Low Blood Concentrations Research Articles

Analysis of Blood Concentrations of Zinc, Germanium, and Lead and Relevant Environmental Factors in a Population Sample from Shandong Province, China.

Trace elements, including zinc (Zn) and germanium (Ge), are essential for health; deficiency or excess levels of trace elements results is harmful. As a result of industrial and agricultural production, Pb widely exists in people’s living environment. It is absorbed mainly through the respiratory and digestive tracts, producing systemic harm. Reference values for a normal, healthy population are necessary for health assessment, prevention and treatment of related diseases, and evaluation of occupational exposures. Reference ranges for the Chinese population have not been established. From March 2009 to February 2010; we collected data and blood samples (n = 1302) from residents aged 6–60 years living in Shandong Province, China. We measured blood concentrations of Zn, Ge, and Pb using inductively coupled plasma mass spectrometry to determine reference ranges. Results were stratified by factors likely to affect the concentrations of these trace elements: sex, use of cosmetics or hair dye, age, alcohol intake, smoking habits, and consumption of fried food. The overall geometric mean (GM) concentrations (95% confidence interval) were 3.14 (3.08–3.20) mg/L for Zn, 19.9 (19.3–20.6) μg/L for Ge, and 24.1 (23.2–25.1) μg/L for Pb. Blood Zn concentrations were higher in women than in men (p < 0.001), while the opposite was found for Pb (p < 0.001) and sex did not influence Ge (p = 0.095). Alcohol use was associated with higher blood concentrations of Zn (p = 0.002), Ge (p = 0.002), and Pb (p = 0.001). The GM concentration of Zn was highest in 20–30-year-olds (p < 0.001), while Pb concentrations were highest in 12–16-year-olds (p < 0.001). Use of hair dye was associated with lower blood concentrations of Ge (p < 0.05). GM blood concentrations of Pb differed significantly between those who consumed fried foods 1–2 times/month (18.7 μg/L), 1–2 times/week (20.9 μg/L), and every day (28.5 μg/L; p < 0.001). Blood Pb concentrations were higher in subjects who used cosmetics (p < 0.05), hair dye (p < 0.05), and who smoked cigarettes (p < 0.001) than in those who did not.

Effects of green tea supplementation on inflammation markers, antioxidant status and blood pressure in NaCl-induced hypertensive rat model

ABSTRACTBackground: Recent studies indicate the important role of chronic inflammation and oxidative stress in the pathogenesis of hypertension. Green tea, due to the high content of catechins, shows high antioxidant activity.Objective: To determine the effect of supplementation with green tea extract on the blood pressure, on the concentration of selected parameters of inflammation and antioxidant status in the model of high-sodium-diet induced hypertension.Design: The study lasted 42 days. The experimental population consisted of 30 rats. The rats were divided into three groups. The rats in the control group were fed a standard diet with 35 g of NaCl per kg of diet, in the second group hypertensive rats were fed a standard diet with NaCl (35 g/kg diet) and with an extract of green tea (2 g/kg diet). The third group consisted of hypertensive rats fed a standard diet with NaCl (35 g/kg diet), and 4 g of green tea extract/kg diet.Results: Supplementation with green tea had no effect on body mass of rats on a high-sodium diet. At the end of the experiment systolic blood pressures in SH2 and SH4 groups were significantly lower than in the control group SK. The SH4 group was characterized by a significantly lower diastolic blood pressure value and concentration of TNF-α in comparison to the SK group. The rats from both SH2 and SH4 groups were characterized by higher total antioxidant status values compared to the control group.Discussion: The mechanism of the beneficial effects of green tea on blood pressure is not clear, but it is believed that it is related to its omnidirectional properties.Conclusions: Supplementation of green tea has a beneficial effect on blood pressure, markers of inflammation and antioxidant status in an experimental model of hypertension.

