Budget impact of using midnight salivary cortisol in the diagnosis of hypercortisolism

BackgroundA single midnight serum cortisol (MSC) test has been reported to possess the best sensitivity and specificity for diagnosing Cushing's syndrome (CS). However, this test requires patient hospitalization, making it costly. This paper aims to compare the hospital budget impact and accuracy of using midnight salivary cortisol (MSVC), as opposed to MSC, in the diagnosis of hypercortisolism.Methods77 patients with at least two high urinary free cortisol (UFC) values (> 360 nmol/24 h) were selected from 611 patients with clinical symptoms of CS. The costs of the method to confirm the diagnosis of hypercortisolism was calculated comparing Option A using MSC (UFCx2, low-dose dexamethasone suppression test [LDDST]) that requires patient hospitalization versus Option B using MSVC (UFCx2, LDDST) in which the evaluation is done outside the Hospital. A budget impact analysis for one year was developed, and a sensitivity analysis in different scenarios was performed. Reproducibility and diagnostic performance of MSVC and MSC were also measured.ResultsSalivary cortisol is a sound analytical method for evaluating free serum cortisol due to its classification accuracy, good imprecision, linearity, and stability. AUC_ROC comparison between MSVC and MSC shows no significant differences. The substitution of the MSC for MSVC in our hospital could save between €16,762 and €132,804 in one year.ConclusionsThe use of MSVC in the diagnosis of hypercortisolism can result in a substantial decrease in the budget impact, without losing diagnosis accuracy and reliability, a significant advantage considering the current emphasis on reducing the financial burden of health care.     

Advantage of salivary cortisol measurements in the diagnosis of glucocorticoid related disorders

Objective

Salivary cortisol in the assessment of glucocorticoid related disorders.

Design-methods

Serum and salivary cortisol were measured in 189 patients (22 Cushing's syndrome, 67 pseudo-Cushing, 11 Addison's disease, 89 controls) at 8:00 and 24:00 h.

Results

Serum and salivary cortisol correlated in the whole study population (r = 0.62, p = 0.000). Morning serum and saliva cortisol in Addison's disease were lower than in controls (6.74 ± 1.69 vs 22.58 ± 1.78 µg/dL, and 0.15 ± 0.25 vs 0.67 ± 0.12 µg/dL) (p < 0.001). Morning serum cortisol was similar in controls and patients with Cushing's syndrome or pseudo-Cushing (22.58 ± 1.78 vs 13.96 ± 6.02 vs 16.13 ± 1.69 µg/dL). Morning serum and salivary cortisol at 8:00 had the same sensitivity to distinguish patients with Addison's disease from healthy controls.24:00am serum cortisol in controls (2.61 ± 0.20 µg/dL) was lower than in the pseudo-Cushing group (6.53 ± 0.77 µg/dL, p < 0.001) and in Cushing's syndrome (10.90 ± 2.36 µg/dL, p = 0.003). 24:00am salivary cortisol in controls (0.0025 ± 0.001 µg/dL) was lower than in patients with Cushing's syndrome (0.58 ± 0.11 µg/dL, p < 0.001) and those higher than in patient with pseudo-Cushing (0.10 ± 0.06 µg/dL, p = 0.001).Both salivary cortisol and serum cortisol presented high specificity (82% and 100%) to detect Cushing's syndrome but salivary cortisol higher sensitivity (saliva 88% and serum 50%).

Conclusion

Morning salivary cortisol is as good as serum as screening test for patients with Addison's disease and nighttime salivary cortisol is more adequate than serum in the screening of Cushing's syndrome.     

Fibrinogen estimates are influenced by methods of measurement and hemodilution with colloid plasma expanders

