High intensity smoking cessation interventions: Cardiac patients of low socioeconomic status and low intention to quit profit most.

BACKGROUND: Without assistance, smokers being admitted to the hospital for coronary heart disease often return to regular smoking within a year. OBJECTIVE: This study assessed the 12-month effectiveness of a telephone and a face-to-face counselling intervention on smoking abstinence among cardiac patients. Differential effects for subgroups varying in their socioeconomic status and intention to quit smoking were also studied. METHODS: A randomised controlled trial was used. During hospital stay, smokers hospitalised for coronary heart disease were assigned to usual care (n = 245), telephone counselling (n = 223) or face-to-face counselling (n = 157). Eligible patients were allocated to an intervention counselling group and received nicotine patches. After 12 months, self-reported continued abstinence was assessed and biochemically verified in quitters. Effects on smoking abstinence were tested using multilevel logistic regression analyses applying the intention-to-treat approach. RESULTS: Compared with usual care, differential effects of telephone and face-to-face counselling on continued abstinence were found in patients with a low socioeconomic status and in patients with a low quit intention. For these patients, telephone counselling increased the likelihood of abstinence threefold (OR = 3.10, 95 % CI 1.32-7.31, p = 0.01), whereas face-to-face counselling increased this likelihood fivefold (OR = 5.30, 95 % CI 2.13-13.17, p < 0.001). Considering the total sample, the interventions did not result in stronger effects than usual care. CONCLUSION: Post-discharge telephone and face-to-face counselling interventions increased smoking abstinence rates at 12 months compared with usual care among cardiac patients of low socioeconomic status and low quit intentions. The present study indicates that patients of high socioeconomic status and high quit motivation require different cessation approaches.

Depression, pregnancy-related anxiety and parental-antenatal attachment in couples using preimplantation genetic diagnosis.

STUDY QUESTION: Do preimplantation genetic diagnosis (PGD) couples experience higher levels of stress during pregnancy and the perinatal period compared with couples who conceive spontaneously (SC) or with ICSI? SUMMARY ANSWER: PGD couples did not experience more psychological stress during pregnancy and beyond than ICSI or SC couples. WHAT IS ALREADY KNOWN: Previous studies have shown that assisted reproduction technology (ART) couples are more prone to pregnancy-related anxieties than SC couples, but display depressed feelings to an equal or lesser extent. However, only one study has focused on a female PGD sample, which may be a more vulnerable group than other ART groups, due to the potentially complex hereditary background, adverse childhood experiences and losses. In that study, PGD women experienced a reduction in state anxiety, and maternal-antenatal attachment did not differ from normative data. Unfortunately, no data exist on pregnancy-related anxiety, depression and parental-antenatal attachment. Valuable information from both parents (e.g.: couples) is also lacking. STUDY DESIGN, SIZE, DURATION: For this longitudinal prospective study questionnaire, data from 185 women and 157 men (157 couples) were collected between February 2012 until April 2014. Data were analysed using multilevel analysis. The couples conceiving after PGD, ICSI or SC were followed from the first trimester of the pregnancy until the third month post-partum. PARTICIPANTS/MATERIALS, SETTING, METHODS: A total of 60 PGD, 58 ICSI and 69 SC couples were initially recruited by various departments of Universitair Ziekenhuis Brussel (UZ Brussel). At each trimester (T1: 12-14 weeks, T2: 20-22 weeks, T3: 30-32 weeks) of pregnancy, depression (EPDS), pregnancy-related anxieties (PRAQ) and parental-antenatal attachment (M/PAAS) were recorded. At T4 (3 months post-partum), depression (EPDS) was assessed again. In the first trimester (T1) broad socio-demographic data and at T4 perinatal health data of both mother and child were recorded. Differences between conception groups over time were analysed using multilevel analyses, taking into account covariation between measurements and within couples. Several perinatal covariates as well as social desirability, coping and adult attachment style were controlled for. MAIN RESULTS AND THE ROLE OF CHANCE: All three conception groups had similar scores for depression during pregnancy and beyond. Also, pregnancy-related anxiety scales did not differ among the three groups. All groups also followed a similar trajectory in time regarding their scores for anxiety, depression and parental-antenatal attachment. ART groups did not give more socially desirable answers than SC controls. The subsequent moderators: coping and adult attachment style did not add any relevant information. No interaction effects occurred between gender and conception groups. LIMITATIONS, REASONS FOR CAUTION: The participants were Caucasian, Dutch-speaking couples, with medium to high socio-economic status, from a single centre. Our data should be replicated by multicultural and multicentre studies. Furthermore, the inclusion of an additional control group of couples who did not opt for PGD but for prenatal diagnosis may point to the most beneficial strategy for the couple. WIDER IMPLICATIONS OF THE FINDINGS: PGD parents invest a similar amount of time and emotion in their future children compared with controls. This implies that successful PGD treatment makes an important psychological contribution towards the well-being of couples given their complex hereditary and family backgrounds. STUDY FUNDING/COMPETING INTERESTS: This research project was funded by grants from the internal research council of the Vrije Universiteit Brussel (OZR), the Flemish Fonds Wetenschappelijk Onderzoek (FWO) and the Wetenschappelijk Fonds Willy Gepts (WGFG). UZ Brussel and the Centre for Medical Genetics have received several educational grants for organizing the data collection, from IBSA, Ferring, Organon, Shering-Plough, Merck and Merck Belgium. M.B. has received consultancy and speaker's fees from Organon, Serono Symposia and Merck.

