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This study aimed to provide real-world safety and effectiveness data of everolimus (EVE) plus exemestane (EXE) in estrogen receptor positive/human epidermal growth factor receptor 2 negative (ERThis prospective observational study was conducted by 19 hospital-based oncologists in Greece. Eligible patients were treated with EVE+EXE in the first-line setting; EVE was initiated according to the approved label.Overall, 75 eligible patients (mean age: 66.9 years; visceral metastases: 49.3%; bone-only metastases: 37.3%) were included in the effectiveness analyses. Over a median (interquartile range) of 12.1 months (range=4.2-20.5 months) of EVE treatment, the median progression-free survival was 18.0 months and the overall response rate was 22.7%. Among patients that received ≥1 EVE dose (n=80), the incidence of EVE-related adverse events was 72.5% (serious: 55.0%); stomatitis (22.5%), fatigue (22.5%), pneumonitis (18.8%); and cough (18.8%) were the most common.In the routine care in Greece, EVE demonstrates clinical benefit and a predictable safety profile.

Male breast cancer (MBC) is a very rare disorder affecting approximately 1 in 833 men. Genetic predisposition is one of the most important risk factors of MBC with BRCA2 being the most commonly mutated gene in males diagnosed with breast cancer. However, a large part of MBC heritability is still unexplained. This study sought to add to the data already available on the genetics of MBC.Our study initially involved comprehensive analysis of BRCA1 and BRCA2, followed by analysis of 43 genes implicated in cancer predisposition in a series of 100 Greek patients diagnosed with MBC between 1995-2015.Pathogenic variants were identified in 13 patients, with BRCA2 being the most commonly affected gene, followed by BRCA1, RAD50, RAD51B, and MSH3.In agreement with previous reports, BRCA2 is the most important genetic factor of MBC predisposition, while the remaining known cancer predisposition genes are each very rarely involved, rendering conclusions as to their cumulative effect difficult to draw.

This study quantifies the change in traffic flow on the M25 motorway in the UK due to the COVID-19 outbreak. Moreover, the impact of the change in traffic flow on non-exhaust PM

The management of acute gout in the hospital setting may be challenging since most patients are elderly with multiple unstable comorbidities. However, there are no prospective clinical trials for hospitalized patients with gout to guide optimal management. Evidence indicates that steroids or adrenocorticotropic hormone (ACTH) may be effective and safe therapeutic options for these patients. This study aimed at directly comparing the efficacy and safety of ACTH vs betamethasone for the treatment of gout in hospitalized patients. This is the first prospective clinical trial for hospitalized patients with gout. We designed a randomized, open label study to assess the efficacy and safety of a single intramuscular injection of either ACTH or betamethasone in hospitalized patients with acute gout. Primary efficacy endpoints were the change in intensity of pain as recorded using a Visual Analogue Scale (VAS) at baseline compared to 24 h (ΔVAS24h), and 48 h. Moreover, we assessed safety and effects on the hypothalamic-pituitary-adrenal (HPA) axis, glucose and lipid homeostasis, bone metabolism, electrolytes and renal function. 38 patients were recruited. Both treatments were highly effective. The mean ± SE ΔVAS24h and ΔVAS48h for ACTH was 4.48 ± 0.29 and 5.58 ± 0.26, respectively. The mean ± SE ΔVAS24h and ΔVAS48h for betamethasone was 4.67 ± 0.32 and 5.67 ± 0.28, respectively. Direct comparison between the two groups at 24 h and 48 h did not show statistically significant differences. Both treatments were well tolerated and safe. The effects on all metabolic parameters were mostly minimal and transient for both treatments. However, ACTH may affect less the HPA axis and bone metabolism compared to betamethasone, thus leading to the conclusion that. ACTH and betamethasone are effective and safe for the management of acute gout in hospitalized patients but that ACTH may associate with less disturbance of the HPA axis and bone metabolism. Our data support the use of both drugs as first line treatments for hospitalized patients with gout.Clinical trial registration: ClinicalTrials.gov NCT04306653.

Lung and airway neutrophils are a hallmark of severe disease in infants with respiratory syncytial virus (RSV)-induced lower respiratory tract infections. Despite their abundance in the lungs during RSV infection of both mice and man, the role of neutrophils in viral control and in immune pathology is not clear. Here, antibody mediated neutrophil depletion was used to investigate the degree to which neutrophils impact the lung immune environment, the control of viral replication and the peak severity of disease after RSV infection of mice. Neutrophil depletion did not substantially affect the levels of inflammatory mediators such as type I interferons, IL-6, TNF-α or IL-1β in response to RSV. In addition, the lack of neutrophils did not change the viral load during RSV infection. Neither neutrophil depletion nor the enhancement of lung neutrophils by administration of the chemoattractant CXCL1 during RSV infection affected disease severity as measured by weight loss. Therefore, in this model of RSV infection, lung neutrophils do not offer obvious benefits to the host in terms of increasing anti-viral inflammatory responses or restricting viral replication and neutrophils do not contribute to disease severity.

The lymphatic system has been proposed to play a crucial role in preventing the development and progression of osteoarthritis (OA). As OA develops and progresses, inflammatory cytokines and degradation by-products of joint tissues build up in the synovial fluid (SF) providing a feedback system to exacerbate disease. The lymphatic system plays a critical role in resolving inflammation and maintaining overall joint homeostasis; however, there is some evidence that the lymphatics can become dysfunctional during OA. We hypothesized that the functional mechanics of lymphatic vessels (LVs) draining the joint could be directly compromised due to factors within SF derived from osteoarthritis patients (OASF). Here, we utilized OASF and SF derived from healthy (non-OA) individuals (healthy SF (HSF)) to investigate potential effects of SF entering the draining lymph on migration of lymphatic endothelial cells (LECs) in vitro, and lymphatic contractile activity of rat femoral LVs (RFLVs) ex vivo. Dilutions of both OASF and HSF containing serum resulted in a similar LEC migratory response to the physiologically endothelial basal medium-treated LECs (endothelial basal medium containing serum) in vitro. Ex vivo, OASF and HSF treatments were administered within the lumen of isolated LVs under controlled pressures. OASF treatment transiently enhanced the RFLVs tonic contractions while phasic contractions were significantly reduced after 1 h of treatment and complete ceased after overnight treatment. HSF treatment on the other hand displayed a gradual decrease in lymphatic contractile activity (both tonic and phasic contractions). The observed variations after SF treatments suggest that the pump function of lymphatic vessel draining the joint could be directly compromised in OA and thus might present a new therapeutic target.

The measurement of total and free cortisol has been studied as a clinical index of adrenal cortisol production in patients with liver cirrhosis. Correlations between free plasma and salivary cortisol have previously been reported in stable cirrhotic patients. Urinary free cortisol constitutes an index of adrenal cortisol production; however, it has never been used in assessing adrenal function in patients with liver cirrhosis.The aim of this observational study was to determine associations between urinary free cortisol, serum total, salivary, measured and calculated plasma free cortisol levels in cirrhotics, determining which of them can be used as an indirect index of free cortisol levels. Moreover, we investigated the potential use of 24 h urinary free cortisol as a prognostic factor for mortality.Seventy-eight outpatients with liver cirrhosis were included. Serum, salivary and urinary free cortisol were measured using the electrochemiluminenscence immunoassay. Plasma free cortisol determination was conducted using a single quadrupole mass spectrometer. The quantification of free cortisol was achieved by determining the signal response on negative ESI-MS mode.Twenty-four hour urinary free cortisol levels correlated with free cortisol determined by mass spectrometer, total cortisol and calculated free cortisol levels. Patients with low levels of urinary free cortisol presented a significantly higher mortality rate compared to those with high levels. The factors associated with death risk were determined by Cox regression. In the multivariate analysis, two models were applied; in the first model, CP score, PVT and urinary free cortisol were found to be significantly related to patients' survival, whereas in the second, MELD score, ascites and urinary free cortisol were independently related to survival.This study suggests that 24 h urinary free cortisol could be considered as a potential index of adrenal cortisol production in patients with liver cirrhosis and it potentially detects patients with a high mortality risk.