BACKGROUND: Measurement of plasma fibrinogen is often required in critically ill patients or massively bleeding patients being resuscitated with colloid plasma expander. This study aimed at evaluating different assays of plasma fibrinogen after in vitro dilution with commonly used plasma expanders and challenged the hypothesis that levels of fibrinogen are estimated significantly higher in plasma diluted with colloid plasma expander compared with isotonic saline. STUDY DESIGN AND METHODS: Fibrinogen measurements were established in plasma samples each diluted in vitro to 30 or 50% with isotonic saline, hydroxyethyl starch (HES) 130/0.4, and human albumin. Fibrinogen levels were assessed using an antigen determination, three photo‐optical Clauss methods, one mechanical Clauss method, a prothrombin‐derived method, and viscoelastic measurement through thromboelastometry. RESULTS: Measurement of fibrinogen levels was significantly different when performed on alternate analytical platforms. By 30 and 50% dilution with HES 130/0.4 coagulation analyzers using the photo‐optical Clauss methods significantly overestimated levels of fibrinogen. Dilution with human albumin did not affect fibrinogen levels except from one analyzer by 50% dilution level. Viscoelastic measurement of fibrin polymerization was reduced at both dilution levels and appeared to reflect the impairment of fibrin polymerization induced by HES 130/0.4 and to a lesser extent human albumin. CONCLUSION: This study demonstrated that different automated coagulation analyzers revealed significantly different levels of fibrinogen. The presence of colloid plasma expander gave rise to erroneous high levels of fibrinogen returned from some coagulation analyzers employing the method of Clauss.     

Determination of salivary cortisol by liquid chromatography-tandem mass spectrometry

Background: Late evening salivary cortisol concentrations are increasingly used as a screening test in suspected Cushing's syndrome partly because of easy sample collection. The cortisol immunoassays are prone to interference by cross-reacting steroids and therefore there is a need for improvement. The high specificity of an LC-MS assay provides a solution to the problem. Methods: Our liquid chromatography-tandem mass spectrometric (LC-MS/MS) analysis utilizes only 0.1 ml of saliva. The samples were extracted with dichloromethane. The extract was evaporated to dryness and cortisol was analysed by LC-MS/MS operating in the negative mode ESI after separation on a reversed-phase column. Results: The calibration curves for analysis of salivary cortisol exhibited consistent linearity and reproducibility in the range of 0.5–20nmol/L. Interassay CVs were 4.3–11% at cortisol concentrations of 0.6–14nmol/L. The lower limit of quantitation (LOQ) was 70pmol/L (signal to noise ratio=10). The mean recovery of the analyte added to saliva samples ranged from 95–106%. The upper limit of the reference range (95%) was 3.0nmol/L. Conclusions: Our method is rapid, sensitive and simple to perform with a routine LC-MS/MS spectrometer.     

Comparison of evaporation techniques for the preparation of salivary cortisol for analysis by liquid chromatography-electrospray tandem mass spectrometry

ObjectiveCompare evaporation techniques in the work-up procedure of saliva samples for cortisol analysis by a previously validated liquid chromatography–tandem mass spectrometry (LC–MS/MS) method.Design and methodsSamples were evaporated using freeze drying, centrifugal concentration, and nitrogen flow and analyzed by LC–MS/MS.ResultsCortisol concentrations detected using each technique did not significantly differ. Factors other than the recovery of cortisol were evaluated.ConclusionsEvaporation using freeze drying/centrifugal concentration is an automated process, reducing overall processing time for analysis of numerous samples.     

Guidelines for the diagnosis of osteoporosis by densitometric methods

BACKGROUND: Osteoporosis is a major health hazard for postmenopausal women and elderly people. Local, national, and international organizations developed clinical practice guidelines for the diagnosis and management of osteoporosis and the prevention of osteoporotic fractures. Low bone mineral density (BMD) is the most important risk factor for fragility fractures. Bone densitometry is the best method to measure BMD in an individual. Many risk factors contribute to the development of osteoporosis and increase the fracture risk independently from BMD. Guidelines must be comprehensive, factual, simple to implement, and should provide the clinician, patients, governments, and payers with the best evidence available. OBJECTIVES: The objectives of this article were to review national and international guidelines to establish a congruent set of parameters that may aid the clinician in the decision-making process for the diagnosis of osteoporosis. DATA SOURCES: An online search of several databases provided 18 guidelines for this review. Comparison among the guidelines was made on 10 different aspects: format, focus, significance of hip and vertebral body fractures, primary diagnostic considerations, BMD measurement technology, interpretation, reporting and follow-up, equipment reliability and quality control, risk factors considered, and methodologic quality of the guidelines. Tables were created for easier comparison on the aspects covered and supported by each guideline. RESULTS: None of the guidelines reviewed fulfills all the requirements of good clinical practice guidelines. CONCLUSIONS: Further works should finally provide all those interested with a more complete and thorough set of guidelines based on the best evidence available.     

