EPHA4 Genetic Variant in a Patient with Epilepsy, Ophthalmological Anomalies, and Neurodevelopmental Delay.

We present the findings of a Whole Exome Sequencing in a 2-year-old boy, conceived via In Vitro Fertilization with donor sperm, who suffers from an undiagnosed neurological syndrome. The following heterozygous variant in the EPHA4 gene was identified and classified as likely pathogenic: c.1655_1656, p.(Ser552CysfsTer23). Subsequent segregation analysis showed that the variant was not inherited from the mother and the sperm donor is not accessible for genetic testing. The presented results can further expand upon the genetic variants considered when diagnosing complex neurological syndromes and shows the importance of access to biological samples from donor banks in genetically ambiguous cases.

[A new paradigm for the development of neurodegenerative diseases on the example of Alzheimer's disease and Parkinson's disease.]

The role of neuronal inflammation developing during the formation of amyloid plaques and Lewy bodies has been investigated. The influence of various exogenous and endogenous factors on the development of neuroinflammation has been established, but the role of various infectious agents in the development of this process has been much less studied. Today, the existence of a universal trigger mechanism of the neurodegenerative process is obvious: a specific pathogen of a bacterial or viral nature (including a long-term persistent in the nervous tissue in a latent state), reactivating, penetrates into certain cerebral structures, where it is influenced by either Aß or resident macrophages of the central nervous system, which, in turn, are activated and induce the release of pro-inflammatory cytokines, leading to the development of neuronal inflammation, autophagy and neurodegeneration. Reactivation of latent, such as herpes, infection in individuals who are carriers of APOE4 significantly increases the risk of developing Alzheimer's disease. Class II genes of the HLA locus (HLA II) may be related to the progression of neurodegenerative diseases. The increase in iron levels in the glia is induced by inflammation, which leads to neurodegeneration. Disruption of the homeostasis of redox-active metals, iron and copper, is an integral part of the pathogenesis of Alzheimer's disease and Parkinson's disease. The developing neuroinflammation leads to the intensification of the processes of peroxidation, oxidation of metals and the development of ferroptosis.

BARTH SYNDROME IN MALE AND FEMALE SIBLINGS CAUSED BY A NOVEL MUTATION IN THE TAZ GENE.

Barth syndrome (BTHS) is an X-linked recessive disease caused by mutations in tafazzin gene (TAZ) which lead to cardiolipin deficiency and mitochondrial dysfunction. Male patients have variable clinical findings, including cardiomyopathy, skeletal myopathy, prepubertal short stature, neutropenia and 3-methylglutaconic aciduria. Female carriers are usually asymptomatic. We report a novel TAZ gene mutation in male and female siblings with left ventricular noncompaction and hypotonia. Additionally, the brother presented an intermittent neutropenia and increased urinary levels of 3-methylglutaconic and 3-methylglutaric acid. The molecular genetic testing showed that both siblings carry the mutation: c.253insC, p.(Arg85Profs*54) in exon 3 of the TAZ gene. This article presents the first case of BTHS in a heterozygous female patient with normal karyotype.

[Efim Anatolyevich Dyskin - the hero of the Defence of Moscow (To the 75th anniversary of the Battle of Moscow 1941-1942)].

Efim Anatolyevich Dyskin - the hero of the Defence of Moscow (To the 75th anniversary of the Battle of Moscow 1941-1942). Efim Dyskin - one of the first artilleryman, who awarded the title of Hero of the Soviet Union for a feat accomplished in the Battle of Moscow. After the war he finished the Military Medical Academy and later became a prominent domestic scientist - anatomist and morphologist, head of the general anatomy department, teacher of high school, Major General of the Medical Service. He created a scientific morphological school that developed guidelines for the features of the morphology of the different species of a gunshot wound and the impact of extreme factors of the military working on the body brow-century. Under the leadership of E.A.Dyskin conducted research on. the status of collateral circulation, functional anatomy of the digestive system, craniology, histoty of military medicine and the Military Medical Academy.

[The complex of neurological symptoms of substance abuse].

