Advanced glycation end-products and its soluble receptor are not independent predictors of incident dysglycaemia or metabolic syndrome in women with polycystic ovary syndrome: a prospective observational study.

BACKGROUND: To evaluate the association of serum advanced glycation end-products (AGEs) and its soluble receptor of AGE (sRAGE) levels with dysglycaemia and metabolic syndrome in women with polycystic ovary syndrome (PCOS). METHODS: This was an analysis of a cohort of women with PCOS who were prospectively recruited for a longitudinal observational study on their endocrine and metabolic profile between January 2010 and December 2013. The association of serum AGEs and sRAGE levels with dysglycaemia and metabolic syndrome at the second-year visit (the index visit) and the sixth-year visit (the outcome visit) were determined. Comparisons of continuous variables between groups were made using the Mann-Whitney U-test. Spearman test was used for correlation analysis. Multivariate binary logistic regression analysis was employed to identify the factors independently associated with the outcome events. RESULTS: A total of 329 women were analysed at the index visit. Significantly lower serum levels of sRAGE (both p < 0.001), but no significant difference in AGEs, were observed in those with dysglycaemia or metabolic syndrome. At the outcome visit, those with incident metabolic syndrome had a significantly lower initial serum sRAGE levels (p = 0.008). The association of serum sRAGE with dysglycaemia and metabolic syndrome at the index visit was no longer significant in multivariate logistic regression after controlling for body mass index, free androgen index and homeostatic model assessment for insulin resistance (HOMA-IR). sRAGE was also not significantly associated with incident metabolic syndrome at the outcome visit on multivariate logistic regression. CONCLUSIONS: Serum sRAGE levels are significantly lower in women with PCOS who have dysglycaemia or metabolic syndrome, and in those developing incident metabolic syndrome in four years. However, it does not have a significant independent association with these outcome measures after adjusting for body mass index, free androgen index and HOMA-IR.

Urine organic acid as the first clue towards aromatic L-amino acid decarboxylase (AADC) deficiency in a high prevalence area.

BACKGROUND: Aromatic L-amino acid decarboxylase deficiency is a rare neurometabolic disease due to impaired decarboxylation of neurotransmitter precursors to its active form. CASE: We retrospectively reviewed 8 cases from 2008 to 2019 with cerebrospinal fluid neurotransmitter analysis performed at our centre. All cases had an elevated urine vanillactic acid and, in most cases, with N-acetylvanilalanine detected. Cerebrospinal fluid analysis showed low downstream metabolites vanillylmandelic acid, homovanillic acid but high 3-O-methyl-L-DOPA, 5-hydroxytryptophan. Cerebrospinal fluid pterins were normal. Genotyping in DDC confirms the diagnosis. Urine organic acid analysis provided the first clue to diagnosis in four of the cases, which then triggered cerebrospinal fluid neurotransmitter and genetic analysis. We also developed a diagnostic decision support system to assist the interpretation of the mass spectrometry data from urine organic acids. CONCLUSIONS: Urine organic acid could be essential in guiding subsequent investigations for the diagnosis of aromatic L-amino acid decarboxylase deficiency. We propose to screen suspected cases first with urine organic acids, specifically looking for vanillactic acid and N-acetylvanilalanine. Suggestive findings should be followed with target analysis for c.714 + 4A > T in ethnically Chinese patients. The assistive tool allowed expedite interpretation of profile data generated from urine organic acids analysis. It may also reduce interpreter's bias when peaks of interest are minor peaks in the spectrum.

Invasive cerebral phaeohyphomycosis in a Chinese boy with CARD9 deficiency and showing unique radiological features, managed with surgical excision and antifungal treatment.

We report this rare case of cerebral phaeohyphomycosis in a previously healthy Chinese boy, who was found to have caspase recruitment domain family member 9 (CARD9) deficiency. Initial radiological features suggested a neoplastic cerebral lesion, while histopathological examination supplemented by internal transcribed sequencing (ITS) of cerebral tissue confirmed the diagnosis of phaeohyphomycosis. He was treated with intravenous (IV) liposomal amphotericin B and voriconazole, guided by plasma and cerebrospinal fluid (CSF) level monitoring at drug initiation. At the 1 year follow-up, the patient demonstrated near complete neurological and radiological recovery.

