A birth experience with cesarean section (CS) can be a cause of the development of post-traumatic stress disorder after a cesarean (PTSD-AC) or profile PTSD, for a percentage of women. So far, there is no data on the frequency of PTSD-AC in Greece and this syndrome is often associated with other mental disorders of the postpartum period. The purpose of this research is to associate the kind of CS with PTSD-AC for Greek mothers and the combination of factors that make them less resistant to trauma. A sample of ahundred and sixty-six mothers who gave birth with emergency cesarean section (EMCS) and elective cesarean section (ELCS) at a Greek University hospital have consented to participate in the two phases of the survey, in the 2nd day postpartum and a follow-up in the 6th week postpartum. Medical/demographic data and a life events checklist (LEC-5) with Criterion A and post-traumatic stress checklist (PCL-5) were used to diagnose PTSD and PTSD Profile. Out of166 mothers enrolled, 160 replied to the follow-up (96.4%), ELCS 97 (97%) and EMCS 63 (95%). Twenty (31.7%) EMCS had PTSD and nine (14.3%) had Profile. One (1%) ELCS had PTSD and 4 (4.1%) had Profile. This survey shows a high prevalence rate of PTSD after EMCS with additional risk factors of preterm labor, inclusion in the Neonatal Intensive Care Unit (NICU), a lack of breastfeeding, and a lack of support from the partner. Posttraumatic stress disorder(PTSD) is a trauma-related stress disorder caused by exposure to real or threatened death, heavy injury or a threat of physical integrity in various forms of exposure, such as direct exposure, exposure as a witness, exposure through information or extreme repeated exposure to the workplace. The disorder, regardless of the type of exposure to trauma, causes symptoms of re-experiencing, avoidance, negative cognitions in the mood and arousal. The disturbance lasts more than a month, not due to the action of any substance or physical condition and causes a significant reduction in the person’s social life . The preOn the other hand, PTSD Profile includes the most important symptoms of PTSD, yet people exposed to the trauma, do not meet all the diagnostic criteria of the disorder. This is partial PTSD, which has been shown to be associated with increased rates of alcoholism, suicidal ideation, overconsumption of health services, and an increase in absences in the working environment.Additionally, a significant reduction in the social and professional life of the individual is observed ,4.For several years, the experience of the birth of a child was viewed by scientists as a positive experience for the mother. In recent years, however, research into women with traumatic birth experiences has increased interest and it is now known that some of these experiences may lead to trauma disturbances. More than 1/3 of women experience birth as a traumatic event , while aThe perinatal period is special for every woman’s life. Most of them experience birth as a pleasant experience, but in a small percentage, this experience becomes a traumatic event, affecting to a significant extent the woman herself and everyone around her. Various conditions seem to affect the development of this disorder, such as pregnancy pathology, complications during birth, emergency cesarean section, history of psychiatric disorders, fear during childbirth, and previous traumatic events in the mother’s life ,8,9,10. Many researchers have been carried out on the effect of the kind of delivery on the development of PTSD postpartum ,13,14,15Every year in Greece, there are about 90,000 births  of whichThis prospective study took place from July to November 2019, at the obstetrics clinic of the General University Hospital of Larissa in Greece. It was approved by the University Hospital of Larisa Ethics Commission. Approval: 18838/08-05-2019.The present study is using a descriptive design for the recording of the prevalence of PTSD-AC within 6 weeks postpartum and the risk factors that may lead to the development of this disorder.Survey participants wereall the women who gave birth with EMCS or ELCS and gave their written consent for their participation. All women had a medical surveillance dossier from which the demographics and medical data were obtained. Excluded from the research were the women with difficulties in understanding the Greek language or other difficulties at a cognitive level which would create a problem in understanding the questions or the measuring tools. Additionally, the underage mothers were excluded, or those who used psychotropic substances or drugs and all those who gave birth with EMCS from other hospitals in the region.The data was collected in 2 stages: the first stage wasthe 2nd day afterchildbirth, and; thesecondstage wasthe 6th week after childbirth. During the firststage that coincides with the recovery of the woman after surgery, from the 160 women who met the criteria for participation, medical and demographic data were collected, old traumatic life events and the identification or not of theCS being a traumatic experience. Inthe second stage, through a telephone interview, respondents answered questions on the PTSD scale. The specific period of time was selected in order to meet the criterion of the duration of symptoms over 4 weeks .All measures were authored by the National Center of PTSD Staff according to the Diagnostic and Statistical Manual (DSM V), and weretranslated and weighted into the Greek language by the investigator midwife.The research-made screening form includes items on demographic, social, medical  and mental characteristics of the participants. Italso included information on the experience of the traumatic cesarean section.This measure of exposure to traumatic events of the past is used with PCL-5 to determine exposure to a traumatic event . The lifTo confirma PTSD diagnosis, 8 criteria must be met. For Criterion A, the person must have been exposed to death, threatened death, serious injury or sexual violence in one of the following ways: (a) direct exposure, (b) witness to the event, (c) information of the event, and (d) exposure in the working space ,34. For The post-traumatic stress checklist (PCL-5) is a self-report measure, which was developed to measure and evaluate PTSD and PTSD Profile symptoms. In the present investigation, the respondents replied via telephone to 20 questions, corresponding to 20 symptoms of the criteria B (re-experiencing), C (avoidance), D (negative thoughts and feelings), and E . All replies are scored by 5-point scales (range zero to four). A score of one or more in the categories of criteria B and C and two or more in categories D and E are considered clinical findings. If all 4 criteria are met in connection with criterion A, the diagnosis of PTSD-AC is considered possible. To determine the severity of the symptoms, the method of the sum of the score of all responses with a PCL score ≥ 33was also used . Dependit-tests were computed for the comparison of mean values when the distribution was normal and the Mann-Whitney test was used for the comparison of median values when the distribution was not normal. Logistic regression analyses were performed in order to identify factors associated with the presence of PTSD.Unadjusted and adjusted odds ratios with 95% confidence intervals were computed from the results of the logistic regression analyses. Statistical significance was set at 0.05 and analyses were conducted using SPSS statistical software .Quantitative variables were expressed as mean values (SD) or as median values (interquartile range = IQR). Qualitative variables are presented with absolute and relative frequencies. For the comparisons of proportions, chi-square and Fisher’s exact tests were used. Student’s Data from 160 women with a mean age of 33.1 years (SD=5.9 years) were analyzed. Sample characteristics in totals according to the type of cesarean section are presented in Pregnancy and delivery characteristics are shown in p < 0.001-The proportion of women with a profile of PTSD was 14.3% in the emergency cesarean section group and 4.1% in the planned cesarean section group, while the corresponding proportions for having PTSD were 31.7% and 1% (n = 160), the proportion who met criterion A is 25.6% (EMCS 54% and ELCS 7.2%) and those who metcriterion B through to E, is between 19-26.3% (EMCS 36.4–52.5% and ELCS 7.2–10.3%). A total of 13, 1% (n = 21) of women after CS met all criteria  according to the DSM V, while 8.1% (n= 13) fulfilled criteria  and missed criteria A and E.Univariate logistic regression analyses with the dependent variable as the presence of PTSD  showed aThe subject of the present investigation was the identification of risk factors that help the development of PTSD-AC in mothers after EMCS and ELCS, in order to implement appropriate preventive measures in perinatal care. The results show that 40% of women experienced CS as a traumatic childbirth experience (EMCS 71.4%-ELCS 19.6%). Criterion A met 25.6% of all CS (EMCS 54%-ELCS 7.2%) . In addiThere are many studies thatindicate the EMCS as a risk factor for the development of postpartum psychological disorders ,38,39 anA remark must be made regarding ours and other findings. This prospective study is the firstto investigate the development of PTSD and PTSD Profile in two groups of high-risk postpartum women (EMCS and ELCS). Furthermore, it is one of the few studieswhere they used all the diagnostic criteria  for PTSD postpartum, according to the DSM-V 8] and  and 8] aThe results of this study showthat preterm labor is associated with PTSD-AC. Only 76.2% of women after EMCS and 87.6% after ELCS had full-term labor and 1/3 of women who met the diagnostic criteria for PTSD or PTSD Profile had preterm labor.A few studies have reported that delivery of a premature infant was a risk factor for the development PTSD and other psychological disorders postpartum ,43. ThisAnother very important factor predicting PTSD-ACwhich is associated with preterm labor and complications during pregnancy is the inclusion of the infant in the NICU. It is known that maternal distress after the inclusion of the infant in the NICUconsists of a complication of anxiety, depressive and PTSD symptoms and is associated negatively with maternal-infant attachment ,45. In oFor many women, breastfeeding is an extension of the birth experience and it has been proven that it can reduce the trauma of medical delivery.When there is a traumatic childbirth experience, breastfeeding can be disappointing due to traumatic reminders of childbirth. All these feelings can lead to a lack of initiation or premature termination of breastfeeding . In thisThere was a significant difference between the PTSD-AC and perinatal support from a spouse. In this study, women with poor support from their spouses were more likely to suffer from PTSD or PTSD Profile (28.6%) compared to the women with good support from their spouse (9.8%), the second groupseems to manage better the consequences of traumatic CS.A lot of studies reveal the relationship between social support and good health and suggest that the psychical reaction to stress is under the influence on the level of family and spouse support . FocusinUnfortunately in Greece, there are few supporting services for women exposed to birth trauma For this reason, support from a partner or spouse is one of the main factors protecting from postnatal PTSD.The present study identified vulnerability postpartum factors in women who had undergone an emergency or elective cesarean section in a Greek Hospital. Traumatic CS experiences were predictive with the adapted diagnostic measurement tool (PCL-5). The measuresrevised to reflect the new diagnostic criteria and now is one of the few validated measures for PTSD. Women in this study who met all the diagnostic criteria  of DSM-5 have a provisional diagnosis of PTSD-AC and women who met criteria  only, have a PTSD Profile. From the present study, it has emerged that the risk factors developing PTSD-AC are: EMCS, preterm labor, inclusion inthe NICU, a lack of breastfeeding, and a lack of support from a spouse during the perinatal period. Health professionals who contact women during the perinatal period should inform them so as to ensure the reduction of the above risk factors.Further research should take place to investigate PTSD after birth with EMCS, especially in countries with high percentages of CS, particularly focusing on the differencesin PTSD rates between EMCS and ELCS.