Standard neurological examination was performed in 85 patients of military service age (the average age was 32,6±5,3 years - from 19 to 44 years) with a confirmed diagnosis of substance abuse, caused by the use of narcotic drugs and psychotropic substances: cocaine and amphetamine in 12 patients, opioids - in 73 patienls. Some symptoms of nervous system damage had statistically characteristic peculiarities for different forms of substance abuse. Mydriasis, signs a bilateral pyramidal insufficiency, hyperkinetic disorder are often characteristic for cocaine and amphetamine abuse. Opioid abuse is characterised by more severe symptoms of nervous system damage, disseminated neurologic symptomatic and polyneurotic disorders. Symptoms of neurasthenia and vegetative-vascular dystonia, which are usually accompanied by the; symptoms of organic lesions of the central and peripheral nervous system, were observed in all patients with substance abuse. In order to detect the symptoms of nervous system damage in patients, which are supposed to be conscribe, it is necessary to take medical history.

A family with fragile X syndrome, Duchenne muscular dystrophy and ichthyosis transmitted by an asymptomatic carrier.

The human X chromosome carries regions prone to genomic instability: deletions in the Xp22.31 region, involving the steroid sulfatase gene (STS) cause X-linked ichthyosis; rearrangements in the Xp21.2 region are associated with Duchenne or Becker muscular dystrophies (DMD or BMD); and the Xq27.3 unstable region, containing the (CGG)n repeat expansion in the FMR1 gene is associated with fragile X syndrome. We report on a family with two affected boys, the elder diagnosed with fragile X syndrome, the younger with DMD, and both suffering from severe ichthyosis. The family was analyzed by polymerase chain reaction, multiplex ligation-dependent probe amplification and haplotype analysis. The mother proved to be an asymptomatic carrier of all three non-contiguous mutation events, involving the STS gene, the DMD gene and a FMR1 expansion. To the best of our knowledge, this is the first description of an asymptomatic carrier of three different X-linked disorders, involving severe genetic rearrangements on both long and short arms of the X chromosomes. The boy with fragile X syndrome has inherited a triple recombinant maternal X chromosome, this way inheriting the FMR1 expansion and ichthyosis, originating most probably from different maternal Xes and excluding the DMD gene deletion. The transmission of these extremely defective maternal chromosomes to the next generation involved several recombinations.

[Modern ideas about pain syndrome in Parkinson's disease].

The analysis of the literature dedicated to modern ideas and achievements in the study of the pathogenesis, the incidence and characteristics of the clinical manifestations of pain syndromes in Parkinson's disease. It is shown that the disease is characterized by a variety of painful phenomena, combining features of the central and peripheral pain. Peripheral mechanisms of pain are realized as a consequence of mixed neuropathy (predominantly axonopathy) sensory and motor fibers. When electroneuromyographic study found a reduction of the amplitude sensory capacity, latency increase and decrease the speed of the pulse.

[Assessment of the significance of dilated perivascular spaces and nocture arterial hypertension in the development of Alzheimer's disease]. / Otsenka znacheniya rasshirennykh perivaskulyarnykh prostranstv i nochnoi arterial'noi gipertenzii v razvitii bolezni Al'tsgeimera.

OBJECTIVE: To study the severity and localization of dilated perivascular spaces (DPVS), the levels of protein markers of amyloidosis and neurodegeneration in the cerebrospinal fluid (CSF) at different daily blood pressure (BP) profiles in patients with Alzheimer's disease (AD) and other types of cognitive impairment. MATERIAL AND METHODS: A total of 119 people, aged 53 to 92 years, including 55 patients with AD, 27 patients with vascular cognitive disorders (VCD), 19 patients with frontotemporal degeneration (FTD). All patients underwent BP monitoring for 24 hours using a standard oscillometric measurement method, lumbar puncture to assess Aß-42 and Aß-40 amyloid protein, total and phosphorylated tau protein in the CSF, magnetic resonance imaging tomography of the brain with subsequent assessment of the severity of expansion and localization of DPVS according to the G.M. Potter scale. RESULTS: In 58.3% of patients with AD, there is no adequate reduction in BP at night in comparison with patients with VCD (p<0.05). A significant degree of expansion of the DPVS turned out to be most typical for patients with AD: grade 3 was detected in 45.7% of patients, and the maximum, grade 4, was detected in 13.4%. At the same time, DPVSs were significantly more often detected in the group of subjects with insufficient reduction in diastolic BP (DBP) at night. A strong inverse correlation was established between the level of Aß-42 in the CSF and the variability of DBP at night (r= -0.92; p<0.05). The decrease in the level of Aß-42 in AD, especially at the prodromal stage, is directly related to the low variability of DBP at night, which is more characteristic of an insufficient decrease or increase in BP during night sleep. CONCLUSION: Patients with AD were characterized by an insufficient decrease in BP at night, which is associated with the severity and degree of maximum expansion of the DPVS. A decrease in the level of Aß-42 amyloid protein in the CSF strongly correlates with the variability of DBP at night.

