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The dysfunction of different cells lies in the pathogenesis of neurological diseases and is usually associated with cellular stress. Various stressors trigger the integrated stress response (ISR) signaling, whose highly conserved mechanism is primarily aimed at protecting a stress-exposed cell to cope as safely as possible with such stressful conditions. On the contrary, if a cell is unable to cope with excessive stress, the ISR can induce apoptosis. The ISR mechanism, whose main stage is the inhibition of translation machinery in favor of the synthesis of specific proteins, including the transcription factors ATF3, ATF4, CEBPA, and CEBPB, which function only as dimers and determine the uniqueness of the ISR response in each individual case, thus ensures different outcomes of the ISR. Inhibition of global protein synthesis is achieved through phosphorylation of eIF2α by PERK, HRI, PKR, or GCN2. To date, a number of compounds have been developed that modulate the ISR, including activators and inhibitors of the abovementioned ISR kinases as well as modulators of p-eIF2α dephosphorylation. They target different ISR stages, allowing a broad ISR modulation strategy. At the same time, there are no drugs that are both exceptionally safe and effective for the treatment of several neurological diseases, so there is an urgent need for new approaches to the treatment of these disorders. In this review, we represent ISR signaling as an important participant in the pathogenesis of neurological diseases. We also describe how various ISR modulators may become a part of future therapies for these diseases., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

Familial hypercholesterolemia (FH) is an autosomal dominant disorder increasing premature cardiovascular diseases risk due to atherosclerosis. Pathogenic mutations in the LDLR gene cause most FH cases. Available treatments are effective not for all LDLR mutations. Testing drugs on FH cell models help develop new efficient treatments. We obtained an iPSC line from peripheral blood mononuclear cells of the patient with heterozygous p.Trp443Arg LDLR mutation. The iPSCs with confirmed patient-specific mutations express pluripotency markers, spontaneously differentiate into three germ layers and demonstrate normal karyotype. Patient-specific iPSCs-derived hepatocyte-like and endothelial cells are promising to develop new targeted therapies for FH., (Copyright © 2022 The Authors. Published by Elsevier B.V. All rights reserved.)

The literature review devoted to pathogenesis of the development of hyper- and hypoaldosteronism is presented. Based on the analysis of Russian and English-written literature known and clinically significant diseases arising due to hyper- and hypoaldosteronism are presented. Pathogenetic mechanisms inducing the development of primary and secondary forms of hyper- and hypoaldosteronism were enlightened. Furthermore the data on mechanisms of formation of hyper- and hypoaldosteronism are given.

Serum levels of vascular endothelium growth factor were measured in 43 patients with adrenal tumors and 25 healthy subjects. The mean blood levels of the factor in patients with adrenal tumors significantly surpassed the control. No correlations between the level of vascular endothelium growth factor, patients age and sex were detected. The levels of this factor were maximum in patients with adrenocortical cancer, but its mean level differed negligibly from that in other morphological variants of tumors. The level of vascular endothelium growth factor tended to increase with increasing the stage of adrenocortical cancer. A direct correlation was revealed between the level of vascular endothelium growth factor and tumor size in adrenocortical cancer and aldosterone-producing adenoma. Presumably, vascular endothelium growth factor is involved into mechanisms of growth, invasion, and metastatic growth of adrenocortical cancer.

The authors of the article analyze more than 30-year experience of surgical treatment of adrenal gland diseases, offering a detailed description of clinical and morphological features of the main nosological forms such as Itsenko-Cushing disease and syndrome, primary hyperaldosteronism, pheochromocytoma, incidentaloma, and malignant adrenal tumors. The paper contains basic diagnostic criteria, indications to operative treatment, and extents of surgery for each of the diseases considered, as well as comparative analysis of peculiarities of conventional ("open"), and endoscopic adrenal gland surgeries. The article demonstrates significance of various immunohistochemical markers in differentiation between malignant and benign adrenal tumors.