It was found that a high concentration of sodium chloride (2 M) leads to considerable dissociation of PAH, which is apparently due to the loosening of polyelectrolytes under the action of ionic strength. At the same time, 0.2 M sodium chloride and ammonium sulfate of the same ionic strength (0.1 M) exert less influence on the amount of dissociated polymer. In the case of ammonium sulfate (0.1 M), the effect is due to the competitive binding of sulfate anions to the amino groups of the polyelectrolyte. However, unlike microcapsules formed on CaCO3 particles containing protein, the dissociation of polyelectrolyte from microcapsules formed on protein-free particles increased with increasing temperature. Apparently, a similar effect is associated with the absence of a distinct shell, which was observed on microcapsules formed on protein-containing CaCO3 particles. The high level of the presence of Fluorescein isothiocyanate (FITC)-labeled Bovine Serum Albumin (BSA) in the supernatant is explained by the large amount of electrostatically bound protein and the absence of a shell that prevents the release of the protein from the microcapsules. In 2 M NaCl, during the observation period, the amount of the released protein did not exceed 70% of the total protein content in the capsules, in control samples, this value does not exceed 8%, which indicates the predominantly electrostatic nature of protein retention in capsules formed on protein-free CaCO3 particles. The increase in protein yield and peeling of PAH with increasing pH is explained by the proximity of pH 7 to the point of charge exchange of the amino group of polyelectrolyte, as a result of the dissociation of the microcapsule.The degradation of polyelectrolyte microcapsules formed on protein-free CaCO Polyelectrolyte microcapsules (PMC), produced by the method of alternately layering oppositely charged polyelectrolytes on microsized dispersed particles, with subsequent destruction and removal of these particles, are the objects of a new rapidly developing field–polymer nanotechnology ,2,3,4,5.The results obtained thus far demonstrate the wide possibilities of using PMC in the development of a new class of chemical and biochemical reactors and the study of the physical and chemical processes in a small volume when creating a new type of probes and highly sensitive sensors and developing original methods for separating mixtures of various organic and inorganic substances in particular, the separation of heavy metal ions from the medium ,7,8,9,10There are several articles describing the release of low molecular weight drugs from polysaccharide microcapsules. Thus, it was shown in ,17,18,19The effect of temperature and the presence of salts on the rearrangement of polyelectrolyte groups is being actively studied. For example, possible mechanisms of influence are demonstrated by B. Schlenof et al. . It was 4)2SO4 in different concentrations, and at pH 5 and 7.4. These microcapsules were prepared by alternately adsorbing the oppositely charged polyelectrolytes on a compound spherulite CaCO3 protein  and polystyrene sulfonate (PSS) and the yield of protein from them in the presence of NaCl and  consisting of polyallylamine (PAH) and polystyrene sulfonate (PSS) and the resulting yield of protein.Polyelectrolytes polystyrenesulfonate sodium (PSS) and polyallylamine hydrochloride (PAH) with a molecular mass of 70 kDa, fluorescein isothiocyanate (FITC) Mw = 389.38, bovine serum albumin (BSA), Ethylenediaminetetraacetic acid disodium salt dihydrate (EDTA) purchased in Sigma , sodium chloride, ammonium sulfate, sodium carbonate, calcium chloride from “Reahim”.To a solution of polyelectrolyte or protein (10 mg/mL) in 50 mM borate buffer, pH 9.0 with stirring (300–400 rpm), FITC was slowly added in the same buffer. The components were fused in a molar ratio of FITC:PAH (BSA) (by amino groups) = 1:100. After 1.5–2 h of incubation, the resulting solution was dialyzed against water (10 L) overnight.2 solution, vigorously agitated on a magnetic stirrer, an equal volume of 0.33 M Na2CO3 solution was rapidly added. Stirring was continued for 30 s. The resulting suspension was maintained until complete precipitation of the formed particles. The process of “ripening” of microspherulites was controlled with the help of a light microscope. Then, the supernatant was decanted, the precipitate was washed with water and used to prepare PMC. The microparticles were obtained with a narrow size distribution with an average diameter of 5 μm.To 0.33 M CaCl3 microspherulites was carried out in solutions of polyelectrolytes with a concentration of 2 mg/mL containing 0.5 M NaCl. Each step of adsorption was followed by a triple wash with a 0.5 M NaCl solution, which was necessary to remove unadsorbed polymer molecules. The particles were separated from the supernatant by centrifugation. After applying the required number of layers, the carbonate kernels were dissolved in a 0.2 M EDTA solution for 12 h. The resulting capsules were washed three times with water to remove nuclear decay products. Capsules containing labeled PAH as the 7th (outer) layer were obtained.Seven-layer polyelectrolyte microcapsules were obtained by alternately adsorbing the oppositely charged polyelectrolytes onto a dispersed microspherulites (core), followed by dissolution of this cores . AlternaPolyelectrolyte microcapsules were incubated in a solution of BSA protein labeled with FITC (6 mg/mL) for 12 h. The resulting microcapsules were washed three times with bidistilled water to remove unadsorbed protein molecules. Registration of the results of inclusion was made by comparing the fluorescence of the protein solution before and after switching on.The dissociation of the microcapsule and the yield of the protein from them were studied by fluorescence spectroscopy. Polyelectrolyte microcapsules, containing FITC-labeled PAH, into which the FITC-labeled BSA was encapsulated, were precipitated by centrifugation at 3000 rpm for 1 min. Further, the fluorescence of the supernatant was measured. Fluorescence spectra were recorded on an Infinite 200 Tecan instrument in a thermostated cuvette with an optical path length of 1 cm when excited with light at a wavelength of 273 nm.3-spherulites—was studied. A decrease in the dissociation of polyelectrolytes with increasing temperature was also demonstrated. The effect was due to the fact that as the temperature is increased, the amount of ionic groups increases in “complementary” segments of polyelectrolyte chains coupled together by the electrostatic interaction and hydrogen bonds between oppositely charged ionic groups structural units. As a result, the contribution of the electrostatic repulsion decreases and the dispersion attraction between chain segments on the inner surface increases. This leads to an enhancement of hydrophobic interactions and, correspondingly, to a “pulling” of polymer chains inward, toward the center of the capsule and decrease the amount of polyelectrolytes in incubation solution [In our previous work , the dissolution . In the 3+ and –SO3- groups polyelectrolytes . When sradation . In the The next stage was the study of the dynamics of protein released from polyelectrolyte microcapsules. In The results of the study of the yield of BSA from polyelectrolyte microcapsules as a function of the pH of the medium are shown in 3 particles and the yield of a protein encapsulated by adsorption. It was found that a high concentration of sodium chloride (2 M) leads to considerable dissociation of PAH, which is apparently due to the loosening of polyelectrolytes under the action of ionic strength. At the same time, 0.2 M sodium chloride and ammonium sulfate of the same ionic strength (0.1 M) exert less influence on the amount of dissociated polymer. However, unlike microcapsules formed on CaCO3 particles containing protein, the dissociation of polyelectrolyte from microcapsules on protein-free particles increased with increasing temperature. A similar effect is apparently associated with the absence of a distinct shell, which was observed on microcapsules formed on protein-containing CaCO3 particles. The high level of the presence of FITC-labeled BSA in the supernatant is explained by the large amount of electrostatically bound protein and the absence of the envelope bounding the protein from the external environment. In 2 M NaCl, during the observation period, the amount of protein released did not exceed 70% of the total protein content in the capsules, in control, this value does not exceed 8%, which allows to speak about the predominantly electrostatic nature of protein retention in sponge type capsules. The increase in protein yield and dissociation of PAH with increasing pH is explained by the proximity of pH 7 to the point of charge exchange of the amino group of the polyelectrolyte as a result of the disintegration of the microcapsule.In this paper, a study was conducted to study the dissociation of polyelectrolyte microcapsules formed on protein-free CaCO