The psychoneuroimmunotherapy of human immune-mediated systemic diseases, including cancer and autoimmune diseases

Until few years ago, the in vivo immune responses were considered to be identical to the reactions occurring in vivo, but the recent discoveries in the Psychoneuroendocrinoimmunology (PNEI) area have demonstrated that the immune system is under a psychoneuroendocrine regulation, which represents the biochemical mediation of the influence of emotions and consciousness states on the immune system, by allowing the possibility to modulate the immune functions by acting on their neuroendocrine control rather than directly on the immune cells. The immune responses are inhibited by the opioid system, mainly by acting on mu-opioid receptors, whereas they are stimulated by the pineal-cannabinergic system functional axis. The metastatic cancer is characterized by low blood concentrations of IL-2 and IL-12, in association with abnormally high levels of TGF-beta, IL-10 and IL-6, with a following decline in TH-1 lymphocytes and an increase in T regulatory (T reg) cell count. The autoimmune diseases are characterized also by enhanced levels of proinflammatory cytokines, namely IL-17, in association with low values of TGF-beta and IL-10 as the consequence of a decline in T reg cell count. Cancer progression is associated with a progressive decline in the endocrine function of the pineal gland, which may release at least three molecules provided by antitumor activity: melatonin, 5-methoxytryptamine and pinealine. The inhibitory effects of opioids on the anticancer immunity may be abrogated by the administration of the long-acting mu-opioid antagonist naltrexone. The deficiency of pineal indole hormones, which play a fundamental anticancer activity, as well that of the main antitumor cytokines, including IL-2 and IL-12, may be simply corrected by their exogenous administration. Finally, IL-17-induced immunoinflammatory response occurring in the autoimmune diseases may be counteracted by cannabinoid agonists, which may inhibit IL-17 secretion. The pineal hormones also may contribute to inhibit the chronic inflammatory response.

236 - Hydrogen Sulfide Increases GSH Biosynthesis, Glucose Uptake and Utilization in Mouse Myotubes

Diabetes is a leading cause of chronic diseases, such as heart disease. Diabetic patients have lower blood concentrations of H 2 S and L-Cysteine (LC). LC undergoes enzymatic breakdown to produce hydrogen sulphide (H 2 S), a gasotransmitter that regulates glucose and lipid homeostasis. Using C2C12 mouse myoblast (differentiated into myotubes) as a model, this study investigates the hypothesis that beneficial effects of LC supplementation are mediated by the upregulation of H 2 S status in diabetic patients. Results show that exogenous administration of Sodium hydrosulfide (NaHS 10µM; 6 hours), a H 2 S donor, significantly ( p 2 S production induced by using CSE siRNA caused an increase in ROS, and down regulation of potent antioxidant GSH biosynthesis enzymes (GCLC, Glutathione Synthetase) but not GGLM. Further, CSE knockdown downregulate Glucose Transporter Type 4 (GLUT4) mRNA level and reduces glucose uptake in C2C12 myotubes. Taken together, these data suggest that the upregulation of physiological levels of H 2 S can have beneficial effects on glucose homeostasis and redox balance via GSH pathway. Further mechanistic studies are under investigation on how H 2 S regulate GSH biosynthesis and L-Cysteine transporter (SLC7A11) in the maintenance of glucose homeostasis. Supported by NIH/NCCIH RO1 AT007442

Neuromuscular and inflammatory responses to handball small-sided games: the effects of physical contact.

The aim of this study was to investigate the influence of physical contact on neuromuscular impairments and inflammatory response during handball small-sided games. Using a counterbalanced design, 12 elite male junior handball players were divided into two groups: contact (C-SSG) and no-contact (NC-SSG), performing both contact and no-contact small-sided games, in reverse order on two training sessions separated by 5days. The methodology and rules were identical for the two SSG regimens, with the only difference being the inclusion or prohibition of upper body use for physical contacts. Upper and lower body neuromuscular performances and blood concentrations of inflammatory cytokine IL-6 were assessed before and immediately after the games. During small-sided games, video analysis was used to establish the physical contact counts. Significant differences were found in most upper and lower limbs muscles kinetic variables and in the physical contact events (all P<0.001) following the two training regimens. There was an increase in IL-6 after C-SSG and no changes following NC-SSG (P<0.05 and P=0.12, respectively). Moreover, a strong correlation was found between the number of physical contacts and IL-6 responses (r=0.971, P<0.001) in C-SSG. This study indicates that an inflammatory response and large upper and lower body neuromuscular impairments result from physical contact in elite handball players. These outcomes outline the specific physiological profile of C-SSG that, in turn, might be used by practitioners and coaches as a practical approach to strategically select exercises in athlete's overall training program.

Oral supplementation with L-homoarginine in young volunteers.