Psychosocial development of full term singletons, born after preimplantation genetic diagnosis (PGD) at preschool age and family functioning: a prospective case-controlled study and multi-informant approach.

STUDY QUESTION: Do full term singletons born after preimplantation genetic diagnosis (PGD) differ in their psychosocial functioning from children born after intracytoplasmic sperm injection (ICSI) and spontaneous conceived controls (SC)? SUMMARY ANSWER: The psychosocial maturation process of 5-6-year-old PGD children is comparable between the three conception groups (PGD, ICSI and SC). WHAT IS ALREADY KNOWN: In general, a lot of research has been published regarding follow-up of children born after artificial reproductive technologies (ART), which mainly is reassuring. But the ART population itself is marked by broad diversity [IVF, ICSI, gamete donation, preimplantation genetic screening (PGS) or PGD] which complicates comparisons. Some literature concerning the socio-emotional development of PGD/PGS children is available and it suggests a normal maturation process. However, the complex reality of PGD families (e.g. safety of the technique and psychological burden of genetic histories) asks for an exclusive PGD sample with matched control groups and a multi-informant approach. STUDY DESIGN, SIZE, DURATION: Between April 2011 and May 2013, the psychosocial wellbeing of preschoolers and their families born after PGD was assessed in a prospective case-controlled, matched follow-up study, with a multi-informant approach. PARTICIPANTS/MATERIALS, SETTING, METHODS: A group of 47 PGD, 50 ICSI and 55 SC 5-6-year-old children participated in a follow-up study performed at the Centre for Medical Genetics of the Universitair Ziekenhuis Brussel (UZ Brussel). Assessments took place in the hospital and in kindergartens. Children performed the Bene-Anthony family relations test (FRT), yielding their perceptions upon family relationships. Parents and teachers completed the child behaviour checklist (CBCL) and Caregiver Teacher Report Form (C-/TRF), respectively. Parental and family functioning were measured by the NEO-FFi, the parenting stress index (PSI), the Greenberger Work-Parenting Investment Questionnaire and the Marlowe-Crowne Social Desirability Scale (MCSDS). Statistical analysis was performed by using analysis of covariance (ANCOVA). MAIN RESULTS AND THE ROLE OF CHANCE: No differences were detected between the psychosocial development of PGD children and the control groups. Parents did not differ in reporting problem behaviour and they were stricter than teachers. Concerning family functioning the ART parents scored comparable with each other. PGD and ICSI mothers were emotionally more stable [NEO-FFi Neuroticism/emotionality: P = 0.013, η(2) = 0.066; 95% confidence interval (CI) 95% (0.003;0.148)]. They experienced less parental stress in general [PSI, Total stress: P = 0.001, η(2) = 0.102, 95% CI (0.02;0.192)] and on different sublevels opposed to their SC counterparts. Yet ART mothers presented higher ratings on the NEO-FFi Conscientiousness [P = 0.011, η(2) = 0.064; 95% CI (0.003;0.144)] indicating a higher feeling of competence and goal directedness. Mediation analysis confirmed: PGD and ICSI mothers who experienced less family stress were emotionally more stable. A power analysis indicated that a sample with 152 children is sufficient to detect a medium size effect with 80% power using ANCOVA. LIMITATIONS, REASONS FOR CAUTION: The current sample comprised only Dutch speaking Caucasians, hence conclusions should be drawn cautiously. Future research should include larger groups, prematures, multiples and children from different cultural backgrounds. WIDER IMPLICATIONS OF THE FINDINGS: This current research is the first to compare PGD preschoolers with matched controls. Concerns about the behavioural effects on the offspring should not inhibit the use of PGD. Furthermore, our findings suggest that on the long run ART procedures might enhance personal resources of women to cope with family stress. These findings are reassuring for women who might feel insecure and anxious during their ART trajectory. STUDY FUNDING/COMPETING INTERESTS: This research project gained funding from the OZR (a grant by the Research group of the Vrije Universiteit Brussel), the FWO (Fonds Wetenschappelijk Onderzoek) and the Wetenschappelijk Fonds Willy Gepts. The UZ Brussel and the Centre of Medical Genetics received funding from pharmaceutical firms for data collection. UZ Brussel and the Centre for Medical Genetics have received many educational grants for organizing the data collection, from IBSA, Ferring, Organon, Shering-Plough, Merck and Merck Belgium. M.B. has received consultancy and speaker's fees from Organon, Serono Symposia and Merck. The other authors have no competing interests. TRIAL REGISTRATION NUMBER: not applicable.

