New born macrosomia in gestational diabetes mellitus.

Gestational diabetes mellitus (GDM) is a metabolic complication of pregnancy. The pathogenesis of GDM is considered to involve ß-cell dysfunction and insulin resistance (IR). GDM is associated with a significant risk of macrosomia in addition to a high probability of metabolic complications for the offspring. The precise mechanism underlying GDM remains unclear. The aim of the present study was to analyse the factors associated with insulin resistance and ß-cell dysfunction involved in the pathophysiology of GDM complicated with macrosomia compared with GDM without macrosomia. In addition, another aim of the present study was to assess the relationship between GDM complicated with macrosomia and anthropometric, clinical and paraclinical parameters. The following group of patients were recruited as part of a case-control study: Patients with GDM without macrosomia, patients with GDM complicated with macrosomia and healthy gestational controls. Blood samples were collected at the third trimester of pregnancy and tested for adiponectin, leptin, insulin, proinsulin and C-peptide. Homeostatic model assessment-IR (HOMA-IR), steady state ß-cell function (HOMA%B), insulin sensitivity (HOMA%S) and body mass index (BMI) were also calculated. All patients diagnosed with GDM showed an impairment in HOMA%B and a decrease in C-peptide maternal serum concentration. Additionally, diabetic status leading to the birth of offspring with macrosomia did not induce changes in the maternal serum levels of insulin, proinsulin, adiponectin or leptin, which was also the case in patients with GDM but not macrosomia. HOMA%B presented a stronger positive correlation with pre-pregnancy BMI and maternal weight gain, and a stronger negative correlation with adiponectin. Furthermore, HOMA%S in this group exhibited strong positive correlations with maternal serum levels of high-density lipoprotein cholesterol (HDL) and aspartate aminotransferase, and a strong negative correlation with pre-pregnancy BMI. In the same patients, HOMA-IR was also found to have a high negative correlation with HDL levels, and highly positive correlations with gestational age and triglyceride levels. In conclusion, the present study suggests that the different correlations among the factors involved in the pathogenesis of GDM may explain the evolution of GDM pregnancy to macrosomia.

Bcl-2 and p53 immunophenotypes in colorectal adenocarcinoma in type 2 diabetes mellitus versus non-diabetic patients.

We aimed to investigate immunohistochemical expression of the p53 tumor suppressor protein, and the B-cell lymphoma-2 (Bcl-2) apoptotic protein in colorectal adenocarcinoma patients with or without type 2 diabetes mellitus (T2DM). Tissue sections from 95 paraffin-embedded colorectal adenocarcinomas, originating from 52 T2DM and 43 non-diabetic patients, were immunostained for p53 [Ventana mouse monoclonal primary antibody (mAb) in vitro diagnostic (IVD) anti-p53, clone Bp53-11] and Bcl-2 (Ventana mAb IVD anti-Bcl-2, clone Bcl-2/124). Immunohistochemistry analysis did not find statistically significant differences between the two groups, but analysis on subgroups of patients in terms of presence or absence of obesity identified overexpression of p53 (>70% of cells) in the T2DM obese patients compared to non-diabetics. Overexpression of p53 was present in 80% of tumor cells coming from T2DM obese patients compared to 37.2% of tumor cells coming from non-diabetics obese and non-obese, and in 36.6% of tumor cells coming from non-diabetic non-obese patients (p=0.024). There was a single non-diabetic obese patient with p53 overexpression. Most cancer cells of T2DM obese patients presented more frequently p53 overexpression by comparison with cancer cells of the T2DM non-obese patients (80% vs 40.5%, p=0.028). Bcl-2/p53 co-expression was an infrequent event in T2DM patients' group. The results of this study suggest that patients with colorectal adenocarcinoma that associate T2DM and obesity exhibit higher p53 protein expression in malignant cells. In conclusion, our research highlights that obesity is a potential key factor in the relationship between T2DM and colorectal cancer.

Weight loss programmes using low carbohydrate diets to control the cardiovascular risk in adolescents (Review).

