the gastrointestinal tract, leads to an increase in serum bicarbonate.

Methods
In a phase 3, double-blind, placebo-controlled trial, patients with CKD (eGFR of 20–40 ml/min per 1.73 m2) and metabolic acidosis (serum bicarbonate of 12–20 mEq/L) from 35 countries were randomized to veverimer or placebo. The primary outcome was the composite end point of CKD progression, defined as the development of ESKD (kidney transplantation or maintenance dialysis), a sustained decline in eGFR of ≥40% from baseline, or death due to kidney failure.

Results
The mean (±SD) baseline eGFR was 29.2±6.3 ml/min per 1.73 m2, and serum bicarbonate was 17.5±1.4 mEq/L; this increased to 23.4±2.0 mEq/L after the active treatment run-in. After randomized withdrawal, the mean serum bicarbonate was 22.0±3.0 mEq/L and 20.9±3.3 mEq/L in the veverimer and placebo groups at month 3, and this approximately 1 mEq/L difference remained stable for the first 24 months. A primary end point event occurred in 149/741 and 148/739 patients in the veverimer and placebo groups, respectively (hazard ratio, 0.99; 95% confidence interval, 0.8 to 1.2; P = 0.90). Serious and overall adverse event incidence did not differ between the groups.

Conclusions
Among patients with CKD and metabolic acidosis, treatment with veverimer did not slow CKD progression. The lower than expected bicarbonate separation may have hindered the ability to test the hypothesis.

Clinical Trial registry name and registration number
VALOR-CKD, NCT03710291.
DEPDC5 mutation and familial focal epilepsy with variable foci: genotype and phenotype of a family
Authors: Aberastury Marina , Fernández Romina , Córdoba Marta , Comas Betiana , Peralta Martín , Agosta Guillermo , Kauffman Marcelo , Silva Walter 
Published: January 2024

ABSTRACTAims. Familial focal epilepsy with variable foci is a relatively rare autosomal disease with an unclear incidence, which is characterized by focal seizures arising from different cortical regions in different family members.Methods. We describe three members of a two‐generation Argentine family with familial focal epilepsy with variable foci syndrome and a DEPDC5 gene mutation.Results. The mean onset age was nine years old. The father experienced episodes with occipital semiology and both siblings exhibited frontal lobe seizures. Their neurological examination and neuroimaging studies were normal. All three patients are currently seizure‐free, in spite of initially experiencing frequent seizures. Complete exome sequencing revealed a new DEPDC5 gene mutation (NM_001242896: c.4718T>C; p.L1573P).Conclusions. This study of a family with clinical characteristics that met all the criteria for familial focal epilepsy with variable foci demonstrates the usefulness of exome sequencing as a diagnostic tool. [Published with video sequence on www.epilepticdisorders.com]
Quinidine therapy and therapeutic drug monitoring in four patients with KCNT1 mutations
Authors: Yoshitomi Shinsaku , Takahashi Yukitoshi , Yamaguchi Tokito , Oboshi Taikan , Horino Asako , Ikeda Hiroko , Imai Katsumi , Okanishi Tohru , Nakashima Mitsuko , Saitsu Hirotomo , Matsumoto Naomichi , Yoshimoto Jun , Fujita Takako , Ishii Atsushi , Hirose Shinichi , Inoue Yushi 
Published: January 2024

ABSTRACTAims. Several recent studies have reported potassium sodium‐activated channel subfamily T member 1 (KCNT1) mutations in epilepsy patients on quinidine therapy. The efficacy and safety of quinidine for epilepsy treatment, however, remains controversial.Methods. We herein report the cases of four patients with KCNT1 mutations treated with quinidine.Results. A reduction in seizures of more than 50% after quinidine treatment was observed in one patient with epilepsy of infancy with migrating focal seizures (EIMFS), whereas two patients with EIMFS and one with focal epilepsy did not achieve apparent seizure reduction. The relationship between quinidine dose and serum quinidine concentration was inconsistent, particularly at high quinidine doses. One patient with EIMFS developed ventricular tachycardia the day after an increase in quinidine dose from 114 to 126 mg/kg/day. The serum trough quinidine concentration and the corrected QT interval (QTc) before arrhythmia onset were 2.4 μg/ml and 420 ms, respectively, and peak serum quinidine concentration after arrhythmia onset was 9.4 μg/ml. Another patient with EIMFS showed aberrant intraventricular conduction with a quinidine dose of 74.5 mg/kg/day and a serum trough concentration of 3.2 μg/ml.Conclusions. Given that serum quinidine levels may elevate sharply after a dose increase, careful monitoring of electrocardiographs and serum concentrations is required. Based on a review of previous reports and our experience with this case, quinidine should be considered as a promising drug for patients with EIMFS harbouring KCNT1 mutations, however, its efficacy remains controversial due to the limited number of cases, and more information on optimal serum concentrations and appropriate titration methods is required.
Berardinelli‐Seip syndrome and progressive myoclonus epilepsy
Authors: Serino Domenico , Davico Chiara , Specchio Nicola , Marras Carlo Efisio , Fioretto Franco 
Published: January 2024

