Significant Dose Effect Research Articles

Thyroid cancer risks among medical radiation workers in South Korea, 1996\u20132015

BackgroundThyroid cancer rates, especially among children, are known to be increased by radiation exposure. However, little is known about the impact of chronic low-dose radiation exposure on thyroid cancer risk in adulthood. This study examined radiation effects on thyroid cancer rates as well as an overall evaluation of thyroid cancer risk among medical radiation workers.MethodsData on all diagnostic medical radiation workers enrolled in the national dosimetry registry between 1996 and 2011 were linked with the cancer registry data through 2015. Standardized incidence ratios (SIRs) were used to compare the observed cancer incidence rates in this population to those for the general population while internal comparisons were used to estimate relative risks (RRs) for occupational history and excess relative risks (ERRs) were used to quantify the radiation dose-response relationship.ResultsOverall, 827 thyroid cancer cases were reported among 93,922 medical radiation workers. Thyroid cancer SIRs were significantly higher than expected for both men (SIR 1.72, 95% confidence interval [CI] 1.53 to 1.91) and women (SIR 1.18, 95% CI 1.08 to 1.28). However, RRs for thyroid cancer by job title and duration of employment showed no particular pattern among diagnostic medical radiation workers. There were no indications of a significant dose effect on thyroid cancer rates for either men (ERR/100 mGy 0.07, 95% CI -0.38 to 0.53) or women (ERR/100 mGy -0.13, 95% CI -0.49 to 0.23). The findings were similar for different job titles or when limited to workers employed for at least one year.ConclusionsWhile thyroid cancer incidence rates among Korean medical radiation workers were somewhat higher than those in the general population, there was no significant evidence that this increase was associated with occupational radiation dose. Additional follow-up together with consideration of other risk factors should provide useful information on thyroid cancer rates in this cohort.

Response to Reduced Nicotine Content in Vulnerable Populations: Effect of Menthol Status.

In this study, we investigated potential effects of being a menthol smoker on response to reduced nicotine content (RNC) cigarettes in smokers especially vulnerable to smoking. Participants were 169 smokers (61 menthol and 108 non-menthol smokers) with comorbid mental illness, substance use disorder, or socioeconomic disadvantage. Participants completed a double-blind study assessing addiction potential, withdrawal/craving, and compensatory smoking across 4 research cigarettes varying in nicotine content from very low levels to commercial levels (0.4, 2.4, 5.2, 15.8mg/g of tobacco). Repeated measures analysis of variance was used to examine potential moderating effects of menthol status. Statistically significant effects of nicotine dose were noted across measures, with higher doses producing greater economic demand and relief from withdrawal/craving. The relationships between nicotine dose and response to RNC cigarettes do not differ by menthol status. Results of this study suggest menthol does not have a differential impact on response to RNC cigarettes across measures of economic demand, withdrawal/craving, or smoking topography. These results suggest that any potential beneficial effects of RNC cigarettes should extend to menthol smokers including those especially vulnerable to smoking.

HLA-DQ2 homozygosis increases tTGA levels at diagnosis but does not influence the clinical phenotype of coeliac disease: A multicentre study.

Magnitude of gluten-specific T-cell responses in coeliac disease (CD) might be dependent on HLA-DQ2 gene dose. We aimed to investigate the effects of HLA-DQB1*02 allele dose on clinical outcomes. We reviewed the charts of all coeliac patients attending to three Hungarian university clinics after 1997 and included those patients, who (a) were diagnosed with CD, (b) underwent high-resolution HLA typing and (c) were ≥18years at the time of data collection. HLA typing was performed to determine DQB1*02 allele dose. Patients were divided into risk groups by DQB1*02 allele dose, as follows: high-, intermediate- and low-risk groups corresponded to a double, single and zero doses, respectively. We used ANOVA and Pearson's chi-squared test to explore association between HLA risk and clinical variables. A total of 727 coeliac patients attended the clinics but only 105 (14.4%) patients were eligible for inclusion. High, intermediate and low HLA risk patients comprised 35.3%, 52.3% and 12.3% of the study population, respectively. Double dose of HLA-DQB1*02 was more frequent in patient with high tTGA level (>10 times the upper limit of normal; p=0.045). Gene dose was not associated with younger age at diagnosis (p=0.549), gender (p=0.739), more severe diagnostic histology (p=0.318), more frequent classical presentation (p=0.846), anaemia (p=0.611), metabolic bone disease (p=0.374), dermatitis herpetiformis (p=0.381) and autoimmune diseases (p=0.837). Our study shows a significant gene dose effect in terms of tTGA level at diagnosis, but no significant association between HLA-DQB1*02 allele dose and the clinical outcomes in CD.