Cardiovascular risk (CVR) is a broad term that includes traditional factors like hypertension, hyper lipidemia, abdominal obesity, hyperinsulinemia or overt type 2 diabetes mellitus (T2DM), and emerging ones such as hypothyroidism or inflammatory diseases. In epidemiologic studies, all of these factors are associated with atherogenesis and have complex interactions between them. They have in common an increased prevalence in the general population beginning in childhood, and are correlated with endothelial damage as demonstrated by echocardiographic modifications of the left ventricle or carotid intima-media thickness. Adolescence is a transition period where behavioural eating patterns develop and have a major impact on cardiovascular risk. To address these patterns, weight-loss programmes under medical supervision for overweight and obese adolescents are developed. It was observed that those who control the quality and quantity of their carbohydrates, by consuming more fruits and vegetables, associated with increased physical activity reduce their CVR. Some limited studies have shown that low carbohydrate diet (LCD) is safe and effective, but one should take into consideration the limited duration and the structure of the LCD. If there is a proper adherence to this type of nutritional intervention, it results in weight loss, improvement in insulin resistance, lipid profile and subclinical hypothyroidism reversal. We reviewed the literature starting from 2009 by searching all the observational, randomised clinical trials and meta-analyses on MEDLINE and SCOPUS databases regarding obesity and related metabolic diseases (dyslipidemia, type 2 diabetes, hypertension, hypothyroidism, LCD) in adolescents and synthesized the nutritional interventions for this population that could decrease CVR.

Evolution of Inflammatory and Oxidative Stress Markers in Romanian Obese Male Patients with Type 2 Diabetes Mellitus after Laparoscopic Sleeve Gastrectomy: One Year Follow-Up.

Geography is one of the key drivers of the significant variation in the etiopathogenic profile and prevalence of type 2 diabetes mellitus (T2DM) and obesity, therefore geographically based data are fundamental for implementing the appropriate interventions. Presently, the selection criteria of T2DM and obesity patients for laparoscopic sleeve gastrectomy (LSG) have not reached a worldwide consensus-highlighting the need for sharing experts' guidance in the preoperative evaluation, choice of the interventional procedure, perioperative management and patient long-term care. The aim of the current study was to evaluate the impact of LSG on T2DM (T2DM) remission in Romanian obese male patients, based on a multiparametric, prospective investigation. We have conducted a randomized controlled study on 41 obese male participants with the body mass index (BMI) ≥ 30 kg/m2, aged 30-65 years, which were randomly divided in two study groups: one receiving conventional treatment and the second undergoing LSG. The clinical and anthropometrical parameters, resting metabolic rate, general biochemical status, adipocytes profile, gastrointestinal hormones levels, proinflammatory, oxidant and antioxidant profiles were determined at three time points: V1 (baseline), V2 (after six months) and V3 (after 12 months). Glycated hemoglobin (HbA1c), blood glucose levels, BMI, weight, visceral fat level, HDL-cholesterol, incretin hormones, proinflammatory and the oxidative stress status were significantly improved in the LSG versus conventional treatment group. This is the first study reporting on the evaluation of metabolic surgery impact on Romanian obese male patients with T2DM. Our results confirm that LSG could contribute to T2DM remission in patients with diabesity, but this beneficial effect seems to be critically influenced by the duration of T2DM rather than by the obesity status. Our results show that, in addition to the parameters included in the prediction algorithm, the proinsulin levels, proinsulin/insulin ratio and the visceral fat percentage could bring added value to the assessment of metabolic status.

Spectral forecast: A general purpose prediction model as an alternative to classical neural networks.

Here, we describe a general-purpose prediction model. Our approach requires three matrices of equal size and uses two equations to determine the behavior against two possible outcomes. We use an example based on photon-pixel coupling data to show that in humans, this solution can indicate the predisposition to disease. An implementation of this model is made available in the supplementary material.

Photon-pixel coupling: A method for parallel acquisition of electrical signals in scientific investigations.