AIM The purpose of the Imadje study was to confirm the efficacy and safety of imatinib, following resection of kit-positive gastrointestinal stromal tumour (GIST), in the adjuvant setting in the Greek population. PATIENTS AND METHODS A total of 34 adult patients already receiving imatinib were enrolled. Recurrence-free (RFS) and overall survival, as well as time to treatment failure and safety were assessed. RESULTS Overall survival could not be estimated in the present study, as no death occurred. Overall, 91.2% of patients were recurrence-free at 36 months, while the median time to treatment failure was 35 months. No new or unexpected safety findings were observed. Mutation analysis in 14 patients showed that the most frequent mutations were located in KIT exon 11 (64.3%) and exon 9 (28.6%). Univariate analysis showed that only surgical resection with a margin classification of R0 was associated with better RFS. CONCLUSION Adjuvant treatment with imatinib for 3 years in patients with intermediate to high risk of recurrence was proven to prolong RFS, while being well-tolerated and not exhibiting a negative impact on patient compliance with therapy.

Selective CDK4/6 inhibitors, such as palbociclib, ribociclib, and abemaciclib, have been approved in combination with hormone therapy for the treatment of patients with HR+, HER2-negative advanced or metastatic breast cancer (mBC). Despite their promising activity, approximately 10 % of patients have de novo resistance, while the rest of them will develop acquired resistance after 24-28 months when used as first-line therapy and after a shorter period when used as second-line therapy. Various mechanisms of resistance to CDK4/6 inhibitors have been described, including cell cycle-related mechanisms, such as RB loss, p16 amplification, CDK6 or CDK4 amplification, and cyclin E-CDK2 amplification. Other bypass mechanisms involve the activation of FGFR or PI3K/AKT/mTOR pathways. Identifying the different mechanisms by which resistance to CDK4/6 inhibitors occurs may help to design new treatment strategies to improve patient outcomes. This review presents the currently available knowledge on the mechanisms of resistance to CDK4/6 inhibitors, explores possible treatment strategies that could overcome this therapeutic problem, and summarizes relevant recent clinical trials.

The aim of the present prospective study was to evaluate the retention and effectiveness of two types of sealants (clear vs. opaque) on early pit and fissure occlusal non-cavitated ICDAS II #1-3, caries lesions of permanent posterior teeth of children.Study Design: 6986 pit and fissure occlusal surfaces were randomly sealed with clear or opaque sealants out of which, 5828 sealants were placed on sound and 1158 on questionable surfaces, while 3508 were clear and 3478 opaque sealants. The mean age of the sample at initial sealant placement was 9.5 (±2.9) years and the follow-up time was 12-48 months. The median (IQR, range) follow-up time was 17.9 (8.7-28.6) months. Study inclusion and exclusion criteria applied to the combined database in order to select the study sample. Teethmate™ F-1 natural and opaque sealants (Kuraray, Hattersheim am Main, Germany) were applied following the standard procedure of preparation with moisture control kept by cotton rolls handled Dri-Angles" and a 30 seconds acid-etch with 37% ortho-phosphoric acid gel was used followed by 10 sec air-water spraying washing and polymerization for 20x2 sec. Sealants were applied on sound tooth surfaces (ICDAS #0) with no visible defects or on surfaces with early caries lesions (ICDAS #1-3), randomly and interchangeably on the upper or lower Jaw. Total retention was considered when all pits and fissures were completely sealed, while partial or complete loss was scored as one code, although was registered separately.Separate analyses were performed for each type of failure (loss of sealant or restoration). Cumulative probabilities of failure over time after sealant placement, overall or by specific characteristics, were calculated using the Kaplan-Meier method. Association between these characteristics and the hazard of failure were investigated using appropriate Cox proportional hazard models.Sealed surfaces with ICDAS II # 1-3, showed 100% higher probability of having a restoration and 60% higher probability of sealant loss, with both differences being statistically significant (aHR=2.03, p=0.046), adjusted for age, sex, type of sealant and location of surface. Opaque sealants presented statistically significant (p 0.009) higher re-application rate, while fissures had 70% statistically significant (p0.001) higher probability for resealing with time compared to pits, with gender not affecting sealant retention while the earlier a sealant was placed on children's teeth, the more probable it was to need resealing or restoration (p0.012).The therapeutic use of sealants on occlusal surfaces of posterior permanent molars with early carious lesions (ICDAS II 1-3) is inferior compared to sound surfaces, showing higher sealant failures and restorations.

Although the suppressive action of synthetic steroids on the hypothalamus-pituitary-thyroid (HPT) axis is established, little is known regarding the effect of the administration of synthetic adrenocorticotropic hormone (ACTH).In the context of a randomized, open label, comparative study assessing the efficacy and safety of ACTH and betamethasone in the treatment of hospitalized patients with acute gout, we compared the effects of these agents on thyroid function tests.Serum TSH, total T4 and T3 and cortisol were measured before and at 24 and 48 h after a single intramuscular dose of synthetic ACTH (1 mg) or betamethasone (6 mg), in 38 hospitalized patients with acute gout and normal thyroid function.The final analysis included 32 patients, due to missing data. The ACTH and betamethasone groups did not differ regarding the mean age, gender, severity of gout attack, and baseline thyroid parameters. In the ACTH group TSH and T4 were significantly decreased at 24 and at 48 h compared to baseline, while T3 was decreased at 24 but not at 48 h. In the betamethasone group T3 remained stable; TSH and T4 decreased significantly from baseline levels at 24 h; at 48 h, TSH had returned to and T4 showed a partial rebound towards pre-treatment values.A single IM administration of 1 mg of synthetic ACTH has more profound and prolonged effects on the HPT axis, lasting for at least 48 h, compared to a single IM dose of 6 mg betamethasone.

Objective(s) Increasing evidence indicates that vitamin D status is linked to severity of liver cirrhosis and patients' survival. However, the potential role of vitamin D-related immunomodulation in hepatic decompensation and patients' mortality in relation to vitamin D deficiency remains unknown. The aim of the current study is to evaluate the association between vitamin D status and vitamin D binding protein (VDBP) levels with serum cytokine and lipopolysaccharide binding protein (LBP) and to examine their role on disease severity and cirrhotics' mortality. Methods One hundred consecutive Caucasian patients with liver cirrhosis were enrolled in the study. 25(OH)D, VDBP, and LBP concentrations were assessed by ELISA. Cytokine tumor necrosis factor-a (TNF-a), interleukin 6 (IL-6), IL-1β, IL-8, IL-10, and IL-12 levels were determined by Cytometric Bead Array. Results 25(OH)D levels were inversely correlated with CP score, MELD, IL-6, and CP stage and VDBP levels with CP score, MELD, IL-6, IL-8, LBP, and CP stage. Cirrhotics with 25(OH)D deficiency and severe deficiency had significantly higher CP score, increased IL-6 levels and lower VDBP levels. In the multivariate analysis, the independent prognostic factors associated with patients' survival were CP stage B [hazard ratio = 6.75; 95% confidence interval (CI) 1.32, 34.43; P = 0.022], CP stage C (hazard ratio = 7.39; 95% CI 1.41, 38.81; P = 0.018), the presence of hepatocellular carcinoma (hazard ratio = 4.50; 95% CI 1.54, 13.13; P = 0.006) and 25(OH)D levels (hazard ratio = 0.87; 95% CI 0.80, 0.95; P = 0.002). Conclusion The results show that vitamin D status and VDBP levels are associated with liver cirrhosis severity and patients' mortality, possibly through a proinflammatory immune response.