Lymphocytes DNA damages and exposure to chlorpyrifos, deltamethrin, penconazole, copper oxicloride

Purpose: The evaluation of the association between different exposure to pesticides and different types of comet images among a group of 26 recruited subject.Material and methods: We have recruited 26 subjects (farmers and not farmers). They were submitted to a blood drawing of 10 mL and a questionnaire was administered to investigate personal habits and work history. By means of the comet assay it was assessed the oxidative DNA damage of peripheral lymphocytes by pesticides in the exposed and non-exposed workers.Result: The data measured by means of the comet were log transformed and the associations (odds ratios – ORs) with the single pesticides were calculated. The regression analysis shows a significant dose effects relationships between the Intensity Score of pesticides exposures tail moment (TM) and other measured parameters. Insecticides TM OR = 17.00 [1.47 – 196.41]. This relationship is independent from the smoking habits.Conclusions: TM values higher than the 75° percentile were significantly associated with the exposure to particular insecticides such as chlorpyriphos, deltamethrin and with other pesticides (near the statistical significance).

Cerebrolysin Reduces Astrogliosis and Axonal Injury and Enhances Neurogenesis in Rats After Closed Head Injury

Background. Cerebrolysin is a neuropeptide preparation with neuroprotective and neurotrophic properties. Our previous study demonstrates that cerebrolysin significantly improves functional recovery in rats after mild traumatic brain injury (mTBI). Objective. To determine histological outcomes associated with therapeutic effects of cerebrolysin on functional recovery after TBI. Methods. In this prospective, randomized, blinded, and placebo-controlled study, adult Wistar rats with mild TBI induced by a closed head impact were randomly assigned to one of the cerebrolysin dose groups (0.8, 2.5, 7.5 mL/kg) or placebo, which were administered 4 hours after TBI and then daily for 10 consecutive days. Functional tests assessed cognitive, behavioral, motor, and neurological performance. Study end point was day 90 after TBI. Brains were processed for histological tissue analyses of astrogliosis, axonal injury, and neurogenesis. Results. Compared with placebo, cerebrolysin significantly reduced amyloid precursor protein accumulation, astrogliosis, and axonal damage in various brain regions and increased the number of neuroblasts and neurogenesis in the dentate gyrus. There was a significant dose effect of cerebrolysin on functional outcomes at 3 months after injury compared with saline treatment. Cerebrolysin at a dose of ⩾0.8 mL/kg significantly improved cognitive function, whereas at a dose of ⩾2.5 mL/kg, cerebrolysin also significantly improved sensorimotor function at various time points. There were significant correlations between multiple histological and functional outcomes 90 days after mTBI. Conclusions. Our findings demonstrate that cerebrolysin reduces astrogliosis and axonal injury and promotes neurogenesis, which may contribute to improved functional recovery in rats with mTBI.

Anthocyanin extracts of lingonberry (Vaccinium vitis‐idaea L.) attenuate serum lipids and cholesterol metabolism in HCD‐induced hypercholesterolaemic male mice

SummaryThis study is aimed to evaluate the hypocholesterolaemic effect of anthocyanin extracts of lingonberry (LAE) in vitro and vivo studies. In vitro, LAE can effectively inhibit the micellisation of cholesterol with significant dose–effect relationship. In animal experiments, after 10‐weeks of LAE administration, lower values of body mass, daily food intake, liver weight, visceral adipose content, TC level, LDL‐C level, fasting blood glucose level and higher HDL‐C level in serum, cholesterol content and total bile acid content in faeces are observed in HCD‐induced hypercholesterolaemic mice compared with model group. These observations suggest that LAE could promote the metabolism of serum cholesterol in HCD‐induced hypercholesterolaemic mice primarily via faecal excretion of cholesterol. Furthermore, LAE may reduce the inflammatory cell infiltration and attenuate steatosis and hepatocellular fat deposit in the liver. Our results indicate that LAE is a potential dietary supplement in cholesterol‐lowering or for hypercholesterolaemic treatment. These findings may provide important basis for further optimisation of dietary anthocyanins utilisation.

