Vol 49, No 3 (2021)

Cover Page

Full Issue

REVIEW

Expression of the immune checkpoint B7-H3 in tumor and its soluble form in serum of patients with bone neoplasms

Kushlinskii N.E., Kovaleva O.V., Alferov A.A., Kuzmin Y.B., Sushentsov E.A., Stilidi I.S.

Abstract

B7-H3, also called CD276, is a type I transmembrane glycoprotein that is encoded on human chromosome 15. It was discovered back in 2001. The original study described it as a positive co-stimulant, as it can stimulate T-cell response and IFN-y production. However, recent researches have shown that B7-H3 is involved in T-cell inhibition. A B7-H3 receptor has not been yet identified, and this may explain the complex immunomodulatory activity of B7-H3, as it can have more than one binding partner with different functions. Expression of the B7-H3 protein has been found on activated immune cells such as T-cells, NK cells and antigen presenting cells. Interestingly, it is overexpressed in a wide range of tumor cells and is associated with disease progression and outcome. The soluble form of this protein is also of particular interest. Increased sB7-H3 levels in the plasma of bone tumor patients might be their important diagnostic criterion.

Almanac of Clinical Medicine. 2021;49(3):179-190
pages 179-190 views

ORIGINAL ARTICLE

The prognostic role of aberrant copy number of DDB1, PRPF19, CDKN1B, с-Myc genes in ovarian cancer patients

Verenikina E.V., Petrusenko N.A., Kecheryukova M.M.

Abstract

Rationale: Ovarian cancer is the leading death cause in gynecological malignancies. More than 70% of the patients are diagnosed with progressing disease extending to outside the true pelvis. The 5-year survival of ovarian cancer patients remains low (about 47%) due to frequent relapses and drug resistance. Identification of markers for early diagnosis and relapse prediction could improve the outcomes of the disease.

Aim: To assess relative copy number of cancer-associated genetic loci c-Myc, CDK12, CDKN1B, PRPF19, ERBB2, DDB1, GAB2, COL6A3 in the tumor cells of ovarian cancer, in order to identify potential prognostic oncomarkers in ovarian cancer patients.

Materials and methods: The study included 50 women aged 27 to 70 years with ovarian cancer T1-3cN0-1M0-1, Gr. 2 (stages I—IV), who received their elective treatment in the National Medical Research Centre for Oncology in 2015 to 2019. The study was based on samples of genomic DNA from paraffinized blocks of tumor and “healthy” tissues. Relative copy numbers of 8 genetic loci (c-Myc, CDK12, CDKN1B, PRPF19, ERBB2, DDB1, GAB2, COL6A3) was assessed by RT-qPCR technique. Relative copy quantitation of a genetic locus was calculated as 2-ΔCt. The dose of the locus studied was considered equal to diploid set (2n) if RCQtumor/healthy was about 1. If RCQtumor/healthy was > 1.5 or < 0.5, then the locus dose was considered increased (≥ 3n) or decreased (≤ 1n), respectively.

Results: For all genetic loci, an increase of relative copy quantitation in the ovarian tumor cells was observed compared to that in “healthy” tissues. There was a significant (р<0.05) aberrant copy quantitation of 4 genes: c-Myc (р = 0.001), DDB1 (р = 0.002), PRPF19 (р = 0.0001), and CDKN1B (р = 0.001). We identified differential thresholds for these genes that made it possible to predict an unfavorable disease course in the patients (р < 0.05). The strongest association with the risk of adverse outcomes was found for increased copy number of PRPF19 (odds ratio (OR) 7.3; р = 0.0001) and c-Myc (OR 6.8; р = 0.001).

Conclusion: In this study, we determined the prognostic value of 4 oncogenic drivers, namely, DDB1, PRPF19, CDKN1B, and с-Myc, whose increased copy number was associated with an adverse disease prognosis in ovarian cancer patients.

Almanac of Clinical Medicine. 2021;49(3):191-196
pages 191-196 views

The role of cystatin C and various methods of glomerular filtration rate calculation in evaluation of renal dysfunction in children with acute infectious diarrhea

Chugunova O.L., Grebеnkina E.Y., Usenko D.V., Volodina I.I., Galeeva E.V., Drozhzhin E.A., Korsunskiy А.А., Legoshina N.Y., Muzyka A.D., Naryshkina M.I., Pavlushkina L.V., Rykova А.S.

