Cholesterol metabolism and non-cholesterol sterol distribution in lipoproteins of type 1 diabetes: the effect of improved glycemic control

In type 1 diabetes, the ratios to cholesterol of serum absorption markers, e.g., cholestanol, are elevated and those of synthesis markers, e.g., lathosterol, are reduced suggesting perturbed cholesterol metabolism. We studied 17 subjects with type 1 diabetes in poor glycemic control at baseline to assess whether improvement of glycemic control affects lathosterol and cholestanol ratios to cholesterol and their distribution in lipoproteins. Cholesterol and the non-cholesterol sterols were assayed directly from serum, and free and ester fractions after thin-layer chromatographic separation of lipoprotein sterols with gas-liquid chromatography. After the 2-6 months follow-up, the mean value of HbA1(c) decreased from 10.8% to 8.6% (p=0.001). Even though the concentrations of serum and lipoprotein cholesterol remained unchanged, the serum lathosterol to cholesterol ratio increased by 28% (p<0.05) and the lathosterol/cholestanol proportion by 23% (p<0.05). The ratios of total and esterified lathosterol to cholesterol in serum, chylomicrons and LDL, and free lathosterol to cholesterol in serum and IDL, were negatively associated with HbA1(c) at baseline and after follow-up, suggesting that the better glycemic control, the higher was cholesterol synthesis. The absorption markers were less consistently associated with HbA1(c). About half of the serum lathosterol and cholestanol was carried in LDL and one-fourth to one-fifth in HDL, but the lathosterol ratios were roughly similar in all lipoproteins. In contrast, cholestanol accumulated in chylomicrons and HDL. Glycemic control did not affect the distributions of lathosterol and cholestanol. In conclusion, improvement in glycemic control increased cholesterol synthesis, but had no effect on cholesterol absorption as measured by the serum or lipoprotein cholestanol to cholesterol ratio. From a clinical point of view, the better the glycemic control, the more antiatherogenic cholesterol metabolism may be in type 1 diabetes.     

Hypertension is not the link between job strain and coronary heart disease in the Whitehall II study

BACKGROUND: Hypertension is assumed to be one of the mechanisms through which job strain (a combination of high work demands and low job control) increases coronary heart-disease risk. However, direct tests of this hypothesis are lacking. METHODS: We examined whether hypertension mediated the association between job strain and incident coronary heart disease among 5630 men and 2456 women free of coronary heart disease at study entry. Job strain was assessed at phase 1 (1985 to 1988); hypertension and systolic and diastolic blood pressure (BP) were assessed at phases 1, 3 (1992 to 1993), and 5 (1997 to 1999); and incident coronary heart disease was assessed from the end of phase 1 to phase 7 (2003 to 2004) (698 events; median follow-up, 16.1 years). RESULTS: After adjustment for age, sex, ethnicity, and employment grade, job strain was associated with an increased incidence of coronary heart disease. Further adjustments, for hypertension, systolic BP, and diastolic BP at phase 1 and across phases 1, 3, and 5, and the slope of hypertension and BP over time, had little effect on this association, although measures of hypertension and BP were strongly related to incident coronary heart disease. CONCLUSIONS: Data, including repeated casual measurements of hypertension and BP, suggest that the development of chronic hypertension is not a key mechanism linking job strain and coronary heart disease. Further research on ambulatory measurements is needed to determine whether episodic BP elevations have a role in this association.     

Effect of Retirement on Sleep Disturbances: the GAZEL Prospective Cohort Study

Objectives:

Changes in health following retirement are poorly understood. We used serial measurements to assess the effect of retirement on sleep disturbances.

Design:

Prospective cohort study.

Setting:

The French national gas and electricity company.

Participants:

Fourteen thousand seven hundred fourteen retired employees (79% men).

Measurements and Results:

Annual survey measurements of sleep disturbances ranging from 7 years before to 7 years after retirement (a mean of 12 measurements). Before retirement 22.2% to 24.6% of participants reported having disturbed sleep. According to repeated-measures logistic-regression analysis with generalized estimating equations estimation, the odds ratio (OR) for having a sleep disturbance in the postretirement period was 0.74 (95% confidence interval 0.71-0.77), compared with having a sleep disturbance in the preretirement period. The postretirement improvement in sleep was more pronounced in men (OR 0.66 [0.63-0.69]) than in women (OR 0.89 [0.84-0.95]) and in higher-grade workers than lower-grade workers. Postretirement sleep improvement was explained by the combination of preretirement risk factors suggesting removal of work-related exposures as a mechanism. The only exception to the general improvement in sleep after retirement was related to retirement on health grounds. In this group of participants, there was an increase in sleep disturbances following retirement.

