Tissue-Engineered Vascular Graft of Small Diameter Based on Electrospun Polylactide Microfibers

Tubular vascular grafts 1.1 mm in diameter based on poly(L-lactide) microfibers were obtained by electrospinning. X-ray diffraction and scanning electron microscopy data demonstrated that the samples treated at T=70°C for 1 h in the fixed state on a cylindrical mandrel possessed dense fibrous structure; their degree of crystallinity was approximately 44%. Strength and deformation stability of these samples were higher than those of the native blood vessels; thus, it was possible to use them in tissue engineering as bioresorbable vascular grafts. The experiments on including implantation into rat abdominal aorta demonstrated that the obtained vascular grafts did not cause pathological reactions in the rats; in four weeks, inner side of the grafts became completely covered with endothelial cells, and fibroblasts grew throughout the wall. After exposure for 12 weeks, resorption of PLLA fibers started, and this process was completed in 64 weeks. Resorbed synthetic fibers were replaced by collagen and fibroblasts. At that time, the blood vessel was formed; its neointima and neoadventitia were close to those of the native vessel in structure and composition

The first experience of using beta-hydroxybutyrate analysis of capillary blood in the diagnosis of non-diabetic hypoglycemia in adults

Background: The diagnostic threshold of β-hydroxybutyrate (BHB) at the moment of hypoglycemia in insulinoma was developed for venous blood many years ago, when there were no alternative ways to measure ketones. Number of works, mainly on patients with diabetes mellitus, found differences in the measurement of this indicator in venous and capillary blood, but the results were contradictory. Moreover, this study was not previously used in the diagnosis of non-diabetic hypoglycemia (NDH) in adults on the territory of the Russian Federation.Aim: To estimate the effectiveness of the method for determining BHB in capillary blood and its place in the diagnosis of NDH.Materials and methods: We conducted an experimental, cross-sectional, comparative study and included patients with suspected NDH who underwent a standard fast test. The BHB level in capillary blood was determined every 6 hours during the fast test and at its completion.Results: Based on the results of the fast test, the participants (n=154) were divided into groups: with hyperinsulinemic variant of NDH and IFRoma (n=98; group 1), with hypoinsulinemic variant of NDH /absence of NDH (n=56; group 2). When comparing the level of BHB at the moment of fasting completion, significant differences were obtained between groups 1 and 2 (p<0.001). According to the ROC analysis, the determination of BHB for differentiation the hyper- and hypoinsulinemic variants of hypoglycemia is characterized by excellent quality of model (AUC=99,1% [98,0%; 100,0%]). The BHB determination in capillary blood has the maximum diagnostic accuracy at a cut-off point of ≤ 1.4 mmol/L (Se 98.0%, Sp 96.4%, PPV 98.0%, NPV 96.4%, Ac 97.4%). Exceeding the diagnostic threshold of BHB was first recorded after 24h of fasting; at the same point, a significant difference was determined when comparing BHB indicators between two consecutive measurements (between 18h and 24h).Conclusion: The BHB determination in capillary blood is a highly sensitive and highly specific additional method for the differential diagnosis of NDH variants. The diagnostic threshold for BHB of capillary blood, which allows differentiating hyper- and hypoketonemic variants of NDH, is ≤1.4 mmol / L. It is advisable to initiate control of BHB in the blood no earlier than 18 hours after the start of the fast test

