Evolution of silent myocardial ischaemia prevalence and cardiovascular disease risk factor management in Type 2 diabetes over a 10-year period: an observational study.

AIMS: To assess the evolution of silent myocardial ischaemia prevalence and of cardiovascular disease risk factor management over 10 years in people with Type 2 diabetes. METHODS: This repeated cross-sectional study prospectively included 770 people with Type 2 diabetes who presented at our centre in the period 1999-2009. All had at least one additional cardiovascular disease risk factor, no history of coronary disease and were screened for silent myocardial ischaemia using myocardial perfusion imaging. The prevalence of silent myocardial ischaemia, clinical and biological variables and treatments were collected and compared among participants screened in three periods: 1999 to 2002; 2003 to 2005; and 2006 to 2009. We also identified predictive factors for silent myocardial ischaemia. RESULTS: Participants had a mean ± sd age of 62.3 ± 9.3 years, 57.4% were men and the mean time from diagnosis of diabetes was 13.4 ± 9.3 years. Overall, silent myocardial ischaemia screening was positive in 13.9% of participants. This prevalence decreased sharply over the 10-year study period (22.6% in 1999-2002, 13.7% in 2003-2005 and 5.9% in 2006-2009; P<0.0001). In parallel, diastolic and systolic blood pressure, HbA1c and LDL cholesterol significantly decreased and glitazone and statin use increased (all P<0.001). Male gender, peripheral artery disease, diastolic blood pressure >80 mmHg and LDL cholesterol >2.6 mmol/l were independently associated with silent myocardial ischaemia. Further adjustment showed the screening period had a significant effect, which erased the effects of diastolic blood pressure and LDL cholesterol. CONCLUSIONS: The prevalence of silent myocardial ischaemia decreased sharply over time, and control of the main cardiovascular disease risk factors improved. Although the causality link cannot be established, the present study supports current recommendations advocating glycaemic control and intensive management of cardiovascular factors instead of systematic screening.

Evidence of a link between resting energy expenditure and bone remodelling, glucose homeostasis and adipokine variations in adolescent girls with anorexia nervosa.

UNLABELLED: Low bone mass is a consequence of anorexia nervosa (AN). This study assessed the effects of energy deficiency on various bone and hormonal parameters. The interrelationships between energy deficiency and bone remodelling, glucose homeostasis and adipokines underscore the importance of preventing energy deficiency to limit demineralisation and hormonal alterations in AN patients. INTRODUCTION: Low areal bone mineral density (aBMD) is a well-known consequence of AN. However, the impact of reduced energy expenditure on bone metabolism is unknown. This study assessed the effects of energy deficiency on bone remodelling and its potential interactions with glucose homeostasis and adipose tissue-derived hormones in AN, a clinical model for reduced energy expenditure. METHODS: Fifty women with AN and 50 age-matched controls (mean age 18.1 ± 2.7 and 18.0 ± 2.1 years, respectively) were enrolled. aBMD was determined with DXA. Resting energy expenditure (REEm), a marker of energy status, was indirectly assessed by calorimetry. Bone turnover markers, undercarboxylated osteocalcin (ucOC), parameters of glucose homeostasis, adipokines and growth factors were concomitantly evaluated. RESULTS: AN patients presented low aBMD at all bone sites. REEm, bone formation markers, ucOC, glucose, insulin, HOMA-IR, leptin and IGF-1 were significantly reduced, whereas the bone resorption marker, leptin receptor (sOB-R) and adiponectin were elevated in AN compared with CON. In AN patients, REEm was positively correlated with weight, BMI, whole body (WB) fat mass, WB fat-free soft tissue, markers of bone formation, glucose, insulin, HOMA-IR, leptin and IGF-1 and negatively correlated with the bone resorption marker and sOB-R. Biological parameters, aBMD excepted, appeared more affected by the weight variation in the last 6 months than by the disease duration. CONCLUSIONS: The strong interrelationships between REEm and bone remodelling, glucose homeostasis and adipokines underscore the importance of preventing energy deficiency to limit short- and long-term bone demineralisation and hormonal alterations in AN patients.

Is Serum Serotonin Involved in the Bone Loss of Young Females with Anorexia Nervosa?

