Variable cartilage degradation in mice with diet-induced metabolic dysfunction: food for thought.

OBJECTIVE: Human cohort studies have demonstrated a role for systemic metabolic dysfunction in osteoarthritis (OA) pathogenesis in obese patients. To explore the mechanisms underlying this metabolic phenotype of OA, we examined cartilage degradation in the knees of mice from different genetic backgrounds in which a metabolic phenotype was established by various dietary approaches. DESIGN: Wild-type C57BL/6J mice and genetically modified mice (hCRP, LDLr-/-. Leiden and ApoE*3Leiden.CETP mice) based on C57BL/6J background were used to investigate the contribution of inflammation and altered lipoprotein handling on diet-induced cartilage degradation. High-caloric diets of different macronutrient composition (i.e., high-carbohydrate or high-fat) were given in regimens of varying duration to induce a metabolic phenotype with aggravated cartilage degradation relative to controls. RESULTS: Metabolic phenotypes were confirmed in all studies as mice developed obesity, hypercholesteremia, glucose intolerance and/or insulin resistance. Aggravated cartilage degradation was only observed in two out of the twelve experimental setups, specifically in long-term studies in male hCRP and female ApoE*3Leiden.CETP mice. C57BL/6J and LDLr-/-. Leiden mice did not develop HFD-induced OA under the conditions studied. Osteophyte formation and synovitis scores showed variable results between studies, but also between strains and gender. CONCLUSIONS: Long-term feeding of high-caloric diets consistently induced a metabolic phenotype in various C57BL/6J (-based) mouse strains. In contrast, the induction of articular cartilage degradation proved variable, which suggests that an additional trigger might be necessary to accelerate diet-induced OA progression. Gender and genetic modifications that result in a humanized pro-inflammatory state (human CRP) or lipoprotein metabolism (human-E3L.CETP) were identified as important contributing factors.

Low serum hyaluronic acid levels associated with spontaneous HBsAg clearance.

PURPOSE: The pathophysiological underlying mechanism of spontaneous HBsAg clearance in hepatitis B virus (HBV) infected patients is largely unknown. However, serum hyaluronic acid (sHA) plays a role in liver fibrosis progression and reversely could serve as a potential biomarker for HBsAg clearance. This study investigates whether low sHA is associated with HBsAg loss in non-Asian HBV patients. METHODS: Non-Asian women living in Amsterdam with known chronic HBV infection between 1990-2003 were invited for a single follow-up visit at the Municipal Health Service Amsterdam between September 2011 to May 2012. Serum hyaluronic acid and liver stiffness measurement together with clinical evaluation, biochemical and virologic blood tests were performed. RESULTS: Of the 160 women, HBsAg loss occurred in 38 (23 %) patients between diagnosis and follow-up. sHA levels were lower in HBsAg negative patients compared to HBsAg positive patients (14.5 [9.4-27.2] ng/mL vs 25.0 [12.3-42.5] ng/mL, p <0.01). A similar distinction in sHA between low and high HBV DNA was noted. sHA had a significant discriminatory ability to differentiate between HBsAg positive and HBsAg negative patients, (AUC 0.65 [95 % CI 0.55-0.75], p < 0.01). In multivariable analysis only sHA level was associated with HBsAg loss (OR 0.4 [0.2-0.9]). Finally, F3-F4 fibrosis (cut-off >8.1 kPa) was diagnosed in 3 % in HBsAg negative patients compared to 10 % in HBsAg positive patients (p = 0.15). CONCLUSION: Serum HA levels are lower in patients who experience spontaneous HBsAg loss compared to HBsAg positive patients.

APOE*3Leiden.CETP transgenic mice as model for pharmaceutical treatment of the metabolic syndrome.