ABSTRACTBerardinelli‐Seip syndrome, or congenital generalized lipodystrophy type 2 (CGL2), is characterized by a lack of subcutaneous adipose tissue and precocious metabolic syndrome with insulin resistance, resulting in diabetes, dyslipidaemia, hepatic steatosis, cardiomyopathy, and acanthosis nigricans. Most reported mutations are associated with mild, non‐progressive neurological impairment. We describe the clinical and EEG data of a patient with progressive myoclonus epilepsy (PME), CGL2, and progressive neurological impairment, carrying a homozygous BSCL2 nonsense mutation. The patient had epilepsy onset at the age of two, characterized by monthly generalized tonic‐clonic seizures. By the age of three, he presented with drug‐resistant ongoing myoclonic absence seizures, photosensitivity, progressive neurological degeneration, and moderate cognitive delay. Molecular analysis of the BSCL2 gene yielded a homozygous c.(1076dupC) p.(Glu360*) mutation. Application of a vagus nerve stimulator led to temporary improvement in seizure frequency, general neurological condition, and EEG background activity. Specific BSCL2 mutations may lead to a peculiar CGL2 phenotype characterized by PME and progressive neurodegeneration. Application of a vagus nerve stimulator, rarely used for PMEs, may prove beneficial, if only temporarily, for both seizure frequency and general neurological condition.
Antiepileptic drugs: evolution of our knowledge and changes in drug trials
Authors: Perucca Emilio 
Published: January 2024

ABSTRACT
Clinical trials provide the evidence needed for rational use of medicines. The evolution of drug trials follows largely the evolution of regulatory requirements. This article summarizes methodological changes in antiepileptic drug trials and associated advances in knowledge starting from 1938, the year phenytoin was introduced and also the year when evidence of safety was made a requirement for the marketing of medicines in the United States. The first period (1938–1969) saw the introduction of over 20 new drugs for epilepsy, many of which did not withstand the test of time. Only few well controlled trials were completed in that period and trial designs were generally suboptimal due to methodological constraints. The intermediate period (1970–1988) did not see the introduction of any major new medication, but important therapeutic advances took place due to improved understanding of the properties of available drugs. The value of therapeutic drug monitoring and monotherapy were recognized during the intermediate period, which also saw major improvements in trial methodology. The last period (1989–2019) was dominated by the introduction of second‐generation drugs, and further evolution in the design of monotherapy and adjunctive‐therapy trials. The expansion of the pharmacological armamentarium has improved opportunities for tailoring drug treatment to the characteristics of the individual. However, there is still inadequate evidence from controlled trials to guide treatment selection for most epilepsy syndromes, particularly in children. Second‐generation drugs had a very modest impact on drug resistance, and a change in paradigm for drug discovery and development is needed, focusing on treatments that target the causes and mechanisms of epilepsy rather than its symptoms. Testing potential disease modifying agents will require innovative trial designs and novel endpoints, and will hopefully lead to introduction of safer and more effective therapies.
Ictal kissing in a patient with right frontal lobe epilepsy
Authors: de Campos António Martins , Rocha Helena , da Costa José Manuel Dias , Rego Ricardo 
Published: January 2024