Recent experimental data suggest that circulating serotonin interacts with bone metabolism, although this is less clear in humans. This study investigated whether serum serotonin interferes with bone metabolism in young women with anorexia nervosa (AN), a clinical model of energy deprivation. Serum serotonin, markers of bone turnover [osteocalcin (OC), procollagen type I N-terminal propeptide (PINP), type I-C telopeptide breakdown products (CTX)], leptin, soluble leptin receptor (sOB-R), and insulin-like growth factor-1 (IGF-1) and its binding protein (IGFBP-3) were assessed. Whole body, spine, hip, and radius areal bone mineral density BMD (aBMD) were assessed by dual-energy X-ray absorptiometry in 21 patients with AN and 19 age-matched controls. Serum serotonin, leptin, IGF-1, IGFBP-3, OC, PINP, and aBMD at all sites, radius excepted, were significantly reduced in AN whereas CTX and sOB-R were increased compared with controls. Serum serotonin levels were positively correlated with weight, body mass index, whole body fat mass, leptin, and IGF-1, and negatively with CTX for the entire population. Low serum serotonin levels are observed in patients with AN. Although no direct link between low serum serotonin levels and bone mass was identified in these patients, the negative relationship between serotonin and markers of bone resorption found in all population nevertheless suggests the implication of serotonin in bone metabolism. Impact of low serum serotonin on bone in AN warrants further studies.

Evaluation of the Minnesota Easy Culture System II Bi-Plate and Tri-Plate for identification of common mastitis pathogens in milk.

The objective of this study was to validate use of the Minnesota Easy Culture System II Bi-Plate and Tri-Plate (University of Minnesota Laboratory for Udder Health, St. Paul) to identify common mastitis pathogens in milk. A total of 283 quarter and composite milk samples submitted to the University of Minnesota Laboratory for Udder Health during the spring of 2010 were cultured simultaneously using 3 methods: standard laboratory culture (reference method) and the Minnesota Easy Culture System II Bi-Plate and Tri-Plate methods. Bi-Plate and Tri-Plate cultures were incubated for 18 to 24h and interpreted by 2 independent, untrained readers within 5h of each other. An experienced technician completed the standard laboratory culture. For each sample, all 3 study personnel recorded the culture result (yes/no) for each of the following diagnostic categories: no bacterial growth (NG), mixed (2 organisms), contaminated (3 or more organisms), gram-positive (GP), gram-negative (GN), Staphylococcus spp., Streptococcus spp., Streptococcus agalactiae, Streptococcus dysgalactiae, Streptococcus uberis, Enterococcus spp., Staphylococcus aureus, coagulase-negative staphylococci, Escherichia coli, Klebsiella spp., and other. For each category, the prevalence, sensitivity, specificity, accuracy, and predictive values of a positive and negative test were calculated, and the agreement between readers and between each reader and the laboratory was assessed. Specificity, overall accuracy, and negative predictive values were generally high (>80%) for the Bi-Plate and Tri-Plate for each category. Sensitivity and positive predictive values were intermediate (>60%) or high (>80%) for the broad categories of NG, GP, GN, Staphylococcus spp. and Streptococcus spp., and for Staph. aureus, but were generally lower (<60%) for other more specific categories. Similarly, interreader agreement (kappa value) was moderate to substantial (40-80%) for the broad categories of NG, GP, GN, Staphylococcus spp. and Streptococcus spp., and for Staph. aureus and E. coli, but was lower for other categories. The Tri-Plate had a higher sensitivity, accuracy, and negative predictive value for Streptococcus spp., and higher interreader agreement for some of the more specific categories. Our conclusion was that Bi-Plate and Tri-Plate results will be most reliable when used to classify infections in broad diagnostic categories such NG, GP, or GN. The Bi-Plate and Tri-Plate will have intermediate ability to identify infections as being caused by Staphylococcus spp., Streptococcus spp., or Staph. aureus.

In peripubertal girls, artistic gymnastics improves areal bone mineral density and femoral bone geometry without affecting serum OPG/RANKL levels.