[Traumatic brain injury as risk factor of Alzheimer's disease and possibilities of pathogenetic therapy]. / Cherepno-mozgovaya travma kak faktor riska bolezni Al'tsgeimera i vozmozhnosti patogeneticheskoi terapii.

The article examines the potential role of brain mechanical damage as a trigger for the development of neurodegenerative changes. Attention is paid to dysfunction of the neurovascular unit, and disruption of the functional and compensatory capabilities of blood flow. The importance of microhemorrhages that occur in the acute period of injury and the formation of first focal and then diffuse neuroinflammation is emphasized. The importance of mitochondrial dysfunction was separately determined as a significant factor in increasing the risk of developing Alzheimer's disease (AD) in patients after traumatic brain injury (TBI). In TBI, there is a decrease in the expression of tight junction (TC) proteins of endothelial cells, such as occludin, claudin, JP, which leads to increased permeability of the blood-brain barrier. TBI, provoking endothelial dysfunction, contributes to the development of metabolic disorders of ß-amyloid and tau protein, which in turn leads to worsening vascular damage, resulting in a vicious circle that can ultimately lead to the development of AD and dementia. Age-related changes in cerebral arteries, which impair perivascular transport of interstitial fluid, are currently considered as an important part of the «amyloid cascade¼, especially against the background of genetically mediated disorders of glial membranes associated with defective aquaporin-4 (encoded by the APOE4). Studies in animal models of TBI have revealed an increase in tau protein immunoreactivity and its phosphorylation, which correlates with the severity of injury. A comprehensive analysis of research results shows that the cascade of reactions triggered by TBI includes all the main elements of the pathogenesis of AD: disorders of energy metabolism, microcirculation and clearance of cerebral metabolic products. This leads to a disruption in the metabolism of amyloid protein and its accumulation in brain tissue with the subsequent development of tauopathy. Cerebrolysin, by modulating the permeability of the blood-brain barrier, blocks the development of neuroinflammation, reduces the accumulation of pathological forms of proteins and may be slow down the progression of neurodegeneration.

[Multi-center open comparative randomized study of efficacy and safety of Akatinol Memantine 20 mg (single-doses) vs Akatinol Memantine 10 mg (double-doses) in patients with vascular dementia]. / Mnogotsentrovoe otkrytoe sravnitel'noe randomizirovannoe issledovanie effektivnosti i bezopasnosti primeneniya preparata Akatinol Memantin, 20 mg (odnokratnyi priem) v sravnenii s preparatom Akatinol Memantin, 10 mg (dvukratnyi priem) u patsientov s sosudistoi dementsiei.

OBJECTIVE: Evaluation of the efficacy and safety of the drug Acatinol Memantine, 20 mg (once daily) in comparison with the drug Acatinol Memantine, 10 mg (twice daily) in patients with moderate to moderate severe vascular dementia. MATERIAL AND METHODS: The study included 130 patients aged 50-85 years of both sexes with instrumentally and clinically confirmed vascular dementia. The patients were randomized into 2 groups. Group I consisted of 65 patients receiving Akatinol Memantine, 20 mg once daily, group II - 65 patients receiving Akatinol Memantine, 10 mg twice daily for 24 weeks. Clinical, parametric and statistical research methods were used. The Alzheimer's disease assessment scale, the cognitive subscale (ADAS-cog), the short mental Status Assessment Scale (MMSE) and the general clinical impression scale for patients condition and illness severity (CGI-C and CGI-S) and the Hamilton Depression Rating scale (HAM-D) were used. Adverse events were collected and analyzed. RESULTS: At week 24, both groups showed statistically significant positive change in ADAS-cog total score: in group I the total score was 27.2±8.76 points (absolute difference from baseline 3.5 points; p<0.01), and in group II - 26.1±7.86 points (absolute difference from baseline 2.5 points; p<0.01) with no statistically significant differences between groups. Evaluation of secondary efficacy criteria (change in ADAS-cog total score at week 12 and MMSE at weeks 4, 12, and 24) also revealed statistically significant benefit in both groups compared to baseline with no significant differences between groups. Statistically significant improvement was noticed on CGI-S and CGI-C scales in both groups. Akatinol Memantine was safe and well tolerated in both groups. CONCLUSION: The study showed no lesser efficacy and safety of Akatinol Memantine, 20 mg (once daily) compared to Akatinol Memantine, 10 mg (twice daily) in patients with moderate and moderately severe vascular dementia.

