Interference of hydroxyphenylpyruvic acid, hydroxyphenyllactic acid and tyrosine on routine serum and urine clinical chemistry assays; implications for biochemical monitoring of patients with alkaptonuria treated with nitisinone.

OBJECTIVES: We have assessed the effect of elevated concentrations of hydroxyphenylpyruvic acid (HPPA), hydroxyphenyllactic acid (HPLA) and tyrosine, on a range of chemistry tests in serum and urine to explore the potential for chemical interference on routine laboratory analyses in patients with alkaptonuria (AKU) treated with nitisinone and similarly implications for patients with hereditary tyrosinemia type 1 (HT-1). MATERIALS AND METHODS: HPPA, HPLA and tyrosine were added separately to pooled serum from subjects without AKU in a range of assays with Roche Modular chemistries. Effects on urine were assessed by changes in urine strip chemistries after mixing a positive control urine with various amounts of the test compounds and reading on a Siemens urine strip meter. RESULTS: No significant effect (p > 0.1) was observed up to 225 µmol/L of HPPA and HPLA, and up to 5000 µmol/L tyrosine, on any of the serum-based assays including those with peroxidase-coupled reaction systems of enzymatic creatinine, urate, total cholesterol, HDL cholesterol and triglyceride. Both the monohydroxy HPPA, and the dihydroxy homogentisic acid (HGA), at increased urine concentrations typical of nitisinone-treated AKU and non-treated AKU respectively, did however show marked negative interference in strip assays for glucose and leucocytes; i.e. those with peroxide-linked endpoints. The effect of increased HPLA was less marked. CONCLUSIONS: In patients with AKU or on nitisinone treatment and HT-1 patients on nitisinone, urine strip chemistry testing should be used sparingly, if at all, to avoid false negative reporting. It is recommended that urine assays should be organised with a suitable specialist laboratory.

Evaluation of CD46 re-targeted adenoviral vectors for clinical ovarian cancer intraperitoneal therapy.

Ovarian cancer accounts for >140 000 deaths globally each year. Typically, disease is asymptomatic until an advanced, incurable stage. Although response to cytotoxic chemotherapy is frequently observed, resistance to conventional platinum-based therapies develop rapidly. Improved treatments are therefore urgently required. Virotherapy offers great potential for ovarian cancer, where the application of local, intraperitoneal delivery circumvents some of the limitations of intravenous strategies. To develop effective, adenovirus (Ad)-based platforms for ovarian cancer, we profiled the fluid and cellular components of patient ascites for factors known to influence adenoviral transduction. Levels of factor X (FX) and neutralizing antibodies (nAbs) in ascitic fluid were quantified and tumor cells were assessed for the expression of coxsackie virus and adenovirus receptor (CAR) and CD46. We show that clinical ascites contains significant levels of FX but consistently high CD46 expression. We therefore evaluated in vitro the relative transduction of epithelial ovarian cancers (EOCs) by Ad5 (via CAR) and Ad5 pseudotyped with the fiber of Ad35 (Ad5T*F35++) via CD46. Ad5T*F35++ achieved significantly increased transduction in comparison to Ad5 (P<0.001), independent of FX and nAb levels. We therefore propose selective transduction of CD46 over-expressing EOCs using re-targeted, Ad35-pseudotyped Ad vectors may represent a promising virotherapy for ovarian cancer.

Pregnancy following Mustard or Senning correction of transposition of the great arteries: a retrospective study.