Direct Renin Inhibition in Non-diabetic chronic Kidney disease (DRINK): a prospective randomized trial.

BACKGROUND: The potential long-term safety and efficacy of aliskiren in nondiabetic chronic kidney disease (CKD) are unknown. We sought to investigate the renoprotective effect of aliskiren on nondiabetic CKD patients. METHODS: In this open-label, parallel, randomized controlled trial, nondiabetic CKD Stages 3-4 patients were randomized to receive aliskiren added to an angiotensin II receptor blocker (ARB) at the maximal tolerated dose, or ARB alone. Primary outcome was the rate of change in estimated glomerular filtration rate (eGFR). Secondary endpoints included rate of change in urine protein-to-creatinine ratio (UPCR), cardiovascular events and hyperkalemia. Composite renal outcomes of doubling of baseline serum creatinine or a 40% reduction in eGFR or incident end-stage renal disease or death were analyzed as post hoc analysis. RESULTS: Seventy-six patients were randomized: 37 to aliskiren (mean age 55.1 ± 11.1 years) and 39 to control (mean age 55.0 ± 9.4 years). Their baseline demographics were comparable to eGFR (31.9 ± 9.0 versus 27.7 ± 9.0 mL/min/1.73 m2, P = 0.05) and UPCR (30.7 ± 12.6 versus 47.8 ± 2.8 mg/mmol, P = 0.33) for treatment versus control subjects. After 144 weeks of follow-up, there was no difference in the rate of eGFR change between groups. Six patients in the aliskiren group and seven in the control group reached the renal composite endpoint (16.2% versus 17.9%, P = 0.84). The cardiovascular event rate was 10.8% versus 2.6% (P = 0.217). The hyperkalemia rate was 18.9% versus 5.1% with an adjusted hazard ratio of 7.71 (95% confidence interval 1.14 to 52.3, P = 0.04) for the aliskiren arm. CONCLUSION: Aliskiren neither conferred additional renoprotective benefit nor increased adverse events, except for more hyperkalemia in nondiabetic CKD patients.

Assessment of population susceptibility to upcoming seasonal influenza epidemic strain using interepidemic emerging influenza virus strains.

Seasonal influenza virus epidemics have a major impact on healthcare systems. Data on population susceptibility to emerging influenza virus strains during the interepidemic period can guide planning for resource allocation of an upcoming influenza season. This study sought to assess the population susceptibility to representative emerging influenza virus strains collected during the interepidemic period. The microneutralisation antibody titers (MN titers) of a human serum panel against representative emerging influenza strains collected during the interepidemic period before the 2018/2019 winter influenza season (H1N1-inter and H3N2-inter) were compared with those against influenza strains representative of previous epidemics (H1N1-pre and H3N2-pre). A multifaceted approach, incorporating both genetic and antigenic data, was used in selecting these representative influenza virus strains for the MN assay. A significantly higher proportion of individuals had a ⩾four-fold reduction in MN titers between H1N1-inter and H1N1-pre than that between H3N2-inter and H3N2-pre (28.5% (127/445) vs. 4.9% (22/445), P < 0.001). The geometric mean titer (GMT) of H1N1-inter was significantly lower than that of H1N1-pre (381 (95% CI 339-428) vs. 713 (95% CI 641-792), P < 0.001), while there was no significant difference in the GMT between H3N2-inter and H3N2-pre. Since A(H1N1) predominated the 2018-2019 winter influenza epidemic, our results corroborated the epidemic subtype.

Independent association of serum vitamin D with anti-Mullerian hormone levels in women with polycystic ovary syndrome.

