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The metabolic syndrome (MetS), a constellation of cardiovascular risk factors, is a growing health challenge worldwide. Most studies on MetS epidemiology are from developed countries. The Middle East is lagging behind in understanding the epidemiology of MetS and its risk factors in the region. This is partly owing to a scarcity of high-quality, nationally representative studies. In a series of recent national surveys, we have studied the epidemiology of MetS and its risk factors in Iran. We review the current situation in the region and highlight current gaps of knowledge and epidemiological concepts that need to be taken into account when doing population-level health programming. We explore the results of our national surveys as successful examples along this path.

Introduction: We recently reported on the Minnesota acute GVHD Risk Score that is based on the number of involved organs and severity of GVHD at onset. Using clinical grouping, descriptive statistics and recursive partitioning, we identified poorly responsive, high-risk (HR) acute GVHD by the number of involved organs and severity of GVHD at onset. Patients with HR GVHD were 3 times less likely to respond to steroid therapy and had >2 fold increased risk of mortality and transplant-related mortality (TRM) than patients in the standard risk (SR) GVHD group. This GVHD Risk Score more accurately predicts response, survival and TRM than other published GVHD risk scores based upon clinical grading criteria (BBMT.2015,21:761). Methods: To validate this Risk Score, we examined a new cohort (2008-2016) of 355 patients (median age 49 years, range Results: All patients had >6 months follow-up after steroid initiation (median 3.2 years). 79 (22%) patients had HR GVHD and 276 (78%) had SR GVHD. Demographics were similar in the two groups (Table). Overall response [complete response (CR)+partial response (PR)] was significantly higher in the 276 SR vs 79 HR GVHD patients at day 14 (71% vs 56%, p Conclusions: This analysis confirms that the Minnesota GVHD Risk Score is a valuable, immediately available bedside tool to define risk in patients with acute GVHD and predicts outcomes better than GVHD clinical grades. These results also demonstrate the importance of age, HCT-CI, graft source, and time to onset of GVHD on outcomes after GVHD therapy. Notably, UCB recipients have better responses to steroid therapy and lower subsequent risk for chronic GVHD than other donor sources. These data suggest that a tailored approach to upfront GVHD therapy based upon the Minnesota acute GVHD Risk Score and other risk factors should be considered in order to improve outcomes in patients with acute GVHD. Further studies are needed to explore why cord blood recipients with acute GVHD respond better than BM/PBSC recipients with a similar severity of GVHD. Disclosures MacMillan: Angiocrine: Membership on an entity's Board of Directors or advisory committees; CSL Behring: Consultancy; Equillium: Consultancy. Holtan:Incyte: Consultancy. Brunstein:Gamidacell: Research Funding. Wagner:Magenta Therapeutics: Consultancy, Research Funding; Novartis: Research Funding. Blazar:Kadmon Corporation, LLC: Consultancy, Research Funding. Weisdorf:SL Behring: Consultancy; Equillium: Consultancy; FATE: Consultancy; Pharmacyclics: Consultancy; Seattle Genetics: Consultancy.

Introduction: Gut bacteria modulate the immune system and influence outcomes of allogeneic hematopoietic cell transplantation (allo-HCT). The presence of Blautia, butyrate-producing Clostridia, and Eubacterium limosum in the stool has been associated with lower mortality after allo-HCT. We previously reported an unexpected association between pre-HCT gut colonization with intrinsically vancomycin-resistant enterococci (iVRE: E. gallinarum and E. casseliflavus) and improved overall survival (OS) due to decreased non-relapse mortality (NRM). In an expanded cohort, now also including patients who were iVRE-colonized early post-HCT (before day +14), we demonstrate that the iVRE association with improved OS is specific to E. casseliflavus. Patients and Methods: We studied allo-HCT recipients at our institution who had at least 1 positive rectal swab or stool culture for iVRE between days -14 and +14. New admissions for HCT were screened for gut VRE colonization weekly until discharge. SpectraTM VRE chromogenic agar medium (ThermoFisher Scientific) was used for species-level identification. Antimicrobial prophylaxis consisted of levofloxacin, acyclovir, and an azole. Cefepime was our empiric antibiotic for neutropenic fever. Results: 66 (23 with E. casseliflavus and 43 with E. gallinarum) of the 873 allograft recipients between 2011-2017 met our inclusion criteria. As expected from the constitutive, rather than acquired, vancomycin resistance of iVRE, the groups did not differ in their prior exposure to different classes of antibiotics. There were no significant differences between the groups in patient-, disease-, or transplant-related characteristics, except a higher frequency of sirolimus-based GVHD prophylaxis in the E. casseliflavus group (35% vs. 12%, P = 0.05). With a median follow up of 30 months, OS was significantly better in patients with E. casseliflavus (91% vs. 62% at 3 years, P = 0.04), due to lower NRM (0 vs. 18% at 3 years, P = 0.05) (Figures 1A and 1B). Only 2 patients with E. casseliflavus died within 3 years post-HCT, both due to relapse. In contrast, 14 patients with E. gallinarum died within 3 years post-HCT: 7 (50%) due to relapse, and 7 (50%) from NRM (4 GVHD, 1 infection, 1 graft failure, and 1 veno-occlusive disease). In multivariable analysis, E. casseliflavus gut colonization was significantly associated with reduced all-cause mortality (hazard ratio 0.20, 95% confidence interval 0.04-0.91, P = 0.04). There were no significant differences between the groups in 180-day acute grade II-IV GVHD (P = 0.19), 1-year chronic GVHD (P = 0.56), 100-day bacteremia (P = 0.59), or 100-day Clostridium difficile infection (P = 0.79). To probe the mechanism of this protection against mortality, we mined 15 E. casseliflavus and 8 E. gallinarum sequenced genomes for 14 shikimate and tryptophan metabolism enzymes. This analysis predicted that E. casseliflavus encodes a larger number of enzymes in the tryptophan metabolism pathway (Figure 1C). Several compounds in this pathway are ligands for the aryl hydrocarbon receptor (AhR). Signals downstream of AhR augment the gut barrier and modulate the immune system, potentially reducing pathogenic injury and inducing protective immune responses. Conclusions: Pre-engraftment gut colonization with E. casseliflavus, but not E. gallinarum, improves survival after allo-HCT. Future mechanistic studies of the interactions between E. casseliflavus and the host can guide the development of novel microbiota-oriented therapeutics in this high-risk patient population. Disclosures Weisdorf: Seattle Genetics: Consultancy; FATE: Consultancy; SL Behring: Consultancy; Pharmacyclics: Consultancy; Equillium: Consultancy.