UNLABELLED: Peripubertal artistic gymnasts display elevated areal bone mineral density at various bone sites, despite delayed menarche and a high frequency of menstrual disorders, factors that may compromise bone health. The concomitant improvement in femoral bone geometry and strength suggested that this type of physical activity might have favourable clinical impact. INTRODUCTION: The purpose of this study is to evaluate the effect of artistic gymnastics (GYM) on areal bone mineral density (aBMD), femoral bone geometry and bone markers and its relationship with the osteoprotegerin (OPG)/rank-ligand (RANKL) system in peripubertal girls. METHODS: Forty-six girls (age 10-17.2 years) were recruited for this study: 23 elite athletes in the GYM group (training 12-30 h/week, age at start of training 5.3 years) and 23 age-matched (± 6 months; leisure physical activity ≤ 3 h/week) controls (CON). The aBMD at whole body, total proximal femur, lumbar spine, mid-radius and skull was determined using dual-X-ray absorptiometry. Hip structural analysis (HSA software) was applied at the femur to evaluate cross-sectional area (CSA, cm(2)), cross-sectional moment of inertia (CSMI, cm(4)), and the section modulus (Z, cm(3)) and buckling ratio at neck, intertrochanteric region and shaft. Markers of bone turnover and OPG/RANKL levels were also analysed. RESULTS: GYM had higher (5.5-16.4%) non-adjusted aBMD and adjusted aBMD for age, fat-free soft tissue and fat mass at all bone sites, skull excepted and the difference increased with age. In the three femoral regions adjusted for body weight and height, CSA (12.5-18%), CSMI (14-18%), Z (15.5-18.6%) and mean cortical thickness (13.6-21%) were higher in GYM than CON, while the buckling ratio (21-27.1%) was lower. Bone markers decreased with age in both groups and GYM presented higher values than CON only in the postmenarchal period. A similar increase in RANKL with age without OPG variation was observed for both groups. CONCLUSION: GYM is associated not only with an increase in aBMD but also an improvement in bone geometry associated with an increase in bone remodelling. These adaptations seem to be independent of the OPG/RANKL system.

Interest of (18)F-FDG PET-CT scanning for staging and management of merkel cell carcinoma: a retrospective study of 15 patients.

BACKGROUND: The additional benefit of 18FDG-Positron Emission Tomography-Computed Tomography (FDG PET-CT) compared with conventional imaging is still a controversial issue in MCC. OBJECTIVES: This study was designed to evaluate the ability of FDG PET-CT to detect secondary lesions clinically inconspicuous and not shown by conventional imaging. METHODS: Clinical records of 15 MCC patients were retrospectively reviewed to investigate the specific interest of FDG PET-CT compared with X-computed tomography (CT). The main endpoint was the ability of FDG PET-CT to detect secondary lesions and the possible resulting changes in disease staging and management compared with pre-FDG PET-CT data including clinical examination, sentinel lymph node biopsy (SLNB), and diagnostic CT. RESULTS: FDG PET-CT was relevant with a single false negative result and led to significant changes in disease staging and management in 46% of patients compared with clinical examination alone. However, additional secondary lesions not detected by CT were evidenced during follow-up in a single patient with an already known metastatic disease, data which did not result in any change in staging and treatment. Sensitivity, specificity, positive predictive value and negative predictive value were respectively 0.66, 1, 1 and 0.8 for SLNB, 0.89, 1, 1 and 0.93 for CT and 0.89, 1, 1 and 0.93 for FDG PET-CT. No additional neoplasm was detected by FDG PET-CT. CONCLUSION: Although FDG PET-CT is of questionable value in MCC management when used in parallel with CT, it may be considered as a valuable option as a single whole-body survey procedure.

Basal plasma leptin levels in healthy elderly males are related to physical fitness without impact on bone metabolism.