Low blood concentrations of the naturally occurring amino acid L-homoarginine (L-hArg) are related to impaired cardiovascular outcome and mortality in humans and animals. L-hArg is a weak substrate of nitric oxide synthase and an inhibitor of arginases in vitro. The aim of our study was to obtain kinetic and dynamic data after oral L-hArg supplementation. In a double-blind, randomized, placebo-controlled crossover study, 20 young volunteers received 125mg L-hArg once daily for 4 weeks. Kinetic parameters (Cmax , Tmax and AUC0-24h ) were calculated after ingestion of single and multiple doses of oral supplementation as primary endpoint. Secondary endpoints that were evaluated were routine laboratory, L-arginine, asymmetric dimethylarginine (ADMA), pulse wave velocity (PWV), augmentation index (AIx), flow-mediated vasodilatation (FMD), corticospinal excitability, i.e. motor threshold (MT), and cortical excitability, i.e. intracortical inhibition (ICI) and facilitation (ICF). One hour after ingestion (Tmax ), L-hArg increased the baseline L-hArg plasma concentration (2.87 ± 0.91μmoll-1 , mean ± SD) by 8.74 ± 4.46 [95% confidence intervals 6.65; 10.9] and 17.3 ± 4.97 [14.9; 19.6] μmoll-1 (Cmax ), after single and multiple doses, respectively. Once-only and 4 weeks of supplementation resulted in AUCs0-24h of 63.5 ± 28.8 [50.0; 76.9] and 225 ± 78.5 [188; 2624] μmoll-1 *h, for single and multiple doses, respectively. Routine laboratory parameters, L-arginine, ADMA, PWV, AIx, FMD, MT, ICI and ICF did not change by L-hArg supplementation compared to baseline. Once daily orally applied 125mg L-hArg raises plasma L-hArg four- and sevenfold after single dose and 4 weeks of supplementation, respectively, and is safe and well tolerated in young volunteers.

Determination of Structural and Morphological Parameters of Human Bulbar Conjunctiva from Optical Diffuse Reflectance Spectra

We have developed a method for on-the-fl y retrieval of the volume concentration of blood vessels, the average diameter of the blood vessels, the blood oxygenation level, and the molar concentrations of chromophores in the bulbar conjunctiva from its diffuse reflectance spectra, measured when the radiation delivery and detection channels are spatially separated. The relationship between the diffuse reflectance spectrum of the conjunctiva and its unknown parameters is described in terms of an analytical model, constructed on the basis of a highly accurate approximation analog of the Monte Carlo method. We have studied the effect of localization of hemoglobin in erythrocytes and localization of erythrocytes in the blood vessels on the power of the retrieval of structural and morphological parameters for the conjunctiva. We developed a device for obtaining video images of the conjunctiva and contactless measurements of its diffuse reflectance spectrum. By comparing simulated diffuse reflectance spectra of the conjunctiva with the experimental measurements, we established a set of chromophores which must be taken into account in the model for reproducing the experimental data within the measurement error. We observed absorption bands for neuroglobin in the experimental spectra, and provided a theoretical basis for the possibility of determining its absolute concentrations in the conjunctiva. We have shown that our method can detect low bilirubin concentrations in blood.

Implications of mercury and lead concentrations on breeding physiology and phenology in an Arctic bird

Although physiological traits and phenology are thought to be evolved traits, they often show marked variation within populations, which may be related to extrinsic factors. For example, trace elements such as mercury (Hg) and lead (Pb) alter biochemical processes within wildlife that may affect migration and breeding. While there is a growing understanding of how contaminants may influence wildlife physiology, studies addressing these interactions in free-living species are still limited. We examined how four non-essential trace elements (cadmium, Hg, Pb and selenium) interacted with physiological and breeding measures known to influence breeding in a free-living population of common eider ducks (Somateria mollissima). We collected blood from female eiders as they arrived at a breeding colony in northern Canada. Blood was subsequently assessed for baseline corticosterone (CORT), immunoglobulin Y (IgY), and the four trace elements. We used model selection to identify which elements varied most with CORT, IgY, arrival condition, and arrival timing. We then used path analysis to assess how the top two elements from the model selection process (Hg and Pb) varied with metrics known to influence reproduction. We found that arrival date, blood Hg, CORT, and IgY showed significant inter-annual variation. While blood Pb concentrations were low, blood Pb levels significantly increased with later arrival date of the birds, and varied negatively with eider body condition, suggesting that even at low blood concentrations, Pb may be related to lower investment in reproduction in eiders. In contrast, blood Hg concentrations were positively correlated with eider body condition, indicating that fatter birds also had higher Hg burdens. Overall, our results suggest that although blood Hg and Pb concentrations were below no-effect levels, these low level concentrations of known toxic metals show significant relationships with breeding onset and condition in female eider ducks, factors that could influence reproductive success in this species.

