Outside-in systems pharmacology combines innovative computational methods with high-throughput whole vertebrate studies

To advance the systems approach in pharmacology, experimental models and computational methods need to be integrated from early drug discovery onward. Here, we propose outside‐in model development, a model identification technique to understand and predict the dynamics of a system without requiring prior biological and/or pharmacological knowledge. The advanced data required could be obtained by whole vertebrate, high‐throughput, low‐resource dose‐exposure‐effect experimentation with the zebrafish larva. Combinations of these innovative techniques could improve early drug discovery.Pharmacolog

Immunological Adaptations to Pregnancy in Women with Type 1 Diabetes

Despite adequate glycemic control, pregnancy outcome of women with type 1 diabetes (T1D) is still unfavorable as compared to healthy women. In a rat-model of T1D under normoglycemic conditions, adverse pregnancy outcome was also observed, which was associated with aberrant immunological adaptations to pregnancy. Because similar processes may occur in women with T1D we studied the systemic immune response in non-pregnant and pregnant women with and without T1D. The systemic immune response was assessed by using flow cytometry to evaluate the number and activational status of subpopulations of lymphocytes, Natural Killer cells and monocytes in peripheral blood of non-pregnant and pregnant women with and without T1D. An increased white blood cell count, an increased Th1/Th2 ratio, increased Natural Killer cell expression of CD335 and enhanced activation of intermediate and non-classical monocytes was observed in pregnant women with T1D vs. healthy pregnant women. Also, the pregnancy outcome (i.e. incidence of preterm delivery and macrosomia) of women with T1D was unfavorable as compared to healthy women. This study showed that in T1D, the immunological adaptations to pregnancy are disturbed. In addition to hyperglycemia, these different immunological adaptations may be responsible for the greater frequency of complications in pregnant women with T1D

Low percentage of clinically relevant pistachio nut and mango co-sensitisation in cashew nut sensitised children

Background: Cashew nut, pistachio nut and mango belong to the Anacardiaceae family and are botanically related. Therefore, cashew nut sensitised children are frequently advised to eliminate cashew nuts and pistachio nuts from their diet. The ‘Improvement of Diagnostic mEthods for ALlergy assessment (IDEAL trial number NTR3572) study showed that cashew nut sensitised children were co-sensitised to pistachio nut in 98% of cases and to mango in 21% of cases. The aim of this follow-up study to IDEAL is to assess the clinical relevance of co-sensitisation to pistachio nut and mango in cashew nut sensitised children. Methods: Children were recruited from the study: ‘Improvement of Diagnostic mEthods for ALlergy assessment (IDEAL trial number NTR3572). Inclusion criterion for the IDEAL study was sensitization to cashew nut as demonstrated by either SPT or sIgE, and a clinical history of reactions to cashew nuts or no previous (known) exposure. Sensitized children who were tolerant to cashew nuts were excluded. Inclusion criterion for this IDEAL follow-up study was co-sensitization to pistachio nut, regardless the result of the DBPCFC with cashew nut. In this follow-up study a double-blind placebo-controlled food challenge with pistachio nut and an open food challenge with mango were performed. Results: Twenty-nine children (mean age of 11.6 years, 62% male) were included. Pistachio nut sensitisation was clinically relevant in only 34% of cashew-sensitised children and only 31% of cashew challenge positive children. None of the children was challenge positive to mango. Conclusion: Although co-sensitisation between cashew nut and pistachio nut was observed in 98%, pistachio nut sensitisation was only clinically relevant in 34% of the children. Therefore, a challenge test with pistachio nut is recommended in children with cashew nut and pistachio nut sensitisation.</p

The association between preoperative body composition and aerobic fitness in patients scheduled for colorectal surgery