The prevalences of diabetes mellitus and hypertension, both of which are components of metabolic syndrome, are known to be increased among patients with multiple myeloma (MM), but remain undetermined among patients with smoldering MM (SMM).Changes in various components of metabolic syndrome were investigated during the follow-up of patients with either MM or SMM compared to healthy controls. The data of 153 patients (105 with MM and 48 with SMM) and 138 controls were accessed from our medical center’s records between 2008 and 2015. We analyzed the patients’ data at diagnosis (baseline) and after 1, 3, and 5 years of follow-up.Patients with SMM had a significantly higher prevalence of diabetes, hypertension, and dyslipidemia at baseline compared to controls. A multivariate Cox regression analysis revealed a higher risk to develop dyslipidemia after 1, 3, and 5 years of follow-up among the SMM patients. The MM patients had a higher risk to develop diabetes after 1 year, hypertension after 5 years, and dyslipidemia after 1, 3, and 5 years of follow-up.These data demonstrate that patients with SMM and those with MM are more prone to develop various components of metabolic syndrome, and they stress the importance of following-up metabolic syndrome components in both groups of patients. Multiple myeloma (MM) is a malignancy of plasma cells that comprises about 10% of hematological cancers. The incidence of MM is expected to almost double in the upcoming decades due to the aging of the population  have resSince most MM patients are diagnosed between the ages of 65–74 years , they ofThe treatment of MM, including steroid therapy, chemotherapy, and bone marrow transplant, may exacerbate the features of metabolic syndrome, which is characterized by hyperglycemia, hypertension, dyslipidemia, and obesity . AccordiMuch less is known about the components of metabolic syndrome in patients with SMM who are not receiving either anti-MM treatment or steroids. The question arises as to whether an increased risk of various components of metabolic syndrome in MM patients is due to the treatment or whether it could be already present at the stage of SMM due to the disease itself. The aim of this study was to examine the prevalence of diabetes mellitus, hypertension, and dyslipidemia in patients with MM and in those with SMM at the time of diagnosis (baseline), and to determine the incidences of these diseases during a follow-up of 1, 3, and 5 years in comparison to a healthy control group.We conducted a prospective historical study on three cohorts: 1) SMM patients who were monitored at Tel Aviv Sourasky Medical Center (TASMC); 2) MM patients who were treated at TASMC; 3) healthy individuals who were undergoing routine medical checkups at the Institute for Preventive Medical Examinations at TASMC and comprised the control group. The sole inclusion criterion for the three groups was age 18 years or over. Diagnoses of MM or SMM were according to the criteria of the International Myeloma Working Group . ExclusiData were collected from the medical records of patients treated in the Hematology Department and in the Institute of Special Medical Examinations at the TASMC between 2008 and 2015. Retrieved information included the patients’ age, sex, date of diagnosis of SMM or MM, date of initiation of medical treatment for MM, background diseases, medical treatment added during the follow-up (unrelated to MM), and baseline height, weight, and body mass index. Also included were the glucose, HbA1c, triglycerides, total cholesterol, high-density lipoprotein cholesterol (HDL-C), and low-density lipoprotein cholesterol (LDL-C) test results at baseline, and after 1, 3, and 5 years of follow-up.The SMM patients were followed for at least 1 year and up to 5 years or until progression to MM, and they were monitored in the hematology clinic without receiving any medication. The SMM patients that progressed to MM were switched to the MM group in the analysis. The MM group received conventional therapy, including prednisone, at diagnosis.The historical control group consisted of healthy individuals who were matched to the patients in the SMM and MM groups by age, sex, and length of follow-up. The same demographic, clinical, and laboratory data of the controls were retrieved from the TASMC database between 2008 and 2015.Diabetes mellitus prior to and during the follow-up period was defined as the presence of at least one of the following: 1) an HbA1C result of 6.5% or above; 2) a record of hypoglycemic medications; 3) a diagnosis of diabetes as recorded by the treating physician. A diagnosis of hypertension prior to and during follow-up was defined according to the presence of one of the following: 1) initiation of treatment for hypertension; 2) the diagnosis of hypertension as recorded by the treating physician.A diagnosis of dyslipidemia prior to and during the follow-up was defined as the appearance of at least one of the following: 1) an LDL-C level of 160 mg/dL or above in the absence of diabetes or hypertension; 2) an LDL-C level of 130 mg/dL or above in the presence of hypertension; 3) an LDL-C level of 100 mg/dL or above in the presence of diabetes or ischemic heart disease; 4) a triglycerides level of 150 mg/dL or above; 5) an HDL-C level lower than 40 mg/dL in males or lower than 50 mg/dL in females; 6) initiation of treatment for dyslipidemia; 7) a new diagnosis of dyslipidemia as recorded by the treating physician.t-test was used to assess changes in various measures between the first and last points of follow-up.Continuous variables with normal distributions are presented as means and standard deviations, and variables without normal distributions are given as medians and interquartile ranges. Categorical variables are presented as numbers and percentages of patients in each group. For the purpose of evaluating metabolic measures, the one-way ANOVA test was performed according to patient groups  by means of the Bonferroni post hoc analysis for multiple comparisons. The paired P value < 0.05 was considered statistically significant. All statistical analyses were performed using IBM SPSS Statistics 22.0 .Categorical variables were compared by the chi-squared test. Cox regression analyses adjusted for sex, age, the follow-up duration, and presence of diabetes, hypertension and dyslipidemia at baseline were performed to determine de novo incidences of diabetes, hypertension and dyslipidemia. A P < 0.001). The prevalence of hypertension and dyslipidemia were significantly higher in the SMM group compared to the control group . The prevalences of hypertension and dyslipidemia were also higher in the MM group than in the control group, but not to a level of significance . The prevalence of ischemic heart disease was 12.5, 14.6, and 6.5% in the MM, SMM, and control groups, respectively (P = NS).A total of 184 patients diagnosed with MM or SMM were treated in the hematological department of the TASMC during the study period. After excluding 31 patients who did not meet inclusion criteria . The use of angiotensin receptor blockers was significantly higher in the SMM group than in the control group . The use of statins was significantly higher in the SMM group than in the MM and control groups .At baseline, the use of ACE inhibitors and hypoglycemic drugs was significantly greater in the MM and SMM groups compared to the control group  and for the SMM group  compared to the control group , hypertension (60.0%), and dyslipidemia (54.0%) among individuals with SMM compared to a healthy control group  at baseline. After 1, 3, and 5 years of follow-up, however, individuals with sustained SMM showed an increased risk of dyslipidemia, but not of diabetes or hypertension compared to the control group. The prevalence of diabetes at baseline (26.5%) was higher for the MM patients than that for the subjects in the control group. During the follow-up, the mean glucose levels and lipid profiles deteriorated significantly among the MM patients. The prevalence of diabetes, hypertension, and dyslipidemia continued to rise during the 5-year follow-up period. After the first year of follow-up, the risk of developing diabetes was higher, as was the risk of developing dyslipidemia, the latter with a subsequent elevation after 3 and 5 years of follow-up. The risk of developing hypertension did not change until 5 years of follow-up, when it was observed to rise. Our 27.0% prevalence of diabetes at MM diagnosis is about twice the rate reported by other studies , 18, 23.Numerous studies have reported associations of diabetes with all-site cancer , includiHypertension is considered as being ubiquitous among MM patients and, until recently, this was believed to be due to the older age of the patients, the fact that more men are affected with the disease, and a consequence of the treatment with steroids. However, the findings of the current study revealed that hypertension was more prevalent among patients with SMM at baseline ─ and therefore not yet treated with steroids ─ than in the control group. Inflammation may also have a role in this setting, since patients with hypertension have an increased level of inflammatory cytokines –40, and According to a national health study conducted on Israelis aged 21 years and older during 2013–2015 (INHIS 3), the prevalences of diabetes, hypertension, and dyslipidemia were 8.4, 20.6, and 30.2%, respectively . The datHyperlipidemic myeloma (HLM) is a rare variant of MM. In a review that summarized 53 cases of HLM, the typical clinical presentation was characterized by IgA myeloma, hyperlipidemia, skin xanthomas, and hyperviscosity . The preIn contrast, hypocholesterolemia is fairly common in MM patients , 44, 45.A recent analysis from the Cancer Research Network showed a protective association between statin use and MM development . This asThis study has a number of limitations largely due to its retrospective design. Some important data were missing, such as smoking in the present or past and details on family history of hyperlipidemia. A systematic follow-up of blood pressure measurements was not done for the MM and SMM groups, thus, individuals were considered to have hypertension only according to documentation of a diagnosis by their primary care physicians or the initiation of treatment for hypertension. In contrast, hypertension was assessed and recorded in the medical records of the individuals of the control group. Another drawback may be selection bias in the interpretation of the findings. Since the patients included in this study were being followed-up in the hematology department of a tertiary hospital, there is a greater chance that their disease would be severe and possibly with more background disease and, as a result, they may not necessarily represent the MM and SMM patients who are treated in the community. Finally, despite efforts to access all relevant clinical and laboratory data, the sample size was small, particularly at the end of the 5-year follow up. Together with missing data, this may explain the lack of statistical significance for some of the analyses.In conclusion, this retrospective cohort study showed that the MM patients had a higher prevalence of diabetes at baseline and had a higher risk to develop diabetes after 1 year, hypertension after 5 years, and dyslipidemia after 1, 3, and 5 years of follow-up compared to the non-MM controls. In addition, individuals with SMM were more prone to develop dyslipidemia after 1, 3, and 5 years of follow-up compared to the controls. These findings support the notion that characteristics of MM itself, and not only its treatment, may be associated with an increased risk of various components of metabolic syndrome and call for future prospective research of those components in SMM and MM patient populations.