Here we describe a novel prototype method for parallel sampling of electrical signals from 200 sensors. The amplified signal from each sensor was remotely converted into a luminous signal on a LED matrix. A digital camera supported by a duralumin skeleton, was installed at 15 cm above an LED matrix inside an opaque box. Images were sampled at discrete time intervals of 5 s. A total of 25,920 images of the LED matrix have been recorded. Thus, 5.2 million measurements have been recorded as light intensities from the LED matrix. Light intensities of individual LEDs from the images were converted into 1 pixel value/LED. Each pixel value was then converted into percentages for evaluation. We used this methodology to measure the temporal variation of the electrical current on the skin of the torso on human volunteers, to assess the presence of a correlation between the electrical activity and diabetes (Ionescu-Tirgoviste et al., 2018). This method also allowed us to compile the first high resolution map of the electrical activity generated by the human skin (Ionescu-Tirgoviste et al., 2018). •A novel method for a parallel acquisition of electrical signals which can be applied in any related field.•It provides the ability to retrieve a large number of electrical channels simultaneously.•It provides for an inexpensive and reliable way to digitize hundreds to thousands of channels at video rate frequencies.

Trends and cyclical variation in the incidence of childhood type 1 diabetes in 26 European centres in the 25 year period 1989-2013: a multicentre prospective registration study.

AIMS/HYPOTHESIS: Against a background of a near-universally increasing incidence of childhood type 1 diabetes, recent reports from some countries suggest a slowing in this increase. Occasional reports also describe cyclical variations in incidence, with periodicities of between 4 and 6 years. METHODS: Age/sex-standardised incidence rates for the 0- to 14-year-old age group are reported for 26 European centres (representing 22 countries) that have registered newly diagnosed individuals in geographically defined regions for up to 25 years during the period 1989-2013. Poisson regression was used to estimate rates of increase and test for cyclical patterns. Joinpoint regression software was used to fit segmented log-linear relationships to incidence trends. RESULTS: Significant increases in incidence were noted in all but two small centres, with a maximum rate of increase of 6.6% per annum in a Polish centre. Several centres in high-incidence countries showed reducing rates of increase in more recent years. Despite this, a pooled analysis across all centres revealed a 3.4% (95% CI 2.8%, 3.9%) per annum increase in incidence rate, although there was some suggestion of a reduced rate of increase in the 2004-2008 period. Rates of increase were similar in boys and girls in the 0- to 4-year-old age group (3.7% and 3.7% per annum, respectively) and in the 5- to 9-year-old age group (3.4% and 3.7% per annum, respectively), but were higher in boys than girls in the 10- to 14-year-old age group (3.3% and 2.6% per annum, respectively). Significant 4 year periodicity was detected in four centres, with three centres showing that the most recent peak in fitted rates occurred in 2012. CONCLUSIONS/INTERPRETATION: Despite reductions in the rate of increase in some high-risk countries, the pooled estimate across centres continues to show a 3.4% increase per annum in incidence rate, suggesting a doubling in incidence rate within approximately 20 years in Europe. Although four centres showed support for a cyclical pattern of incidence with a 4 year periodicity, no plausible explanation for this can be given.

Rates and Causes of Death among Adult Diabetes Patients in Romania.

Aims: To study the age and sex-dependent mortality rates and causes of death in a large Romanian diabetes cohort as compared with the general population. Methods: All adult patients aged 20-64 years, receiving a free diabetes prescription in a major urban area during 2001-2008 were included and followed-up for death until December 31, 2011. Crude mortality rates and standardized mortality rate ratios (SMR) against general population (data from the National Institute of Statistics) were calculated. Years lost due to diabetes were computed assuming the general population mortality rates for ages below 20 and above 64 years. Results: During the 11 years study period, 49,328 diabetes patients (mean age at baseline 53.0 ± 8.8 years) contributed 297,370 person-years and 5,053 deaths. All cause mortality rates (per 1000 person years) increased with age and was 3.4 in 20-24 years age group and 25.7 in 60-64 year age group, while the corresponding SMR decreased from 6.0 to 1.5. Diabetes patients aged 20-24 years had a life expectancy of 48.6 years, which was 6.6 years less compared with the corresponding general population (55.2 years). The gap was 7.0 years in women and 5.8 years in men. Diabetes patients aged 20-24 years lost 196 minutes of life daily due to diabetes in women and 182 minutes in men. Conclusions: Mortality rates increased, while mortality rate ratios against general population decreased with age. Men had higher mortality rates, but women had higher mortality rate ratios in the gender analysis.

Maps of electrical activity in diabetic patients and normal individuals.