Yoga as a Complementary Therapy for Smoking Cessation: Results From BreathEasy, a Randomized Clinical Trial.

There is evidence that Yoga may be helpful as an aid for smoking cessation. Yoga has been shown to reduce stress and negative mood and may aid weight control, all of which have proven to be barriers to quitting smoking. This study is the first rigorous, randomized clinical trial of Yoga as a complementary therapy for smokers attempting to quit. Adult smokers (N = 227; 55.5% women) were randomized to an 8-week program of cognitive-behavioral smoking cessation and either twice-weekly Iyengar Yoga or general Wellness classes (control). Assessments included cotinine-verified 7-day point prevalence abstinence at week 8, 3-month, and 6-month follow-ups. At baseline, participants' mean age was 46.2 (SD = 12.0) years and smoking rate was 17.3 (SD = 7.6) cigarettes/day. Longitudinally adjusted models of abstinence outcomes demonstrated significant group effects favoring Yoga. Yoga participants had 37% greater odds of achieving abstinence than Wellness participants at the end of treatment (EOT). Lower baseline smoking rates (≤10 cigarettes/day) were also associated with higher likelihood of quitting if given Yoga versus Wellness (OR = 2.43, 95% CI = 1.09% to 6.30%) classes at EOT. A significant dose effect was observed for Yoga (OR = 1.12, 95% CI = 1.09% to 1.26%), but not Wellness, such that each Yoga class attended increased quitting odds at EOT by 12%. Latent Class Modeling revealed a 4-class model of distinct quitting patterns among participants. Yoga appears to increase the odds of successful smoking abstinence, particularly among light smokers. Additional work is needed to identify predictors of quitting patterns and inform adjustments to therapy needed to achieve cessation and prevent relapse. This study adds to our knowledge of the types of physical activity that aid smoking cessation. Yoga increases the odds of successful smoking abstinence, and does so in a dose-response manner. This study also revealed four distinct patterns of smoking behavior among participants relevant to quitting smoking. Additional work is needed to determine whether variables that are predictive of these quitting patterns can be identified, which might suggest modifications to therapy for those who are unable to quit.

Effects of 28 Days of Oral Dimethandrolone Undecanoate in Healthy Men: A Prototype Male Pill

Dimethandrolone (DMA) has androgenic and progestational activity. Single oral doses of DMA undecanoate (DMAU) were well tolerated and reversibly suppressed serum LH and testosterone (T) in men. Assess safety, tolerability, pharmacokinetics (PK), and pharmacodynamics (PD) of oral DMAU. Double-blind, randomized, placebo-controlled study. Two academic medical centers. Healthy men (18 to 50 years). One hundred men received DMAU [0, 100, 200, or 400 mg, formulated in castor oil/benzyl benzoate (C) or powder (P)] for 28 days. Subjects underwent 24-hour PK sampling on days 1 and 28 and twice weekly ambulatory visits throughout treatment. Primary outcomes were safety and tolerability parameters (vitals, laboratory data, mood, and sexual function scores) and adverse events. Secondary outcomes were drug PK profiles and PD effects (serum LH, FSH, and sex hormones). Eighty-two subjects completed the study and were included in the analysis. There were no serious adverse events. No clinically significant changes developed in safety laboratory parameters. A significant dose effect was seen for weight, hematocrit, high-density lipoprotein cholesterol, corrected QT interval, and sexual desire. Serum 24-hour average concentrations of DMAU and DMA showed dose-related increases (P < 0.001). All six subjects in the P400 group and 12 of 13 subjects in the C400 group achieved marked suppression of LH and FSH (<1.0 IU/L) and serum T (<50 ng/dL). Daily oral administration of DMAU for 28 days in healthy men is well tolerated. Doses of ≥200 mg markedly suppress serum T, LH, and FSH. These results support further testing of DMAU as a male contraceptive.