Cognitive and psychomotor development of 5- to 6-year-old singletons born after PGD: a prospective case-controlled matched study.

STUDY QUESTION: Do preschool preimplantation genetic diagnosis (PGD) children differ in their cognitive and psychomotor development from children born after ICSI and spontaneous conception (SC)? SUMMARY ANSWER: The cognitive development of PGD pre-schoolers was comparable to children born after ICSI and SC but motor development differed between ICSI and SC groups. STUDY DESIGN, SIZE DURATION: The cognitive abilities and motor skills of 5- to 6-year-old singletons born after PGD (n = 47) were assessed in comparison with 49 ICSI and 48 SC children in a prospective, case-controlled, matched follow-up study between April 2011 and May 2013. PARTICIPANTS/MATERIALS, SETTING, METHODS: PGD singletons, ICSI and SC children of preschool age were examined with the Wechsler Preschool and Primary Scale of Intelligence (WPSSI-III-NL) and the Movement ABC (M ABC). The WPSSI-III-NL revealed scores for Full IQ, Verbal IQ and Performance IQ. The M ABC yields a total score and comprising scores for measurements of balance, dexterity and ball skills. Since embryo biopsy is the only technical difference between the PGD and ICSI procedures, ICSI children were included as controls. These children were part of a Dutch-speaking cohort of children conceived after assisted reproduction technology (ART) at the Universitair Ziekenhuis Brussel (UZ Brussel) who received longitudinal follow-up. The SC children acted as a second control group similar to the fertile PGD sample and in contrast to the ICSI group. The SC group was recruited through announcements in a variety of media. The children were matched for age, gender, birth order and educational level of the mother. The assessments carried out for the ART groups were blinded whenever possible. The data were analysed using analysis of covariance (ANCOVA) and partial eta squared (η(2)), which was used as a measurement of effect size. MAIN RESULTS AND THE ROLE OF CHANCE: The overall cognitive development of PGD singletons did not differ from controls [P = 0.647, η(2) = 0.006; 95% confidence interval (CI) (0, 0.043)]. The partial IQ scores for Verbal and Performance intelligence revealed similar results. Analysis of motor development based on the total score as well as subscales did indicate a significant difference between the three conception groups [P = 0.033, η(2) = 0.050, 95% CI (0, 0.124)]. Post hoc analysis indicated that the significant difference was situated between performances of ICSI and SC children. Balance capacities [P = 0.004, η(2) = 0.079, 95% CI (0.025, 0.163)] and its post hoc analysis yielded equivalent results. Motor capacities of PGD singletons, however, did not differ from any of the two other conception groups. LIMITATIONS, REASONS FOR CAUTION: Given that we only assessed Caucasian singletons born after PGD, caution is required when drawing more general inferences from our results. The small sample size may be a limitation. A priori power analysis, however, revealed that at least 52 children per group were needed to detect a medium effect and 80% power using ANCOVA. Originally our sample met this threshold but we had to exclude six cases in order to remove outliers and due to missing data. WIDER IMPLICATIONS OF THE FINDINGS: Long-term follow-up of children born after embryo biopsy, in this case for PGD, is needed to confirm that the development of these children remains comparable to ICSI and SC children. Our findings do support the safety of the PGD technique and will reassure patients with hereditary genetic diseases regarding the health of their future offspring conceived with PGD. STUDY FUNDING/COMPETING INTERESTS: Funding for this study was obtained from the OZR (Research group of the Vrije Universiteit Brussel), the FWO (Fonds Wetenschappelijk Onderzoek) and the Wetenschappelijk Fonds Willy Gepts. The UZ Brussel and the Centre of Medical Genetics received funding from pharmaceutical firms for data collection. UZ Brussel and the Centre for Medical Genetics have received many educational grants for organizing the data collection, from IBSA, Ferring, Organon, Shering-Plough, Merck and Merck Belgium. M.B. has received consultancy and speaker's fees from Organon, Serono Symposia and Merck.

