Inhibition of 7α,26-dihydroxycholesterol biosynthesis promotes midbrain dopaminergic neuron development.

Dysregulated cholesterol metabolism has been linked to neurodegeneration. We previously found that free, non-esterified, 7α,(25R)26-dihydroxycholesterol (7α,26-diHC), was significantly elevated in the cerebrospinal fluid of patients with Parkinson's disease (PD). In this study we investigated the role of 7α,26-diHC in midbrain dopamine (mDA) neuron development and survival. We report that 7α,26-diHC induces apoptosis and reduces the number of mDA neurons in hESC-derived cultures and in mouse progenitor cultures. Voriconazole, an oxysterol 7α-hydroxylase (CYP7B1) inhibitor, increases the number of mDA neurons and prevents the loss of mDA neurons induced by 7α,26-diHC. These effects are specific since neither 7α,26-diHC nor voriconazole alter the number of Islet1+ oculomotor neurons. Furthermore, our results suggest that elevated 24(S),25-epoxycholesterol, which has been shown to promote mDA neurogenesis, may be partially responsible for the effect of voriconazole on mDA neurons. These findings suggest that voriconazole, and/or other azole CYP7B1 inhibitors may have implications in PD therapy development.

A Greek physician's portrait in Windsor Castle.

To the visitor to Windsor Castle, the Thomas Lawrence portraits in the Waterloo Chamber represent the most important contributors to the military defeat of Napoleon Bonaparte, by British, Prussian, Russian and Austrian forces at the Battle of Waterloo. Nevertheless, only few individuals realise that a Greek physician, Count Ioannis Capodistrias, a native of the island of Corfu, stands among these leading personalities as a diplomat, the Russian Minister of Foreign Affairs, who contributed remarkably to European unity in the early nineteenth century and as a statesman ('Governor' of Greece) with a tragic end to his life, after establishing a Greek State practically from ruins.

Seasonal variation of type 1 diabetes mellitus diagnosis in Greek children.

OBJECTIVE: The aim of the study was to investigate the seasonal variation of type 1 diabetes mellitus (T1DM) diagnosis in Greek children. DESIGN: The study group consisted of 1148 patients (604 males and 544 females) who were diagnosed with T1DM during the period 1978-2008. The mean age at diagnosis was 8.32 ± 5.01 years. The date of birth and the date at diagnosis were recorded from the patients' files. RESULTS: Significantly more children were diagnosed with T1DM during the cold months as opposed to the warm months (p=0.001), with no differences between boys and girls. When children were categorized into the age groups ≤ 3 and >3 years old the seasonal variation pattern was different in younger ages suggesting that environmental factors which possibly interfere with T1DM diagnosis may have a different effect in those of younger than older age. With regard to date of birth, significantly more children with diabetes were born during the Spring-Summer than in Autumn-Winter (p=0.004). CONCLUSIONS: The results of the study support the concept of seasonality in T1DM diagnosis, implying a possible relationship between clinical expression of T1DM and various climatic factors. Seasonal variation at diagnosis appears to be different in younger compared to older children.

Oligomenorrhoea in adolescents with type 1 diabetes mellitus: relationship to glycaemic control.

OBJECTIVE: To investigate oligomenorrhoea in adolescents with type 1 diabetes and the possible relationship with glycaemic control. STUDY DESIGN: The study group consisted of 81 female adolescents with type 1 diabetes whose mean age was 15.0 years (range 12-18). The control group consisted of 205 healthy adolescents with a mean age of 15.5 years (range 12-18). Data on menstruation were collected by two parallel self-administered questionnaires. Oligomenorrhoea was defined as having a menstrual cycle longer than 36 days throughout the past year (5-6/year). The metabolic control of diabetes was evaluated by calculating the mean value of HbA1c during the past year. RESULTS: Age of menarche was greater for adolescents with type 1 diabetes (12.2 ± 1.4 vs. 11.7 ± 1.2, p < 0.000) compared to healthy age-matched controls. Logistic regression analysis with oligomenorrhoea as the dependent binary variable revealed an odds ratio equal to 7.8 (95% CI 3.411-17.853) for adolescents with type 1 diabetes (p < 0.000). Finally, a second logistic regression analysis, concerning only adolescents with type 1 diabetes and with the same binary variable, estimated an odds ratio of 4.8 (95% CI 1.784-13.057, p < 0.002) for HbA1c, and an odds ratio of 5.3 (95% CI 1.821-15.130, p < 0.002) for the frequency of hypoglycaemia. CONCLUSION: In adolescents with type 1 diabetes, menarche occurs later and oligomenorrhoea is more frequent. The relative risk of having oligomenorrhoea is greater when there is an increased value of HbA1c or when hypoglycaemia is more frequent.