INTRODUCTION: Patients with severe acute graft-versus-host disease (aGVHD) are at high risk of death due to damaged organs and tissues. We have previously shown that severe aGVHD is characterized by an imbalance of circulating tissue repair factors, with elevated amphiregulin (AREG) and very low ( PATIENTS AND METHODS: Twenty-six patients received hCG/EGF in addition to standard aGVHD therapy. We treated 13 patients with onset Minnesota High Risk aGVHD with high-dose steroids (methylprednisolone 48 mg/m2) plus subcutaneous (SQ) injections of hCG/EGF every other day for 7 days. In the 2nd line therapy cohort, we treated 13 patients with hCG/EGF SQ every other day for 14 days, recognizing the time to response may be longer in this cohort relative to those with onset aGVHD, along with increased steroids (steroid dependent, N=5) and intensified immune suppression (steroid refractory, N=8). We then assessed response after 7 days in High Risk aGVHD and after 14 days in steroid dependent/refractory aGVHD. In both cohorts, patients with a complete or partial response (CR/PR) at the end of the initial dosing period were eligible to receive maintenance hCG/EGF SQ twice weekly for up to 5 weeks, whereas patients with no response (NR) received no further study drug doses and received best available therapy from their treating physicians. Initial hCG dosing was at 500 units hCG/m2 SQ, escalating to 2,000 units hCG/m2 in cohorts of 2, with dose assignment by the continual reassessment method. We analyzed GVHD-associated plasma biomarkers and enumerated circulating CD4+FoxP3+CD127- Tregs and CD8+ T lymphocytes during therapy. RESULTS: HCG/EGF was well tolerated, with no dose-limiting toxicities. The median EGF dose was 50,833 pg/ml. The most common treatment emergent side effect was edema (N=16, 62%). At day 28 of study, responses for initial therapy were 8/13 CR (62%), 0/13 PR (0%), and 5/13 NR (38%), higher than institutional historical (n=269) 26% CR, 16% PR, 57% NR (Figure 1A). Responses for 2nd line therapy were 7/13 CR (54%), 1/13 PR (8%), 5/13 NR (38%), 4 of which were deaths (31%), improved relative to historical outcomes (n=85) of 18% CR, 19% PR, 63% NR (including 16% deaths, Figure 1A). Cytopenias were not worse during hCG/EGF; responders had a slight leukocytosis (day 7 median white blood cells [WBC] 9.7 x 109/L), returning to baseline (WBC 5.8 x 109/L, p=0.015) by day 56. Patients had increases in serum hCG (median 1.5 vs 138 IU/L, p CONCLUSIONS: HCG/EGF is a novel and well-tolerated adjunct therapy in high-risk and steroid-dependent/refractory aGVHD, associated with minimal toxicity and encouraging response rates. The mechanisms of benefit may include immunomodulation via Treg expansion despite high-dose steroids and facilitation of tissue repair with detectable increases in circulating EGF. The optimal dose and duration of hCG/EGF are under investigation, with ongoing dose escalation in patients with steroid-refractory aGVHD based upon these initial results. Decreasing plasma AREG over time may reflect successful treatment of life-threatening aGVHD. Figure 1 Figure 1. Disclosures Holtan: Incyte: Consultancy. Bachanova:Gamida Cell: Research Funding; Kite Pharma: Membership on an entity's Board of Directors or advisory committees; GT Biopharma: Research Funding. Brunstein:Gamidacell: Research Funding. Ustun:novartis: Speakers Bureau. Wagner:Novartis: Research Funding; Magenta Therapeutics: Consultancy, Research Funding. Blazar:Kadmon Corporation, LLC: Consultancy, Research Funding. MacMillan:Angiocrine: Membership on an entity's Board of Directors or advisory committees; CSL Behring: Consultancy; Equillium: Consultancy. Weisdorf:SL Behring: Consultancy; FATE: Consultancy; Equillium: Consultancy; Seattle Genetics: Consultancy; Pharmacyclics: Consultancy.