Abstract

Rationale: Acute infectious diarrhea (AID) is the fourth leading cause of death among children < 5 years worldwide. Kidney damage is one of the poorly studied aspects of pediatric AID. The level of serum cystatin C is independent on gender and age, and it is highly informative even in the early stages of renal dysfunction.

Aim: To optimize diagnosis of renal dysfunction in children with moderate AID through comparison of different methods of glomerular filtration rate (GFR) calculation and determination of serum cystatin C level.

Materials and methods: Observational cross-sectional study enrolled 80 children in pediatric hospital with moderate AID not followed by hemolytic uremic syndrome. Serum creatinine and serum cystatin C levels were determined in all the patients in acute period with GFR calculating according to Schwartz equation in unmodified (1976) and modified (2009) versions. GFR was also calculated using a single-factor equation based on serum cystatin C level.

Results: GFR in acute period, calculated according to unmodified and to modified Schwartz equation was in patients < 3 years (n = 40) 115.47 ± 3.33 ml/min/1.73 m2 and 98.56 ± 2.84 ml/min/1.73 m2 (p < 0.001), in patients 3-7 years 132.13 ± 4.2 ml/min/1.73 m2 and 108.85 ± 3.84 ml/min/1.73 m2 (p < 0.001), respectively. Increased serum cystatin C level (> 950 ng/ml) occurred in 18 patients (22%). In other patients level of serum cystatin C remained within the reference range or lower. The risk of acute kidney injury development based on two indicators - GFR according to the modified Schwartz equation and GFR according to the equation used cystatin C level - occurred in 4 (10%) patients aged 1-3 years and in 1 (2.5%) child in the age group 3-7 years; risk, based on one indicator - the calculation of GFR according to the formula using cystatin C - in 8 (20%) and 9 (22.5%) children, respectively, and based on the assessment of only GFR according to the modified Schwartz equation - in 3 (7.5%) children of both age groups.

Conclusion: We have confirmed that the GFR values calculated with usage of unmodified Schwartz equation (1976) are higher than those calculated with usage of modified Schwartz equation (2009) and taking into account the level of cystatin C.

Thus, usage of unmodified Schwartz equation for GFR calculation in infants and preschool children seems incorrect. Level of serum cystatin C is promising marker permitted to select patients with risk of acute kidney injury development among children in acute period of moderate AID.

Almanac of Clinical Medicine. 2021;49(3):197-206
pages 197-206 views

New coronavirus infection in children in the Moscow region: clinical, epidemiological and treatment aspects

Meskina E.R., Khadisova M.K., Stashko T.V., Bitsueva A.V.

Abstract

Aim: To assess clinical and epidemiological characteristics, as well as treatment results in COVID-19 pediatric patients hospitalized to the Department of infectious disease in the Moscow region. Materials and methods: We retrospectively analyzed medical records of 124 pediatric patients aged from 1 month to 17 years with confirmed (63.7%) and highly probable (proven epidemiological association with the infection source) COVID-19 infection. The children were hospitalized from March 25, 2020 to August 11, 2020. Among patients that were hospitalized during this time period, 43% had pneumonia and 30% had acute respiratory disorders. All cases of pneumonia were confirmed by computed tomography. The children were treated according to the standard Russian guidelines.