AIM: Although cardiopulmonary exercise testing (CPET) is considered the gold standard, a preoperative abdominal CT scan might also provide information concerning preoperative aerobic fitness for risk assessment. This study aimed to investigate the association between preoperative CT‐scan‐derived body composition variables and preoperative CPET variables of aerobic fitness in colorectal surgery. METHOD: In this retrospective cohort study, CT images at level L3 were analysed for skeletal muscle mass, skeletal muscle radiation attenuation, visceral adipose tissue (VAT) mass and subcutaneous adipose tissue mass. Regression analyses were performed to investigate the relation between CT‐scan‐derived body composition variables, CPET‐derived aerobic fitness and other preoperative patient‐related variables. Logistic regression analysis was performed to predict a preoperative anaerobic threshold (AT) ≤ 11.1 ml/kg/min as cut‐off for having a high risk for postoperative complications. RESULTS: Data from 78 patients (45 men; mean [SD] age 74.5 [6.4 years]) were analysed. A correlation coefficient of 0.55 was observed between absolute AT and skeletal muscle mass index. Absolute AT (R (2) of 51.1%) was lower in patients with a lower skeletal muscle mass index, together with higher age, lower body mass and higher American Society of Anesthesiologists (ASA) score. Higher ASA score (odds ratio 5.64; P = 0.033) and higher VAT mass (odds ratio 1.02; P = 0.036) were associated with an increased risk of an AT ≤ 11.1 ml/kg/min. CONCLUSION: Body composition variables from the preoperative CT scan were moderately associated with preoperative CPET‐derived aerobic fitness. Higher ASA score and higher VAT mass were associated with an increased risk of an AT ≤ 11.1 ml/kg/min

Difference in signalling between various hormone therapies in endometrium, myometrium and upper part of the vagina

BACKGROUND: Combined hormone treatments in post-menopausal women have different clinical responses on uterus and vagina; therefore, we investigated differences in steroid signalling between various hormone therapies in these tissues. METHODS: A total of 30 post-menopausal women scheduled for hysterectomy were distributed into four subgroups: control-group (n = 9), Tibolone-group (n = 8); estradiol (E(2))-group (n = 7); E(2) + medroxyprogesterone acetate (MPA)-group (n = 6). Medication was administered orally every day for 21 days prior to removal of uterus and upper part of the vagina. Tissue RNA was isolated, and gene expression profiles were generated using GeneChip technology and analysed by cluster analysis and significance analysis of microarrays. Apoptosis and cell proliferation assays, as well as immunohistochemistry for hormone receptors were performed. RESULTS: 21-days of treatment with E(2), E(2) + MPA or tibolone imposes clear differential gene expression profiles on endometrium and myometrium. Treatment with E(2) only results in the most pronounced effect on gene expression (up to 1493 genes differentially expressed), proliferation and apoptosis. Tibolone, potentially metabolized to both estrogenic and progestagenic metabolites, shows some resemblance to E(2) signalling in the endometrium and, in contrast, shows significant resemblance to E(2) + MPA signalling in the myometrium. In the vagina the situation is entirely different; all three hormonal treatments result in regulation of a small number (4-73) of genes, in comparison to signalling in endometrium and myometrium. CONCLUSION: Endometrium and myometrium differentially respond to the hormone therapies and use complet

Multicentre Double-Blind Placebo-Controlled Food Challenge Study in Children Sensitised to Cashew Nut

Few studies with a limited number of patients have provided indications that cashew-allergic patients may experience severe allergic reactions to minimal amounts of cashew nut. The objectives of this multicentre study were to assess the clinical relevance of cashew nut sensitisation, to study the clinical reaction patterns in double-blind placebo-controlled food challenge tests and to establish the amount of cashew nuts that can elicit an allergic reaction.A total of 179 children were included (median age 9.0 years; range 2-17 years) with cashew nut sensitisation and a clinical history of reactions to cashew nuts or unknown exposure. Sensitised children who could tolerate cashew nuts were excluded. The study included three clinical visits and a telephone consultation. During the first visit, the medical history was evaluated, physical examinations were conducted, blood samples were drawn and skin prick tests were performed. The children underwent a double-blind placebo-controlled food challenge test with cashew nut during the second and third visits. The study showed that 137 (76.5%) of the sensitised children suspected of allergy to cashew nut had a positive double-blind placebo-controlled food challenge test, with 46% (63) manifesting subjective symptoms to the lowest dose of 1 mg cashew nut protein and 11% (15) developing objective symptoms to the lowest dose. Children most frequently had gastro-intestinal symptoms, followed by oral allergy and skin symptoms. A total of 36% (49/137) of the children experienced an anaphylactic reaction and 6% (8/137) of the children were treated with epinephrine.This prospective study demonstrated a strikingly high percentage of clinical reactions to cashew nut in this third line population. Severe allergic reactions, including anaphylaxis requiring epinephrine, were observed. These reactions were to minimal amounts of cashew nut, demonstrated the high potency of this allergens.www.ncbi.nlm.nih.gov/pubmed NTR3572