Enhanced Predictive Power of Quantitative TWA during Routine Exercise Testing in the Finnish Cardiovascular Study

Introduction: We examined whether quantification of T-wave alternans (TWA) enhances this parameter's capacity to evaluate the risk for total and cardiovascular mortality and sudden cardiac death (SCD).
Methods and Results: The Finnish Cardiovascular Study (FINCAVAS) enrolled consecutive patients (n = 2,119; 1,342 men and 777 women) with a clinically indicated exercise test with bicycle ergometer. TWA (time domain-modified moving average method) was analyzed from precordial leads, and the results were grouped in increments of 10 μV. Hazard ratios (HR) for total and cardiovascular mortality and SCD were estimated for preexercise, routine exercise, and postexercise stages. Cox regression analysis was performed. During follow-up of 47.1 ± 12.9 months (mean ± standard deviation [SD]), 126 patients died: 62 were cardiovascular deaths, and 33 of these deaths were sudden. During preexercise, TWA ≥ 20 μV predicted the risk for total and cardiovascular mortality (maximum HR >4.4 at 60 μV, P < 0.02 for both). During exercise, HRs of total and cardiovascular mortality were significant when TWA measured ≥50 μV, with 90 μV TWA yielding maximum HRs for total and cardiovascular death of 3.1 (P = 0.03) and 6.4 (P = 0.002), respectively. During postexercise, TWA ≥60 μV indicated risk for total and cardiovascular mortality, with maximum HR of 3.4 at 70 μV (P = 0.01) for cardiovascular mortality. SCD was strongly predicted by TWA levels ≥60 μV during exercise, with maximum HR of 4.6 at 60 μV (P = 0.002), but was not predicted during pre- or postexercise.
Conclusion: Quantification of TWA enhances its capacity for determination of the risk for total and cardiovascular mortality and SCD in low-risk populations. Its prognostic power is superior during exercise compared to preexercise or postexercise.     

A THREE-STEP PROCEDURE FOR ASSESSING BIOEQUIVALENCE IN THE GENERAL MIXED MODEL FRAMEWORK

Bioavailability data arising from a standard two-period cross-over study are routinely analysed to establish bioequivalence between test and reference formulations. Current regulatory guidelines only require evidence of equivalence in average bioavailability for the assessment of bioequivalence. Under normality assumptions, this is achieved by demonstrating equivalence between the formulation means (step 1). However, the equivalence of formulation variances should also be assessed to get evidence of population bioequivalence (step 2), since a difference in variability of bioavailability may also pose significant problems in drug safety and efficacy. On the other hand, even population bioequivalence does not ensure that an individual subject could be expected to respond similarly to the two formulations. Therefore, whenever individual bioequivalence is the ultimate goal, the magnitude of intra-subject correlation should always be examined as the final stage (step 3). In this paper, these three successive concepts of bioequivalence are cast into the general mixed model framework and a stepwise testing procedure for the global assessment of bioequivalence is proposed. In addition to this, important issues addressed in the regulatory guidelines, such as verification of the model assumptions and application of the log-transformation, are discussed. Lastly, an example is presented to illustrate the proposed three-step procedure on the original and log-transformed scale of measurement.     

Experimental sports drinks with minimal dental erosion effect

Abstract – The effects of new experimental sports drinks on dental enamel were studied in vitro using bovine tooth specimens. Profilometric analysis was used to measure the loss of tooth material after immersion of the specimens in the drinks. Thereafter the specimens' surface hardness was measured and scanning electron microphotographs were taken. In addition, 13 commercial sports drinks and experimental drinks containing either citric acid or malic acid were tested for their capacity to dissolve hydroxyapatite in vitro. The erosive effect increased markedly with decreasing pH. The citric acid containing drinks were more erosive than malic acid containing drinks. No erosion was observed with the malic acid containing drink (pH 5.90) but the drink of similar composition containing citric acid caused an erosion 1.3± 1.1μm deep and a commercial citric acid containing drink caused a lesion 12.3± 4.5μm deep after 120 min immersion. Softening of enamel was greater in specimens immersed in citric acid than in those immersed in malic acid containing drink. The in vitro hydroxyapatite dissolving effect of the commercial sports drink samples studied (all having a pH under 4.22) was markedly greater (0.48–4.38 mmol/l) than that of the malic acid containing experimental drink (pH 5.50, Ca⁺⁺ concentration in the supernatant 0.19 mmol/l) and of the similar citric acid containing drink (0.35 mmol/l). The hydroxyapatite dissolving effect of both drinks started to be marked at a pH level of about 5.0 but increased thereafter exponentially with decreasing pH. At pH levels above 4.0 the hydroxyapatite dissolving effect of citric acid containing drinks was greater than that of malic acid containing drinks.     

