Search results for: myocardial fibrosis

Authors: Kenichi Yamahara, Makiko Ohshima, Shunsuke Ohnishi, Hidetoshi Tsuda, Akihiko Taguchi, Toshihiro Soma, Hiroyasu Ogawa, Jun Yoshimatsu, Tomoaki Ikeda

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We have previously reported the therapeutic potential of rat fetal membrane(FM)-derived mesenchymal stem cells (MSCs) using various rat models including hindlimb ischemia, autoimmune myocarditis, glomerulonephritis, renal ischemia-reperfusion injury, and myocardial infarction. In this study, 1) we isolated and characterized MSCs from human amnion and chorion; 2) we examined their differences in the expression profile of growth factors and cytokines; and 3) we investigated the therapeutic potential and difference of these MSCs using murine hindlimb ischemia and acute graft-versus-host disease (GVHD) models. Isolated MSCs from both amnion and chorion layers of FM showed similar morphological appearance, multipotency, and cell-surface antigen expression. Conditioned media obtained from amnion- and chorion-derived MSCs inhibited cell death caused by serum starvation or hypoxia in endothelial cells and cardiomyocytes. Amnion and chorion MSCs secreted significant amounts of angiogenic factors including HGF, IGF-1, VEGF, and bFGF, although differences in the cellular expression profile of these soluble factors were observed. Transplantation of human amnion or chorion MSCs significantly increased blood flow and capillary density in a murine hindlimb ischemia model. In addition, compared to human chorion MSCs, human amnion MSCs markedly reduced T-lymphocyte proliferation with the enhanced secretion of PGE2, and improved the pathological situation of a mouse model of GVHD disease. Our results highlight that human amnionand chorion-derived MSCs, which showed differences in their soluble factor secretion and angiogenic/immuno-suppressive function, could be ideal cell sources for regenerative medicine.

Keywords: amnion, chorion, fetal membrane, mesenchymal stem cells

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Authors: Jianming Cai

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Exposure to ionizing radiation causes severe damage to human body and an safe and effective radioprotector is urgently required for alleviating radiation damage. In 2008, flagellin, an agonist of TLR5, was found to exert radioprotective effects on radiation injury through activating NF-kB signaling pathway. From then, the radioprotective effects of TLR ligands has shed new lights on radiation protection. CpG-ODN is an unmethylated oligonucleotide which activates TLR9 signaling pathway. In this study, we demonstrated that CpG-ODN has therapeutic effects on radiation injuries induced by γ ray and 12C6+ heavy ion particles. Our data showed that CpG-ODN increased the survival rate of mice after whole body irradiation and increased the number of leukocytes as well as the bone marrow cells. CpG-ODN also alleviated radiation damage on intestinal crypt through regulating apoptosis signaling pathway including bcl2, bax, and caspase 3 etc. By using a radiation-induced pulmonary fibrosis model, we found that CpG-ODN could alleviate structural damage, within 20 week after whole–thorax 15Gy irradiation. In this model, Th1/Th2 imbalance induced by irradiation was also reversed by CpG-ODN. We also found that TGFβ-Smad signaling pathway was regulated by CpG-ODN, which accounts for the therapeutic effects of CpG-ODN in radiation-induced pulmonary injury. On another hand, for high LET radiation protection, we investigated protective effects of CpG-ODN against 12C6+ heavy ion irradiation and found that after CpG-ODN treatment, the apoptosis and cell cycle arrest induced by 12C6+ irradiation was reduced. CpG-ODN also reduced the expression of Bax and caspase 3, while increased the level of bcl2. Then we detected the effect of CpG-ODN on heavy ion induced immune dysfunction. Our data showed that CpG-ODN increased the survival rate of mice and also the leukocytes after 12C6+ irradiation. Besides, the structural damage of immune organ such as thymus and spleen was also alleviated by CpG-ODN treatment. In conclusion, we found that TLR9 ligand, CpG-ODN reduced radiation injuries in response to γ ray and 12C6+ heavy ion irradiation. On one hand, CpG-ODN inhibited the activation of apoptosis induced by radiation through regulating bcl2, bax and caspase 3. On another hand, through activating TLR9, CpG-ODN recruit MyD88-IRAK-TRAF6 complex, activating TAK1, IRF5 and NF-kB pathway, and thus alleviates radiation damage. This study provides novel insights into protection and therapy of radiation damages.

Keywords: TLR9, CpG-ODN, radiation injury, high LET radiation

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Authors: E. M. D. Akuoko, Eliana Vasquez Osorio, Marcel Van Herk, Marianne Aznar

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Radiotherapy is an integral part of treatment for many patients with breast cancer. However, side effects can occur, e.g., fibrosis or erythema. If patients at higher risks of radiation-induced side effects could be identified before treatment, they could be given more individual information about the risks and benefits of radiotherapy. We hypothesize that breast density is correlated with the risk of side effects and present a novel method for automatic evaluation based on radiotherapy planning CT scans. Methods: 799 supine CT scans of breast radiotherapy patients were available from the REQUITE dataset. The methodology was first established in a subset of 114 patients (cohort 1) before being applied to the whole dataset (cohort 2). All patients were scanned in the supine position, with arms up, and the treated breast (ipsilateral) was identified. Manual experts contour available in 96 patients for both the ipsilateral and contralateral breast in cohort 1. Breast tissue was segmented using atlas-based automatic contouring software, ADMIRE® v3.4 (Elekta AB, Sweden). Once validated, the automatic segmentation method was applied to cohort 2. Breast density was then investigated by thresholding voxels within the contours, using Otsu threshold and pixel intensity ranges based on Hounsfield units (-200 to -100 for fatty tissue, and -99 to +100 for fibro-glandular tissue). Volumetric breast density (VBD) was defined as the volume of fibro-glandular tissue / (volume of fibro-glandular tissue + volume of fatty tissue). A sensitivity analysis was performed to verify whether calculated VBD was affected by the choice of breast contour. In addition, we investigated the correlation between volumetric breast density (VBD) and patient age and breast size. VBD values were compared between ipsilateral and contralateral breast contours. Results: Estimated VBD values were 0.40 (range 0.17-0.91) in cohort 1, and 0.43 (0.096-0.99) in cohort 2. We observed ipsilateral breasts to be denser than contralateral breasts. Breast density was negatively associated with breast volume (Spearman: R=-0.5, p-value < 2.2e-16) and age (Spearman: R=-0.24, p-value = 4.6e-10). Conclusion: VBD estimates could be obtained automatically on a large CT dataset. Patients’ age or breast volume may not be the only variables that explain breast density. Future work will focus on assessing the usefulness of VBD as a predictive variable for radiation-induced side effects.

Keywords: breast cancer, automatic image segmentation, radiotherapy, big data, breast density, medical imaging

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Authors: Aliya Hisam, Zia Ul Haq, Sohail Aziz, Patrick Doherty, Jill Pell

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Objective: To determine the effectiveness of Mobile health augmented Cardiac rehabilitation (MCard) on health-related quality of life (HRQoL) among post-acute coronary syndrome(post-ACS) patients. Methodology: In a randomized controlled trial, post-ACS patients were randomly allocated (1:1) to an intervention group (received MCard; counseling, empowering with self-monitoring devices, short text messages, in addition to standard post-ACS care) or control group (standard post-ACS care). HRQoL was assessed by generic Short Form-12 and MacNew quality of life myocardial infarction (QLMI) tools. Participants were followed for 24 weeks with data collection and analysis at three-time points (baseline, 12 weeks and 24 weeks). Result: At baseline, 160 patients (80 in each group; mean age 52.66+8.46 years; 126 males, 78.75%) were recruited, of which 121(75.62%) continued and were analyzed at 12-weeks and 119(74.37%) at 24-weeks. The mean SF-12 physical component score significantly improved in the MCard group at 12 weeks follow-up (48.93 vs. control 43.87, p<.001) and 24 weeks (53.52 vs. 46.82 p<.001). The mean SF-12 mental component scores also improved significantly in the MCard group at 12 weeks follow-up (44.84 vs. control 41.40, p<.001) and 24 weeks follow-up (48.95 vs 40.12, p<.001). At 12-and 24-week follow-up, all domains of MacNew QLMI (social, emotional, physical and global) were also statistically significant (p<.001) improved in the MCard group, unlike the control group. Conclusion: MCard is feasible and effective at improving all domains of HRQoL. There was an improvement in physical, mental, social, emotional and global domains among the MCard group in comparison to the control group. The addition of MCard programs to post-ACS standard care may improve patient outcomes and reduce the burden on the health care setting.