AIM: Investigated the relationship between leptin levels or bone remodelling and physical fitness level in healthy elderly participants. METHODS: Twenty women and 18 men (mean age 72.7 years, range 59-90) performed a maximal incremental exercise test to evaluate their maximal oxygen uptake (VOmax). Basal blood concentrations of bone biochemical markers (BM) and leptin were analysed. RESULTS: Women presented higher values of leptin than men (+34.7%, P=0.024), but no difference related to gender was observed for the other biological parameters. Leptin levels were positively correlated with Body Mass Index (BMI) in both genders. Whether adjusted or not for BMI, leptin was negatively correlated with VOmax only in men (r=-0.55, P=0.02 and r=-0.57, P=0.01, respectively). No relationship between VOmax or leptin and BM was observed, except for leptin and osteocalcin in men (r=-0.66, P=0.015). CONCLUSION: Our data suggest that neither physical fitness nor leptin level seems to have a noticeable effect in the regulation of bone cell activity in healthy elderly participants. In this specific population, physical fitness plays a crucial role on leptin secretion, independently of BMI variation, and this action appears to be sex-dependent.

Confidence Interval Constraint-Based Regularization Framework for PET Quantization.

In this paper, a new generic regularized reconstruction framework based on confidence interval constraints for tomographic reconstruction is presented. As opposed to usual state-of-the-art regularization methods that try to minimize a cost function expressed as the sum of a data-fitting term and a regularization term weighted by a scalar parameter, the proposed algorithm is a two-step process. The first step concentrates on finding a set of images that rely on the direct estimation of confidence intervals for each reconstructed value. Then, the second step uses confidence intervals as a constraint to choose the most appropriate candidate according to a regularization criterion. Two different constraints are proposed in this paper. The first one has the main advantage of strictly ensuring that the regularized solution will respect the interval-valued data-fitting constraint, thus preventing over-smoothing of the solution while offering interesting properties in terms of spatial and statistical bias/variance trade-off. Another regularization proposition based on the design of a smoother constraint also with appealing properties is proposed as an alternative. The competitiveness of the proposed framework is illustrated in comparison to other regularization schemes using analytical and GATE-based simulation and real PET acquisition.

Intra arterial treatment of hepatocellular carcinoma: Comparison of MELD score variations between radio-embolization and chemo-embolization.

PURPOSE: The purpose of this study was to assess liver function deterioration, as assessed using the model for end-stage liver disease (MELD) score variations, following transarterial chemo-embolization (TACE) versus selective internal radiation therapy (SIRT) in patients with unresectable unilobar hepatocellular carcinomas (HCC). PATIENTS AND METHODS: We retrospectively evaluated all patients who underwent a single conventional TACE or SIRT procedure in our department from May 2013 to May 2018 for unilobar unresectable HCC. A total of 86 patients (76 men, 20 women; mean age, 65.5 years) were included. There were 63 patients in the TACE group [56 men, 7 women; mean age, 65.1±9.6 (SD) years] and 23 patients in the SIRT group [20 men, 3 women; mean age, 70±9.2 (SD) years]. Delta MELD, defined as post treatment minus pre-treatment MELD score, was considered for liver function deterioration and compared between patients who underwent single lobar treatment of SIRT versus TACE. RESULTS: Patients in SIRT group had significant higher tumor burden, alpha-fetoprotein serum level, and rates of macroscopic vessel invasion. Mean pre-treatment MELD scores did not differ between TACE [mean, 8.41±1.71 (SD); range: 7.24-9.24] and SIRT groups [mean, 8.36±1.74 (SD); range: 7.07-9.21] (P=0.896) as well as Child-Pugh class and albumin-bilirubin (ALBI) grade distribution. However, following treatment, mean DeltaMELD was greater in TACE group (mean, 0.83±1.83 [SD]; range: -0.30--1.31) than in SIRT group (mean, -0.13±1.06 [SD]; range: -0.49-0.32) (P=0.021). At multivariate analysis, SIRT treatment was independently associated with a lower DeltaMELD score than TACE (R=-0.955 [-1.68; -0.406]; P=0.017;). CONCLUSION: Whereas performed in patients with higher tumor burden, SIRT resulted in lower degrees of liver function worsening as assessed using MELD score variations.

Evaluation of a new gridding method for fully 3D direct Fourier PET reconstruction based on a two-plane geometry.

This study investigated how the choice of fixed planes for the representation of the projection data of a cylindrical positron emission tomography (PET) scanner simplifies the frequency interpolation required by the 3D Fourier slice theorem (3D-FST). A new gridding algorithm based on a two-plane geometry and requiring only 1D interpolations in the Fourier domain was compared with the direct implementation of the 3D-FST. We show that the use of two orthogonal planes leads to signal to noise ratios similar to those achieved with the 3D-FST algorithm from projection data acquired with up to two times more count rates, while the resolution remains similar.