Conclusions:

Repeated measurements provide strong evidence for a substantial and sustained decrease in sleep disturbances following retirement. The possibility that the health and well-being of individuals are significantly worse when in employment than following retirement presents a great challenge to improve the quality of work life in Western societies in which the cost of the aging population can only be met through an increase in average retirement age.

Citation:

Vahtera J; Westerlund H; Hall M; Sjösten N; Kivimäki M; Salo P; Ferrie JE; Jokela M; Pentti J; Singh-Manoux A; Goldberg M; Zins M. Effect of retirement on sleep disturbances: the GAZEL prospective cohort study. SLEEP 2009;32(11):1459-1466.     

Long Working Hours and Sleep Disturbances: The Whitehall II Prospective Cohort Study

Study Objective:

To examine whether exposure to long working hours predicts various forms of sleep disturbance; short sleep, difficulty falling asleep, frequent waking, early waking and waking without feeling refreshed.

Design:

Prospective study with 2 measurements of working hours (phase 3, 1991–1994 and phase 5, 1997–1999) and 2 measurements of subjective sleep disturbances (phase 5 and phase 7, 2002–2004).

Setting:

The Whitehall II study of British civil servants.

Participants:

Full time workers free of sleep disturbances at phase 5 and employed at phases 5 and 7 (n = 937–1594) or at phases 3, 5, and 7 (n = 886–1510).

Measurements and Results:

Working more than 55 hours a week, compared with working 35–40 hours a week, was related to incident sleep disturbances; demographics-adjusted odds ratio (95% CI) 1.98 (1.05, 3.76) for shortened sleeping hours, 3.68 (1.58, 8.58) for difficulty falling asleep; and 1.98 (1.04, 3.77) for waking without feeling refreshed. Repeat exposure to long working hours was associated with odds ratio 3.24 (1.45, 7.27) for shortened sleep, 6.66 (2.64, 16.83) for difficulty falling asleep, and 2.23 (1.16, 4.31) for early morning awakenings. Some associations were attenuated after adjustment for other risk factors. To a great extent, similar results were obtained using working hours as a continuous variable. Imputation of missing values supported the findings on shortened sleep and difficulty in falling asleep.

Conclusion:

Working long hours appears to be a risk factor for the development of shortened sleeping hours and difficulty falling asleep.

Citation:

Virtanen M; Ferrie JE; Vahtera J; Elovainio M; Singh-Manoux A; Marmot MG; Kivimäki M. Long working hours and sleep disturbances: the whitehall II prospective cohort study. SLEEP 2009;32(6):737–745.     

Bordetella pertussis Strains with Increased Toxin Production Associated with Pertussis Resurgence

Before childhood vaccination was introduced in the 1940s, pertussis was a major cause of infant death worldwide. Widespread vaccination of children succeeded in reducing illness and death. In the 1990s, a resurgence of pertussis was observed in a number of countries with highly vaccinated populations, and pertussis has become the most prevalent vaccine-preventable disease in industrialized countries. We present evidence that in the Netherlands the dramatic increase in pertussis is temporally associated with the emergence of Bordetella pertussis strains carrying a novel allele for the pertussis toxin promoter, which confers increased pertussis toxin (Ptx) production. Epidemiologic data suggest that these strains are more virulent in humans. We discuss changes in the ecology of B. pertussis that may have driven this adaptation. Our results underline the importance of Ptx in transmission, suggest that vaccination may select for increased virulence, and indicate ways to control pertussis more effectively.     

Contribution of parental and school personnel smoking to health risk behaviours among Finnish adolescents

Background  

This study compared parental smoking with school personnel smoking in relation to adolescents' smoking behaviours, alcohol use, and illicit drug use.     

Quantitative real-time RT-PCR assay for PCA3

Objectives:To develop a quantitative, internally standardized real-time RT-PCR assay for prostate cancer antigen 3 (PCA3), a non-translated gene found to be prostate-specific and highly overexpressed in cancer, and examine the role of PCA3 in peripheral blood with a small sample cohort.Design and methods:The RT-PCR assay for PCA3 is based on target-specific lanthanide probes. Peripheral blood from 91 prostatic cancer/disorder patients and healthy controls was assayed for PCA3 and prostate-specific antigen (PSA) expression.Results:The dynamic range of the assay reaches over eight orders of magnitude and the limit of quantification is 800 copies per milliliter blood. Peripheral blood from 2/9 patients with metastasized cancers were PCA3 positive, whereas all the other samples were negative. Eight samples were PSA positive.Conclusions:The degree of PCA3 positivity in circulating cells from prostate cancer patients is low compared to that of PSA. In contrast to some previous reports, we found no PCA3 expression in healthy individuals.     