ABSTRACTWhen performing pre‐surgical evaluation of patients with refractory epilepsy, the analysis of seizure semiology is one of the key elements used to generate a hypothesis about the location of the epileptogenic zone. Ictal kissing is a very rarely observed ictal automatism described in patients with temporal lobe epilepsy. We present a 62‐year‐old man who was referred to our epilepsy centre for comprehensive evaluation. During prolonged video‐EEG monitoring, six focal‐onset hyperkinetic seizures were registered. In five seizures, the patient repeatedly produced sonorous kisses “into the air”. Initial ictal EEG pattern consisted of rhythmic theta or alpha activity at the right fronto‐polar and fronto‐medial electrodes. MRI depicted focal cortical dysplasia located in the right prefrontal medial cortex. This case suggests that ictal kissing can also occur in the setting of right frontal lobe epilepsy; we therefore believe that this observation expands the anatomo‐clinical correlation for this rare ictal automatism. [Published with video sequences].
Self‐stimulation in an adult misdiagnosed with focal epilepsy
Authors: Correia Pedro , Hartl Elizabeth , Noachtar Soheyl 
Published: January 2024

ABSTRACTSelf‐stimulation is a normal part of development and a common behaviour in children before puberty, but very rare in adults. The stereotyped semiology can sometimes raise the suspicion of epilepsy. We present a 30‐year‐old patient who came to our epilepsy monitoring unit for differential diagnosis of nocturnal episodes, interpreted elsewhere as hypermotor status epilepticus associated with a known diagnosis of focal epilepsy and septo‐optic dysplasia. The recorded events during video‐EEG were consistent with psychogenic self‐stimulating behaviour, which improved with psychotherapy. Disturbed sexual development with hypopituitarism and poor eyesight, androgen replacement therapy, alongside a protective environment provided by her parents, were the identified predisposing factors for this uncommon entity in an adult. [Published with video sequence].
Epileptic encephalopathy with microcephaly in a patient with asparagine synthetase deficiency: a video‐EEG report∗
Authors: Costa Paola , Zanus Caterina , Faletra Flavio , Ventura Giulia , di Marzio Giulia Maria , Cervesi Chiara , Carrozzi Marco 
Published: January 2024

ABSTRACTAsparagine synthetase deficiency is a rare autosomal recessive neurometabolic disorder caused by mutations in the asparagine synthetase gene. It is characterized by congenital microcephaly, intellectual disability, progressive cerebral atrophy, and intractable seizures. A decrease in asparagine in CSF or plasma guides subsequent investigations in some cases, but normal values are described in other cases. Therefore, reaching a diagnosis is challenging and relies on exome sequencing. We report the case of a child with progressive microcephaly, irritability, startle reflexes, and jitteriness since birth. Focal clonic and myoclonic seizures, status epilepticus, and infantile spasms appeared in the first months of life. At first, the EEG showed multifocal epileptic activity which later turned into modified hypsarrhythmia and discontinuous activity. Brain MRI showed brain atrophy, a simplified gyral pattern, and poor myelination. Plasma asparagine levels were normal. Due to remote parental consanguinity, a study of contiguous regions of runs of homozygosity was performed, showing a 5‐Mb region (chr7:95629078–100679007) including the asparagine synthetase gene. The molecular analysis of this gene led to identification of a novel homozygous missense mutation, c.761G>T(p.Gly254Val), in our patient. The peculiar electroclinical phenotype may lead to diagnostic suspicion and molecular analysis which may benefit genetic counselling. [Published with video sequence].
Management of epilepsy in pregnancy: a report from the International League Against Epilepsy Task Force on Women and Pregnancy
Authors: Tomson Torbjörn , Battino Dina , Bromley Rebecca , Kochen Silvia , Meador Kimford , Pennell Page , Thomas Sanjeev V. 
Published: January 2024

ABSTRACT
The risks associated with use of antiepileptic drugs during pregnancy are a major concern for all women with epilepsy with childbearing potential. These risks have to be balanced against foetal and maternal risks associated with uncontrolled seizures. This report from the International League Against Epilepsy Task Force on Women and Pregnancy aims to provide a summary of relevant data on these risks as a basis for expert opinion recommendations for the management of epilepsy in pregnancy. The report reviews data on maternal and foetal risks associated with seizures as well as teratogenic risks associated with antiepileptic drug exposure, including effects on intrauterine growth, major congenital malformations, and developmental and behavioural outcomes. The impact of pregnancy on seizure control and on the pharmacokinetics of antiepileptic drugs are also discussed. This information is used to discuss how treatment may be optimized before conception and further managed during pregnancy.