Pim Kinase Inhibition Disrupts CXCR4 Signalling in Megakaryocytes and Platelets by Reducing Receptor Availability at the Surface.

A key step in platelet production is the migration of megakaryocytes to the vascular sinusoids within the bone marrow. This homing is mediated by the chemokine CXCL12 and its receptor CXCR4. CXCR4 is also a positive regulator of platelet activation and thrombosis. Pim-1 kinase has been shown to regulate CXCR4 signalling in other cell types, and we have previously described how Pim kinase inhibitors attenuate platelet aggregation to CXCL12. However, the mechanism by which Pim-1 regulates CXCR4 signalling in platelets and megakaryocytes has yet to be elucidated. Using human platelets, murine bone marrow-derived megakaryocytes, and the megakaryocyte cell line MEG-01, we demonstrate that pharmacological Pim kinase inhibition leads to reduced megakaryocyte and platelet function responses to CXCL12, including reduced megakaryocyte migration and platelet granule secretion. Attenuation of CXCL12 signalling was found to be attributed to the reduced surface expression of CXCR4. The decrease in CXCR4 surface levels was found to be mediated by rapid receptor internalisation, in the absence of agonist stimulation. We demonstrate that pharmacological Pim kinase inhibition disrupts megakaryocyte and platelet function by reducing constitutive CXCR4 surface expression, decreasing the number of receptors available for agonist stimulation and signalling. These findings have implications for the development and use of Pim kinase inhibitors for the treatment of conditions associated with elevated circulating levels of CXCL12/SDF1α and increased thrombotic risk.

Burden of Diarrhoeagenic Escherichia coli in Santa Rosa, Guatemala in active health-services surveillance during 2008-2009 and 2014-2015.

OBJECTIVE: To describe the epidemiology of laboratory-confirmed Diarrhoeagenic Escherichia coli (DEC) cases from active facility-based surveillance in Guatemala. METHODS: We collected clinical and risk factor data on enrolled patients (aged 0-52 years) with acute diarrhoea at government healthcare facilities (1 hospital and 6 clinics) in Santa Rosa, Guatemala, during 2008-2009 and 2014-2015. Stool samples were analysed, E. coli identified through culture and biochemical tests, PCR amplification of genes encoding pathotype-specific virulence factors identified specific DEC pathotypes. Healthcare-seeking adjusted incidence rates were calculated. RESULTS: A total of 3041 diarrhoea cases were captured by surveillance (647 hospitalisations (H), 2394 clinic visits (CV)); general E. coli prevalence was 17.9%. DEC pathotypes were identified in 19% (n = 95/497) and 21% (n = 450/2113) in diarrhoea H and CV, respectively. Enteropathogenic E. coli (EPEC) was most frequently isolated (8.2% (n = 41) in diarrhoea H, 12.0% (n = 255) in diarrhoea CV), followed by ETEC (6.8% (n = 34) in H, 6% (n = 128) in CV) and STEC (0.6% (n = 3) in H, 0.6% (n = 13) in CV). We did not find evidence of a difference in severity between DEC and non-DEC diarrhoea. Incidence of DEC clinic visits and hospitalisations was 648.0 and 29.3, respectively, per 10,000 persons aged ≤5 years and 36.8 and 0.4, respectively, per 10,000 persons aged >5 years. CONCLUSIONS: DEC pathotypes, especially EPEC and ETEC, were detected frequently from patients presenting with diarrhoeal illness in Santa Rosa, Guatemala. Our findings suggest that preventive interventions should be prioritised for young children.

Killer Cell Immunoglobulin-like Receptors (KIR) and Human Leucocyte Antigen C (HLA-C) Increase the Risk of Long-Term Chronic Liver Graft Rejection.