SMARTDIAB: a communication and information technology approach for the intelligent monitoring, management and follow-up of type 1 diabetes patients.

SMARTDIAB is a platform designed to support the monitoring, management, and treatment of patients with type 1 diabetes mellitus (T1DM), by combining state-of-the-art approaches in the fields of database (DB) technologies, communications, simulation algorithms, and data mining. SMARTDIAB consists mainly of two units: 1) the patient unit (PU); and 2) the patient management unit (PMU), which communicate with each other for data exchange. The PMU can be accessed by the PU through the internet using devices, such as PCs/laptops with direct internet access or mobile phones via a Wi-Fi/General Packet Radio Service access network. The PU consists of an insulin pump for subcutaneous insulin infusion to the patient and a continuous glucose measurement system. The aforementioned devices running a user-friendly application gather patient's related information and transmit it to the PMU. The PMU consists of a diabetes data management system (DDMS), a decision support system (DSS) that provides risk assessment for long-term diabetes complications, and an insulin infusion advisory system (IIAS), which reside on a Web server. The DDMS can be accessed from both medical personnel and patients, with appropriate security access rights and front-end interfaces. The DDMS, apart from being used for data storage/retrieval, provides also advanced tools for the intelligent processing of the patient's data, supporting the physician in decision making, regarding the patient's treatment. The IIAS is used to close the loop between the insulin pump and the continuous glucose monitoring system, by providing the pump with the appropriate insulin infusion rate in order to keep the patient's glucose levels within predefined limits. The pilot version of the SMARTDIAB has already been implemented, while the platform's evaluation in clinical environment is being in progress.

An insulin infusion advisory system for type 1 diabetes patients based on non-linear model predictive control methods.

In this paper, an Insulin Infusion Advisory System (IIAS) for Type 1 diabetes patients, which use insulin pumps for the Continuous Subcutaneous Insulin Infusion (CSII) is presented. The purpose of the system is to estimate the appropriate insulin infusion rates. The system is based on a Non-Linear Model Predictive Controller (NMPC) which uses a hybrid model. The model comprises a Compartmental Model (CM), which simulates the absorption of the glucose to the blood due to meal intakes, and a Neural Network (NN), which simulates the glucose-insulin kinetics. The NN is a Recurrent NN (RNN) trained with the Real Time Recurrent Learning (RTRL) algorithm. The output of the model consists of short term glucose predictions and provides input to the NMPC, in order for the latter to estimate the optimum insulin infusion rates. For the development and the evaluation of the IIAS, data generated from a Mathematical Model (MM) of a Type 1 diabetes patient have been used. The proposed control strategy is evaluated at multiple meal disturbances, various noise levels and additional time delays. The results indicate that the implemented IIAS is capable of handling multiple meals, which correspond to realistic meal profiles, large noise levels and time delays.

A communication and information technology infrastructure for real time monitoring and management of type 1 diabetes patients.

This paper is focused on the integration of state-of-the-art technologies in the fields of telecommunications, simulation algorithms, and data mining in order to develop a Type 1 diabetes patient's semi to fully-automated monitoring and management system. The main components of the system are a glucose measurement device, an insulin delivery system (insulin injection or insulin pumps), a mobile phone for the GPRS network, and a PDA or laptop for the Internet. In the medical environment, appropriate infrastructure for storage, analysis and visualizing of patients' data has been implemented to facilitate treatment design by health care experts.

VEGF isoforms and receptors expression throughout acute acetaminophen-induced liver injury and regeneration.