The human exposome affects child development and health later in life, but its personal external levels, variability, and correlations are largely unknown. We characterized the personal external exposome of pregnant women and children in eight European cities. Panel studies included 167 pregnant women and 183 children (aged 6-11 years). A personal exposure monitoring kit composed of smartphone, accelerometer, ultraviolet (UV) dosimeter, and two air pollution monitors were used to monitor physical activity (PA), fine particulate matter (PM2.5), black carbon, traffic-related noise, UV-B radiation, and natural outdoor environments (NOE). 77% of women performed the adult recommendation of >= 150 min/week of moderate to vigorous PA (MVPA), while only 3% of children achieved the childhood recommendation of >= 60 min/day MVPA. 11% of women and 17% of children were exposed to daily PM2.5 levels higher than recommended >= 25 mu g/m(3)). Mean exposure to noise ranged from Lden 51.1 dB in Kaunas to Lden 65.2 dB in Barcelona. 4% of women and 23% of children exceeded the recommended maximum of 2 Standard-Erythemal-Dose of UV-B at least once a week. 33% of women and 43% of children never reached the minimum NOE contact recommendation of >= 30 min/week. The variations in air and noise pollution exposure were dominated by between-city variability, while most of the variation observed for NOE contact and PA was between-participants. The correlations between all personal exposures ranged from very low to low (Rho

Cytosolic calcium (Ca2+) is a ubiquitous second messenger that influences numerous aspects of cellular function. In many cell types, cytosolic Ca2+ concentrations are characterized by periodic pulses, whose dynamics can influence downstream signal transduction. Here, we examine the general question of how cells use Ca2+ pulses to encode input stimuli in the context of the response of lymphatic endothelial cells (LECs) to fluid flow. Previous work shows that fluid flow regulates Ca2+ dynamics in LECs and that Ca2+-dependent signaling plays a key role in regulating lymphatic valve formation during embryonic development. However, how fluid flow might influence the Ca2+ pulse dynamics of individual LECs has remained, to our knowledge, little explored. We used live-cell imaging to characterize Ca2+ pulse dynamics in LECs exposed to fluid flow in an in vitro flow device that generates spatial gradients in wall shear stress (WSS), such as are found at sites of valve formation. We found that the frequency of Ca2+ pulses was sensitive to the magnitude of WSS, while the duration of individual Ca2+ pulses increased in the presence of spatial gradients in WSS. These observations provide an example of how cells can separately modulate Ca2+ pulse frequency and duration to encode distinct forms of information, a phenomenon that could extend to other cell types.

The 2015 American Thyroid Association risk stratification system (ATA RSS) is used in patients with differentiated thyroid carcinoma (DTC) to assess their risk of persistent/recurrent disease. Our aims were to validate the 2015 ATA RSS in a registry of DTC patients and to examine whether the addition of factors not included in it, such as pre-radioactive iodine therapy stimulated thyroglobulin (pre-RAI sTg), gender, and age could increase its predictive ability.We studied 403 patients with DTC, treated at a tertiary center from 1990 to 2018 and subjected to total thyroidectomy. All patients had received RAI therapy, except those with low-risk papillary microcarcinoma.Of our patients, 81.9% were women and 91.1% had papillary thyroid carcinoma. After a median follow-up of 5.0 years, 53 cases of persistent and 21 cases of recurrent disease were recorded. The proportion of variance explained (PVE) regarding the outcome (presence or absence of recurrent/persistent disease) using the 2015 ATA RSS alone was 18.3% (persistence) and 16.9% (recurrence), increasing to 74.4% and 52.0%, respectively, when pre-RAI sTg was added to the logistic regression model. Gender and age were not associated with the disease outcome. In ROC analysis, pre-RAI sTg had a high predictive value for persistent (AUC 0.983, 95% CI 0.962-1.000) and recurrent disease (AUC 0.856, 95% CI 0.715-0.997). The optimal cut-offs and sensitivity, specificity, and positive and negative predictive value for pre-RAI sTg were the following: for persistence 12.75 ng/ml, 100%, 90.5%, 64%, and 100%, and for recurrence 8.05 ng/ml, 77.8%, 85.5%, 36.8%, and 97%.The 2015 ATA RSS displayed moderate performance in predicting recurrent/persistent disease in patients with DTC, which improved with the inclusion of pre-RAI sTg values; pre-RAI sTg was an independent predictor of the disease outcome, with high negative prognostic value.

The role of patients' metabolic clinical and biochemical profile in NAFLD has not been extensively explored.The aim of the study was to assess the role of metabolic health in NAFLD patients and to examine liver disease progression in these populations.The medical charts of 569 patients diagnosed with fatty liver were thoroughly reviewed; 344 patients were excluded because of other chronic liver diseases. Metabolically healthy people were defined as those who met none of the following criteria: blood pressure ≥ 130/85 mmHg or under hypertension treatment, fasting glucose ≥ 100 mg/dl or under diabetes treatment, serum triglycerides150 mg/dl, high density lipoprotein-cholesterol40/50 mg/dl for men/women. Study participants were followed-up over a median period of 22 months.The present observational case-control study included 225 NAFLD patients; 14 (6.2%) were metabolically healthy. Metabolically healthy participants were younger (p = 0.006), had lower age at diagnosis (p = 0.002), lower levels of γ-GT (p = 0.013), fasting glucose (p 0.001) and triglycerides (p 0.001) and higher HDL-cholesterol (p = 0.005) compared to metabolically non-healthy. By the last follow up assessment, 8 metabolically healthy patients had developed dyslipidemia; 1 patient (14.4%) had presented liver disease progression compared to 8 patients (10.5%) from the unhealthy group (p = 0.567). In multivariate analysis, diabetes mellitus (p = 0.017) and hemoglobin levels (p = 0.009) were the sole independent predictors of disease progression. No significant difference was observed in liver disease progression-free survival rates among the two patient groups (p = 0.503).Metabolically healthy NAFLD patients presented with a favorable biochemical profile; however, they were diagnosed with NAFLD at a younger age and the liver disease progression risk was similar to that of metabolically unhealthy patients. These findings suggest that metabolically healthy NAFLD may not constitute a benign condition and patients could potentially be at increased risk of metabolic syndrome and liver disease progression.

One-way valves in the lymphatic system form from lymphatic endothelial cells (LECs) during embryonic development and are required for efficient tissue drainage. Although fluid flow is thought to guide both valve formation and maintenance, how this occurs at a mechanistic level remains incompletely understood. We built microfluidic devices that reproduce critical aspects of the fluid flow patterns found at sites of valvulogenesis. Using these devices, we observed that LECs replicated aspects of the early steps in valvulogenesis: cells oriented perpendicular to flow in the region of maximum wall shear stress (WSS) and exhibited enhanced nuclear localization of FOXC2, a transcription factor required for valvulogenesis. Further experiments revealed that the cell surface protein E-selectin was required for both of these responses. Our observations suggest that spatial gradients in WSS help to demarcate the locations of valve formation, and implicate E-selectin as a component of a mechanosensory process for detecting WSS gradients., Using microfluidic systems, Michalaki et al show that lymphatic endothelial cells exposed to wall shear stress orient in the direction perpendicular to flow and show increased nuclear FOXC2 levels in a manner dependent on E-selectin, a transmembrane adhesion protein. These data provide insights into how lymphatic vessels respond to local flow-mediated mechanical cues.

The multi-scale dynamics of a two-compartment with first order absorption Target-Mediated Drug Disposition (TMDD) pharmacokinetics model is analysed, using the Computational Singular Perturbation (CSP) algorithm. It is shown that the process evolves along two Slow Invariant Manifolds (SIMs), on which the most intense components of the model are equilibrated, so that the less intensive are the driving ones. The CSP tools allow for the identification of the components of the TMDD model that (i) constrain the evolution of the process on the SIMs, (ii) drive the system along the SIMs and (iii) generate the fast time scales. Among others, such diagnostics identify (i) the factors that determine the start and the duration of the period in which the ligand-receptor complex acts and (ii) the processes that determine its degradation rate. The counterintuitive influence of the process that transfers the ligand from the tissue to the main compartment, as it is manifested during the final stage of the process, is studied in detail.