The mean blood content of interleukin-6 in patients with adrenal tumors was much higher than in healthy donors. No correlations were revealed between interleukin-6 level, patients sex and age, stage and duration of the disease. Interleukin-6 concentration was maximum in patients with adrenocortical cancer. A negative correlation was found between interleukin-6 level and blood cortisol concentration in patients with cortisol-producing adenoma. In patients with aldosterone-producing adenoma, interleukin-6 level tended to correlate negatively with plasma renin activity.

An analysis of 149 cases of primary hyperparathyroidism has shown that 83 (55.7%) patients had different kinds of pathology of the thyroid gland. The authors recommend to perform thorough revision and biopsy of the thyroid tissue in all the patients operated upon for primary hyperparathyroidism.

We compared plasma content of soluble Fas antigen (sFas) in 59 patients with tumors and tumor-like pathologies of the adrenal cortex and medulla and 60 healthy donors (control). The incidence and content of sFas in the plasma from patients with adrenal tumors was significantly higher than in healthy donors. A direct correlation was found between sFas content and patient's age. The maximum sFas concentrations were found in patients with pheochromocytoma and aldosterone-producing adenoma. In patients with adrenocortical cancer plasma content of sFas was lower than in patients with tumors of other morphological types. Plasma sFas content in patients with adrenocortical cancer directly correlated with the size of tumors. Our results suggest that sFas plays a role in the pathogenesis of primary adrenal tumors.

The review presents current data on production, release and reception of natriuretic peptides (NUP) with special focus on NUP effects on blood circulation, urination in arterial hypertension and cardiac failure; analyses interaction between NUP and renin-angiotensin-aldosterone system, effects of new drugs influencing these systems.

Serum content of soluble Fas antigen was measured by enzyme immunoassay in 60 healthy donors, 31 patients with adrenal tumors, and 16 patients with diffuse-and-nodular hyperplasia of the adrenal cortex accompanying primary aldosteronism and Cushing's disease. sFas was more often detected in the serum from patients with tumors of the adrenal cortex and medulla and diffuse-and-nodular hyperplasia of the adrenal cortex and its content varied in a wider range in patients compared to healthy donors. No correlations were found between the incidence of sFas, its content, sex, and age of healthy donors and patients. The highest content of sFas was found in patients with pheochromocytoma and primary aldosteronism. sFas probably plays a role in the pathogenesis of adrenal tumors and hyperplasia.

Enzyme immunoassay (ELISA) was used to estimate the levels of plasminogen activators of urokinase (uPA) and tissue (tPA) types and one of their inhibitors (PAI-I) in the cytosolic fraction of the thyroid in 129 patients with malignant and benign tumors and various non-cancer diseases of the gland. Tumors from patients with thyroid cancer displayed the lowest levels of tPA and the highest levels of uPA and PAI-I, while those from patients with benign thyroid diseases, including adenoma, had high concentrations of tPA and relatively low levels of uPA and PAI-I in the tissue of the diseased organ. At the same time, the lowest levels of uPA and PAI-I were found in patients suffering from toxic goiter with and without adenomatosis. In terms of uPA and PAI-I levels, patients with nodular colloidal goiter were intermediate between those with toxic goiter and adenoma, on the one hand, and those with thyroid cancer, on the other.

Neuroendocrine tumors of the pancreas were studied by histology, immunohistochemistry and electron microscopy. Tumors associated with organic hyperinsulinism showed heterogeneity in their ultrastructure, functional and proliferation activity. More than half of these tumors are multihormonal and 15% of them developed from polypotent cells which are capable for several types of differentiation.

A comparative study of the mitotic index (MI) and karyometric indices in 15 adrenocortical tumors with clinical syndrome of hypercorticism allowed to distinguish between adenomas and carcinomas. Carcinomas with hypercorticoidism symptoms have common features with inactive carcinomas but are different by lower expression of malignancy criteria (polymorphism, atypia, necrotic foci, capsule and vessel invasion), higher MI, increasing deficiency of cell division and larger nuclear size of tumor cells. Such tumors may be included into the prognostic group of risk.