AIMS: This study aimed to investigate systematically (i) the appropriate dietary conditions to induce the features of the MetS in APOE*3Leiden.humanCholesteryl Ester Transfer Protein (E3L.CETP) mice and (ii) whether the response of this model to different antidiabetic and hypolipidemic drugs is similar as in humans. METHODS: Male obese, IR and dyslipidemic E3L.CETP mice were treated with antidiabetic drugs rosiglitazone, liraglutide or an experimental 11ß-hydroxysteroid-dehydrogenase-1 (HSD-1) inhibitor, or with hypolipidemic drugs atorvastatin, fenofibrate or niacin for 4-6 weeks. The effects on bw, IR and plasma and liver lipids were assessed. RESULTS: Rosiglitazone, liraglutide and HSD-1 inhibitor significantly decreased glucose and insulin levels or IR. Liraglutide and HSD-1 inhibitor also decreased bw. Atorvastatin, fenofibrate and niacin improved the dyslipidemia and fenofibrate and niacin increased high-density lipoprotein (HDL) cholesterol. In addition, hepatic triglycerides were significantly decreased by treatment with rosiglitazone and liraglutide, while hepatic cholesterol esters were significantly decreased by rosiglitazone and atorvastatin. CONCLUSIONS: We conclude that the E3L.CETP mouse is a promising novel translational model to investigate the effects of new drugs, alone or in combination, that affect IR, diabetic dyslipidemia and non-alcoholic fatty liver disease (NAFLD).

Rabid puppy-dog imported into the Netherlands from Morocco via Spain, February 2012.

In February 2012 a rabid puppy dog was imported into Amsterdam, the Netherlands from Morocco via Spain. In a joint action between the Netherlands' Food and Consumer Product Safety Authority, the Public Health Service of Amsterdam and the Centre for Infectious Disease Control all exposed human and animal contacts were traced and, when necessary, provided with post-exposure prophylaxis. During the importation, the international legislations with respect to vaccination requirements were not fully obeyed by veterinarians and custom services.

Two cases of mild IgM-negative measles in previously vaccinated adults, the Netherlands, April and July 2011.

We describe two cases of mild, modified measles in fully vaccinated adults in the Netherlands. The mildness of disease, the lack of an IgM antibody response, the relatively low amounts of virus detected and the fact that no additional cases were reported, suggests that these vaccinated patients were less contagious than unvaccinated patients.

Evaluation of a risk assessment questionnaire to assist hepatitis C screening in the general population.

Many individuals with hepatitis C virus (HCV) infection are undiagnosed. This study evaluates a risk assessment questionnaire, developed for use online to target blood-screening for HCV. Two hundred and eighty-nine patients with known HCV status completed a written questionnaire on prominent HCV risk factors. Questionnaires generated advice to seek testing if at least one risk factor was reported. Agreement of the testing advice with the HCV status of respondents was evaluated. Subsequently, we validated our questionnaire among 985 patients of an outpatient clinic for sexually transmitted infections. The post-test-probability-of-disease (PTPD) and diagnostic gain (PTPD minus prior probability of disease) were calculated. The questionnaire's sensitivity and specificity were 84.6% and 63.8%, respectively, and higher in the STI clinic patients. The PTPD of positive testing advice was 72.5% given HCV prevalence of 53.0%, yielding a diagnostic gain of 19.5%. Applying the estimated prevalence in the general Dutch population (0.1-0.4%), and the anticipated prevalence in the online project (1.0-6.0%), yielded diagnostic gains of 0.13-0.53% and 1.3-7.0%, respectively. We conclude that our questionnaire succeeded in selecting at-risk individuals as its testing advice agreed well with the HCV status. We suggest that the questionnaire be used online as a selection tool for HCV blood-screening in the general population.

Leptin deficiency per se dictates body composition and insulin action in ob/ob mice.