Keywords: acute coronary syndrome, mobile health augmented cardiac rehabilitation (MCard), cardiovascular diseases, cardiac rehabilitation, health-related quality of life, short form 12, MacNew QLMI

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Authors: A. Kherraf, M. Bouziane, L. Azzouzi, R. Habbal

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Introduction: Hypocalcaemia is a rare cause of heart failure. We report the clinical case of a young patient with reversible dilated cardiomyopathy secondary to hypocalcaemia in the context of hyperparathyroidism. Clinical case: We report the clinical case of a 23-year-old patient with a history of thyroidectomy for papillary thyroid carcinoma 3 years previously, who presented to the emergency room with a progressive onset dyspnea and edema of the lower limbs. Clinical examination showed hypotension at 90/70 mmHg, tachycardia at 102 bpm, and edema of the lower limbs. The ECG showed a regular sinus rhythm with a prolonged corrected QT interval to 520ms. The chest x-ray showed cardiomegaly. Echocardiography revealed dilated cardiomyopathy with biventricular dysfunction and a left ventricular ejection fraction of 45%, as well as moderate mitral insufficiency by restriction of the posterior mitral leaflet, moderate tricuspid insufficiency, and a dilated inferior vena cava with a pulmonary arterial pressure estimated at 46 mmHg. Blood tests revealed severe hypocalcemia at 38 mg / l with normal albumin and thyroxine levels, as well as hyperphosphatemia and increased TSH. The patient received calcium intake and vitamin D supplementation and was treated with beta blockers, ACE inhibitors, and diuretics with good progress and progressive normalization of cardiac function. Discussion: The cardiovascular manifestations of hypocalcaemia usually appear with deeply low serum calcium levels. This can lead to hypotension, arrhythmias, ventricular fibrillation, prolonged QT interval, or even heart failure. Heart failure is a rare and serious complication of hypocalcemia but most often characterized by complete normalization of myocardial function after treatment. The etiology of the hypocalcaemia, in this case, was probably related to accidental parathyroid removal during thyroidectomy. This is why careful monitoring of calcium levels is recommended after surgery. Conclusion: Hypocalcemic heart failure is rare but reversible heart disease. Systematic monitoring of serum calcium should be performed in all patients after thyroid surgery to avoid any complications related to hypoparathyroidism.

Keywords: hypocalcemia, heart failure, thyroid surgery, hypoparathyroidism

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Authors: Masuma Novak, Daniel Novak

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Background: Sweden along with other Nordic countries has the highest incidence of type 1 diabetes mellitus (T1DM) worldwide. The trend is increasing globally. The diagnosis is often given at the emergency clinic when children arrive with cardinal symptom of T1DM. Children with T1DM are known to have an increased risk of microvascular- and macrovascular complications. A family history of cardiovascular complications may further increase their risk. Clinically evident diabetes-related vascular complications are however rarely visible in childhood and adolescence, whereby an intensive diabetes treatment and normoglycemic control is a goal for every child. This study is a risk evaluation of children with T1DM based on their family’s cardiovascular history. Method: Since 2005 the Better Diabetes Diagnosis (BDD) study is a nationwide Swedish prospective cohort study that recruits new-onset T1DM who are less than 18 years old at time of diagnosis. For each newly diagnosed child, blood samples are collected for specific HLA genotyping and islet autoantibody assays and their family’s cardiovascular history is evaluated. As part of the BDD study, during the years 2010-2013 all children diagnosed with T1DM at the Queen Silvia’s Children’s Hospital in Sweden were asked about their family’s cardiovascular history. Questions regarded maternal and paternal high blood pressure, stroke, and myocardial infarction before the age of 55 years, and hyperlipidemia were answered. A maximum risk score of eight was possible. All children are clinically observed prospectively for early functional and structural abnormalities such as protein uremia, blood pressure, and retinopathy. Results: A total of 275 children aged 0 to 18 years were diagnosed with T1DM at the Queen Silvia’s Children’s Hospital emergency clinic during this four year period. The participation rate was 99.7%. 26.4% of the children had no hereditary cardiovascular risk factors. 22.7 % had one risk factor and 18.8% had two risk factors. 14.8% had three risk factors. 9.7% had four risk factors and 7.5% had five risk factors or more. Conclusion: Among children with T1DM in Sweden there is a difference in hereditary cardiovascular risk factors. These results indicate that children with T1DM who also have increased hereditary cardiovascular risk factors should be monitored closely with early screening for functional and structural cardiovascular abnormalities. This is a very preliminary and ongoing study which will be complemented with the cardiovascular risk analysis among children without T1DM.

Keywords: children, type I diabetes, emergency clinic, CVD risk

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Authors: Walid Al-Qerem, Ruba Zumot

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Background: The rise of obesity among children and adolescents remains a primary challenge for healthcare providers globally and in the Middle East. The aim of the present study is to determine the prevalence of obesity among 5-20 years old Jordanians based on CDC criteria. Method: A total of 5722 Jordanians (37% males; 63% females) aged 5-20 years data were retrieved from the Jordanian Ministry of Health electronic database (Hakeem). As per the CDC selection criteria, the chosen data pertains exclusively to healthy Jordanian children and adolescents who are medically sound, not suffering from health conditions, and not undergoing any treatments that could hinder normal growth patterns, such as severe infection, chronic kidney disease (CKD), Down’s syndrome, attention deficit hyperactivity disorder, cancer, heart disease, lung disease, cystic fibrosis, Crohn’s disease, type 1 diabetes, hormonal disturbances, any stress-related conditions, hormonal therapy such as corticosteroids, Growth hormones (GHS) or gonadotropin-releasing hormone agonists, insulin, and amphetamines or any other stimulants. In addition, participants with missing or invalid data values for anthropometric measurements were excluded from the study. Weight for age and body mass index for age were analyzed comparatively for Jordanian children and adolescents against the international growth standards. The Z-score for each record was computed based on CDC equations. As per CDC classifications, BMI for age percentiles, values ≥85th and < 95th are classified as overweight, and value at ≥ 95th is classified as obesity. Results: The average age of the evaluated sample was 12.33 ±4.39 years (10.79 ±3.39 for males and 13.23 ± 4.66 for females). The mean weight for males and females were 33.16±14.17 Kg and 133.54±17.17 cm for males, 43.86 ±18.82 Kg, and 142.19±18.35 for females, while for BMI the mean was for boys and girls 17.81±3.88 and 20.52±5.03 respectively. The results indicated that based on CDC criteria, 8.9% of males were classified as children/adolescents with overweight, and 9.7% were classified as children/adolescents with obesity, while in females, 17.8% were classified as children/adolescents with overweight and 10.2% were classified as children/adolescents with obesity. Discussion: The high prevalence of obesity reported in the present study emphasizes the importance of applying different strategies to prevent childhood obesity, including encouraging physical activity, promoting healthier food options, and behavioral changes. Conclusion: The results presented in this study indicated the high prevalence of overweight/obesity among Jordanian adolescents and children, which must be tagged by healthcare planners and providers.

Keywords: CDC, obesity, childhood, Jordan

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Authors: Chengcao Sun, Cuili Yang, Shujun Li, Ruilin Xue, Liang Wang, Yongyong Xi, Dejia Li

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Backgrounds: Sulforaphane, one of the most important isothiocyanates in the human diet, is known to have chemopreventive and antioxidant activities in different tissues via activation of NF-E2-related factor 2 (Nrf2)-mediated induction of antioxidant/phase II enzymes, such as heme oxygenase-1 (HO-1) and NAD(P)H quinone oxidoreductase 1 (NQO1). However, its effects on muscular dystrophy remain unknown. This work was undertaken to evaluate the effects of Sulforaphane on Duchenne muscular dystrophy (DMD). Methods: 4-week-old mdx mice were treated with SFN by gavage (2 mg/kg body weight per day) for 8 weeks. Blood was collected from eye socket every week, and tibial anterior, extensor digitorum longus, gastrocnemius, soleus, triceps brachii muscles and heart samples were collected after 8-week gavage. Force measurements and mice exercise capacity assays were detected. GSH/GSSG ratio, TBARS, CK and LDH levels were analyzed by spectrophotometric methods. H&E staining was used to analyze histological and morphometric of skeletal muscles of mdx mice, and Evas blue dye staining was made to detect sarcolemmal integrity of mdx mice. Further, the role of Sulforaphane on Nrf2/ARE signaling pathway was analyzed by ELISA, western blot and qRT-PCR. Results: Our results demonstrated that SFN treatment increased the expression and activity of muscle phase II enzymes NQO1 and HO-1 with Nrf2 dependent manner. SFN significantly increased skeletal muscle mass, muscle force (~30%), running distance (~20%) and GSH/GSSG ratio (~3.2 folds) of mdx mice, and decreased the activities of plasma creatine phosphokinase (CK) (~45%) and lactate dehydrogenase (LDH) (~40%), gastrocnemius hypertrophy (~25%), myocardial hypertrophy (~20%) and MDA levels (~60%). Further, SFN treatment also reduced the central nucleation (~40%), fiber size variability, inflammation and improved the sarcolemmal integrity of mdx mice. Conclusions: Collectively, these results show that SFN can improve muscle function, pathology and protect dystrophic muscle from oxidative damage in mdx mice through Nrf2 signaling pathway, which indicate Nrf2 may have clinical implications for the treatment of patients with muscular dystrophy.