OBJECTIVE: This study aimed at investigating the association of serum vitamin D (25(OH)D) and anti-Mullerian hormone (AMH) levels in women with polycystic ovary syndrome (PCOS) as well as non-PCOS healthy ovulatory women and the possible confounding effects of adiposity and androgen. METHOD: This was a cross-sectional study conducted on serum samples collected from 451 women diagnosed with PCOS as well as 244 age-matched healthy ovulatory women in a tertiary gynaecology out-patient clinic and a family planning clinic. RESULTS: Serum 25(OH)D level was significantly higher in women recruited during summer and autumn than those recruited in winter and spring. Both serum 25(OH)D and AMH levels peaked during summer in women with PCOS. In ovulatory women, only serum 25(OH)D but not AMH level showed such seasonal variation. Serum 25(OH)D level in women with PCOS significantly correlated positively with AMH, AMH/antral follicle count (AFC) ratio, serum total testosterone, sex-hormone-binding globulin and quantitative insulin-sensitivity check index and inversely with body mass index (BMI), insulin, triglycerides and homeostatic model assessment of insulin resistance. After controlling for BMI, 25(OH)D level remained significantly correlated positively with serum AMH, AMH/AFC and total testosterone, and inversely with triglycerides. 25(OH)D level was an independent predictor of serum AMH level after controlling for age, BMI and free androgen index in women with PCOS. CONCLUSION: Serum 25(OH)D level is an independent factor significantly associated with AMH level in women with PCOS but not in ovulatory women.

Low population serum microneutralization antibody titer against the predominating influenza A(H3N2) N121K virus during the severe influenza summer peak of Hong Kong in 2017.

The 2017 Hong Kong influenza A(H3N2) summer season was unexpectedly severe. However, antigenic characterization of the 2017 circulating A(H3N2) viruses using ferret antisera did not show significant antigenic drift. We analyzed the hemagglutinin amino acid sequences of A(H3N2) virus circulating in Hong Kong in 2017, and found that viruses with hemagglutinin N121K substitution, which was rare before 2017, emerged rapidly and dominated in 2017 (52.4% of A[H3N2] virus in 2017 contains N121K substitution). Microneutralization assay using archived human sera collected from mid-2017 showed that the geometric mean microneutralization titer was 3.6-fold lower against a 2017 cell culture-grown circulating A(H3N2)-N121K virus (3391/2017 virus) than that against the cell culture-grown 2016-2017 A(H3N2) seasonal influenza vaccine-like vaccine virus (4801/2014 virus) (13.4 vs 41.8, P < 0.0001). Significantly fewer serum specimens had a microneutralization titer of 40 or above against 3391/2017 virus than that against 4801/2014 virus (26.4% vs 60.0%, P < 0.0001). Conversely, the geometric mean hemagglutination inhibition titer was slightly higher against 3391/2017 virus than that against the 4801/2014 virus (96.9 vs 55.4, P < 0.0001). Moreover, 59.1% of specimens had a significantly lower microneutralization antibody titer (≥4-fold) against 3391/2017 virus than that against 4801/2014 virus, but none for hemagglutination titer (P < 0.0001). Similar results of microneutralization and hemagglutination titers were observed for day 21-post-vaccination sera. Hence, the 2017 A(H3N2) summer peak in Hong Kong was associated with a low-microneutralization titer against the circulating virus. Our results support the use of microneutralization assay with human serum in assessing population susceptibility and antigenic changes of A(H3N2) virus. Novel and available immunization approach, such as topical imiquimod followed by intradermal vaccination, to broaden the neutralizing antibody response of influenza vaccine should be considered.

Glucuronide and Sulfate Conjugates of Bisphenol A: Chemical Synthesis and Correlation Between Their Urinary Levels and Plasma Bisphenol A Content in Voluntary Human Donors.

