Exploring the Grey Zone between Type 1 and Type 2 Diabetes

T1D is most common in children and young adults and is characterized by autoimmune destruction of insulin producing pancreatic beta cells, presence of certain risk genotypes such as HLA-DQB1, INS VNTR, PTPN22 and need of insulin for survival. In adults the same situation is often referred to as Latent Autoimmune Diabetes in Adults (LADA), with age at onset after 35 years and non-insulin requiring at least for 6 month after diagnosis. On the other hand, T2D is characterized by impaired insulin secretion and/or insulin resistance, which coexists with excessive hepatic glucose production and abnormal fat metabolism. Environmental factors causing insulin resistance are puberty, pregnancy, weight gain (central obesity “apple type”) and sedentary lifestyle. Usually T2D is diagnosed after 40 years of age and in some cases is diagnosed when patients develop vascular and neuropathic complications. TCF7L2 is by far the strongest T2D-associated gene. Maturity-onset diabetes of the young (MODY) is a monogenic form of diabetes inherited in an autosomal dominant fashion (individual has one copy of a mutant gene and one normal gene on a pair of autosomal chromosomes) characterized by nonketotic diabetes, age at onset before 25 years and primarily defect in beta-cell function. Until now, mutations in six genes have been identified as the cause of different forms of MODY, i.e. HNF-4 (MODY 1), glucokinase (GCK) (MODY 2), HNF-1 (MODY 3), IPF1 (MODY 4), HNF-1ß, formerly TCF2 (MODY 5) and NeuroD1 (MODY6). The goal of this thesis was to genetically dissect autoimmune (T1D and LADA) and non-autoimmune (T2D and MODY) diabetes in young (15-34 years old)and middle-aged (40-59 years old) Swedish diabetic patients for proper diagnosis and treatment of the disease in the future. To fulfill our goals we have selected 1642 young (15-34 years old) adult diabetic patients from Diabetes Incidence Study in Sweden (DISS) and 1619 middle-aged (40-59 years old) diabetic patients from Diabetes Registry in Southern Sweden. We determined genetic markers: HLA-DQB1 (study I and II), PTPN22, Ins VNTR, TCF7L2 (study II), PPARG, KCNJ11, IGF2BP2, WFS1, CDKAL1, JAZF1, CDKN2A/2B, HHEX, SLC30A8 and FTO (study III) and MODY genes- HNF-4 , GCK, HNF-1 and HNF-1ß, formerly TCF2 (study IV), measured islet antibodies (ICA, IA-2A and GADA) and C-peptide (marker of beta-cell function instead of insulin). In Study I we evaluated whether HLA-DQB1 genotypes facilitates the classification of diabetes as compared with islet antibodies among young (15-34 years) adult diabetic patients. Islet antibodies were found among 83% clinically considered to have T1D, 23% with T2D and 45% with unclassifiable diabetes.fpC-peptide concentrations after diagnosis were markedly lower in patients with than in those without islet antibodies. Irrespective of clinical classification, patients with islet antibodies showed increased frequencies of at least one risk HLA-DQB1 genotypes compared with patients without. Antibody negative patients with risk HLA-DQB1 genotypes had significantly lower fasting fpC-peptide concentrations than those without risk genotypes. We concluded that Assessment of islet antibodies is necessary for an etiological classification of diabetic patients. HLA-DQB1 genotyping does not improve the classification in patients with islet antibodies. However, in patients without islet antibodies, HLA-DQB1 genotyping together with fpC-peptide measurement may be of value in the differentiation between idiopathic T1D versus T2D. In Study II we evaluated whether genetic markers associated with T1D (HLADQB1,INS VNTR and PTPN22) and T2D (TCF7L2) could help to discriminate between autoimmune and non-autoimmune diabetes in young (15-34 years) and middle-aged (40-59 years) diabetic patients. Frequency of risk genotypes HLADQB1, PTPN22 CT/TT, INS VNTR class I/I and INS VNTR class IIIA/IIIA was increased in young and middle-aged GADA+ compared with GADA- patients. T2D-associated genotypes of TCF7L2 CT/TT of rs7903146 were significantly more common in young GADA- than in GADA+ patients. No such difference was seen in middle-aged patients, in whom the frequency of the CT/TT genotypes of TCF7L2 was similarly increased in GADA- and GADA+ groups. We concluded that common variants in the TCF7L2 gene help to differentiate young but not middle aged GADA+ and GADA- diabetic patients, suggesting that young GADA- patients have T2D and that middle-aged GADA+ patients (LADA) are different from their young GADA-positive (T1D) counterparts and share genetic features with T2D. In Study III we genotyped a panel of 10 novel T2D-associated risk genotypes in young (15-34 years) and middle-aged (40-59 years) GADA+ and GADA- diabetic patients and evaluated how they would modify the clinical phenotype. Young GADA- patients had increased frequency of risk variants in the PPARG, IGF2BP2, WFS1, JAZF1 and CDKN2A/2B genes compared with an elderly nondiabetic control group. Also risk variants in JAZF1 (AA) and CDKN2A/2B (TT) were more common in GADA- than in GADA + young diabetic patients. As expected middle-aged GADA- patients had increased prevalence of risk variants in the PPARG, IGF2BP2, WFS1, CDKAL1, JAZF1, SLC30A8, CDKN2A/2B, KCNJ11 and FTO genes compared with non-diabetic controls with no significant difference compared with GADA+ patients. Middle-aged GADA diabetic patients with more risk alleles (≥12) had decreased C-peptide concentrations than patients with less risk alleles (≤9). Also, GADA+ patients with more risk alleles had an earlier age at onset than GADA+ patients with less risk alleles. Distribution of T2D-associated risk alleles was quite similar inmiddle-aged patients regardless of presence of GADA. T2D- associated risk genotypes modify the disease phenotype (age at onset and C-peptide) in middleaged but not in young diabetic patients. In Study IV we evaluated whether common variants in MODY genes can discriminate between autoimmune and non-autoimmune diabetes in young adult diabetic patients and screened antibody negative diabetic patients with 3 members with diabetes in the family for HNF-4 , GCK and HNF-1 mutations. No significant difference in frequency of common variants in MODY genes was seen between Ab+ and Ab- individuals. In Ab+ diabetic patients carriers of the T2D-associated T allele of the HNF-1 gene had higher age at onset of diabetes, but severe symptoms of diabetes (weight reduction and/or polyuria) than G allele carriers. Finally, in Ab- diabetic patients carriers of the T2D-associated G allele of HNF-1ß gene had less frequent weight reduction and/or polyuria and ketonuria at diagnosis than A allele careers. One patient had frameshift mutation in exon 4 designated “Pro291fsinsC” in the HNF-1 gene. Common variants in MODY genes do not discriminate between young patients with autoimmune and non-autoimmune diabetes but they do influence onset and presentation of the disease. Our studies show that genetic markers clearly improve the classification of diabetes and together with islet antibodies they might be of help for diagnosis and treatment of different diabetic subgroups