Keywords: sulforaphane, duchenne muscular dystrophy, Nrf2, oxidative stress

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Authors: I. V. Palamarchuk, N. V. Zaichko

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Background and Aims: Galectin-3 is a marker of subclinical cardiac injury and is elevated in individuals with type 2 diabetes mellitus; while hydrogen sulfide (H₂S), metabolite of sulfur-containing amino acids, is considered having antifibrogenic effects. This study was designed to investigate whether metformin and its combination with NaHS can influence plasma galectin-3 and cystathionine-γ-lyase/hydrogen sulfide (CSE/H₂S) system in diabetic rat’s heart. Methods: 32 healthy male rats (180-250 g) were divided into 4 groups. To induct diabetes, rats (group 2-4) were injected with streptozotocin (STZ, 40 mg/kg/i.p., 0.1 M citrate buffer (pH 4.5). Rats from 3d (STZ+Metf) and 4th (STZ+Metf+NaHS) groups were given metformin (500 mg/kg/day) orally, and rats from 4th (STZ+Metf+NaHS) group were injected sodium hydrosulfide (NaHS, 3 mg/kg/i.p.) once per day starting from 3 to 28 day after streptozotocin injection. Rats of first group (control) were administered the equivalent volumes of 0.9% NaCl. Plasma galectin-3 was measured by ELISA. Rats’ hearts were sampled for determination of H2S by reaction with N,N-Dimethyl-p-phenylenediamine. Determination of CSE gene expression was performed in real time using PCR in the presence of SYBR Green I, using DT-Light detecting amplifier ('DNA-technology', Russia). Results: Induction of streptozotocin diabetes (STZ-diabetes, group 2) was followed by low myocardial H2S concentration and CSE expression (by 35%, p < 0.05 and 60.5%, p < 0.001 respectively, than that in controls), while plasma galectin-3 in this group was significantly higher than in controls (by 3.8 times, p < 0.05). Administration of metformin (group 3) resulted in significantly higher H₂S concentration (by 28.5%, p < 0.05), whereas CSE expression was only by 6% more than that in STZ-diabetes, as well as plasma galectin-3 was only by 14.8% lower in comparison with untreated diabetic rats. The inhibition of H₂S generation and CSE activity by diabetes was greatly attenuated in STZ+Metf+NaHS group. The combination of metformin with NaHS significantly stimulated H₂S production (by 48%, p < 0.05 and 15%, p < 0.05 more than STZ-diabetes and STZ+Metf respectively) and CSE gene expression (by 64.8%, p < 0.05 compared to STZ-diabetes and by 55.4%,p < 0.05 compared to STZ+Metf). Besides, plasma galectin-3 in rats receiving metformin and NaHS was significantly lower by 42%, p < 0.05 and 32.5%, p < 0.05 compared to STZ-diabetes and STZ+Metf groups respectively. Conclusions: To summarize, dysfunction of CSE/H2S system and galectin-3 stimulation was found in streptozotocin-induced diabetic rats. Metformin and its combination with exogenous H2S effectively prevented the development of metabolic changes induced by diabetes. These findings suggest that CSE/H₂S system can be integrated into pathogenesis of diabetic complications through modulation of pro-inflammatory and pro-fibrogenic mediator galectin-3.

Keywords: cystathionine-γ-lyase, diabetic heart, galectin-3, hydrogen sulfide, metformin, sodium hydrosulfide

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Authors: Ledi Neçaj

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Introduction: Cardio-respiratory rehabilitation is the set of coordinated interventions needed to provide the best physical, psychological, and social conditions so that patients with chronic or post-acute cardiopulmonary disease, with their efforts, maintain or resume optimal functioning in society through improved health behaviors. Purpose: To study the effectiveness of the application of Cardio-Respiratory Rehabilitation in the typology of patients with chronic or post-acute cardiomyopathy and chronic respiratory diseases in order to facilitate their therapeutic use and to improve the overall quality of life. Material and Method: This is a prospective study including patients with COPD and cardiac disease who were included in the rehabilitation program during the period January 2019 - November 2021. The study was conducted at the University Hospital Center "Mother Teresa" in Tirana, University Hospital "SHEFQET NDROQI", AMERICAN Hospital, HYGEA Hospital, and "Our Lady of Good Counsel, Tirana". An individual chart was used to collect sociodemographic, physical, clinical, and functional examinations for each patient. Results: The study included 253 patients, with a mean age of 62.1 (± 7.9) years, ranging from 48 to 82 years. (67.6%) of the patients were males, and (32.4%) female. Male patients predominated in all age groups, with a statistically significant difference with females (p<0.01). The most common cardiac pathologies are coronary artery bypass (24%), cerebral stroke (9%), myocardial infarction (17%), Stent placement (8%) (p<0.01). Correlation matrix of risk factors found a significant correlation of alcohol consumption with diabetes, smoking, dyslipidemia, sedentary life, obesity, AVC, and hypertension. Functional capacity estimated by change in metabolic equivalents (MET) improved by 46% from 4. ±2.2 to 7.2± .8 METs (p<0.01). Duration of exercise after rehabilitation was increased by 21% compared to baseline (p<0.01). The mean score of all three subscales of the questionnaire: symptoms (p=0.03), activity (p<0.01), and impact (p<0.01) after rehabilitation, was lower compared to pre-rehabilitation. Conclusions: The rehabilitation program has impacted on improving the quality of life, reducing symptoms, reducing the impact of negative factors on daily life, and reducing dyspnea during daily activities.

Keywords: cardio-respiratory rehabilitation, physical exercise, quality of life, diseases

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Authors: Mende Mensa Sorato, Majid Davari, Abbas Kebriaeezadeh, Nizal Sarrafzadegan, Tamiru Shibru, Behzad Fatemi

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Markov model, like cardiovascular disease (CVD) policy model based simulation, is being used for evaluating the cost-effectiveness of hypertension treatment. Stroke, angina, myocardial infarction (MI), cardiac arrest, and all-cause mortality were included in this model. Hypertension is a risk factor for a number of vascular and cardiac complications and CVD outcomes. Objective: This systematic review was conducted to evaluate the comprehensiveness of this model across different regions globally. Methods: We searched articles written in the English language from PubMed/Medline, Ovid/Medline, Embase, Scopus, Web of Science, and Google scholar with a systematic search query. Results: Thirteen cohort studies involving a total of 2,165,770 (1,666,554 hypertensive adult population and 499,226 adults with treatment-resistant hypertension) were included in this scoping review. Hypertension is clearly associated with coronary heart disease (CHD) and stroke mortality, unstable angina, stable angina, MI, heart failure (HF), sudden cardiac death, transient ischemic attack, ischemic stroke, subarachnoid hemorrhage, intracranial hemorrhage, peripheral arterial disease (PAD), and abdominal aortic aneurism (AAA). Association between HF and hypertension is variable across regions. Treatment resistant hypertension is associated with a higher relative risk of developing major cardiovascular events and all-cause mortality when compared with non-resistant hypertension. However, it is not included in the previous CVD policy model. Conclusion: The CVD policy model used can be used in most regions for the evaluation of the cost-effectiveness of hypertension treatment. However, hypertension is highly associated with HF in Latin America, the Caribbean, Eastern Europe, and Sub-Saharan Africa. Therefore, it is important to consider HF in the CVD policy model for evaluating the cost-effectiveness of hypertension treatment in these regions. We do not suggest the inclusion of PAD and AAA in the CVD policy model for evaluating the cost-effectiveness of hypertension treatment due to a lack of sufficient evidence. Researchers should consider the effect of treatment-resistant hypertension either by including it in the basic model or during setting the model assumptions.

Keywords: cardiovascular disease policy model, cost-effectiveness analysis, hypertension, systematic review, twelve major cardiovascular events

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Authors: Laura M. Hovsepyan, Gayane S. Ghazaryan, Hasmik V. Zanginyan

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Hypertension (HD) is the most common cardiovascular pathology that causes disability and mortality in the working population. Most often, heart failure (HF), which is based on myocardial remodeling, leads to death in hypertension. Recently, endothelial dysfunction (EDF) or a violation of the functional state of the vascular endothelium has been assigned a significant role in the structural changes in the myocardium and the occurrence of heart failure in patients with hypertension. It has now been established that tissues affected by inflammation form increased amounts of superoxide radical and NO, which play a significant role in the development and pathogenesis of various pathologies. They mediate inflammation, modify proteins and damage nucleic acids. The aim of this work was to study the processes of oxidative modification of proteins (OMP) and the production of nitric oxide in hypertension. In the experimental work, the blood of 30 donors and 33 patients with hypertension was used. For the quantitative determination of OMP products, the based on the reaction of the interaction of oxidized amino acid residues of proteins and 2,4-dinitrophenylhydrazine (DNPH) with the formation of 2,4-dinitrophenylhydrazones, the amount of which was determined spectrophotometrically. The optical density of the formed carbonyl derivatives of dinitrophenylhydrazones was recorded at different wavelengths: 356 nm - aliphatic ketone dinitrophenylhydrazones (KDNPH) of neutral character; 370 nm - aliphatic aldehyde dinirophenylhydrazones (ADNPH) of neutral character; 430 nm - aliphatic KDNFG of the main character; 530 nm - basic aliphatic ADNPH. Nitric oxide was determined by photometry using Grace's solution. Adsorption was measured on a Thermo Scientific Evolution 201 SF at a wavelength of 546 nm. Thus, the results of the studies showed that in patients with arterial hypertension, an increased level of nitric oxide in the blood serum is observed, and there is also a tendency to an increase in the intensity of oxidative modification of proteins at a wavelength of 270 nm and 363 nm, which indicates a statistically significant increase in aliphatic aldehyde and ketone dinitrophenylhydrazones. The increase in the intensity of oxidative modification of blood plasma proteins in the studied patients, revealed by us, actually reflects the general direction of free radical processes and, in particular, the oxidation of proteins throughout the body. A decrease in the activity of the antioxidant system also leads to a violation of protein metabolism. The most important consequence of the oxidative modification of proteins is the inactivation of enzymes.