Bisphenol A (BPA) glucuronide and sulfate conjugates are major products of Phase II metabolism of BPA in humans. In the past, their determination in body fluids usually involves tedious enzymatic hydrolysis and multiresidual analysis. The recent availability of authentic standards of these conjugates enables our better understand of the human metabolism of BPA and the distribution of their metabolites in body fluids. In this work, we report the chemical synthesis and purification of BPA mono- and di-glucuronide and BPA mono- and di-sulfate. Their levels, as well as that of BPA, in 140 paired human plasma and urine samples collected randomly from voluntary donors in Hong Kong SAR, China, were determined by solid-phase extraction and liquid chromatography-tandem mass spectrometry (LC-MS/MS). BPA was found in more than 135 human plasma and urine samples. Its Phase II metabolites, ranging from N.D. to 36.7 µg g-1-creatinine, also were detected in 139 of the 140 urine samples. Good correlation (r = 0.911) between molar concentration of BPA in the plasma and that of "total urinary BPA" (i.e., ln [(BPA + ∑ BPA phase II conjugate)molar concentration]) was observed. Direct quantification of Phase II metabolites of BPA in human urine can be a useful assessment tool for population exposure to this potent endocrine disrupting chemical.

Fumarylacetoacetate Hydrolase Knock-out Rabbit Model for Hereditary Tyrosinemia Type 1.

Hereditary tyrosinemia type 1 (HT1) is a severe human autosomal recessive disorder caused by the deficiency of fumarylacetoacetate hydroxylase (FAH), an enzyme catalyzing the last step in the tyrosine degradation pathway. Lack of FAH causes accumulation of toxic metabolites (fumarylacetoacetate and succinylacetone) in blood and tissues, ultimately resulting in severe liver and kidney damage with onset that ranges from infancy to adolescence. This tissue damage is lethal but can be controlled by administration of 2-(2-nitro-4-trifluoromethylbenzoyl)-1,3-cyclohexanedione (NTBC), which inhibits tyrosine catabolism upstream of the generation of fumarylacetoacetate and succinylacetone. Notably, in animals lacking FAH, transient withdrawal of NTBC can be used to induce liver damage and a concomitant regenerative response that stimulates the growth of healthy hepatocytes. Among other things, this model has raised tremendous interest for the in vivo expansion of human primary hepatocytes inside these animals and for exploring experimental gene therapy and cell-based therapies. Here, we report the generation of FAH knock-out rabbits via pronuclear stage embryo microinjection of transcription activator-like effector nucleases. FAH-/- rabbits exhibit phenotypic features of HT1 including liver and kidney abnormalities but additionally develop frequent ocular manifestations likely caused by local accumulation of tyrosine upon NTBC administration. We also show that allogeneic transplantation of wild-type rabbit primary hepatocytes into FAH-/- rabbits enables highly efficient liver repopulation and prevents liver insufficiency and death. Because of significant advantages over rodents and their ease of breeding, maintenance, and manipulation compared with larger animals including pigs, FAH-/- rabbits are an attractive alternative for modeling the consequences of HT1.

Glucuronide and sulfate conjugates of tetrabromobisphenol A (TBBPA): Chemical synthesis and correlation between their urinary levels and plasma TBBPA content in voluntary human donors.

3,3',5,5'-Tetrabromobisphenol-A (TBBPA) is an important brominated flame retardant in epoxy, vinyl esters and polycarbonate resins. Previous studies have already shown the occurrence of its Phase II metabolites, TBBPA-glucuronide and sulfate conjugates, in human urine, after oral administration of TBBPA. The main objective of this work is to examine correlations among level of TBBPA in human blood and those of its Phase II metabolites in human urine. Four water-soluble TBBPA conjugates were synthesized, purified and characterized. An analytical protocol using solid-phase extraction and liquid chromatography-electrospray tandem mass spectrometry (SPE-LC-MS/MS) quantification was developed for the simultaneous analysis of these glucuronide and sulfate conjugates in human urine samples. TBBPA and its Phase II metabolites in paired human plasma and urine samples collected randomly from 140 voluntary donors in Hong Kong SAR, China, were determined. One or more TBBPA conjugates were detected in all of the urine samples, with concentration ranging from 0.19 to 127.24µgg-1-creatinine. TBBPA was also quantified in >85% of the plasma and urine samples. Strong correlations were observed between TBBPA content in plasma and the total amount of TBBPA-related compounds in urine.