Teamwork Principles of Modern Maanagement

There is no organization functioning without setbacks, managers often feel the necessity to improve capability of the organization. The organization efficiency may be improved through solution of problems raised between people and concentration to their involvement. The key problem of organization development is a disfunctional conflict going on between groups. This is exactly the purpose of efforts directed to strategic changes. The purpose for development of relations between groups to change dependances, stereotypes and perceptions being in groups about each other. Relations existing between groups may be improved through some approaches1 . Especially popular method for solution of a problem is emphasized2 . Whether to contradict each other’s goals? Whether perceptions are distorted? The stereotypes are created on what grounds? Is misunderstanding of intentions the reason of some differences? Whether various groups define words and concepts differently? – The answer to these questions will help us to define accurately the nature of the conflict following elucidation of the disputes causes, the groups may move to integration stage which starts by working over decision-making that will improve relationships between groups

Attention Deficit Hyperactivity Disorder

Attention deficit hyperactivity disorder (ADHD) is a mental disorder of the neurodevelopmental type. The disorder represents one of the common causes of referral for behavioral problems in children to medical and mental health doctors all around the world. The diagnosis can be done by DSM-V criteria. According to DSM-V, there are three main subtypes of ADHD: ADHD-inattentive type, ADHD-hyperactive-impulsive type, and ADHD-combined type. The etiology of ADHD is not definitively known. A genetic imbalance of catecholamine metabolism in the cerebral cortex appears to play a primary role. Various environmental factors may play a secondary role. Cognitive impairments in a variety of domains have been found in ADHD as well as impairment in overall intellectual function. A meta-analysis of children and adolescents with ADHD showed impairments in several aspects of executive functioning. The most important part of any intervention plan for a child with ADHD is the physical, behavioral and neuromotor/neuropsychological examination. Medication should be started with one of the stimulants. Both d-amphetamine and methylphenidate have been shown to be effective for improvement of hyperactivity, concentration problems, learning disorders, and other comorbidities

