Peter Dalgaard

Breast cancer mortality in Copenhagen after introduction of mammography screening: cohort study

Abstract Objectives To evaluate the effect on breast cancer mortality during the first 10 years of the mammography service screening programme that was introduced in Copenhagen in 1991. Design Cohort study. Setting The mammography service screening programme in Copenhagen, Denmark. Participants All women ever invited to mammography screening in the first 10 years of the programme. Historical, national, and historical national control groups were used. Main outcome measures The main outcome measure was breast cancer mortality. We compared breast cancer mortality in the study group with rates in the control groups, adjusting for age, time period, and region. Results Breast cancer mortality in the screening period was reduced by 25% (relative risk 0.75, 95% confidence interval 0.63 to 0.89) compared with what we would expect in the absence of screening. For women actually participating in screening, breast cancer mortality was reduced by 37%. Conclusions In the Copenhagen programme, breast cancer mortality was reduced without severe negative side effects for the participants.

Cerebral blood flow increases evoked by electrical stimulation of rat cerebellar cortex: relation to excitatory synaptic activity and nitric oxide synthesis

The purpose of this study was to examine mechanisms involved in the coupling of neuronal activity to cerebral blood flow (CBF). CBF was measured in rat cerebellum using laser-Doppler flowmetry during stimulus-evoked neuronal activity and related to the distribution of the extracellular field potential. Local electrical stimulation of the cerebellar cortex activated a narrow beam of parallel fibers (PFs) 100 microns across and evoked increases of CBF along (On-B) and perpendicular (Off-B) to the beam. Increases of CBF and field potentials were recorded for a distance of up to 1500 microns along the activated beam, and perpendicular to the beam, in a zone approximately 1000 microns wide, i.e. about 10 times wider than the zone in which synaptic excitation took place. CBF increased as a function of stimulus frequency up to 75 Hz, the response being larger On-B than Off-B. TTX abolished both the field potentials and the CBF responses at all frequencies, suggesting that action potentials were mechanistically related to the evoked CBF increases. CBF changes were unchanged by picrotoxin, a blocker of GABA(A) receptors, consistent with the idea that inhibitory synaptic activity does not contribute to CBF increases. The latency to the CBF rise was much shorter On-B than Off-B for the same distance from the stimulating electrode. This may suggest that the CBF response Off-B is dependent on diffusion of vasoactive substances from neuronal structures activated by the parallel fibers On-B. Nitric oxide (NO) synthase inhibition with NG-nitro-L-Arginine increased the time latency to onset of CBF rise by 2-4 times and attenuated the evoked CBF increase by approximately 50%. Sodium nitroprusside, a NO donor, increased baseline CBF, but did not reverse the effects of L-NNA. Thus the initial part of the evoked CBF rise is probably mediated by NO, which also contributes to the later part of the response. This study provides insight into the distribution and mechanism of neurally evoked increases of CBF, of putative importance for the interpretation of activation studies in animals and humans.

Nonlinear curve fitting

Curve fitting problems occur in many scientific areas. The typical case is that you wish to fit the relation between some response y and a one-dimensional predictor x, by adjusting a (possibly multidimensional) parameter β.

Fluorescein transport across the human blood-retina barrier in the direction vitreous to blood. Quantitative assessment in vivo.

Abstract. Inward and outward movement of fluorescein across the human blood‐retina barrier was studied in five healthy volunteers, using a differential spectrofluorometry method that eliminates the contribution of fluorescein glucuronide to the total fluorescence in the vitreous and in plasma. The inward permeability across the blood‐retina barrier, which is presumed to be passive, and the diffusion coefficient in the vitreous for fluorescein was calculated from data obtained 1 h after intravenous injection of fluorescein. The rate of elimination of fluorescein from the vitreous across the blood‐retina barrier was estimated from data obtained 7 to 12 h after injection of fluorescein. The calculations were based upon the free plasma fluorescein decay curve and the preretinal fluorescein gradient in the vitreous. The mean inward permeability of fluorescein was 1.39 times 10−7 cm/sec (range: 0.70‐2.06 times 10−7 cm/sec), whereas the mean outward permeability was 1.51 times 10−5 cm/sec (range: 1.14‐1.73 times 10−5 cm/sec). We have thus found that the movement of fluorescein across the blood‐retina barrier is highly asymmetric, the outward transport being more than 100 times faster than the passive inward leakage. This could indicate the presence of an active pumping mechanism in the blood‐retina barrier, responsible for fluorescein transport in the direction from the vitreous to the blood.

Lack of correlation between vasodilatation and pharmacologically induced immediate headache in healthy subjects.