Serum adiponectin is independently associated with the metabolic syndrome in Hong Kong, Chinese women with polycystic ovary syndrome.

OBJECTIVE: To evaluate the association of serum adiponectin level with the metabolic syndrome in Chinese women with polycystic ovary syndrome (PCOS). METHODS: This was a cross-sectional study carried out in Hong Kong Chinese women with PCOS at a university-affiliated tertiary hospital between January 2010 and January 2011. Clinical and biochemical parameters of the women were analysed. Prediction of the metabolic syndrome was determined by receiver-operator characteristic (ROC) curves, univariate and multivariate logistic regression analyses. RESULTS: A total of 116 women diagnosed to have PCOS were analysed. The area under the ROC curve of adiponectin for the prediction of metabolic syndrome was 0.820, 95% confidence interval (CI) 0.737-0.886. Univariate binary logistic regression showed that testosterone, sex hormone-binding globulin (SHBG), free androgen index (FAI), waist circumference, body mass index (BMI), quantitative insulin-sensitivity check index (QUICKI), homeostasis model assessment of insulin resistance (HOMA-IR) and adiponectin were significantly associated with the metabolic syndrome. On multivariate logistic regression analysis, adiponectin (p = 0.020), HOMA-IR, age (p = 0.011) and BMI (p = 0.019) were independently associated with the metabolic syndrome, but not FAI (p = 0.256). CONCLUSIONS: Serum adiponectin is independently associated with the metabolic syndrome in Chinese women with PCOS. Further longitudinal follow-up studies are needed to determine whether serum adiponectin adds to the prediction of long-term cardiometabolic morbidity conferred by age, BMI and measures of insulin resistance.

Metabolomic Profiling of Plasma from Patients with Tuberculosis by Use of Untargeted Mass Spectrometry Reveals Novel Biomarkers for Diagnosis.

Although tuberculosis (TB) is a reemerging disease that affects people in developing countries and immunocompromised populations in developed countries, the current diagnostic methods are far from optimal. Metabolomics is increasingly being used for studies on infectious diseases. We performed metabolome profiling of plasma samples to identify potential biomarkers for diagnosing TB. We compared the plasma metabolome profiles of TB patients (n = 46) with those of community-acquired pneumonia (CAP) patients (n = 30) and controls without active infection (n = 30) using ultrahigh-performance liquid chromatography-electrospray ionization-quadrupole time of flight mass spectrometry (UHPLC-ESI-QTOFMS). Using multivariate and univariate analyses, four metabolites, 12R-hydroxy-5Z,8Z,10E,14Z-eicosatetraenoic acid [12(R)-HETE], ceramide (d18:1/16:0), cholesterol sulfate, and 4α-formyl-4ß-methyl-5α-cholesta-8-en-3ß-ol, were identified and found to have significantly higher levels in TB patients than those in CAP patients and controls. In a comparison of TB patients and controls, the four metabolites demonstrated area under the receiver operating characteristic curve (AUC) values of 0.914, 0.912, 0.905, and 0.856, sensitivities of 84.8%, 84.8%, 87.0%, and 89.1%, specificities of 90.0%, 86.7%, 86.7%, and 80.0%, and fold changes of 4.19, 26.15, 6.09, and 1.83, respectively. In a comparison of TB and CAP patients, the four metabolites demonstrated AUC values of 0.793, 0.717, 0.802, and 0.894, sensitivities of 89.1%, 71.7%, 80.4%, and 84.8%, specificities of 63.3%, 66.7%, 70.0%, and 83.3%, and fold changes of 4.69, 3.82, 3.75, and 2.16, respectively. 4α-Formyl-4ß-methyl-5α-cholesta-8-en-3ß-ol combined with 12(R)-HETE or cholesterol sulfate offered ≥70% sensitivity and ≥90% specificity for differentiating TB patients from controls or CAP patients. These novel plasma biomarkers, especially 12(R)-HETE and 4α-formyl-4ß-methyl-5α-cholesta-8-en-3ß-ol, alone or in combination, are potentially useful for rapid and noninvasive diagnosis of TB. The present findings may offer insights into the pathogenesis and host response in TB.