Electronic energy levels of porphyrins are influenced by the local chemical environment

Self-assembled islands of 5,10,15,20-tetrakis(pentafluoro-phenyl)porphyrin (2HTFPP) on Au(111) contain two bistable molecular species that differ by shifted electronic energy levels. Interactions with the underlying gold herringbone reconstruction and neighboring 2HTFPP molecules cause approximately 60% of molecules to have shifted electronic energy levels. We observed the packing density decrease from 0.64 ± 0.04 molecules per nm² to 0.38 ± 0.03 molecules per nm² after annealing to 200 °C. The molecules with shifted electronic energy levels show longer-range hexagonal packing or are adjacent to molecular vacancies, indicating that molecule–molecule and molecule–substrate interactions contribute to the shifted energies. Multilayers of porphyrins do not exhibit the same shifting of electronic energy levels which strongly suggests that molecule–substrate interactions play a critical role in stabilization of two electronic species of 2HTFPP on Au(111).

Self-assembled islands of 5,10,15,20-tetrakis(pentafluoro-phenyl)porphyrin (2HTFPP) on Au(111) contain two bistable molecular species that differ by shifted electronic energy levels.

The packing of two-dimensional self-assembled monolayers is facilitated by molecule–surface and molecule–molecule interactions. At low coverage, molecules with repulsive intermolecular interactions can adsorb at preferred surface-adsorption sites,^1–4 while at higher concentrations the preferred surface site may be sacrificed to increase density and maximize intermolecular interactions.^3–6 Surface adsorption can change the conformational structure of a molecule to maximize these interactions resulting in a conformational shape not found in bulk crystals or solvated molecules.^4,7–10 Rational manipulation of shape and local environment can fine tune the electronic properties of the adsorbate.Porphyrins consist of four pyrrole-like moieties connected with methine bridges. The high level of conjugation, with 18 π electrons in the shortest cyclic path, allow porphyrins to strongly absorb light in the visible region, 400–700 nm.^11–13 Porphyrins are known as the color of life molecule.^14,15 Heme, an iron–porphyrin complex, is responsible for transporting oxygen through the bloodstream and gives red blood cells their bright color.¹⁶ Chlorophyll, a partially hydrogenated porphyrin, is responsible for the green color in plants and plays a critical role in photosynthesis.¹⁶ The strong interaction with light, overall chemical stability, and diversity through functionalization makes pyrrolic macrocycles ideal candidates for use in photovoltaics,^17–21 chemical sensors,^22–25 catalysis,^26–28 and molecularly based devices.^29–32The existence of bistable switchable states is the first step towards use of porphyrins in applications of molecular memory storage or binary devices.³³ Pyrrolic macrocycles have been shown to exhibit bistable switching behavior on surfaces including induced conformational switching,^34–36 orientational flip-flopping,^37–41 and tautomerization.^42–46 Examples include subphthalocyanine arrays that adsorb with a shuttlecock shape and exhibit scanning tunneling microscopy (STM) induced reversible orientational switching on Cu(100),³⁷ and current from the STM tip that has been used to induce hydrogen tautomerization in naphthalocyanine on an NaCl bilayer on Cu(111).⁴²Confinement to two dimensions through adsorption of 2HTFPP onto a surface creates a complex heterogeneous environment with influences from the substrate and neighboring molecules. In this study, we characterize the local density of states of 2HTFPP adsorbed on Au(111), and found that the local chemical environment can cause the energies of molecular orbitals to shift. This creates an environment where chemically identical molecules exist as two species on the surface.The sample was prepared using an Au(111) substrate on mica (Phasis) that was cleaned through several rounds of annealing and argon sputtering. Images were collected at ultra-high vacuum and 77 K with a low-temperature scanning tunnelling microscope (LT-STM, Scienta Omicron) under constant current mode. The tips were mechanically etched 0.25 mm Pt80/Ir20 wire (NanoScience Instruments). The sample was prepared at room temperature by depositing 1 mM solution of 2HTFPP dissolved in dichloromethane via pulsed-solenoid valve in a vacuum chamber onto the clean gold or 2HTFPP dissolved in dimethylformamide via drop-casting and annealing to 200 °C.⁴⁷The electronic structure of 2HTFPP, neutral TFPP, and dianionic TFPP were calculated using density functional theory (DFT). The structures were optimised using the B3LYP^48,49 density functional approximation and the 6-311+G(d) basis set. A harmonic vibrational frequency analysis confirmed the structure was in a local minimum on the ground state potential energy surface without imaginary frequencies. All calculations were performed on Gaussian 16 Rev. A.03.