Obese humans are often insulin- and leptin resistant. Since leptin can affect glucose metabolism, it is conceivable that a lack of leptin signal transduction contributes to insulin resistance. It remains unclear whether leptin affects glucose metabolism via peripheral and/or central mechanistic routes. In the present study, we aimed: (i) to determine the relative contributions of lack of leptin signal transduction and adiposity to insulin resistance and (ii) to establish the impact of central leptin action on glucose metabolism. To address the first point, ob/ob mice were subjected to severe calorie restriction, so that their body weight became similar to that of wild-type mice. Insulin sensitivity was measured in obese ob/ob, lean (food restricted) ob/ob and lean, weight-matched wild-type mice. To address the second point, leptin (or vehicle) was i.c.v. infused to the lateral cerebral ventricle of ob/ob mice and insulin sensitivity was determined. Hyperinsulinaemic euglyceamic clamps were used to quantify insulin sensitivity. Food restriction barely affected body composition, although it profoundly curtailed body weight. Insulin suppressed hepatic glucose production (HGP) to a greater extent in lean ob/ob than in obese ob/ob mice, but its impact remained considerably less than in wild-type mice (% suppression: 11.8 +/- 8.9 versus 1.3 +/- 1.1 versus 56.6 +/- 13.0%/nmol, for lean, obese ob/ob and wild-type mice, respectively; P < 0.05). The insulin-mediated glucose disposal (GD) of lean ob/ob mice was also in between that of obese ob/ob and wild-type mice (37.5 +/- 21.4 versus 25.1 +/- 14.6 versus 59.6 +/- 17.3 mumol/min/kg/nmol of insulin, respectively; P < 0.05 wild-type versus obese ob/ob mice). Leptin infusion acutely enhanced both hepatic insulin sensitivity (insulin-induced inhibition of HGP) and insulin-mediated GD (9.1 +/- 2.4 versus 5.0 +/- 2.7%/nmol of insulin, and 25.6 +/- 5.6 versus 13.6 +/- 4.8 mumol/min/kg/nmol of insulin, respectively; P < 0.05 for both comparisons) in ob/ob mice. Both a lack of leptin signals and adiposity may contribute to insulin resistance in obese individuals. Diminution of central leptin signalling can critically affect glucose metabolism in these individuals.

Gut-brain axis: regulation of glucose metabolism.

Obesity and type II diabetes mellitus have reached epidemic proportions. From this perspective, knowledge about the regulation of satiety and food intake is more important than ever. The gut releases several peptides upon feeding, which affect hypothalamic pathways involved in the regulation of satiety and metabolism. Within the hypothalamus, there are complex interactions between many nuclei of which the arcuate nucleus is considered as one of the most important hypothalamic centres that regulates food intake. The neuropeptides, which are present in the hypothalamus and are involved in regulating food intake, also play a key role in regulating glucose metabolism and energy expenditure. In synchrony with the effects of those neuropeptides, gastrointestinal hormones also affect glucose metabolism and energy expenditure. In this review, the effects of the gastrointestinal hormones ghrelin, cholecystokinin, peptide YY, glucagon-like peptide, oxyntomodulin and gastric inhibitory polypeptide on glucose and energy metabolism are reviewed. These gut hormones affect glucose metabolism at different levels: by altering food intake and body weight, and thereby insulin sensitivity; by affecting gastric delay and gut motility, and thereby meal-related fluctuations in glucose levels; by affecting insulin secretion, and thereby plasma glucose levels, and by affecting tissue specific insulin sensitivity of glucose metabolism. These observations point to the notion of a major role of the gut-brain axis in the integrative physiology of whole body fuel metabolism.

Ghrelin differentially affects hepatic and peripheral insulin sensitivity in mice.

AIMS/HYPOTHESIS: This study was conducted to evaluate the effects of ghrelin on insulin's capacity to suppress endogenous glucose production and promote glucose disposal in mice. To establish whether the growth hormone secretagogue (GHS) receptor can mediate the putative effect of ghrelin on the action of insulin, we also determined the metabolic effects of growth hormone releasing peptide 6 (GHRP-6), a specific GHS receptor agonist. In addition, we explored the biological significance of des-ghrelin (unacylated ghrelin) in this experimental context. MATERIALS AND METHODS: Vehicle (n=8), ghrelin (n=9), GHRP-6 (n=9), des-ghrelin (n=8) or a combination of des-ghrelin and ghrelin (n=7) were infused i.v. for 3 h. Simultaneously, endogenous glucose production and glucose disposal were measured by (14)C-glucose dilution during a hyperinsulinaemic-euglycaemic clamp. Tissue-specific glucose uptake in muscle and adipose tissue was measured using (3)H-2-deoxyglucose. RESULTS: During hyperinsulinaemia, glucose disposal was 31% higher in mice treated with ghrelin than in those treated with vehicle (77+/-16 and 59+/-8 micromol kg(-1) h(-1), respectively, p<0.05). This was in accordance with enhanced 2-deoxyglucose uptake in muscle in ghrelin-treated animals. In contrast, endogenous glucose production was less effectively suppressed by insulin during ghrelin infusion (46+/-22 vs 71+/-11% in controls, p<0.05). GHRP-6 did not affect insulin action. Des-ghrelin hampered insulin's capacity to inhibit endogenous glucose production, whereas it did not affect glucose disposal. The restraining effects of des-ghrelin and ghrelin on hepatic insulin action were abolished by simultaneous administration of both peptides. CONCLUSIONS/INTERPRETATION: Ghrelin hampers insulin's capacity to suppress endogenous glucose production, whereas it reinforces the action of insulin on glucose disposal, independently of food intake and body weight. These metabolic effects are unlikely to be mediated by the GHS receptor. Furthermore, simultaneous administration of des-ghrelin abolishes the inhibitory effect of ghrelin on hepatic insulin action.