Keywords: hypertension (HD), oxidative modification of proteins (OMP), nitric oxide (NO), oxidative stress

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Authors: Kamil Ganaev, Elina Vlasova, Andrei Shiryaev, Renat Akchurin

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De novo atrial fibrillation (AF) after coronary artery bypass grafting (CABG) is a common complication. To date, there are no data on the possible effect of diffuse lesions of coronary arteries on the incidence of postoperative AF complications. Methods. Patients operated on-pump under hypothermic conditions during the calendar year (2020) were studied. Inclusion criteria - isolated CABG and achievement of complete myocardial revascularization. Patients with a history of AF moderate and severe valve dysfunction, hormonal thyroid pathology, initial CHF(Congestive heart failure), as well as patients with developed perioperative complications (IM, acute heart failure, massive blood loss) and deceased were excluded. Thus 227 patients were included; mean age 65±9 years; 69% were men. 89% of patients had a 3-vessel lesion of the coronary artery; the remainder had a 2-vessel lesion. Mean LV size: 3.9±0.3 cm, indexed LV volume: 29.4±5.3 mL/m2. Two groups were considered: D (n=98), patients with diffuse coronary heart disease, and L (n=129), patients with local coronary heart disease. Clinical and demographic characteristics in the groups were comparable. Rhythm assessment: continuous bedside ECG monitoring up to 5 days; ECG CT at 5-7 days after CABG; daily routine ECG registration. Follow-up period - postoperative hospital period. Results. The Median follow-up period was 9 (7;11) days. POFP (Postoperative atrial fibrillation) was detected in 61/227 (27%) patients: 34/98 (35%) in group D versus 27/129 (21%) in group L; p<0.05. Moreover, the values of revascularization index in groups D and L (3.9±0.7 and 3.8±0.5, respectively) were equal, and the mean time Cardiopulmonary bypass (CPB) (107±27 and 80±13min), as well as the mean ischemic time (67±17 and 55±11min) were significantly longer in group D (p<0.05). However, a separate analysis of these parameters in patients with and without developed AF did not reveal any significant differences in group D (CPB time 99±21.2 min, ischemic time 63±12.2 min), or in group L (CPB time 88±13.1 min, ischemic time 58.7±13.2 min). Conclusion. With the diffuse nature of coronary lesions, the incidence of AF in the hospital period after isolated CABG definitely increases. To better understand the role of severe coronary atherosclerosis in the development of POAF, it is necessary to distinguish the influence of organic features of atrial and ventricular myocardium (as a consequence of chronic coronary disease) from the features of surgical correction in diffuse coronary lesions.

Keywords: atrial fibrillation, diffuse coronary artery disease, coronary artery bypass grafting, local coronary artery disease

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Authors: Atefeh Abdollahi, Maryam Bahreini, Babak Choobi Anzali, Fatemeh Rasooli

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Introduction: Triage becomes the main part of organization of care in Emergency department (ED)s. It is used to describe the sorting of patients for treatment priority in ED. The accurate triage of injured patients has reduced fatalities and improved resource usage. Besides, the nurses’ knowledge and skill are important factors in triage decision-making. The ability to define an appropriate triage level and their need for intervention is crucial to guide to a safe and effective emergency care. Methods: This is a prospective cross-sectional study designed for emergency nurses working in four public university hospitals. Five triage workshops have been conducted every three months for emergency nurses based on a standard triage Emergency Severity Index (ESI) IV slide set - approved by Iranian Ministry of Health. Most influential items on triage performance were discussed through brainstorming in workshops which then, were peer reviewed by five emergency physicians and two head registered nurses expert panel. These factors that might distract nurse’ attention from proper decisions included patients’ past medical diseases, the natural tricks of triage and system failure. After permission had been taken, emergency nurses participated in the study and were given the structured questionnaire. Data were analysed by SPSS 21.0. Results: 92 emergency nurses enrolled in the study. 30 % of nurses reported the past history of chronic disease as the most influential confounding factor to ascertain triage level, other important factors were the history of prior admission, past history of myocardial infarction and heart failure to be 20, 17 and 11 %, respectively. Regarding the concept of difficulties in triage practice, 54.3 % reported that the discussion with patients and family members was difficult and 8.7 % declared that it is hard to stay in a single triage room whole day. Among the participants, 45.7 and 26.1 % evaluated the triage workshops as moderately and highly effective, respectively. 56.5 % reported overcrowding as the most important system-based difficulty. Nurses were mainly doubtful to differentiate between the triage levels 2 and 3 according to the ESI VI system. No significant correlation was found between the work record of nurses in triage and the uncertainty in determining the triage level and difficulties. Conclusion: The work record of nurses hardly seemed to be effective on the triage problems and issues. To correct the deficits, training workshops should be carried out, followed by continuous refresher training and supportive supervision.

Keywords: assessment, education, nurse, triage

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Authors: Cristian Sirbu-Dragomir, Stefan-Mihai Sofian, Adrian Predescu

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This paper aims to study Tesla pumps for circulating biofluids. It is desired to make a small pump for the circulation of biofluids. This type of pump will be studied because it has the following characteristics: It doesn’t have blades which results in very small frictions; Reduced friction forces; Low production cost; Increased adaptability to different types of fluids; Low cavitation (towards 0); Low shocks due to lack of blades; Rare maintenance due to low cavity; Very small turbulences in the fluid; It has a low number of changes in the direction of the fluid (compared to rotors with blades); Increased efficiency at low powers.; Fast acceleration; The need for a low torque; Lack of shocks in blades at sudden starts and stops. All these elements are necessary to be able to make a small pump that could be inserted into the thoracic cavity. The pump will be designed to combat myocardial infarction. Because the pump must be inserted in the thoracic cavity, elements such as Low friction forces, shocks as low as possible, low cavitation and as little maintenance as possible are very important. The operation should be performed once, without having to change the rotor after a certain time. Given the very small size of the pump, the blades of a classic rotor would be very thin and sudden starts and stops could cause considerable damage or require a very expensive material. At the same time, being a medical procedure, the low cost is important in order to be easily accessible to the population. The lack of turbulence or vortices caused by a classic rotor is again a key element because when it comes to blood circulation, the flow must be laminar and not turbulent. The turbulent flow can even cause a heart attack. Due to these aspects, Tesla's model could be ideal for this work. Usually, the pump is considered to reach an efficiency of 40% being used for very high powers. However, the author of this type of pump claimed that the maximum efficiency that the pump can achieve is 98%. The key element that could help to achieve this efficiency or one as close as possible is the fact that the pump will be used for low volumes and pressures. The key elements to obtain the best efficiency for this model are the number of rotors placed in parallel and the distance between them. The distance between them must be small, which helps to obtain a pump as small as possible. The principle of operation of such a rotor is to place in several parallel discs cut inside. Thus the space between the discs creates the vacuum effect by pulling the liquid through the holes in the rotor and throwing it outwards. Also, a very important element is the viscosity of the liquid. It dictates the distance between the disks to achieve a lossless power flow.

Keywords: lubrication, temperature, tesla-pump, viscosity

Procedia PDF Downloads 156

Authors: Sushil Kumar Singh, Kumar Rahul, Vivek Tewarson, Sarvesh Kumar, Shobhit Kumar

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Objective: Rheumatic mitral stenosis continues to be a major public health problem in developing countries. When the left atrium (LA) is unable to fill the left ventricle (LV) at normal LA pressures due to impaired relaxation and impaired compliance, diastolic dysfunction occurs. The assessment of left ventricular (LV) diastolic function and filling pressures is of clinical importance to identify underlying cardiac disease, its treatment, and to assess prognosis. 2D echocardiography can detect diastolic dysfunction with excellent sensitivity and minimal risk when compared to the gold standard of invasive pressure-volume measurements. Material and Method: This was a one-year study consisting of twenty-nine patients of isolated rheumatic severe mitral stenosis. Data was analyzed preoperative and post operative (at one month follow-up). Transthoracic 2D echocardiographic parameters of the diastolic function are transmitral flow, pulmonary venous flow, mitral annular tissue doppler, and color M-mode doppler. In our study, mitral valve orifice area, ejection fraction, deceleration time, E/A-wave, E/E’-wave, myocardial performance index of left ventricle (Tei index ), and Mitral inflow propagation velocity were included for echocardiographic evaluation. The statistical analysis was performed on SPSS Version 15.0 statistical analysis software. Result: Twenty-nine patients underwent successful closed mitral commissurotomy for isolated mitral stenosis. The outcome measures were observed pre-operatively and at one-month follow-up. The majority of patients were in NYHA grade III (69.0%) in the preoperative period, which improved to NYHA grade I (48.3%) after closed mitral commissurotomy. Post-surgery mitral valve area increased from 0.77 ± 0.13 to 2.32 ± 0.26 cm, ejection fraction increased from 61.38 ± 4.61 to 64.79 ± 3.22. There was a decrease in deceleration time from 231.55 ± 49.31 to 168.28 ± 14.30 ms, E/A ratio from 1.70 ± 0.54 from 0.89 ± 0.39, E/E’ ratio from 14.59 ± 3.34 to 8.86 ± 3.03. In addition, there was improvement in TIE index from 0.50 ± 0.03 to 0.39 ± 0.06 and mitral inflow propagation velocity from 47.28 ± 3.71 to 57.86 ± 3.19 cm/sec. In peri-operative and follow-up, there was no incidence of severe mitral regurgitation (MR). There was no thromboembolic incident and no mortality.