To compare the diagnostic performance of the automated caries detection system (ACDS) for the detection and diagnosis of occlusal caries with the histological appearance of the lesions. Eighteen posterior permanent teeth were used, out of which 40 sections were made and 53 areas were evaluated. Teeth with hypoplastic and/or hypomineralised areas or sealants on the occlusal surfaces were excluded from the study. The teeth that were used for this study were a subgroup of the teeth used in the study that introduced ACDS system. This subgroup consisted of teeth having in their occlusal surfaces early carious lesions classified as international caries detection and scoring system (ICDAS) 0, 1, 2 and 3 after clinical examination by the examiners. Histological preparations were classified by experienced examiners based on the Ekstrand, Ricketts and Kidd (ERK) system and for the respective occlusal surfaces by the ACDS system based on ICDAS II system. There were two threshold limits considered as carious in either system ICDAS ≥ 2 or ≥ 3 and ERK index ≥ 2 or ≥ 3 and all possible combinations were analysed. Statistical methods of weighted version of kappa coefficient, Kendall’s tau-b correlation coefficient and p-values using the Fisher’s exact method were used at the confidence level of 0.05. Intra-examiner kappa coefficient agreement was 0.87 and 0.89 while the inter-examiner for the two trials were 0.87 and 0.92. The ICDAS3-ERK3 combination between the ACDS and histological sections presented the best agreement with kappa coefficient 0.76, agreement 92.5%, sensitivity 100% and specificity 91.1%. ICDAS3-ERK3 combination between the optical examination of the examiners compared to the histological preparations showed kappa coefficient 0.87, agreement 96.2%, sensitivity 100%, Specificity 95.6%. The evidence supports the view that ACDS classification of occlusal surfaces based on the ICDAS system are comparable with classification to that of an examiner and with the histology of the lesion. The use of ACDS has the distinct advantage though of removing the subjectivity of the examiner since it performs the classification without any intervention by him.

Several polymorphisms in the vitamin D receptor (VDR) are associated with the occurrence of chronic liver disease. Here, we investigated the association between BsmI, ApaI, TaqI and FokI VDR polymorphisms and the severity of liver cirrhosis in relation to serum cytokine and lipopolysaccharide binding protein (LBP) levels and their role on survival in cirrhotic patients. We found that patients harboring the BB genotype had higher MELD score, and they were mainly at CP stage C; patients harboring the AA genotype had increased LBP, IL-1β and IL-8 levels, and they were mostly at CP stage C; TT genotype carriers had higher MELD score and they were mainly at CP stage C and FF genotype carriers had lower IL-1β levels when compared to Bb/bb, Aa/aa, Tt/tt and Ff/ff genotypes respectively. In the multivariate analysis ApaI, BsmI and TaqI polymorphisms were independently associated with liver cirrhosis severity. In the survival analysis, the independent prognostic factors were CP score, MELD and the FF genotype. Our results indicate that the ApaI, TaqI and BsmI polymorphisms are associated with the severity of liver cirrhosis, through the immunoregulatory process. Survival is related to the FF genotype of FokI polymorphism, imparting a possible protective role in liver cirrhosis.

In the recent Greek ages the most devastating epidemics were plague, smallpox, leprosy and cholera. In 1816 plague struck the Ionian and Aegean Islands, mainland Greece, Constantinople and Smyrna. The Venetians ruling the Ionian Islands effectively combated plague in contrast to the Ottomans ruling all other regions. In 1922, plague appeared in Patras refugees who were expelled by the Turks from Smyrna and Asia Minor. Inoculation against smallpox was first performed in Thessaly by the Greek women, and the Greek doctors Emmanouel Timonis (1713, Oxford) and Jakovos Pylarinos (1715, Venice) made relevant scientific publications. The first leper colony opened in Chios Island. In Crete, Spinalonga was transformed into a leper island, which following the Independence War against Turkish occupation and the unification of Crete with Greece in 1913, was classified as an International Leper Hospital. Cholera struck Greece in 1853-1854 brought by the French troops during the Crimean War, and again during the Balkan Wars (1912-13) when the Bulgarian troops brought cholera to northern Greece. Due to successive wars, medical assistance was not always available, so desperate people turned many times to religion through processions in honor of local saints, for their salvation in epidemics., Posljednjih su stoljeća razarajuće za Grke bile epidemije kuge, boginja, gube i kolere. Godine 1816. kuga je pogodila otoke u Jonskom i Egejskom moru, kopnenu Grčku, Konstantinopol i Smirnu. Mlečani koji su vladali Jonskim otocima uspješno su se borili protiv kuge, za razliku od Osmanlija koji su upravljali ostalim regijama. Godine 1922. kuga se pojavila kod prognanika iz Patra, koje su Turci protjerali iz Smirne i Male Azije. Cijepljenje protiv malih boginja najprije je provedeno u Tesali i izvodile su ga grčke žene, a grčki liječnici Emmanouel Timonis (1713., Oxford) i Jakovos Pylarinos (1715., Venecija) napisali su relevantne znanstvene publikacije. Prva kolonija gubavaca otvorena je na otoku Chiosu. Na Kreti je Spinalonga pretvorena u otok gubavaca koji je nakon rata za nezavisnost protiv turske okupacije i ujedinjenja Krete s Grčkom 1913. bio klasificiran kao Međunarodna bolnica za gubavce. Kolera je pogodila Grčku 1853. – 1854., a donijeli su je francuski vojnici tijekom Krimskog rata i opet tijekom balkanskih ratova (1912. – 1913.) kada su bugarske postrojbe donijele koleru u sjevernu Grčku. Zbog uzastopnih ratova medicinska pomoć nije bila uvijek dostupna, tako da su se očajni ljudi više puta okretali religiji procesijama u čast lokalnih svetaca, za svoj spas u vrijeme epidemija.

ContextAdrenal and extra-adrenal cortisol production may be involved in the development of metabolic syndrome (MetS).ObjectiveTo investigate the activity of the hypothalamic–pituitary–adrenal (HPA) axis and the expression of HSD11B1, nuclear receptor subfamily 3, group C, member 1 (glucocorticoid receptors) α (NR3C1α) and β (NR3C1β) in the liver, subcutaneous adipose tissue (SAT) and visceral adipose tissue (VAT) of severely obese patients with and without MetS.MethodsThe study included 37 severely obese patients (BMI ≥40 kg/m2), 19 with MetS (MetS+ group) and 18 without (MetS− group), studied before and during bariatric surgery. Before the day of surgery, urinary free cortisol (UFC) and diurnal variation of serum and salivary cortisol were estimated. During surgery, biopsies of the liver, VAT and SAT were obtained. The expression of HSD11B1, NR3C1α and NR3C1β was evaluated by RT-PCR.ResultsUFC and area under the curve for 24-h profiles of serum and salivary cortisol were lower in the MetS− group. In the MetS− group, mRNA levels ofHSD11B1in liver exhibited a negative correlation with liver NR3C1α (LNR3C1α) and VAT expression of HSD11B1 was lower than the MetS+ group.ConclusionsWe observed a downregulation of the NR3C1α expression and lower VAT mRNA levels ofHSD11B1in the MetS− group, indicating a lower selective tissue cortisol production and action that could protect these patients from the metabolic consequences of obesity. In the MetS− group, a lower activity of the HPA axis was also detected. Taken together, cortisol in tissue and systematic level might play a role in the development of MetS in severely obese patients.