Estimating the effects of variation in viremia on mosquito susceptibility, infectiousness, and R0 of Zika in Aedes aegypti.

Zika virus (ZIKV) is an arbovirus primarily transmitted by Aedes mosquitoes. Like most viral infections, ZIKV viremia varies over several orders of magnitude, with unknown consequences for transmission. To determine the effect of viral concentration on ZIKV transmission risk, we exposed field-derived Ae. aegypti mosquitoes to four doses (103, 104, 105, 106 PFU/mL) representative of potential variation in the field. We demonstrate that increasing ZIKV dose in the blood-meal significantly increases the probability of mosquitoes becoming infected, and consequently disseminating virus and becoming infectious. Additionally, we observed significant interactions between dose and days post-infection on dissemination and overall transmission efficiency, suggesting that variation in ZIKV dose affects the rates of midgut escape and salivary gland invasion. We did not find significant effects of dose on mosquito mortality. We also demonstrate that detecting virus using RT-qPCR approaches rather than plaque assays potentially over-estimates key transmission parameters, including the time at which mosquitoes become infectious and viral burden. Finally, using these data to parameterize an R0 model, we showed that increasing viremia from 104 to 106 PFU/mL increased relative R0 3.8-fold, demonstrating that variation in viremia substantially affects transmission risk.

NF-κB-94ins/del ATTG Genotype Contributes to the Susceptibility and Imbalanced Th17 Cells in Patients with Immune Thrombocytopenia.

Background The NLRP3 inflammasome plays important roles in the pathogenesis of autoimmune diseases. However, the role of the NLRP3 inflammasome in the pathophysiology of immune thrombocytopenia (ITP) remains unclear. Methods RT-PCR was used to examine the polymorphism and expression of genes involved in the NLRP3 inflammasome in ITP patients. T helper cells and apoptosis of PBMC from ITP patients were analyzed by flow cytometry. The antiplatelet autoantibodies in plasma were determined by modified monoclonal antibody-specific immobilization of platelet antigens (MAIPA). Results We found that the NF-κB-94ins/del ATTG genotype contributed to the susceptibility of ITP. Furthermore, the platelet counts of ITP patients with the WW genotype or WD genotype were lower than those with the DD genotype of NF-κB-94ins/del ATTG. Compared with controls, NF-κB gene expression was significantly decreased and WW or WD genotype ITP patients displayed higher mRNA expression than DD individuals. Similarly, the mRNA expression of NLRP3 was also increased in the WW genotype. There was a significant gene dose effect of the percentage of Th17 cells for the WW, WD, and DD genotypes (WW < WD < DD) in the unstimulated group and no significant difference was found after being stimulated. The activation of the NLRP3 inflammasome could upregulate Th17 in ITP patients. Conclusion The NF-κB-94ins/del ATTG genotype might serve as a novel biomarker and potential target for ITP.

Chemoradiotherapy in Children with Undifferentiated Nasopharyngeal Carcinoma

Undifferentiated nasopharyngeal carcinoma (UNC) differs from other epithelial tumors of the head and neck by a close connection with lymphatic tissue, epidemiology, and biological characteristics that determine the clinical course of the disease and therapeutic approaches. In this histological variant, a high titer of antibodies to the Epstein–Barr virus (EBV) was observed in blood of 100% of patients. Absence of specific symptoms, polymorphic clinical picture, and latent disease course lead to the detection of a tumor in children only at stages III–IV. Radiotherapy (RT), as the only method for the treatment of UNC, has been used for almost 30 years in all age groups of patients regardless of the disease stage. In most studies, 1.8–2 Gy per day and 50–70 Gy per course were applied to irradiate the nasopharynx and the affected lymph nodes. Modern treatment protocols require the use of conformal irradiation using magnetic resonance imaging (MRI) and computer tomography (CT) with contrast enhancement to form a three-dimensional model of RT planning. High efficacy and a radiosensitive effect were observed when platinum-based antineoplastic drugs were administered. The chemotherapy (CTx) regimens for pediatric patients included cisplatin, cyclophosphamide, and methotrexat which were administered both before and after RT. Maintenance therapy with interferon-β also positively affected the treatment results. Combined approaches allowed to increase the level of five-year overall survival rate up to 70–90%. The analysis of complications and long-term treatment effects in children with UNC showed a significant effect of total focal dose and irradiation technique on early radiation reactions from local tissues in the form of dermatitis, mucositis, and xerostomia, as well as on delayed radiation complications and development of second tumors. The review demonstrates the main therapeutic approaches to the treatment of children with UNC both in the historical aspect and according to current trends.