Hematopoietic cell transplantation (HCT) is curative for many malignancies and genetic disorders but is hampered by significant early morbidity related to infection, regimen-related toxicities, acute graft versus host disease (GVHD), and risk of relapse. An excess risk of early death may be predicted by biomarkers associated with tissue healing, inflammation, and angiogenesis, as complementary to clinical variables. We have previously shown that pre-transplant low levels of one such biomarker, epidermal growth factor (EGF), is associated with poor survival after HCT. We have also shown that another EGF receptor ligand, amphiregulin (AREG), is elevated at the onset of aGVHD and is associated with a poor prognosis, especially if markedly elevated relative to EGF. AREG is active in type 2 immune responses and in dampening localized inflammation, but it found in the circulation in the states of unresolved tissue damage. We hypothesized that an elevated AREG relative to EGF prior to HCT would be associated with poor survival. To test this hypothesis, we measured pre-HCT plasma EGF and AREG in 142 pediatric and adult HCT recipients from 2015-2017, with patients undergoing HCT for both malignant and non-malignant disease using various stem cell sources, GVHD prophylaxis, and conditioning regimens. We measured baseline plasma concentration of factors associated with tissue damage and repair, AREG by ELISA and EGF, vascular endothelial growth factor-A (VEGF-A), and placental growth factor (PlGF) by multiplex. We determined the optimal cutpoint for dichotomized analyses of AREG/EGF based on overall survival (OS) through 12 months post-transplant by method of Contal and O'Quigley, choosing a point that maximizes the log-rank statistic. Patients (table) had a median 2.1 years of follow-up and a median baseline AREG/EGF ratio of 0.3 (IQR 0.1 - 1.7). A high baseline AREG/EGF ratio (cutoff of ≥2.5, in 30 patients, 21%) was associated with a >2-fold increased risk of all-cause mortality after HCT (HR 2.1, p = 0.037, Figure 1A). Clinical factors such as age, donor type, conditioning, disease, and overall comorbidity were not related to baseline AREG/EGF ratio. However, more patients with a baseline high AREG /EGF ratio had infections requiring systemic treatment at the time of transplant (26.7% vs 11.6%, p=0.039), higher rates of recent C. difficileinfections (23.3% vs 9.7%, p=0.046), suggesting a vulnerability to dysbiosis. Furthermore, a high AREG/EGF ratio at baseline was associated with other plasma biomarkers associated with tissue injury, with lower VEGF-A levels (61 vs 226 pg/ml, p In this large and broad cohort of allograft recipients, over 20% of pediatric and adult HCT recipients have an elevated plasma AREG/EGF ratio prior to transplantation. These patients have a biomarker profile of unresolved tissue injury (low VEGF-A and high PlGF) and more frequent infections at the time of transplantation, including C. difficile. Further research into the systemic effects of dysbiosis may clarify the pathophysiology of this elevated AREG/EGF ratio and unresolved tissue injury. If confirmed, baseline AREG/EGF could identify patients most likely to benefit from novel tissue and/or microbial restorative therapies prior to HCT. Figure 1. Figure 1. Disclosures MacMillan: Equillium: Consultancy; CSL Behring: Consultancy; Angiocrine: Membership on an entity's Board of Directors or advisory committees. Weisdorf:Equillium: Consultancy; FATE: Consultancy; Seattle Genetics: Consultancy; SL Behring: Consultancy; Pharmacyclics: Consultancy. Holtan:Incyte: Consultancy.

Various polymorphisms occur in cytokine genes involved in inflammatory processes in Graves' ophthalmopathy (GO). Anti-inflammatory cytokines such as transforming growth factor- β (TGF-β), interleukin-10 (IL-10) and interleukin-4 (IL-4) are among those believed to be involved in the disease process. In this study, we investigated the association between 8 polymorphisms within the mentioned cytokines and GO.The following polymorphisms were studied in 50 patients with GO, 57 Graves' patients without GO and 140 healthy individuals using polymerase chain reaction with sequence-specific primers: TGF-β (+869C/T, +915G/C), IL-10 (-1082A/G, -819C/T, -592C/A) and IL-4 (-1098T/G, -590T/C, -33C/T). A corrected p value less than 0.05 was considered statistically significant.The TGF-β +915C allele (Odds Ratio [OR] = 2.20) and CC genotype (OR = 7.50) as well as +869C allele (OR = 2.21) showed significant correlations with GO. Regarding IL-4 polymorphisms, the -1098G allele (OR = 2.09) and GG genotype (OR = 7.49), and the -33T allele (OR = 2.05) and TT genotype (OR = 4.00) were significantly associated with GO. The IL-10 -819TT genotype (OR = 5.00) was significantly correlated with GO.This is the first study to show that polymorphisms in anti-inflammatory cytokine genes are associated with susceptibility to GO.

Obesity is a rapidly progressing pandemic and a central feature of the metabolic syndrome. There is no solid evidence on the recent trends of obesity in Iran. In this study we present the secular trends of overweight and obesity among Iranian adults (25-64 years old) within an 8-year period (1999-2007).The analyses were performed on the datasets of three cross-sectional national surveys: The National Health Survey-1999 (n = 21,576), National Surveys of Risk Factors for Non-Communicable Diseases (SuRFNCD)-2005 (n = 70,945), and SuRFNCD-2007 (n = 4,186).The overall prevalence of obesity increased from 13.6% in 1999 to 19.6% in 2005 and 22.3% in 2007 [odds ratio (OR) = 1.08 per year; P0.001]. For overweight subjects, the rates were, respectively, 32.2%, 35.8% and 36.3% (OR = 1.02 per year; P0.001). During these years, the mean body mass index (BMI) (kg/m(2)) increased from 25.03 in 1999, to 26.14 in 2005, and 26.47 and 2007 (P0.001). The increase in prevalence of obesity was seen in both males (OR = 1.09 per year; P0.001) and females (OR = 1.07 per year; P0.001) and both urban (OR = 1.07 per year; P0.001) and rural (OR = 1.10 per year; P0.001) residents.In conclusion, the present study highlighted the rapid growth of obesity during recent years in Iran. Our findings indicate the crucial necessity of primary prevention programs to counteract this undesired condition.

Chromosomally integrated human herpesvirus-6 (ciHHV-6) can be transmitted from parent to child or via allogeneic hematopoietic cell transplantation (HCT). We report a case of ciHHV-6 transmitted via syngeneic HCT, and vertically across 3 generations. ciHHV-6 was transmitted from a parent to the patient and her identical twin, and from the patient to her son. The patient underwent syngeneic HCT as rescue from chemotherapy-induced aplasia during which ciHHV-6 was re-transmitted to her, this time from her identical twin. This is the first report, to our knowledge, of a patient acquiring ciHHV-6 once via germline from a parent and again via syngeneic HCT from an identical twin.