Here, data related to the electrical activity of the human skin are presented in detail. The 3D electrical activity maps in normal and diabetic individuals are shown and described using raw data obtained with Photon-Pixel coupling. Average electrical activity matrices are shown by subject, gender and group. Distributions of the electrical activity data are shown in connection with the ventral and dorsal side of the human torso. For a better understanding of the electrical activity data, critical parameters of the individuals that participated in the study are also presented.

The electrical activity map of the human skin indicates strong differences between normal and diabetic individuals: A gateway to onset prevention.

The human skin is not only the largest organ, but also the most important candidate for novel non-invasive methods of investigation. Here we describe a large-scale prototype for determining the real-time distribution of the electrical activity from the surface of the human skin. A collection of 200 sensors have been placed across the entire trunk surface. The output of each sensor was remotely inserted into a 20 × 10 LED matrix for a parallel capture of the signals. Continuous observations of the electrical activity pattern were made above the LED matrix by a digital camera in an obscure environment. A total of 5.2 million measurements (25,920 maps) have been recorded as light intensities from the LED matrix and converted into percentages for evaluation. A total of 36 individuals were divided equally into two groups and subjected to a short glucose tolerance test for 1 h; one group with established Type 2 Diabetes (T2D) and the other group without diabetes. The electrical activity pattern and the average signal intensity of normal individuals (37% ±â€¯8.1) and diabetic individuals (58% ±â€¯7.8), showed a significant difference of 21%. The average signal intensity on the ventral side (VS) and dorsal side (DS) of the torso exhibited different behaviors in diabetics and non-diabetics. On average, diabetic individuals have shown an electrical activity of higher intensity on DS (DS = 60%, VS = 55%), while the normal group has shown a higher intensity on VS (DS = 36%, VS = 39%).

The Autoimmunity's Footprint in Pediatrics: Type 1 Diabetes, Coeliac Disease, Thyroiditis.

The present case report aims to describe and discuss the approach for the management of difficult endotracheal intubation in an adult with Down syndrome undergoing cataract surgery. A 26-year-old female with Down syndrome and a validated diagnosis of cataract requiring surgery was examined in order to assess the degree of difficulty of endotracheal intubation. Patients with Down syndrome have characteristic craniofacial abnormalities which require a thorough pre-operative assessment to anticipate and prepare for a difficult endotracheal intubation. Before the surgery, a series of clinical and paraclinical examinations were conducted. Although cataract surgery generally requires loco-regional anesthesia, in our case it was performed under general anesthesia. Indicators of potentially difficult intubation were macroglossia, prognathism, short neck, limited degree of head extension and obesity. The pre-operative examinations, which revealed a high degree of endotracheal intubation, allowed the anesthetist to achieve a better peri- and intra-operative management of the patient.

Markers of Oxidative Stress and Antioxidant Defense in Romanian Patients with Type 2 Diabetes Mellitus and Obesity.

Type 2 diabetes mellitus (T2DM) is strongly associated with obesity. The adipose tissue secretes bioactive adipokines leading to low grade inflammation, amplified by oxidative stress, which promotes the formation of advanced glycation end products and eventually leads to dyslipidemia and vascular complications. The aim of this study was to correlate anthropometric, biochemical and oxidative stress parameters in newly diagnosed (ND) T2DM patients and to investigate the role of oxidative stress in T2DM associated with obesity. A group of 115 ND- T2DM patients was compared to a group of 32 healthy subjects in terms of clinical, anthropometric, biochemical and oxidative stress parameters. ND-T2DM patients had significantly lower adiponectin, glutathione (GSH) and gluthatione peroxidase (GPx) and elevated insulin, proinsulin, HOMA-IR index, proinsulin/insulin (P/I) and proinsulin/adiponectin (P/A) ratio, fructosamine, and total oxidant status (TOS). The total body fat mass was positively correlated with total oxidant status (TOS). Positive correlations were found between TOS and glycated hemoglobin (HbA1c), and between TOS and glycaemia. Negative correlations were identified between: GPx and glycaemia, GPx and HbA1c, and also between GSH and fructosamine. The total antioxidant status was negatively correlated with the respiratory burst. The identified correlations suggest the existence of a complex interplay between diabetes, obesity and oxidative stress.