The indications for levothyroxine replacement therapy for subclinical hypothyroidism (SH) remain a subject of debate, especially when prescribed for older adults. The results of the recent TRUST trial indicate that levothyroxine does not improve clinical symptom scores among elderly patients with SH. While there is much concern regarding the dilemma of introducing or withholding levothyroxine, less attention may be paid to the differential diagnosis of an elevated TSH level, which is the prerequisite for diagnosing SH. Herein, we review these issues facing endocrinologists and internists/generalists either in practice or in training. When a patient presents abnormal thyroid test results compatible with SH, a series of issues need to be addressed before the implementation of replacement therapy is considered: first, an isolated TSH elevation not linked to a primary thyroid pathology should be excluded; second, the persistent nature of the patient’s TSH elevation and SH profile should be verified; third, SH symptoms and potential complications relevant for the specific patient should be documented; fourth, expectations from levothyroxine substitution therapy for SH in the specific patient should be clarified. Only then can the decision be made whether levothyroxine substitution should be introduced or not.

Sleep apnea syndrome (SAS) is an established cardiovascular risk factor in the general population related to inflammation and oxidative stress and is very common among hemodialysis patients. Cardiovascular disease and its complications is the main cause of death among hemodialysis patients. The aim of the present study was to investigate the role of SAS in the promotion of inflammation and oxidative stress and thus in the augmentation of cardiovascular risk in hemodialysis patients.Thirty-seven hemodialysis patients underwent an overnight full polysomnography study. The following morning blood samples were obtained and TNF-α (tumor necrosis factor-α), IL-6 (interleukin-6), MPO (myeloperoxidase), and oxLDL (oxidized low density lipoprotein) were measured.We investigated the correlation of patients' markers of inflammation and oxidative stress with their sleep parameters (total sleep time, AHI, apnea/hypopnea index; RDI, respiratory disturbance index; DI, desaturation index, mean and minimum SpOThese results indicate that, in hemodialysis patients, the severity of SAS and nocturnal hypoxia correlated positively with markers of inflammation and oxidative stress.

BACKGROUND AND AIMS Critical illness-related corticosteroid insufficiency has been reported in acute variceal bleeding (AVB). In cirrhosis, free serum cortisol (FC) is considered optimal to assess adrenal function. Salivary cortisol (SC) is considered a surrogate for FC. We evaluated FC and its prognostic role in AVB. METHODS Total serum cortisol, SC, cortisol-binding globulin, and FC (Coolens' formula) were evaluated in AVB (n=38) and in stable cirrhosis (CC) (n=31). A Cox proportional hazards model was evaluated for 6-week survival. RESULTS In AVB, the median FC and SC levels were higher with worse liver dysfunction [Child-Pugh (CP) A/B/C: 1.59/2.62/3.26 μg/dl, P=0.019; CPA/B/C: 0.48/0.897/1.81 μg/ml, P

Aging and its underlying pathophysiological background has always attracted the attention of the scientific society. Defined as the gradual, time-dependent, heterogeneous decline of physiological functions, aging is orchestrated by a plethora of molecular mechanisms, which vividly interact to alter body homeostasis. The ability of an organism to adjust to these alterations, in conjunction with the dynamic effect of various environmental stimuli across lifespan, promotes longevity, frailty or disease. Endocrine function undergoes major changes during aging, as well. Specifically, alterations in hormonal networks and concomitant hormonal deficits/excess, augmented by poor sensitivity of tissues to their action, take place. As hypothalamic–pituitary unit is the central regulator of crucial body functions, these alterations can be translated in significant clinical sequelae that can impair the quality of life and promote frailty and disease. Delineating the hormonal signaling alterations that occur across lifespan and exploring possible remedial interventions could possibly help us improve the quality of life of the elderly and promote longevity.

BACKGROUND The current trend in the management of low risk differentiated thyroid carcinoma is to follow less aggressive strategies. OBJECTIVE To assess the long-term morbidity and mortality outcomes of low-risk papillary thyroid carcinoma (PTC) patients undergoing minimal intervention. DESIGN We retrospectively analyzed 137 patients with low-risk PTC (stage I: n=77; stage II: n=60). Of these patients, 107 (Group 1) had macro-PTC and underwent near-total thyroidectomy and received postoperatively 50mCi RAI. The remaining 30 patients (Group 2) had micro-PTC (

AIM This in vitro study was to classify questionable for caries occlusal surfaces (QCOS) of permanent teeth according to ICDAS codes 1, 2, and 3 and to compare them in terms of enamel mineral composition with the areas of sound tissue of the same tooth. METHODS Partially impacted human molars (60) extracted for therapeutic reasons with QCOS were used in the study, photographed via a polarised light microscope and classified according to the ICDAS II (into codes 1, 2, or 3). The crowns were embedded in clear self-cured acrylic resin and longitudinally sectioned at the levels of the characterised lesions and studied by SEM/EDX, to assess enamel mineral composition of the QCOS. Univariate and multivariate random effect regressions were used for Ca (wt%), P (wt%), and Ca/P (wt%). RESULTS The EDX analysis indicated changes in the Ca and P contents that were more prominent in ICDAS-II code 3 lesions compared to codes 1 and 2 lesions. In these lesions, Ca (wt%) and P (wt%) concentrations were significantly decreased (p = 0.01) in comparison with sound areas. Ca and P (wt%) contents were significantly lower (p = 0.02 and p = 0.01 respectively) for code 3 areas in comparison with codes 1 and 2 areas. Significantly higher (p = 0.01) Ca (wt%) and P (wt%) contents were found on sound areas compared to the lesion areas. CONCLUSIONS The enamel of occlusal surfaces of permanent teeth with ICDAS 1, 2, and 3 lesions was found to have different Ca/P compositions, necessitating further investigation on whether these altered surfaces might behave differently on etching preparation before fissure sealant placement, compared to sound surfaces.

Metabolic syndrome (MetS) is correlated with the activity of hypothalamic-pituitary-adrenal axis (HPA), but the underlying mechanism still remains elusive. The aim of this study was to investigate the HPA axis function in patients with MetS. This case-control study included 159 people. They were divided into 2 groups. The first group included 73 healthy volunteers (control group: 19 males, 54 females, mean±SD: 49.9±7.5 years old, with BMI: 27.9±4.42 kg/m 2 ) and the second group included 86 patients with MetS (case group: 48 males, 38 females, mean±SD: 52.2±7.6 years old, with BMI: 30.5±5.35 kg/m 2 ). An oral glucose tolerance test (OGTT) was performed for all subjects after a 12-h overnight fast, and blood samples were obtained for determination of ACTH, cortisol, insulin, C-peptide, and glucose levels. Serum cortisol after an overnight dexamethasone suppression test was determined in both groups. Patients with MetS had serum cortisol levels after an overnight dexamethasone suppression test significantly higher than controls. During OGTT plasma ACTH levels were higher at all time points in patients with MetS compared to controls, whereas serum cortisol levels were comparable between the 2 groups. Plasma ACTH during OGTT was also correlated with most of the components of MetS. The HPA axis in patients with MetS seems to be more active as evidenced by the higher cortisol levels after the overnight dexamethasone suppression test and by the higher ACTH levels during OGTT. This functional hypercortisolism might be involved in the pathogenesis of the metabolic syndrome.