OBJECTIVE: To determine pregnancy outcome in women with atrial switch repair for transposition of the great arteries (TGA) and to compare follow up with a control group of childless women with the same repair. DESIGN: Retrospective cohort study. SETTING: Tertiary care medical centre. POPULATION: About 21 patients compared with 15 controls. METHODS: Review of records from joint cardiac-obstetric clinic 1993-2013. MAIN OUTCOME MEASURES: Occurrence of cardiovascular events: maternal death, heart failure, arrhythmia, thromboembolic events, worsening systemic ventricular function, worsening tricuspid valve regurgitation and newly detected baffle problems. RESULTS: There were 34 pregnancies in 21 women. Mean follow up was 100 months. No deaths or recurrence occurred. Events (few arrhythmias, thromboembolic events and baffle issues) were common in both groups: 13 (62%) patients and eight (53%) controls (P = 0.736). Worsening of ventricular function was similar in both groups: six (29%) patients and four (27%) controls (P = 0.899). Worsening tricuspid regurgitation was more common in patients [11 (52%)] than controls (0)] (P < 0.001). Labour was induced in 76% cases: 32% for cardiac deterioration, 37% to control timing of delivery, and 26% for intrauterine growth restriction. Delivery was vaginal in 84% cases. Median gestational age was 37 (30-40) weeks, median birthweight 2525 g (1460-3530). In all, 38% babies were premature and 38% were small-for-gestational-age. CONCLUSIONS: Cardiac events after atrial repair for TGA are equally common in pregnant women and non-pregnant controls, although worsening tricuspid regurgitation occurs more frequently in pregnancy. Induction of labour is to be expected but vaginal delivery is achievable in most cases. Infants are likely to be premature and small-for-gestational-age. TWEETABLE ABSTRACT: Pregnancy in atrial repair for TGA: cardiac events similar to controls, prematurity and small babies likely.

Polymorphisms in TNC and COL5A1 genes are associated with risk of superficial digital flexor tendinopathy in National Hunt Thoroughbred racehorses.

REASONS FOR PERFORMING THE STUDY: To explore whether genetic susceptibility is a potential risk factor for superficial digital flexor (SDF) tendinopathy in Thoroughbred (TB) racehorses. OBJECTIVES: To identify informative single nucleotide polymorphisms (SNPs) that capture genetic diversity across a range of candidate genes and to investigate, in a case-control study, their association with SDF tendinopathy in UK National Hunt TB racehorses in training. STUDY DESIGN: Case-control candidate gene association study. METHODS: This study used in silico gene assembly and DNA sequencing to screen candidate genes for SNPs. Seven candidate genes were selected using a hypothesis-driven approach: tenascin-C (TNC), collagen, type 1, α 1 (COL1A1), collagen, type 5, α 1 (COL5A1), matrix metalloproteinase type 3 (MMP3), matrix metalloproteinase type 13 (MMP13), fibromodulin (FMOD) and cartilage oligomeric matrix protein (COMP). The SNPs were validated in DNA isolated from 48 TB racehorses and used to genotype 270 racehorses with SDF tendinopathy and 270 yard-matched controls. Genotyping of cases and controls was performed using SNaPshot™. RESULTS: Racehorses heterozygous for the TNC BIEC2-696469 polymorphism were less likely to have SDF tendinopathy than racehorses homozygous for the wild-type allele (odds ratio [OR] 0.56, 95% confidence interval [CI] 0.36-0.85, P = 0.01). This finding remained significant after adjustment for age and racing background (OR 0.57, 95% CI 0.36-0.92, P = 0.03). Racehorses homozygous for the novel COL5A1 COL5A1_01 variant allele were nearly 3 times more likely to have SDF tendinopathy than those homozygous for the wild-type allele (OR 2.82, 95% CI 1.25-6.35, P = 0.01); this association remained significant after adjustment for age and racing background (OR 2.77, 95% CI 1.18-6.53, P = 0.03). CONCLUSIONS: Results suggest that sequence variants in TNC and COL5A1 genes are associated with SDF tendinopathy in TB racehorses. In future genetic markers may be used to identify horses at risk of SDF tendinopathy.

Interferences of homogentisic acid (HGA) on routine clinical chemistry assays in serum and urine and the implications for biochemical monitoring of patients with alkaptonuria.