Hepatic Glucose-6-Phosphatase Activity in Non-Insulin Dependent Diabetics

ABSTRACT The role of glucose-6-phosphatase (G6Pase) in postreceptional glucose handling in non-insulin dependent diabetics (NIDDs) was investigated by comparing the enzyme values in diagnostic liver biopsy samples with fasting blood glucose (BG), immunoreactive insulin (IRI) and plasma antipyrine half-life (T/2). The NIDDs, treated with sulphonylureas, had elevated serum aminotransferase and alkaline phosphatase values associated with fatty liver with or without fibrosis. G6Pase activity was reduced in the NIDDs compared with subjects who had undergone gallstone surgery (p<0.001), insulin dependent diabetics (p<0.001), and age- and sex-matched non-diabetics (p<0.001). G6Pase was inversely related to BG and antipyrine T/2, but not to IRI or conventional liver function tests. Therapy with phenobarbital and medroxyprogesterone acetate, known inducers, increased G6Pase activity, shortened antipyrine T/2, reduced BG and did not alter IRI, in four NIDDs. Low liver G6Pase activity in NIDDs may hence be one factor underlying the impaired glycemic control.     

VALIDITY OF THE PROSTATE SPECIFIC ANTIGEN TEST FOR PROSTATE CANCER SCREENING: FOLLOWUP STUDY WITH A BANK OF 21,000 SERA IN FINLAND

PURPOSE: We investigate the validity of prostate specific antigen (PSA) as a screening test for prostate cancer. MATERIALS AND METHODS: A registry of serum samples drawn from 1968 to 1976 from 21,387 men was linked to the Finnish Cancer Registry. During followup from 1968 to 1991, 104 prostate cancers were identified. A matched case control design with incidence density sampling and nested in the serum sample bank was applied, and PSA was assessed. RESULTS: The estimated sensitivity of the test was 44% and specificity 94% at a cutoff of 4.0 microg./l. in the total material. The sensitivity had improved to 86% in patients diagnosed in 5 years after the sample drawing. The test had a better sensitivity (93%) and specificity (96%) in men younger than 65 years at the time of the sample drawing compared to those older. The sensitivity further improved to 100% with a cutoff of 2.5 microg./l. CONCLUSIONS: PSA is a valid screening test for prostate cancer, which compares favorably with mammography for breast cancer. However, until an effect on mortality has been shown, routine screening cannot be recommended.     

ALCOHOL INTAKE CORRELATED WITH SERUM TRACE ELEMENTS

Alcohol intake and serum copper, selenium, magnesium, iron andzinc were investigated in 85 subjects, 48 males and 37 females.Alcohol intake was measured with a questionnaire probing alcoholintake during the preceding 30 days. Mean average daily intakeamong males was 119.7 g (range 0–622.3 g) and among females32 1 g (range 0–378.5 g), and the mean consumption perdrinking day among males was 208.5 g (range 0–666.7 g)and among females 63.8 g (range 0–63.8 g). Among malesalcohol intake per drinking day correlated positively with serumcopper (r = 0.50; P < 0.001) and negatively with serum selenium(r = -0.49; P < 0.001) and magnesium (r = 0.40; P < 0.01).Likewise, among females alcohol intake per drinking day correlatedpositively with serum copper (r = 0.54; P < 0.01) and negativelywith serum magnesium (r = –0.36; P < 0.05). Serum seleniumconcentration was negatively and significantly correlated withaverage daily intake (r = –0.34; P < 0.05) but notwith intake per drinking day. No significant correlations werefound between alcohol intake and serum zinc or iron levels.Only two men, both abstainers, had abnormally low serum zinclevel, and two other men (average daily alcohol intake <37g) and two women (average daily alcohol intake <15 g) hadabnormally high serum iron level. Alcohol intake was associatedwith high serum copper and low serum magnesium and seleniumlevels.     