Acetaminophen (APAP) is a widely-used analgesic and a known hepatotoxic agent. Vascular endothelial growth factor (VEGF) is a growth factor with multiple functional roles. VEGF plays an important role in angiogenesis and hepatic regeneration. The aim of this study was to determine the expression of VEGF isoforms and its receptors throughout liver regeneration after the administration of a toxic dose of APAP in rats. Ten groups of adult male rats received a dose of 3.5 g/kg b.w. of APAP per os. The rats were killed post administration at 0-288 h. Blood and liver tissue were extracted. Determination of serum transaminases and alkaline phosphatase activities was performed. Liver injury and regeneration were assessed with hematoxylin-eosin specimens, morphometric analysis, hepatic thymidine kinase assay and Ki-67 expression. Reverse transcription-polymerase chain reaction and immunohistochemical methods were used for assessment of VEGF isoforms and receptors differential expression. High activities of aspartate aminotransferase were observed at 24 and 36 h with another peak of activity at 192 h post administration. Alanine aminotransferase was highest at 36 h. Alkaline phosphatase was increased post 24 h being higher at 72,192 and 240 h. Centrilobular necrosis was observed at 48-72 h and thorough restoration of the liver microarchitecture was observed at 288 h. Liver regeneration lasted from 24-192 h according to the results from thymidine kinase activity and Ki-67 expression. VEGF and VEGF receptor-2 m-RNA levels presented with a three-peak pattern of expression at 12-24, 72-96 and 192-240 h post administration. Significant difference was noted between periportal and centrilobular immunohistochemical expression. VEGF proves to play a critical role during APAP-induced liver regeneration as it presents with three points of higher expression. The first two time points are associated with the initial inflammatory reaction to the noxious stimulus and the hepatocyte regenerative process where as the third one is indicative of the potential involvement of VEGF in processes of remodeling.

Neural network based glucose - insulin metabolism models for children with Type 1 diabetes.

In this paper two models for the simulation of glucose-insulin metabolism of children with Type 1 diabetes are presented. The models are based on the combined use of Compartmental Models (CMs) and artificial Neural Networks (NNs). Data from children with Type 1 diabetes, stored in a database, have been used as input to the models. The data are taken from four children with Type 1 diabetes and contain information about glucose levels taken from continuous glucose monitoring system, insulin intake and food intake, along with corresponding time. The influences of taken insulin on plasma insulin concentration, as well as the effect of food intake on glucose input into the blood from the gut, are estimated from the CMs. The outputs of CMs, along with previous glucose measurements, are fed to a NN, which provides short-term prediction of glucose values. For comparative reasons two different NN architectures have been tested: a Feed-Forward NN (FFNN) trained with the back-propagation algorithm with adaptive learning rate and momentum, and a Recurrent NN (RNN), trained with the Real Time Recurrent Learning (RTRL) algorithm. The results indicate that the best prediction performance can be achieved by the use of RNN.

Genetics of type 1 diabetes mellitus.

Type 1 Diabetes Mellitus is a complex and polygenic disease due to gene-environment interactions. The role of genetic background of diabetes has been extensively investigated. However, final conclusions have not yet been reached. Family and twin studies have shown that genetic factors are important contributors to the genetic risk of the disease. Although more than 18 diabetes-predisposing genes have been reported to date, only the major histocompatibility complex (HLA) region on chromosome 6p21 (IDDM1) and the insulin gene on chromosome 11p15 (IDDM 2) have been conclusively associated with susceptibility to type 1 diabetes. However, it has been shown recently that cytotoxic lymphocyte antigen 4 (CTLA4) on chromosome 2q33 (IDDM12) and LYP/PTPN22 on chromosome 1p13 also contribute to the genetic risk of T1DM. The article reviews the recent advances in this field. By identifying new loci or reanalyzing the known ones and with the help of more powerful studies, it is possible in the future to be able to shed more light on the complex field of the genetics of type 1 diabetes and to further understand the pathophysiology of the disease, which will allow us eventually to treat or prevent it.

HLA alleles and type 1 diabetes mellitus in low disease incidence populations of Southern Europe: a comparison of Greeks and Albanians.