OBJECTIVES: We have assessed the effect of elevated concentrations of homogentisic acid (HGA) as in alkaptonuria (AKU), on a range of routine chemistry tests in serum and urine. DESIGN AND METHODS: HGA was added to pooled serum and a range of assays was analysed with Roche Modular chemistries. Effects on urine were assessed by diluting normal urine with urine from a patient with AKU, adding HGA to urine and after lowering output of urinary HGA with nitisinone treatment. RESULTS: Serum enzymatic creatinine showed 30% negative interference with 100µmol/L HGA and >50% at 400µmol/L. Serum urate 100 to 480µmol/L was reduced up to 20% at 100 and to 50% with 400µmol/L HGA. Serum cholesterol between 3 and 11mmol/L was reduced by 0.5mmol/L with 400µmol/L HGA. Urine enzymatic creatinine and urate with >2mmol/L HGA showed concentration dependent negative interference up to 80%. A positive interference in urine total protein by benzethonium turbidometric assay was observed, with 10mmol/L HGA equivalent to 1g/L protein. Jaffe creatinine, Na, K, Cl, Mg, Ca, phosphate, ALT, GGT, ALP activities and urea in serum and or urine were not affected by increases in HGA. CONCLUSIONS: To avoid interferences by HGA in alkaptonuria concentration of HGA should be established before samples are assayed with peroxidase assays and benzethonium urine protein.

Evaluation of NFKB1A variants in patients with knee osteoarthritis.

A key feature of osteoarthritis (OA) is articular cartilage loss mediated by numerous catabolic factors including pro-inflammatory cytokines. Cytokine expression is modulated by the nuclear factor κB (NF-κB) family of transcription factors that are in turn, regulated by the inhibitor of NF-κB IκBα encoded by NFKB1A. We examined eight, previously reported common germline polymorphisms to determine whether NFKB1A variants are associated with knee OA. Eight common single-nucleotide polymorphisms (SNPs) across the NFKB1A gene were genotyped in 189 cases with knee OA and 197 healthy controls. Allele, genotype and haplotype frequencies were compared between case and control groups and stratified according to gender due to the increased prevalence of female OA. Serum concentrations of four biochemical markers elevated in OA were compared with genotype for each knee OA case. None of the SNPs showed an association with knee OA; however, stratification of the data for gender showed an increased frequency of the rs8904 variant allele in the female knee OA case group (P = 0.02). Six common haplotypes were identified (H1-H6). H6 was marginally more prevalent in the knee OA group (P = 0.05). The rs8904 variant was associated with increased levels of hyaluronan (HA), a marker of synovial inflammation at 12 and 24 months compared to baseline levels. The nearby rs696 variant demonstrated increased levels of C-reactive protein (CRP) at 12 months and HA at 12 and 24 months. A reduction in CRP levels at 12 months was observed for the rs2233419 variant. These findings provide evidence for the association of NFKB1A variants and knee OA.

Association between CCL2 haplotypes and knee osteoarthritis.

We examined five single nucleotide polymorphisms (SNPs) and reconstructed 5-locus haplotypes of the CCL2 gene, in knee osteoarthritis (OA) cases and in controls. The CCL2 rs2857657 variant (G) allele was observed more frequently in female knee OA cases than in controls. One haplotype (H5) was observed exclusively in the control group (f = 2.3%). Genetic variation in the CCL2 gene may be associated with knee OA.

Low-molecular-weight heparin or warfarin for anticoagulation in pregnant women with mechanical heart valves: what are the risks? A retrospective observational study.

The management of anticoagulation in pregnant women with mechanical heart valves is complex. The maternal and fetal outcomes of 32 pregnancies in 15 women on three different anticoagulation regimens were compared. Anticoagulation with low-molecular-weight heparin (n=4), warfarin (n=22) and combination therapy (n=6) resulted in adverse maternal events in four (100%), three (50%) and three (14%) women, and resulted in fetal losses in one (25%), 17(77%) and three (50%) pregnancies, respectively. Whereas the rate of fetal loss in the warfarin group was high, all women in the LMWH and half of those in the combination group had serious adverse maternal events, including valve thrombosis, maternal death and postpartum haemorrhage.