USE OF METHODS OF MATHEMATIC STATISTICS FOR PROCESSING OF MEDICAL-BIOLOGICAL DATA FOR REVELATION OF THE ROLE OF CHEMICAL ELEMENTS IN ETHIOPATHOGENESIS OF HUMAN DISEASES

Aim of paper was to appraise the possibility of use of the traditional mathematical statistics methods for biomedical data to processing for determining the role of aluminium, chrome, niobium and lead in functioning of human blood-forming system. An effect of the abovementioned microelements on immunocompetent and blast cells was examined. Methods. To solve the indicated purposes, it were examined the venous blood leukoconcentrate in 48 of the examined persons. The standard methods of statistics were applied to the obtained data, namely the construction of spreading plot, elements of correlation and regression analysis. Results. It was obtained, that the reaction of immunocompetent and blast cells is ambivalent and depends upon the level of micronutrient status in human organism. Micronutrient biogenic effect is observed upon its low concentration in blood. An abiogenic effect arises upon the high level of micronutrient status in biological media of human. Conclusions. Notwithstanding the obtained results, the generally accepted approaches haven’t provided the possibility to determine the faithful character of immunocompetent and blast cells reaction on the level of micronutrient status in human organism and require the elaboration and development of the new approaches considering the revealed nonlinear relation.

Detection Limits for Blood on Fabrics Using Attenuated Total Reflection Fourier Transform Infrared (ATR FT-IR) Spectroscopy and Derivative Processing.

Attenuated total reflection Fourier transform infrared spectroscopy (ATR FT-IR) was used to detect blood stains based on signature protein absorption in the mid-IR region, where intensity changes in the spectrum can be related to blood concentration. Partial least squares regression (PLSR) was applied for multivariate calibrations of IR spectra of blood dilutions on four types of fabric (acrylic, nylon, polyester, and cotton). Gap derivatives (GDs) were applied as a preprocessing technique to optimize the performance of calibration models. We report a much improved IR detection limit (DL) for blood on cotton (2700× in dilution factor units) and the first IR DL reported for blood on nylon (250×). Due to sample heterogeneity caused by fabric hydrophobicity, acrylic fabric produced variable ATR FT-IR spectra that caused poor DLs in concentration units compared to previous work. Polyester showed a similar problem at low blood concentrations that lead to a relatively poor DL as well. However, the increased surface sensitivity and decreased penetration depth of ATR FT-IR make it an excellent choice for detection of small quantities of blood on the front surface of all fabrics tested (0.0010 µg for cotton, 0.0077 µg for nylon, 0.011 µg for acrylic, and 0.0066 µg for polyester).

Associations of Selected Cytokines Levels in Organ Transplant Recipients Without and With Malignant Skin Neoplasms.

Skin malignancies are the most prevalent neoplasms seen in organ transplant recipients (OTRs). Immunosuppressive treatment has been attributed to play a causative role in malignancy development. The aim of the study was to assess cytokine concentrations involved in cytotoxic and regulatory responses in patients after organ transplantation (Tx). We compared two OTR subgroups: those with malignant skin tumors and those without any known changes developed after Tx. We enrolled 102 patients, 63: 3-360 (median: min-max) months after Tx, aged 54.3 ± 9.9 (mean ± SD) years (38.2% females). Seventeen patients werediagnosed with malignant skin neoplasms. The most frequent treatment schemes werecyclosporine A - mycophenolate mofetil - glucocorticosteroids (GS) (37.4%), mycophenolate mofetil-tacrolimus - GS (15.2%), and azathioprine-cyclosporine A-GS (14.1%). A 5-mL sample of venous blood was obtained from participants of two subgroups: those with malignant skin tumors and those without any known changes. The blood was tested for interleukin 2 (IL-2), interferon gamma, IL-10, and transforming growth factor beta concentrations (Multicytokine Flex Set, ELISA). The Kruskal-Wallis test was used to compare variables; P< .05 was considered valid. Age, gender distribution, and time from transplantation did not differ across the two subgroups. We found significantly lower blood concentrations of IL-2 and IL-10 in patients with post-transplantation skin cancers versus patients without any known skin changes (0pgmL(-1) vs. 21.22 pgmL(-1), and 4.93 pgmL(-1) vs. 7.36 pgmL(-1), respectively). The differences between interferon gamma and transforming growth factor beta levels were insignificant across studied groups. Our findings suggest that immunosuppressive response assessed by cytokine IL-2 and IL-10 levels may be used in the risk stratification for the development of skin cancer in organ recipient patients.