In spite of a large size, mesenchymal tumor of the small pelvis was not diagnosed clinically, and hypoglycemia was considered as a manifestation of hyperinsulinism. The tumor was identified as mesenchymal, most likely fibrosarcoma, immunohistochemically. The use of antibodies against insulin, glucagon and somatostatin showed the disturbance in the balance of cells in the hyperplastic islands of the pancreas. Multifocal hyperplasia of the islands is considered as a compensatory adaptive reaction to paraneoplastic extrapancreatic hypoglycemia.

Surgical material from 51 patients operated on for insulinoma is studied. Three histological variants of insulinoma are distinguished: adenoma-like, insular-ductal and carcinoid-like. The structure of Langerhans islands outside the tumour is described and the diagnostic criteria of insuloma-microadenoma are presented. Multiple nests of the endocrine cells are regarded either as a manifestation of the multifocal island pathology or as a marker of non-diagnosed insuloma. There is a need of distinguishing between the terms related to the nosology and histogenesis of endocrine pancreatic tumours.

T-cellular immunity was studied in 104 patients with autoimmune thyroiditis to assess the function of the thyroid and treatment method. A reliable reduction of the activity of T-lymphocyte receptor system, lymphopoiesis activation, and their relationship with the thyroid status were revealed. Plasmapheresis as monotherapy was used in 22 patients. It brought about a short-term positive effect, this necessitating search for other methods of immuno-rehabilitation. In 82 patients it was supplemented with immunocorrective therapy (thymalin) and in 49 with hypothyrosis with substitution therapy (L-thyroxine, thyroidin). Combined therapy helped attain a stable clinical and immunological effect. Subpopulation composition of T-lymphocytes recovered, their functional activity normalized (follow-up period 1 year).

The role of mutagenic factors in the onset of diffuse toxic goiter (DTG) was studied in 49 families of probands with DTG. The evidence obtained on the order in which the child was born in the proband's family, age of the parents at the time of DTG child delivery, implications of occupational factors in DTG onset does not rule out mutagenic effects in the origin of DTG and thus feasibility of the key gene influence on the disease predisposition.

Effectivity of radiodiagnosis has been analyzed in 158 patients with adrenal disease, among them 112 and 117 hormone-active tumors, while 46 subjects had 54 hormone-inactive tumors. Computed tomography proved more sensitive in detection of hormone-active tumors and hyperplasia of the adrenals than ultrasonography (97% versus 62%). Radioimmunoassay of the blood outflowing from the adrenals adjuvant to their venography appeared informative in 18 out of 21 procedures. Computed tomography was also more effective in identification of adrenal hormone-inactive tumors (adenomas, metastases, cancer, etc.), its sensitivity being 100% against 44% for ultrasonography. In large-size tumors aortography only warrants determination of the tumor organic origin reliably. The diagnostic model is proposed for adrenal diseases. It uses stage-by-stage and purposeful application of radiologic investigations.

Thirty-one patients with insulinoma of the pancreas verified during operation were examined. The localization of the tumor was detected by ultrasonic examination in 9.7%, by X-ray computed tomography in 38.9%, by angiographic study in 32.1%, and by endoscopic retrograde pancreatocholangiography in 11.1% of cases. Complex use of the methods allowed the localization of the tumor to be determined in 48.4% of cases. The smallest diameter of insulinoma diagnosed during ultrasonic examination and endoscopic retrograde pancreatocholangiography was 1.5 cm, X-ray computed tomography and angiography demonstrated tumors measuring 1.0 cm in diameter. The diagnostic efficacy of the methods increases when the tumor is located in the body and tail of the pancreas. The examination scheme for patients with suspected insulinoma must include ultrasonic study and X-ray computed tomography; when their results are negative angiography must be resorted to.