Measurement of serum aldosterone in picomolar level by LC-MS/MS using charge-tagged technique.

Aldosterone is a mineralocorticoid steroid hormone, the measurement of which in the clinical laboratory is principally performed for the investigation of primary hyperaldosteronism. Primary hyperaldosteronism is a specifically treatable and potentially curable form of hypertension, which typically presents as drug-resistant hypertension and, in up to 37% of cases, hypokalemia. Accurate measurement of aldosterone concentration is essential for correct diagnosis. The serum concentrations of aldosterone are in the picomolar range and therefore sensitive aldosterone assays are required. With the advancement in instrumentation of LC-MS/MS, the picomolar range of aldosterone can be easily measured by the newer models, but for those with a less sensitive instrument, special technique for sample preparation to enhance assay sensitivity is required. This work described the use of charge-tagging for the picomolar measurement of serum aldosterone in a less sensitive LC-MS/MS instrument. The assay was linear up to 3000 pmol/L with lower limit of quantitation at 80 pmol/L. The mean relative recovery was 96.5% with a range of 89.3-101.6% for aqueous calibrators and the mean relative recovery was 94.8% with a range of 87.5-101.4% for serum calibrators. Intra-assay CVs range from 8.2% to 11.3%, and inter-assay CVs ranged from 8.5% to 13.5% at concentration range from 229 to 1720 pmol/L. The LC-MS/MS method compared well (y = 1.04x + 8.97) with the in-use radioimmunoassay method. There was no significant difference found (p = 0.7135) between results determined by LC-MS/MS and radioimmunoassay method.

Azacytidine sensitizes acute myeloid leukemia cells to arsenic trioxide by up-regulating the arsenic transporter aquaglyceroporin 9.

BACKGROUND: The therapeutic efficacy of arsenic trioxide (As2O3) in acute myeloid leukemia (AML) is modest, which is partly related to its limited intracellular uptake into the leukemic cells. As2O3 enters cells via the transmembrane protein aquaglyceroporin 9 (AQP9). Azacytidine, a demethylating agent that is approved for the treatment of AML, has been shown to have synergistic effect with As2O3. We tested the hypothesis that azacytidine might up-regulate AQP9 and enhances As2O3-mediated cytotoxicity in AML. METHODS: Arsenic-induced cytotoxicity, the expression of AQP9, and the intracellular uptake of As2O3 were determined in AML cell lines and primary AML cells with or without azacytidine pre-treatment. The mechanism of AQP9 up-regulation was then investigated by examining the expression of transcription factors for AQP9 gene and the methylation status of their gene promoters. RESULTS: As2O3-induced cytotoxicity in AML cell lines was significantly enhanced after azacytidine pre-treatment as a result of AQP9 up-regulation, leading to increased arsenic uptake and hence intracellular concentration. Blocking AQP9-mediated As2O3 uptake with mercury chloride abrogated the sensitization effect of azacytidine. AQP9 promoter does not contain CpG islands. Instead, azacytidine pre-treatment led to increased expression of HNF1A, a transcription activator of AQP9, through demethylation of HNF1A promoter. HNF1 knockdown abrogated azacytidine-induced AQP9 up-regulation and almost completely blocked intracellular As2O3 entry, confirming that azacytidine enhanced As2O3-mediated cell death via up-regulation of HNF1A and hence increased AQP9 and As2O3 intracellular concentration. Azacytidine sensitization to As2O3 treatment was re-capitulated also in primary AML samples. Finally, azacytidine did not enhance arsenic toxicity in a liver cell line, where HNF1A was largely unmethylated. CONCLUSIONS: Azacytidine sensitizes AML cells to As2O3 treatment, and our results provide proof-of-principle evidence that pharmacological up-regulation of AQP9 potentially expands the therapeutic spectrum of As2O3. Further clinical trial should evaluate the efficacy of azacytidine in combination with As2O3 in the treatment of AML.