Chronic liver rejection (CR) represents a complex clinical situation because many patients do not respond to increased immunosuppression. Killer cell immunoglobulin-like receptors/Class I Human Leukocyte Antigens (KIR/HLA-I) interactions allow for predicting Natural Killer (NK) cell alloreactivity and influence the acute rejection of liver allograft. However, its meaning in CR liver graft remains controversial. KIR and HLA genotypes were studied in 513 liver transplants using sequence-specific oligonucleotides (PCR-SSO) methods. KIRs, human leucocyte antigen C (HLA-C) genotypes, KIR gene mismatches, and the KIR/HLA-ligand were analyzed and compared in overall transplants with CR (n = 35) and no-chronic rejection (NCR = 478). Activating KIR (aKIR) genes in recipients (rKIR2DS2+ and rKIR2DS3+) increased CR compared with NCR groups (p = 0.013 and p = 0.038). The inhibitory KIR (iKIR) genes in recipients rKIR2DL2+ significantly increased the CR rate compared with their absence (9.1% vs. 3.7%, p = 0.020). KIR2DL3 significantly increases CR (13.1% vs. 5.2%; p = 0.008). There was no influence on NCR. CR was observed in HLA-I mismatches (MM). The absence of donor (d) HLA-C2 ligand (dC2-) ligand increases CR concerning their presence (13.1% vs. 5.6%; p = 0.018). A significant increase of CR was observed in rKIR2DL3+/dC1- (p = 0.015), rKIR2DS4/dC1- (p = 0.014) and rKIR2DL3+/rKIR2DS4+/dC1- (p = 0.006). Long-term patient survival was significantly lower in rKIR2DS1+rKIR2DS4+/dC1- at 5-10 years post-transplant. This study shows the influence of rKIR/dHLA-C combinations and aKIR gene-gene mismatches in increasing CR and KIR2DS1+/C1-ligands and the influence of KIR2DS4+/C1-ligands in long-term graft survival.

Fruit consumption and cardiometabolic risk in the PREDIMED-plus study: A cross-sectional analysis.

BACKGROUND AND AIMS: Total fruit consumption is important for cardiovascular disease prevention, but also the variety and form in which is consumed. The aim of the study was to assess the associations between total fruit, subgroups of fruits based on their color and fruit juices consumption with different cardiometabolic parameters. METHODS AND RESULTS: A total of 6633 elderly participants (aged 55-75 years) with metabolic syndrome from the PREDIMED-Plus study were included in this analysis. Fruit and fruit juice consumption was assessed using a food frequency questionnaire. Linear regression models were fitted to evaluate the association between exposure variables (total fruit, subgroups based on the color, and fruit juices) and different cardiometabolic risk factors. Individuals in the highest category of total fruit consumption (≥3 servings/d) had lower waist circumference (WC) (ß = -1.04 cm; 95%CI:-1.81, -0.26), fasting glucose levels (ß = -2.41 mg/dL; 95%CI(-4.19, -0.63) and LDL-cholesterol (ß = -4.11 mg/dL; 95%CI:-6.93, -1.36), but, unexpectedly, higher systolic blood pressure (BP) (ß = 1.84 mmHg; 95%CI: 0.37, 3.30) and diastolic BP (ß = 1.69 mmHg; 95%CI:0.83, 2.56) when compared to those in the lowest category of consumption (<1 servings/d). Participants consuming ≥1 serving/day of total fruit juice had lower WC (ß = -0.92 cm; 95%CI:-1.56, -0.27) and glucose levels (ß = -1.59 mg/dL; 95%CI:-2.95, -0.23) than those consuming <1 serving/month. The associations with cardiometabolic risk factors differed according to the color of fruits. CONCLUSION: Fruit consumption is associated with several cardiometabolic risk factors in Mediterranean elders with metabolic syndrome. The associations regarding BP levels could be attributed, at least partially, to reverse causality bias inherent to the cross-sectional design of the study.

Psychiatric comorbidities go unrecognized in patients with epilepsy: "You see what you know".

Patients with epilepsy (PWE) have a significantly higher prevalence of psychiatric comorbid disorders involving depression, anxiety, psychotic, and attention-deficit disorders compared with the general population or patients with other chronic medical conditions. Currently, there is no systematic approach in the evaluation and management of psychiatric comorbidities in these patients. In addition, neurologists are not trained to recognize these disorders, and consequently, they remain undertreated. Despite the high prevalence of psychiatric comorbidities in patients evaluated for epilepsy surgery, most epilepsy centers in North America do not include a psychiatric evaluation as part of the presurgical work-up. Despite the intimate relationship between psychiatric comorbidities and epilepsy, collaboration between epileptologists and psychiatrists is sparse at best and nonexistent at worse. The purpose of this paper was to highlight and try to understand the causes behind the persistent lack in communication between neurologists and psychiatrists, the gap in the training of neurologists on psychiatric aspects of neurologic disorders and vice versa and to propose new initiatives to fix the problem. This article is part of the Special Issue "Obstacles of Treatment of Psychiatric Comorbidities in Epilepsy".

