Plasma lipid profiles discriminate bacterial from viral infection in febrile children.

Fever is the most common reason that children present to Emergency Departments. Clinical signs and symptoms suggestive of bacterial infection are often non-specific, and there is no definitive test for the accurate diagnosis of infection. The 'omics' approaches to identifying biomarkers from the host-response to bacterial infection are promising. In this study, lipidomic analysis was carried out with plasma samples obtained from febrile children with confirmed bacterial infection (n = 20) and confirmed viral infection (n = 20). We show for the first time that bacterial and viral infection produces distinct profile in the host lipidome. Some species of glycerophosphoinositol, sphingomyelin, lysophosphatidylcholine and cholesterol sulfate were higher in the confirmed virus infected group, while some species of fatty acids, glycerophosphocholine, glycerophosphoserine, lactosylceramide and bilirubin were lower in the confirmed virus infected group when compared with confirmed bacterial infected group. A combination of three lipids achieved an area under the receiver operating characteristic (ROC) curve of 0.911 (95% CI 0.81 to 0.98). This pilot study demonstrates the potential of metabolic biomarkers to assist clinicians in distinguishing bacterial from viral infection in febrile children, to facilitate effective clinical management and to the limit inappropriate use of antibiotics.

Exploring strengths and limits of urinary D-chiro inositol phosphoglycans (IPG-P) as a screening test for preeclampsia: A systematic review and meta-analysis.

Preeclampsia is a severe complication of human pregnancy as it leads to significant maternal and perinatal mortality and morbidity worldwide. A prompt recognition of women that develop this syndrome can improve clinical management, increase surveillance and, finally, improve outcomes. Different methods (based on history, ultrasound, serum and urinary biomarkers) were proposed a screening tests for this disease but their performance showed limited results. Urinary inositol phosphoglycans P-type (IPG-P) were shown to identify in advance most of the women who will develop preeclampsia in case-control and longitudinal studies, so we undertook a systematic review and meta-analysis of published studies. Seven studies met the entry criteria so were evaluated. All case-control studies showed excellent statistical performances in a quality statistical assessment. The meta-analysis considered three longitudinal, prospective studies that showed high sensitivity and specificity with ranges of 0.82- 0.99 and 0.90-1.00, respectively. Univariate measures of accuracy revealed a positive and negative likelihood ratio respectively of 3.61 (95% CI 1.56-5.67) and -2.35 (95% CI -3.79 to -0.91). By univariate approach, we found a pooled logarithm of diagnostic odds ratio of 6.15 (95% CI 2.64-9.67). A limitation of this analysis is that, although conducted in different settings (UK, Italy, France, South Africa, and Mauritius) and different clinical groups, they were based on a single academic group. According to our findings, IPG-P test showed very encouraging results as a rapid noninvasive screening test for preeclampsia. Further studies are needed to verify and to validate the reported findings.

Pioglitazone Therapy Increases Insulin-Stimulated Release of d-Chiro-Inositol-Containing Inositolphosphoglycan Mediator in Women with Polycystic Ovary Syndrome.

BACKGROUND: Insulin resistance in women with polycystic ovary syndrome (PCOS) may be mediated, in part, by a deficiency in the insulin-stimulated release of a d-chiro-inositol-inositolphosphoglycan (DCI-IPG) mediator of insulin action. Supporting this idea, several studies have reported improved insulin sensitivity in both lean and obese women with PCOS after oral administration of DCI. Pioglitazone improves insulin sensitivity in women with PCOS, but it is unknown whether this may be contributed by enhanced insulin-stimulated release of the DCI-IPG second messenger. The study aimed to determine if pioglitazone increases release of biologically active DCI-IPG per unit insulin released during an oral glucose tolerance test (OGTT). METHODS: A randomized, double-blind placebo-controlled trial was conducted in 32 women with PCOS at a tertiary referral center in Venezuela. The intervention comprised administration of pioglitazone 45 mg daily or matched placebo for 6 months. Outcome measures included area under curves (AUC) of DCI-IPG (AUCDCI-IPG), insulin (AUCinsulin), and the ratio of AUCDCI-IPG to AUCinsulin during a 2-hr OGTT. RESULTS: After treatment with pioglitazone, AUCinsulin during the OGTT decreased and whole body insulin sensitivity, as determined by the Matsuda index, increased significantly only in the pioglitazone group. The ratio of AUCDCI-IPG/AUCinsulin increased in the pioglitazone group by 1.85-fold (P < 0.0001) with no significant change in the placebo group. Change in Matsuda index correlated with change in DCI-IPG released per unit of insulin during OGTT (r = 0.47, P < 0.01). CONCLUSION: In women with PCOS, pioglitazone increased insulin-stimulated release of the DCI-IPG second messenger of insulin action, which may contribute to its insulin-sensitizing effect in these women.