Long-term disease control of a non-operable neuroendocrine tumor of the lung with lanreotide: a case study.

Bronchopulmonary neuroendocrine tumors (NETs) are malignant tumors that represent approximately 20% of all lung cancers. The therapeutic option for advanced or metastatic bronchopulmonary NETs is mainly palliation of symptoms; options need to be individualized and, therefore, rely on the knowledge of multidisciplinary teams. Somatostatin analogs have been widely used in NETs for control of hormonal syndromes and are currently under evaluation for their antiproliferative activity. Here, we present a case of NET of the lung, for which we achieved long-term disease control with a treatment comprising the somatostatin analog lanreotide Autogel(®) in a patient with limited therapeutic options due to considerable comorbidity, while preserving his quality of life.

Genotoxicity of hormonal steroids.

Hormonal steroids have a widespread use in medicine and their side effects are continuously debated. The possible genotoxic activity of steroids has been the subject of many investigations. The natural estrogens estradiol, estrone and estriol are generally negative in the ICH core battery of tests, but several positive results have been obtained when using additional endpoints of genotoxicity. The genotoxic activity of the 4-hydroxy metabolites of estradiol and estrone is well established. The synthetic steroidal estrogens have a comparable profile of negative and positive test results. Cyproterone acetate and some of its analogues have a special position within the group of progestins. Their genotoxic potential has been established. Other progestins are generally negative in the routine tests. Anti-glucocorticoids, anti-progestins, corticosteroids, androgens, anabolics and anti-androgens appear to be devoid of genotoxic activities. The genotoxic potential of estradiol, estrone and cyproterone acetate with its analogues may play no role under normal physiological and therapeutic conditions. The metabolic conditions that are needed for the formation of DNA-reactive metabolites and oxygen radicals may not be present in humans. Epidemiological cancer data seem to support this view. The importance of thresholds in the dose-effect-relationship of genotoxicity data and their use in risk assessment is discussed.

FDG-PET, 99mtc-HMPAO white blood cell SPET and bone scintigraphy in the evaluation of painful total knee arthroplasties.

Fluorine-18 fluorodeoxyglucose positron emission tomography (FDG-PET), technetium-99m hexamethylpropylene amine oxime (HMPAO)-labelled white blood cell (WBC) scintigraphy and bone scintigraphy were used in the evaluation of total knee arthroplasties (TKAs). We prospectively included 21 patients who had a three-phase bone scan for exclusion of infection of TKAs. Four hours after injection of 185 MBq 99mTc-HMPAO-labelled WBCs, planar and single-photon emission tomographic (SPET) imaging was performed. Planar imaging was repeated at 24 h p.i. Consecutively images of the knees were obtained with a dedicated PET system 60 min following the injection of 370 MBq of FDG. Focal tracer uptake was scored on SPET and PET visually (0=no uptake, 4=intense uptake). In addition, SUV (standardised uptake value) per voxel was calculated from attenuation-corrected PET images using the MLAA algorithm. Focal uptake at the bone-prosthesis interface was used as the criterion for infection before and after correlation with the third phase of the bone scan. Final diagnosis was based on operative findings, culture and clinical outcome. In the infected TKAs, the WBC scan showed focal activity of grade 2 (n=2), 3 (n=l) or 4 (n=2). PET scan revealed focal activity of grade 4 (n=5) or 3 (n=1). WBC scan alone had a specificity for infection of 53% [positive predictive value (PPV) 42%, sensitivity 100%], compared with 73% for PET scan (PPV 60%, sensitivity 100%). Considering only lesions at the bone-prosthesis interface that were also present on the third phase of the bone scan, we found a specificity of 93% (PPV 83%) for WBC scan. Using these criteria, a specificity of 80% (PPV 67%) was obtained for PET scan. Two out of three false-positive PET scans were due to loosening of the TKA. It is concluded that WBC scintigraphy in combination with bone scintigraphy has a high specificity in the detection of infected TKAs. FDG-PET seems to offer no additional benefit.