⁵⁰ Simulated STM images were computed using the Tersoff and Hamann approximation^51,52 as done by Kandel and co-workers.^53,54 The tunneling current was modeled as a function of tip position, and the surface was modeled as a featureless and constant density of states to reproduce a constant current experiment. Through the Tersoff and Hamann approximation the tunneling current leads to information on the local density of states at a specific energy and a discrete location.Pulse-depositing 2HTFPP in vacuum via a pulsed-solenoid valve resulted in ordered islands of the adsorbate, Fig. 1. The formation of close-packed islands, despite submonolayer coverage, indicates attractive intermolecular interactions between adsorbates. 2HTFPP has a packing density of 0.64 ± 0.04 molecules per nm² with a 1-molecule unit cell and rectangular packing.Open in a separate windowFig. 1(a–c) Unoccupied and (d–f) occupied electron states of 2HTFPP. All scale bars are 5 nm. (e) Two bistable species, diffuse square outlined in green and a double-dot feature outlined in white. (f) 2HTFPP appears as double-dot features. The white box indicates the 1-molecule, rectangular unit cell. Images taken with a tunneling current of 5 pA.Changing the polarity of the bias voltage of the STM sample allows unoccupied (positive voltage) or occupied (negative voltage) molecular orbitals to be imaged along with the topography of the surface. The unoccupied electron states, Fig. 1a–c, have an even distribution of electron density across the molecule and appear as diffuse squares. As the magnitude of the bias voltage is increased, a larger number of electronic energy levels are included in the measurement. Increasing the magnitude of the negative bias voltage from −0.25 V to −1.5 V, Fig. 1d and f, results in a change in contrast from a diffuse square to a bright double-dot feature. Imaging at −0.75 V, an intermediate voltage between these two energy levels, we observe two species—a mixture of diffuse squares and double-dot features, Fig. 1e. These species are differentiated from one another by having the same ground state molecular orbitals at shifted energies. If all the molecules on the surface were equivalent, we would expect to image the same molecular orbitals of each molecule at each bias voltage. At −0.75 V we do not observe the same orbital shape for each molecule, but we observe influence of the HOMO−2 and HOMO−3 energy levels in approximately 60% of that adsorbed 2HTFPP. Interaction with the local chemical environment causes the energy levels to be shifted enough to be included at a bias voltage with a smaller magnitude.We investigated the possibility that the two species were chemically different. If a gold atom formed a complex with the porphyrin, we would expect the displacement of the inner pyrrolic hydrogens. It was also possible that the presence of the STM tip was altering the adsorbates. Smykalla et al. reported that the STM tip can reversibly remove and replace the pyrrolic hydrogens which changes the shape and contrast of the porphyrin in the STM images.⁵⁵ Deng and Hipps reported a small shift in orbital energies of 0.04 eV for vapor-deposited metallo-porphyrins on Au(111) due to the height of the tip.⁵⁶ We observed a march larger shift of orbital energies and used DFT to calculate shapes of the occupied and unoccupied molecular orbitals of gas phase 2HTFPP, TFPP with the inner pyrrolic hydrogens removed, dianionic TFPP with the inner pyrrolic protons removed, and Au-TFPP with a gold atom coordinated to the porphyrin, Fig. 1 in ESI.^† We used the electronic structure calculations to make theoretical STM images. We found that the double-dot feature was only present in the occupied orbitals of 2HTFPP, Fig. 2. Theoretical STM images of Au-TFPP, Fig. 2 in ESI,^† does not show the double-dot feature. This suggests that intact 2HTFPP molecules make up the close-packed islands, and both detected species are chemically equivalent. The shift in electronic energy levels is due to the heterogeneous local chemical environment.Open in a separate windowFig. 