Results: The children had been infected with SARS-CoV-2 mostly from family members (75%; 95% confidence interval (CI) 66.4-82.3). In the families of the children with pneumonia, the number of pneumonia cases in their relatives was higher than in the families of the children with acute respiratory infections (1.7 ±1.0 vs. 1.1 ± 0.5 respectively; р < 0.001). The mean age of the hospitalized children was 8 years (7.4-9.6), with an even age distribution. The main COVID-19 signs and symptoms were as follows: fever (75.8%; 95% CI 67.3-83.0), cough (66.1%; 95% CI 57.1-74.4]), fatigues (38.7%; 95% CI 30.1-47.9), and hyposmia (33.9%; 95% CI 25.6-42.9). The severe disease course was rare (2.4%; 95% CI 0.5-6.9). The rates of positive reverse transcriptase polymerase chain reaction tests for SARS-CoV-2 were rapidly decreased at repeated tests: at day 3, 63.7% of the tests were positive, at day 7, 21.8% and at day 14, 5.6% (р < 0.001). The prevalence of pneumonia was 56.4% without any age differences, with mostly minimal areas of lung abnormalities (78.6%). The severity of pneumonia and duration of clinical manifestations in the patients treated with a III generation cephalosporin or its combination with a macrolide were similar. Cough duration in those, who were treated with ipratropium bromide / fenoterol inhalations including their combination with budesonide, was higher than in those who did not use inhalation treatment. Pyrexia of > 5 days duration can be a predictor of pneumonia in a pediatric patient with COVID-1 9 (odds ratio 4.55 (2.1-9.9), sensitivity 61.4%, specificity 74.1%).

Conclusion: The results obtained are important to develop further treatment strategies for children with COVID-1 9.

Almanac of Clinical Medicine. 2021;49(3):207-218
pages 207-218 views

CLINICAL OBSERVATION

A clinical case of cystic fibrosis patient with pathogenic N1303K genotype variant with assessment of the CFTR channel function by intestinal current measurement and forskolin-induced swelling in rectal organoids

Kondratyeva E.I., Odinaeva N.D., Sherman V.D., Efremova A.S., Melyanovskaya Y.L., Bulatenko N.V., Bukharova T.B., Goldshtein D.V.

Abstract

Rationale: Cystic fibrosis is a common monogenic disease related to pathogenic nucleotide sequence variants in the Cystic Fibrosis Transmembrane conductance Regulator (CFTR) (ABCC7) gene. The CFTR gene consists of 27 exons and is located in the 31.1 region on the long arm of chromosome 7 (7q31.1). The use of the sequencing method has led to the accumulation of new information about the diversity of genetic variants in cystic fibrosis. This information is important considering approaches to the development of targeted therapy for the disease, based on an individual genotype. No targeted therapy has been developed for the N1303K class II genetic variant. The function of the chloride channel in this mutation has not been compared with that in class II mutations like F508del.

Materials and methods: We have analyzed medical files of a patient with cystic fibrosis and F508del/N1303K CFTR genotypes, including the results of rectal biopsy samples. The assessments included measurement of the intestinal potential difference and forskolin-induced swelling assay (FIS) in rectal organoids, with the results being analyzed in relation to the clinical data.

Results: The results of intestinal current measurements (ICM) confirm that the N1303K genetic variant is “severe” and leads to the loss of the working CFTR protein, which is consistent with the clinical manifestations. The mean short circuit currency density (ΔISC) in response to amiloride (sodium channel stimulation) was -39 ± 1.22 µA/cm2, to forskolin (chloride channel stimulation) 3.83 ± 1.43 µA/cm2, to carbachol 6 ± 2.47 µA/cm2, and to histamine 8.5 ± 3.02 µA/cm2.

FIS results indicate that the VX-770 potentiator and the VX-809 corrector have a weak effect on the stimulation of organoids by forskolin in the genetic variant N1303K: organoid swelling was non-significant (about 20% from their baseline size).

Conclusion: The use of the ICM method and FIS assay in human intestinal organoids makes it possible to quantify the work of the CFTR protein and determine the in vitro effectiveness of targeted therapy in patients with cystic fibrosis. CFTR modulators are ineffective in patients with N1303K mutation in the compound-heterozygous condition with F508del, despite both pathogenic variants belong to class II.

Almanac of Clinical Medicine. 2021;49(3):219-225
pages 219-225 views

The case of paroxysmal kinesigenic dyskinesia: a long way from a symptom to the diagnosis

Kim N.L., Yamin M.A.

Abstract

Paroxysmal kinesigenic dyskinesia belongs to the group of primary dyskinesias, which also includes paroxysmal non-kinesigenic dyskinesia and exercise-induced paroxysmal dyskinesia. Due to the rarity of this disease group, as well as to the existence of a wide spectrum of disorders associated with transient movement abnormalities, the diagnosis is often difficult. A thorough analysis of clinical presentation, objective registration of paroxysmal events (video-electroencephalography monitoring) is helpful in the diagnosis. The most common causes of paroxysmal kinesigenic dyskinesia are mutations in the PRRT2 gene, while paroxysmal non-kinesigenic dyskinesia is caused by the MR1 gene mutations.