New synthetic flavonoids as potent protectors against doxorubicin-induced cardiotoxicity.

A series of 3,7-disubstituted-2(3',4'-dihydroxyphenyl) flavones has been studied as potential cardioprotective agents in doxorubicin antitumor therapy. The influence of substituents on the 3 and 7 position of the flavone nucleus on antioxidant activity cytotoxicity and cardioprotective properties was explored to improve the activity of our lead compound 7-monohydroxyethylrutoside. In the protection against Fe(2+)/vitamin C-induced microsomal lipid peroxidation (LPO assay), IC(50) values ranged from 0.2 to 37 microM. In general, the 3-substituted flavones were the most potent compounds in this assay. The cytotoxicity of the new compounds was tested (up to 250 microM) in hepatocytes. LDH leakage ranged from 2.6-29.2%, whereas the GSH concentrations decreased to 87.3-41.3%. Only four compounds out of this series protected the isolated mouse left atrium against doxorubicin-induced toxicity. Because of the positive inotropic effect of 8d (N-(3-(3',4'-dihydroxyflavon-7-yl)oxypropyl)-N,N,N-trimethylammonium chloride) and 10c (3-hydroxyethoxy-7,3',4'-trihydroxyflavone) on the atrium, compounds 9i (3',4'-dihydroxy-3-glucosylflavone) and 10d (N-(3-(7,3',4'-trihydroxyflavon-3-yl)oxypropyl)-N,N,N-trimethylammonium chloride) were selected to be evaluated as cardioprotective agents in vivo.

Frederine, a new and promising protector against doxorubicin-induced cardiotoxicity.

The flavonoid 7-monohydroxyethylrutoside (monoHER) can protect against doxorubicin-induced cardiotoxicity. A drawback of monoHER therapy would be the relatively high dose needed to obtain complete protection (500 mg/kg in mice). Therefore, we synthesized a series of new compounds with improved antioxidant properties. After characterization of antioxidant activity, cardioprotection in vitro, and possible toxic properties in hepatocytes, we selected Frederine for additional investigations in vivo. In the present study, it was found that this compound did not induce weight loss or (gross) organ changes in mice in a treatment schedule of 170 mg/kg i.p., 5 times/week during 2 weeks. We recorded the electrocardiogram telemetrically in mice during and 2 weeks after the combined treatment with doxorubicin (4 mg/kg, i.v.) and 5 times Frederine (68 mg/kg, i.p.; equimolar to 100 mg/kg monoHER) for 6 weeks. Complete protection against doxorubicin-induced cardiotoxicity was found, indicating that Frederine is at least 5 times more potent than monoHER. Frederine did not have a negative influence on the antiproliferative effects of doxorubicin on A2780, OVCAR-3, and MCF-7 cells in vitro and on OVCAR-3 xenografts grown in nude mice when administered 5 min before doxorubicin (8 mg/kg i.v.) and 4 days thereafter with an interval of 24 h. It can be concluded that we succeeded in designing a better cardioprotector than monoHER. Therefore, Frederine merits further investigation as a possible protector against doxorubicin-induced cardiotoxicity in cancer patients.

Intravenous cyclosporine versus intravenous corticosteroids as single therapy for severe attacks of ulcerative colitis.