Suppressive or replacement doses of levothyroxine (LT4) are affected by the rate and extent of the active ingredient absorbed, as well as by the lean body mass. Obesity has reached epidemic proportions worldwide and is related with many comorbidities. The aim of this study was to determine the pharmacokinetic parameters of LT4 in severely obese individuals and compared them with similar data in lean control subjects.We studied 62 euthyroid subjects who had negative tests for anti-thyroid peroxidise antibodies (Ab-TPO). Thirty eight of these subjects were severely obese but otherwise healthy (severe obese subjects [SOS] group). Twenty-four were healthy control subjects (control group), with a body mass index of 23.3 ± 1.7 kg/m(2). Subjects received 600 μg oral sodium LT4 after an overnight fast. Serum triiodothyronine (T3), T4, and thyroid-stimulating hormone were measured at baseline. Serum T4 and T3 was measured 0.5, 1, 1.5, 2, 2.5, 3, and 4 hours after LT4 administration.Baseline serum T4 and thyroid-stimulating hormone concentrations were higher in the SOS group than in the control group; serum T3 was similar in the two groups. The corrected area under the curve and the maximum T4 concentration after LT4 administration were lower, whereas the time to maximum concentration from the baseline was higher in SOS than in the control group. The estimated plasma volume was higher in the SOS than in the control group. Mean serum T3 levels increased gradually during the four hours after LT4 administration in the control group. In contrast, they decreased gradually in the SOS group.Severely obese individuals may need higher LT4 suppressive or replacement doses than normal-weight individuals due, among other factors, to impaired LT4 pharmacokinetic parameters. The latter could be attributed to their higher plasma volume and/or to delayed gastrointestinal LT4 absorption. T4 conversion to T3 might be defective in severe obesity.

Aims and background c-kit (CD117) is a transmembrane tyrosine kinase that acts as a type III receptor for mast cell growth factor. In recent years, the role of c-kit in the development of preinvasive and invasive breast carcinomas has been investigated. The aim of our study was to detect c-kit expression in the entire spectrum of common benign and malignant breast lesions in correlation with a well-studied myoepithelial or stem-cell like marker (p63). Methods and study design We evaluated 270 cases of benign and malignant breast lesions including fibrocystic disease, fibroadenoma, sclerosing adenosis, atypical ductal hyperplasia, ductal/lobular carcinoma in situ, and ductal/lobular/mixed type carcinoma. C-kit staining was evaluated in the cytoplasm/cell membrane in epithelial and myoepithelial cells and p63 in the nuclei of myoepithelial cells. Results c-kit was highly expressed (85.3%) in benign lesions (fibrocystic disease, sclerosing adenosis, fibroadenoma), and p63 expression was 95.5% in the aforementioned lesions. c-kit distribution in preinvasive and invasive lesions was as follows: ductal/lobular carcinoma in-situ, 43%/35%; ductal/lobular carcinoma, 36%/39%; and mixed type carcinoma, 20%. c-kit was highly expressed in myofibroblast/fibroblast cells only in grade III ductal/lobular carcinomas. c-kit was totally absent in stromal cells in benign lesions and in situ carcinomas whereas expression was weak in grade I and II carcinomas. Conclusions Combined overexpression of c-kit and p63 is indicative of benign breast lesions. In contrast, there is reduced expression of c-kit in in situ and invasive breast carcinomas, with simultaneous overexpression in the stromal cells. This suggests that c-kit may play a role in breast cancer progression. Free full text available at www.tumorionline.it

AIM: This was to evaluate the microleakage of 3 different sealants, applied on sound and questionably carious occlusal surfaces with and without a bonding agent. METHODS: A total of 120 human molars were selected, photographed with a digital video microscope, and assigned by 3 independent examiners, according to the criteria of ICDAS II, in 2 groups of 60 teeth each. Group A: teeth with deep, clear, sound occlusal surfaces (ICDAS II, code 0). Group B: teeth with questionable occlusal surfaces, having deep, stained pits and fissures with probable incipient, but non-cavitated, carious lesions (ICDAS II, codes 1 and 2). Each group was divided into 2 subgroups of 30 teeth each (bonding or no bonding) and then into 3 subgroups of 10 teeth each according to the type of sealant used: one conventional (Conseal®) and 2 fluoridated (Conseal F® and Teethmate F®). After the application of the bonding agent and the sealant to the appropriate teeth, all specimens were subjected to thermal cycling and immersed in a 10% methylene blue dye solution for 4 hours. Average and summed microleakage for each sample were estimated from dye penetration scores on 3 mesiodistal sections of the tooth across the sealed occlusal surface. Nonparametric Friedman’s 2-way ANOVA by ranks and Conover-Inman pair wise comparisons were used for differences at the 0.05 level of significance. RESULTS: According to Friedman’s 2-way ANOVA by ranks analysis, although there were no significant differences between the different sealants (χ2= 0.048, df = 2, P =.976), there were significant differences between the sound and questionably carious occlusal surfaces (χ2 = 24, df = 3,.000). Conover-Inman pair wise comparisons showed no differences between the groups using and not using bonding agents, on sound (SNB-SWB, P =.4561) or questionable occlusal surfaces (QNB-QWB, P =.0842). CONCLUSIONS: Sealant microleakage on questionably carious occlusal surfaces was statistically significantly higher than that of sound occlusal surfaces. Using a bonding agent or fluoridated FS did not influence microleakage significantly, either on sound or on questionable fissured surfaces.

ObjectiveRelative corticosteroid insufficiency may be common in critically ill patients and is associated with a poor outcome; however, the response of the hypothalamic–pituitary–adrenal (HPA) axis in nursed patients is not known. Our aim was to evaluate the response of HPA axis to the severity of illness in non-critically ill nursed (NCIN) patients and the clinical outcome.Subjects and methodsFifty-six nursed patients who were divided into four groups (stroke, mild disease, sepsis and severe sepsis) as well as a control group (n=15) were studied. At admission (day 1), cortisol and ACTH were measured and a low-dose (1 μg) corticotrophin test was performed, followed 2 h later by a standard-dose (250 μg) corticotrophin test. Diurnal variation of cortisol was obtained on day 2. A second identical set of low-dose and standard-dose corticotrophin tests were performed on day 5 or 6 (recovery phase).ResultsIn patients with stroke and severe sepsis, cortisol had the highest values and its diurnal variation was abolished. Dissociation of ACTH and cortisol was found in all patients.The Δmax of cortisol after the 1-μg corticotrophin test did not differ among the groups, while after the 250-μg corticotrophin test, it was borderline higher in controls. The ratio of responders (Δmax of cortisol ≥9 μg/dl) to non-responders after 1- or 250-μg corticotrophin test did not differ among patients and controls. All patients had a good outcome without glucocorticoid treatment.ConclusionsDepending on the severity of illness, mild alterations in the HPA axis occurred. However, relative corticosteroid insufficiency was not confirmed in NCIN patients.

Capecitabine has been developed as a prodrug of FU, with the goal of improving tolerability and intratumor drug concentration through tumor-specific conversion to the active drug. The purpose of this article is to review the available information on capecitabine with respect to clinical efficacy for tumors of the digestive tract, adverse – effect profile, documented drug interactions, dosage and administration, and future directions of ongoing research. Relevant Englishlanguage literature was identified through searches of NCI, PubMed, ASCO.org and ESMO, ECCO meetings proceedings.

Objective To study the clinical and laboratory characteristics of patients with severe sepsis and baseline hyperglycemia and investigate the impact of hyperglycemia on the final outcome. Patients A total of 265 patients admitted with severe sepsis in 3 major hospitals in South-Western Greece, during a 1-year period, were included in the study. Patients were divided in 3 groups according to their glycemic profile at admission: patients with stress hyperglycemia (group SH, n = 47), with diabetes mellitus (group DM, n = 65), and with normal glucose level (group NG, n = 153). Hyperglycemia was defined as an admission or in-hospital fasting glucose level of ≥126 mg/dL or a random blood glucose level of ≥200 mg/dL on ≥2 determinations. Results A total of 42.2% of patients with severe sepsis had baseline hyperglycemia with 17.7% having sepsis-induced stress hyperglycemia. No family history was noted in the SH group. A higher percentage of septic patients with stress hyperglycemia died compared with patients with normal glucose levels (42.5% versus 13.7%) and diabetics (42.5% versus 24.6%). Group DM had also a poorer prognosis than group NG (24.6% versus 13.7%). A positive correlation was detected between the fasting blood glucose levels of group SH and the severity of sepsis indicated by sepsis-related organ failure assessment score. Conclusion Baseline hyperglycemia, including stress-induced hyperglycemia, is common in patients with severe sepsis. Stress-induced hyperglycemia is related to a more severe disease and poorer prognosis.