Nicolae Constantin Paulescu: the first explicit description of the internal secretion of the pancreas

The purpose of this article is to describe the research of Nicolae Constantin Paulescu and to emphasize his role in the discovery of insulin. METHODS: We made a thorough review of the literature and research in the Romanian Academy Archive in order to find adequate references. RESULTS: In 1912 N.C. Paulescu analysed the clinical and biochemical alterations in diabetic patients and in dogs after performing a pancreatectomy, that apart hyperglycemia and glycosuria (carbohydrate metabolism), had noted also changes in lipid and protein metabolism. In 1916 he started the experiments with a pancreas extract obtained by his original method, that was injected intravenously to the diabetic dogs. The results of his first experiments showed: "The pancreatic extract injected into a peripheral vein produce: 1) A diminution and even a temporary suppression of diabetic hyperglycemia, which may be replaced by hypoglycemia; 2) A diminution or even temporary suppression of glycosuria; 3) A diminution of blood urea; 4) A diminution of urinary urea. In other words, the intravenous injection of the pancreatic extract has as effect the disappearance of diabetic symptoms. The attenuation of the diabetic syndrome begins immediately after the injection. It reaches a maximum after 2 hours,- and it lasts for about 12 hours". He concluded as such: "This discovery,- which sheds a bright light over the pathogenesis of diabetes gives us also the key for the treatment of this syndrome". In 1921, Paulescu had published extensively his data in two outstanding French journals 8 months before the first publication of Banting and Best from February 1922. It is clear that insulin has been discovered in Europe. CONCLUSION: Paulescu thought that a new hormone - Pancreine, that he discovered is the key element in the treatment of diabetes, but his outstanding research was unfairly neglected.

Prevalence of diabetes mellitus and prediabetes in the adult Romanian population: PREDATORR study.

BACKGROUND: The PREDATORR (PREvalence of DiAbeTes mellitus, prediabetes, overweight, Obesity, dyslipidemia, hyperuricemia and chronic kidney disease in Romania) study is the first national study analyzing the prevalence of diabetes mellitus (DM) and prediabetes, and their association with cardiometabolic, sociodemographic, and lifestyle risk factors in the Romanian population aged 20-79 years. METHODS: This was an epidemiological study with a stratified, cross-sectional, cluster random sampling design. Sociodemographic, lifestyle, and anamnestic data were collected through self- and interviewer-administered questionnaires, and biochemical assays and oral glucose tolerance tests were performed. RESULTS: In all, 2728 participants from 101 clinics of general practitioners were randomly selected, with a probability proportional to population size according to the 2002 Romanian Census. The participation rate was 99.6%. Impaired glucose regulation (prediabetes, known and unknown DM) was found in 28.1% of the study population. The overall age- and sex-adjusted prevalence of DM was 11.6% (95% CI 9.6%-13.6%), of which 2.4% (95% CI 1.7%-3.1%) had unknown DM. The prevalence of DM increased with age and was higher in men than in women. The age- and sex-adjusted prevalence of prediabetes was 16.5% (95%CI 14.8%-18.2%), with the highest percentage in the 60-79 year age group and in women. Obesity, abdominal obesity, dyslipidemia, low education level, and a family history of diabetes were associated with glucose metabolism disorders. CONCLUSIONS: The PREDATORR study shows a high prevalence of impaired glucose regulation in the adult Romanian population, providing data on the prevalence of DM and prediabetes and their association with several risk factors.

Structural Properties of Gene Promoters Highlight More than Two Phenotypes of Diabetes.

Genome-wide association studies (GWAS) published in the last decade raised the number of loci associated with type 1 (T1D) and type 2 diabetes (T2D) to more than 50 for each of these diabetes phenotypes. The environmental factors seem to play an important role in the expression of these genes, acting through transcription factors that bind to promoters. Using the available databases we examined the promoters of various genes classically associated with the two main diabetes phenotypes. Our comparative analyses have revealed significant architectural differences between promoters of genes classically associated with T1D and T2D. Nevertheless, five gene promoters (about 16%) belonging to T1D and six gene promoters (over 19%) belonging to T2D have shown some intermediary structural properties, suggesting a direct relationship to either LADA (Latent Autoimmune Diabetes in Adults) phenotype or to non-autoimmune type 1 phenotype. The distribution of these promoters in at least three separate classes seems to indicate specific pathogenic pathways. The image-based patterns (DNA patterns) generated by promoters of genes associated with these three phenotypes support the clinical observation of a smooth link between specific cases of typical T1D and T2D. In addition, a global distribution of these DNA patterns suggests that promoters of genes associated with T1D appear to be evolutionary more conserved than those associated with T2D. Though, the image based patterns obtained by our method might be a new useful parameter for understanding the pathogenetic mechanism and the diabetogenic gene networks.