Urinary bromophenol glucuronide and sulfate conjugates: Potential human exposure molecular markers for polybrominated diphenyl ethers.

One possible source of urinary bromophenol (BP) glucuronide and sulfate conjugates in mammalian animal models and humans is polybromodiphenyl ethers (PBDEs), a group of additive flame-retardants found ubiquitously in the environment. In order to study the correlation between levels of PBDEs in human blood plasma and those of the corresponding BP-conjugates in human urine, concentrations of 17 BDE congeners, 22 OH-BDE and 13 MeO-BDE metabolites, and 3 BPs in plasma collected from 100 voluntary donors in Hong Kong were measured by gas chromatograph tandem mass spectrometry (GC-MS). Geometric mean concentration of ΣPBDEs, ΣOH-BDEs, ΣMeO-BDEs and ΣBPs in human plasma were 4.45 ng g(-1) lw, 1.88 ng g(-1) lw, 0.42 ng g(-1) lw and 1.59 ng g(-1) lw respectively. Concentrations of glucuronide and sulfate conjugates of 2,4-dibromophenol (2,4-DBP) and 2,4,6-tribromophenol (2,4,6-TBP) in paired samples of urine were determined by liquid chromatography tandem triple quadrupole mass spectrometry (LC-MS/MS). BP-conjugates were found in all of the parallel urine samples, in the range of 0.08-106.49 µg g(-1)-creatinine. Correlations among plasma concentrations of ΣPBDEs/ΣOH-BDEs/ΣMeO-BDEs/ΣBPs and BP-conjugates in urine were evaluated by multivariate regression and Pearson product correlation analyses. These urinary BP-conjugates were positively correlated with ΣPBDEs in blood plasma, but were either not or negatively correlated with other organobromine compounds in blood plasma. Stronger correlations (Pearson's r as great as 0.881) were observed between concentrations of BDE congeners having the same number and pattern of bromine substitution on their phenyl rings in blood plasma and their corresponding BP-conjugates in urine.

LDH is an adverse prognostic factor independent of ISS in transplant-eligible myeloma patients receiving bortezomib-based induction regimens.

BACKGROUND: Serum lactate dehydrogenase (LDH) has been an adverse prognostic factor for myeloma but does not feature in the International Staging System (ISS). We examined whether elevated serum LDH at diagnosis remains an adverse risk factor independent of ISS for survivals transplant-eligible myeloma patients receiving early/frontline bortezomib-based induction, followed by autologous stem cell transplantation (ASCT). PATIENTS: Seventy-seven transplant-eligible Chinese patients received three induction regimens [staged approach (N = 25), PAD (N = 19), VTD (N = 33)], followed by ASCT and thalidomide maintenance. RESULTS: Five-year overall (OS) and event-free (EFS) survivals were 66.4% and 36.2%. There was no difference in demographics, complete remission/near complete remission (CR/nCR rates postinduction or ASCT, and survivals among patients induced by the three induction regimens. Elevated LDH was associated with male gender (P = 0.006), ISS III (P = 0.042) and serum ß2-microglobulin (P = 0.040). Univariate analysis showed that elevated LDH, ISS III, high ß2-microglobulin, and failure to attain CR/nCR post-ACST were risk factors adversely impacting both OS and EFS. Multivariate analysis showed that elevated LDH was the only factor impacting both OS (P = 0.007) and EFS (P = 0.008). CONCLUSION: In this uniformly treated cohort of transplant-eligible myeloma patients, elevated serum LDH is an adverse risk factor independent of ISS for both OS and EFS. Bortezomib-based induction/ASCT regimen had not abolished the adverse impact of elevated LDH.

Vascular protective effects of statin-related increase in serum 25-hydroxyvitamin D among high-risk cardiac patients.