Sexual risk behaviour among Surinamese and Antillean migrants travelling to their countries of origin.

OBJECTIVES: To examine travel related sexual risk behaviour among migrants living in Amsterdam. METHODS: People originating from Surinam (n = 798) and the Netherlands Antilles (n = 227) were recruited in order to study the heterosexual spread of HIV within ethnic groups. Log binomial regression was used to study determinants for homeland travel over the past 5 years; logistic regression was used to study determinants of unprotected sex on these visits. RESULTS: Of the migrants, 38% of men and 42% of women visited their homeland. Visits were most likely among men who had lived > or =7 years in the Netherlands, were employed, had a high educational level and were/had been married. For women, visiting was associated with older age and living in the Netherlands for > or =8 years. Of migrants visiting their homeland, 47% of men and 11% of women acquired a local sexual partner. For male travellers, Surinamese origin (adjusted OR 10.66; 95% CI 1.72 to 104.48) and a history of > or =1 sexually transmitted infection (STI) (adjusted OR 12.51; 95% CI 3.75 to 46.95) were associated with having unprotected sex with local partners. For women, having >1 partner in the past 5 years (OR 13.57; 95% CI 2.57 to 250.28) was associated with unprotected sex with local partners. CONCLUSION: Migrants are at substantial risk for HIV and STIs while visiting their homeland. It is important to reach migrants, who are likely to engage in unprotected sex during visits, for pretravel health education. Additional research on risk behaviour in the homeland and the Netherlands is needed to identify migrants with high risk behaviour.

Intracerebroventricular administration of melanotan II increases insulin sensitivity of glucose disposal in mice.

AIMS/HYPOTHESIS: The present study was conducted to evaluate the effects of central administration of melanotan II (MTII), a melanocortin-3/4 receptor agonist, on hepatic and whole-body insulin sensitivity, independent of food intake and body weight. METHODS: Over a period of 24 h, 225 ng of MTII was injected in three aliquots into the left lateral ventricle of male C57Bl/6 mice. The animals had no access to food. The control group received three injections of distilled water. Whole-body and hepatic insulin sensitivity were measured by hyperinsulinaemic-euglycaemic clamp in combination with [(3)H]glucose infusion. Glut4 mRNA expression was measured in skeletal muscle. RESULTS: Plasma glucose and insulin concentrations under basal and hyperinsulinaemic conditions were similar in MTII- and placebo-treated mice. Endogenous glucose production (EGP) and glucose disposal in the basal state were significantly higher in MTII-treated mice than in the control group (71+/-22 vs 43+/-12 micromol.min(-1).kg(-1), p<0.01). During hyperinsulinaemia, glucose disposal was significantly higher in MTII-treated mice (151+/-20 vs 108+/-20 micromol.min(-1).kg(-1), p<0.01). In contrast, the inhibitory effect of insulin on EGP was not affected by MTII (relative decrease in EGP: 45+/-27 vs 50+/-20%). Glut4 mRNA expression in skeletal muscle was significantly increased in MTII-treated mice (307+/-94 vs 100+/-56%, p<0.01). CONCLUSIONS/INTERPRETATION: Intracerebroventricular administration of MTII acutely increases insulin-mediated glucose disposal but does not affect the capacity of insulin to suppress EGP in C57Bl/6 mice. These data indicate that central stimulation of melanocortin-3/4 receptors modulates insulin sensitivity in a tissue-specific manner, independent of its well-known impact on feeding and body weight.