A priori selection of the regularization parameters in emission tomography by Fourier synthesis.

This paper describes how the stability of the inverse problem underlying emission tomography can be measured and controlled in clinical settings. We show how the Lanczos approximation provides a way to regularize a certain class of iterative reconstruction algorithms through a given level of noise or resolution in the slices and for a given acquisition protocol. Moreover, we show how the same Lanczos approximation can be used to decide when the iterative reconstruction algorithm actually converges for a given machine precision. These ideas are illustrated by means of reconstructions of simulated and actual emission datasets.

Response of bone metabolism related hormones to a single session of strenuous exercise in active elderly subjects.

OBJECTIVE: To evaluate the effect of strenuous exercise on bone metabolism and related hormones in elderly subjects. METHODS: Twenty one active elderly subjects (11 men and 10 women; mean age 73.3 years) showing a mean theoretical Vo2max of 151.4% participated. Concentrations of plasma ionised calcium (iCa), serum intact parathyroid hormone (iPTH), 25-hydroxyvitamin D (25(OH)D), and 1.25-dihydroxy-vitamin D3 (1.25(OH)2D3), as well as the bone biochemical markers type I collagen C-telopeptide for bone resorption and osteocalcin and bone alkaline phosphatase for bone formation, were analysed before and after a maximal incremental exercise test. RESULTS: At basal level, iPTH was positively correlated with age (r = 0.56, p < 0.01) and negatively correlated with 25(OH)D (r = -0.50; p < 0.01) and 1.25(OH)2D3 (r = -0.47; p < 0.05). Moreover, 25(OH)D and 1.25(OH)2D3 levels were negatively correlated with age (r = -0.50, p < 0.01 and r = -0.53, p < 0.01, respectively). After exercise, iCa and 25(OH)D decreased (p < 0.001 and p = 0.01, respectively) while iPTH increased (p < 0.001). The levels of 1.25(OH)2D3, bone biochemical markers, haematocrit, and haemoglobin were unchanged. The variations in iCa and 25(OH)D were not related to age and/or sex. The iPTH variation was directly related to basal iPTH levels (p < 0.01) and indirectly related to age. CONCLUSIONS: In active elderly subjects, strenuous exercise disturbed calcium homeostasis and bone related hormones without immediate measurable effect on bone turnover. Although an increase in iPTH could have an anabolic action on bone tissue, our findings from our short term study did not allow us to conclude that such action occurred.

No differences in morphological characteristics between hyperplastic condyle and class III condyle.

The aim of this research was to compare the condylar morphology of patients with unilateral condylar hyperplasia (UCH) and patients with a class III skeletal relationship using cone beam computed tomography (CBCT). A prospective study was conducted on patients with facial asymmetry attending the division of oral and maxillofacial surgery of the study university in Chile. Fifteen patients with UCH and 15 with a class III skeletal relationship were selected. Linear measurements of the condylar processes were obtained at a scale of 1:1 using the software Ez3D Viewer Plus. Analysis of variance (ANOVA) and the paired t-test were used, considering P<0.05. Patients with UCH presented statistical differences between the hyperplastic condyle and non-hyperplastic condyle for anteroposterior and mediolateral diameters, condylar neck length, and ramus height. Patients with a class III skeletal relationship showed no differences between the right and left sides; the morphology of their condyles was similar to the condyles with hyperplasia and presented statistical differences when compared with the non-hyperplastic condyles (one-way ANOVA, P<0.05). The condylar morphology of UCH patients could be related to the development of a class III skeletal relationship. These findings provide an insight into the possibility of some class III patients presenting bilateral condylar hyperplasia.

Interaction of amiodarone with racemic warfarin and its separated enantiomorphs in humans.