Keywords: closed mitral valvotomy, mitral stenosis, open mitral commissurotomy, balloon mitral valvotomy

Procedia PDF Downloads 55

Authors: José Ramón López-Mínguez, Estrella Suárez-Corchuelo, Sergio López-Tejero, Luis Nombela-Franco, Xavier Freixa-Rofastes, Guillermo Bastos-Fernández, Xavier Millán-Álvarez, Raúl Moreno-Gómez, José Antonio Fernández-Díaz, Ignacio Amat-Santos, Tomás Benito-González, Fernando Alfonso-Manterola, Pablo Salinas-Sanguino, Pedro Cepas-Guillén, Dabit Arzamendi, Ignacio Cruz-González, Juan Manuel Nogales-Asensio

Abstract:

Background and objectives: The treatment of patients with non-valvular atrial fibrillation (NVAF) who need coronary stenting is challenging. The objective of the study was to determine whether left atrial appendage occlusion (LAAO) could be a feasible option and benefit these patients. To this end, we studied the impact of LAAO plus antiplatelet drugs vs oral anticoagulants (OAC) (including direct OAC) plus antiplatelet drugs in these patients’ long-term outcomes. Methods: The results of 207 consecutive patients with NVAF who underwent coronary stenting were analyzed. A total of 146 patients were treated with OAC (75 with acenocoumarol, 71 with direct OAC) while 61 underwent LAAO. The median follow-up was 35 months. Patients also received antiplatelet therapy as prescribed by their cardiologist. The study received the proper ethical oversight. Results: Age (mean 75.7 years), and the past medical history of stroke were similar in both groups. However, the LAAO group had more unfavorable characteristics (history of coronary artery disease [CHA2DS2-VASc], and significant bleeding [BARC ≥ 2] and HAS-BLED). The occurrence of major adverse events (death, stroke/transient ischemic events, major bleeding) and major cardiovascular events (cardiac death, stroke/transient ischemic attack, and myocardial infarction) were significantly higher in the OAC group compared to the LAAO group: 19.75% vs 9.06% (HR, 2.18; P = .008) and 6.37% vs 1.91% (HR, 3.34; P = .037), respectively. Conclusions: In patients with NVAF undergoing coronary stenting, LAAO plus antiplatelet therapy produced better long-term outcomes compared to treatment with OAC plus antiplatelet therapy despite the unfavorable baseline characteristics of the LAAO group.

Keywords: stents, atrial fibrillation, anticoagulants, left atrial appendage occlusion

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Authors: Rashmi Shukla, Yamini Bhusan Tripathi

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Diabetic nephropathy (DN) is characterized as diabetic kidney disease which involves many pathways e.g. hyperactivated protein kinase c (PKC), polyol pathway, excess production of advanced glycation end product (AGEs) & free radical accumulation etc. All of them results to hypoxia followed by apoptosis of podocytes, glomerulosclerosis, extracellular matrix (ECM) accumulation and fibrosis resulting to irreversible changes in kidney. This is continuously rising worldwide and there are not enough specific drugs, to retard its progress. Due to increasing side effects of allopathic drugs, interest in herbal remedies is growing. Earlier, we have reported that PTY-2 (a phytomedicine, derived from Pueraria tuberosa Linn.) inhibits the accumulation of extracellular matrix (ECM) through activation of MMP-9. Present study exhibited the therapeutic potential of Pueraria tuberosa in the prevention of podocytes apoptosis and modulation of nephrin expression in streptozotocin (STZ) induced DN rats. DN rats were produced by maintaining persistent hyperglycemia for 8 weeks by intra-peritoneal injection of 55 mg/kg streptozotocin (STZ). These rats were randomly divided in 2 groups, i.e. DN control, and DN+ water extract of Pueraria tuberosa (PTW). One group of age-matched normal rats served as non-diabetic control (group-1), The STZ induced DN rats (group-2) and DN+PTW treated rats (group-3). The PTW was orally administered (0.3g/kg) daily to group-2 rats and drug vector (1 ml of 10% tween 20) in control rats. The treatments were continued for 20 days and blood and urine samples were collected. Rats were then sacrificed to investigate the expression Bcl2, Bax and nephroprotective protein i.e. nephrin in kidney glomerulus. The effect of PTW was evaluated, we have found that the PTW significantly(p < .001) reversed the raised serum urea, serum creatinine, urine protein and improved the creatinine clearance in STZ induce diabetic nephropathy in rats and also significantly(p < .001) prevented the rise in urine albumin excretion. The Western blot analysis of kidney tissue homogenate showed increased expression of Bcl2 in PTW treated rats. The RT-PCR showed the increased expression and accumulation of nephrin mRNA. The confocal photomicrographs also supported the reduction of Bax and a simultaneous increase in Bcl2 and nephrin in glomerular podocytes. Hence, our finding suggests that the nephroprotective role of PTW is mediated via restoration of nephrin thus prevents the podocytes apoptosis and ameliorates diabetic nephropathy. The clinical trial of PTW would prove to be a potential food supplement/ drug of alternative medicine for patients with diabetic nephropathy in early stage.

Keywords: Pueraria tuberosa, diabetic nephropathy, anti-apoptosis, nephrin

Procedia PDF Downloads 190

Authors: Alexandru Achim, Tamás Szűcsborus, Viktor Sasi, Ferenc Nagy, Zoltán Jambrik, Attila Nemes, Albert Varga, Călin Homorodean, Olivier F. Bertrand, Zoltán Ruzsa

Abstract:

Aim: Our study aimed to establish the safety and the technical success of distal radial access for balloon aortic valvuloplasty (DR-BAV). The secondary objective was to determine the effectiveness and appropriate role of DR-BAV within half year follow-up. Methods: Clinical and angiographic data from 32 consecutive patients with symptomatic aortic stenosis were evaluated in a prospective pilot single-center study. Between 2020 and 2021, the patients were treated utilizing dual distal radial access with 6-10F compatible balloons. The efficacy endpoint was divided into technical success (successful valvuloplasty balloon inflation at the aortic valve and absence of intra- or periprocedural major complications), hemodynamic success (a reduction of the mean invasive gradient >30%), and clinical success (an improvement of at least one clinical category in the NYHA classification). The safety endpoints were vascular complications (major and minor Valve Academic Research Consortium (VARC)-2 bleeding, diminished or lost arterial pulse or the presence of any pseudo-aneurysm or arteriovenous fistula during the clinical follow-up) and major adverse events, MAEs (the composite of death, stroke, myocardial infarction, and urgent major aortic valve replacement or implantation during the hospital stay and or at one-month follow-up). Results: 32 patients (40 % male, mean age 80 ± 8,5) with severe aortic valve stenosis were included in the study and 4 patients were excluded. Technical success was achieved in all patients (100%). Hemodynamic success was achieved in 30 patients (93,75%). Invasive max and mean gradients were reduced from 73±22 mm Hg and 49±22 mm Hg to 49±19 mm Hg and 20±13 mm Hg, respectively (p = <.001). Clinical success was achieved in 29 patients (90,6%). In total, no major adverse cardiac or cerebrovascular event nor vascular complications (according to VARC 2 criteria) occurred during the intervention. All-cause death at 6 months was 12%. Conclusion: According to our study, dual distal radial artery access is a safe and effective option for balloon aortic valvuloplasty in patients with severe aortic valve stenosis and can be performed in all patients with sufficient lumen diameter. Future randomized studies are warranted to investigate whether this technique is superior to other approaches.

Keywords: mean invasive gradient, distal radial access for balloon aortic valvuloplasty (DR-BAV), aortic valve stenosis, pseudo-aneurysm, arteriovenous fistula, valve academic research consortium (VARC)-2

Procedia PDF Downloads 56

Authors: Nadeem Yousuf Khan

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This paper proposes the formation of a digital emergency response system (dERS) in the aged, long-term care, and chronic disease setups in the post-COVID healthcare ecosystem, focusing on the Asia Pacific market where the aging population is increasing significantly. It focuses on the use of digital technologies such as wearables, a global positioning system (GPS), and mobile applications to build an integrated care system for old folks with co-morbidities and other chronic diseases. The paper presents a conceptual framework of a connected digital health ecosystem that not only provides proactive care to registered patients but also prevents the damages due to sudden conditions such as strokes by alerting and treating the patients in a digitally connected and coordinated manner. A detailed review of existing digital health technologies such as wearables, GPS, and mobile apps was conducted in context with the new post-COVID healthcare paradigm, along with a detailed literature review on the digital health policies and usability. A good amount of research papers is available in the application of digital health, but very few of them discuss the formation of a new framework for a connected digital ecosystem for the aged care population, which is increasing around the globe. A connected digital emergency response system has been proposed by the author whereby all registered patients (chronic disease and aged/long term care) will be connected to the proposed digital emergency response system (dERS). In the proposed ecosystem, patients will be provided with a tracking wrist band and a mobile app through which the control room will be monitoring the mobility and vitals such as atrial fibrillation (AF), blood sugar, blood pressure, and other vital signs. In addition to that, an alert in case if the patient falls down will add value to this system. In case of any variation in the vitals, an alert is sent to the dERS 24/7, and dERS clinical staff immediately trigger that alert which goes to the connected hospital and the adulatory service providers, and the patient is escorted to the nearest connected tertiary care hospital. By the time, the patient reaches the hospital, dERS team is ready to take appropriate clinical action to save the life of the patient. Strokes or myocardial infarction patients can be prevented from disaster if they are accessible to engagement healthcare. This dERS will play an effective role in saving the lives of aged patients or patients with chronic co-morbidities.