Incidence and etiology of infectious diarrhea from a facility-based surveillance system in Guatemala, 2008-2012.

BACKGROUND: Diarrhea is a major cause of morbidity and mortality, yet incidence and etiology data are limited. We conducted laboratory-based diarrhea surveillance in Guatemala. METHODS: A diarrhea case was defined as ≥3 loose stools in a 24-h period in a person presenting to the surveillance facilities. Epidemiologic data and stool specimens were collected. Specimens were tested for bacterial, parasitic, and viral pathogens. Yearly incidence was adjusted for healthcare seeking behaviors determined from a household survey conducted in the surveillance catchment area. RESULTS: From November 2008 to December 2012, the surveillance system captured 5331 diarrhea cases; among these 1381 (26%) had specimens tested for all enteric pathogens of interest. The adjusted incidence averaged 659 diarrhea cases per 10,000 persons per year, and was highest among children aged < 5 years, averaging 1584 cases per 10,000 children per year. Among 1381 (26%) specimens tested for all the pathogens of interest, 235 (17%) had a viral etiology, 275 (20%) had a bacterial, 50 (4%) had parasites, and 86 (6%) had co-infections. Among 827 (60%) specimens from children aged < 5 years, a virus was identified in 196 (23%) patients; 165 (20%) had norovirus and 99 (12%) rotavirus, including co-infections. Among 554 patients aged ≥5 years, 103 (19%) had a bacterial etiology, including diarrheagenic Escherichia coli in 94 (17%) cases, Shigella spp. in 31 (6%), Campylobacter spp. in 5 (1%), and Salmonella spp. in 4 (1%) cases. Detection of Giardia and Cryptosporidium was infrequent (73 cases; 5%). CONCLUSIONS: There was a substantial burden of viral and bacterial diarrheal diseases in Guatemala, highlighting the importance of strengthening laboratory capacity for rapid detection and control and for evaluation of public health interventions.

The relationship between mood disorder and insomnia depends on race in US veterans with epilepsy.

PURPOSE: Few data exist on race, medical/psychiatric comorbidities, and insomnia symptoms in US veterans with epilepsy. Our aims were to examine 1) whether insomnia symptom prevalence was different between Black and White veterans and 2) whether predictors of insomnia symptoms varied by race. METHODS: This retrospective, cross-sectional study included veterans evaluated in an epilepsy clinic over the course of 1.5years. Individuals completed standardized assessments for epilepsy and sleep complaints. Insomnia criteria were met by 1) report of difficulty with sleep initiation, maintenance, or premature awakenings accompanied by daytime impairment or 2) sedative-hypnotic use on most days of the month. Demographics, medical/psychiatric comorbidities, and medications were determined per electronic medical record review. Hierarchical multivariable logistic regression analyses were performed to determine if race, medical/mental health comorbidities, and the potential interaction of race with each comorbid condition were associated with insomnia. RESULTS: Our sample consisted of 165 veterans (32% Black). The unadjusted prevalence of insomnia was not different between Black and White veterans (42% vs 39%, p=0.68). In adjusted analyses, the association between mood disorder and insomnia varied by race. Depressed White veterans had over 11-times higher predicted odds of insomnia (OR 11.4, p<0.001) than non-depressed White veterans, while depressed Black veterans had 4-times higher predicted odds of insomnia (OR 4.1, p=0.06) than non-depressed Black veterans. Although mood disorder diagnosis was associated with insomnia for both racial groups, White veterans had a stronger association between mood disorder diagnosis and insomnia than Black veterans. CONCLUSIONS: The relationship between mood disorder diagnosis and insomnia was stronger for White than Black veterans with epilepsy. Future studies are needed to explore mental health symptoms and psychosocial determinants of insomnia with larger samples of minority individuals with epilepsy.

Examining Adherence Among Challenging Patients in Public and Private HIV Care in Argentina.