Relationship between clozapine dose, serum concentration, and clinical outcome in children and adolescents in clinical practice.

Information on dose- and concentration-related clinical effects of clozapine treatment in children and adolescents is scarce. This study aimed to examine the relationship between dose, serum concentration, and clinical outcome as well as the influencing factors thereof in paediatric patients treated with clozapine. Data from a routine Therapeutic Drug Monitoring (TDM) service between 2004 and 2014 were studied in 68 patients, aged 11-18years. Severity of illness, therapeutic effectiveness and adverse drug reactions (ADRs) were assessed by standardized means. A relationship between the daily dose (mean 319mg, 4.9mg/kg) and serum concentration (mean 387ng/ml) of clozapine was found with the variation in dose explaining 30% of the variability in clozapine serum concentrations. Also gender contributed to the variability, however, no influence of age or concomitant medications was detected. Furthermore, a significant association was found between clozapine serum concentration and the occurrence of ADRs. Patients without ADRs had a lower mean serum concentration than those with mild (261.4 vs 407.3ng/ml, P=0.018) and moderate ADRs (261.4 vs 416.3ng/ml, P=0.028). As clozapine was estimated to be effective in lower blood concentrations, guidance on a possibly lower therapeutic range of clozapine serum levels in paediatric patients is provided. With ADRs increasing under higher concentrations, TDM is strongly recommended in paediatric clozapine therapy for individualized dosing. Dose adjustment in females also might be reasonable according to gender-related differences in serum concentrations. However, regarding the limitations of this study results should be validated in larger studies with more standardized designs.

Green tea and quercetin sensitize PC-3 xenograft prostate tumors to docetaxel chemotherapy.

BackgroundChemotherapy with docetaxel (Doc) remains the standard treatment for metastatic and castration-resistance prostate cancer (CRPC). However, the clinical success of Doc is limited by its chemoresistance and side effects. This study investigated whether natural products green tea (GT) and quercetin (Q) enhance the therapeutic efficacy of Doc in CRPC in mouse models.MethodsMale severe combined immunodeficiency (SCID) mice (n = 10 per group) were inoculated with androgen-independent prostate cancer PC-3 cells subcutaneously. When tumors were established the intervention started. Mice were administered with GT + Q, Doc 5 mg/kg (LD), GT + Q + LD Doc, Doc 10 mg/kg (HD) or control. The concentration of GT polyphenols in brewed tea administered as drinking water was 0.07 % and Q was supplemented in diet at 0.4 %. Doc was intravenously injected weekly for 4 weeks, GT and Q given throughout the study.ResultsGT + Q or LD Doc slightly inhibited tumor growth compared to control. However, the combination of GT and Q with LD Doc significantly enhanced the potency of Doc 2-fold and reduced tumor growth by 62 % compared to LD Doc in 7-weeks intervention. A decrease of Ki67 and increase of cleaved caspase 7 were observed in tumors by the mixture, along with lowered blood concentrations of growth factors like VEGF and EGF. The mixture significantly elevated the levels of tumor suppressor mir15a and mir330 in tumor tissues. An increased risk of liver toxicity was only observed with HD Doc treatment.ConclusionsThese results provide a promising regimen to enhance the therapeutic effect of Doc in a less toxic manner.

The therapeutic use of cannabinoids: Forensic aspects

Since 2013 in the Italian market has been introduced the Nabiximols, a drug containing two of the main active cannabinoids: Δ9-tetrahydrocannabinol (Δ9-THC) and cannabidiol (CBD). This drug has been approved in Italy in the treatment of Multiple Sclerosis (MS). It is an oral spray formulation and each puff of 100μl contains 2.7mg of Δ9-THC and 2.5mg of CBD.In the present study we analyzed urine and blood samples collected from a group of 20 patients treated with Nabiximols in order to evaluate: blood Δ9-THC concentrations in relation to the dose administered and the duration of treatment and the potentiality of this medication to be used for drug habit. MethodsThe study was conducted on a sample group of patients affected by MS, of both sexes, age: 49–61 years, treated with Nabiximols for short (28 days) or long-term.The results of our study allow affirming that it is unlikely to use this medication for drug habit or to sale it in the black market because of the low blood concentrations available and of its high costs. These statements were confirmed by: (a) the low Δ9-THC concentrations in the pharmaceutical formulation; (b) the low blood concentrations produced by Nabiximols administration, more than 10 times smaller than the blood concentrations known to produce psychotropic effects; (c) the presence of CBD (Δ9-THC natural antagonist); (d) the route of administration (inhaled, not smoked).