Keywords: aged care, atrial fibrillation, digital health, digital emergency response system, digital technology

Procedia PDF Downloads 86

Authors: Asghar Arif

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Lung cancer has been recognized as one of the greatest common cancers, causing the annual mortality rate of about 1.2 million people in the world. Lung cancer is the most prevalent cancer in men and the third-most common cancer among women (after breast and digestive cancers).Recent evidences have shown the inflammatory process as one of the potential factors of cancer. Tuberculosis (TB), pneumonia, and chronic bronchitis are among the most important inflammation-inducing factors in the lungs, among which TB has a more profound role in the emergence of cancer.TB is one of the important mortality factors throughout the world, and 205,000 death cases are reported annually due to this disease. Chronic inflammation and fibrosis due to TB can induce genetic mutation and alternations. Parenchyma tissue of lung is involved in both diseases of TB and lung cancer, and continuous cough in lung cancer, morphological vascular variations, lymphocytosis processes, and generation of immune system mediators such as interleukins, are all among the factors leading to the hypothesis regarding the role of TB in lung cancer Some reports have shown that the induction of necrosis and apoptosis or TB reactivation, especially in patients with immune-deficiency, may result in increasing IL-17 and TNF_α, which will either decrease P53 activity or increase the expression of Bcl-2, decrease Bax-T, and cause the inhibition of caspase-3 expression due to decreasing the expression of mitochondria cytochrome oxidase. It has been also indicated that following the injection of BCG vaccine, the host immune system will be reinforced, and in particular, the rates of gamma interferon, nitric oxide, and interleukin-2 are increased. Therefore, CD4 + lymphocyte function will be improved, and the person will be immune against cancer.Numerous prospective studies have so far been conducted on the role of TB in lung cancer, and it seems that this disease is effective in that particular cancer.One of the main challenges of lung cancer is its correct and timely diagnosis. Unfortunately, clinical symptoms (such as continuous cough, hemoptysis, weight loss, fever, chest pain, dyspnea, and loss of appetite) and radiological images are similar in TB and lung cancer. Therefore, anti-TB drugs are routinely prescribed for the patients in the countries with high prevalence of TB, like Pakistan. Regarding the similarity in clinical symptoms and radiological findings of lung cancer, proper diagnosis is necessary for TB and respiratory infections due to nontuberculousmycobacteria (NTM). Some of the drug resistive TB cases are, in fact, lung cancer or NTM lung infections. Acid-fast staining and histological study of phlegm and bronchial washing, culturing and polymerase chain reaction TB are among the most important solutions for differential diagnosis of these diseases. Briefly, it is assumed that TB is one of the risk factors for cancer. Numerous studies have been conducted in this regard throughout the world, and it has been observed that there is a significant relationship between previous TB infection and lung cancer. However, to prove this hypothesis, further and more extensive studies are required. In addition, as the clinical symptoms and radiological findings of TB, lung cancer, and non-TB mycobacteria lung infections are similar, they can be misdiagnosed as TB.

Keywords: TB and lung cancer, TB people, TB servivers, TB and HIV aids

Procedia PDF Downloads 48

Authors: Geum Yeon Sim, Jasal Patel, Anand Kumthekar, Stanley Wainapel

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A 65-year-old right-hand dominant African-American man, formerly employed as a security guard, was referred to Rehabilitation Medicine with bilateral hand stiffness and weakness. His past medical history was only significant for myelofibrosis, diagnosed 4 years earlier, for which he was receiving scheduled blood transfusions. Approximately 2 years ago, he began to notice stiffness and swelling in his non-dominant hand that progressed to pain and decreased strength, limiting his hand function. Similar but milder symptoms developed in his right hand several months later. There was no history of prior injury or exposure to cold. Physical examination showed enlargement of metacarpophalangeal (MCP) and proximal interphalangeal (PIP) joints with finger flexion contractures, Swan-neck and Boutonniere deformities, and associated joint tenderness. Changes were more prominent in the left hand. X-rays showed mild osteoarthritis of several bilateral PIP joints. Anti-nuclear antibodies, rheumatoid factor, and cyclic citrullinated peptide antibodies were negative. MRI of the hand showed no erosions or synovitis. A rheumatology consultation was obtained, and the cause of his symptoms was attributed to myelofibrosis-related arthropathy with secondary osteoarthritis. The patient was tried on diclofenac cream and received a few courses of Occupational Therapy with limited functional improvement. Primary myelofibrosis (PMF) is a rare myeloproliferative neoplasm characterized by clonal proliferation of myeloid cells with variable morphologic maturity and hematopoietic efficiency. Rheumatic manifestations of malignancies include direct invasion, paraneoplastic presentations, secondary gout, or hypertrophic osteoarthropathy. PMF causes gradual bone marrow fibrosis with extramedullary metaplastic hematopoiesis in the liver, spleen, or lymph nodes. Musculoskeletal symptoms are not common and are not well described in the literature. The first reported case of myelofibrosis related arthritis was seronegative arthritis due to synovial invasion of myeloproliferative elements. Myelofibrosis has been associated with autoimmune diseases such as systemic lupus erythematosus, progressive systemic sclerosis, and rheumatoid arthritis. Gout has been reported in patients with myelofibrosis, and the underlying mechanism is thought to be related to the high turnover of nucleic acids that is greatly augmented in this disease. X-ray findings in these patients usually include erosive arthritis with synovitis. Treatment of underlying PMF is the treatment of choice, along with anti-inflammatory medications. Physicians should be cognizant of recognizing this rare entity in patients with PMF while maintaining clinical suspicion for more common causes of joint deformities, such as rheumatic diseases.

Keywords: myelofibrosis, arthritis, arthralgia, malignancy

Procedia PDF Downloads 66

Authors: E. Steen, B. Dewulf, N. Müller, C. Vandycke, Y. Vandekerckhove

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Introduction: The care for a ST-elevation myocardial infarction (STEMI) patient is time-critical. Reperfusion therapy within 90 minutes of initial medical contact is mandatory in the improvement of the outcome. Primary percutaneous coronary intervention (PCI) without previous fibrinolytic treatment, is the preferred reperfusion strategy in patients with STEMI, provided it can be performed within guideline-mandated times. Aim of the study: During a one year period (January 2013 to December 2013) the files of all consecutive STEMI patients with urgent referral from non-PCI facilities for primary PCI were reviewed. Special attention was given to a subgroup of patients with prior out-of-hospital medical contact generated by the 112-system. In an effort to reduce out-of-hospital system delay to definitive care a change in pre-hospital 112 dispatch strategies is proposed for these time-critical patients. Actual time recordings were compared with travel time simulations for two suggested scenarios. A first scenario (SC1) involves the decision by the on scene ground EMS (GEMS) team to transport the out-of-hospital diagnosed STEMI patient straight forward to a PCI centre bypassing the nearest non-PCI hospital. Another strategy (SC2) explored the potential role of helicopter EMS (HEMS) where the on scene GEMS team requests a PCI-centre based HEMS team for immediate medical transfer to the PCI centre. Methods and Results: 49 (29,1% of all) STEMI patients were referred to our hospital for emergency PCI by a non-PCI facility. 1 file was excluded because of insufficient data collection. Within this analysed group of 48 secondary referrals 21 patients had an out-of-hospital medical contact generated by the 112-system. The other 27 patients presented at the referring emergency department without prior contact with the 112-system. The table below shows the actual time data from first medical contact to definitive care as well as the simulated possible gain of time for both suggested strategies. The PCI-team was always alarmed upon departure from the referring centre excluding further in-hospital delay. Time simulation tools were similar to those used by the 112-dispatch centre. Conclusion: Our data analysis confirms prolonged reperfusion times in case of secondary emergency referrals for STEMI patients even with the use of HEMS. In our setting there was no statistical difference in gain of time between the two suggested strategies, both reducing the secondary referral generated delay with about one hour and by this offering all patients PCI within the guidelines mandated time. However, immediate HEMS activation by the on scene ground EMS team for transport purposes is preferred. This ensures a faster availability of the local GEMS-team for its community. In case these options are not available and the guideline-mandated times for primary PCI are expected to be exceeded, primary fibrinolysis should be considered in a non-PCI centre.

Keywords: STEMI, system delay, HEMS, emergency medicine

Procedia PDF Downloads 295

Authors: Hanan M. Hassan, Laila Abouzeid, Lamya H. Al-Wahaibi, George S. G. Shehatou, Ali A. El-Emam

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Cancer is a major public health problem and the second leading cause of death worldwide. In 2020, cancer diagnosis and treatment have been negatively affected by the coronavirus 2019 (COVID-19) pandemic. During the quarantine, because of the limited access to healthcare and avoiding exposure to COVID-19 as a contagious disease; patients of cancer suffered deferments in follow-up and treatment regimens leading to substantial worsening of disease, death, and increased healthcare costs. Thus, this study is designed to investigate the molecular mechanisms by which adamantne derivatives attenuate hepatocllular carcinoma experimentally and theoretically. There is a close association between increased resistance to anticancer drugs and defective apoptosis that considered a causative factor for oncogenesis. Cancer cells use different molecular pathways to inhibit apoptosis, BAX and Bcl-2 proteins have essential roles in the progression or inhibition of intrinsic apoptotic pathways triggered by mitochondrial dysfunction. Therefore, their balance ratio can promote the cellular apoptotic fate. In this study, the in vitro cytotoxic effects of seven synthetic adamantyl isothiorea derivatives were evaluated against five human tumor cell lines by MTT assay. Compounds 5 and 6 showed the best results, mostly against hepatocellular carcinoma (HCC). Hence, in vivo studies were performed in male Sprague-Dawley (SD) rats in which experimental hepatocellular carcinoma was induced with thioacetamide (TAA) (200 mg/kg, i.p., twice weekly) for 16 weeks. The most promising compounds, 5 and 6, were administered to treat liver cancer rats at a dose of 10 mg/kg/day for an additional two weeks, and the effects were compared with doxorubicin (DR), the anticancer drug. Hepatocellular carcinoma was evidenced by a dramatic increase in liver indices, oxidative stress markers, and immunohistochemical studies that were accompanied by a plethora of inflammatory mediators and alterations in the apoptotic cascade. Our results showed that treatment with adamantane derivatives 5 and 6 significantly suppressed fibrosis, inflammation, and other histopathological insults resulting in the diminished formation of hepatocyte tumorigenesis. Moreover, administration of the tested compounds resulted in amelioration of EGFR protein expression, upregulation of BAX, and lessening down of Bcl-2 levels that prove their role as apoptosis inducers. Also, the docking simulations performed for adamantane showed good fit and binding to the EGFR protein through hydrogen bond formation with conservative amino acids, which gives a shred of strong evidence for its hepatoprotective effect. In most analyses, the effects of compound 6 were more comparable to DR than compound 5. Our findings suggest that adamantane derivatives 5 and 6 are shown to have cytotoxic activity against HCC in vitro and in vivo, by more than one mechanism, possibly by inhibiting the TLR4-MyD88-NF-κB pathway and targeting EGFR signaling.