Carotid endarterectomy (CEA) is safe and effective in reducing the risk of stroke in symptomatic severe carotid artery stenosis. Having information about cross-clamping (CC) intolerance before surgery may reduce the complication rate. The purpose of this study was to assess the usefulness of magnetic resonance angiography (MRA) and magnetic resonance angiography perfusion (P-MR) in determining the risk of CC intolerance during CEA. Material and methods: 40 patients after CEA with CC intolerance were included in Group I, and 15 with CC tolerance in Group II. All patients underwent MRA of the circle of Willis (CoW), P-MR with or without Acetazolamide; P(A)-MR in the postoperative period. Results: CoW was normal in the MRA in three cases (7.5%) in Group I, and in eight (53%) in Group II. We found P-MR abnormalities in all patients from Group I and in 40% from Group II. Using a calculated cut-off point of 0.322, the patients were classified as CC tolerant with 100% sensitivity or as CC intolerant with 95% specificity. After evaluating P-MR or MRA alone, the percentage of false negative results significantly increased. Conclusion: The highest value in predicting cross-clamping intolerance is achieved by using analysis of P(A)-MR and MRA of the CoW in combination. Neurological complications during and after internal carotid artery (ICA) endarterectomy (CEA) occur as a result of intraoperative embolization, hypoperfusion during the ICA cross-clamping (CC), intracranial hemorrhage or hyperperfusion syndrome ,2.The risk of intraoperative neurological complications is particularly high in patients who do not tolerate CC, and extremely high in the case of acute thrombosis of the operated artery or repeated operations. Predicting the occurrence of CC intolerance should affect the operational technique and the selection of a surgical team experienced in using shunts .The methods used to evaluate the anatomy of the circle of Willis led to too many false-positive results . As a coThe purpose of this study was to preoperatively assess the risk of cerebral ischemia during carotid CC using different diagnostic tests. Our goal was also to investigate factors affecting cerebral ischemia during carotid CC.Patients who presented ischemic symptoms within 2 to 60 s after CC, and the operation was cancelled, were included in the study (Group I). A group of patients without symptoms of cerebral ischemia after CC that underwent CEA, was studied as controls (Group II).Preoperatively, carotid ultrasound examination (DUS), magnetic resonance angiography (MRA) of the extracranial and intracranial arteries and magnetic resonance brain perfusion tests (P-MR) with and without Acetazolamide (PA-MR) were performed on all patients.The DUS study was performed using a Siemens  ultrasound machine with the use of both linear (5.1–9 MHz) and convex (2.8–5.1 MHz) probes. The level of ICA stenosis was assessed according to the NASCET criteria.A GE Healthcare  Signa Excite 1.5 T, 8-channel magnetic resonance scanner was used to perform MRA and P-MRA. Brain perfusion was assessed using Functool  2-MR Standard software on a GE Advantage Workstation.In order to evaluate the intracranial arteries, MRA was performed using the time of flight (TOF) technique with 3D reconstruction. The posterior communicating arteries (PCoA) were examined by performing T2-dependent images in the FSE sequence (slice thickness 1 mm).P-MR was performed after administration of a contrast, Prohance 2–3 mmol/kg, by an automatic syringe at a rate of 5 mL/s. Venflon (1.2–1.4 mm) was used for the administration of the contrast which was put into the ulnar vein in the area of elbow flexion. The subject of the analysis was the difference in cerebral perfusion parameters expressed in the mean time of flow, in the cases of the basic examination and the PA-MR. Differences of up to 10% in brain perfusion between similar region of interest (ROI) points of the symmetrical structures of the hemispheres were considered a normal variant.The arterial input function (AIF) was determined for the area of the middle cerebral artery (MCA). Values from perfusion measurement points in symmetric structures of the brain (region of interest—ROI) were used to calculate the parameters of the cerebral circulation—mean transit time (MTT).In the brain perfusion images, the difference in the flow between the analogous ROI points of the symmetrical structures of the left and right hemispheres was determined: semiovale centre—near the middle furrow; the white matter of the frontal lobes—anterior horns of the ventricular system; white matter of the occipital lobes—posterior horns of the ventricular system; hill; the hemisphere of the cerebellum. Perfusion maps were compared in the baseline study (first day) and in the PA-MR (second day). Two independent diagnostics evaluated the results. SPSS package ver.14.0  was used for the statistical calculations.t tests were performed. For the purposes of the study, the W index was created, derived from the logistic model, which determines the measurement of intolerance to CC depending on the number and type of pathology in the circle of Willis.In order to search for variables related to tolerance to CC, student’s During the analysis of MRA results, a numerical value from 0 to 2 was assigned to each artery . In addition, a developmental variant in the form of carotization (PCoA as a branch of ICA) of the posterior cerebral arteries (PCA) was considered. Depending on the occurrence of the above variant, 1 or 2 points were added. The sum of all values was used to express the measurement of intolerance to CC .An optimal model predicting the probability of obtaining a positive result of the dependent variable resistance to CC is described by the following formula:DA—difference Acetazolamide. Difference in the flow between the corresponding ROI points of the symmetrical structures of the left and right hemispheres of the brain, expressed as a percentage , W index—considered the arteries 1–7 listed in the diagram, HT—hypertension. “1” In the absence of hypertension and “2” in the presence of hypertension .We obtained a numerical value in the range from 0 to 1. The higher the value, the higher the probability of CC tolerance. The receiver operating characteristic (ROC) curve is a tool for assessing the accuracy of the classifier and supports the decision system under conditions of uncertainty.The ROC analysis was performed to create an algorithm in a controlled manner, based on which it will be possible to determine the efficiency of CC .Using a cut-off point equal to or greater than 0.322, the patient can be correctly assigned to one of two groups. TP (Group II) with CC tolerance, sensitivity = 100%, and TN (Group I) with CC intolerance, specificity = 95%. The accuracy of classification (ACC) was 96.2%.A total of 40 patients, 14 women and 26 men between the ages of 51 and 84 (average of 68.1), were included in this study (Group I); 27.5% of the patients were asymptomatic. All had ipsilateral ICA stenosis > 70% and underwent an attempt at CEA. All 40 patients developed ischemic symptoms during CC with withdrawal from the elective CEA (Group I). The time of appearance of neurological symptoms during CC ranged from 2 to 60 s (average 21 s). These patients represented 4.8% of the 833 CEAs performed during the same period at our institution.The control group (Group II) included 15 patients with cross-clamping tolerance, operated on by a single surgeon (P.M.), who gave their informed consent to perform pre- and postoperative examinations (lack of funding limited the number of patients entered in the study). In this group were 4 women and 11 men, aged 66 to 83 (average 69.8); 26.6% of the patients were asymptomatic. At least one comorbidity occurred in 54 patients (98.2%) .In both groups, DUS study on the operated side showed ICA stenosis above 70%. There weren’t any occlusions or near-occlusions.The contralateral ICA was occluded in six patients from Group I. Stenosis in the range of 0–49% was in, 50–69% in 22 and above 70% in 6 patients. In Group II; 0–49% stenosis was found in two, 50–69% in nine, above 70% in two and occlusion in two patients.The circle of Willis had a normal anatomy in three patients from Group I (7.5%) and in eight from Group II (53%). Other patients from both groups had single or multiple abnormalities .The only pathology found in Group II was bilateral (three patients) or unilateral (five patients) lack of posterior communicating artery (PCoA). In Group I the first segment of the anterior cerebral artery (A1) was absent in 21 patients (52.5%). Twelve patients (30%) had decreased A1 signal. In 12 cases (30%) the anterior communicating artery (ACoA) was absent . In 29 cIn Group I, 24 patients (60%) had abnormalities in cerebral perfusion parameters on P-MR without Acetazolamide. In 15 patients there was a reduction in perfusion in the hemisphere on the affected side. In PA-MR, perfusion disorders were found in all subjects. In 28 cases, they appeared on the affected side .In Group II in one patient (6.6%), after the basic P-MR, perfusion disorders on the operated side were observed. In six cases (40%) with PA-MR the differences between the hemispheres were greater than 10%. They corresponded to the operated side.Statistically significant results indicating the relationship between the variable tolerance to CC and potential predictors of tolerance to CC are presented in There were 14 student’s t tests counted in the whole sample. The independent variable is the resistance to CC, measured on two levels: positive CC (intolerance) and negative CC (tolerance). All tests were carried out at a significance level of 5.0%.A cut-off point for the true positive rate group of patients with a prediction value (P) equal to or greater than 0.322 was marked. The cut-off value was based on a set false positive rate of 5.0%—the maximum prediction error of CC tolerance .2 factor. However, a much better criterion is the assessment of the ROC curve. The ACC criterion is also a practical criterion , the predictive power of the indicators of tolerance to CC differ significantly. The difference in the power of prediction can be expressed by several variables. The easiest and the most abstract one is Rriterion .The best predictive power indicators are obtained from the analysis of PA-MR and the MRA analysis in combination. This is also confirmed by data from ROC analyses: the error of incorrectly predicting CC intolerance  was 0% while the information obtained from both the PA-MR and MRA were used. However, based only on the PA-MR the FN error increased to 15.4%, and based only on the MRA study the risk of error was 45.4%.CC intolerance is influenced by many factors, including demographic and epidemiological . Age, seThe combined analysis of the results of PA-MR and MRA showed that the most important predictor of tolerance to CC is the combined result of PA-MR and MRA of intracranial arteries, and also the W index calculated on their basis. The third variable significantly related to CC tolerance is hypertension.The analyses conducted did not show a significant effect on resistance to cross-clamping of factors such as contralateral stenosis of ICA and the presence of neurological symptoms in the preoperative period. The study groups were small. We treat the results as a trend and understand that a large cohort would be necessary.The analysis of the data enabled the derivation of the formula shown earlier by which the measurement of the effects of CC (probability) can be determined.p (obtained from the formula given above) is equal to or greater than 0.322, then the risk of positive clamping is minimal.We wanted to determine the two classes of the patients (CC tolerance vs. CC intolerance) before the planned operation. The result of the ROC analysis was used to determine the cut-off point. The ROC model assumes that the error of incorrect prediction of condition (FP) will not exceed 5%. After taking this assumption into consideration in regard to the results of PA-MR and MRA, the cut-off point was determined to have the value of 0.322. In practice, the use of this value means that if the value of The methods used to predict cerebral ischemia during CEA can be divided into two groups. The first one assesses this risk intraoperatively using methods ranging from the simplest, such as the assessment of the neurological status of patients operated under regional anesthesia or the assessment of the backflow pressure , to thosSuch a complication rate is of course acceptable in symptomatic patients. Advances in best medical treatment may mean that in asymptomatic patients this percentage of neurological complications will be too high. Excluding patients with potential cross-clamping intolerance from surgical treatment and offering them, for example, stenting may further reduce this complication rate.Chongruksut et al. , based oThere are publications describing serious complications after shunt application ,21. A liDetermining the risk of CC intolerance before surgery seems to be of much more practical importance. In patients with a small benefit from surgery, it may affect the decision to continue the optimal medical treatment alone , while iMost of the publications refer to prediction of CC intolerance based on the anatomy of the circle of Willis ,23. CorrOur own observations and the literature data show that in the subgroup of patients with high CC intolerance the percentage of neurological complications during CEA is unacceptable ,27. In oImplementation of anatomical and functional brain examinations increases the chance of predicting cross-clamping intolerance during carotid endarterectomy. The highest value in predicting clamping intolerance is achieved through a combined analysis of PA-MR and MRA of the circle of Willis. The important variable significantly related to CC tolerance is hypertension.