Degradation and Mechanism of Mechanical Properties of Polyimide Film Irradiated by Gamma Ray

Polyimide (PI) films might be damaged under space high energy particle irradiation. In this paper, the mechanical properties and mechanism of polyimide film is studied with the 60Co radiation source, the thermo-gravimetric analysis and the XPS analysis. Significant total dose effect is found in the mechanical properties of the PI film under gamma ray radiation. The tensile strength and rupture elongation of polyimide film increase first and then decrease exponentially with the increase of irradiation dose. The corresponding initial decomposition temperature of the gamma ray-radiated polyimide film changed from 570°C to 590°C for weight-loss ratio of 2%. From XPS analysis, it can be found that there were rupture and crosslink of chemical bond in polyimide film. In early stage of gamma ray radiation, the rupture of C-N bond and following crosslink is for the increase of mechanical properties of polyimide film, and as the increase of radiation, the rupture of C=O and −N(CO)bond, formation of C-N bond, release of N was for the decrease of mechanical properties of polyimide films.

Complex enzyme combined with ultrasound extraction technology, physicochemical properties and antioxidant activity of Hedysarum polysaccharides

In this study, complex enzymes combined with ultrasonic extraction technology（MC） were used, to select optimal extraction combinations by single factor and orthogonal test, with Hedysarum polysaccharides yield and content as the comprehensive indexes. The components, physicochemical properties and antioxidant activity of Hedysarum polysaccharides from complex enzyme combined with ultrasonic extraction（HPS-MC）and the Hedysarum polysaccharides from hot water extraction（HPS-R）were analyzed. The results showed that：complex enzymes had significant effect on the yield and content of Hedysarum polysaccharides, and the ultrasonic power could significantly improve the content of Hedysarum polysaccharides. The optimum technological parameters were as follows: complex enzyme ratio 1:1, ultrasonic power 105 W, ultrasonic time 60 min, and enzymatic hydrolysis pH 5, achieving （14.01±0.64）% and （92.45±1.47）% respectively for the yield and content of Polysaccharides. As compared with HPS-R, the molecular weight, absolute viscosity and protein content of HPS-MC were decreased, while the content of uronic acid was increased. In the antioxidant system, the concentration of polysaccharide was within the range of 1-7 g·L⁻¹; the antioxidant activity of HPS-MC was higher than that of HPS-R, and HPS-MC (80%) with the lowest molecular weight showed a significant dose effect relationship with the increase of the experimental concentration. In conclusion, MC is a simple, convenient, economical and environmentally friendly extraction technology, and the Hedysarum polysaccharides extracted by this method have obvious antioxidant activity.

Adolescent smokers’ response to reducing the nicotine content of cigarettes: Acute effects on withdrawal symptoms and subjective evaluations