The maternal ITPK1 gene polymorphism is associated with neural tube defects in a high-risk Chinese population.

BACKGROUND: Epidemiological surveys and animal studies have revealed that inositol metabolism is associated with NTDs, but the mechanisms are not clear. Inositol 1,3,4-trisphosphate 5/6-kinase (ITPK1) is a pivotal regulatory enzyme in inositol metabolic pathway. The objective was to assess the potential impact of the maternal ITPK1 genotypes on the inositol parameter and on the NTD risk in a NTD high-risk area in China. METHODOLOGY/RESULTS: A case-control study of pregnant women affected with NTDs (n = 200) and controls (n = 320) was carried out. 13 tag SNPs of ITPK1 were selected and genotyped by the Sequenom MassArray system. We found that 4 tag SNPs were statistically significant in spina bifida group (P<0.05). MACH was used to impute the un-genotyped SNPs in ITPK1 locus and showed that 3 meaningful SNPs in the non-coding regions were significant. We also predicted the binding capacity of transcription factors in the positive SNPs using the bioinformatics method and found that only rs3783903 was located in the conserved sequence of activator protein-1 (AP-1). To further study the association between biochemical values and genotypes, maternal plasma inositol hexakisphosphate (IP6) levels were also assessed using LC-MS. The maternal plasma IP6 concentrations in the spina bifida subgroup were 7.1% lower than control (136.67 vs. 147.05 ng mL(-1), P<0.05), and significantly lower in rs3783903 GG genotype than others (P<0.05). EMSA showed a different allelic binding capacity of AP-1 in rs3783903, which was affected by an A→G exchange. The RT-PCR suggested the ITPK1 expression was decreased significantly in mutant-type of rs3783903 compared with wild-type in the 60 healthy pregnancies (P<0.05). CONCLUSIONS/SIGNIFICANCE: These results suggested that the maternal rs3783903 of ITPK1 might be associated with spina bifida, and the allele G of rs3783903 might affect the binding of AP-1 and the decrease of maternal plasma IP6 concentration in this Chinese population.

Detection of myo-inositol tris pyrophosphate (ITPP) in equine following an administration of ITPP.

Myo-Inositol tris pyrophosphate (ITPP) is a powerful allosteric modulator of haemoglobin that increases oxygen-releasing capacity of red blood cells. It is capable of crossing the red blood cell membrane unlike its open polyphosphate analog myo-inositol hexakisphosphate (IHP). Systemic administration of ITPP enhanced the exercise capacity in mice. There have been rumours of its abuse in the horse racing industry to enhance the performance of racing horses. In this paper, the detection of ITPP in equine plasma and urine after an administration of ITPP is reported. A Standardbred mare was administered 200 mg of ITPP intravenously. Urine and plasma samples were collected up to 120 h post administration and analyzed for ITPP by liquid chromatography-tandem mass spectrometry. ITPP was detected in post administration plasma samples up to 6 hours. The peak concentration was detected at 5 min post administration. In urine, ITPP was detected up to 24 h post administration. The peak concentration was detected at 1.5 h post administration.

Detection of myo-inositol trispyrophosphate in equine urine and plasma by hydrophillic interaction chromatography-tandem mass spectrometry.

Myo-inositol trispyrophosphate (ITPP) is a new drug capable of increasing the amount of oxygen in hypoxic tissues. Studies have shown that administration of ITPP increases the maximal exercise capacity in normal mice as well as mice with severe heart failure. The properties of ITPP make it an ideal candidate as a doping agent to enhance performance in racehorses. While there have been speculations in the horseracing industry that the covert use of ITPP is already widespread, no reported method exists for the detection of ITPP in equine biological samples. ITPP is a difficult-to-detect drug due to its hydrophilic nature; the complexity of equine biological matrices also adds to the problem. This paper describes for the first time a method for the detection and confirmation of ITPP in equine urine and plasma. ITPP was isolated from the sample matrices by solid-phase extraction and the extract was analyzed by hydrophilic interaction chromatography-tandem mass spectrometry. ITPP could be detected at low ppb levels in both fortified equine plasma and urine with good precision, fast instrumental turnaround time, and negligible matrix interferences. To our knowledge, this is the first report of a validated method for the detection and unequivocal confirmation of low levels of ITPP in any biological fluid.

Insulin-stimulated release of D-chiro-inositol-containing inositolphosphoglycan mediator correlates with insulin sensitivity in women with polycystic ovary syndrome.

