Evangelos Bozas

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 patients 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 patients data, supporting the physician in decision making, regarding the patients 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 patients glucose levels within predefined limits. The pilot version of the SMARTDIAB has already been implemented, while the platforms evaluation in clinical environment is being in progress.

Virus Antibody Survey in Different European Populations Indicates Risk Association Between Coxsackievirus B1 and Type 1 Diabetes

Enteroviruses (EVs) have been connected to type 1 diabetes in various studies. The current study evaluates the association between specific EV subtypes and type 1 diabetes by measuring type-specific antibodies against the group B coxsackieviruses (CVBs), which have been linked to diabetes in previous surveys. Altogether, 249 children with newly diagnosed type 1 diabetes and 249 control children matched according to sampling time, sex, age, and country were recruited in Finland, Sweden, England, France, and Greece between 2001 and 2005 (mean age 9 years; 55% male). Antibodies against CVB1 were more frequent among diabetic children than among control children (odds ratio 1.7 [95% CI 1.0–2.9]), whereas other CVB types did not differ between the groups. CVB1-associated risk was not related to HLA genotype, age, or sex. Finnish children had a lower frequency of CVB antibodies than children in other countries. The results support previous studies that suggested an association between CVBs and type 1 diabetes, highlighting the possible role of CVB1 as a diabetogenic virus type.

Aging-related changes in IGF-II and c-fos gene expression in the rat brain

The protein products of growth factor genes such as IGF‐II and cellular oncogenes such as c‐fos are believed to be necessary for the support of normal neuronal function. Steady‐state levels of c‐fos and IGF‐II mRNA were determined in the brain of young and old rats, using Northern analysis. Both RNAs were found to be decreased in the brain of aged rats. Age‐related decrease was detected in the hippocampus, hypothalamus, striatum, cerebral cortex and cerebellum, for IGF‐II mRNA, and in the cerebral cortex and cerebellum for c‐fos mRNA. Furthermore, changes in the degree and pattern of DNA methylation were noted at both gene loci, in the aged rat brain. Our results could reflect changes at the genomic level possibly related to the process of aging and the accompanying decline in brain function.

A Randomized Controlled Trial for the Effectiveness of Progressive Muscle Relaxation and Guided Imagery as Anxiety Reducing Interventions in Breast and Prostate Cancer Patients Undergoing Chemotherapy.

Objective. To test the effectiveness of guided imagery (GI) and progressive muscle relaxation (PMR) as stress reducing interventions in patients with prostate and breast cancer who undergo chemotherapy. Methods. Patients were randomly assigned to either the control group or the intervention group (PMR and GI). Patients were observed for a total duration of 3 weeks and assessed with the SAS and BECK-II questionnaires for anxiety and depression, respectively, in addiotion to two biological markers (saliva cortisol and saliva amylase) (trial registration number: NCT01275872). Results. 256 patients were registered and 236 were randomly assigned. In total 104 were randomised to the control group and 104 to the intervention group. Interventions mean anxiety score and depression score changes were significantly different compared to the controls (b = −29.4, p < 0.001; b = −29.4, p < 0.001, resp.). Intervention groups cortisol levels before the intervention (0.30 ± 0.25) gradually decreased up to week 3 (0.16 ± 0.18), whilst the control groups cortisol levels before the intervention (0.21 ± 0.22) gradually increased up to week 3 (0.44 ± 0.35). The same interaction appears for the Amylase levels (p < 0.001). Conclusions. The findings showed that patients with prostate and breast cancer undergoing chemotherapy treatment can benefit from PMR and GI sessions to reduce their anxiety and depression.

Protooncogene c-fos Involvement in the Molecular Mechanism of Rat Brain Sexual Differentiation