Type 1 diabetes (T1D) appears most frequently in childhood, with an alarming increasing incidence in the last decades. Although the genetic predisposition is a major risk factor, it cannot solely explain the complex etiology of T1D which is still not fully understood. In this paper, we reviewed the most recent findings on the role of early nutrition and the involvement of the gut microbiota in the etiopathogenesis of T1D. The main conclusions that are withdrawn from the current literature regarding alleviating the risk of developing T1D through nutrition are the encouragement of long-term breast-feeding for at least the first 6 months of life and the avoidance of early complementary foods and gluten introduction (before 4 months of age) as well as cow milk introduction before 12 months of life. These detrimental feeding habits create a gut microbiota dysbiotic state that can contribute to the onset of T1D in infancy. Finally, we discussed the possibility to introduce probiotics, prebiotics and post-biotics in the prevention of T1D. Diabetes is a serious issue tackled globally. It's considered one of the top 10 causes of death in adults. According to the International Diabetes Federation Atlas, in 2019, the number of people with diabetes was ~463 million . A similThe etiology of T1D is complex and not fully understood; the genetic susceptibility along with environmental triggers can contribute to the development of the disease . GeneticCurrently, there is no clear evidence of the impact of nutritional and environmental factors in the development of autoimmunity and T1D. Understanding their pathogenetic role could be a crucial strategy for the prevention of the disease in early infancy. In this review we will discuss the most recent findings on the role of early nutrition and the involvement of the gut microbiota in the etiopathogenesis of T1D.Recent studies show that β-cells autoimmunity develops in the first years of life; indeed, in most cases autoantibodies can be detected by 2 years of age . This leMany retrospective and prospective studies have been conducted to define the role of dietary factors in the development of T1D; however, results are still controversial. The inconsistency of these results might also reflect the influence of genetic background on the individual susceptibility to external factors. Moreover, most of these studies focused on adult diet, whereas recent researches highlighted the role of infant feeding practices and early nutrition in the development of T1D . HereaftBreastfeeding has several beneficial effects on maternal and child health , and manIn-vitro studies demonstrated that HBM-derived Lactobacilli have anti-bacterial activity against Staphylococcus aureus in vitro, and it also inhibits adhesion of Salmonella enterica in infected mice  that promote the maturation of immune system and modulate its functions , 28, 29.ted mice . HBM inhted mice . HBM-derman milk . In addiman milk . A case–immunity .According to World Health Organization (WHO) recommendations for infant feeding, exclusive breast-feeding represents the ideal nutritional strategy during the first 6 months of life for its beneficial effects on maternal and infant health . After 6Evidence from systematic reviews revealed that complementary feeding initiation before 3–4 months of age is associated with higher risk of allergic conditions, while gluten introduction before 4 months can be linked to the development of celiac disease and type 1 diabetes mellitus . The TypAccording to current recommendations for infant feeding, cow milk introduction should be avoided before 12 months of life: early exposure has been linked to higher risk of developing allergy and to occult gastrointestinal blood . In the In the last decade, studies on rodents revealed a potential diabetogenic effect of gluten by inducing an immune dysregulation . AccordiThe most recent opinion of experts regarding the appropriate age for introducing complementary foods concluded that gluten introduction before or after 6 months of age has neither beneficial nor negative effect on the risk of developing T1D. Gluten can be introduced between 4 and 12 months, but earlier introduction (before 4 months) is associated with the development of celiac disease in children at higher risk , 58. TheIncreasing attention has been recently focused on the potential role of micronutrients intake during early life in etiology of T1D. As clearly outlined in a recent review, vitamin D and E and zinc are the most studied factors .Vitamin D is commonly known for regulating of calcium and phosphate metabolism but also exerts several immunomodulatory effects on innate and adaptive immune system. Association between low levels of serum 25-hydroxyvitamin D have been linked to increased risk of many immune-related disorders, including T1D . RecentlThe action of vitamin A to control immune response has led to a growing hypothesis of potential role of vitamin A in T1D as an autoimmune disease. Vitamin A regulates the adaptive and innate immune responses by different mechanisms for example, by its ability to transform Th1 to Th2 lymphocytes. A recent review reported that both vitamin A and all-trans retinoic acid effectively induced immune tolerance that inhibited islet inflammation and progression to diabetes . FurtherRecent research has been focused on the potential role of oxidative stress induced by free radicals in the pathogenesis of T1D. Based on this assumption, micronutrients with antioxidant properties as vitamin C (ascorbic acid), zinc (Zn) and selenium (Se) may play a role in the pathogenesis and exacerbation of this disease. Mattila et al. examined plasma ascorbic acid concentration in children at high genetic risk of T1D (within the TEDDY study), initially at 6 and 12 months and then annually up to 6 years of age. The Authors found that higher plasma ascorbic acid levels were associated with decreased islet autoimmunity risk, but not with T1D risk progression .Results from animal studies revealed that selenium-dependent proteins (seleno-proteins) with redox properties are involved in glucose metabolism, given that insulin release and signaling are influenced by the cellular redox potential . SignifiConsistent evidence from literature shows that the gut microbiota can influence the innate and adaptive immune system , 75, and−/− NOD mice that developed T1D under germ-free conditions in contrast to pathogen-free conditions , are linked to the pancreatic lymph nodes . MoreovePrevotella  at the development phase, and the cessation of breast milk resulted in faster maturation of the gut microbiome, marked by the phylum Firmicutes , where 1,113 infants with HLA-conferred susceptibility to T1D were sorted into 3 groups and given respectively cow milk formula, hydrolyzed formula or bovine insulin-free formula during the first 6 months of life. The primary finding was that infant fed with insulin-free formula had a lower incidence of beta-cell autoimmunity by 3 years of age . In addinversion .It is demonstrated that the diet composition  affects the microbiota composition and the intestinal function . More imBifidobacteria genera  metabolites of the gut microbiota associated to the cardiovascular risk, demonstrated that healthy young men consuming yogurt or acidified milk for 2 weeks showed decreased levels of TMAO and different microbiome composition  and it is challenging the clinicians with complex immunological and clinical management. At the date, the insulin and a gluten-free diet (GFD) are still the only recommended treatments for T1D and the celiac disease, respectively. However, these treatments pose certain challenges to both the clinicians and the patients, as GFD has a high glycemic index that affects the glycemic control. Moreover, intermittent gluten intake by these patients due to non-compliance with GFD stimulates the autoreactive immune cells which in turn result in an augmented immune response . A randoNeisseria spp., and Haemophilus spp. and a lower abundance of Lactobacillus and Bifidobacterium  and an increase of potentially unhealthy bacteria  , resulting in heterogeneous data. Children affected by celiac disease have microbial dysbiosis, and this is thought to contribute to the pathogenesis of CD. The function of Th17 cells, that play a role in the inflammatory response against gliadin peptides, is influenced by the microbiome . Childreacterium . The gluacterium . Moreovediaceae) . TherefoBifidobacterium strains as probiotics showed a reduction in the gut inflammation and the production of proinflammatory cytokines which consequently improve the gut barrier's function. It was also demonstrated that probiotics can reduce the toxicity of gliadin by degrading the proinflammatory gluten peptides and reducing their immunogenicity , decreases the risk of developing diabetes in non-obese diabetic (NOD) mice  and Rikenellaceae. In addition, probiotic VLS#3 reduces the expression of proinflammatory cytokine IL-1β and increases the production of pro-tolerogenic and immunomodulatory factors, such as indoleamine 2,3-dioxygenase (IDO) and IL- 33. Moreover, VLS#3 stimulates the differentiation of tolerogenic dendritic cells (CD103+) and limits the expansion and the differentiation of inflammatory T-cells (Th1 and Th17) in the intestinal tract, the spleen and the pancreatic lymph nodes. The combination of VLS#3 with RA induces proliferation of T-regulatory cells in the intestinal mucosa. VLS3# also increases the expression of zonulin-1 in the intestinal mucosa, promoting the integrity of the intestinal barrier  mice . The mic barrier . The TED barrier . By cont barrier . HoweverPrebiotics are non-digestible carbohydrates that can have a role in modulating the immune system and the gut microbiome, contributing to the development of autoimmune diseases such as T1D . StudiesA different strategy to prevent the development of autoimmunity and T1D can be the supplementation of microbial products , such as SCFA, in order to modulate the microbiota and the immune system. The SCFAs  have indeed an anti-inflammatory and immunomodulatory function. They promote the T-regulatory cells function, modulate cytokines' production, increase the expression of anti-microbial peptides, reduce oxidative stress and regulate the epithelial barrier function by increasing the expression of tight junction and the production of mucin . A studyThe probiotic, prebiotic and post-biotic therapeutic approach looks extremely interesting, but it still requires more clinical trials to confirm the efficacy and specificity of the treatment in T1D patients of different age groups, with different environment, diets and genetic backgrounds.The T1D is a complex disorder with an unclear etiopathogenesis and an increased incidence in the last decades that presumes the contribution of multiple factors: genetics, age, environment, and diet. In this review, we focused our attention on the role of early diet as a modular of the gut microbiota and, indirectly, of the immune system . We hypoThe key messages from this paper are that promoting long-term breast-feeding during the first 6 months of life, avoiding early complementary foods and gluten introduction (before 4 months of age), and avoiding cow milk introduction before 12 months of life, may reduce the risk of developing T1D. The gut microbiota is affected by early nutrition, and the gut microbiota dysbiosis in infancy may contribute to the onset of T1D. Therefore, there is a need to plan randomized clinical trials testing the role of probiotics, prebiotics and post-biotics in T1D prevention.AT and EV planned the manuscript and discussed the content. CM and AP wrote the introduction and about the clinical aspect of T1DM. SV and MA wrote the sections on early nutrition and probiotics. SA and FE wrote the microbiome sections and formatted the references. SA created the figure and formatted the final version of the manuscript. AT and EV reviewed and finalized the manuscript. GZ supervised and reviewed the manuscript. All Authors approved the submitted version of the manuscript.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