BACKGROUND & AIMS: Cyclosporine has been effective in patients with steroid-refractory attacks of ulcerative colitis (UC). We investigated the effects of intravenous (IV) cyclosporine as single IV therapy (without glucocorticosteroids) for severe UC and compared these with the response to glucocorticosteroids. METHODS: Patients with a severe attack of UC were randomized to treatment with IV cyclosporine, 4 mg x kg(-1) x day(-1), or with methylprednisolone, 40 mg/day, in a randomized, double-blind, controlled trial. After 8 days, patients who had a response received the same medication orally in combination with azathioprine. Patients were followed up clinically, endoscopically, and by scintigraphy. Renal function was assessed using urinary inulin clearances. Endpoints were clinical improvement, discharge from the hospital, and remission up to 12 months after intravenous therapy. RESULTS: Thirty patients were included. After 8 days, 8 of 15 patients (53%) who received methylprednisolone had a response to therapy vs. 9 of 14 (64%) receiving cyclosporine. In nonresponders, 3 of 7 methylprednisolone patients and 1 of 3 cyclosporine patients improved when both treatments were combined. No serious drug-related toxicity was observed with either treatment. At 12 months, 7 of 9 patients (78%) initially controlled with cyclosporine maintained their remission vs. 3 of 8 (37%) initially treated with methylprednisolone. No clinically significant decrease of renal function was observed. CONCLUSIONS: Cyclosporine monotherapy is an effective and safe alternative to glucocorticosteroids in patients with severe attacks of UC.

Flavonoids as peroxynitrite scavengers: the role of the hydroxyl groups.

It has been reported that flavonoids efficiently protect against peroxynitrite toxicity. Two pharmacophores have been identified in flavonoids, namely the catechol group in ring B and the hydroxyl (OH) group at the 3-position. In this study, this structure-activity relationship was further examined. It was found that catechol (1,2-dihydroxybenzene) is a potent peroxynitrite scavenger, whereas phenol (hydroxybenzene) is not. Of the flavonols tested without a catechol group in ring B, kaempferol (OH groups at positions 3,5,7,4') and galangin (OH groups at positions 3,5,7) are also potent scavengers, whereas apigenin (OH groups at positions 5,7,4') and chrysin (OH groups at positions 5,7) are not. This confirms the importance of the OH group at the 3-position. However, the synthetic flavonol TUM 9761 and 3-hydroxyflavone (OH group only at position 3) are poor scavengers. Based on these results, the structure-activity relationship on the peroxynitrite scavenging activity of flavonols was refined. The catechol in ring B remains important. Also the 3-OH group remains important, but the activity of this pharmacophore is influenced by the substituents at position 5 and at position 7.

The utility of SPECT in determining the relationship between radiation dose and salivary gland dysfunction after radiotherapy.

Salivary gland scintigraphy (SGS) is used to depict salivary gland dysfunction after radiotherapy (RT). The aim of this study was to investigate the utility of SGS combined with single photon emission computed tomography (SPECT). Twenty-one patients with a carcinoma of head and neck underwent SGS before and 1 month after RT. After injection of 370 MBq 99Tcm-pertechnetate, a biplanar dynamic acquisition (12 x 1 min) was started, followed by a SPECT acquisition during 4 min. Carbachol was then injected and a second dynamic study (16 x 1 min) was performed, again followed by a SPECT acquisition. The salivary excretion fraction (SEF) was calculated both from the geometric mean planar image for each parotid and from the SPECT data for each transverse plane through the parotids. The RT-induced changes in the SEF (dSEF) were correlated with the mean radiation dose calculated using tomography-based dosimetry. The mean radiation dose to the parotids was 44 Gy (range 4.4-68.1 Gy). The mean range of the variation in radiation dose to the transverse slices within the parotids of a patient was 24 Gy (range 6.2-51.9 Gy). Considering all transverse planes through the parotids in all patients, a linear correlation was found between the dSEF calculated using SGS-SPECT and the radiation dose (r=0.45, P=0.0001). Thirteen patients had a variation in radiation dose within the parotids of more than 20 Gy. In nine of these a significant intra-individual correlation between radiation dose and the dSEF of the transverse parotid slices was found (r range 0.55-0.97; P value range 0.037-0.0001). In conclusion, SGS-SPECT can be used for monitoring radiation-induced parotid gland dysfunction. It offers the unique possibility for the assessment of intra-individual dose-dysfunction curves in patients with large variations in the radiation dose within the parotids.