Tumour necrosis factor receptor superfamily member 11B polymorphisms and association with knee osteoarthritis in women.

We examined single-nucleotide polymorphisms (SNPs) across the tumour necrosis factor receptor superfamily member 11B (TNFRSF11B) gene and knee OA. We identified alleles in a VNTR region in intron 3 that was observed exclusively in women OA cases (P = 0.007, Pc = 0.042). Our results reveal that a previously unreported association between a VNTR genotype in TNFRSF11B and knee OA in women.

Results of screening for intracranial aneurysms in patients with coarctation of the aorta.

BACKGROUND AND PURPOSE: IAs are found in 2.3% of adults; the mean age at detection is 52 years. Prevalence is <0.5% in young adults. Early studies suggest that 10%-50% of patients with aortic coarctation have IAs. Screening recommendations are variable. We sought to examine the prevalence of IAs through screening with MRA. MATERIALS AND METHODS: Consecutive patients older than 16 years of age with coarctation undergoing brain MRA between May 1999 and October 2007 were included. MRA was performed by using a 1.5T scanner with a 3D time-of-flight protocol; simultaneous MR imaging was performed of the heart and aorta. Cerebral MRAs were double-reported by a neuroradiologist. Statistics are described as mean ± SD and median ± range. Continuous variables were compared by using Student t tests and Mann-Whitney U tests (categoric variables, by using the Fisher exact test). RESULTS: One hundred seventeen MRAs were double-reported. The median age was 29 ± 11 years (range, 16-59 years). IAs were found in 12 patients (10.3%). The mean diameter of IAs was 3.9 mm (range, 2.0-8.0 mm). Patients with aneurysms were older (median, 37 years; range, 16-50 years) than those without (median, 23 years; range, 16-59 years; Z = -2.01, P = .04). Hypertension was more common in those with IAs (IA 83% versus no IA 43%, P = .01). There was no association between ascending aortopathy, bicuspid aortic valves, and IAs. CONCLUSIONS: Patients with coarctation have a higher prevalence of IAs, occurring at an earlier age than in population studies. Whether routine screening is appropriate for this group of patients is unclear. Hypertension is likely to be an important pathophysiologic factor.

Evaluation of IL18 and IL18R1 polymorphisms: genetic susceptibility to knee osteoarthritis.

We examined single-nucleotide polymorphisms (SNPs) in IL18 and IL18/R1 genes and knee OA. IL18 rs1946518 wild-type allele was more frequently observed in cases (P = 0.04). Haplotype 1 was more frequently observed in cases (P = 0.04). Genetic variation in the promoter region of IL18, but not IL18R1, may be associated with OA.

Measuring sexual behaviour in the era of HIV/AIDS: the experience of Demographic and Health Surveys and similar enquiries.

OBJECTIVES: To review the sexual behaviour data collected in the Demographic and Health Surveys (DHS) and other similar national surveys from the perspective of data quality. METHODS: Two indicators of premarital and higher risk sexual behaviour were analysed for 31 surveys in 10 countries in sub-Saharan Africa and Latin America and the Caribbean. The analysis focused on the internal consistency of trends and gender differences in the reported indicators. RESULTS: The authors found fluctuating trends in premarital sex in sub-Saharan Africa but consistent increases in Latin America and the Caribbean. Changes in questionnaire design do not seem to contribute to these trends and there is evidence that the increase in premarital sex is genuine in Latin America. Trends in sex with non-spousal, non-cohabiting partners show large fluctuations and inconsistencies between surveys in some countries but not others. Men are consistently more likely to report non-marital sexual partners than women and unmarried women are less likely than unmarried men to report casual partners. CONCLUSIONS: Surveys are potentially a valuable source of information on sexual behaviour but there are sufficient grounds for concern to warrant considerable caution in the use of survey data to monitor trends in sexual behaviour. Survey findings must be evaluated carefully and interpreted in the context of other available information. These results caution against placing heavy emphasis on short term changes in sexual behaviour between individual surveys and highlight the need for attention to quality in data collection.