To evaluate a stereoselective interaction for amiodarone and racemic warfarin, we performed a prospective study with its separated enantiomorphs. Single oral doses of racemic warfarin, 1.5 mg/kg, were administered to six normal subjects, with and without oral amiodarone, 400 mg daily, for the hypoprothrombinemic duration. Both the hypoprothrombinemia (P less than 0.001) and plasma warfarin concentrations (P less than 0.01) were significantly increased. The experiments were repeated separately with the R- and S-warfarin enantiomorphs. S-warfarin with amiodarone significantly increased both the hypoprothrombinemia (P less than 0.001) and plasma warfarin concentrations (P less than 0.01). R-warfarin with amiodarone significantly increased both the hypoprothrombinemia (P less than 0.001) and plasma warfarin concentrations (P less than 0.001). Thus amiodarone augmented the anticoagulant effect nonstereoselectively by reduced metabolic clearance of both warfarin enantiomorphs. Amiodarone and racemic warfarin can be a dangerous combination, particularly when either drug is added to a stabilized regimen of the other drug, unless the prothrombin times are monitored carefully.

The mechanism of the warfarin-rifampin drug interaction in humans.

The mechanism of the drug interaction in humans between warfarin and rifampin was investigated by monitoring the elimination kinetics and metabolic disposition of a single oral dose of pseudoracemic warfarin by GC/MS. The decrease in hypoprothrombinemia observed with concomitant administration of therapeutic doses of rifampin was accompanied by a substantial decrease in the elimination half-lives of both warfarin enantiomers. Rifampin increased the clearance of (R)-warfarin threefold and the clearance of (S)-warfarin twofold. The excretion profiles for warfarin and its metabolites in urine and feces were similar for both control and treated subjects with the exception that 4'-hydroxywarfarin (stereoselective for the (S)-enantiomer) was observed when rifampin was administered. 4'-Hydroxywarfarin is a metabolite of the drug hitherto undetected in vivo in humans. Based on formation clearance values estimated for 6-, 7-, and 8-hydroxywarfarin, rifampin appears to increase the clearance of the parent drug by induction of the cytochrome P-450 isozyme(s) responsible for aromatic hydroxylation.

The effect of sulfinpyrazone on the disposition of pseudoracemic phenprocoumon in humans.

The effect of sulfinpyrazone on the pharmacokinetics and disposition of the enantiomers of pseudoracemic phenprocoumon was assessed by analyzing serial plasma, urine, and fecal samples for parent drug and metabolites by GC/MS. Essentially all of the administered dose could be accounted for either as parent drug, known metabolites, or their conjugates. Phenprocoumon and the 7-hydroxymetabolite represented the major materials recovered. All drug-related materials excreted into the urine were extensively conjugated. Sulfinpyrazone treatment did not affect the hypoprothrombinemia produced by phenprocoumon nor did it significantly alter the plasma elimination kinetics of the individual (R)- and (S)-enantiomers. However, an apparent increased free fraction of both enantiomers in plasma and inhibition of 7-hydroxylation of (S)-phenprocoumon were observed in the presence of sulfinpyrazone. The results of this study are contrasted with those of a previous study on the interaction between sulfinpyrazone and the structurally similar coumarin anticoagulant warfarin.

The mechanism of the interaction between amiodarone and warfarin in humans.

Amiodarone decreased the total body clearance of both (R)- and (S)-warfarin in normal subjects but did not change volumes of distribution. Warfarin excretion products were quantified and clearance and formation clearance values calculated. Amiodarone and metabolites inhibited the reduction of (R)-warfarin to (R,S)-warfarin alcohol-1 and the oxidation of both (R)- and (S)-warfarin to phenolic metabolites. Inhibition of warfarin hydroxylation by amiodarone in human liver microsomes was compared with the in vivo results. In agreement, the in vitro data indicates that amiodarone is a general inhibitor of the cytochrome P450 catalyzed oxidation of both enantiomers of warfarin, but the metabolism of (S)-warfarin is more strongly inhibited than that of (R)-warfarin. These data suggest that the enhanced anticoagulant effect observed when amiodarone and warfarin are coadministered is attributable to inhibition of P4502C9, the isozyme of P-450 primarily responsible for the conversion of (S)-warfarin to its major metabolite, (S)-7-hydroxywarfarin.

Mechanisms of the stereoselective interaction between miconazole and racemic warfarin in human subjects.