A 3D map of the islet routes throughout the healthy human pancreas.

Islets of Langerhans are fundamental in understanding diabetes. A healthy human pancreas from a donor has been used to asses various islet parameters and their three-dimensional distribution. Here we show that islets are spread gradually from the head up to the tail section of the pancreas in the form of contracted or dilated islet routes. We also report a particular anatomical structure, namely the cluster of islets. Our observations revealed a total of 11 islet clusters which comprise of small islets that surround large blood vessels. Additional observations in the peripancreatic adipose tissue have shown lymphoid-like nodes and blood vessels captured in a local inflammatory process. Our observations are based on regional slice maps of the pancreas, comprising of 5,423 islets. We also devised an index of sphericity which briefly indicates various islet shapes that are dominant throughout the pancreas.

Relevant infrastructural alterations in a pancreatic neuroendocrine tumor: an insulinoma case.

In this study, we focus our interest on some peculiar infrastructural abnormalities detected in an insulinoma case. Tumor pancreatic endocrine cells proliferated detrimental to exocrine counterpart, so that extensive areas of prevalent ß-tumor cells can be seen. Two phenotypes of ß-tumor cells can be identified: (1) ß-tumor cells with full euchromatic and nucleolated nuclei and (2) ß-tumor cells with heterochromatic and shrink nuclei. Because of stroma alteration, including basement membrane, cell-extracellular matrix junctions are also compromised. The mostly striking and important finding in this report for a case of insulinoma is the high fragility of plasma membrane of both two phenotypes of ß-tumor cells. Cell-cell junctions, especially desmosomal junctions are severely altered, almost missing, plasma membranes showed shedding membrane vesicles and extensive dissolutions leading to pseudo-syncytia formation. Extravasated blood cells, including inflammatory cells contribute to the dramatic and extensive destructive areas of epithelial cells as well as stroma counterpart. Moreover, also the inner cell cytomembranes exhibit abnormalities: many ß-tumor cells have excessive dilatations of nuclear envelope and endoplasmic reticulum. All above severe infrastructural abnormalities, especially down regulation of cell-cell and cell-extracellular matrix adhesions and plasma membranes fragility might result in aberrant cell behavior and, consequently, much care should be taken for the postoperatory patient evolution.

Cancer specific mortality in insulin-treated type 2 diabetes patients.

AIMS: To test the hypothesis that cumulative exposure to insulin and long-acting insulin analogs might be associated with cancer mortality in diabetes patients. METHODS: All consecutive diabetes patients aged over 40 years, residing in a major urban area were screened at their first diabetes outpatient visit between 01/01/2001-12/31/2008 (n = 79869). Exclusion criteria were insulin treatment at screening, no insulin treatment until 12/31/2008, less than 6 months of glucose-lowering treatment alone before insulin initiation, insulin prescription before glargine became available, age <40/≥ 80 years at first insulin prescription, and <6 months of insulin exposure. A total 4990 subjects were followed-up for death based on death certificate, until 12/31/2011. Adjusted time-dependent competing risk regression analysis, with daily updates of treatment modalities was performed. Results are expressed for every 10,000 IU of cumulative dose or one year of cumulative time exposure to insulin. RESULTS: Mean baseline age was 62 ± 9 years, and follow-up 4.7 ± 1.9 years. Glargine cumulative dose was associated with lower cancer mortality risk (subhazard ratio, SHR: 0.94 (95%CI 0.89-0.99, p = 0.033)). Cumulative exposure limited to that attained one year prior to death revealed lower SHRs for cumulative time (0.94 (95%CI 0.89-0.99, p = 0.018)) and cumulative dose of glargine (0.92 (95%CI 0.86-0.98, p = 0.014)). Glargine cumulative time and cumulative dose were significant predictors for lower pancreatic and breast cancer mortality, but not for deaths from lung, colorectal, female genital, liver, and urinary tract cancer. No increased hazards were found for any other subtypes of insulins. CONCLUSIONS: The cumulative dose exposure to insulin glargine was associated with a lower risk of cancer mortality in general, and of breast and pancreatic cancer in particular. This effect remained even after additional "fixed" cohort or propensity score analyses.