2DFT, theoretical STM images, and comparison with experimental STM images of 2HTFPP. HOMO and HOMO−1 have a diffuse square shape, while HOMO thru HOMO−3 exhibit the double dot feature. Both of these shapes were experimentally observed at −0.75 V.The packing of adsorbates is a balance between molecule–molecule and molecule–substrate interactions. We observed various packing densities and unit cells that were dependent on sample preparation. Preparation with the pulsed-solenoid valve at room temperature created a 1-molecule unit cell with a packing density of 0.64 ± 0.04 molecules per nm², Fig. 1. Annealing the sample to 200 °C resulted in a 1-molecule unit cell with a packing density of 0.38 ± 0.03 molecules per nm², Fig. 4. Annealing altered both the adsorption sites and intermolecular ordering of 2HTFPP, and we no longer observed two electronic species on the surface. Annealing to 200 °C may remove excess solvent and provide the energy needed for the adsorbed species to leave the preferred adsorption site and maximize intermolecular interactions. This suggests that the local chemical environment plays a critical role in the creation of two bistable species. The surface of Au(111) undergoes herringbone reconstruction with packing of the surface gold atoms.^57,58 The surface consists of both face-centered cubic packing (fcc) and hexagonally-close packed (hcp) gold atoms with strained transition areas. The three different domains create a heterogeneous surface electronic structure.⁵⁹ To investigate the relationship of species 1 and species 2 with the underlying substrate we characterized the images using Fast Fourier Transform (FFT). FFT converts an image from real space to frequency space and can reveal longer-range ordering of molecular assemblies.Open in a separate windowFig. 42HTFPP after annealing to 200 °C. The unit cell has dimensions of 1.6 nm × 1.6 nm and the monolayer has a packing density of 0.38 molecules per nm². The bright double-dot features are doubly stacked porphyrins, the start of a second layer. The image was taken with a bias voltage of −10.0 mV and a tunneling current of 10 pA.In order to focus the FFT on one species at a time, white circles were placed over each double dot feature, Fig. 3a and b. FFT were taken of the images with the circles to determine the packing of the adsorbates, Fig. 3c and d. Hexagonal ordering as well as longer-range rectangular packing can be seen in the FFT, Fig. 3c, of the locations of the double-dot features in the image showing two species of 2HTFPP, Fig. 3a. We observed rectangular packing of 2HTFPP when the magnitude of the bias voltage was large enough for all of the adsorbed porphyrins to exhibit bright double-dot features, Fig. 3b and d. The presences of hexagonal packing for one species, but not the overall self-assembled island suggests that the adsorption site on the underlying gold herringbone reconstruction is playing a role in the shift of electronic energy levels. We did not observe the two species after annealing to 200 °C, suggesting that solvent and intermolecular interactions may influence the location of the adsorption site on Au(111). We also observed that the double-dot features in Fig. 3a were more likely to exist around molecular defects and edges of the close-packed island suggesting that intermolecular interactions also play a role in the shift of the electronic energies of the molecular orbitals.Open in a separate windowFig. 3(a) Circles placed over each 2HTFPP molecule with bright double dot features at −0.75 V and (b) −1.5 V (c) is FFT of (a) showing hexagonal order (d) is FFT of (b) showing rectangular order.Pulse deposition with a solenoid valve into vacuum has been shown to create meta-stable molecular motifs due to the rapid evaporation of solvent.⁵³ We planned to directly compare room-temperature pulse deposition with drop-casting but were unable to resolve drop-cast porphyrins prior to annealing. Drop-casting followed by annealing resulted in an alternate packing of 0.21 molecules per nm², Fig. 3 in ESI.^† Despite the fluorinated phenyl group inverting the polarity of the ring, we observe π stacking of pentafluorophenyl rings after pulse-depositing and annealing to 200 °C, Fig. 4. Although this is unexpected, Blanchard et al. have previously observed face-to-face π stacking in the crystal structure of pentafluorophenyl substituted ferrocenes.⁶⁰Several molecules on top of the self-assembled island, the start of a second layer, appear with bright double-dot features, Fig. 4. We did not observe the coexistence of two electronic species in the second layer of 2HTFPP.In conclusion, we observed two bistable species of 2HTFPP on Au(111) with non-degenerate electronic energy levels. DFT and theoretical STM images suggest that the two species are both 2HTFPP and not chemically altered through adsorption or interaction with the STM tip. The species with the affected electronic energy levels appear near molecular vacancies and exhibit longer-range hexagonal packing indicating that the two species are created through molecule–substrate and molecule–molecule interactions. Annealing to 200 °C decreases the packing density and alters the molecule–molecule and molecule–surface interactions. Adding a second layer of adsorbate only exhibits one electronic species which strongly suggests that the local chemical environment plays a critical role in the shift of the electronic energies of the molecular orbitals of 2HTFPP.     