BackgroundMandating a reduction in the nicotine content of cigarettes to a minimally addictive level could dramatically reduce smoking rates in the US. However, little is known about the effects of reduced nicotine content cigarettes in adolescents. MethodsFollowing overnight abstinence, adolescent daily smokers (ages 15–19, n = 50) reported on their craving, withdrawal, and positive and negative affect pre- and post- ad lib smoking of one cigarette containing varying nicotine content (15.8, 5.2, 1.3 and 0.4 mg/g of tobacco) in the laboratory and reported their subjective evaluations of each cigarette. Carbon monoxide (CO) boost from pre- to post-cigarette was calculated to determine if lower-nicotine cigarettes led to differential acute changes in toxicant exposure. ResultsAll four nicotine cigarette types significantly reduced abstinence-induced craving, withdrawal, and negative affect (all p’s < .05). Mixed models evaluating the effect of nicotine content, with nicotine dependence level and gender included as covariates, revealed a significant effect of nicotine content on craving and subjective evaluations: higher nicotine content resulted in greater reductions in craving and increases in both positive and negative subjective evaluations. There were no significant effects of nicotine dose on withdrawal symptoms, negative affect, or CO boost. ConclusionsThese results suggest that lower nicotine cigarettes might result in reduced abuse liability compared to higher nicotine content cigarettes due to reduced positive subjective effects, while still reducing withdrawal, in adolescents. These results highlight the potential feasibility of this policy approach and support continued research on how a nicotine reduction policy may affect adolescent smoking patterns.

The Effect Of Two Low-dose Strength/Balance Programs On The Physical Function Of Mobility-limited Older Adults

BACKGROUND: Strength and balance training are critical to maintaining physical function and delaying the onset of major mobility disability in older adults (OAs). The minimum amount of this training required to yield clinically meaningful improvements in physical function is not clear. PURPOSE: To evaluate the effect of two low dose strength/balance programs on physical function in mobility-limited OAs. METHODS: Twenty community-dwelling OAs with mobility limitations were randomized to one of two strength/balance doses (n=10/dose), held 3x/week at a local YMCA for 10 wks. Eligible participants were ≥ 65 yrs of age, exhibited mild to moderate mobility impairment (short physical performance battery (SPPB) score of 3-9 out of 12), sedentary (<125 minutes/week of any kind of physical activity, determined by 7-day pre-baseline accelerometry), and had no major medical issues that would preclude exercise. Exercise doses were as follows: Low dose (L): 1 set each of chair stands, hip abduction, step-up and back with head turns, toe raises, and a balance stand). Higher dose (H): 2 sets of the previous mentioned exercises were performed. Each exercise had three variations of difficulty to accommodate different participant abilities and the number of reps were based on an RPE of 7 out of 10. Participants were assessed on SPPB score and 400m walk speed before and after the intervention by individuals blinded to which dose that participant was randomized to. Clinically meaningful improvements were defined as an SPPB improvement of 0.5 points and a 400m walk speed improvement of 0.05 m/sec. Data was analyzed using a t-paired test. Results are expressed as means (+ std deviation). RESULTS: SPPB score improved by 2.5 (+ 1.1) points among the entire cohort (p<0.001). Improvement was significant for each dose alone (L: 1.5 (+ 0.6), p<0.05), (H: 3.0 (+ 0.82), p<0.001). The improvement in SPPB score in the higher dose was significantly different from that observed with the lower dose (p<0.05). There was no significant effect of either dose on 400m walk speed. CONCLUSION: A 10 wk strength/balance program performed 3x/week and consisting of a single set each of select strength/balance exercises was sufficient to elicit clinically meaningful improvements in physical function for OAs with mild to moderate mobility limitations.

25-Hydroxyvitamin D Threshold for the Effects of Vitamin D Supplements on Bone Density: Secondary Analysis of a Randomized Controlled Trial.

Most trials of vitamin D supplementation have shown no benefits on bone mineral density (BMD), although severe vitamin D deficiency causes osteomalacia, which is associated with profound BMD deficits. Recently, the ViDA-BMD study from New Zealand demonstrated a threshold of baseline 25-hydroxyvitamin D (25OHD; 30 nmol/L) below which vitamin D supplementation did benefit BMD. We have now reexamined data from a similar trial in Aberdeen to determine whether a baseline 25OHD threshold of 30 nmol/L is also observed in that database. The Aberdeen study recruited 305 postmenopausal women in late winter and randomized them to receive placebo, vitamin D 400 IU/d, or vitamin D 1000 IU/d over 1 year. As previously reported, BMD loss at the hip was reduced by vitamin D 1000 IU/d only, and there was no significant treatment effect of either dose at the lumbar spine. In the present analysis, when the trial participants were grouped according to whether their baseline 25OHD was ≤30 nmol/L or above this threshold, significant treatment effects were apparent at both the spine and hip in those with baseline 25OHD ≤30 nmol/L, but no significant effects were apparent in those with baseline 25OHD above this level. There was evidence of a similar threshold for effects on parathyroid hormone, but no groups showed changes in bone turnover markers during the study. It is concluded that vitamin D supplements only increase bone density in adults with nadir 25OHD ≤30 nmol/L. This moves us further toward a trial-based definition of vitamin D deficiency in adults with adequate calcium intakes and suggests that supplement use should be targeted accordingly. Future trials of vitamin D supplementation should focus on individuals with 25OHD concentrations in this range. © 2018 American Society for Bone and Mineral Research.