A field trial on the effects of pure sodium propionate and a combination with herbal extracts on short term development of subclinical ketosis

While glucogenic substances in ketosis prevention are commonly used, there is a lack of clinical studies about the effectiveness of ketosis therapy in particular by means of sodium propionate and herbal extracts. Fresh cows between 5 and 50 days in milk of 25 Swiss and German dairy farms were tested weekly for ketone bodies in blood. From 283 cows, 121 (42.8%) exceeded the threshold of 1.0mmol/l blood-β-hydroxybutyrate (BBHB). Thereof 84 cows were randomly assigned to three treatments on each farm. Treatment SP-H was composed of sodium propionate (120g per application) and an aqueous extract of seven herbs (13.5g drug equivalent per application), treatment SP comprised pure sodium propionate (120g per application) and treatment PL was a placebo. All preparations were fluid (in total 350ml per application) and were supplemented with organic molasses (2%) and water. Applications were given orally twice a day shortly after milking for a period of four days. During an observation period of two weeks, milk yield and milk parameters (acetone, protein, urea), body condition score and BBHB were recorded. All three treatment groups had similar initial conditions, except for a non-significantly lower ketone body concentration in blood and milk in group PL.The results indicated a reduction of ketone bodies in all three treatment groups. Mean values in group SP never differed significantly from those of group PL regarding the observed parameters. During the first week of observation milk-acetone (MAC) concentration was reduced in all treatment groups: mean values in group SP-H were on the lowest level and differed significantly from those in group SP (p=0.035) and PL (p<0.001). The second week of observation did not reveal any significant difference between the assessed parameters. The largest reduction in BBHB concentration after two weeks showed group SP-H with a difference by trend to group SP (p=0.06), but not to group PL. There were no significant differences between the groups concerning the other recorded parameters. Compared to placebo or pure sodium propionate a combination of sodium propionate with herbal extracts seemed to have slight advantages in a four days therapy of subclinical ketotic fresh cows.

Sustained release of risperidone from biodegradable microspheres prepared by in-situ suspension-evaporation process

Risperidone-loaded poly (d,l-lactide-co-glycolide) (PLGA) microspheres were prepared with a suspension-evaporation process with an aqueous suspension containing an in situ-formed aluminum hydroxide inorganic gel (SEP-AL process) and evaluated for encapsulation efficiency, particle size, surface morphology, glass transition temperature, in vitro drug release profile, and in vivo behavior. The SEP-AL microspheres were compared with conventional oil-in-water (O/W) emulsion solvent evaporation method using polyvinylalcohol (PVA) as an emulsifier (CP-PVA process). The microspheres were spherical in shape. DSC measurements showed that risperidone crystallinity was greatly reduced due to the homogeneous distribution of risperidone in PLGA microspheres. In vitro drug release profile from the microspheres showed a sigmoidal pattern of negligible initial burst up to 24h and minimal release (time-lag) for 7days. After the lag phase, slow release took a place up to 25days and then rapid release occurred sharply for 1 week. In vivo rat pharmacokinetic profile from the microspheres showed very low blood concentration level at the initial phase (up to 24h) followed by the latent phase up to 21days. At the 3rd week, main phase started and the blood concentration of the drug increased up to the 5th week, and then gradually decreased. The risperidone-loaded PLGA microspheres produced by SEP-AL process showed excellent controlled release characteristics for the effective treatment of schizophrenia patients.