The paper describes a clinical case of a 13 year old patient with acute, movement-associated, shortterm dystonic, choreic and ballistic hyperkinesis attacks. The patient had been treated with the diagnosis of epilepsy, tics, and dystonia for a long time without any effect. During diagnostic workup, a mutation in the PRRT2 gene intron was identified by a new generation sequencing of gene panel. Despite of this mutation has not been previously described, taking into account the type of Informed consent statement hyperkinesis attacks, association of their onset to movements, as well as the data of instrumental assessments, the diagnosis of paroxysmal kinesi-genic dyskinesia was made. Treatment with carbamazepine was successful with complete control over hyperkinesis.

The diagnosis of paroxysmal dyskinesias remains based on the analysis of clinical picture and the trigger type. Molecular genetic diagnostics, with consideration of the most frequent causal mutations related to these conditions, can minimize both time and financial costs.

Almanac of Clinical Medicine. 2021;49(3):226-230
pages 226-230 views

Severe brain trauma to the fetus in a car accident: Literature review and a clinical case

Vostrikov N.A., Ponomareva I.V., Cheremisinov O.V., Sherman M.A.

Abstract

Car accidents are the main cause of trauma during pregnancy. Even a non-severe accident is associated with a high risk of injury and unfavorable outcome for the fetus, especially in the event of placental abruption. Major agents leading to a trauma could also include safety belt and safety airbags. Blunt abdominal trauma during a car accident is associated with such type of intrauterine injury as fetal skull fractures and various intracranial hemorrhages. Despite a common viewpoint on relatively high death rates in this population, it is not infrequent that fetal trauma has a favorable outcome without any clinically significant neurological deficiency.

The paper presents an analysis of the main outcomes of intrauterine brain injury and associated factors. As an illustration, we describe a case of a car accident related brain injury to a fetus at 38 week of gestation, with skull fracture, brain contusion, and subarachnoidal, epidural and subdural, parenchymal and intraventricular hemorrhages induced by the safety belt, with the mother being virtually uninjured. After treatment, the patient was discharged from the hospital in a satisfactory state, without clinically significant neurological symptoms and signs. A 8-months follow-up of the infant showed some delay in brain maturation manifesting as benign epileptiform discharges of childhood and magnetic resonance imaging patterns.

It is highly likely, that the leading factors ensuring a favorable outcome of a intrauterine severe brain trauma (without fatal trauma to the mother and fetus) are as follows: correct obstetric strategy, late gestational age and absence of a massive parenchymal and/or intraventricular bleeding. After the short-term clinical recovery from a severe intrauterine brain trauma and in addition to it, proper follow-up of the child is essential because of a high risk of long-term cerebral and functional abnormalities, mostly paroxysmal, behavioral and cognitive.

Almanac of Clinical Medicine. 2021;49(3):231-238
pages 231-238 views

LECTURE

Demyelinating diseases of the central nervous system in children: lecture for practicing pediatricians

Kotov A.S., Panteleeva M.V., Mukhina E.V.

Abstract

Demyelinating diseases (DD) are autoimmune disorders that morphologically manifest mainly with myelin destruction in the central nervous system (CNS). Recently, there has been a continuous increase in DD of the CNS, including those in the pediatric population. Despite the active development of strategies for the diagnosis of DD and verification of its forms, the differential diagnosis of DD and other diseases associated with abnormalities in the brain white matter structure on magnetic resonance imaging continues to be problematic. We examined 123 patients with suspected DD CNS. The diagnosis was confirmed in 102 of them. The most common form of DD CNS was multiple sclerosis found in 79 of 102 subjects. Much less frequent were anti-MOG-associated disorders (5 patients), neuromyelitis optica spectrum disorders (3 patients), and acute disseminated encephalomyelitis (2 patients). The main clinical, laboratory and neuroimaging characteristics of each of these disorders and the main difficulties in the treatment of pediatric patients with DD CNS are described.

Almanac of Clinical Medicine. 2021;49(3):239-244
pages 239-244 views

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