Treatment engagement, retention and adherence to care are required for optimal HIV outcomes. Yet, patients may fall below the treatment recommendations for achieving undetectable viral load or not be retained in care. This study examined the most challenging patients in Buenos Aires, Argentina, those non-adherent to HIV care. Men (n = 61) and women (n = 59) prescribed antiretrovirals (ARVs) and non-adherent to treatment in the prior 3-6 months were enrolled and assessed regarding adherence, knowledge, motivation and attitudes regarding treatment. Private clinic patients had lower viral load and higher self-reported adherence than public clinic patients. Motivations to be adherent and positive beliefs regarding ARVs were associated with increased adherence in public clinic participants. Increased self-efficacy was associated with increased adherence among participants from both clinics. Results support patient and provider interventions that strengthen the characteristics supporting adherence, engagement and retention in public and private clinic settings.

Respiratory syncytial virus infection in Guatemala, 2007-2012.

BACKGROUND: Respiratory syncytial virus (RSV) is a major cause of acute respiratory illness (ARI). Little is known about RSV disease among older children and adults in Central America. METHODS: Prospective surveillance for ARI among hospital patients and clinic patients was conducted in Guatemala during 2007-2012. Nasopharyngeal and oropharyngeal swab specimens were tested for RSV, using real-time reverse-transcription polymerase chain reaction. RESULTS: Of 6287 hospitalizations and 2565 clinic visits for ARI, 24% and 12%, respectively, yielded RSV-positive test results. The incidence of RSV-positive hospitalization for ARI was 5.8 cases/10 000 persons per year and was highest among infants aged <6 months (208 cases/10 000 persons per year); among adults, the greatest incidence was observed among those aged ≥ 65 years (2.9 cases/10 000 persons per year). The incidence of RSV-positive clinic visitation for ARI was 32 cases/10 000 persons per year and was highest among infants aged 6-23 months (186 cases/10 000 persons per year). Among RSV-positive hospital patients with ARI, underlying cardiovascular disease was associated with death, moribund discharge, intensive care unit admission, or mechanical ventilation (odds ratio, 4.1; 95% confidence interval, 1.9-8.8). The case-fatality proportion among RSV-positive hospital patients with ARI was higher for those aged ≥ 5 years than for those aged <5 years (13% vs 3%; P < .001). CONCLUSIONS: The incidences of RSV-associated hospitalization and clinic visitation for ARI were highest among young children, but a substantial burden of ARI due to RSV was observed among older children and adults.

Respiratory syncytial virus circulation in seven countries with Global Disease Detection Regional Centers.

BACKGROUND: Respiratory syncytial virus (RSV) is the leading cause of lower respiratory tract infections in young children globally, with the highest burden in low- and middle-income countries where the association between RSV activity and climate remains unclear. METHODS: Monthly laboratory-confirmed RSV cases and associations with climate data were assessed for respiratory surveillance sites in tropical and subtropical areas (Bangladesh, China, Egypt, Guatemala, Kenya, South Africa, and Thailand) during 2004-2012. Average monthly minimum and maximum temperatures, relative humidity, and precipitation were calculated using daily local weather data from the US National Climatic Data Center. RESULTS: RSV circulated with 1-2 epidemic periods each year in site areas. RSV seasonal timing and duration were generally consistent within country from year to year. Associations between RSV and weather varied across years and geographic locations. RSV usually peaked in climates with high annual precipitation (Bangladesh, Guatemala, and Thailand) during wet months, whereas RSV peaked during cooler months in moderately hot (China) and arid (Egypt) regions. In South Africa, RSV peaked in autumn, whereas no associations with seasonal weather trends were observed in Kenya. CONCLUSIONS: Further understanding of RSV seasonality in developing countries and various climate regions will be important to better understand the epidemiology of RSV and for timing the use of future RSV vaccines and immunoprophylaxis in low- and middle-income countries.

Prevalence and genetic diversity of norovirus among patients with acute diarrhea in Guatemala.