The promising role of 18F-FDG PET in detecting infected lower limb prosthesis implants.

UNLABELLED: The purpose of this study was to evaluate the feasibility of using 18F-FDG and PET for the detection of infection associated with lower limb arthroplasty. METHODS: Seventy-four prostheses in 62 patients in whom infection was suspected after artificial hip or knee placement were studied with this technique. Images were obtained 60 min after an intravenous injection of FDG. The images were interpreted as positive for infection if tracer uptake was increased at the bone-prosthesis interface. A final diagnosis was made by surgical exploration or clinical follow-up for 1 y. PET results were compared with the follow-up outcome in all patients. RESULTS: The sensitivity, specificity, and accuracy of PET for detecting infection associated with knee prostheses were 90.9%, 72.0%, and 77.8%, respectively. The sensitivity, specificity, and accuracy of PET for detecting infection associated with hip prostheses were 90%, 89.3%, and 89.5%, respectively. Overall, the sensitivity was 90.5% and the specificity was 81.1% for detection of lower limb infections. CONCLUSION: FDG PET is a useful imaging modality for detecting infections associated with lower limb arthroplasty and is more accurate for detecting infections associated with hip prostheses than for detecting infections associated with knee prostheses.

Synthesis of novel 3,7-substituted-2-(3',4'-dihydroxyphenyl)flavones with improved antioxidant activity.

A series of 3,7-disubstituted-2-(3',4'-dihydroxyphenyl)flavones was synthesized as potential cardioprotective agents in doxorubicin antitumor therapy. The influence of substituents on the 3 and 7 positions of the flavone nucleus on radical scavenging and antioxidant properties was explored to improve the antioxidant activity of our lead compound monoHER. In the TEAC assay most compounds had a similar potency (3.5-5 times as potent as trolox), but in the LPO assay IC(50) values ranged from 0.2 to 37 microM. In general, the 3-substituted flavones (9a-j) were the most potent compounds in the LPO assay. The number of hydroxyl groups is not the only prerequisite for antioxidant activity. Substitution in ring A of the flavonoid is not necessary for high activity, but the presence of a 7-OH group significantly modifies the antioxidant activity. The compounds are good antioxidants, which makes it interesting to evaluate them as cardioprotective agents.

Flavonoids can replace alpha-tocopherol as an antioxidant.

Endogenous antioxidants such as the lipid-soluble vitamin E protect the cell membranes from oxidative damage. Glutathione seems to be able to regenerate alpha-tocopherol via a so-called free radical reductase. The transient protection by reduced glutathione (GSH) against lipid peroxidation in control liver microsomes is not observed in microsomes deficient in alpha-tocopherol. Introduction of antioxidant flavonoids, such as 7-monohydroxyethylrutoside, fisetin or naringenin, into the deficient microsomes restored the GSH-dependent protection, suggesting that flavonoids can take over the role of alpha-tocopherol as a chain-breaking antioxidant in liver microsomal membranes.

7-monohydroxyethylrutoside protects against chronic doxorubicin-induced cardiotoxicity when administered only once per week.

Doxorubicin is a very effective antitumor agent, but its clinical use is limited by the occurrence of a cumulative dose-related cardiotoxicity, resulting in congestive heart failure. 7-Monohydroxyethylrutoside (monoHER), a flavonoid belonging to the semisynthetic hydroxyethylrutoside family, has been shown to protect against doxorubicin-induced cardiotoxicity when administered i.p. at a dose of 500 mg/kg five times/week in combination with a weekly i.v. dose of doxorubicin. Such a dosing schedule would be very inconvenient in clinical practice. We therefore investigated a dosing schedule of one administration of monoHER just before doxorubicin. The electrocardiogram was measured telemetrically in mice after the combined treatment of doxorubicin (4 mg/kg, i.v.) with one dose of monoHER (500 mg/kg, i.p., administered 1 h before doxorubicin) for 6 weeks. These data were compared with the five times/week schedule (500 mg/kg, i.p., administered 1 h before doxorubicin and every 24 h for 4 days). The increase of the ST interval was used as a measure for cardiotoxicity. It was shown that 500 mg/kg monoHER administered only 1 h before doxorubicin provided complete protection against the cardiotoxicity. This protection was present for at least 10 weeks after the last treatment. Because of the short half-life of monoHER, these results suggest that the presence of monoHER is only necessary during the highest plasma levels of doxorubicin.