ПОСЛЕОПЕРАЦИОННАЯ КОГНИТИВНАЯ ДИСФУНКЦИЯ – ЧТО МЫ ЗНАЕМ И КУДА ДВИГАТЬСЯ ДАЛЕЕ

The authors reviewed the literature and presented results of their own research of post-operative cognitive dysfunction confirming its social importance. The development of post-operative cognitive dysfunction is to be perceived as a real fact despite the differences in the published epidemiological data. Currently, there are no grounds to correlate it directly with the general anesthesia given to patients, and there is no evidence that a certain method of anesthesia or a certain drug can reduce the frequency of post-operative clinical decline. There are numerous factors within genesis of post-operative cognitive decline and they are not studied well. All suspected mechanisms (neurotoxicity of the used agents, and other factors of anesthesia and surgery; impairment of information neuro-transmission mechanisms; neuroinflammation developing as a response to trauma) can initiate the complex neuro-physiological reactions causing cognitive dysfunction.The authors presented experimental data about morphofunctional changes in neurons and cerebellar cortex microglia after laparotomy and anesthesia with sevoflurane followed by the exposure to it in a special box for 6 hours (induction of 8 vol. % with the air flow of 2 l/min., maintaining 2 vol. % of sevoflurane with the air flow of 1 l/min.). They demonstrated that neuroinflammation was not the key factor of the detected neuronal damage. Purkinje neurons were damaged the most, since they were fairy sensitive to energy metabolic disorders, promoting the death of other neurons of the molecular layer. Neurons of the granular layer with the low level of energy metabolism were the most resistant to the impact provided by surgery/anesthesia. These data confirmed the importance of multifactorial approach when assessing the genesis of cognitive dysfunction. This research is to be continued and aimed to find out predictors of post-operative cognitive decline and to optimize anaesthesiologic support of surgery and other invasive interventions to provide a balance between their aggressiveness and effectiveness of protection, especially in senile patients who already have some cognitive dysfunctions. Авторы представили итоги анализа литературы и результатов некоторых собственных исследований по проблеме послеоперационной когнитивной дисфункции (ПОКД) и подтвердили ее социальную значимость. Факт развития послеоперационных когнитивных нарушений следует воспринимать как реальность, несмотря на различие в публикуемых эпидемиологических данных. Однако на сегодня нет оснований связывать их исключительно с влиянием проводимой пациенту общей анестезии, так же как нет и четких доказательств способности того или иного метода анестезии и лекарственного препарата снизить частоту возникновения ПОКД. Генез ПОКД многофакторный и до конца не изучен. Все предполагаемые механизмы (нейротоксичность используемых средств, а также иных факторов анестезии и операции; нарушение нейротрансмиссионных механизмов передачи информации; развивающееся в ответ на травму нейровоспаление) могут быть ответственны за инициацию сложных нейрофизиологических процессов, приводящих к когнитивной дисфункции.Представлены полученные авторами в эксперименте данные о морфофункциональных изменениях нейронов и микроглии коры мозжечка после лапаротомии с использованием анестезии севофлураном и последующей его экспозиции в специальном боксе в течение 6 ч (индукция 8 об. % в потоке воздуха 2 л/мин, поддержание ‒ 2 об. % севофлурана и поток воздуха 1 л/мин). Они показали, что нейровоспаление не явилось ключевым фактором выявленного повреждения нейронов. В большей степени страдали клетки Пуркинье, весьма чувствительные к нарушению энергетического обмена, которые вовлекали в процесс гибели другие нейроны молекулярного слоя. Нейроны зернистого слоя с низким уровнем энергетического обмена оказались более устойчивы по отношению к действию факторов операции/анестезии. Эти данные подтвердили важность многофакторного подхода к оценке генеза когнитивных нарушений. Следует продолжать исследования, направляя их на выявление предикторов развития ПОКД и на оптимизацию анестезиологического сопровождения операций и иных инвазивных вмешательств для обеспечения соответствия между степенью их агрессивности и эффективности защиты, особенно у пожилых пациентов с имеющимися когнитивными нарушениями.

Effect of glucocorticoids on bone metabolism in replacement therapy of adrenal insufficiency. Literature review

Adrenal insufficiency (AI) is a syndrome caused by disturbance in the synthesis and secretion of hormones of the adrenal cortex, which ensure the vital activity, energy and water-salt homeostasis. The widest hormonal deficiency is observed in primary hypocorticism, when the synthesis of not only glucocorticoids (GC) and adrenal androgens, but also mineralocorticoids is disrupted. Lifelong replacement therapy with GCs for this pathology may be associated with a risk of bone loss and osteoporosis. However, at present, there are no clear guidelines for diagnosis of bone condition, including and bone mineral density (BMD) monitoring during treatment with GCs in patients with AI. This review summarizes collected data on the key pathogenetic links of glucocorticoid-induced osteoporosis, incidence of decreased BMD and fractures in patients with AI. In this review factors that influence bone metabolism in this cohort of patients are considered: the type and the dose of prescribed GCs, the type (primary, secondary, HH in congenital adrenal cortex dysfunction) and the duration of AI, age, gender, and the presence of concomitant endocrine disorders (hypogonadism, growth hormone (GH) deficiency). In addition, the review presents data on the effect of adrenal androgen replacement therapy and recombinant GH therapy on bone metabolism in secondary AI