Decreasing STD incidence and increasing condom use among Chinese sex workers following a short term intervention: a prospective cohort study.

OBJECTIVE: To describe the impact of a repeating behavioural intervention focused on preventive education and provision of STD testing and treatment services to female sex workers. METHODS: A prospective cohort study of 966 sex workers (first of its kind in China) was conducted in Guangzhou from March 1998 to October 1999. At each visit information was collected on sexual behaviour, condom use and knowledge about HIV transmission and condom use, education was given, STD were diagnosed, and treatment was provided free of charge. We evaluated trends in condom use, knowledge about HIV transmission and condom use, and STD incidences. Generalised estimating equations were applied to control for repeated measurements. RESULTS: The proportion of consistent condom use increased from the intake through the third follow up visit (from 30% to 81%), as well as the proportion of having good knowledge on HIV transmission (4.3% to 98.6%) and condom use (23.6% to 79.3%). The incidence of gonorrhoea, trichomoniasis, and chlamydia decreased over each follow up visit; from 17.5/100 person years (PY), 22.4/100PY, 65.9/100PY at the first follow up visit to 5.1/100PY, 3.0/100PY, 16.1/100PY at the third follow up visit, for each STD respectively. CONCLUSIONS: STD care and prevention programmes targeting sex workers are feasible in China and, more importantly, intervention consisting of prevention education and STD care is likely to reduce unprotected sexual behaviour and STD incidence in this group at high risk for HIV and other STD infection.

Determinants of high-risk sexual behavior among immigrant groups in Amsterdam: implications for interventions.

OBJECTIVES: To determine predictors for sexual risk behavior among immigrant men in Amsterdam. METHODS: From May 1997 to July 1998, 650 men from Surinam, the Antilles, and Ghana were recruited by convenience sampling. Multivariate logistic regression was used to find independent predictors for 1) multiple sex partners (>sexual 1 partner in the past year), 2) unprotected sex with casual partners in The Netherlands, 3) sexual activity in country of origin, and 4) unprotected sex in country of origin. RESULTS: 1) Multiple sex partners were reported by 50% of respondents. Independent predictors were a recent infection with a sexually transmitted disease (STD), youth, low educational level, Afro-Surinamese origin, lack of a long-term relationship and history of commercial sex contact. 2) Unprotected sex occurred in 24% of casual partnerships. Independent predictors were a recent STD infection, low educational level, use of hard drugs, age between 20 and 29, few sexual partners, unprotected sex in country of origin, and a partner from the respondent's ethnic group. 3) During the past 5 years, 24% were sexually active in country of origin. Independent predictors were Ghanaian origin, age over 20, a relatively high income, and multiple partners. 4) Unprotected sex occurred in 39% of the partnerships in country of origin. Independent predictors were low educational level, history of STDs, lack of health insurance, Ghanaian origin, frequent visits to home country, few sexual partners, and unprotected sex with casual partners in The Netherlands. CONCLUSION: Among immigrant men in Holland, important target groups for AIDS prevention programs have been identified. Men who visit their country of origin should be made aware of the risk of sexual contact with local women. Furthermore, it should be taken into account that immigrant men use condoms less frequently with women of their own ethnic group than with Dutch women.

High prevalence of syphilis and other sexually transmitted diseases among sex workers in China: potential for fast spread of HIV.

OBJECTIVES: In China, in the early 1980s, sexually transmitted diseases (STD) started to increase steeply. Sex workers and their clients appeared to play an important role in the spread of STD. Prostitution is illegal in China, and therefore no specific services exist for sex workers unless they are arrested and detained in re-education centres. Staff of a maternal and neonatal hospital in Guangzhou felt the need for an STD care and prevention programme for sex workers outside detention, and started a programme within their hospital, which was unique in the Chinese context. METHODS: From March 1998 to mid-October 1999 sex workers were recruited through various outreach methods, and were interviewed, counselled and examined for the presence of STD/HIV. RESULTS: A total of 966 women, originating from all over China but working in Guangzhou, entered the programme. The median duration of prostitution was one year, and the median number of clients was seven per week. Antibodies to HIV were present in 1.4%. The prevalence of STD was very high: syphilis 14%, Chlamydia trachomatis 32%, gonorrhoea 8% and trichomoniasis 12.5%. Knowledge about STD/HIV transmission and condom use was poor. CONCLUSION: Given the high prevalence of STD, the potential for the further spread of HIV is clearly present. STD care and prevention programmes for these women, outside detention, are urgently needed, and appear also to be feasible in China.