AIM: To investigate the protective effects of statin-related increase in serum 25-hydroxyvitamin D [25(OH)D] on vascular function among high-risk cardiovascular patients. METHODS: We studied 443 high-risk cardiovascular patients (coronary disease 83%, ischemic stroke 21%; mean age 68 ±â€Š10 years; men 77%). Serum 25(OH)D was measured by ELISA assay. Carotid intima-media thickness (IMT) and brachial flow-mediated dilatation were measured by high-resolution vascular ultrasound. Circulating CD34KDR and CD133KDR endothelial progenitor cells (EPCs) were measured by flow cytometry. RESULTS: Three hundred and twenty-nine (74%) patients were statin users. Serum 25(OH)D was higher among statin users than nonusers (30.2 ±â€Š12.8 versus 26.8 ±â€Š8.5 ng/ml; P = 0.009), which remained significant after multivariable adjustment [B = +3.8, 95% confidence interval (CI) 0.6 to 6.9, P = 0.019). Serum 25(OH)D was associated with reduced carotid IMT (R = -0.11, P = 0.026), and increased circulating CD34KDR EPC (R = 0.13, P = 0.030) and CD133KDR EPC (R = 0.15, P = 0.012). Adjusted for potential confounders, serum 25(OH)D remained independently associated with reduced carotid IMT (B = -0.003, 95% CI -0.005 to 0.000, P = 0.017), and increased circulating CD34KDR EPC [B = 0.006, 95% CI 0.002 to 0.009, P = 0.001, log, unit (×10/ml)] and CD133KDR EPC [B = 0.004, 95% CI 0.001 to 0.008, P = 0.016, log, unit (×10/ml)]. Interaction test showed no multiplicative effect between statins and serum 25(OH)D on carotid IMT or EPCs. Serum 25(OH)D was negatively associated with HbA1c (B = -0.010, 95% CI -0.019 to -0.001, P = 0.035). There was no significant association between serum 25(OH)D and brachial flow-mediated dilatation (R = -0.045, P = 0.344). CONCLUSION: In patients with cardiovascular disease, statin use is associated with increased serum 25(OH)D, which is independently associated with reduced carotid atherosclerotic burden, increased circulating EPCs, and improved glycemic control. These may partially explain the pleotrophic effects of statins.

Worsened arterial stiffness in high-risk cardiovascular patients with high habitual carbohydrate intake: a cross-sectional vascular function study.

BACKGROUND: Previous studies suggested that high dietary carbohydrate intake is associated with increased cardiovascular risk through raised triglyceride and decreased high-density lipoprotein-cholesterol levels. However, the relation between carbohydrate intake and arterial stiffness has not been established. The purpose of this study was to examine this relation among high-risk cardiovascular patients. METHODS: We studied the relation between dietary macronutrient intake and arterial stiffness in 364 patients with documented cardiovascular diseases or risk equivalent (coronary artery diseases 62%, ischemic stroke 13%, diabetes mellitus 55%) and in 93 age-and-sex matched control subjects. Dietary macronutrient intake was assessed using a validated food-frequency questionnaire (FFQ) for Chinese. Heart-ankle pulse wave velocity (PWV) was measured non-invasively with a Vascular Profiling System (VP2000, Colin Corp. USA). A dietary pattern with ≥60% total energy intake derived from carbohydrates was defined as a high-carbohydrate diet according to the Dietary Reference Intakes (DRI) for Chinese. RESULTS: Subjects who consumed a high-carbohydrate diet had significantly higher mean PWV than those who did not consume a high-carbohydrate diet (P = 0.039). After adjustment for potential confounders, high-carbohydrate diet was associated with significantly increased PWV [B = 73.50 (10.81 to 136.19), P = 0.022]. However, there was no significant association between high-carbohydrate diet and PWV in controls (P = 0.634). CONCLUSIONS: High-carbohydrate diet is associated with increased arterial stiffness in patients with established cardiovascular disease or risk equivalent.