Background: Previous studies report on smoking in Iran but recent national data on tobacco use (including cigarette, water-pipe and pipe) have not been reported. Methods: In 2007, 5287 Iranians aged 15 to 64 years were sampled from all provinces as part of a national cross-sectional survey of non-communicable disease (NCD) risk factors. Data were collected using the standardized stepwise protocol for NCD risk factor surveillance of the World Health Organization. Use of tobacco products was calculated as the sum of smoking cigarettes/cigars (smoking currently or daily any amount of factory/hand-made cigarettes or cigars), pipes (daily), and water pipes (daily). Results: Total current and daily tobacco use were 14.8% (burden: 7.3 million) and 13.7% (burden: 6.7 million) when extrapolated to the Iranian population aged 15-64. The prevalence of current and daily cigarette smoking was 12.5% (6.1 million; 23.4% males and 1.4% females) and 11.3% (5.6 million; 21.4 males and 1.4 females); former smokers comprised 1.7 million or 3.4% of the Iranian population (6.2% males and 0.6% females; mean cessation age: 34.1). The mean age of starting to smoke was 20.5 years (24.2 males and 20.4 females). The prevalence of water-pipe smoking was 2.7% (burden: 1.3 million; 3.5% males and 1.9% females). Water-pipe smokers used it on average 3.5 times per day (2.8 males and 4.5 females). Conclusion: The prevalence of tobacco use has not escalated over the two past decades. Nonetheless, the burden is high and therefore warrants preventive public health policies.

Leptin is correlated with several features of metabolic syndrome; however, possible confounders (eg, obesity) of this association are not known. This study evaluated the relationship between leptin, metabolic syndrome, and insulin resistance in an Iranian population and further investigated whether this relationship is confounded by obesity or central obesity.A total of 387 participants (18-65 years old) who referred to a large university general hospital for routine health examinations were categorized into 2 groups with (n = 130) and without (n = 257) metabolic syndrome. Fasting plasma glucose, insulin, lipids, and leptin levels were measured and the homeostasis model assessment of insulin resistance (HOMA-IR) was calculated. Metabolic syndrome was defined according to the National Cholesterol Education Program Adult Treatment Panel III (NCEP ATP III) criteria.Age- and sex-adjusted leptin levels were significantly higher in patients with than those without metabolic syndrome (29.62 +/- 1.67 vs. 18.50 +/- 1.21 ng/mL, P0.001). After adjustment for age, sex, and body mass index (BMI), leptin values were significantly correlated with HOMA-IR (P0.001), metabolic syndrome, and its components (P0.05). After adjustment for waist circumference, however, these associations were no longer statistically significant.We demonstrated that high leptin levels are associated with insulin resistance and metabolic syndrome independent of BMI but these associations are significantly mediated through the effects of central obesity.

Metabolic syndrome (MetS) is a common health problem in developing countries. We aimed to assess the association between different aspects of physical activity and MetS in our country. A standardized international questionnaire (Global Physical Activity Questionnaire) recommended by the World Health Organization was used in the third national survey of risk factors of noncommunicable diseases (SuRFNCD-2007) to collect physical activity data from a nationally representative sample of Iranian adults. Physical activity was evaluated in 3 domains: work, commuting, and recreational activities. Both duration and intensity of activity were considered. Biochemical measurements were carried out, and MetS was defined by the International Diabetes Federation and the Adult Treatment Panel III criteria. The data collected from a total of 3296 individuals were analyzed. The national prevalence of MetS was estimated to be between 24% and 30%, depending on sex and the criteria used. The prevalence of MetS among individuals with high-, moderate-, and low-category activity was 18.7% +/- 1.5%, 25.8% +/- 2.0%, and 27.9% +/- 2.0%, respectively (P < .001). These rates were 12.6% +/- 1.6%, 26.0% +/- 1.5%, and 34.1% +/- 3.2% among individuals with vigorous activity, with nonvigorous activity, and without activity, respectively (P < .001). We demonstrated a significant linear association between the number of metabolic abnormalities and lower levels of various aspects of physical activity (total physical activity, duration of domain-specific activity, and duration of intensity-specific activity; P < .001 for all). Notably, the risk for MetS increased 1.28-fold with every 30-min/d reduction in vigorous-intensity activity (95% confidence interval = 1.15-1.42, P < .001). The results of the present study should be considered for future public health programs in Iran.

Artificial neural networks (ANN) have not been used in chronic subdural hematoma (CSDH) outcome prediction following surgery. We used two methods, namely logistic regression and ANN, to predict using eight variables CSDH outcome as assessed by the Glasgow outcome score (GOS) at discharge. We had 300 patients (213 men and 87 women) and potential predictors were age, sex, midline shift, intracranial air, hematoma density, hematoma thickness, brain atrophy, and Glasgow coma score (GCS). The dataset was randomly divided to three subsets: (1) training set (150 cases), (2) validation set (75 cases), and (3) test set (75 cases). The training and validation sets were combined for regression analysis. Patients aged 56.5 +/- 18.1 years and 228 (76.0%) of them had a favorable outcome. The prevalence of brain atrophy, intracranial air, midline shift, low GCS, thick hematoma, and hyperdense hematoma was 142 (47.3%), 156 (52.0%), 177 (59.0%), 82 (27.3%), 135 (45.0%), and 52 (17.3%), respectively. The regression model did not show an acceptable performance on the test set (area under the curve (AUC) = 0.594; 95% CI, 0.435-0.754; p = 0.250). It had a sensitivity of 69% and a specificity of 46%, and correctly classified 50.7% of cases. A four-layer 8-3-4-1 feedforward backpropagation ANN was then developed and trained. The ANN showed a remarkably superior performance compared to the regression model (AUC = 0.767; 95% CI, 0.652-0.882; p = 0.001). It had a sensitivity of 88% and a specificity of 68%, and correctly classified 218 (72.7%) cases. Considering that GOS strongly correlates with the risk of recurrence, the ANN model can also be used to predict the recurrence of CSDH.

The cytotoxic T lymphocyte associated antigen-4 (CTLA-4) gene, is one of the candidate genes for susceptibility to Graves' disease. This study aimed to investigate the association of Graves' disease and Graves' ophthalmopathy with polymorphisms at position +49 in exon 1 and positions -318 and -1147 in the promoter region of CTLA-4 gene in Iranian patients.A total of 205 unrelated Iranian patients with Graves' disease who were referred to the outpatient endocrine clinic of a large university general hospital and 103 sex-matched healthy controls were included in this study. Venous blood was obtained, genomic DNA was extracted by a salting out method, and the polymorphisms at positions +49, -318 and -1147 of the CTLA-4 gene were determined using the PCR-restriction fragment length polymorphism method (PCR-RFLP). Genotype and allele frequencies were determined.The frequency of the G allele at position +49 was significantly higher in patients with Graves' disease than in the control group (27.1% vs. 15.1%, OR=2.096, 95%CI=1.350-3.253 and p0.01). Significant trends were not seen for the other two polymorphisms studied. In patients with ophthalmopathy, the frequency of the G allele at position +49 was higher than in those without ophthalmopathy (33.8% vs. 20.0%, OR=2.043, 95%CI=1.304-3.202 and p0.01).The results of this study suggest that the G allele at position +49 in exon1 of the CTLA-4 gene is associated with Graves' disease and Graves' ophthalmopathy in Iranian patients.