Nontoxic nodular goiter (NTNG) is common in endemic goiter regions. Thyroxine (T4) is often used to treat NTNG. There is little information regarding T4 treatment in regions that have recently become iodine sufficient. We studied the effect of T4 treatment on thyroid function tests in southwestern Greece (SWG), a recently iodine-sufficient area.We studied 827 residents of SWG (group A) to determine goiter prevalence, thyroid function, and urinary iodine concentration (UIC). Group B: 385 consecutive patients with thyroid dysfunction. Of these, 89 had NTNG and followed for 10 years on T4 treatment, and 296 had hyperthyroidism. Group C: 29 patients with NTNG, treated with triiodothyronine (T3) 50 mug/day and followed for 6 months. Measurements included serum T4 and 24-hour radioactive iodine uptake (RAIU) before and at the end of T3 administration.The median UIC in group A was 114 microg/L. In group B (89 patients), the incidence of newly diagnosed hyperthyroidism was 5-7% per year with a cumulative percentage of 33% at the 10th year. The initial thyrotropin (TSH) was lower (0.78 +/- 0.51 mIU/L) in those who developed thyrotoxicosis compared to those who remained euthyroid (1.17 +/- 0.74 mIU/L) (p0.05). In 296 thyrotoxic patients, the incidence of autoimmune hyperthyroidism and toxic multi-nodular goiter (TMNG) was similar. In group C, 10/29 patients remained euthyroid and the 24-hour RAIU decreased by 49% during T3 treatment. Similarly, serum T4 decreased by 49%. In the remaining patients who developed hyperthyroidism, 24-hour RAIU and T4 were decreased by 19% and 22%, respectively.In SWG, a recently iodine-sufficient region, the risk of developing hyperthyroidism in patients with NTNG after administration of 100-150 microg T4 is relatively high in those whose serum TSH before T4 treatment is in the lower normal range. Therefore, T4 treatment should be avoided in these patients.

Transient hyperglycemia is commonly observed in non-diabetic subjects during surgery. We undertook this study to investigate (1) insulin secretion pattern and glucose levels during elective surgery, and (2) the role of pre-operative fasting in the development of surgery-induced hyperglycemia.We examined 21 severely obese normal glucose tolerant patients, who underwent bariatric surgery. From the 21 operated subjects, 14 remained fasted while seven patients received 75 g glucose the preoperative night. They sampled at baseline and from the onset of operation frequently for 9 h thereafter, for measuring serum insulin and glucose.Hyperglycemia developed within 1 h from the onset of operation and lasted 9 h. The administration of 75 g glucose the preoperative night prevented surgery-induced hyperglycemia. Insulin profile analyzed by deconvolution analysis was similar between fasted patients and those who received 75 g glucose. Serum insulin was suppressed at the beginning of the surgery and reached baseline values 4 h thereafter.Hyperglycemia occurred within 1 h from the beginning of surgery and sustained for at least 9 h while insulin levels are suppressed or unaltered compared to baseline values in euglycemia. The administration of 75 g glucose the preoperative night prevents surgery-induced hyperglycemia without altering the profile of insulin secretion.

The severity of motorway accidents that occurred on the hard shoulder (HS) is higher than for the main carriageway (MC). This paper compares and contrasts the most important factors affecting the severity of HS and MC accidents on motorways in England.Using police reported accident data, the accidents that occurred on motorways in England are grouped into two categories (i.e., HS and MC) according to the location. A generalized ordered logistic regression model is then applied to identify the factors affecting the severity of HS and MC accidents on motorways. The factors examined include accident and vehicle characteristics, traffic and environment conditions, as well as other behavioral factors.Results suggest that the factors positively affecting the severity include: number of vehicles involved in the accident, peak-hour traffic time, and low visibility. Differences between HS and MC accidents are identified, with the most important being the involvement of heavy goods vehicles (HGVs) and driver fatigue, which are found to be more crucial in increasing the severity of HS accidents.Measures to increase awareness of HGV drivers regarding the risk of fatigue when driving on motorways, and especially the nearside lane, should be taken by the stakeholders.

The incidence of multiple primary malignant neoplasms (MPMN) has dramatically increased. The purpose of this retrospective study was to present the 12-year experience at a University Hospital in patients with MPMN and to investigate the role of genetic factors in their pathogenesis.The medical records of 7516 cancer patients, treated in our Institution from 2000 to 2012, were reviewed. Diagnosis of MPMN was based on the Warren and Gates' criteria.Among 7516 patients, 39 (0.5%) (10 men, mean age 70.0±6.98 years, and 29 women, mean age 64.7±8.24 years) presented with MPMN. Eighty-two percent of them developed 2 primary malignant neoplasms (PMNs), whereas 3 PMNs were developed in 7 patients. Breast cancer was the most common cancer type diagnosed among female patients (59%); 14 and 3 had 2 and 3 PMNs, respectively. Eight had a family history of breast cancer while in 3 genetic testing revealed mutations in BRCA1 and BRCA2 genes. The second most common type of malignancy was colorectal cancer (24%); 5 developed 2 PMNs, whereas 2 developed 3 PMNs. Five patients had a family history of colorectal cancer. Colon cancer was the most frequent neoplasm among male patients (50%; 3 developed 2 and 2 3 PMNs. In 2 patients the family history was positive for colorectal cancer.Although many factors may contribute to MPMN development, positive family history and inherent mutations significantly predispose to MPMN appearance. Thus, management of MPMN patients should be based on a detailed family history and genetic testing.

Objective: The role of self-conscious emotions (SCEs) including shame, guilt, humiliation and embarrassment are of increasing interest within health. Yet, little is known about SCEs in the experience of chronic pain. This study explored prevalence and experience of SCEs in chronic pain patients compared to controls and assessed the relationship between SCEs and disability in pain patients.Design and measures: Questionnaire assessment comparing musculoskeletal pain patients (n = 64) and pain-free control participants (n = 63). Pain was assessed using the McGill Pain Questionnaire; disability, using the Roland–Morris Disability Questionnaire; and six SCEs derived from three measures (i) Test of Self-Conscious Affect-3 yielding subscales of shame, guilt, externalisation and detachment (ii) The Brief Fear of Negative Evaluation Scale and (iii) The Pain Self-Perception Scale assessing mental defeat.Results: Significantly greater levels of shame, guilt, fear of negative evaluation and mental defeat were observed in chronic pain patients compared to controls. In the pain group, SCE variables significantly predicted affective pain intensity; only mental defeat was significantly related to disability.Conclusion: Findings highlight the prevalence of negative SCEs and their importance in assessment and management of chronic pain. The role of mood in this relationship is yet to be explored.

Aims and Background The understanding of hormonal therapies in postmenopausal women with metastatic breast cancer has advanced greatly in the past several decades. With the introduction of orally active, potent and selective third-generation aromatase inhibitors (anastrozole, letrozole and exemestane), approaches to the treatment of hormone-sensitive advanced breast cancer are undergoing reevaluation. For treatment of advanced or metastatic disease that has progressed on tamoxifen, all three agents are active. The purpose of the study was to assess the antitumor efficacy and tolerance of exemestane administered as third-line hormonal therapy to postmenopausal women with metastatic breast cancer refractory to letrozole and anastrozole. Study design Sixty postmenopausal women with stage IV hormone receptor-positive carcinoma of the breast were enrolled in the study. All patients had received two prior hormonal manipulations and had measurable or assessable disease. All adverse events were monitored. Results Objective tumor response was achieved in 12 (20%) patients (95% CI, 9.6-30.4). The overall clinical benefit was 38.3% (95% CI, 21.2-49.3), and the median duration of objective tumor response was 20 months (range, 9-26). The median time to death was 17.4 months (95% CI, 16.14-18.66). Conclusions Exemestane represents an active and well-tolerated treatment option in pretreated patients with advanced breast cancer who have received standard first- and second-line hormonal therapies. By extending the sequence of hormonal therapy, disease progression and the need for chemotherapy may be significantly delayed.

