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King K.,University of New South Wales | Smith S.,University of New South Wales | Smith S.,South Eastern Area Laboratory Services SEALS Pathology | Chapman M.,University of New South Wales | Sacks G.,University of New South Wales
Human Reproduction | Year: 2010

BACKGROUND: Increased peripheral blood natural killer (NK) cell activity has been associated with unexplained reproductive failure including recurrent (three or more) miscarriages (RM). Studies have reported abnormalities in both numbers (absolute and proportion) and activation. This study assessed numerous NK cell parameters to determine which (if any) are altered in women with RM compared with controls, which parameter best differentiated women with RM from controls, and what NK levels should be considered high. METHODS: Luteal-phase blood samples from women with RM (n = 104) and controls (n = 33) were analysed by four-colour flow cytometry. NK cells were analysed as a percentage of lymphocytes, total NK concentration, CD56Dim subtype concentration and percentage, activated CD69+CD56Dim subtype concentration and percentage and CD56+Bright:CD56+Dim subtype ratio. Women with RM were analysed in two subgroups: those positive in ≥1 RM screening tests (karyotype, uterine, antiphospholipid syndrome, thrombophilia) (n = 48) and those who had negative screening tests (n = 56). RESULTS: Women with RM had significantly higher NK percentage (P < 0.001), and significantly lower CD56+Bright:CD56+Dim ratio (P < 0.05) than controls. NK percentage was the only significantly higher variable in the RM screening test negative subgroup (P < 0.01). A ROC analysis (AUC = 0.71) found that an NK percentage >18% was highly specific for women with RM (97.0%), and defined 12.5% of women with RM as having high NK percentage, compared with 2.9% of controls. CONCLUSION: Women with RM have altered peripheral blood NK parameters. NK cells as a percentage of lymphocytes best discriminated RM and control populations. Women with RM and high NK levels may have an immunological disorder. Source

Sacks G.,IVFAustralia | Sacks G.,University of New South Wales | Yang Y.,University of New South Wales | Gowen E.,University of New South Wales | And 5 more authors.
American Journal of Reproductive Immunology | Year: 2012

Problem: To analyse the peripheral blood NK cells in women with repeated IVF failure (RIF) and a fertile control group to determine which parameters best differentiate the two populations. Methods: Peripheral blood from the luteal phase of 171 women with RIF and 33 fertile controls was analysed by four-colour flow cytometry for NK cell concentration, subset differentiation and the activation marker CD69. Results: Women with RIF had significantly increased NK cell numbers as determined by concentration (P < 0.05) and percentage of lymphocytes (P < 0.001), increased concentration of the CD56 dim subtype (P < 0.05), and increased concentration of activated CD56 dim CD69 + cells (P = 0.0001). There was no correlation between any NK cell parameters with the length of infertility or number of embryo transfer cycles. Conclusions: Peripheral blood NK cell activity is significantly higher in women with RIF than in fertile controls. Future trials of immune therapy in women undergoing IVF should target those with high NK activity. © 2012 John Wiley & Sons A/S. Source

James L.P.,University of Arkansas for Medical Sciences | Chiew A.,Clinical and Experimental Toxicology Unit | Abdel-Rahman S.M.,Childrens Mercy Hospitals and Clinics | Letzig L.,University of Arkansas for Medical Sciences | And 3 more authors.
European Journal of Clinical Pharmacology | Year: 2013

Purpose: Acetaminophen (APAP) protein adducts are a biomarker of APAP metabolism, reflecting oxidation of APAP and generation of the reactive metabolite N-acetyl-p-benzoquinone imine. High levels of adducts correspond to liver toxicity in patients with APAP-related acute liver failure. Adduct formation following low-dose exposure to APAP has not been well studied. APAP protein adducts were measured in blood samples collected from fasted individuals who participated in a crossover study of APAP (80 mg/kg) comparing extended release (ER) and immediate release (IR) formulations. Methods: Adducts were quantified in all postdose blood samples using a validated high-performance liquid chromatography electrochemical detection (HPLC-EC) assay. Results: Comparison of pharmacokinetic parameters for adducts did not reveal significant differences between ER and IR formulations, with one exception. Formation rates for adducts were faster for IR than the ER formulation (0.420 ± 0.157 vs. 0.203 ± 0.080 1/h), respectively. Maximum plasma concentrations (C max) of adducts for IR and ER were 0.108 (±0.020) and 0.100 (±0.028) nmol/ml serum, respectively, and were two orders of magnitude lower than adduct levels previously reported in adults with acute liver failure secondary to APAP. Conclusions: APAP protein adducts are rapidly formed following nontoxic ingestion of APAP at levels significantly lower than those associated with acute liver failure. © 2012 Springer-Verlag. Source

Chiew A.,Clinical and Experimental Toxicology Unit | Day P.,South Eastern Area Laboratory Services SEALS Pathology | Salonikas C.,South Eastern Area Laboratory Services SEALS Pathology | Naidoo D.,South Eastern Area Laboratory Services SEALS Pathology | And 2 more authors.
EMA - Emergency Medicine Australasia | Year: 2010

Background: Panadol Extend (PEx) is an over-the-counter, modified-release formulation of paracetamol. Each 665mg tablet contains 69% slow-release and 31% immediate-release paracetamol. In simulated human overdose, PEx exhibits lower and later peak serum concentrations and a lower area-under-the-curve (AUC) than comparable doses of immediate-release paracetamol (APAP-IR). The lower AUC might result from incomplete absorption of paracetamol or simultaneous metabolism with absorption.Objective: Do differences in pharmacokinetics (PK) between PEx and APAP-IR result from incomplete absorption or simultaneous absorption and metabolism of paracetamol?Methods: Cross-over study of 80mg/kg of PEx or APAP-IR in nine volunteers. Serial plasma paracetamol, glucuronide, sulphate and cysteine metabolite estimates performed over 24h. Peak plasma concentration (Cmax), AUC(0-∞), time to peak concentration (Tmax) and elimination half-life (t1/2) were compared.Results: PEx exhibited significantly lower paracetamol Cmax (252.33μmol/L vs 565.56μmol/L, P= 0.0421), AUC(0-∞) (2133μmol/h/L vs 2637μmol/h/L, P= 0.0004) and delayed Tmax (2.889h vs 1.389h, P= 0.0189) than APAP-IR. Sulphate metabolite PK parameters for both preparations, PEx vs APAP-IR, showed similar AUC(0-∞) (1369μmol/h/L vs 1089μmol/h/L), Tmax (3.889h vs 4.444h), Cmax (95.889μmol/L vs 95.889μmol/L) and t1/2 (3.895h vs 3.810h). Glucuronide metabolite concentrations revealed that PEx produced a lower Cmax (257.44μmol/L vs 335.22μmol/L, P= 0.0239) than APAP-IR. All other pharmacokinetic parameters were similar. Cysteine metabolite was not detected.Conclusion: There were minor differences between the PK parameters of the two major paracetamol metabolites of these two preparations in simulated overdose. The variability in paracetamol AUC seen between the two preparations in moderate overdose might be explained by concurrent metabolism of paracetamol during slower absorption with PEx. © 2010 The Authors. EMA © 2010 Australasian College for Emergency Medicine and Australasian Society for Emergency Medicine. Source

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