Keywords: adamantane, EGFR, HCC, apoptosis

Procedia PDF Downloads 126

Authors: Mitali Saha, Soma Das

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The fabrication of nanoscale materials for use in chemical sensing, biosensing and biological analyses has proven a promising avenue in the last few years. Cholesterol has aroused considerable interest in recent years on account of its being an important parameter in clinical diagnosis. There is a strong positive correlation between high serum cholesterol level and arteriosclerosis, hypertension, and myocardial infarction. Enzyme-based electrochemical biosensors have shown high selectivity and excellent sensitivity, but the enzyme is easily denatured during its immobilization procedure and its activity is also affected by temperature, pH, and toxic chemicals. Besides, the reproducibility of enzyme-based sensors is not very good which further restrict the application of cholesterol biosensor. It has been demonstrated that carbon nanotubes could promote electron transfer with various redox active proteins, ranging from cytochrome c to glucose oxidase with a deeply embedded redox center. In continuation of our earlier work on the synthesis and applications of carbon and metal based nanoparticles, we have reported here the synthesis of carbon nanotubes (CCNT) by burning coconut oil under insufficient flow of air using an oil lamp. The soot was collected from the top portion of the flame, where the temperature was around 6500C which was purified, functionalized and then characterized by SEM, p-XRD and Raman spectroscopy. The SEM micrographs showed the formation of tubular structure of CCNT having diameter below 100 nm. The XRD pattern indicated the presence of two predominant peaks at 25.20 and 43.80, which corresponded to (002) and (100) planes of CCNT respectively. The Raman spectrum (514 nm excitation) showed the presence of 1600 cm-1 (G-band) related to the vibration of sp2-bonded carbon and at 1350 cm-1 (D-band) responsible for the vibrations of sp3-bonded carbon. A nonenzymatic cholesterol biosensor was then fabricated on an insulating Teflon material containing three silver wires at the surface, covered by CCNT, obtained from coconut oil. Here, CCNTs worked as working as well as counter electrodes whereas reference electrode and electric contacts were made of silver. The dimensions of the electrode was 3.5 cm×1.0 cm×0.5 cm (length× width × height) and it is ideal for working with 50 µL volume like the standard screen printed electrodes. The voltammetric behavior of cholesterol at CCNT electrode was investigated by cyclic voltammeter and differential pulse voltammeter using 0.001 M H2SO4 as electrolyte. The influence of the experimental parameters on the peak currents of cholesterol like pH, accumulation time, and scan rates were optimized. Under optimum conditions, the peak current was found to be linear in the cholesterol concentration range from 1 µM to 50 µM with a sensitivity of ~15.31 μAμM−1cm−2 with lower detection limit of 0.017 µM and response time of about 6s. The long-term storage stability of the sensor was tested for 30 days and the current response was found to be ~85% of its initial response after 30 days.

Keywords: coconut oil, CCNT, cholesterol, biosensor

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Authors: Lina Paola Orozco Marin, Yuliet Montoya Osorio, John Bustamante Osorno

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Ischemic events can culminate in acute myocardial infarction by irreversible cardiac lesions that cannot be restored due to the limited regenerative capacity of the heart. Cell therapy seeks to replace these injured or necrotic cells by transplanting healthy and functional cells. The therapeutic alternatives proposed by tissue engineering and cardiovascular regenerative medicine are the use of biomaterials to mimic the native extracellular medium, which is full of proteins, proteoglycans, and glycoproteins. The selected biomaterials must provide structural support to the encapsulated cells to avoid their migration and death in the host tissue. In this context, the present research work focused on developing a natural thermosensitive hydrogel, its physical and chemical characterization, and the determination of its biocompatibility in vitro. The hydrogel was developed by mixing hydrolyzed bovine and porcine collagen at 2% w/v, chitosan at 2.5% w/v, and beta-glycerolphosphate at 8.5% w/w and 10.5% w/w in magnetic stirring at 4°C. Once obtained, the thermosensitivity and gelation time were determined, incubating the samples at 37°C and evaluating them through the inverted tube method. The morphological characterization of the hydrogels was carried out through scanning electron microscopy. Chemical characterization was carried out employing infrared spectroscopy. The biocompatibility was determined using the MTT cytotoxicity test according to the ISO 10993-5 standard for the hydrogel’s precursors using the fetal human ventricular cardiomyocytes cell line RL-14. The RL-14 cells were also seeded on the top of the hydrogels, and the supernatants were subculture at different periods to their observation under a bright field microscope. Four types of thermosensitive hydrogels were obtained, which differ in their composition and concentration, called A1 (chitosan/bovine collagen/beta-glycerolphosphate 8.5%w/w), A2 (chitosan/porcine collagen/beta-glycerolphosphate 8.5%), B1 (chitosan/bovine collagen/beta-glycerolphosphate 10.5%) and B2 (chitosan/porcine collagen/beta-glycerolphosphate 10.5%). A1 and A2 had a gelation time of 40 minutes, and B1 and B2 had a gelation time of 30 minutes at 37°C. Electron micrographs revealed a three-dimensional internal structure with interconnected pores for the four types of hydrogels. This facilitates the exchange of nutrients, oxygen, and the exit of metabolites, allowing to preserve a microenvironment suitable for cell proliferation. In the infrared spectra, it was possible to observe the interaction that occurs between the amides of polymeric compounds with the phosphate groups of beta-glycerolphosphate. Finally, the biocompatibility tests indicated that cells in contact with the hydrogel or with each of its precursors are not affected in their proliferation capacity for a period of 16 days. These results show the potential of the hydrogel to increase the cell survival rate in the cardiac cell therapies under investigation. Moreover, the results lay the foundations for its characterization and biological evaluation in both in vitro and in vivo models.

Keywords: cardiac cell therapy, cardiac ischemia, natural polymers, thermosensitive hydrogel

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Authors: Orkide Donma, Mustafa M. Donma

Abstract:

Childhood obesity, which may lead to increased risk for heart diseases in children as well as adults, is one of the most important health problems throughout the world. Prevalences of morbid obesity and metabolic syndrome (MetS) are being increased during childhood age group. MetS is a cluster of metabolic and vascular abnormalities including hypercoagulability and an increased risk of cardiovascular diseases (CVDs). There are also some relations between some components of MetS and leukocytes. The aim of this study is to investigate complete blood cell count parameters that differ between morbidly obese boys and girls with MetS diagnosis. A total of 117 morbid obese children with MetS consulted to Department of Pediatrics in Faculty of Medicine Hospital at Namik Kemal University were included into the scope of the study. The study population was classified based upon their genders (60 girls and 57 boys). Their heights and weights were measured and body mass index (BMI) values were calculated. WHO BMI-for age and sex percentiles were used. The values above 99 percentile were defined as morbid obesity. Anthropometric measurements were performed. Waist-to-hip and head-to-neck ratios as well as homeostatic model assessment of insulin resistance (HOMA-IR) were calculated. Components of MetS (central obesity, glucose intolerance, high blood pressure, high triacylglycerol levels, low levels of high density lipoprotein cholesterol) were determined. Hematological variables were measured. Statistical analyses were performed using SPSS. The degree for statistical significance was p ≤ 0.05. There was no statistically significant difference between the ages (11.2±2.6 years vs 11.2±3.0 years) and BMIs (28.6±5.2 kg/m² vs 29.3±5.2 kg/m²) of boys and girls (p ≥ 0.05), respectively. Significantly increased waist-to-hip ratios were obtained for boys (0.94±0.08 vs 0.91±0.06; p=0.023). Significantly elevated values of hemoglobin (13.55±0.98 vs 13.06±0.82; p=0.004), mean corpuscular hemoglobin concentration (33.79±0.91 vs 33.21±1.14; p=0.003), eosinophils (0.300±0.253 vs 0.196±0.197; p=0.014), and platelet (347.1±81.7 vs 319.0±65.9; p=0.042) were detected for boys. There was no statistically significant difference between the groups in terms of neutrophil/lymphocyte ratios as well as HOMA-IR values (p ≥ 0.05). Statistically significant gender-based differences were found for hemoglobin as well as mean corpuscular hemoglobin concentration and hence, separate reference intervals for two genders should be considered for these parameters. Eosinophils may contribute to the development of thrombus in acute coronary syndrome. Eosinophils are also known to make an important contribution to mechanisms related to thrombosis pathogenesis in acute myocardial infarction. Increased platelet activity is observed in patients with MetS and these individuals are more susceptible to CVDs. In our study, elevated platelets described as dominant contributors to hypercoagulability and elevated eosinophil counts suggested to be related to the development of CVDs observed in boys may be the early indicators of the future cardiometabolic complications in this gender.