Structure of the sense of coherence scale in a nationally representative sample: the Finnish Health 2000 survey

Objective  To examine the structure of the sense of coherence (SOC) scale in a general population. Methods  This study analysed the responses of 6,217 subjects aged 30 years and over who participated in the Finnish Health 2000 survey (response rate 77.4%). Participants completed an abbreviated 12-item version of the SOC scale. Two alternative structures were tested using confirmatory factor analysis: a one-factor model, with all scale items loaded onto a single latent factor representing the SOC construct, versus a second-order factor model, with scale items loaded onto their corresponding latent factors representing the three SOC components (comprehensibility, manageability and meaningfulness), which are, in turn, dependent on one single higher-order SOC construct. Results  The one-factor model was fitted to the data after allowing the errors of comprehensibility item 5 and manageability item 6 to correlate, as was done in previous studies among Finnish adults. The comparative fit index (CFI), Tucker–Lewis index (TLI) and root mean square error of approximation (RMSEA) for the one-factor model were, respectively, 0.97–0.98, 0.96–0.97 and 0.05–0.09 across both sexes and three age groups. The second-order factor model had correlations between latent factors higher than 1, even after alternative model modifications, casting doubts on this more complex structure. Conclusion  These data suggest that the components of comprehensibility, manageability and meaningfulness should be merged when measuring SOC with the 12-item SOC scale in the Finnish general population.     

Cognitive representation of orientation: a case study

Although object orientation in the human brain has been discussed extensively in the literature, the nature of the underlying cognitive representation(s) remains uncertain. We investigated orientation perception in BC, a patient with bilateral occipital and parietal damage from a herpes encephalitis infection. Our results show that in addition to general inaccuracy in discriminating and reproducing line orientations, her errors take the form of left-right mirror reflections across a vertical coordinate axis. We propose that in BC, the cognitive impairment is in failing to represent the direction of tilt for line orientations. Our results suggest that there exists a level of representation in the human brain at which line orientations are represented compositionally, such that the direction of a line orientation's tilt from a vertical mental reference meridian is coded independently of the magnitude of its angular displacement. Reflection errors across a vertical axis were observed both in visual and tactile line orientation tasks, demonstrating that these errors arise at a supra-modal level of representation not restricted to vision, or, alternatively, that visual-like representations are being constructed from the tactile input.     

Measurement of GABAA receptor binding in vivo with [11C]flumazenil: a test-retest study in healthy subjects

[(11)C]Flumazenil is widely used in positron emission tomography (PET) studies to measure GABA(A) receptors in vivo in humans. Although several different methods have been applied for the quantification of [(11)C]flumazenil binding, the reproducibility of these methods has not been previously examined. The reproducibility of a single bolus [(11)C]flumazenil measurements was studied by scanning eight healthy volunteers twice during the same day. Grey matter regions were analyzed using both regions-of-interest (ROI) and voxel-based analysis methods. Compartmental kinetic modelling using both arterial and reference region input function were applied to derive the total tissue distribution volume (V(T)) and the binding potential (BP) (BP(P) and BP(ND)) of [(11)C]flumazenil. To measure the reproducibility and reliability of each [(11)C]flumazenil binding parameter, absolute variability values (VAR) and intraclass correlation coefficients (ICC) were calculated. Tissue radioactivity concentration over time was best modelled with a 2-tissue compartmental model. V(T) showed with all methods good to excellent reproducibility and reliability with low VARs (mean of all brain regions) (5.57%-6.26%) and high ICCs (mean of all brain regions) (0.83-0.88) when using conventional ROI analysis. Also voxel-based analysis methods yielded excellent reproducibility (VAR 5.75% and ICC 0.81). In contrast, the BP estimates using pons as the reference tissue yielded higher VARs (8.08%-9.08%) and lower ICCs (0.35-0.80). In conclusion, the reproducibility of [(11)C]flumazenil measurements is considerably better with outcome measures based on arterial input function than those using pons as the reference tissue. The voxel-based analysis methods are proper alternative as the reliability is preserved and analysis automated.