Data Mining-Based Identification of Nonlinear Systems

This chapter presents identification methods using associative search of analogs and wavelet analysis. It investigates the properties of data mining-based identification algorithms which allow to predict: (i) the approach of process variables to critical values and (ii) process transition to chaotic dynamics. The methods proposed are based on the modeling of human operator decision-making. The effectiveness of the methods is illustrated with an example of product quality prediction in oil refining. The development of fuzzy analogs of associative identification models is further discussed. Fuzzy approach expands the application area of associative techniques. Finally, state prediction techniques for manufacturing resources are developed on the basis of binary models and a machine learning procedure, which is named associative rules search

The Keele STarT Back Screening Tool Questionnaire: linguistic adaptation of the Russian language version

Introduction. The original English-language questionnaire for identifying the risks of developing chronic back pain The Keele STarT Back Screening Tool was developed in 2007 and adapted for use in many languages. The article describes the linguistic adaptation of the Russian version of the questionnaire The Keele STarT Back Screening Tool conducted in accordance with generally accepted rules.Aim. Linguistic adaptation of the Russian-language version of The Keele STarT Back Screening Tool.Materials and methods. Linguistic adaptation was carried out in five stages: 1) direct translation by three translators; 2) development of one version of direct translation; 3) reverse translation by two native English speakers; 4) development of one reverse version and its discussion by a committee of experts; 5) preliminary testing of the Russian version in a group of 30 patients (10 men and 20 women) aged from 28 to 84 years (average age 61.3 ± 8.7 years) with acute back pain, who in the period of April-June 2022 were on outpatient or inpatient treatment at the Clinic of Nervous Diseases of Sechenov University for nonspecific back pain (n = 21) and radiculopathy (n = 9).Results and discussion. All patients reported that the wording of the questionnaire items was clear and did not raise additional questions. The response time to the questions ranged from 30 seconds to 2 minutes 20 seconds (on average – 1 minute 18 seconds).Conclusion. The adapted Russian version of The Keele STarT Back Screening Tool questionnaire to identify the risks of developing chronic back pain did not cause comments from patients and experts. This version can be used to confirm its psychometric properties

Fetal Stress, Inflammatory Marker and Childhood Asthma

Background: Asthma research has focused on postnatal exposures, but there is recent evidence to indicate immune responses might be initiated in fetal period. Systemic Inflammatory processes during pregnancy might affect fetal lung development that could increase propensity in the child to develop lung diseases.Objective: To identify the association of C-reactive protein (CRP) levels in Pregnant (with stress in second trimester), newborn blood samples (cord blood) with childhood wheezing.Methods: Serum CRP concentrations (Turbidimetric method) were measured in maternal blood on the 13-17 weeks of gestation in 32 pregnant women and in the newborn  cord blood after delivery. During1 year the frequency of wheezing diseases evaluated by the International Study on Asthma and Allergy in Childhood (ISAAC). Results: Maternal C-reactive protein was associated with the wheezing and lower respiratory tract infections r=.413*; - p=0.019. Compared to children with cord blood C-reactive protein high level had increased risks of wheezing, r=572;  p=0.001Conclusion: Our results suggest that elevated maternal and Cord blood CRP levels are associated with wheezing and lower respiratory tract infections in the first  years and predictive  asthma young in life

National plans and awareness campaigns as priorities for achieving global brain health

Neurological conditions are the leading cause of death and disability combined. This public health crisis has become a global priority with the introduction of WHO's Intersectoral Global Action Plan on Epilepsy and Other Neurological Disorders 2022–2031 (IGAP). 18 months after this plan was adopted, global neurology stakeholders, including representatives of the OneNeurology Partnership (a consortium uniting global neurology organisations), take stock and advocate for urgent acceleration of IGAP implementation. Drawing on lessons from relevant global health contexts, this Health Policy identifies two priority IGAP targets to expedite national delivery of the entire 10-year plan: namely, to update national policies and plans, and to create awareness campaigns and advocacy programmes for neurological conditions and brain health. To ensure rapid attainment of the identified priority targets, six strategic drivers are proposed: universal community awareness, integrated neurology approaches, intersectoral governance, regionally coordinated IGAP domestication, lived experience-informed policy making, and neurological mainstreaming (advocating to embed brain health into broader policy agendas). Contextualised with globally emerging IGAP-directed efforts and key considerations for intersectoral policy design, this novel framework provides actionable recommendations for policy makers and IGAP implementation partners. Timely, synergistic pursuit of the six drivers might aid WHO member states in cultivating public awareness and policy structures required for successful intersectoral roll-out of IGAP by 2031, paving the way towards brain health for all.</p