Noroviruses (NoVs) are a leading cause of acute gastroenteritis outbreaks and sporadic cases of diarrhea in industrialized countries. To study the prevalence and genetic diversity of NoVs in Guatemala, stool specimens were collected from hospitalized and ambulatory patients presenting with diarrhea (≥3 loose or liquid stools in a 24-hr period) who were enrolled in a prospective surveillance system in the Departments of Santa Rosa (October 2007 to August 2010) and Quetzaltenango (August 2009 to August 2010), Guatemala. Specimens were tested for rotavirus, enteric bacteria, and parasites by routine methods and for genogroups I and II NoV by real-time reverse transcription-PCR. A total of 2,403 stool specimens were collected from hospitalized (n = 528) and ambulatory patients (n = 1,875). Overall, 341 (14%) samples tested positive for NoVs including 114 (22%) hospitalized and 227 (12%) ambulatory patients. NoVs disease peaked during the winter (November-January) months. Among the 341 NoVs-positive patients, 32 (9%) were also positive for rotavirus, 32 (9%) for bacteria, and 9 (3%) for protozoa. Nucleotide sequences were obtained from 84 samples collected from hospitalized children aged <5 years of age, which could be grouped into nine GII and three GI genotypes with GII.4 (74%) and GI.8 (10%) being the most common. This is the first study on the prevalence of NoVs among hospitalized and ambulatory patients with diarrhea in Guatemala. The findings highlight the need to implement laboratory diagnostics for NoVs to improve appropriate clinical management of diarrheal diseases and guide vaccine development.

Comorbidity and polypharmacy impact neurobehavioral symptoms and symptom validity failure among post-9/11 veterans with mild traumatic brain injury.

Objective: The study aimed to examine the association between post-concussive comorbidity burdens [post-traumatic stress disorder (PTSD), depression, and/or headache] and central nervous system (CNS) polypharmacy (five or more concurrent medications) with reported neurobehavioral symptoms and symptom validity screening among post-9/11 veterans with a history of mild traumatic brain injury (mTBI). Setting: Administrative medical record data from the Department of Veterans Affairs (VA) were used in the study. Participants: Post-9/11 veterans with mTBI and at least 2 years of VA care between 2001 and 2019 who had completed the comprehensive traumatic brain injury evaluation (CTBIE) were included in the study. Design: Retrospective cross-sectional design was used in the study. Main measures: Neurobehavioral Symptom Inventory (NSI), International Classification of Diseases, Ninth Revision, and Clinical Modification diagnosis codes were included in the study. Results: Of the 92,495 veterans with a history of TBI, 90% had diagnoses of at least one identified comorbidity (PTSD, depression, and/or headache) and 28% had evidence of CNS polypharmacy. Neurobehavioral symptom reporting and symptom validity failure was associated with comorbidity burden and polypharmacy after adjusting for sociodemographic characteristics. Veterans with concurrent diagnoses of PTSD, depression, and headache were more than six times more likely [Adjusted odds ratio = 6.55 (99% CI: 5.41, 7.92)]. to fail the embedded symptom validity measure (Validity-10) in the NSI. Conclusion: TBI-related multimorbidity and CNS polypharmacy had the strongest association with neurobehavioral symptom distress, even after accounting for injury and sociodemographic characteristics. Given the regular use of the NSI in clinical and research settings, these findings emphasize the need for comprehensive neuropsychological evaluation for individuals who screen positively for potential symptom overreporting, the importance of multidisciplinary rehabilitation to restore functioning following mTBI, and the conscientious utilization of symptom validity measures in research efforts.

Management of older hospitalized patients with type 2 diabetes using linagliptin: Lina-Older study.

BACKGROUND: Older patients managed with intensive antidiabetic therapy are more likely to be harmed. Our study's primary endpoint was to analyze the safety and efficacy of linagliptin in combination with basal insulin versus basal-bolus insulin in patients with 75 years of age or older hospitalized in medicine and surgery departments in real-world clinical practice. METHODS: We retrospectively enrolled non-critically patients ≥75 years with type 2 diabetes admitted to medicine and non-cardiac surgery departments with admission glycated hemoglobin <8%, admission blood glucose <240 mg/dL, and without at-home injectable therapies managed with our hospital's antihyperglycemic protocol (basal-bolus or linagliptin-basal regimens) between January 2016 and December 2018. To match each patient who started on the basal-bolus regimen with a patient who started on the linagliptin-basal regimen, a propensity matching analysis was used. RESULTS: Postmatching, 198 patients were included in each group. There were no significant differences in mean daily blood glucose levels after admission (P=0.203); patients with mean blood glucose 100-140mg/dL (P=0.134), 140-180mg/dL (P=0.109), or >200mg/dL (P=0.299); and number and day of treatment failure (P=0.159 and P=0.175, respectively). The total insulin dose and the number of daily injections were significantly lower in the linagliptin-basal group (both, P<0.001). Patients on the basal-bolus insulin regimen had more total hypoglycemic events than patients on the linagliptin-basal insulin regimen (P<0.001). CONCLUSIONS: The linagliptin-basal insulin regimen was an effective alternative with fewer hypoglycemic events and daily insulin injections than intensive basal-bolus insulin in very old patients with type 2 diabetes with mild-to-moderate hyperglycemia treated at home without injectable therapies.