Some actions of insulin are mediated by inositolphosphoglycan (IPG) mediators. Deficient release of a putative D-chiro-inositol-containing (DCI) IPG mediator may contribute to insulin resistance in women with polycystic ovary syndrome (PCOS). Previously, we demonstrated that oral DCI supplementation improved ovulation and metabolic parameters in women with PCOS. However, whether oral DCI mediates an increase in the release of the DCI-IPG mediator and an improvement in insulin sensitivity in women with PCOS is unknown. We conducted a randomized controlled trial of DCI supplementation vs placebo in 11 women with PCOS who were assessed at 2 time points 6 weeks apart. Plasma DCI, DCI-IPG release during oral glucose tolerance test (AUC(DCI-IPG)), and insulin sensitivity (S(i)) by frequently sampled intravenous glucose tolerance test were assessed at baseline and end of study. The study was terminated early because of a sudden unavailability of the study drug. However, in all subjects without regard to treatment assignment, there was a positive correlation between the change in AUC(DCI-IPG)/AUC(insulin) ratio and the change in S(i) during the 6-week period (r = 0.69, P = .02), which remained significant after adjustment for body mass index (P = .022) and after further adjustment for body mass index and treatment allocation (P = .0261). This suggests that, in women with PCOS, increased glucose-stimulated DCI-IPG release is significantly correlated with improved insulin sensitivity. The significant relationship between DCI-IPG release and insulin sensitivity suggests that the DCI-IPG mediator may be a target for therapeutic interventions in PCOS.

Inositol phosphoglycan P-type in healthy and preeclamptic pregnancies.

An association between inositol phosphoglycan P-type (P-IPG) and preeclampsia has been demonstrated over recent years. This molecule can mediate many of the metabolic and growth promoting effects of insulin. Dysregulation of the mediator family is associated with insulin resistance. An increased concentration of P-IPG has been reported in preeclamptic placenta, although its precursor (GPI) was undetectable in those placental samples. Insulin administration, that induces P-IPG release in normal human placenta, was shown not to cause production/release of the mediator from preeclamptic placental tissue as a consequence of a disturbed insulin signalling. Amniotic fluid is enriched of this mediator, with further increase during preeclampsia. We have found that the fetus released increasing amounts of P-IPG in the urine between 13 and 18 weeks of gestation, reaching a plateau beyond 20 weeks. Cord blood of infants of preeclamptic mothers showed an increased content of soluble P-IPG compared to controls and to the mother.

P-type inositol phosphoglycans in serum and amniotic fluid in active pre-eclampsia.

OBJECTIVES: Abnormal secretion of P-type inositol phosphoglycans (IPG-P) has been described in maternal urine of pre-eclamptic women. The aim of this study was to determine the origin of production of IPG-P. We examined the IPG-P content of maternal and fetal serum, maternal urine and amniotic fluid in both normal pregnancy and pre-eclampsia. DESIGN: Established extraction and bioactivity assay techniques were used to compare total IPG-P levels in serum samples, and a polyclonal-antibody-based ELISA to assay the amniotic fluid and urine samples in matched pairs of women. SUBJECTS: Eleven women with pre-eclampsia requiring caesarean section (subjects), 11 pregnant women requiring elective caesarean section for reasons other than pre-eclampsia (controls). RESULTS: Our data confirm the abnormal level of IPG-P in maternal urine during pre-eclampsia. Moreover, IPG-P levels were higher in umbilical sera than in maternal sera samples. Amniotic fluid as well as urine ELISA results were significantly higher in the pre-eclamptic group compared with normal controls. Total IPG-P bioactivity in serum did not vary between serum compartments in normal pregnancy. Uterine vein IPG-P levels were lower in pre-eclampsia when compared with normal pregnancy. A possible correlation was observed between urine and amniotic fluid levels in normal women. No correlation was observed between measured blood levels and those in urine and amniotic fluid. CONCLUSIONS: It is hypothesized that steady state equilibrium of IPG-P in serum in normal pregnancy is disrupted in pre-eclampsia. Additionally, an abnormal IPG-P sub-fraction, detectable in urine and amniotic fluid, may be present and involved in the pathophysiology of the syndrome, although sites of production of this abnormal form remain unclear.

Inositol tripyrophosphate: a new membrane permeant allosteric effector of haemoglobin.

Nine inositol tripyrophosphate (ITPP) salts have been synthesized. Their ability to act as allosteric effectors of haemoglobin (Hb) has been measured in vitro with free Hb and whole blood. All the synthesized compounds bound to free Hb and were also able to cross, to a certain extent, the plasma membrane of the red blood cells (RBCs) in whole blood samples, lowering the affinity of Hb for oxygen. The oxy-haemoglobin dissociation curves were significantly shifted towards higher values of oxygen partial pressures, both for free Hb and for intracellular Hb in whole blood.