Detailed analyses of the crucial functions of Zn transporter proteins in alkaline phosphatase activation

Numerous zinc ectoenzymes are metalated by zinc and activated in the compartments of the early secretory pathway before reaching their destination. Zn transporter (ZNT) proteins located in these compartments are essential for ectoenzyme activation. We have previously reported that ZNT proteins, specifically ZNT5-ZNT6 heterodimers and ZNT7 homodimers, play critical roles in the activation of zinc ectoenzymes, such as alkaline phosphatases (ALPs), by mobilizing cytosolic zinc into these compartments. However, this process remains incompletely understood. Here, using genetically-engineered chicken DT40 cells, we first determined that Zrt/Irt-like protein (ZIP) transporters that are localized to the compartments of the early secretory pathway play only a minor role in the ALP activation process. These transporters included ZIP7, ZIP9, and ZIP13, performing pivotal functions in maintaining cellular homeostasis by effluxing zinc out of the compartments. Next, using purified ALP proteins, we showed that zinc metalation on ALP produced in DT40 cells lacking ZNT5-ZNT6 heterodimers and ZNT7 homodimers is impaired. Finally, by genetically disrupting both ZNT5 and ZNT7 in human HAP1 cells, we directly demonstrated that the tissue-nonspecific ALP-activating functions of both ZNT complexes are conserved in human cells. Furthermore, using mutant HAP1 cells, we uncovered a previously-unrecognized and unique spatial regulation of ZNT5-ZNT6 heterodimer formation, wherein ZNT5 recruits ZNT6 to the Golgi apparatus to form the heterodimeric complex. These findings fill in major gaps in our understanding of the molecular mechanisms underlying zinc ectoenzyme activation in the compartments of the early secretory pathway

A case of 17-beta-hydroxysteroid dehydrogenase deficiency type 3 in adult endocrinologist practice

17β-Hydroxysteroid dehydrogenase 3 deficiency (17HSD3) is a rare autosomal recessive cause of 46, XY disorders of sex development resulting from HSD17B3 gene mutations, in which conversion of androstenedione to testosterone is impared. The clinical signs of 17HSD3 deficiency depend on the residual activity of the enzyme. The diagnosis of 17HSD3 deficiency is based on reduced testosterone/androstenedione ratio (T/AD < 0.8). Patients are usually assigned at birth and raise as female. If the diagnosis is made before puberty, gonadectomy is recommended, taking into account the risk of masculinization during the puberty and estrogen therapy initiation in this period. If the diagnosis of 17HSD3 deficiency is established during puberty, when virilization manifests, the therapeutic strategy is based on the results of comprehensive psychological testing and gender identity of a patient. In patients with more pronounced masculinization or diagnosis established shortly after birth, who are assigned at birth and raise as male, testosterone therapy is used to achieve a male phenotype. The 17HSD3 deficiency and virilization often result in a change of gender identity during puberty. The article presents a clinical case of 17-βhydroxysteroid dehydrogenase type 3 deficiency with late diagnosis due to parental will. The diagnostic approaches and management of the disease are also described

Genetic predictors of insulin-producing pancreatic tumor

Insulinoma is the most common functioning tumor of the pancreas. Approximately 5% of its cases are associated with the multiple endocrine neoplasia syndrome type 1 (MEN1), caused by mutation in the MEN1 gene. MEN1 can be manifested by pituitary and parathyroid adenomas, pancreatic neuroendocrine tumors, tumors of the thyroid gland, adrenals, intestine, carcinoids of lungs and other organs. However, in 5–10% of the patients with clinical manifestation of this syndrome, MEN1 mutations cannot be identified. Moreover, the disease can be caused by various abnormalities (mutations, polymorphisms, etc.) in other genes. More than 30 genes, associated with insulin-producing pancreatic tumors, have been described in the literature. With a known germinal mutation, the prognosis and management of patients with insulinoma can be determined by the hereditary disease with which the tumor is associated. The article emphasizes the need to search for new genetic markers that predispose to the development of insulinoma. The necessity of extended genetic testing of patients with insulinomas is discussed, primarily of young patients with multifocal lesions, family history and associated disorders