Fiber concentrate from orange (Citrus sinensis L.) bagase: characterization and application as bakery product ingredient.

Orange is a tropical fruit used in the juice industry, yielding important quantities of by products. The objective of this work was to obtain a dietary fiber-rich orange bagasse product (DFROBP), evaluate its chemical composition and its use in the preparation of a bakery product (muffin). Muffins containing two different levels of DFROBP were studied regarding chemical composition, in vitro starch digestibility, predicted glyceamic index and acceptability in a sensory test. DFROBP showed low fat and high dietary fiber contents. The soluble and insoluble dietary fiber fractions were balanced, which is of importance for the health beneficial effects of fiber sources. DFROBP-containing muffins showed the same rapidly digestible starch content as the reference muffin, whilst the slowly digestible starch level increased with the addition of DFROBP. However, the resistant starch content decreased when DFROBP increased in the muffin. The addition of DFROBP to muffin decreased the predicted glyceamic index, but no difference was found between the muffins prepared with the two DFROBP levels. The sensory score did not show difference between control muffin and that added with 10% of DFROBP. The addition of DFROBP to bakery products can be an alternative for people requiring low glyceamic response.

The Military Injuries: Understanding Post-Traumatic Epilepsy Study: Understanding Relationships among Lifetime Traumatic Brain Injury History, Epilepsy, and Quality of Life.

Understanding risk for epilepsy among persons who sustain a mild (mTBI) traumatic brain injury (TBI) is crucial for effective intervention and prevention. However, mTBI is frequently undocumented or poorly documented in health records. Further, health records are non-continuous, such as when persons move through health systems (e.g., from Department of Defense to Veterans Affairs [VA] or between jobs in the civilian sector), making population-based assessments of this relationship challenging. Here, we introduce the MINUTE (Military INjuries-Understanding post-Traumatic Epilepsy) study, which integrates data from the Veterans Health Administration with self-report survey data for post-9/11 veterans (n = 2603) with histories of TBI, epilepsy and controls without a history of TBI or epilepsy. This article describes the MINUTE study design, implementation, hypotheses, and initial results across four groups of interest for neurotrauma: 1) control; 2) epilepsy; 3) TBI; and 4) post-traumatic epilepsy (PTE). Using combined survey and health record data, we test hypotheses examining lifetime history of TBI and the differential impacts of TBI, epilepsy, and PTE on quality of life. The MINUTE study revealed high rates of undocumented lifetime TBIs among veterans with epilepsy who had no evidence of TBI in VA medical records. Further, worse physical functioning and health-related quality of life were found for persons with epilepsy + TBI compared to those with either epilepsy or TBI alone. This effect was not fully explained by TBI severity. These insights provide valuable opportunities to optimize the resilience, delivery of health services, and community reintegration of veterans with TBI and complex comorbidity.

Effect of a lifestyle intervention program with energy-restricted Mediterranean diet and exercise on the serum polyamine metabolome in individuals at high cardiovascular disease risk: a randomized clinical trial.