Powerful antioxidant α-lipoic acid (LA) exhibits limited therapeutic efficiency due to its pharmacokinetic properties. Therefore, the purpose of this work was to evaluate the ability of silica-based composites of LA as well as its amide , as new oral drug formulations, to control their release and maintain their therapeutic concentration and antioxidant activity in the body over a long time. The composites synthesized at different sol–gel synthesis pH and based on silica matrixes with various surface chemistry were investigated. The release behavior of the composites in media mimicking pH of digestive fluids  was revealed. The effects of chemical structure of the antioxidants, synthesis pH, surface chemistry of the silica matrixes in the composites as well as the pH of release medium on kinetic parameters of the drug release and mechanisms of the process were discussed. The comparative analysis of the obtained data allowed the determination of the most promising composites. Using these composites, modeling of the release process of the antioxidants in accordance with transit conditions of the drugs in stomach, proximal, and distal parts of small intestine and colon was carried out. The composites exhibited the release close to the zero order kinetics and maintained the therapeutic concentration of the drugs and antioxidant effect in all parts of the intestine for up to 24 h. The obtained results showed that encapsulation of LA and LM in the silica matrixes is a promising way to improve their bioavailability and antioxidant activity. Oxidative stress is the basis of many pathological processes in the body, leading to various diseases and, ultimately, aging ,2,3. Antα-Lipoic acid (LA) and its amide   are poweHowever, LA is rapidly absorbed in the GIT, exhibits extensive presystemic metabolism, and has a low half-life in the body (0.5–1.5 h) ,12,13. TEncapsulation (loading) of drugs in biologically relevant materials is promising way to create novel drug formulations with improved physicochemical and pharmacological properties. The encapsulation of LA in chitosan beads promoted sustained release of the drug in vitro ,17. The Colloid silica is promising material for creation of new drug formulations. Especially, silica materials are suitable for the development of oral drug formulations, because colloid silica is biodegradable and recognized as safe food additive . FurtherThe composites were synthesized using sol–gel technology. It is well known that an important factor influencing the kinetics of the release of encapsulated drugs is their interaction with the capsule material. Literature data show that electrostatic interactions ,30, hydrThe replacement of OH group in LA molecule with an amino group leads to changes in properties of LM compared to LA , which, in turn, should have an effect on the physicochemical and functional properties of their composites with silica. Therefore, in this work, the effect of chemical structure of the antioxidants on the release properties was evaluated.The release kinetics from the prepared composites was investigated using two methods. Firstly, the individual release profiles of LA and LM from the composites in buffer solutions with pH 1.6, 6.8, and 7.4 mimicking digestive fluids were obtained in order to determine mechanisms of the release processes and elucidate the effect of release medium pH on LA and LM release kinetics. On the basis of comparative analysis of the obtained results, the most promising composites were chosen. In order to mimic an in vivo situation, modeling of LA and LM release process from the composites with regard to the change in pH and residence time of the drugs in different segments of the gastrointestinal tract (GIT)  ,35,36 wa2PO4·2H2O) and disodium hydrogen phosphate (Na2HPO4·12 H2O)  were used to prepare buffer solutions with pH 6.0, 6.5, 6.8, and 7.4. Citric acid , sodium hydroxide , and hydrochloric acid  (CAS 7647-01-0) were used to prepare buffer solution with pH 1.6. The buffer solutions were prepared using doubly distilled deionized water.DL-α-Lipoic acid (LA) (>99.0%) (CAS 1077-28-7) was purchased from Tokyo Chemical Industry Co., LTD . (±) α-Lipoamide (LPA) (96%) (CAS 940-69-2) was purchased from Toronto Research Chemicals . Tetraethoxysilane (TEOS) , ethanol (EtOH) , (3-mercaptopropyl)trimethoxysilan (MPTMOS) (95%) (CAS 4420-74-0), , (3-aminoporopyl)triethoxysilane (APTEOS) (99%) (CAS 919-30-2) , methyltrimetoxysilane (MTMOS) (98%+)(CAS 1185-55-3) , and 2,2-Diphenyl-1-picrylhydrazyl (DPPH) (CAS 1898-66-4)  were used without further purification. Sodium dihydrogen phosphate  with a Zetasizer Nano ZS . Before DLS measurements, the samples were dispersed in deionized water and sonicated for 10 min to destruct agglomerates.The release profiles of the antioxidants were obtained by incubation of 0.25 g of the composite in 100 mL 50 mM buffer  under stirring (100 rpm) at 37 °C. At appropriate time intervals, 5 mL samples were withdrawn and replaced by fresh buffer. The withdrawn samples were centrifuged at 10,000 rpm for 10 min. The amount of released drug was calculated from the absorbance at a wavelength of 332 nm measured spectrophotometrically  using the calibration curves obtained at given pH. The release profiles were obtained by plotting the cumulative percentage of released drug as function of release time.Firstly, 0.25 g of the composite was suspended in 100 mL of aqueous HCl solution with pH corresponding to gastric juice pH (1.6 ± 0.2). The suspension was stirred (100 rpm) at 37 °C. Aliquots of 5 mL were withdrawn at fixed time intervals, centrifuged at 10,000 rpm for 10 min, and assayed by UV/VIS spectroscopic method to determine the amount of dissolved drug using calibration plots at given pH. The sample volumes were replaced with the same amounts of fresh medium. After release time corresponding to mean transit time through stomach (2 h) , the solb) and time (tb) as well as maximum amount of the released drugs (M∞) were determined from the concentration dependences of the released antioxidants as has been described earlier [k0, k1, H-Ck, and k, are the zero order, the first order, the Hixon–Crowell, and the Korsmeyer–Peppas constants, respectively; oQ and tQ are the initial amount of drug in solution and the cumulative amount of drug released at time t, respectively; tM, ∞M are the cumulative amount of released drug at time t and overall released amount, respectively; n is the exponent of release (related to the drug release mechanism) in function of time t.The release data were analyzed by model-dependent approach. Before the fitting the experimental release profiles to kinetic models, the burst release , which was designed as pure DPPH solution. For determination of radical scavenging activity, pure DPPH solution was added to each sample in 1:1 ratio. The reaction mixture was incubated at room temperature for 15 min, and the absorbance at 515 nm was measured against blank samples. Decreased absorbance of the reaction mixture indicated increased superoxide anion scavenging activity. All data are an average of triplicate analyses. The antioxidant activity was calculated in percentage using the Equation (5):n = 3). For release data, linear or non-linear least-squares regressions were performed, and the model parameters were calculated. The model that best fit the release data was evaluated based on the correlation coefficient (R2). In some cases, the fitting experimental release profiles with the zero-order and the first-order models showed close values of correlation coefficients (R2). Therefore, the model that described the data properly was determined on the basis of comparison of the root mean square error (RMSE) (Equation (6)) [AIC) (Equation (7)) [iy and iymod are the experimental and predicted by model ith values of variable, m is the number of data points, and p is the number of parameters of model. The model that shows the minimal values for the SSR, RMSE, and AIC gives the best description of the release data.All the experiments were performed in triplicate. The experimental results are expressed as the mean ± standard deviation (ion (6))  and Akaiion (7)) . The criThe purpose of this work was to evaluate the ability of silica-based composites of the drugs to control their release and maintain therapeutic concentration and antioxidant effect in the body over a long time. In order to develop such composites, it is necessary to select optimal silica matrix and optimize synthesis conditions of the composites. For this purpose, the composites of LA and LM with silica materials having various surface chemistry were prepared at different sol–gel synthesis pH, and their release properties were investigated. As an example, The elucidation of the effects of chemical structures of the drugs, surface chemistry of the silica matrixes, pH of sol–gel synthesis, as well as pH of release media on kinetics and mechanisms of the drug release was the main task of this work. However, the comparative analysis of the obtained data showed that, in most cases, it is impossible to elucidate the individual effects, because they overlap, and the observed phenomena are the result of influence of two or more effects on the drug release. Nevertheless, some