[Early diagnosis of dementia with the help of MR-morphometry in patients with Parkinson's disease].

54 patients with idiopathic Parkinson's disease were examined. 1,5 Tesla MRI with T1 gradient-echo protocol and following calculating by FreeSurfer software was performed. Dementia was revealed in 23 patients. Significant changes of different zones of brain-cortex were revealed in patients with Parkinson's disease accompanied by dementia. Changes were revealed in the hemispheres, particularly in frontal, temporal and occipital lobes. Thickness of lingual medial occipitotemporal gyrus can be used as a criterion for dementia prognosis. Individual patient monitoring and cortex alteration evaluation allow prognosticating increasing risk of cognitive disorders development and prescribing proper therapy.

[Diagnosis and treatment of early forms of cognitive impairment: possibilities of influencing neuronal energy metabolism. Resolution of the Council of Experts]. / Diagnostika i lechenie rannikh form kognitivnykh narushenii. Vozmozhnosti vozdeistviya na energeticheskii metabolizm neironov. Rezolyutsiya Soveta ekspertov.

Diagnosis and treatment of early forms of cognitive impairment: possibilities of influencing neuronal energy metabolism. Resolution of the Council of Experts.

[Psychological, psychiatric and neurological aspects of COVID-19]. / Psikhologicheskie, psikhiatricheskie i nevrologicheskie aspekty COVID-19.

OBJECTIVE: To analyze neurological, psychological and psychiatric aspects of COVID-19, as well as to study the current state of the problem. MATERIAL AND METHODS: The study included 103 patients with COVID-19. The main research method was clinical/psychopathological. To study the impact of activities related to the care of patients with COVID-19 in a hospital setting, the medical and psychological state of 197 hospital workers involved in the treatment of patients with COVID-19 was assessed. The level of anxiety distress was assessed with the Psychological Stress Scale (PSM-25), distress indicators corresponded to values of more than 100 points. The severity of anxiety and depressive symptoms was assessed using the Hospital Anxiety and Depression Scale (HADS). RESULTS: When considering psychopathological disorders in the context of COVID-19, it is necessary to distinguish between two main groups of disorders: mental disorders during the pandemic, and mental disorders directly caused by the causative agent SARS-CoV-2. The analysis of psychological and psychiatric aspects in various periods of the initial stage of COVID-19 showed that each of them was characterized by specific features depending on the nature of the influence of different pathogenic factors. In the structure of nosogenic mental disorders in patients with COVID-19 (103 patients), the following clinical forms were identified: acute reaction to stress (9.7%), anxiety-phobic disorders (41.7%), depressive symptoms (28.1%), hyponosognosic nosogenic reactions (20.5%). At the same time, the majority of the patients had manifestations of somatogenic asthenia (93.2%). A comparative analysis of neurological and psychological/psychiatric aspects of COVID-19 showed that the main mechanisms of the impact of highly contagious coronaviruses, including the SARS-CoV-2, on the central nervous system are: cerebral thrombosis and cerebral thromboembolism, damage to the neurovascular unit, neurodegeneration, including that induced by cytokines, and immune-mediated demyelinating nerve damage. CONCLUSION: Neurological and psychological/psychiatric aspects of COVID-19 should be taken into account both at the stage of disease treatment and in the post-infection period due to the pronounced neurotropism of SARS-CoV-2 and its effect on the neurovascular unit. Along with helping patients, an important aspect is the preservation of the mental health of medical personnel working in hospitals for infectious diseases, due to special working conditions and a high level of professional stress.

Analysis of the genes encoding neuroligins NLGN3 and NLGN4 in Bulgarian patients with autism.