BACKGROUND: Many food items included in the Mediterranean diet (MedDiet) are rich in polyamines, small aliphatic amines with potential cardioprotective effects. The consumption of a MedDiet could increase polyamine concentrations. Based on experimental models, polyamine concentrations may be also influenced by physical activity (PA). OBJECTIVES: We aimed to evaluate whether an intervention based on an energy-restricted MedDiet (er-MedDiet) and PA promotion, in comparison with an energy-unrestricted MedDiet and traditional health care, influences the serum pattern of polyamines and related metabolites in subjects at high risk of cardiovascular disease (CVD). METHODS: This was a substudy from the PREDIMED-Plus trial, an ongoing randomized clinical trial including 6874 participants allocated either to an intensive weight-loss lifestyle intervention based on er-MedDiet, PA promotion, and behavioral support (er-MedDiet + PA group), or to an energy-unrestricted MedDiet and traditional health care group (MedDiet group). A total of 75 patients (n = 38, er-MedDiet + PA group; n = 37, MedDiet group) were included in this study. Serum concentrations of arginine, ornithine, polyamines, and acetyl polyamines at baseline and 26 wk of intervention were measured by an ultra-high-performance LC-tandem MS platform. RESULTS: At week 26, study groups had similar adherence to the MedDiet but patients randomly assigned to the er-MedDiet + PA group showed significantly lower mean energy intake (-340.3 kcal/d; 95% CI: -567.3, -113.4 kcal/d; P = 0.004), higher mean PA (1290.6; 95% CI: 39.9, 2541.3 metabolic equivalent tasks · min/d; P = 0.043), and higher mean decrease in BMI (in kg/m2) (-1.3; 95% CI: -1.8, -0.6; P < 0.001) than the MedDiet group. However, no significant differences in serum polyamines or related metabolites were found between study groups after 26 wk of intervention and no significant between-group differences were found in glycated hemoglobin, HDL-cholesterol, or triglyceride concentrations. CONCLUSIONS: In individuals at high CVD risk, an er-MedDiet with increased PA did not result in significant changes of serum concentrations of polyamines or related metabolites in comparison with an energy-unrestricted MedDiet and no increase in PA. This trial was registered at isrctn.com as ISRCTN89898870.

KIR+ CD8+ T Lymphocytes in Cancer Immunosurveillance and Patient Survival: Gene Expression Profiling.

Killer-cell immunoglobulin-like receptors (KIR) are expressed by natural killer (NK) and effector T cells. Although KIR+ T cells accumulate in oncologic patients, their role in cancer immune response remains elusive. This study explored the role of KIR+CD8+ T cells in cancer immunosurveillance by analyzing their frequency at diagnosis in the blood of 249 patients (80 melanomas, 80 bladder cancers, and 89 ovarian cancers), their relationship with overall survival (OS) of patients, and their gene expression profiles. KIR2DL1+ CD8+ T cells expanded in the presence of HLA-C2-ligands in patients who survived, but it did not in patients who died. In contrast, presence of HLA-C1-ligands was associated with dose-dependent expansions of KIR2DL2/S2+ CD8+ T cells and with shorter OS. KIR interactions with their specific ligands profoundly impacted CD8+ T cell expression profiles, involving multiple signaling pathways, effector functions, the secretome, and consequently, the cellular microenvironment, which could impact their cancer immunosurveillance capacities. KIR2DL1/S1+ CD8+ T cells showed a gene expression signature related to efficient tumor immunosurveillance, whereas KIR2DL2/L3/S2+CD8+ T cells showed transcriptomic profiles related to suppressive anti-tumor responses. These results could be the basis for the discovery of new therapeutic targets so that the outcome of patients with cancer can be improved.

Duration of refractory status epilepticus and outcome: loss of prognostic utility after several hours.

PURPOSE: Outcome for patients with status epilepticus (SE) depends strongly on etiology. Duration of SE is also predictive, at least in the first 2 h, but beyond this it is unclear that duration of SE influences outcome significantly. We sought to determine the influence of duration of SE on outcome in patients with prolonged SE, and to compare this influence with that of other factors. METHODS: We reviewed the clinical course and outcome of 119 patients with SE, diagnosed by both clinical manifestations and electroencephalography (EEG) evidence. Using univariate and multivariate analyses, we sought predictors of outcome (survival vs. death or vegetative state) among age, etiology (epilepsy, anoxia or severe hypoxia, or other), presence of earlier epilepsy, multiple medical problems, presentation in coma, and type of SE (focal or generalized). RESULTS: Median duration of SE was 48 h. Survival was greater with a shorter duration, especially when <10 h (69% vs. 31% for longer duration; p < 0.05). Epilepsy as the etiology, and an earlier diagnosis of epilepsy offered a favorable prognosis (p < 0.01), but only the former on multivariate analysis. Coma and SE caused by anoxia/hypoxia were unfavorable factors. Once corrected for etiology, presentation in coma, and type of SE (focal or generalized), duration of SE did not have a significant effect on outcome. Overall mortality was high, 65%, but 10 patients survived SE lasting over 3.5 days. CONCLUSIONS: A duration of <10 h was associated with better outcome in SE, but this was not significant once etiology, presentation in coma, and type of SE were accounted for. Etiology of SE is still the primary determinant of outcome. Unless it follows anoxia, prolonged SE should not be considered a hopeless condition.