In vitro screening of antitumour agents for cardiotoxicity by means of isolated mouse left atria.

Cardiotoxicity, a side-effect that can occur after treatment with an anticancer drug, has severe clinical implications. Therefore, a model is desired to screen new anticancer drugs or drug combinations for possible cardiotoxic side-effects. In the present study we tested the applicability of the electrically stimulated isolated mouse left atrium model using a wide range of anticancer drugs with known cardiotoxicity. It appeared that the cardiotoxicity observed in our model, i.e. the negative or positive inotropic effects of the drugs on the isolated atrium, corresponded with the observed cardiotoxicity in animals and/or humans. It is therefore concluded that our model can be used to wam for possible cardiotoxic side-effects of anticancer drugs in vivo.

Extension of a predictive substrate model for human cytochrome P4502D6.

1. Metoprolol, indoramine, codeine, tamoxifen and prodipine, compounds which are clinically used, and MDMA (ecstasy) were fitted in a small molecule model for substrates of human cytochrome P4502D6. 2. For both the R- and S-enantiomer of metoprolol, the R- and S-enantiomer of MDMA, and for indoramine and codeine (all proven substrates of cytochrome P4502D6) an acceptable fit in the substrate model was obtained. 3. For tamoxifen, for which the involvement of cytochrome P4502D6 in the 4-hydroxylation is uncertain, no acceptable fit could be obtained in the substrate model. 4. For prodipine, a competitive inhibitor of P4502D6, for which the involvement of P4502D6 in the metabolism is uncertain, no acceptable fit in the substrate model could be obtained. 5. The substrate model was extended in a direction in which two large known substrates extend from the original substrate model. This extension did not change the flat hydrophobic region of the original substrate model.

Acute exposure to ozone does not influence neuroreceptor density and sensitivity in guinea pig lung.

The effects of acute exposure of guinea pigs to 3 ppm of ozone for 2 h on the receptor density and sensitivity of the muscarinergic-, the histaminergic- and the beta-adrenergic receptor systems were studied, in order to provide more insight in the complex mechanisms underlying the well known ozone-induced changes in receptor functionality. The exposure to ozone did not change either the total amount of receptors present in lung tissue, nor the receptor sensitivity of the systems studied. Although no effects were observed, this does not yet fully exclude the receptor system for being a target of ozone exposure. The receptor function can be changed after exposure to ozone, e.g., the coupling with the G-protein can be influenced. Furthermore, the G-protein itself may have been altered or changes can occur at lower levels in the receptor signal transmission route leading to functional changes after stimulation of the receptor with an agonist.

A refined substrate model for human cytochrome P450 2D6.

Cytochromes P450 (P450s) constitute a large superfamily of heme-containing enzymes, capable of oxidizing and reducing a variety of substrates. Cytochrome P450 2D6 is a polymorphic member of the P450 superfamily and is absent in 5-9% of the Caucasian population as a result of a recessive inheritance of gene mutations. Recently, the importance of aspartic acid 301 (Asp301) for the catalytic activity of P450 2D6, as indicated by a preliminary homology model, was confirmed by site-directed mutagenesis experiments. In this study, the heme moiety and the I-helix containing Asp301 were incorporated into the previously derived substrate model for P450 2D6, in the spatial orientations as derived from a recently improved protein model for P450 2D6, thereby incorporating steric restrictions and orientational preferences into the substrate model. The direction of well-defined hydrogen bonds formed between Asp301 and basic nitrogen atoms of P450 2D6 substrates was incorporated into the substrate model as well. Also, the position(s) of the basic nitrogen atom(s) of the substrates was/were allowed more flexibility. This was established through the attachment of an aspartic acid residue (representing Asp301) to the (protonated) basic nitrogen atom(s) of the substrates and superimposing the C alpha- and C beta-atoms of this aspartic acid residue in the fitting procedure instead of the basic nitrogen atoms. A variety of 8 substrates of P450 2D6 (comprising 17 known P450 2D6 dependent metabolic pathways) has been incorporated successfully into this refined and more restrictive substrate model.