Collection and analysis of published scientific information as preparatory work for the setting of Dietary Reference Values for Vitamin D

In recent years, there has been much attention for the global high prevalence of low blood concentrations of 25(OH)D, as an indicator of vitamin D status. These 25(OH)D concentrations primarily depend upon the level of sun exposure. However, also dietary vitamin D intake is of importance, especially at higher latitudes during winter. To get insight in the amount of oral vitamin D needed to achieve and maintain an adequate 25(OH)D blood concentration, the aim of this review was to systematically investigate the intake-status relationship for vitamin D under minimal endogenous vitamin D synthesis, as preparatory work for the setting of Dietary Reference Values for vitamin D. Searches were conducted in Medline, Embase and Cochrane. All published prospective cohort studies with the vitamin D intake-status relationship as the primary aim of investigation, as well as all trials, issued through 23-7-2014 and covering all ages, were included in this review, which resulted in 7,807 unique hits. Subsequently, 1,323 potentially relevant articles were identified by title and abstract screening. Hand searches led to the inclusion of 22 additional potentially relevant papers. Thus, in total, 1,345 full-text papers were screened. After full text screening, 56 articles met the predefined inclusion criteria, resulting in the inclusion of 65 studies, i.e. 57 trials and 8 prospective cohort studies, in infants, children or adults (one article corresponding to one to three studies). Two of the included studies were conducted in infants, eight in children or adolescents, and 55 in adults. The majority of the studies examined the impact of vitamin D3. Most trials studies showed a dose-response relation between vitamin D intake and status. However, as the impact of a similar dose of vitamin D on 25(OH)D concentration substantially differed across the studies, it is difficult to quantify this dose-response relationship. Therefore, the exact nature of the vitamin D dose-response relationship warrants further investigation, for instance by performing meta-regression analyses.

Abstract A78: Serum metabolomics, cytokine measurements, and tumor RNA-seq identified phospholipids correlated with a molecular subclass as strong predictor for outcome in high-grade serous ovarian cancer.

Abstract Background: Currently, the field of ‘omics’ is still growing, giving step by step deeper insight into the biological system of cancer. Increasing evidence suggests that alterations in cancer metabolism might have a tremendous impact on survival and could guide new treatment strategies. Therefore, including metabolic phenotyping in a study design would allow better understanding of the biological function and status of tumor cells and their hosts. Epithelial ovarian cancer (EOC) is very heterogeneous in both, local tumor spread and survival. Molecular subtypes presenting with distinct whole-genome expression profiles and significant survival differences have been described and awareness of the molecular alterations is required to identify new targets for therapy. In this study, serum metabolite changes were identified and evaluated as potential prognostic markers in a test set of 65 high grade serous EOC (HGSOC) patients. The prognostic impact was validated in an independent cohort of 165 EOC patients. Methods: Targeted metabolomics was performed on serum using the AbsoluteIDQ p180 kit (Biocrates Life Sciences), measuring 188 metabolites. In addition to a test and validation set of 65 HGSOC and 165 serous advanced stage EOC patients, the metabolomics profile of 62 healthy women was determined. In a subset of patients 16 cancer biomarkers and 40 chemokines were measured using Luminex bead-based assays and whole genome transcriptomes were assessed from different tumor tissues (primary, metastatic, and ascitic) by RNA sequencing. Results: 53 metabolites were significantly negatively correlated to overall survival (OS). Thereof, the majority (43) constituted glycerophospholipids (GPhL), followed by five acylcarnitines, four sphingolipids and one biogenic amine. A non-linear dimensionality reduction approach was used to reduce the information of the 43 GPhLs to three dimensions. The first showed the strongest impact on OS and revealed, as GPhL predictor, a significant impact on OS in uni- and multivariate (HR 0.38; p&amp;lt;0.001) Cox regression analyses, i.e. low GPhL concentrations in blood lead to worse OS. To determine the biologic background of these changes in the serum lipidome, correlations to cytokines and tumor markers were evaluated. IL6, CXCL2, osteopontin, and CCL23 were significantly negatively and leptin and sEGFR positively correlated to the GPhL-predictor. In a next step, RNA sequencing of different tumor tissues identified 393 genes negatively correlated (i.e. the carbohydrate-responsive element-binding protein, ChREPB) and 429 genes positively correlated (i.e. complete respiratory chain, many histones) with the GPhL-predictor. To provide more profound survival analysis, a validation was performed using expression data initially used for validation of a molecular subclassification with a tremendous impact on OS in 165 serous advanced stage EOC patients (Pils et al. Cancer Sci. 103:1334). Using the 50 most significantly up- and the 50 down-regulated genes a robust predictor was built. This gene predictor represents the GPhL-predictor and had a significant independent impact on OS (HR 0.66; p=0.004). In addition to this validation of the survival impact, a very strong correlation between the observed GPhL changes (via the gene predictor) and the molecular subclass was found, indicating a functional connection between these molecular subclasses and the serum lipidome. Conclusion: Targetd metabolomics revealed a strong independent impact of the serum concentrations of glycerophospholipids on HGSOC outcome in the test and a validation cohort. Transcriptomics data indicate changes in the energy metabolism of the tumor. Interestingly, the lipidome-changes were strongly correlated to a previously described molecular subclass in serous EOC. Citation Format: Stefanie Aust, Anna Bachmayr-Heyda, Katharina Auer, Nyamdelger Sukhbaatar, Samuel M. Meier, Christopher Gerner, Dietmar Pils. Serum metabolomics, cytokine measurements, and tumor RNA-seq identified phospholipids correlated with a molecular subclass as strong predictor for outcome in high-grade serous ovarian cancer. [abstract]. In: Proceedings of the AACR Special Conference on Advances in Ovarian Cancer Research: Exploiting Vulnerabilities; Oct 17-20, 2015; Orlando, FL. Philadelphia (PA): AACR; Clin Cancer Res 2016;22(2 Suppl):Abstract nr A78.