Many studies have supported a genetic aetiology for autism. Neuroligins are postsynaptically located cell-adhesion molecules. Mutations in two X-linked neuroligin genes, NLGN3 and NLGN4, have been implicated in pathogenesis of autism. In order to confirm these causative mutations in our autistic population and to determine their frequency we screened 20 individuals affected with autism. We identified one patient with a point mutation in NLGN4 gene that substituted a Met for Thr 787 - c.2360C > T, p.(Thr787Met) and three patients with identical polymorphisms in the same gene: c.933C > T, p.(Thr311Thr) in combination with c.[1777C > T+1779C > G, p.(Leu593Leu)]. All patients tested for NLGN3 mutations were negative. These results indicate that mutations in these genes are responsible for at most a small fraction of autism cases.

[New approach to gait disorders therapy in late stages of Parkinson's disease].

We conducted an open noncontrolled study of efficacy of repetitive transcranial magnetic stimulation (rTMS) of the dorsolateral prefrontal cortex (DLPFC) combined with acetylcholinesterase inhibitor (galantamine) therapy in 30 Parkinson's disease patients with cognitive impairment and higher level of gait disorders. Galantamine dose gradually increase to maximum of 16 mg/day (8 weeks) before rTMSand after that we start rTMS for 10 consecutive days. Cognitive, neuropsychiatric and motor symptoms were assessed clinically at baseline and at end of 10 weeks combined therapy using the Mini Mental State Examination (MMSE), Freezing Of Gait (FOG), Clinical Gait And Balance Scale (GABS), Tinetti scale, the clock drawing test, the Frontal Assessment Battery (FAB), PDQ-39 and Beck Depression Inventory (BDI). The metabolism in the frontal lobes, caudate nucleus, thalamus were assessed in 9 patients at baseline and end of rTMS by [18F]FDG-PET. Changes in total point scores on the scales at the ends of 10 weeks were compared with the baseline. Results were significant in the FOG (p = 0.00002), GABS (p = 0.000006), MMSE (p = 0.0001), FAB (0 = 0.003), PDQ-39 (p = 0.00009), BDI (p = 0.00004). Improvements in gait and decreases in freezing and falls were seen in the end of study period. Our study demonstrated the beneficial effect of rTMS of the DLPFC combined with acetylcholinesterase inhibitor treatment on metabolism in the frontal lobes, caudate nucleus, thalamus ([18F]FDG-PET), improving of gait and cognitive functions in PD patients.

[Prospects of use of research results for drugs with anitihypoxic and antioxidative properties in neuroprotective treatment strategies (Opinion of the Council of Experts dated 26 March 2022)]. / Perspektiva ispol'zovaniya rezul'tatov issledovaniya preparatov s anitigipoksantnymi i antioksidantnymi svoistvami v neiroprotektivnoi strategii lecheniya (Zaklyuchenie soveta ekspertov ot 26 marta 2022 g.).

Cerebrovascular diseases are one of the main causes of death and permanent disability. Effective and timely neuroprotective therapy can reduce the burden of cerebrovascular disease. The possibilities of neuroprotection as a method of prevention and medical rehabilitation of acute and chronic cerebrovascular diseases are addressed.

[Roadmap for ecosystem-based approach for patients with Alzheimer disease in Russia: current needs, barriers, and possible solutions (resolution of the scientific and practical experts meeting)]. / Dorozhnaya karta po okazaniyu pomoshchi patsientu s bolezn'yu Al'tsgeimera v Rossii v formate ekosistemy: tekushchie potrebnosti, bar'ery i vozmozhnye resheniya (rezolyutsiya nauchno-prakticheskoi vstrechi ekspertov).

The care of a patient with Alzheimer's disease (AD) is considered from the perspective of an ecosystem, that is, a systemic approach describing effective partnership, collaboration and research aimed at creating value, involving all participants in the AD patient journey. The effectiveness of this ecosystem is only possible with the involvement of all stakeholders in its development, including patients, healthcare professionals at all levels, government agencies, private companies, and patient organizations. The unmet health care and information needs of patients with AD are a consequence of barriers in the AD ecosystem. Key barriers for the patient include low awareness and stigmatization of the disease in society, lack of quality epidemiological data, difficulties in timely diagnosis, lack of prevention programs, unpreparedness of most physicians to conduct AD patient rehabilitation, and other factors. Based on the analysis of the ecosystem of AD and the patient pathway, 10 main directions (strategies) necessary for the formation of the ecosystem were identified: conducting research in the diagnosis and epidemiology of AD, creating and implementing a cognitive health program, forming a legal framework, raising public awareness, optimizing patient routing for timely diagnosis, organizing a network of memory clinics/laboratories, creating a register of patients with dementia, developing digital solutions and supporting social projects.