We opted in this study to evaluate the association between metabolic syndrome (MetS) and microalbuminuria in type 2 diabetes. A total of 800 adults (344 males; age 54.8 ± 9.6 years) with type 2 diabetes were studied. MetS was defined by the International Diabetes Federation criteria and microalbuminuria by urinary albumin excretion between 30 and 299 mg/day on at least two of three occasions. Patients with macroalbuminuria and those with poor renal function were not included. Microalbuminuria was present in 237 (29.6%) patients with MetS and increased in prevalence with increasing numbers of metabolic abnormalities (P

The lack of an effective antioxidant system in beta-cells, which renders them susceptible to oxidative stress, is to date without explanation. The particular weakness of beta-cells in females, in both humans and mice, is another unexplained observation. We hypothesise that reactive oxygen species (ROS) in beta-cells, by their negative effect on insulin synthesis/secretion, play a fitness-enhancing role for the whole organism. Under stress conditions, the release of stress hormones produces insulin resistance and, owing to ROS preventing beta-cells from secreting insulin at the level required to maintain homeostasis, diverts glucose to insulin-independent tissues such as the brain and the foetus. We suggest that pancreatic beta-cells lost part of their antioxidant defence in association with brain evolution, and lost even more in females when placental mammals evolved. The unusual antioxidant status of beta-cells may thus be explained as an instance of co-evolution of the brain, cortisol and corticosteroid receptors, and beta-cells in the endocrine pancreas.

Metabolic syndrome (MetS) is a cluster of metabolic risk factors for cardiovascular disease. This study aimed to compare the prevalence of MetS and its components in different degrees of obesity in Iranian subjects.A total of 2309 adults were divided into four groups according to their body mass index (BMI): 1511 subjects were non-obese (BMI30 kg/m(2)); 535 were moderately obese (BMIor =30-35); 176 were severely obese (BMIor =35-40) and 87 were morbidly obese (BMIor =40). Fasting blood samples were obtained and plasma glucose, lipids, insulin and HbA1c were measured. The homeostasis model assessment of insulin resistance (HOMA-IR) was calculated. The prevalence of MetS, according to the definitions of the International Diabetes Federation (IDF) and National Cholesterol Education Program Adult Treatment Panel III (ATPIII), was compared across increasing grades of BMI.Prevalence of MetS gradually rose with increasing grades of obesity (p0.001), from 31.9% in the non-obese to 69.0% in the morbidly obese according to the IDF criteria and from 31.2% to 62.1% according to the ATPIII criteria. After controlling for age and sex, one grade increase in the BMI category was associated with 2.5-3 times higher risk of MetS depending on the definition used. In addition, HOMA-IR was significantly correlated with BMI in all subjects (r=0.343, p0.001) and in moderately (r=0.184, p0.01), severely (r=0.147, p0.01) and morbidly (r=0.101, p0.05) obese participants separately.MetS and its components, including high blood pressure, central obesity, hyperglycemia, IR, hypertriglyceridemia and low high-density lipoprotein-cholesterol increase in parallel with increasing obesity grades.

Background Laparoscopic techniques for placement of peritoneal dialysis catheters are becoming increasingly popular. In this paper, we report the results of one-port laparoscopic placement of Tenckhoff catheters in 79 patients in our center. Method Videoscopic monitoring was performed via a port inserted in the left upper quadrant and the catheter was placed via a pull-apart sheath through an incision near the umbilicus. The tip and the deep cuff of the catheter were placed into the true pelvis (on the urinary bladder) and into the rectus sheath respectively. A subcutaneous tunnel was created and a point midway on the umbilico-crestal line was selected as the exit site of the catheter. Catheters were capped for 2 weeks before initiation of peritoneal dialysis. Mean duration of the operation was 25 minutes. Results Four patients died during the follow-up period, all due to other medical problems, and 4 patients underwent renal transplantation. During a 48-month follow-up, catheter-related complications were catheter migration (1.3%; month 1), dialysate leakage (1.3%; month 1), port-site hernia (3.8%; after 6 months), exit-site infection (2.5%; months 1 and 9), and bacterial peritonitis (2.5%; after 6 months). Catheter survival was 97.2% in our series. Conclusion We obtained a low complication rate and a high catheter survival rate with this one-port laparoscopic technique.

Aims Central obesity, a prominent feature of metabolic syndrome (MetS), is commonly assessed by gender- and ethnicity-specific waist circumference (WC) cut-off values. Since 2006, the recommended WC cut-offs by the International Diabetes Federation (IDF) for Europeans are used in Iran because of limited data availability. The purpose of this study was to determine optimal cut-off points for the diagnosis of MetS in Iran. Methods A total of 2752 adults (1046 men) were studied. Subjects with two or more of the following risk factors from the IDF criteria were considered to have multiple risk factors: hyperglycemia (FBG ≥ 100 mg/dL or diagnosed diabetes), high blood pressure (SBP ≥ 130 mmHg, DBP ≥ 85 mmHg, or using antihypertensive drugs), low HDL ( 150 mg/dL). Results The WC cut-off yielding maximum sensitivity plus specificity for predicting the presence of multiple risk factors was 91.5 cm in men and 85.5 cm in women. Sensitivity and specificity were 77% (86%) and 58% (50%) in men (women), respectively. MetS prevalence was estimated to be approximately 27% in Tehran. Conclusions WC cut-offs recommended by the IDF are not appropriate for use in Iran.