Keywords: children, complete blood count, gender, metabolic syndrome

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Authors: Pengzhou Lu, Liming Xin, Payam Tavakoli, Zhonghua Lin, Roberto V. P. Ribeiro, Mitesh V. Badiwala

Abstract:

Ex vivo Heart Perfusion (EVHP) has been developed as an alternative strategy to expand cardiac donation by enabling resuscitation and functional assessment of hearts donated from marginal donors, which were previously not accepted. EVHP parameters, such as perfusion flow (PF) and perfusion pressure (PP) are crucial for optimal organ preservation. However, with the heart’s constant physiological changes during EVHP, such as coronary vascular resistance, manual control of these parameters is rendered imprecise and cumbersome for the operator. Additionally, low control precision and the long adjusting time may lead to irreversible damage to the myocardial tissue. To solve this problem, an automatic heart perfusion system was developed by applying a Human-Machine Interface (HMI) and a Programmable-Logic-Controller (PLC)-based circuit to control PF and PP. The PLC-based control system collects the data of PF and PP through flow probes and pressure transducers. It has two control modes: the RPM-flow mode and the pressure mode. The RPM-flow control mode is an open-loop system. It influences PF through providing and maintaining the desired speed inputted through the HMI to the centrifugal pump with a maximum error of 20 rpm. The pressure control mode is a closed-loop system where the operator selects a target Mean Arterial Pressure (MAP) to control PP. The inputs of the pressure control mode are the target MAP, received through the HMI, and the real MAP, received from the pressure transducer. A PID algorithm is applied to maintain the real MAP at the target value with a maximum error of 1mmHg. The precision and control speed of the RPM-flow control mode were examined by comparing the PLC-based system to an experienced operator (EO) across seven RPM adjustment ranges (500, 1000, 2000 and random RPM changes; 8 trials per range) tested in a random order. System’s PID algorithm performance in pressure control was assessed during 10 EVHP experiments using porcine hearts. Precision was examined through monitoring the steady-state pressure error throughout perfusion period, and stabilizing speed was tested by performing two MAP adjustment changes (4 trials per change) of 15 and 20mmHg. A total of 56 trials were performed to validate the RPM-flow control mode. Overall, the PLC-based system demonstrated the significantly faster speed than the EO in all trials (PLC 1.21±0.03, EO 3.69±0.23 seconds; p < 0.001) and greater precision to reach the desired RPM (PLC 10±0.7, EO 33±2.7 mean RPM error; p < 0.001). Regarding pressure control, the PLC-based system has the median precision of ±1mmHg error and the median stabilizing times in changing 15 and 20mmHg of MAP are 15 and 19.5 seconds respectively. The novel PLC-based control system was 3 times faster with 60% less error than the EO for RPM-flow control. In pressure control mode, it demonstrates a high precision and fast stabilizing speed. In summary, this novel system successfully controlled perfusion flow and pressure with high precision, stability and a fast response time through a user-friendly interface. This design may provide a viable technique for future development of novel heart preservation and assessment strategies during EVHP.

Keywords: automatic control system, biomedical engineering, ex-vivo heart perfusion, human-machine interface, programmable logic controller

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Authors: Mei Chen, Yingping Hou, Michelle Hao, Soheil Aghamohammadzadeh, Esteban Terzo, Roger Clark, Vijay Modur

Abstract:

Background: Recessive Dystrophic Epidermolysis Bullosa (RDEB) is a genetic skin condition characterized by skin tearing and unremitting blistering upon minimal trauma. Repeated blistering, fibrosis, and scarring lead to aggressive squamous cell carcinoma later in life. RDEB is caused by mutations in the COL7A1 gene encoding collagen type VII (C7), the major component of anchoring fibrils mediating epidermis-dermis adherence. Nonsense mutations in the COL7A1 gene of a subset of RDEB patients leads to premature termination codons (PTC). Similarly, most Junctional Epidermolysis Bullosa (JEB) cases are caused by nonsense mutations in the LAMB3 gene encoding the β3 subunit of laminin 332. Currently, there is an unmet need for the treatment of RDEB and JEB. Zikani Therapeutics has discovered an array of macrocyclic compounds with ring structures similar to macrolide antibiotics that can facilitate readthrough activity of nonsense mutations in the COL7A1 and LAMB3 genes by acting as Ribosome Modulating Agents (RMAs). The medicinal chemistry synthetic advancements of these macrocyclic compounds have allowed targeting the human ribosome while preserving the structural elements responsible for the safety and pharmacokinetic profile of clinically used macrolide antibiotics. Methods: C7 expression was used as a measure of readthrough activity by immunoblot assays in two primary human fibroblasts from RDEB patients (R578X/R578X and R163X/R1683X-COL7A1). Similarly, immunoblot assays in C325X/c.629-12T > A-LAMB3 keratinocytes were used to measure readthrough activity for JEB. The relative readthrough activity of each compound was measured relative to Gentamicin. An imaging-based fibroblast migration assay was used as an assessment of C7 functionality in RDEB-fibroblasts over 16-20 hrs. The incubation period for the above experiments was 48 hrs for RDEB fibroblasts and 72 hours for JEB keratinocytes. Results: 9 RMAs demonstrated increased protein expression in both patient RDEB fibroblasts. The highest readthrough activity at tested concentrations without cytotoxicities increased protein expression up to 179% of Gentamicin (400 µg/ml), with favored readthrough activity in R163X/R1683X-COL7A1 fibroblasts. Concurrent with protein expression, fibroblast hypermotility phenotype observed in RDEB was rescued by reducing motility by ~35% to WT levels (the same level as 690 µM Gentamicin treated cells). Laminin β3 expression was also shown to be increased by 6 RMAs in keratinocytes to 33-83% of (400 µg/ml) Gentamicin. Conclusions: To date, 9 RMAs have been identified that enhance the expression of functional C7 in a mutation-dependent manner in two different RDEB patient fibroblast backgrounds (R578X/R578X and R163X/R1683X-COL7A1). A further 6 RMAs have been identified that enhance the readthrough of C325X-LAMB3 in JEB patient keratinocytes. Based on the clinical trial conducted by us with topical gentamycin in 2017, Zikani’s RMAs achieve clinically significant levels of read-through for the treatment of recessive dystrophic and Junctional Epidermolysis Bullosa.

Keywords: epidermolysis bullosa, nonsense mutation, readthrough, ribosome modulation

Procedia PDF Downloads 77

Authors: Alla Ovsyannikova, Oksana Rymar, Elena Shakhtshneider, Mikhail Voevoda

Abstract:

In Siberia endocrinologists increasingly noted young patients with the course of diabetes mellitus differing from 1 and 2 types. Therefore we did a molecular genetic study for this group of patients to verify the monogenic forms of diabetes mellitus in them and researched the characteristics of this pathology. When confirming the monogenic form of diabetes, we performed a correction therapy for many patients (transfer from insulin to tablets), prevented specific complications, examined relatives and diagnosed their diabetes at the preclinical stage, revealed phenotypic characteristics of the pathology which led to the high significance of this work. Materials and Methods: We observed 5 patients (4 families). We diagnosed MODY (Maturity Onset Diabetes of the Young) during the molecular genetic testing (direct automatic sequencing). All patients had a full clinical examination, blood samples for biochemical research, determination of C-peptide and TSH, antibodies to b-cells, microalbuminuria, abdominal ultrasound, heart and thyroid ultrasound, examination of ophthalmologist. Results: We diagnosed 3 rare types of MODY: two women had MODY8, one man – MODY6 and man and his mother - MODY12. Patients with types 8 and 12 had clinical features. Age of onset hyperglycemia ranged from 26 to 34 years. In a patient with MODY6 fasting hyperglycemia was detected during a routine examination. Clinical symptoms, complications were not diagnosed. The patient observes a diet. In the first patient MODY8 was detected during first pregnancy, she had itchy skin and mostly postprandial hyperglycemia. Upon examination we determined glycated hemoglobin 7.5%, retinopathy, non-proliferative stage, peripheral neuropathy. She uses a basic bolus insulin therapy. The second patient with MODY8 also had clinical manifestations of hyperglycemia (pruritus, thirst), postprandial hyperglycemia and diabetic nephropathy, a stage of microalbuminuria. The patient was diagnosed autoimmune thyroiditis. She used inhibitors of DPP-4. The patient with MODY12 had an aggressive course. In the detection of hyperglycemia he had complaints of visual impairment, intense headaches, leg cramps. The patient had a history of childhood convulsive seizures of non-epileptic genesis, without organic pathology, which themselves were stopped at the age of 12 years. When we diagnosed diabetes a patient was 28 years, he had hypertriglyceridemia, atherosclerotic plaque in the carotid artery, proliferative retinopathy (lacerocoagulation). Diabetes and early myocardial infarction were observed in three cases in family. We prescribe therapy with sulfonylureas and SGLT-2 inhibitors with a positive effect. At the patient's mother diabetes began at a later age (30 years) and a less aggressive course was observed. She also has hypertriglyceridemia and uses oral hypoglycemic drugs. Conclusions: 1) When young patients with hyperglycemia have extrapancreatic pathologies and diabetic complications with a short duration of diabetes we can assume they have one of type of MODY diabetes. 2) In patients with monogenic forms of diabetes mellitus, the clinical manifestations of hyperglycemia in each succeeding generation are revealed at an earlier age. Research had increased our knowledge of the monogenic forms of diabetes. The reported study was supported by RSCF, research project No. 14-15-00496-P.

Keywords: diabetes mellitus, MODY diabetes, monogenic forms, young patients

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