POSTOPERATIVE COGNITIVE DYSFUNCTION – WHAT WE KNOW AND WHERE WE GO

The authors reviewed the literature and presented results of their own research of post-operative cognitive dysfunction confirming its social importance. The development of post-operative cognitive dysfunction is to be perceived as a real fact despite the differences in the published epidemiological data. Currently, there are no grounds to correlate it directly with the general anesthesia given to patients, and there is no evidence that a certain method of anesthesia or a certain drug can reduce the frequency of post-operative clinical decline. There are numerous factors within genesis of post-operative cognitive decline and they are not studied well. All suspected mechanisms (neurotoxicity of the used agents, and other factors of anesthesia and surgery; impairment of information neuro-transmission mechanisms; neuroinflammation developing as a response to trauma) can initiate the complex neuro-physiological reactions causing cognitive dysfunction.The authors presented experimental data about morphofunctional changes in neurons and cerebellar cortex microglia after laparotomy and anesthesia with sevoflurane followed by the exposure to it in a special box for 6 hours (induction of 8 vol. % with the air flow of 2 l/min., maintaining 2 vol. % of sevoflurane with the air flow of 1 l/min.). They demonstrated that neuroinflammation was not the key factor of the detected neuronal damage. Purkinje neurons were damaged the most, since they were fairy sensitive to energy metabolic disorders, promoting the death of other neurons of the molecular layer. Neurons of the granular layer with the low level of energy metabolism were the most resistant to the impact provided by surgery/anesthesia. These data confirmed the importance of multifactorial approach when assessing the genesis of cognitive dysfunction. This research is to be continued and aimed to find out predictors of post-operative cognitive decline and to optimize anaesthesiologic support of surgery and other invasive interventions to provide a balance between their aggressiveness and effectiveness of protection, especially in senile patients who already have some cognitive dysfunctions

SECONDARY (ENDOCRINE) HYPERTENSION: LECTURE

Hypertension is a  very common disease with high morbidity and reduction in quality of life. Endocrine disorders are the most common cause of secondary hypertension affecting ~3% of the population. Primary aldosteronism can be the cause of endocrine hypertension more often than other endocrine disorders. Other less common causes of endocrine hypertension include Cushing syndrome, pheochromocytoma, thyroid disorders, and hyperparathyroidism. Endocrine hypertension is potentially curable if the underlying cause is identified and treated accordingly. Younger age at manifestation of resistance to multiple antihypertensive drugs, together with other clinical signs of an endocrine disorder, should raise the suspicion and prompt the appropriate evaluation

Clinical case of factitious hypoglycemia

Hypoglycemic syndrome (HGS) is a significant decrease glucose in blood, manifested by neurological symptoms, and stopped by the introduction of glucose. Among the many causes of HGS the special place is taken by the factitious hypoglycemia, as one of the variants of Munchausen syndrome. Hypoglycemia in such cases is achieved by the intentional introduction of hypoglycemic drugs. The most commonly used medications are sulfonylurea derivatives, which are affordable, inexpensive and legal. The close collaboration of clinicians with the laboratory service plays a key role in the diagnosis of factitious hypoglycemia. Since the results of biochemical and hormonal analyzes in patients with hypoglycemia due to reception of oral hypoglycemic medications and pancreatogenous HGS are identical, the only way to differentiate these conditions is by detection of insulin secretagogue substances in the blood (or urine).The determination of oral hypoglycemic medications in cases of suspicion of artificial reception is not implemented in Russia. Factitious hypoglycemia in most cases is the diagnosis of exclusion, and its confirmation if often based on detection of medications among the personal effects of patient. This is a significant difficulty given the ethical standards. However, since 2018 we conduct in our Centre the determination of 7 oral hypoglycemic medications (glibenclamide, gliquidone, gliclazide, glimepiride, glipizide, nateglinide and repaglinide) in patient’s blood using the liquid chromatography–tandem mass spectrometry (LC-MS). This article presents a clinical case of a patient without diabetes mellitus taking glibenclamide and detection of this drug using highly selective LC-MS