Epigenetic Aging in Major Depressive Disorder.

Major depressive disorder is associated with an increased risk of mortality and aging-related diseases. The authors examined whether major depression is associated with higher epigenetic aging in blood as measured by DNA methylation (DNAm) patterns, whether clinical characteristics of major depression have a further impact on these patterns, and whether the findings replicate in brain tissue. DNAm age was estimated using all methylation sites in blood of 811 depressed patients and 319 control subjects with no lifetime psychiatric disorders and low depressive symptoms from the Netherlands Study of Depression and Anxiety. The residuals of the DNAm age estimates regressed on chronological age were calculated to indicate epigenetic aging. Major depression diagnosis and clinical characteristics were assessed with questionnaires and psychiatric interviews. Analyses were adjusted for sociodemographic characteristics, lifestyle, and health status. Postmortem brain samples of 74 depressed patients and 64 control subjects were used for replication. Pathway enrichment analysis was conducted using ConsensusPathDB to gain insight into the biological processes underlying epigenetic aging in blood and brain. Significantly higher epigenetic aging was observed in patients with major depression compared with control subjects (Cohen's d=0.18), with a significant dose effect with increasing symptom severity in the overall sample. In the depression group, epigenetic aging was positively and significantly associated with childhood trauma score. The case-control difference was replicated in an independent data set of postmortem brain samples. The top significantly enriched Gene Ontology terms included neuronal processes. As compared with control subjects, patients with major depression exhibited higher epigenetic aging in blood and brain tissue, suggesting that they are biologically older than their corresponding chronological age. This effect was even more profound in the presence of childhood trauma.

Population pharmacokinetics of oxaliplatin after intraperitoneal administration with hyperthermia in Wistar rats

BackgroundThe evaluation of the efficacy and toxicity of hyperthermic intraoperative peritoneal chemotherapy presents some difficulties, due in part to the lack of information about the pharmacokinetic behavior of the drugs administered in this procedure. The aim of this study was to characterize the population pharmacokinetics of hyperthermic intraoperative peritoneal oxaliplatin in Wistar rats and to evaluate the effect of treatment-related covariates dose, instillation time and temperature on the pharmacokinetic parameters. MethodsOxaliplatin peritoneal and plasma concentrations from 37 rats treated by either intravenous or intraperitoneal oxaliplatin administrations under different instillation times, temperatures and doses were analyzed according to a population pharmacokinetic approach using the software NONMEM V7.3®. ResultsIntraperitoneal (n = 115) and plasma (n = 263) concentrations were successfully described according to a two-compartment model with first order absorption. No significant effect of dose, temperature and instillation time on pharmacokinetic parameters was found. However, an abrupt decrease in the elimination process was observed, reflected in the structural pharmacokinetic model through a modification in clearance. The typical parameters values and the interindividual variability (CV %) in clearance, central and peripheral volume of distribution were 3.25 mL/min (39.1%), 53.6 mL (37.8%) and 54.1 mL (77.3%), respectively. Clearance decreased to 0.151 mL/min (39.1%) when the instillation was still ongoing, at 31.4 min. One of the possible reasons behind the clearance decrease would be an alteration of renal function due to surgery and/or hyperthermia. ConclusionsThis study described the deterioration of the drug elimination process due to the procedure, and estimated the time at which this deterioration is most likely to occur. In addition, dose, instillation time and temperature had no influence in the PK parameters.