Gene promoters show chromosome-specificity and reveal chromosome territories in humans.

BACKGROUND: Gene promoters have guided evolution processes for millions of years. It seems that they were the main engine responsible for the integration of different mutations favorable for the environmental conditions. In cooperation with different transcription factors and other biochemical components, these regulatory regions dictate the synthesis frequency of RNA molecules. Predominantly in the last decade, it has become clear that nuclear organization impacts upon gene regulation. To fully understand the connections between Homo sapiens chromosomes and their gene promoters, we analyzed 1200 promoter sequences using our Kappa Index of Coincidence method. RESULTS: In order to measure the structural similarity of gene promoters, we used two-dimensional image-based patterns obtained through Kappa Index of Coincidence (Kappa IC) and (C+G)% values. The center of weight of each promoter pattern indicated a structure similarity between promoters of each chromosome. Furthermore, the proximity of chromosomes seems to be in accordance to the structural similarity of their gene promoters. The arrangement of chromosomes according to Kappa IC values of promoters, shows a striking symmetry between the chromosome length and the structure of promoters located on them. High Kappa IC and (C+G)% values of gene promoters were also directly associated with the most frequent genetic diseases. Taking into consideration these observations, a general hypothesis for the evolutionary dynamics of the genome has been proposed. In this hypothesis, heterochromatin and euchromatin domains exchange DNA sequences according to a difference in the rate of Slipped Strand Mispairing and point mutations. CONCLUSIONS: In this paper we showed that gene promoters appear to be specific to each chromosome. Furthermore, the proximity between chromosomes seems to be in accordance to the structural similarity of their gene promoters. Our findings are based on comprehensive data from Transcriptional Regulatory Element Database and a new computer model whose core is using Kappa index of coincidence.

Eukaryotic genomes may exhibit up to 10 generic classes of gene promoters.

BACKGROUND: The main function of gene promoters appears to be the integration of different gene products in their biological pathways in order to maintain homeostasis. Generally, promoters have been classified in two major classes, namely TATA and CpG. Nevertheless, many genes using the same combinatorial formation of transcription factors have different gene expression patterns. Accordingly, we tried to ask ourselves some fundamental questions: Why certain genes have an overall predisposition for higher gene expression levels than others? What causes such a predisposition? Is there a structural relationship of these sequences in different tissues? Is there a strong phylogenetic relationship between promoters of closely related species? RESULTS: In order to gain valuable insights into different promoter regions, we obtained a series of image-based patterns which allowed us to identify 10 generic classes of promoters. A comprehensive analysis was undertaken for promoter sequences from Arabidopsis thaliana, Drosophila melanogaster, Homo sapiens and Oryza sativa, and a more extensive analysis of tissue-specific promoters in humans. We observed a clear preference for these species to use certain classes of promoters for specific biological processes. Moreover, in humans, we found that different tissues use distinct classes of promoters, reflecting an emerging promoter network. Depending on the tissue type, comparisons made between these classes of promoters reveal a complementarity between their patterns whereas some other classes of promoters have been observed to occur in competition. Furthermore, we also noticed the existence of some transitional states between these classes of promoters that may explain certain evolutionary mechanisms, which suggest a possible predisposition for specific levels of gene expression and perhaps for a different number of factors responsible for triggering gene expression. Our conclusions are based on comprehensive data from three different databases and a new computer model whose core is using Kappa index of coincidence. CONCLUSIONS: To fully understand the connections between gene promoters and gene expression, we analyzed thousands of promoter sequences using our Kappa Index of Coincidence method and a specialized Optical Character Recognition (OCR) neural network. Under our criteria, 10 classes of promoters were detected. In addition, the existence of "transitional" promoters suggests that there is an evolutionary weighted continuum between classes, depending perhaps upon changes in their gene products.