The Effect of Chlorpyrifos, an Organophosphorus Pesticide, on Glucose Uptake in Whole Blood

Background: The sub-chronic organophosphorous pesticide exposure increases insulin resistance and thereby the risk of developing Diabetes mellitus. Its acute exposure also leads to hyperglycemia. However, the mechanism is not clearly understood. Hence the present study explores the effect of low and high concentrations of chlorpyrifos, an organophosphorous pesticide on glucose uptake by whole blood and its possible mechanism. Methods: Level of hemolysis was determined at 2 and 4 hours of 1% DMSO (Dimethyl sulfoxide) and chlorpyrifos (0.3 and 10 mg/ml) exposure. The whole blood was treated in vitro with vehicle i.e., 1% DMSO or high (10 mg/mL) or low (0.3 mg/mL) concentrations of chlorpyrifos dissolved in DMSO. Then plasma glucose was assayed by glucose oxidase method at 2 and 4 hours of DMSO/chlorpyrifos exposures. Results: There was no effect of DMSO or 0.3 mg/ml chlorpyrifos treatment on hemolysis even after 4 hours. 10 mg/ml chlorpyrifos causes 2% and 14% hemolysis at 2 and 4 hours respectively. Plasma glucose level decreased in a time dependent manner after collection of blood (15.9% at 2 hours and 34.2% at 4 hour) in presence of DMSO. Chlorpyrifos did not influence glucose uptake by whole blood in low concentration but suppressed it in high concentration. Conclusion: Chlorpyrifos does not impair glucose uptake at low concentration in whole blood probably because major glucose uptake in blood is insulin independent. The impaired glucose uptake at high concentration is mostly due to toxic metabolic impairment and partly due to its hemolytic effect.

Oral tacrolimus oil formulations for enhanced lymphatic delivery and efficient inhibition of T-cell’s interleukin-2 production

Oral oil formulations have been reported to deliver drugs into the lymph. Lymphatic delivery of immunomodulatory drugs can more efficiently expose the drugs to T-cells in lymph, consequently induce higher efficacy and lower side effects. In this study, effects of tacrolimus oral oil formulations on drug blood exposure, and on inhibition of T-cell’s interleukin-2 (IL-2) production were investigated in rats. Oil formulations (sunflower oil, cacao butter, medium chain triglyceride, and palm oil) dissolving tacrolimus showed lower drug blood concentration than a solid dispersion formulation (SDF). The sunflower oil, and cacao butter formulations suppressed drug blood exposure to 50% of the SDF, and inhibited T-cell’s IL-2 production similar to the SDF. In vitro digestion tests indicated that slower digestion of the oils might reduce amount and rate of tacrolimus blood absorption. The cacao butter formulations showed 3.0 times more rapid tacrolimus absorption to lymphatic fluid than the SDF. Ratio of the rate constants of absorption into lymph to that into blood was higher in oil formulations (15 times in cacao butter, 15 times sunflower oil, and 3.5 times palm oil) than in the SDF. These results indicated that the oral oil formulations might be suitable for reduced tacrolimus blood concentration for low systemic side effects, and keep high lymph concentration for high efficacy in organ transplantation patients.