Can a single dose of human papillomavirus (HPV) vaccine prevent cervical cancer? Early findings from an Indian study

BackgroundHuman papillomavirus (HPV) vaccination is a major strategy for preventing cervical and other ano-genital cancers. Worldwide HPV vaccination introduction and coverage will be facilitated if a single dose of vaccine is as effective as two or three doses or demonstrates significant protective effect compared to ‘no vaccination’. MethodsIn a multi-centre cluster randomized trial of two vs three doses of quadrivalent HPV vaccination (Gardasil™) in India, suspension of the vaccination due to events unrelated to the study led to per protocol and partial vaccination of unmarried 10–18 year old girls leading to four study groups, two by design and two by default. They were followed up for the primary outcomes of immunogenicity in terms of L1 genotype-specific binding antibody titres, neutralising antibody titres, and antibody avidity for the vaccine-targeted HPV types and HPV infections. Analysis was per actual number of vaccine doses received. This study is registered with ISRCTN, number ISRCTN98283094; and with ClinicalTrials.gov, number NCT00923702. FindingsOf the 17,729 vaccinated girls, 4348 (25%) received three doses on days 1, 60, 180 or later, 4979 (28%) received two doses on days 1 and 180 or later, 3452 (19%) received two doses on days 1 and 60, and 4950 (28%) received one dose. One dose recipients demonstrated a robust and sustained immune response against HPV 16 and 18, albeit inferior to that of 3- or 2-doses and the antibody levels were stable over a 4 year period. The frequencies of cumulative incident and persistent HPV 16 and 18 infections up to 7 years of follow-up were similar and uniformly low in all the vaccinated study groups; the frequency of HPV 16 and 18 infections were significantly higher in unvaccinated age-matched control women than among vaccine recipients. The frequency of vaccine non-targeted HPV types was similar in the vaccinated groups but higher in the unvaccinated control women. ConclusionOur results indicate that a single dose of quadrivalent HPV vaccine is immunogenic and provides lasting protection against HPV 16 and 18 infections similar to the three- and two-dose vaccine schedules, although the study suffer from some limitations. Data on long term protection beyond 7 years against HPV infection and cervical precancerous lesions are needed before policy guidelines regarding a single dose can be formulated and implemented. Significant and long-lasting protective effect of a single dose can be a strong argument to introduce one dose of the HPV vaccine in many low income countries where the current standard of care for cervical cancer prevention is ‘no intervention’.

Effects of a Multi-Ingredient Energy Supplement on Cognitive Performance and Cerebral-Cortical Activation

ABSTRACTThis study assessed whether a multi-ingredient energy supplement (MIES) could enhance cerebral-cortical activation and cognitive performance during an attention-switching task. Cerebral-cortical activation was recorded in 24 young adults (12 males, 12 females; 22.8 ± 3.8 yrs) via electroencephalography (EEG) both at rest and during the attention-switching task before (pretest) and 30 min after (posttest) consumption of a single serving of a MIES (MIES-1), two servings of a MIES (MIES-2), or a placebo (PL) in a double-blinded, randomized crossover experimental design. EEG upper-alpha power was assessed at rest and during the task, wherein d′ (Z[hit rate]–Z[false alarm rate]) and median reaction time (RT) for correct responses to targets on attention-hold and attention-switch trials were analyzed. For both d′ and RT, the Session (MIES-1, MIES-2, PL) × Time (pretest, posttest) interaction approached statistical significance (p = .07, η2p = 0.106). Exploring these interactions with linear contrasts, a significant linear effect of supplement dose on the linear effect of time was observed (ps ≤.034), suggesting the pretest-to-posttest improvement in sensitivity to task target stimuli (d′) and RT increased as a function of supplement dose. With respect to upper-alpha power, the Session × Time interaction was significant (p < .001, η2p = 0.422). Exploring this interaction with linear contrasts, a significant linear effect of supplement dose on the linear effect of time was observed (p < .001), suggesting pretest-to-posttest increases in cerebral-cortical activation were a function of supplement dose. In conclusion, our findings suggest that MIES can increase cerebral-cortical activation and RT during task performance while increasing sensitivity to target stimuli in a dose-dependent manner.