Type 1 diabetes mellitus (DM1) is caused by environmental factors acting on genetically susceptible individuals. HLA-DQA1 and -DQB1 are major genetic determinants of the disease. Greece and Albania represent the low DM1 incidence countries of South-Eastern Europe. The HLA-DQA1 and -DQB1 associations with DM1 were investigated in these two groups, as reference for comparisons to the high-risk populations of Northern Europe. One hundred and thirty Greeks and 64 Albanians with DM1 were studied; 1,842 Greeks and 186 Albanians were analysed as controls. The samples were typed for six HLA-DQB1 alleles, using time-resolved fluorometry to detect the hybridisation of lanthanide labelled oligonucleotides with PCR products. Individuals positive for DQB1*0201 were selectively typed for three DQA1 alleles. In both populations DQB1*0201 increased the risk for DM1 while DQB1*0301 was protective. DQB1*0302 was associated with lower risk than *0201, while *0602 and *0603 were protective in Greeks but not in Albanians. It was also shown that DQA1 has a modifying effect, altering the risk conferred by the susceptible DQB1*0201. The low incidence of DM1 in these two countries correlates with the high frequency of the protective allele DQB1*0301 and the low impact of the susceptible DQB1*0302.

Estimation of genetic risk for type 1 diabetes.

The most important gene loci defining risk of type 1 diabetes mellitus (T1DM) are located within the HLA gene region. HLA-DQ molecules are of primary importance but HLA-DR gene products modify the risk conferred by HLA-DQ. The risk associated with an HLA genotype is defined by the particular combination of susceptible and protective alleles. The highest risk is associated with a combination of two different risk haplotypes (7% risk to develop T1DM in Finland) whereas protective genotypes covering 69% of population have a risk of less than 0.2%). The complicated analysis of HLA genotypes is simplified by strong linkage disequilibrium between HLA-DRB1, -DQA1 and -DQB1 loci. In many cases one can deduce the alleles of other loci based on determination of the alleles in one locus. Differences between various populations in the frequency of marker alleles and in the linkages between them has to be taken into account. We have developed PCR based typing methods that utilize blood spot samples, microtiter plate format and lanthanide labeled oligonucleotide probes to define HLA-DQ and -DR alleles relevant for T1DM risk. Typing is run stepwise so that after initial HLA-DQB1 typing only those samples will be further analyzed in which -DQA1 or -DRB1 typing is informative and expected to contribute to the risk estimation. This method has been used to screen more than 50,000 newborn infants in Finland over a time period of 6 years, and it has been able to identify most children who have developed T1D during the follow-up period. The efficiency of the procedure has also been tested in Finnish and Greek populations.

Transition of the adolescent from the children's to the adults' diabetes clinic.

The transition of adolescents with type 1 diabetes mellitus (T1DM) from pediatric to adult diabetological care is a critical phase that requires special attention. A considerable proportion of adolescents encounters certain difficulties during this transition, which can negatively affect adjustment and glycemic control. Etiological factors include: (a) the adolescent's separation anxiety elicited by the process of departing from the pediatrician who functions as a secure base in a period of developmental turmoil; (b) certain developmental factors that adversely affect glycemic control and the patient-physician cooperation; (c) the tendency of the adult diabetologist to focus more on medical than on psychosocial components; (d) the lack of the appropriate preparatory work which would: (i) help the adolescent to successfully cope with the difficulties that may arise due to the transition and (ii) make feasible the establishment of the proper pediatrician-adult diabetologist cooperation required for the development of a continuum in diabetological care through which the adolescent's special needs can be best met. Practical propositions about certain basic problem-solving components concerning the transition from the pediatric to adult diabetes clinic are briefly discussed.

Developmental aspects ofL-valine uptake by mouse intestine.

14C-L-Valine uptake by intestinal segments of mice of various ages, ranging between 20-day fetuses and adults, was studied in vitro. 1 mML-Valine was accumulated against a concentration gradient by processes which showed saturation kinetics. There appeared to be a two-fold increase ofL-valine accumulation after the 2nd postnatal day and a three-fold increase in adult mice. Fetal transport of valine only occurred at pH 7.4 but was not Na+ dependent. In contrast, valine transport became increasingly Na+ dependent and the pH optimum widened, ranging between 5-8. A series of amino acids, including representatives of the imino acid and dibasic groups, failed to inhibit valine uptake while leucine and isoleucine manifested mutual inhibition with valine. It is speculated that in the mouse intestine,L-valine is transported by at least two mechanisms, one functioning in the fetus, not requiring Na+, but pH dependent and another which developes postnatally, is Na-dependent and functions over a wide pH optimum.