Dietary fibre: a roughage guide.

The concept of dietary fibre is a complex one that incorporates the physical and physiological functions of fibre and its effects both systemically and local to the gastro-intestinal tract. Dietary fibre can be usefully classified according to its solubility and fermentability, which allows rational clinical application. Fibres may act in several ways including by gel-forming effects in the stomach and small intestine, by its fermentation by colonic bacteria, by a 'mop and sponge' effect, and via concomitant changes in other aspects of the diet. These actions lead to potentially beneficial effects in the gastro-intestinal tract and systemically, such as lowering serum cholesterol and improving glycaemic control. Dietary fibre has been implicated in multiple clinical situations but, although an extensive literature on putative actions and proposed physiological bases is available, high-level evidence of efficacy is limited. Nevertheless, encouraging the intake of a high-fibre diet is likely to have a range of health benefits and physicians are encouraged to follow simple practical guidelines in their everyday practice.

The role of changes in contraceptive use in the decline of induced abortion in Turkey.

The induced abortion rate in Turkey declined from a peak of 4.5 abortions per 100 women in 1988 to 2.4 in 1998. This study examines the extent to which the decline in abortion in Turkey can be attributed to increased use of modern contraceptives. Trends in induced abortion rates and in contraceptive use are examined among Turkish women together with fertility preferences, changes in the contraceptive behavior associated with abortion, and changes in the propensity to abort unwanted pregnancies. The analysis includes a number of simulations that examine what abortion levels might be in different contraceptive-use scenarios. Results indicate that the decline in abortion is due to a decrease in the number of abortions associated with traditional method failure. This decrease is related to three factors: a shift from traditional method use to modern method use, a decline in the traditional method failure rate, and a decline in the proportion of pregnancies resulting from traditional method failures that are aborted.

The impact of family planning service provision on contraceptive-use dynamics in Morocco.

This article uses linked data from the 1995 Morocco DHS calendar and the 1992 Morocco DHS service-availability module to study the effect of service environment on contraceptive discontinuation, switching, and adoption of a modern method following a birth. The 1995 Morocco DHS also collected information on the source of supply for each episode of use of a modern method recorded in the calendar, allowing study of the association between the source of supply and discontinuation and switching rates. Multilevel event-history models are used to evaluate the impact of individual-level sociodemographic characteristics and community-level indicators of family planning service provision. The findings show that the presence of a nearby public health center is associated with higher modern-method adoption after a birth and lower method-failure rates; the presence of a pharmacy is associated with lower discontinuation due to side effects or health concerns. The degree of method-choice potential has a positive impact on both the rate of switching from the pill to another modern method and on modern-method adoption after a birth.

PIP: This study examined the relationship between the service context and the separate components of contraceptive adoption and continuation in Morocco. Data were obtained on contraceptive adoption and continuation from the 1995 Demographic and Health Survey (DHS) among 4753 women 15-49 years old (3324 were interviewed in 1992) and on the service context from the 1992 DHS Service Availability Module. Four reasons were given for switching or discontinuation. Switching was due to pregnancy, adopting another modern method, adopting a traditional method, or not using any method. Event history analysis (discrete time) findings reveal that the number of methods available significantly increased postpartum adoption and only weakly related to switching from the pill. Women who used a nongovernment source were more likely to discontinue using for method related reasons and to stop using the pill at discontinuation. The availability of public health centers within 5 km increased postpartum method adoption. The availability of pharmacies in the community significantly decreased the risk of discontinuing the pill because of side effects and health concerns. One caveat is that considerable unexplained cluster level variation is likely to be due to service quality measures, which were not available. Estimates could also be biased due to endogeneity of variables.

Contraceptive failure and its subsequent effects in China: a two-stage event history analysis.