interesting facts and regularities were revealed.b is 3.9%). Usually, the burst effect is attributed to release of the drug located on or near the surface of particles and weakly bound to the matrix. The data presented in The APMS-based composites exhibited the lowest release of the drugs (not greater than 3.5%) in all tested release media, with the exception of the LA–APMS (pH 3) and LM–APMS (pH 7) composites in the medium with pH 1.6. . These rIn contrast to other composites, upon synthesis of the APMS-based composites, solutions of the antioxidants were added in the reaction mixtures with high pH due to a very high basicity of 3-aminopropyl triethoxysilane (APTEOS) used as modifier of the silica matrix. Then, the pH of the resulting mixtures was quickly adjusted to final values (pH 3 or pH 7) by addition of HCl. The indicated conditions led to formation of the composites having higher particle size and polymodal particle size distributions . Figure n < 0.43) [In addition to the low amount of the released drugs, the indicated APMS-composites exhibited the lowest release rate. In order to determine the kinetic parameters and mechanisms of release of the antioxidants, the experimental release profiles were fitted with different kinetic models. The obtained results are presented in  < 0.43) ,42. The  < 0.43) ,45.As for specific behavior of the LA–APMS (pH 3) and LM–APMS (pH 7) composites in the medium with pH 1.6, it can be attributed to weak hydrogen bonds between neutral forms of the drugs  diffusion can be a consequence of relatively strong interaction (hydrogen bonds) of uncharged LA with the weakly deprotonated matrix in the LA–MMS (pH 3) composite [n = 0.51–0.84) and shows a good fit to the zero order kinetic model. As applied to the composites based on porous non-swelling matrixes, the mechanism of anomalous diffusion includes the simultaneous action of two mechanisms: diffusion of a drug through the pores of the matrix to the surface of particles and disintegration(erosion)/degradation of the matrix [2 = 0.96–0.97)  . It is lThe effect of chemical structure of the studied antioxidants on their release from the composites is manifested in the fact that, in most cases, the release rate and the maximum amount of the released drug from the composites prepared under the same conditions are higher for LA than for LM, regardless of the pH of the release medium. This effect is demonstrated in The analysis of the individual release profiles of the antioxidants allowed us to identify the features of the drug release in the media with given pH values that mimic biological fluids. However, when taken orally, a drug passes through various parts of the gastrointestinal tract (GIT), which differ in the acidity of the medium and the time of transit through them. One of the conditions of maintaining constant concentration of drug during its passage through the GIT is the independence of the drug release rate from pH and time of transit through the different parts of the GIT. In this work, the modeling of the process of release of LA and LM from the synthesized composites was carried, taking into account the change in the medium pH and residence time of the drugs in different segments of the GIT.Based on the analysis of the data presented in -the drug release from the composites follows the zero order kinetics in all tested media, i.e., the kinetic law of the release is uniform in all digestive fluids; the zero order release is ideal behavior for drug formulation, which allows for a constant quantity of drug to be released over an extended period of time, resulting in uniform and sustained drug delivery;-the drug release is controlled by anomalous diffusion; this means that the silica matrixes disintegrate/degrade during the release process, and this promotes their rapid elimination from the body;-the release rates in the medium with pH 6.8 and 7.4 are close, i.e., it is supposed that the drug release in intestine does not depend on pH; a higher release rate in the medium with pH 1.6 allows reaching a certain concentration level in the intestinal media.The cumulative release profiles and concentration/time curves for the LA–MMS (pH 7) and LM–MPMS (pH 7) composites mimicking the drug release according to the GIT transit conditions are presented in The pH values in different segments of the GIT were chosen on the basis of analysis of literature data ,33,34. Tmax in blood plasma after oral administration of different formulations of LA [max for the indicated formulations is reached after taking a dose of 600 mg, and the time to reach the maximum plasma concentration does not exceed 3 h. The samples of the studied composites contain only 61 mg and 46 mg per 1 g of the composites of LA and LM, respectively, but are able to maintain the indicated concentration in the release media for up to 24 h. Bernkop–Schnürch et al. [The data in ns of LA . Howeverh et al.  showed tIt is well known that the therapeutic effect of LA and LM is associated with their antioxidant activity. It is interesting to see how the antioxidant activity of the released drugs will change with the changing pH of the biological fluids in different segments of the GIT. Based on the comparative analysis of in vitro kinetics and mechanisms of the release of LA and LM from their composites with colloid silica with different surface chemistry and prepared at different sol–gel synthesis pH, it was shown that some composites can be a promising platform for development of novel oral formulations of the drugs with controlled release. The LA–MMS (pH 7) and LM–MPMS (pH 7) composites exhibited the release close to the zero order kinetics under conditions mimicking the drug transit through gastrointestinal tract. The composites containing only 61 mg and 46 mg/g of LA and LM, respectively, are able to maintain for up to 24 h a concentration similar to the concentration of LA in blood plasma after administration of 600 mg of some clinically used oral formulations. The antioxidant effect of the released drugs depends on the drug concentration in the release media. The composites exhibit the antioxidant effect for a long period of time (up to 24 h).


Out of all types of accidents, falling into water, immersion and the resulting drowning, are among the unintentional accidents in children which can be prevented. The purpose of this study was to investigate the status of drowning of children aged 1 to 59 months outside hospital in Tabriz from 2013 to 2017.In this descriptive cross-sectional study, the mortality data of children and referrals from suburban cities affiliated to Tabriz University of Medical Sciences were investigated.Of 14 reported deaths in children due to drowning, three cases (21%) were drowned in the swimming pool/traditional Iranian pool (howz), four cases (29%) due to flood, and seven cases (50%) in natural water resources and rivers. Sixty percent of deaths had occurred in rural and 40% in urban areas. The most common age was 12 months to 4 years old. Since children under the age of 5 and especially between the ages of 1-4 years old were the groups with the highest risk of drowning, this age group should be focused for prevention strategies, by fencing the pools, preventing children from playing under the bridges and on the way of flood, and not leaving them alone.Drowning, Tabriz, Children aged 1-59 months


Cardiovascular disease (CVD), such as heart ischemic or coronary artery disease, continues to be one of the major causes of death worldwide. Risk factors that have been considered to contribute to CVD development involve genetic features in combination with age and factors such as dyslipidemia, atherosclerosis, and hypertension. Additionally, the severity of these diseases is strongly affected by excess caloric intake and a lack of physical activity in a patient's lifestyle   and proposed as an alternative regimen to traditional ET to improve cardiovascular health in individuals with CVD : a sedentary control group (CTRL), an endurance training group (ETr), and a high-intensity interval training group (HIITr). Animals from the second group received an endurance training treatment before in vitro ischemia/reperfusion injury on the Langendorff apparatus (ETr), and the animals from the third group received a high-intensity interval training treatment prior to in vitro ischemia/reperfusion injury on the Langendorff apparatus (HIITr). The experimental protocol was approved by the Faculty of Medical Sciences Ethics Committee for the welfare of experimental animals, University of Kragujevac, number 01-13340/1 and by the Ministry of Agriculture, Forestry and Water Management, Authority for Veterinary of Serbia number 323-07-04422/2017-05 and followed the Guidelines for the Care and Use of Laboratory Animals.The present study was carried out on 36 male Wistar albino rats . They were housed under controlled environmental conditions, at room temperature (22 ± 2°C) with an established photo-period of 12 h light/day in the Institute of Cardiovascular Physiology, Faculty of Medical Sciences, University of Kragujevac. For research purposes, all experimental animals were obtained from the Military Medical Academy, Belgrade, Serbia. The rats had free access to food and tap water—Two different modes of intensive exercise training were used on rats: traditional endurance training (ETr) and high-intensity interval training (HIITr). ETr and HIITr programs were progressive in nature and programmed after the animals completed an initial graded treadmill exercise test to assess specific work capacity. The exercise protocols included treadmill running at 0% inclination  following treatments. Thirty-six hours after the last physical capacity test, after a short-term ketamine/xylazine narcosis, the animals were killed by cervical dislocation  and premedicated with heparin as an anticoagulant . Immediately after the restoration of a normal heart rhythm, a sensor  was inserted into the left ventricle for continuous monitoring of cardiac function through a created entrance to the left atrium of the heart and damaged mitral valve.The composition of the non-recirculating Krebs–Henseleit perfusate was as follows (mM): NaCl 118, KCI 4.7, CaCI2O. CTRL underwent perfusion for 1 h and 30 min without any intervention. In the CTRL group, hearts were subjected to ischemic preconditioning lasting 5 min before global ischemia  for 30 min followed by 1 h of reperfusion. Both rat exercise groups (ETr and HIITr) went through the same ischemia/reperfusion injury protocol 36 h after following the exercise protocol. After stabilization, the hearts were under global ischemia for 30 min followed by 1 h of reperfusion. Using the sensor