107 patients with Itsenko-Cushing disease were examined for heredity: family history was analyzed in 75 cases, dermatoglyphics was assessed in 44 cases, I- and II-class HLA antigens were studied in 68 cases. The patients were found to have hereditary loading both by Itsenko-Cushing and other diseases (hypertension, atherosclerosis, autoimmune disorders). Clinico-genealogical evaluation made it possible to identify forms of the disease which are inherited autosome-recessively and autosome-dominantly. However, in the majority of patients the disease onset had multifactorial nature, as there were HLA-antigen associations by DR4, DR5, DR7, DRw53, DQw3. Pilot experience with genetic study of the disease showed its genetic determination in some forms, its association with hypertension and atherosclerosis, approaches to prevention, prognosis, classification. Practical recommendations on detailed family history collection in patients with Itsenko-Cushing disease have been developed.

The incidence rate of HLA class I and II antigens has been studied in 168 and 82 patients with diffuse toxic goiter, respectively. Positive association is found for HLA antigens A2, A3, A28, B8, B15, B17, Cw4, DR5; negative one with antigens A24, Bw4, Bw6, Cw1, Cw2, Cw3, Cw5, DR9. Prevalence of antigens B15, B17, Cw4, DR5 is associated with thyrotoxicosis severity, A2 with recurrent toxic goiter. Antigen B8 plays the role of an immunogenetic marker of endocrine ophthalmopathy.

Effect of extracorporeal UV irradiation of the blood on the clinical picture and hormonal profile of patients with the polycystic ovaries syndrome was under study. 119 women were administered 582 sessions, and in 54 of these the results were followed up for 1-25 months. A good clinical effect was achieved in 88.9% of these cases, it consisted in recovery of the cycle rhythm (70.7%), pregnancy (29.2%), reduction of hirsutism manifestations (19.04%), decrease of galactorrhea (41.7%), cessation or alleviation of headaches (86.2%), body mass reduction (40%), arterial pressure normalization (43.8%). Well-being of the majority of women was improved by therapy. 17-ketosteroids excretion normalized and persisted normal in a month after the treatment. Blood LH level and the LH/FSH ratio significantly reduced in those in whom these values were elevated in disease. Elimination of hyperandrogenism and a trend to normalization of gonadotropin secretion, resulting from extracorporeal UV irradiation of the blood, indicate that such treatment modality is pathogenetically grounded and justify its use in the treatment of women with the polycystic ovaries syndrome.

Ninety-seven patients suffering from Itsenko [correction of Icenko]-Cushing disease were examined. Analysis was made first of all of the clinical and laboratory signs pointing to the presence of other endocrine diseases to distinguish two groups of patients. The first group included subjects who did not manifest any concomitant diseases. The number of men and women was the same. The second group was made up of patients with associated Itsenko [correction of Icenko]-Cushing disease and other endocrine diseases. In this particular group, women were predominant. The first group patients demonstrated the predominance of the DR7 incidence, the second group that of the DR5. The method of estimating HLA associations identified is proposed. It allows distinguishing specific and nonspecific associations. In Itsenko [correction of Icenko]-Cushing disease, DR7 association is specific, whereas B8 and DR5 associations are unspecific. A specific polyendocrine autoimmune syndrome associated with Itsenko [correction of Icenko]-Cushing disease was revealed. A concept of the pathogenesis of Itsenko [correction of Icenko]-Cushing disease is advanced.

Incidence of class I and II HLA antigens was studied in 69 patients suffering from Icenko--Cushing syndrome. Positive association was reported for antigens DRw53, DQw3, DR4, DR5, negative for antigen DR2. Antigen combinations DR5, DR7 and DR4, DR5 proved more prevalent. The risk to develop the disease rose 2-3-fold in case of HLA-DR5 phenotype occurrence with antigen DR4 or DR7. Association with DRw53 and DQw3 antigens showing wide specificity seemed most significant.

Radiation methods were used for examining 176 patients with hormonal-active tumors and 12 patients with hormonal-nonactive tumors. The correct diagnosis of tumor of the adrenals was established with the help of oxysuprarenography in 51.9%. Ultrasonic examination was used in 78.8% and roentgen computed tomography--in 93.5%. Differential diagnostics of the Itsenko--Cushing disease and Cushing syndrome, due to corticosteroma is possible on the basis of the whole complex of findings of USI, RCT and venography with determination of the level of cortisol, aldosterone, catecholamine in blood flowing from the adrenals.