Brain sexual differentiation is mediated through testosterone, which acts during the perinatal period in the form of both 5α-dihydrotestosterone and estradiol. In order to gain insight into the molecular mechanisms involved, we studied induction of c-fos, an index of functional neuronal activation, in the 2-day-old female rat brain after injection of a masculinizing dose of testosterone. Administration of testosterone resulted in induction of c-fos gene expression in the hypothalamus, as determined by Northern analysis. Following immunocytochemistry, we demonstrated an increase in the number of Fos-positive nuclei in the median and medial preoptic nucleus, the medial preoptic area extending to the lateral preoptic area, and the peri- and paraventricular area. In an effort to see whether testosterone acted as 5α-dihydrotestosterone or as estradiol, we injected either steroid and looked at fos induction. Estradiol mimicked the effect of testosterone, while 5α-dihydrotestosterone was without effect. Furthermore, injection of an estrogen receptor blocker, clomiphene, together with testosterone, abolished the testosterone-induced increase in Fos-positive nuclei, thus confirming the finding that testosterone induces c-fos by acting through estrogen receptors. Electrophoretic mobility shift assays showed that nuclear extracts from 2-day-old female hypothalamus contain a protein, most probably the estrogen receptor, which binds specifically to oligodeoxynucleotides with the sequence of either vitERE, the consensus estrogen-responsive element (ERE) found in the vittelogenin gene, or fosERE, the ERE found in the 3′-untranslated region of the mouse c-fos gene. This suggests that the effect of testosterone-derived estradiol on c-fos expression is a direct one, mediated by binding of estrogen receptors to an ERE in the c-fos gene-regulatory regions.

NMDA receptor mediated changes in IGF-II gene expression in the rat brain after injury and the possible role of nitric oxide.

This study was undertaken in order to investigate the role of insulin‐like growth factor (IGF)‐II, c‐fos, N‐methyl‐D‐aspartate (NMDA) receptors, and nNOS in the cellular processes following a penetrating brain injury. IGF‐II mRNA levels, as determined by Northern analysis, were decreased at 4, 8, and 24 h after brain injury, in the lesioned, compared to the contralateral intact hemisphere. Forty‐eight and 72 h after the injury, there was no difference between the lesioned and the contralateral intact hemisphere in IGF‐II mRNA levels. c‐fos mRNA levels followed a parallel, but opposite course: They were increased at 4, 8 and 24 h after the injury, while at 48 and 72 h c‐fos mRNA levels in the lesioned hemisphere did not differ from those in the intact. Administration of MK‐801 reversed the injury‐induced decrease in IGF‐II mRNA levels. Administration of MK‐801 resulted in an increase in IGF‐II mRNA in both the intact and the lesioned hemispheres. Brain injury resulted in an increase in nNOS immunopositive cells in the hippocampal formation, which was detectable at 4 and 12, but not 48 h after the injury. These results suggest that IGF‐II, c‐fos, NMDA receptors and nNOS are involved in the cellular responses to brain injury.

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.

Altered serum stress neuropeptide levels in critically ill individuals and associations with lymphocyte populations

OBJECTIVE Potential physiological correlates of stress and the role of stress neuropeptides, other than those of the hypothalamic-pituitary-adrenal axis, in critical illness have not been addressed. We investigated: (a) serum levels of stress neuropeptides (ACTH, substance P (SP), neuropeptide Y (NPY), cortisol, prolactin) in critically ill individuals compared to matched controls, (b) associations with lymphocyte counts, (c) associations among stress neuropeptide levels, and (d) associations with perceived intensity of stress, critical illness severity and survival. METHODS Correlational design with repeated measures. Thirty-six critically ill patients were followed up for 14 days compared to 36 healthy matched controls. Stress was assessed by the ICUESS scale. Correlations, cross-sectional comparisons and multiple regression models were pursued. RESULTS For the first time, we report lower SP (Difference of means (DM) = 2928-3286 ng/ml, p < 0.001) and NPY (DM = 0.77-0.83 ng/ml, p < 0.0001) levels in critically ill individuals compared to controls. Cortisol levels were higher (DM = 140-173 ng/ml, p<0.0001) and lymphocyte population counts (p < 0.002) were lower in patients throughout the study. NPY levels associated with lymphocyte (r = 0.411-0.664, p < 0.04), T-lymphocyte (r = 0.403-0.781, p< 0.05), T-helper (r = 0.492-0.690, p < 0.03) and T-cytotoxic cell populations (r = 0.39-0.740, p < 0.03). On day 1, cortisol levels exhibited associations with lymphocyte (r = -0.452, p = 0.01), T-cell (r = -0.446, p = 0.02), T-helper (r = -0.428, p = 0.026) and T-cytotoxic cells ( r = -0.426, p = 0.027). ACTH levels associated with NK cell counts (r = 0.326-0.441, p < 0.05). Associations among stress neuropeptides levels were observed throughout (p < 0.05). ACTH levels associated with disease severity (r = 0.340-0.387, p < 0.005). A trend for an association between ACTH levels and intensity of stress was noted (r = 0.340, p = 0.057). CONCLUSION The significantly lowered NPY and SP levels and the associations with cortisol, ACTH and lymphocytes suggest that the role of these peptides in critical illness merit further investigation. Future studies need to address associations between these neuropeptides and functional immune cell responses and inflammatory markers in critical illness.