Characterization of C-11 or I-123 Labelled β-CIT-FP and β-CIT-FE Metabolism Measured in Monkey and Human Plasma. Identification of Two Labelled Metabolites with HPLC

β-CIT-FP and β-CIT-FE which are novel fluoroalkyl derivatives of 2β-carbomethoxy-3β-(4-iodophenyl)tropane (β-CIT), have recently been labelled with¹¹C or¹²³I and used for imaging the dopamine transporter with positron emission tomography (PET) or single photon emission tomography (SPET). The metabolite pattern of these novel tracers was studied with HPLC in plasma in monkeys and in urine and plasma in humans. Four labelled metabolites were found of which two were identified, the¹²³I-labelled free acid and¹¹C- or¹²³I-labelled nor-β-CIT. The latter was detected only in small amounts (<4 per cent). Furthermore, a polar metabolite and an unknown lipophilic¹¹C- or¹²³I-labelled metabolite were found. The amount of this unidentified labelled metabolite of [¹¹C]β-CIT-FP or [¹¹C]β-CIT-FE in monkey plasma was 21±8 per cent and 16±9 per cent at 60 min after injection, respectively. In conclusion, four types of labelled metabolites were found after injection of¹¹C- or¹²³I-labelled β-CIT-FP and β-CIT-FE in monkeys and humans of which one may hamper the quantitation of the dopamine transporter by PET or SPET.     

Electron microscopic stereological study of collagen fibrils in bovine articular cartilage: volume and surface densities are best obtained indirectly (from length densities and diameters) using isotropic uniform random sampling

Results obtained by the indirect zonal isotropic uniform random (IUR) estimation were compared with those obtained by the direct point and interception counting methods on vertical (VS) or IUR sections in a stereological study of bovine articular cartilage collagen fibrils at the ultrastructural level. Besides comparisons between the direct and indirect estimations (direct IUR vs indirect IUR estimations) and between different sampling methods (VS vs IUR sampling), simultaneous comparison of the 2 issues took place (direct VS vs indirect IUR estimation). Using the direct VS method, articular cartilage superficial zone collagen volume fraction (V_v 41%) was 67% and fibril surface density (S_v 0.030 nm²/nm³) 15% higher (P<0.05) than values obtained by the indirect IUR method (V_v 25% and S_v 0.026 nm²/nm³). The same was observed when the direct IUR method was used: collagen volume fraction (V_v 40%) was 63% and fibril surface density (S_v 0.032 nm²/nm³) 21% higher (P<0.05) than those obtained by the indirect IUR technique. Similarly, in the deep zone of articular cartilage direct VS and direct IUR methods gave 50 and 55% higher (P<0.05) collagen fibril volume fractions (V_v 43 and 44% vs 29%) and the direct IUR method 25% higher (P<0.05) fibril surface density values (S_v 0.025 vs 0.020 nm²/nm³) than the indirect IUR estimation. On theoretical grounds, scrutiny calculations, as well as earlier reports, it is concluded that the direct VS and direct IUR methods systematically overestimated the V_v and S_v of collagen fibrils. This bias was due to the overprojection which derives from the high section thickness in relation to collagen fibril diameter. On the other hand, factors that during estimation tend to underestimate V_v and S_v, such as profile overlapping and truncation (‘fuzzy’ profiles), seemed to cause less bias. As length density (L_v) and collagen fibril diameter are minimally biased by the high relative section thickness, the indirect IUR method, based on utilisation of these estimates, is here regarded as representing a ‘gold standard’. The sensitivity of these 3 methods was also tested with cartilage from an in vitro loading experiment which caused tissue compression. In the superficial zone of articular cartilage V_v and S_v of collagen fibrils increased (P<0.05). This difference in the stereological estimates was only detected by the indirect IUR estimation but not by the direct VS or direct IUR methods. This indicated that the indirect IUR estimation was more sensitive than the direct VS or direct IUR estimations. On the basis of these observations, the indirect zonal IUR estimation can be regarded as the technique of choice in the electron microscopic stereology of cartilage collagen.