Abnormal high-density lipoproteins (HDL) metabolism is a major cardiovascular risk factor in type 2 diabetes mellitus (DM2). Lecithin:cholesterol acyltransferase (LCAT) increases HDL size by transferring 2-acyl groups from lecithin or phosphatidylethanolamine to unesterified cholesterol. The purpose of this study was to determine the independent correlates of LCAT activity in DM2 patients.A total of 45 (male: 20) consecutive adult DM2 patients aging 50.0+/-7.0 years (range: 40-64 years) with a median diabetes duration of 4 years (range: 2-18) were studied. Exclusion criteria were: smoking, positive history of cardiovascular, thyroid, renal or liver disease, pregnancy, treatment with metformin, insulin, lipid lowering drugs, angiotensin-converting enzyme inhibitors, aspirin or antioxidant supplements. Univariate and multivariate analyses were performed.From a comprehensive list of variables studied, only HbA1c (rho=-0.951) and oxidized LDL (rho=-0.779) had statistically significant correlation with LCAT activity (p0.001). These two variables were themselves strongly correlated to each other (rho=0.809, p0.001). To eliminate potential confounding effects, we performed multivariate analysis, where HbA1c emerged as a strong independent predictor of LCAT activity (adjusted OR=-0.928, p0.001).Glycemia-induced glycation of HDL decreases LCAT activity. The fact that HbA1c is an accurate measure of glycation and can therefore reflect glycated HDL levels explains the association found in the present study. In conclusion, HbA1c provides an easy-to-assess, accurate measure of LCAT activity in DM2.

Rhabdoid tumor of the kidney (RTK) is a rare and highly malignant neoplasm of infancy, with a strong tendency for early metastasis to distant regions. RTK is unique in its significant association with primary or metastatic brain tumors. The authors report the first case of RTK presenting initially with hemiplegia. The patient was found thereafter to have RTK concurrent with pulmonary metastases, a brain tumor, and a cerebral ischemic lesion. Intensive chemotherapy consisting of carboplatin and etoposide alternating with cyclophosphamide was unsuccessful and the patient died 5 months later because of severe respiratory distress resulting from widespread pulmonary metastases.

The object of this study was to determine the relationship between outcome (assessed by Glasgow Outcome Scale) and recurrence in chronic subdural haematoma (CSDH). Eighty-two consecutive patients who underwent surgery for CSDH were included in this study. The relationship between the following variables and CSDH recurrence was studied: sex; age; history of trauma; Glasgow Coma Scale (GCS) at the time of admission (stage 1: GCS12, stage 2: GCS: 8 - 12, stage 3: GCS8); interval between head injury (when a history of trauma was present) and surgery; presence of a midline shift on CT scans; presence of intracranial air 7 days after surgery; haematoma density; haematoma width; presence of brain atrophy; and Glasgow Outcome Scale (GOS, both quantitative and non-quantitative) at the time of discharge. Throughout the analysis, p0.05 was considered statistically significant. The results showed lower GCS (p0.001), higher GOS (p0.001), presence of intracranial air 7 days after surgery (p=0.002), and a high density haematoma (p0.001) were significantly associated with recurrence of CSDH. It was concluded that GOS is related with recurrence in CSDH.

Acute myeloid leukemia presenting with extensive bone marrow necrosis, leukemia cutis and testicular involvement: successful treatment with allogeneic hematopoietic stem cell transplantation

A large number of elderly patients with acute myeloid leukemia (AML) are not offered treatments with curative intent, such as allogeneic stem cell transplantation (SCT), because of fears of toxicity and perceived futility of intensive treatment. Therefore, the outcomes of SCT in elderly AML patients remain poorly defined. We performed a meta-analysis of all previous articles up until September 22, 2015 of SCT in AML patients >60 years. The primary endpoints were relapse-free survival (RFS) and overall survival (OS) at 6 months and at 1, 2, and 3 years. A total of 13 studies (749 patients) were included. The pooled estimates and 95% confidence intervals (CI) for RFS at 6 months, 1 year, 2 years, and 3 years were 62% (95% CI, 54% to 69%), 47% (95% CI, 42% to 53%), 44% (95% CI, 33% to 55%), and 35% (95% CI, 26% to 45%), respectively. The corresponding numbers for OS were 73% (95% CI, 66% to 79%), 58% (95% CI, 50% to 65%), 45% (95% CI, 35% to 54%), and 38% (95% CI, 29% to 48%), respectively. We found no evidence of publication bias in our primary endpoints, with the exception of relapse, where there appeared to be a relative lack of small studies with high relapse rates. Sensitivity analysis did not identify an overtly influential study for our primary endpoints, with 1 exception in 2-year RFS analysis. The present analysis argues against significant publication bias and demonstrates consistency among reports despite differences in patient-, disease-, center-, and transplantation-related characteristics. Our results suggest that reduced-intensity SCT is a viable treatment option for elderly AML patients with a 3-year RFS of 35% for those over the age of 60. These results argue against using age per se as the sole criterion against SCT and would help remove some of the barriers that often preclude curative intent treatment. Correct identification of patients who would benefit from SCT can improve outcomes in this frequently undertreated population.