Establishment of reference intervals for the salivary cortisol circadian cycle,by electrochemiluminescence (ECLIA), in healthy adults

ObjectivesTo determine salivary cortisol reference intervals in a healthy adult population, at 6 different time points during a 24-hour (h) period.MethodsIn a prospective study, salivary cortisol concentrations were measured upon waking, one-hour post-waking and at specific times of the day: at 12 h00, 16 h00, 20 h00 and midnight. Samples were analyzed by the first and second-generation electrochemiluminescence assays (ECLIA) from Roche Cobas Cortisol®.ResultsSalivary cortisol values were obtained from 134 healthy volunteers. Reference intervals for the first-generation assay were 6.14–33.19 nmol/L (95% prediction interval) at waking, 5.42–28.06 nmol/L one-hour post-waking, 3.62–16.23 nmol/L at 12 h00, 2.78–15.27 nmol/L at 16 h00, 2.08–14.90 nmol/L at 20 h00 and 2.09–16.92 nmol/L at midnight. Mean salivary cortisol values were 14.63 nmol/L at waking and 6.44 nmol/L at midnight. Reference intervals for the second-generation assay were 1.50–22.02 nmol/L (2.5th to 97.5th percentiles) at waking, 1.50–20.87 nmol/L one-hour post-waking, 1.50–12.51 nmol/L at 12 h00, 1.50–13.03 nmol/L at 16 h00, 1.50–9.52 nmol/L at 20 h00 and 1.50–6.28 nmol/L at midnight. Values for the second-generation assay at all 6 different time points were almost half of the first-generation assay. The second-generation assay showed a better correlation with LC-MS/MS (r = 0,97).ConclusionOur study confirms that reference intervals for salivary cortisol are not comparable across first and second-generation Roche Cobas Cortisol® assays. Furthermore, the second-generation assay has a better correlation with LC-MS/MS and a better analytical performance (accuracy and precision).     

四种检验方法在细菌性阴道炎诊断的临床价值

目的探讨4种检验方法对细菌性阴道炎的临床诊断作用与应用价值。方法选取该院2012年7月至2014年5月80例疑似细菌性阴道炎患者,分别使用胺试验、线索细胞检查、乳酸杆菌检查、细菌性阴道炎(BV)快速检测法进行检测,并对4种方法的检测结果作比较分析。结果乳酸杆菌检测阳性率为80.0%,线索细胞检查为78.75%,传统检查法(胺试验、pH值)为62.50%与61.25%、BV快速检测法为77.50%。BV快速检测法检出阳性率显著高于传统检测法,差异有统计学意义(P0.05);传统检测法检测结果与其他3种比较,诊断结果最差。结论 BV快速检测法对细菌性阴道炎的检测速度较快且检出率较高,具有临床价值。     

唾液检测对口干症的临床诊断作用

目的探讨唾液生化检测对口干症的初步临床诊断作用。方法采用吐唾法分别采集30例口干症患者和30例健康人非刺激性混合唾液,测定唾液流率、pH值,使用全自动生化分析仪检测Na^＋、K^＋浓度,计算Na^＋／K^＋及单位时间分泌总量,井进行t检验。结果口干症病例组的唾液流率、pH值、K^＋单位时间分泌总量明显低于健康对照组,差异有统计学意义（P〈0．05）;而Na^＋、K^＋浓度和Na^＋／K^＋比值明显高于健康对照组,差异有统计学意义（P〈0．05）。结论唾液检测作为一种简便、无创的检查手段,对口干症的早期初步诊断具有一定临床价值。     

Predictive properties of impaired glucose tolerance for cardiovascular risk are not explained by the development of overt diabetes during follow-up