Miconazole decreased the total body clearance of both (R)- and (S)-warfarin in normal subjects but did not change volumes of distribution. Miconazole inhibited the oxidation of both (R)- and (S)-warfarin to phenolic metabolites, although (S)-warfarin was inhibited to the greater extent. In particular, (S)-7-hydroxylation, the pathway primarily responsible for termination of the anticoagulant effect, was most strongly inhibited. Inhibition of warfarin hydroxylation by miconazole in human liver microsomes and the in vivo results showed a good rank order correlation. The enhanced anticoagulant effect observed when miconazole and warfarin are coadministered may result from inhibition of P4502C9, the isozyme of P450 primarily responsible for the conversion of (S)-warfarin to (S)-7-hydroxy-warfarin. Because miconazole inhibits a number of P450 isozymes, in addition to P4502C9, it can be expected to lead to interactions with other drugs whose primary metabolism is controlled by these enzymes.

The warfarin-sulfinpyrazone interaction: stereochemical considerations.

To allow the simultaneous evaluation of the interaction between sulfinpyrazone and each enantiomer of racemic warfarin, pseudoracemic warfarin (1:1 12C-R(+) and 13C-S(-)warfarin) was given to six normal subjects both before and during oral sulfinpyrazone dosing. Serial blood and urine samples were analyzed for unchanged warfarin and its metabolic products by GC/MS. A mass balance of an oral dose of pseudoracemic warfarin, containing a tracer quantity of 14C-warfarin, was carried out in one of the subjects by monitoring 14C levels in urine and feces for 15 days. Concomitant sulfinpyrazone dosing markedly increased hypoprothrombinemia, decreased clearance of (S)-warfarin, and increased clearance of (R)-warfarin. Sulfinpyrazone also decreased the urinary excretion of warfarin-related products but increased their fecal excretion by an equivalent amount. Virtually all of the administered warfarin dose could be accounted for either as unchanged drug or known metabolites. Pharmacokinetic analysis of the data suggests the following: At least four distinct enzymes (two oxidases and two reductases) are involved in the metabolism of warfarin. Sulfinpyrazone increases the hypoprothrombinemia caused by warfarin primarily by inhibition of the cytochrome P-450-mediated oxidation of (S)-warfarin, the biologically more potent enantiomer. The increased clearance of (R)-warfarin results not from induction, but from its selective displacement from plasma protein binding sites.

Cardiac surgery for adults with mental retardation. Dilemmas in management.

In summary, cardiac surgery for adults with mental retardation raises a series of controversial legal, economic, ethical, medical, and nursing dilemmas. During the past 20 years, many improvements have taken place in the care of these patients. However, in the future, judicial and statutory mandates requiring high-quality medical care for persons with mental retardation may conflict increasingly with hospital cost-control legislation and thereby affect clinical decisions. For example, it is conceivable that elective repair of an ostium secundum atrial septal defect in an asymptomatic patient will expend the limited resources necessary to carry out emergency revascularization in a symptomatic patient with impending myocardial infarction. This issue becomes even more delicate when the asymptomatic patient is a mentally retarded ward of the state, and the symptomatic patient is a middle-aged man supporting a wife and several college-age children. There may be no easy solution to this problem, and it will provide the grist for many bioethicists. Fortunately, from a practical point of view, we do not currently have to choose between these patients to receive treatment. Our hope is that health care for mentally retarded patients will not be compromised. We believe that decisions about patient management should be based on enlightened clinical judgment rather than on preconceived notions about this population. In the quest for optimal health care delivery, the special needs of these patients should be considered when cardiac catheterization and possible cardiac surgery are contemplated. Although we have presented an approach to a patient with cardiac disease requiring cardiac surgery, we believe that this approach can be utilized for any retarded patient requiring acute medical care. Currently, because there has not been much training in this area, many physicians and nurses lack first-hand experience in caring for the mentally retarded. This inexperience may lead to difficulty in making appropriate decisions. Therefore, we advocate additional exposure in medical and nursing school curricula to the complex health care needs of this population. In conclusion, there appear to be two major issues that pose dilemmas: first, acceptance of the rights of this population to optimal medical management and, second, implementation of appropriate diagnostic and therapeutic strategies.