Pilot Investigation of the Association Between Serum Stress Neuropeptide Levels and Lymphocyte Expression of Fas and Fas Ligand in Critical Illness

Introduction: In critical illness, apoptotic loss of immunocytes is associated with immunosuppression. Aim: To explore expression of Fas/Fas ligand (FasL) on B and T cells from critically ill patients without sepsis compared to matched controls and associations with disease severity and neuropeptide Y (NPY), cortisol, adrenocorticotropic hormone (ACTH), and prolactin (PRL) levels. Methods: Repeated-measures correlational design with 36 critically ill patients (14-day follow-up) and 36 controls. Disease severity was assessed using the Multiple Organ Dysfunction Score (MODS) and Multi Organ Failure scale. Fas/FasL values were standardized for viable cell counts. An enzyme-linked immunosorbent assay (NPY) and electrochemiluminescence immunoassay (cortisol, ACTH, and PRL) were employed. Results: Fas and FasL expression on T-helper (p < .0001–.03) and T-cytotoxic cells (p < .0001–.002) and Fas expression on B cells (p < .0001–.03) were higher in patients. MODS severity was associated with FasL expression on cytotoxic T cells (r = .752–.902, p = .023–.037). There was an inverse association between Day 1 NPY levels and Fas expression on T-helper cells (r = −.447, p = .019). On the day of maximum severity, we report for the first time an inverse association between NPY levels and FasL expression on helper (r = −.733, p = .016) and cytotoxic (r = −.862, p = .003) T cells. Cortisol levels were positively associated with counts of FasL-positive helper (r = .828) and cytotoxic (r = .544, p < .05) T cells. Conclusion: Results suggest a potential role for stress neuropeptides in lymphocyte survival and activation in critical illness.

Validation of Greek Versions of the Neonatal Infant Pain Scale and Premature Infant Pain Profile in Neonatal Intensive Care Unit

Background: The Neonatal Infant Pain Scale and the Premature Infant Pain Profile have been used widely in neonatal intensive care units for pain assessment. Aim: This study reports the evaluation and validation of these scales in full‐term newborns who were hospitalized in two Greek neonatal intensive care units. Evaluation and validation of the Neonatal Infant Pain Scale and the Premature Infant Pain Profile in full‐term newborns who were hospitalized in two Greek neonatal intensive care units. Materials and Methods: This is a cross‐sectional study. Two neonatal intensive care units at a large General Childrens Hospital in Greece. A total of 81 full‐term newborns. This cross‐sectional study was conducted in two neonatal intensive care units at a large General Childrens Hospital in Greece. We studied 81 full‐term newborns, who were exposed to various painful routine procedures. A single measurement was taken from each neonate. Two observers were present during each procedure and evaluated pain using both the Neonatal Infant Pain Scale and Premature Infant Pain Profile. Internal consistency coefficient Cronbachs &agr;, internal class agreement coefficient, and &kgr; factor were appropriately measured. Results: The weighting of the Neonatal Infant Pain Scale and Premature Infant Pain Profile pointed out an excellent coherence between the two scales and agreement among the researchers. The internal consistency coefficient Cronbachs &agr; was >.8 and the internal class agreement coefficient was >.98 for both scales, which indicates an excellent consistency between scales. The &kgr; factor for Neonatal Infant Pain Scale was >.73 and for the Premature Infant Pain Profile it was >.6, which indicates a significant agreement among investigators. Conclusions: The Neonatal Infant Pain Scale and Premature Infant Pain Profile were successfully adjusted in Greek standards with reliability between the scales and among the researchers. Moreover, they constitute reliable tools for the evaluation of neonatal procedural pain in full‐term newborns in Greece.