within the left ventricle, the following parameters of myocardial function were determined:The hearts from all groups underwent a 20-min stabilization perfusion period at CPP of 70 cm HMaximum rate of pressure development in the left ventricle (dp/dt max)Minimum rate of pressure development in the left ventricle (dp/dt min)Systolic left ventricular pressure (SLVP)Diastolic left ventricular pressure (DLVP)Heart rate (HR).Coronary flow (CF) was measured flowmetrically and collected at the following intervals: in stabilization (S), in reperfusion at the first, third, fifth, and tenth minute, and 15-min intervals following the 10th minute (R1–R60).The following oxidative stress parameters were determined spectrophotometrically  using collected samples of the coronary venous effluent:The index of lipid peroxidation, measured as thiobarbituric acid reactive substances (TBARS)The level of nitrite .The level of hydrogen peroxide  was based on the oxidation of phenol red by hydrogen peroxide in a reaction catalyzed by horseradish peroxidase (HRPO)  was subsequently added. For the blank probe, an adequate volume of Krebs–Henseleit solution was used instead of coronary venous effluent. The level of H2O2 was measured at 610 nm.The measurement of the level of hydrogen peroxide  and lancet . After 5 min of rest, blood was taken from the tail vein, and changes in lactate levels in response to training were calculated as the difference in the sum of lactate concentration after training vs. health control and group exposed to other exercise protocols . IBM SPSS Statistics 22.0 for Windows was used for statistical analysis of data. By statistical analysis, the results in the group itself were compared especially referring to three points of interest: stabilization point (S), first minute of reperfusion (R1), and last minute of reperfusion (R60). Values of p < 0.05 were considered to be statistically significant, while values of p < 0.01 were considered to be highly statistically significant.Values were expressed as the mean ± standard error. Before statistical analysis, all data were checked for normality using the one-sample Kolmogorov–Smirnov test. Biochemical data were evaluated using one-way analysis of variance  in comparison to the stabilization period and last moment of reperfusion (R60). The value of this parameter in R1 was similar to the stabilization period (S) in the HIITr and ETr groups, but the hearts from the HIITr group showed a better response in the other point of reperfusion period (after ischemia) and less fluctuation in this cardiodynamic parameter compared to those in the ETr group .The most prominent changes of dp/dt min were observed at the end of reperfusion (R60) in comparison to the stabilization (S) and first point of reperfusion (R1) in the ETr group, while in the control group at the last point of the recovery period (R60), dp/dt min value was higher compared to the values before ischemia (S). On the other hand, the values of this parameter in the HIITr group were similar at the first and last points of reperfusion to the period of stabilization .At the end of the recovery period (R60) in the control group, the value of SLVP was significantly decreased in comparison to the values in stabilization (S). Also, a rise in values of SLVP was noticed at the first point of reperfusion (R1) compared to the stabilization point (S) in the HIITr and ETr groups, while at the end of the 60-min reperfusion, the value of SLVP in the HIIT group returned to the value detected before ischemia, which was not noticed in the ETr group where the value of SLVP remained increased after the period of reperfusion .A significant increase in the DLVP values in all groups during the period of reperfusion was noticed compared with the stabilization period. Furthermore, at the end of the observed period (R60), the DLVP values in all groups did not return to the value before ischemia .The most significant drop in HR was observed in the HIITr group at the first point of reperfusion (R1) when compared with the stabilization period (S). However, in the remaining periods of reperfusion, the value of HR in this group stayed constant and returned to the same value before ischemia. In the other two groups, control, and ETr, HR values were significantly decreased at the end of the recovery period (R60) in comparison with the values in stabilization (S) .In the control group, the CF value was the same at the first point of reperfusion (R1) compared with the stabilization period (S), while there was a prominent decrease at the last point of reperfusion (R60) when compared with the stabilization period (S). Additionally, in the HIITr group, a rise in CF during the observed points of interest was noticed, while in the ETr group, CF was remarkably decreased in the first point of reperfusion (R1) as well as other points of the observed period .The index of lipid peroxidation in coronary venous effluent did not differ significantly in the control and HIITr group, while in the ETr group, there was a rise in the first minute of reperfusion (R1) compared with the value at the end of the recovery period (R60) . Values There was a drop in ficantly . NotablyThe level of ry (R60) . A prono2O2 did not differ significantly, while an increase in H2O2 at the stabilization period (S) in control group was noticed in comparison with the end of reperfusion period (R60). Interestingly, in the ETr group, it was a remarked significant difference in the H2O2 level among all points of interest. At the stabilization period (S), H2O2 was increased compared with the first (R1) and the last period of recovery (R60), and, also there was a significant increase in H2O2 at the first period of reperfusion (R1) in comparison with the end of the observed period (R60)  . Additiop < 0.01) as well as in comparison with ETr (p < 0.05). Moreover, a higher lactate value was observed in the group exposed to physical activity of moderate intensity in comparison with the control group (p < 0.05). Values of lactate levels are demonstrated in After HIIT, the level of lactate was significantly increased compared with the health control group  and high intensity interval training (HIITr). Using the Langendorff apparatus, we collected cardiodynamic parameters and coronary flow.In the present study, through different experiments, we demonstrated numerous positive and beneficial effects of exercise in general. However, our main goal was to show that cardioprotection, via cardiac improvements, can occur with only 15 min of high intensity exercise. Besides, the fact that HIITr has gained great scientific attention, underlying mechanisms for its cardioprotective abilities, still remains unclear. To examine the effects of exercise intensity in providing cardioprotection in an ischemic insult, we created I/R on a rat heart model in vivo I/R injury for at least 7 days following detraining, while there were no statistically significant differences on values of heart rate and mean arterial blood pressure among the experimental group   and less fluctuation in almost all observed cardiodynamic parameters, specifically regarding heart rate and coronary flow . Our datIn a sedentary group where we applied just I/R protocol, a low and slow response from hearts during reperfusion was noticed. Values at the end of the reperfusion period (R60) were significantly different from those at the beginning (S), especially regarding coronary flow, systolic left ventricular pressure, and dp/dt min. In relation to the percentage change between the points of interest, the hearts from the ETr group had less fluctuation in the examined parameters compared with those of the control group, while the HIITr group incurred even less change than ETr.2+ release and return into the sarcoplasmatic reticulum. In this way, muscle strength is stronger, and fatigue is reduced  and vagus nerve influence as the left anterior descending artery (LAD) ligation model. Another limitation of the study is the absence of results regarding the systemic effects of the two training regimes, which could certainly affect cardiac changes. In summary, although performed on an animal model, this study may help in the better understanding of the differences between the effects of HIITr/ETr training regimes on I/R injury. Therefore, it proves the beneficial impact of HIITr in cardioprotection. Also, our results can be of interest in explaining both exercise protocols' impact on redox status as well as for the possible clinical impact in the design of therapeutic strategies for cardioprotection. However, we were not able to investigate the possible physiological and molecular changes in both exercise protocols, which would be useful in highlighting unknown molecular mechanisms for cardioprotection. Accordingly, our future plans will be directed to reveal the possible expression and role of many molecules as well as the activation of the different pathways during both training regimes included in the reduction of cardiovascular risks.In the present study, we perceived the main functional differences between the two different styles of exercise that require very different time commitments, while both styles created beneficial cardiac adaptations. The main conclusion of this research is that preconditioning with five sessions of HIITr performed over a 5-week period may also be superior in protecting the heart against I/R injury. Given that a “lack of time” is the most often cited reason for not exercising regularly, this represents a more time-efficient training method for improving cardiac function than a more time-consuming ETr. Moreover, it seems that HIITr can encourage oxidative stress within the heart, which can be of interest for the elucidation of the impact of different exercise protocols on cardiac redox homeostasis.The datasets generated for this study are available on request to the corresponding author.This study was carried out in accordance with the recommendations of European Directive for welfare of laboratory animals no: 2010/63/EU and Good Laboratory Practice (GLP) principles. The protocol for the current study was approved by the Ethics committee for experimental animal well-being of the Faculty Of Medical Sciences at the University of Kragujevac, Serbia (No: 01-13340/1).MRan, VZ, IS, and MRav performed the experiments and collected the data. BJ and TT performed the statistical analyses. JB, IM, JJ, OM, and NJ performed the biochemical analyses and collected the biochemical data from the study. VJ and SB designed the study. All authors contributed to the interpretation of the results and the writing of the manuscript.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.