Background: The causal relationship between experimental headache and vasodilatation has not been fully clarified. In the present study, we combined headache and vascular data from eight experimental studies and conducted detailed statistical analyses. Given that substances used in all these experiments were vasodilators we examined a possible correlation between headache scores and increases in arterial diameter. Methods: We identified nine studies and retrieved raw data in 89 healthy subjects (46 females, 43 males), mean age 27 years (range 18–59 years). The following variables were collected: maximal median headache intensity scores on a verbal rating scale (VRS) during immediate headache (0–120 minutes); the mean velocity of blood flow in the middle cerebral artery (VmeanMCA); and the diameter of the frontal branch of the superficial temporal artery (STA) during the maximal median headache intensity. Results: The scatter plots show no relationship between maximal headache score and the relative changes in VmeanMCA and diameter of the STA. The main analyses of covariance showed a significant effect only of heart rate on headache (p = .014). The interaction tests were insignificant for all variables. Conclusions: The major outcome is a finding of no linear relationship between experimental immediate headache and dilatation of the MCA or STA.

Differential spectrofluorometry in the human vitreous: blood-retina barrier permeability to fluorescein and fluorescein glucuronide

A method is described for the separate quantitation of fluorescein and fluorescein glucuronide in the vitreous by differential spectrofluorometry. An ocular fluorometer was equppied with monochromatic laser excitation at two rapidly interchangeable wavelengths. The data analysis accounts for absorption of light in the cornea, lens, and extrinsic ocular fluorophores. Examination of seven patients with insulin-dependent diabetes and different degrees of diabetic retinopathy demonstrated that both fluorescein and fluorescein glucuronide enter the eye through the blood-retina barrier. The mean ratio between the permeabilities of fluorescein glucuronide and fluorescein was 0.9 (range, 0.3–1.9). Thus, differences in the molecular size and lipid solubility of the two substances appear to be of little or no importance for their inward penetration of the barrier. No association was found between the relative permeability and the degree of retinopathy.

Fitting Numerical Solutions of Differential Equations to Experimental Data: A Case Study and Some General Remarks

A simple and efficient algorithm for least-squares estimation of the parameters of a numerically solved diffusion model is presented. The algorithm has been specially developed for the analysis of data obtained by vitreous fluorophotometry (a method in clinical eye research), but it has several straightforward generalizations which are also outlined in the paper.

Lens fluorescence in relation to nephropathy in insulin-dependent diabetes mellitus

The relationship between diabetic nephropathy and blue-green lens fluorescence, lens transmittance, and other lens fluorometry parameters was studied in patients with long-term insulin-dependent diabetes mellitus. The findings in 10 patients who presented with diabetic nephropathy were compared with those of 11 patients of comparable age and duration of diabetes but without nephropathy. Diabetic nephropathy was associated with increased lens fluorescence (P=0.04) and decreased lens transmittance (P=0.045). We propose that lens changes may be responsible for various psychophysical abnormalities in diabetic patients and that our results explain the correlation of these abnormalities with the degree of microangiopathy.

A model for determining the effect of mammography service screening.

In an overview, Swedish mammography screening trials demonstrated a 29% reduction in breast cancer mortality in women aged 50–69 and no effect on total mortality. Three Danish regions introduced mammography screening in the 1990s. The authors developed a method to evaluate the effect of mammography service screening on breast cancer mortality and validated it applying it to total mortality, where no effect was expected. Study groups and historical and national control groups were analysed using Poisson regression. Total mortality in the screening regions and periods was close to that expected in the absence of screening. A small (3%) excess risk, also seen in a non-screening area, probably results from regional differences changing over time. The effect of this is inseparable from the screening effect. The design is adequate for analysing the effect of mammography service screening on breast cancer mortality.

Linkage analysis of quantitative trait loci in the presence of heterogeneity

Variance component modeling for linkage analysis of quantitative traits is a powerful tool for detecting and locating genes affecting a trait of interest, but the presence of genetic heterogeneity will decrease the power of a linkage study and may even give biased estimates of the location of the quantitative trait loci. Many complex diseases are believed to be influenced by multiple genes and therefore genetic heterogeneity is likely to be present for many real applications of linkage analysis. We consider a mixture of multivariate normals to model locus heterogeneity by allowing only a proportion of the sampled pedigrees to segregate trait-influencing allele(s) at a specific locus. However, for mixtures of normals the classical asymptotic distribution theory of the maximum likelihood estimates does not hold, so tests of linkage and/or heterogeneity are evaluated using resampling methods. It is shown that allowing for genetic heterogeneity leads to an increase in power to detect linkage. This increase is more prominent when the genetic effect of the locus is small or when the percentage of pedigrees not segregating trait-influencing allele(s) at the locus is high.