[Features of neurologic semiotics at chronic obstructive pulmonary disease].

Chronic obstructive pulmonary disease (COPD) is actual pathology, when it forms the mixed hypoxemia. In the conditions of a chronic hypoxemia structures of organism with high level of metabolic processes, namely brain tissues, suffer. Character of defeat of the central nervous system at that pathology is insufficiently studied. In this article we studied and analysed the presence of such changes as depression, anxiety, cognitive impairment and features of neurologic semiotics at COPD in 50 patients.

[Some psychiatric and neurological aspects of the asymptomatic and mild course of COVID-19]. / Nekotorye psikhiatricheskie i nevrologicheskie aspekty bessimptomnogo i legkogo techeniya COVID-19.

OBJECTIVE: To study neurological and mental disorders associated with the inapparent and mild course of COVID-19. MATERIAL AND METHODS: The study included 50 patients (mean age 35.2±11.4 years) admitted to a psychiatric hospital due to depressive spectrum disorders. Patients were divided into two groups: patients (n=16) who had IgG antibodies to SARS-CoV-2 (main group) and patients (n=34) without a history of COVID-19 (comparison group). RESULTS AND CONCLUSION: Patients of the main group showed a difference in the structure of asthenic disorders compared with the comparison group. Also, there was a significant predominance of the severity of asthenic symptoms and anxiety in the structure of psychopathological disorders in depressive spectrum disorders. The viral intoxication contributes to the formation of a kind of asthenic «soil¼ (with characteristic manifestations). In the future, in the case of the development of any stress-associated disorder, more pronounced psychopathological disorders are noted compared with patients of the comparison group. The authors describe a variant of the course of COVID-19, in which the development of ischemic stroke was the first clinical manifestation of the disease. These disorders are based on the pronounced neurotropic effect of SARS-CoV-2 and its effect on the neurovascular unit.

[Cholinergic profile as a target of rational therapy of central nervous system diseases and injuries]. / Kholinergicheskii profil' kak mishen' ratsional'noi terapii zabolevanii i travm tsentral'noi nervnoi sistemy.

AIM: A comparative analysis of the clinical efficacy of cholinergic drugs and acetylcholinesterase inhibitors (IHE), as well as their combination, in the treatment of cerebrovascular disease and consequences of intracranial injury according to clinical, instrumental and laboratory dynamic observations. MATERIAL AND METHODS: Ninety patients with cerebrovascular pathology, including 45 with chronic brain ischemia stage 2 (ICD-10 I67) and 45 with sequelae of intracranial injury (ICD-10 T90.5), were enrolled in the study. Complex treatment of patients included basic and specific therapy. The groups were divided into 3 subgroups of 15 people: the neuromidin group, the gliatilin group and the neuromidin + gliatilin group. The duration of treatment was 2 months. All patients underwent a comprehensive clinical, neurophysiological and laboratory examination prior to therapy, after 1 month and 2 month from the beginning of therapy: a study of cholinesterase activity in the blood, testing on MMSE and Hamilton scales, transcranial magnetic stimulation with determination of Central motor conduction time and somatosensory evoked potentials with calculation of Central afferent conduction time. RESULTS: Prior to treatment, a significant positive strong correlation was found between the age of patients and the level of CE activity in serum (Rs=0.77; p=0.0001). The treatment resulted in a significant (p<0.05) improvement of all parameters (except for MMSE that showed a trend towards improvement) in the neuromidin and the neuromidin + gliatilin subgroups of each group compared to those in the gliatilin subgroups. In addition, after 2 months from the beginning of treatment, there was a significant decrease in the activity of CE in serum in the neuromidin and the neuromidin + gliatilin subgroups. CONCLUSION: The study of deviations of the 'cholinergic profile' (the level of CE activity in the blood) in patients with cerebral pathology and the strategy using cholinergic drugs, IHE and their combination for the treatment of neuropsychiatric disorders, is one of the important directions in the optimization of combined therapy of patients of this profile.