Hepatosplenic T-cell lymphoma (HSTCL) is a rare but aggressive type of non-Hodgkin lymphoma that primarily involves the sinusoids of the liver, red pulp of the spleen and the sinuses of the bone marrow. The specific rearrangement of the expressed T-cell receptor chain genes (TCR-αβ vs γδ) determines the subtype of the disease (HSαβTCL vs HSγδTCL). HSαβTCL is the rarer subtype with fewer than 30 cases reported in the literature.1 HSγδTCL is classically described in patients with inflammatory bowel disease treated with azathioprine, those on chronic immunosuppression following solid organ transplantation,2, 3 and patients treated with TNF-α inhibitors.4 On the other hand, most reported cases of HSαβTCL do not seem to have an underlying immune-related condition.1 Hepatosplenomegaly, cytopenias and stage IVB diseases are typical. Common cytogenetic abnormalities include isochromosome 7q and trisomy 8, and neoplastic T cells are usually CD4-CD8−.5 HSTCL has a tendency to affect younger individuals with a median age of 20–30 years. Whereas males are significantly more commonly affected with the γδ subtype (male:female (M:F) ratio of 10:1),3 the αβ subtype has a slight female preponderance (F:M ratio of 1.5:1).1 Without allogeneic stem cell transplantation (allo-SCT), HSTCL is an almost invariably fatal disease characterized by chemorefractoriness, unremitting clinical course, and a 5-year overall survival (OS) of 1.5 years compared with the group with RFS

ABSTRACT The prognosis of patients with relapsed/refractory peripheral T-cell lymphoma (PTCL) remains poor and current treatments are typically of limited benefit. Histone deacetylase (HDAC) inhibitors have proven effective for the treatment of relapsed/refractory PTCL. To date approved HDAC inhibitors for patients with T-cell lymphoma are vorinostat, romidepsin and, recently, belinostat. Here we review the pharmacology and the clinical activity of belinostat. Belinostat is a well-tolerated HDAC inhibitor that has shown activity in heavily pretreated patients with relapsed/refractory PTCL. Several clinical trials are currently investigating the use of belinostat in different cancers and in combination with other chemotherapeutic agents.

There is a rich history behind the extinct entity 'T-cell chronic lymphocytic leukemia (T-CLL)' and the now-established replacement, small-cell variant of T-cell prolymphocytic leukemia (T-PLL-sv). Herein, we review the history of the events, observations, and discussions that led to this replacement. We also provide a systematic analysis of all previously reported cases of T-PLL-sv as well as our four new additional cases. Despite the higher frequency of a normal karyotype and perhaps an overrepresented CD4(-) CD8(-) immunophenotype among these patients (compared to T-PLL in general) as well as bland morphology (that makes them superficially appear more similar to B-CLL), we argue that the current World Health Organization (WHO)-based classification as T-PLL-sv is adequate and should continue for the time being. Morphologically, T-PLL-sv represents approximately one-fifth of all T-PLL cases. However, morphology alone does not determine the clinical course and should not be the basis for clinical decision making and prognostication. We propose a clonal evolution model in which mature T-cell leukemias classified in the past as T-CLL are perhaps T-PLL diagnosed early in the course of the disease. Future research using next-generation sequencing, comparative genomic hybridization, and molecular array studies, including serial analyses of individual cases over time, is needed to better identify this rarely diagnosed, inherently controversial form of T-cell leukemia.

[Figure][1] A 67-year-old man presented with easy bruising, fatigue, pancytopenia (white blood cell count, 1.9 × 109/L; hemoglobin, 10.8 g/dL; platelets, 89 × 109/L), and low-grade disseminated intravascular coagulation (international normalized ratio, 1.3; partial thromboplastin time, 22

A mathematical model using simple concepts of repeated games is proposed to model the course and prognosis of factitious disorders. Although simple, the model seems capable of explaining the yet unknown mechanisms underlying the variable course of factitious disorders. One of the notable results of this study is the significant effect of involved physicians in the treatment process on the course of the disease. Particularly, the doctor's error rate in realizing whether the symptoms are real or factitious can considerably affect the course of the disease. This is the first paper to apply a mathematical model to factitious disorders.

A 55-year-old female with a history of chronic idiopathic thrombocytopenic purpura (ITP) presented in the spring of 2012 to the emergency department (ED) with a 1-day history of severegeneralizedheadache,nausea,andvomiting.Adiagnosis

A 48-year-old man presented with fevers, chills, weight loss, multiple liver masses, and several superficial and deep venous thromboses in lower extremities. Cancer work up was negative. A liver biopsy grew Fusobacterium nucleatum. To our knowledge, F. nucleatum infection presenting with multiple liver masses and Trousseau-like syndrome has not been reported earlier.

[Figure][1] A 35-year-old man with prolonged aplasia (62 days) after 2 inductions for acute myeloid leukemia (AML), underwent a myeloablative, matched-sibling, A-to-O allogeneic stem cell transplantation. Despite rapid neutrophil and platelet recovery, he remained red blood cell aplastic (

Cytomegalovirus (CMV) disease in pediatric acute lymphoblastic leukemia in the nontransplant setting is very rare. We report our experience with 4 such cases, and review the literature (n=12). The median age at diagnosis was 10 years and 50% of patients were males. Among the 11 cases with available information at the time of diagnosis, CMV disease occurred during maintenance therapy in 10 patients. Fever was present in 9 cases. CMV disease manifested as retinitis in 6, hepatosplenic disease in 3, pneumonitis in 1, and hemophagocytic lymphohistiocytosis in 1 patient. One patient had both CMV retinitis and CMV-related hemophagocytic lymphohistiocytosis. Four of the 7 patients with retinitis complained of visual disturbance at diagnosis. CMV viremia was present in 10 patients. Three patients had at least 1 relapse and developed permanent visual defects, and 1 patient developed recurrent retinal detachment. In conclusion, prolonged immunosuppression is the major etiology and retinitis is the most common manifestation of CMV disease. As a significant number of patients with retinitis are asymptomatic, early diagnosis and treatment is important to prevent permanent visual loss.

A selective explanation for the evolution of multicellular organisms from unicellular ones requires knowledge of both selective pressures and factors affecting the response to selection. Understanding the response to selection is particularly challenging in the case of evolutionary transitions in individuality, because these transitions involve a shift in the very units of selection. We develop a conceptual framework in which three fundamental processes (growth, division, and splitting) are the scaffold for unicellular and multicellular life cycles alike. We (i) enumerate the possible ways in which these processes can be linked to create more complex life cycles, (ii) introduce three genes based on growth, division and splitting that, acting in concert, determine the architecture of the life cycles, and finally, (iii) study the evolution of the simplest five life cycles using a heuristic model of coupled ordinary differential equations in which mutations are allowed in the three genes. We demonstrate how changes in the regulation of three fundamental aspects of colonial form (cell size, colony size, and colony cell number) could lead unicellular life cycles to evolve into primitive multicellular life cycles with group properties. One interesting prediction of the model is that selection generally favors cycles with group level properties when intermediate body size is associated with lowest mortality. That is, a universal requirement for the evolution of group cycles in the model is that the size-mortality curve be U-shaped. Furthermore, growth must decelerate with size.