Morbidly obese subjects may present with abnormal thyroid function tests but the reported data are scarce. Therefore, we studied the thyroid parameters in 144 morbidly obese patients, 110 females and 34 males, to assess the prevalence of hypothyroidism. Eleven percent (11.8%) carried the diagnosis of hypothyroidism and were undergoing levothyroxine (LT4) replacement therapy, 7.7% had newly diagnosed subclinical hypothyroidism, 0.7% had subclinical hyperthyroidism and 7.7% were euthyroid with positive antibodies (anti-thyroid peroxidase antibodies [TPOAb]). From the 144 subjects, we selected a cohort of 78 euthyroid subjects with negative TPOAb, who did not receive LT4 replacement or suppression therapy (the experimental group) and compared them to 77 normal-weight euthyroid subjects, TPOA-negative, matched for age and gender who served as controls. The experimental group had higher serum levels of triiodothyronine (T3), thyroxine (T4), free triiodothyronine (FT3), and thyrotropin (TSH) compared to the control group. Serum TSH concentration was associated with fasting serum insulin levels and insulin resistance but not with serum leptin levels, body mass index (BMI), fat mass, and lean body mass. In conclusion, in morbidly obese individuals, the prevalence of overt and subclinical hypothyroidism was high (19.5%). The morbidly obese subjects have higher levels of T3, FT3, T4, and TSH, probably the result of the reset of their central thyrostat at higher level.

End-stage renal disease is considered a factor predisposing to increased risk of tuberculosis with frequent extrapulmonary localization. Although extrapulmonary tuberculosis has been observed for decades, disseminated tuberculosis, a major cause of morbidity and mortality in immunocompromised hosts, remains rather neglected. We report an unusual case of an immunocompromised patient with a late diagnosis and delayed treatment of genitourinary tuberculosis that subsequently led to the diagnosis of vertebral and miliary tuberculosis (disseminating tuberculosis). Therefore, increased awareness is warranted from physicians dealing with hemodialysis patients in order to avoid delays in diagnosis and treatment initiation.

OBJECTIVE: Adequate dietary iodine intake is necessary for normal thyroid gland function at all times, and most particularly during pregnancy. Increased iodine loss is cited, among other factors, as responsible for the increased iodine demand in this period. Our aim was to compare renal iodine excretion between women during all three pregnancy trimesters with that of their spouses and thereby to estimate the iodine intake in an a large sample of pregnant women in urban areas in Greece. DESIGN: Four hundred twenty-four healthy pregnant women were included prospectively (residents of Athens n=218, residents of Patras n=206). The spouses of 177 of these women following the same diet were also studied. Determinations included serum FT4, TSH and aTPO and urinary iodine excretion (UIE). RESULTS: No difference was found either in median UIE throughout pregnancy or between the UIE of the pregnant women and their spouses during the trimesters. Throughout pregnancy, mild iodine deficiency was noted and was classified as mild in 60%, moderate in 30% and severe in 10% of the women studied. Users of iodized salt had significantly higher median UIE compared with non-users. Serum FT4 levels decreased and TSH increased as pregnancy progressed. CONCLUSIONS: Our study indicates that renal iodine excretion is not increased during pregnancy. This finding needs to be confirmed by further investigation in other populations with different iodine intakes. Thus, increased iodine requirements in pregnancy are possibly due to extra-renal causes. The population of pregnant women in Greek urban areas is mildly-and often moderately and severely-iodopenic and needs to be treated accordingly.

The etiology of the prompt decline in serum T3 in patients with nonthyroidal illness syndrome has not been adequately explained. It has been attributed to various parameters, including test artifacts, inhibitors of T4 and T3 binding to proteins, decreased 5′-deiodinase activity, and circulating cytokines. Currently, much attention is centered on the role of IL-6 and TNFα in developing the nonthyroidal illness syndrome through an effect on the hypothalamus, pituitary, and possibly 5′-deiodinase activity. We therefore studied the relation of the endogenous serum IL-6 and TNFα rise early in the course of nonthyroidal illness syndrome to the early decline in serum T3 in 19 apparently healthy individuals, aged 43 ± 16 yr, who underwent elective abdominal surgery for cholelithiasis or gastroplasty. Serum T3, free T3, T4, free T4, rT3, TSH, IL-6, and TNFα were measured before and at various time intervals up to 42 h after skin incision. We observed a prompt decline in serum T3 30 min before skin incision, which continued to decline throughout the observational period. The magnitude of the decline reached 20% from the baseline value at 2 h. The early decline of T3 was attenuated and lasted from the 2–8 h, probably due to the sharp increase in serum TSH that started immediately after the entrance to the operating room and lasted for 2 h. In contrast, serum T4 and free T4 concentrations were increased soon after skin incision and remained elevated during the first postoperative day. Serum rT3 increased approximately 6 h after the initiation of surgery and remained elevated thereafter. Serum IL-6 remained essentially undetectable for 2 h after skin incision, whereas serum T3 was low. Two hours after skin incision, serum IL-6 increased sharply and remained elevated throughout the observational period. Serum TNFα remained essentially undetectable throughout the postoperative period. Serum cortisol increased rapidly upon entrance to the operating room and remained elevated throughout the postoperative period. We conclude that the decline in serum T3 early in the course of nonthyroidal illness syndrome is not due to increased serum IL-6 or TNFα levels. The brisk TSH secretion soon after the onset of the syndrome attenuates the decline in serum T3 due to T3 secretion from the thyroid. The early and brisk cortisol response to surgery may at least in part explain the early decrease in serum T3 in nonthyroidal illness syndrome.

The endothelial cells that line blood and lymphatic vessels undergo complex, collective migration and rearrangement processes during embryonic development, and are known to be exquisitely responsive to fluid flow. At present, the molecular mechanisms by which endothelial cells sense fluid flow remain incompletely understood. Here, we report that both the G-protein-coupled receptor sphingosine 1-phosphate receptor 1 (S1PR1) and its ligand sphingosine 1-phosphate (S1P) are required for collective upstream migration of human lymphatic microvascular endothelial cells in an in vitro setting. These findings are consistent with a model in which signalling via S1P and S1PR1 are integral components in the response of lymphatic endothelial cells to the stimulus provided by fluid flow.

The aim if this study is to evaluate parental readiness to implement changes in specific life-style behaviours for preventing or reducing obesity in children.Eighty-seven parents of overweight or obese children participated in this cross-sectional study. Parents completed a questionnaire for the assessment of their perceptions about their children's weight and their readiness to take action in general, as well as in relation to ten obesogenic life-style behaviours. The transtheoretical model with the five stages of change (precontemplation, contemplation, preparation, action and maintenance) was used for this assessment. A total readiness score was calculated for the 10 behaviours.A total of 4.6% of parents were in the precontemplation-contemplation stage for overall weight management. However, this percentage was greater for particular behaviours, such as allowing children to self-regulate their food intake, having family meals, reducing screen time and increasing physical activity. Child's body mass index, paternal education level and parental perception about child's excessive weight being attributed to over-consumption of sweets and salty snacks were significantly associated with total readiness score.The results of the present study indicate that the high readiness for general action reported by parents of overweight/obese children does not necessarily imply their readiness to engage in changes in specific life-style behaviours.