OBJECTIVE: To evaluate the relationship of impaired glucose tolerance (IGT) at baseline to coronary heart disease (CHD) incidence, and cardiovascular disease (CVD) and total mortality at follow-up, and to analyze whether the relationship is independent of the subsequent development of diabetes during follow-up. RESEARCH DESIGN AND METHODS: A baseline screening survey for diabetes was performed in 1987 using a 2-h 75-g oral glucose tolerance test. A total of 1234 men and 1386 women aged 45-64 years, who were free of diabetes at baseline, were followed up for 10 years. During the follow-up, 153 subjects had an incident CHD event, 224 died, and 100 deaths were due to cardiovascular causes. Multivariate adjusted (adjusted for age, sex, waist-to-hip ratio, systolic blood pressure, cholesterol, HDL cholesterol, and smoking) hazard ratio (HR) was estimated using Cox regression analysis. RESULTS: In subjects who had IGT at baseline and who did not progress to diabetes during the follow-up, the multivariate adjusted HR (95% CI) was 1.49 (0.95-2.34) for CHD incidence, 2.34 (1.42-3.85) for CVD mortality, and 1.65 (1.13-2.40) for all-cause mortality. CONCLUSIONS: Baseline IGT was an independent risk predictor for cardiovascular morbidity and mortality and for total mortality, which was not confounded by the subsequent development of overt diabetes.     

Plasma levels of thioridazine and metabolites are influenced by the debrisoquin hydroxylation phenotype

The pharmacokinetics of thioridazine and its metabolites were studied in 19 healthy male subjects: 6 slow and 13 rapid hydroxylators of debrisoquin. The subjects received a single 25 mg oral dose of thioridazine, and blood samples were collected during 48 hours. Concentrations of thioridazine and metabolites in serum were measured by HPLC. Slow hydroxylators of debrisoquin obtained higher serum levels of thioridazine with a 2.4-fold higher Cmax and a 4.5-fold larger AUC(0-infinity) associated with a twofold longer half-life compared with that of rapid hydroxylators. The side-chain sulphoxide (mesoridazine) and sulphone (sulphoridazine), which are active metabolites, appeared more slowly in serum and had lower Cmax values, but comparable AUC. The thioridazine ring-sulphoxide attained higher Cmax and 3.3-fold higher AUC in slow hydroxylators than in rapid hydroxylators of debrisoquin. Thus the formation of mesoridazine from thioridazine and the 4-hydroxylation of debrisoquin seem to be catalyzed by the same enzyme, whereas the formation of thioridazine ring-sulphoxide is probably formed mainly by another enzyme.     

涎腺区肿块的CT诊断

目的 探讨涎腺肿瘤的CT表现，了解其影像特点。方法 分析经手术及病理证实的涎腺肿瘤16例．包括涎腺良性肿瘤6例，恶性肿瘤5例，涎腺外肿块4例(神经鞘瘤2例，淋巴结转移2例)，另有慢性腮腺炎1例。结果 6例涎腺良性肿瘤中5例呈圆形或椭圆形，1例呈多结节分叶，增强后均匀强化。6例肿物较边缘清楚．密度较均匀。5例涎腺恶性肿瘤轮廓不规则，边界不清楚并伴有不同程度的周围结构受侵，密度不均匀，增强后明显强化。结论 涎腺区肿块的部位、边界、包膜、密度及茎突移位情况是鉴别肿瘤良恶性的主要依据，认为CT对肿瘤与其他疾病的鉴别及涎腺内外肿瘤的鉴别具有重要临床价值。     

The antinociceptive effects of intrathecally administered cannabinoids are influenced by lipophilicity.

Previous research has demonstrated that intravenously administered cannabinoids produce potent antinociception in rodents. The present study examined the ability of 16 cannabinoid analogs to produce antinociception and hypothermia after intrathecal administration. Fifteen of the compounds tested produced significant increases in the tail-flick response to radiant heat. This effect was stereoselective because N-methyl-dextronantradol, the inactive stereo-isomer of the potent cannabinoid analog N-methyl-levonantradol, failed to elevate tail-flick latencies above baseline values. In general, the drugs tended to be more effective in producing hypothermia than antinociception. A positive correlation found between the ED50 values in producing antinociception and lipophilicity indicated that the most lipid-soluble drugs were the least active. In contrast, no apparent relationship between cannabinoid-induced hypothermia and lipophilicity was found. The finding that the antinociceptive effects of spinally administered cannabinoids is inversely related to lipophilicity is similar to that reported for the opiates.