A 56-year-old female was with petechiae. She had a history of hormone receptor-positive ductal carcinoma in situ of the left breast 11 years before this presentation, treated with bilateral mastectomy and oophorectomy due to a deleterious germline heterozygous BRCA2 mutation (1282insT). Several members of her family from the paternal side were affected by breast or endometrial cancer. Ten years later, she had a left axillary recurrence, treated with three cycles of neoadjuvant FEC-T (fluorouracil, epirubicin, and cyclophosphamide followed by docetaxel), left axillary lymph node dissection (with involvement of all 13 lymph nodes), and adjuvant radiation and anastrozole. Her blood counts upon presentation were WBC 13.1 9 10/L, Hb 9.6 g/dL, and platelets 77 9 10/L. The smear showed 43 % myeloid blasts. A bone marrow specimen was hypercellular (80 %) and demonstrated mild trilineage dysplasia; 7 % eosinophils; and 52 % myelomonocytic blasts expressing CD13, CD33, CD34, CD117, HLA-DR, myeloperoxidase (subset) by flow, and aNBE (subset) by enzyme cytochemistry, and negative for additional T cell, B-cell, and monocytic markers. Her karyotype was 46,XX,inv(16)(p13.1q22), and molecular studies did not show a KIT D816 mutation or a TP53 mutation by fluorescence in situ hybridization (FISH). A diagnosis of BRCA2-associated therapy-related acute myeloid leukemia (t-AML)-M4Eo with inv(16)(p13.1q22) was established. She achieved a complete remission with standard induction chemotherapy, but developed catastrophic intracranial bleeding due to severe thrombocytopenia following the first consolidation and died. BRCA2-associated t-AML has been reported only once before [1]. By participating in error-free repair of doublestrand DNA damage, BRCA1 and BRCA2 have an important role in maintaining genomic integrity, especially in rapidly dividing cells [2]. In BRCA-deficient cells, the alternate, error-prone, double-strand DNA break repair mechanisms predominate, leading to genomic instability [3]. Accordingly, BRCA1 loss results in augmented mutation accumulation after exposure to genotoxic damage and has been suggested to be a pathogenetic mechanism in t-AML [4]. Mutations in the so-called guardian of the genome, TP53, are found in up to one-third of cases of t-AML [5]. Contrary to previous belief, there is now evidence that TP53-mutated hematopoietic clones are already present before, rather than caused by cytotoxic therapy [6, 7]. These somatic mutations occur randomly during normal hematopoiesis. TP53-mutated cells have a selective survival advantage over their unmutated counterparts when exposed to chemotherapy or radiation. This is because unmutated cells that develop irreparable DNA damage as a result of genotoxic insult go in cell cycle arrest or undergo apoptosis, whereas TP53-mutated cells continue to survive, proliferate, and accumulate more mutations, one of which may eventually be an AML-driving mutation and cause t-AML. By definition, germline BRCA mutations are present before exposure to cytotoxic therapy. Therefore, they are not able per se to provide any selective advantage for a A. Rashidi (&) Division of Oncology, Washington University School of Medicine, 660 S. Euclid Ave., Campus Box 8056, St. Louis, MO 63110, USA e-mail: arashidi@dom.wustl.edu

Prompt all- trans retinoic acid administration and early death in acute promyelocytic leukemia: what does the evidence say?

Haploidentical transplantation using G-CSF-mobilized T-cell replete PBSCs and post-transplantation CY after non-myeloablative conditioning is safe and is associated with favorable outcomes

Programmed cell death (PCD) is an ancient phenomenon and its origin and maintenance in unicellular life is unclear. We report that programmed death provides differential fitness effects that are species specific in the model organism Chlamydomonas reinhardtii . Remarkably, PCD in this organism not only benefits others of the same species, but also has an inhibitory effect on the growth of other species. These data reveal that the fitness effects of PCD can depend upon genetic relatedness.

Due to the rarity of the disease, the characteristics of acute myeloid leukemia following solid organ transplantation (post-transplant AML; PT-AML) are unclear; furthermore, it is not known for certain whether PT-AML is a separate entity or not. We provide a systematic review of all previously reported cases of PT-AML in the English literature (n = 51). 45% of cases occurred after renal transplantation, and 72% were males. The median age at diagnosis of AML was 50 yr, with a median transplant-to-AML interval of 3.8 yr and a rapid decline in incidence after 5 yr. 26% of patients were asymptomatic at the time of presentation, and 42% were pancytopenic. M0/M1/M2, M3, M4/M5, and M6/M7 subtypes comprised 17%, 25%, 39%, and 19% of all cases, respectively. 36% of patients had unfavorable cytogenetic risk disease. The median overall survival was only 3 months. We observed several transplant-specific features: (i) The transplant-to-AML interval follows two very different patterns between renal vs. liver transplant patients. (ii) All 4 cases of donor cell leukemia occurred after liver transplant. (iii) Unfavorable risk disease was marginally significantly more common among renal compared with liver transplant patients (P = 0.057). Our results suggest that PT-AML is a separate entity with distinct characteristics, which need to be investigated further in future research. Heavy post-transplant immunosuppression likely plays a key role in the pathogenesis of PT-AML.

The clinical spectrum of Buerger’s disease (TAO; thromboangiitis obliterans) seems to be changing. Considering the lack of any formal studies on the epidemiology of this disease in Iran, we evaluated the data of 198 confirmed cases of TAO during the period 1996–2006. Diagnosis was based on Papa’s scoring system. All patients were male and aged at the time of diagnosis 40.5 ± 10.1 years. All patients were smokers for a duration of 22.2 ± 11.6 years. There was a strong seasonal variation for admission with winter admissions being significantly the most common (P