PIP: This study examined sociodemographic and contraceptive use factors that affect contraceptive failure (CF) during the first 8.5 years of contraceptive use and pregnancy outcomes in China. Data were obtained from complete fertility and contraceptive histories among 17,887 currently married women, aged 15-57 years, included in the 1988 Two-per-Thousand Fertility Survey. 4053 contraceptive use periods during 1980-88 ended in failure. The methods of Trussel and Hammerslough (1983) were used to estimate method-specific hazard models of CF. Findings of relative risk indicate that for male and female sterilization, duration of use and number of living children were determinants of CF among only rural couples. The rate of CF was greatest in the first few months and declined to almost zero after 36 months. Rural women with 3 or more children had a significantly higher rate of CF. The effect of female sterilization had a smaller effect on duration. Significant determinants of CF for mixed methods were duration of use, age at start of use, and number of living children. Risk of CF, after 1984, was lower by 18-32% depending upon method. 61.7% and 62.4% of CFs for male and female sterilization, respectively, resulted in live births. 45.0% of IUD CFs and under 25.0% of reversible method CFs resulted in live births. Number of living children was a significant determinant of a live birth outcome. More children was related to a greater risk of a live birth. The demographic impact of CFs varied by method and area of residence.^ieng

Subacute exposure to cadmium chloride induces HSP-72 in rat liver.

Two groups of rats (n = 5) weighing 175-185 g were implanted (sc) with osmotic minipumps to deliver (0.5 microliter/hr) deionized water or cadmium chloride (CdCl2; 0.2 M) for 14 days. On completion of subacute treatment, liver and kidneys were collected from control and CdCl2 treated groups for analysis. We report that, subacute exposure to CdCl2 results in significant Cd accumulation in liver and kidneys, and heat-shock-protein 72 (HSP-72) induction in the liver. Results affirm a role for liver HSP-72 in Cd-toxicity.

Intention to use contraceptives and subsequent contraceptive behavior in Morocco.

In this article, the relationship between stated intention to use contraceptives and subsequent use during a three-year period in Morocco is examined. Longitudinal data are drawn from two Demographic and Health Surveys: the 1992 Morocco DHS and the 1995 Morocco Panel Survey. Reported contraceptive intentions in 1992 have a strong predictive effect on subsequent contraceptive use even after controlling for other characteristics of respondents, and the strength of the effect is second only to that of previous contraceptive use. Women who in 1992 said they intended to use contraceptives in the future but did not do so are the most likely to have had an unmet need for contraception in 1995. Weakly held fertility preferences reported by some of the women surveyed in 1992 appear to have been a contributing factor in the subsequent failure of these women to act upon their intention to practice contraception.

PIP: Research carried out in Morocco indicated that stated intentions to use contraception are a strong predictor of subsequent use. The data were derived from the 1992 Morocco Demographic and Health Survey and the 1995 Morocco Panel Survey. Among all categories of nonusers questioned in 1992, 52% stated that they intended to use a method at some time in the future. This intention was strongest among women who were currently pregnant, especially when the pregnancy was mistimed or unwanted (76%). Women who wanted no more children were more likely to intend to use a method (61%) than those who wanted a child soon (28%). Women who had used a method in the past were twice as likely (73%) to intend to use contraception as never-users (37%). Other factors associated with an increased likelihood of future use intentions included spousal communication about family size, radio exposure, female education, and age 35-49 years. When multivariate analysis was performed, odds ratios greater than 2.0 were observed among women who did not want more children compared with those who wanted another child within 2 years, women who found family planning messages in the media acceptable compared with those who did not, and women who listened regularly to the radio compared with those without such access. There was a strong association--second only to the effect of previous contraceptive use--of contraceptive use intentions reported in 1992 with whether any method was used in the 1992-95 interval. Among women who stated they intended to use in the next 12 months, 76% reported subsequent use; 30% of those who stated they did not intend to use contraception changed their minds. The predictive effect of contraceptive intentions was weaker among women who had not given birth in the 5 years preceding the survey than among those with a recent birth.