National trends in diabetes mellitus hospitalization in Spain 1997-2010: Analysis of over 5.4 millions of admissions.

AIMS: To analyze national trends in the rates of hospitalizations (all-cause and by principal discharge diagnosis) in total diabetic population of Spain. METHODS: We carried out a nation-wide population-based study of all diabetic patients hospitalized between 1997 and 2010. All-cause hospitalizations, hospitalizations by principal discharge diagnosis, mean age, Charlson Comorbidity Index, readmission rates and length of hospital stay were examined. Annual rates adjusted for age and sex were analyzed and trends were calculated. RESULTS: Over 14-years-period, all-cause hospitalizations of diabetic patients increased significantly, with an average annual percentage change of 2.5 (95%CI: 1.5-3.5; Ptrend < 0.01). The greatest increase was observed in heart failure (5.4; 95%CI: 4.8-6.0; Ptrend < 0.001), followed by neoplasms (4.9; 95%CI: 3.6-5.8; Ptrend < 0.001), pneumonia (2.7; 95%CI: 2.0-4.0; Ptrend < 0.001), stroke (2.4; 95%CI: 1.6-3.4; Ptrend < 0.001), chronic obstructive pulmonary disease (2.0; 95%CI: 1.4-3.4; Ptrend < 0.001) and coronary artery disease (1.6; 95%CI: 1.1-2.3; Ptrend < 0.01). The adjusted number of all-cause hospitalizations of patients with diabetes per 100,000 inhabitants increased 2.6-fold. The increase in hospitalizations was significantly higher among patients ≥75 years old. Males experienced a greater increase in all-cause, neoplasm, heart failure, chronic obstructive pulmonary disease, and pneumonia hospitalizations (p < 0.01 for all). Hospitalized diabetic patients were progressively older and had more comorbidities, higher readmission rates and shorter hospital stays (p < 0.05 for all). CONCLUSIONS: Hospitalizations of diabetic patients more than doubled in Spain during the study period. Heart failure and neoplasms experienced the greatest annual increases and remained the principal causes of hospitalization, probably associated with advanced age and comorbidities of hospitalized diabetics. Coronary and cerebrovascular diseases experienced a lower annual increase, suggesting an improvement in cardiovascular care in diabetes in Spain.

Type 2 Diabetes Is Associated with a Different Pattern of Serum Polyamines: A Case⁻Control Study from the PREDIMED-Plus Trial.

Objective: Polyamines are naturally occurring cationic molecules present in all living cells. Dysregulation of circulating polyamines has been reported in several conditions, but little is known about the levels of serum polyamines in chronic metabolic disorders such as type 2 diabetes (T2D). Therefore, the aim of this study was to evaluate the polyamine-related metabolome in a cohort of metabolic syndrome individuals with and without T2D. Design and methods: This was a nested case⁻control study within the PREDIMED-Plus trial that included 44 patients with T2D and 70 patients without T2D. We measured serum levels of arginine, ornithine, polyamines, and acetyl polyamines with an ultra-high performance liquid chromatography tandem mass spectrometry platform. Results: Our results showed that serum putrescine, directly generated from ornithine by the catalytic action of the biosynthetic enzyme ornithine decarboxylase, was significantly elevated in patients with T2D compared to those without T2D, and that it significantly correlated with the levels of glycosylated hemoglobin (HbA1c). Correlation analysis revealed a significantly positive association between fasting insulin levels and spermine. Multiple logistic regression analysis (adjusted for age, gender and body weight index) revealed that serum putrescine and spermine levels were associated with a higher risk of T2D. Conclusions: Our study suggests that polyamine metabolism is dysregulated in T2D, and that serum levels of putrescine and spermine are associated with glycemic control and circulating insulin levels, respectively.