virus may be disrupted by predicted climate change. Proc R Soc Lond B Biol Sci 2000; 267: 1741–44. Roggendorf M, Lenz P, Fielder M, Roggendorf H, Kaiser R, Jäger G. Comparison of clinical course of tick-borne encephalitis with and without administration of specific TBE-immunoglobulin. In: Süss J, Kahl O , eds. 4th International Potsdam Symposium on Tick-borne Diseases: tickborne encephalitis and lyme borreliosis. Lengerich, Germany: Pabst Science Publishers, 1997: 144–52.
Authors’ reply Sir—Sarah Randolph challenges our findings that increases in TBE incidence since the mid-1980s in Stockholm County, Sweden, are related to changes in climate during the same period. We hope that such misunderstandings and misinterpretations of the results of our report will be further avoided by the following clarifications. First, the criticism is based on weak historical European data. We used incidence data from Stockholm County, a high TBE endemic area in Sweden, which has a continuing TBE surveillance programme that includes epidemiological data since the late 1950s. All cases of encephalitis admitted in the area have been, when clinically relevant, serologically tested for TBE virus. Epidemiological information has been obtained from confirmed cases. In the rest of Europe, including other parts of Sweden, the registration of TBE cases has been non-existent or inconsistent, or affected by other non-causative factors. TBE data from the early 1940s and 1950s are difficult to compare with later data. During this time, various viral encephalitis, including poliovirus, causing neurological symptoms were flourishing in Sweden and the former Czechoslovakia. Similarities in the clinical picture could have led to overreporting of TBE cases, since the serological methods used at the time (IgM detection was not available) could not distinguish between acute and previous TBE infections, and the latter were frequently subclinical since only one of four TBE infections develop symptoms in the central nervous system. Reanalyses of Swedish national data from 1956 and 1958 showed that only 50% of these cases could be completely confirmed. This type of serological method was used until the mid 1970s in Sweden, but the clinical and epidemiological follow-up of positive TBE cases in our study region made the degree of over-reporting from 1960 to the mid-70s low. Over-reporting of TBE cases from this early part of our study period would, however, further strengthen our results.
Second, the design of our study did enable us to not only look at the direct climatic effects on the tick’s life cycle dynamics, but also to cover indirectly other climate dependent factors of interest for disease transmission, such as host animal availability and human leisure activities. Third, Randolph criticises our graphs. There are different ways of designing the illustrations, but the observations made, and the conclusions, remain unchanged. Remarks based on comparisons of one explanatory variable at a time may be interesting, but since our results show that the combined effects of five explanatory variables during 2-year cycles are accompanied by the variations in TBE incidence, these remarks are not relevant to the results. Finally, our results are in concordance with previous findings showing that the northward spread of ticks in Sweden and the increased tick abundance in Stockholm County during the 1980s and 1990s are related to similar changes in seasonal climatic conditions.1 *Elisabet Lindgren, Rolf Gustafson Natural Resources Management, Department of Systems Ecology, Stockholm University, SE-106 91 Stockholm, Sweden 1
Lindgren E, Tälleklint L, Polfeldt T. Impact of climatic change on the northern latitude limit and population density of the diseasetransmitting European tick, Ixodes ricinus. Environ Health Perspect 2000; 108: 119–23.
Dichlorodiphenylethylene serum concentrations and effect on birthweight Sir—Matthew Longnecker and colleagues (July 14, 2001, p 110)1 note a positive association between maternal serum concentrations of the dichlorodiphenyltrichloroethane (DDT) metabolite, dichlorodiphenylethylene (DDE), and preterm and small-for-gestationalage babies at birth. They conclude that this effect is causal. They suggest several underlying mechanisms: DDE interfering in prostaglandin synthesis, or DDE acting as a placentar (neuro)toxin. I believe, however, that these mechanisms do not sufficiently address the issue of confounding. DDE is a hydrophobic compound, practically insoluble in water and completely soluble in organic solvents.2 Longnecker and colleagues are aware of a binding of DDE to albumin, but reportedly too few samples were analysed to exclude albumin as a Next to potential confounder.1
albumin, DDE can also associate to lipoproteins.3 With colleagues, I have studied distribution of lipophilic vitamins A and E over the lipoproteins, and noted that hydrophobicity of the vitamin and the lipoprotein mass concentration are strong determinants.4 Reportedly, 25% of serum DDE concentration is associated with lipoproteins.3 Consequently, next to albumin, the serum lipoprotein concentrations could also be confounding factors to the above mentioned associations. Accordingly, multivariate analysis including adjustment for plasma lipids resulted in a lower odds ratio. Assessment of the individual plasma lipoprotein concentrations would confirm this positive association more strongly, but the long term storage at ⫺20ºC may induce lipoprotein denaturation, thus complicating DDE analysis. This remains an important question to answer. If true, lifestyle variables are important. The reported positive association between the socioeconomic index and smoking behaviour with the preterm and small-for-gestational-age index is suggestive.1 The principle of a hydrophobic ligand whose serum concentration under chronic intake is determined by the lipoprotein concentration, is examplified by the vitamin E status, which should always be considered in relation to the plasma cholesterol concentration. The same is probably true for other hydrophobic ligands such as nutrients, toxins, and drugs, in as much as their hydrophobicity mainly favours a binding to lipoproteins more than one to albumin. Pierre N M Demacker Laboratory of General Internal Medicine, University Medical Centre Nijmegen, 6500 HB Nijmegen, Netherlands (e-mail: [email protected]
Longnecker MP, Klebanoff MA, Zhou H, Brock JW. Association between maternal serum concentration of the DDT metabolite DDE and preterm and small-for-gestationalage babies at birth. Lancet 2001; 358: 110–14. Budavari S, ed. Merck index: an encyclopedia of chemicals, drugs and biologicals, 11th edn. Rahway, NY, USA: Merck, 1989. Noren K, Weistand C, Karper F. Distribution of PCB congeners, DDE, hexachlorobenzene, and methylsulfunyl metabolities of PCB and DDE among various fractions of human blood plasma. Arch Environ Contam Toxicol 1999; 37: 408–14. Demacker PNM, Hectors MPC, Stalenhoef AFH. Chylomicron processing in familial dysbetalipoproteinemia and familial hyperlipidemia studied with vitamin A and E as markers: a new physiological concept. Atherosclerosis 2000; 149: 169–80.
THE LANCET • Vol 358 • November 17, 2001
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