Comparative model-based analysis of screening programs for Chlamydia trachomatis infections.

The design of a screening program for asymptomatic genital infections with Chlamydia trachomatis, requires decisions about which sex or age group should be targeted and whether partner referral should be included in the program. To investigate the effects of various screening programs on the prevalence and incidence of asymptomatic C. trachomatis infections in women, in May 1996 to April 1997 in Bilthoven, the Netherlands, the authors used a stochastic simulation model for C. trachomatis transmission in an age-structured, heterosexual population with a sexually highly active core group. Different screening scenarios were implemented over a time period of 10 years. Prevalence, incidence, and the fraction of infected persons found by partner referral were computed. Through screening of men and women between ages 15 and 24 years (baseline scenario), the prevalence of asymptomatic infections in women could be reduced from 4.2% to 1.4% in 10 years. Increasing the age range of screening up to ages 29 or 34 years led to prevalences of 0.4% and 0.06%, respectively, after 10 years. About 28% of all infected persons were found via partner referral. There are considerable indirect positive effects of screening on those population groups that are not included in the screening because of the reduced risk of becoming infected. Partner referral contributes substantially to prevalence reduction.

Pregnancies before and after HIV diagnosis in a european cohort of HIV-infected women. European Study on the Natural History of HIV Infection in Women.

OBJECTIVES: Because most HIV-infected women are of reproductive age, we investigated whether their reproduction planning was affected by their HIV diagnosis. DESIGN: The European women study is a prospective, multicentre cohort of 485 HIV-infected women with a known interval of seroconversion. METHODS: The incidence of pregnancy was measured with person-time methods. Generalized estimating equation analysis was used to determine risk factors for pregnancy and pregnancy outcomes. RESULTS: In 449 women, the age-adjusted incidence of pregnancies decreased from 8.6 before HIV diagnosis to 8.2 and 6.0 per 100 person-years in 0-4 and over 4 years after HIV diagnosis, respectively (P = 0.14). The proportion of induced abortions increased from 42% before to 53% after HIV diagnosis (P < 0.05). The risk of spontaneous abortion did not increase as a result of HIV infection. Since 1995, the proportion of births increased (P = 0.009), whereas that of induced abortions decreased (P = 0.01) compared with earlier years. An increased risk of pregnancy after HIV diagnosis was found in northern and central European women compared with southern European women; there was a lower risk in single women than in women with a steady partner. Of all pregnant women, single women, women between 15 and 25 years of age, and women with multiple partners were at increased risk for induced abortion both before and after HIV diagnosis. CONCLUSION: The incidence of pregnancy decreased with HIV disease progression. Pregnancies after HIV diagnosis appear to be related largely to social and cultural attitudes. The number of induced abortions was high before HIV diagnosis and it significantly increases thereafter.

Cost-effectiveness of screening programs for Chlamydia trachomatis: a population-based dynamic approach.

BACKGROUND: Models commonly used for the economic assessment of chlamydial screening programs do not consider population effects. GOAL: To develop a novel dynamic approach for the economic evaluation of chlamydial prevention measures and to determine the cost-effectiveness of a general practitioner-based screening program. STUDY DESIGN: The dynamic approach was used to estimate the cost-effectiveness of a screening program for the first 10 years of screening in The Netherlands. Screening involved a ligase chain reaction test on urine followed by standardized therapies and partner referral. Eligible persons were sexually active, 15 to 24 years, visited a general practitioner, and had no symptoms of sexually transmitted diseases. The heterosexual model population, which consisted of persons 15 to 64 years, had a total chlamydial prevalence of 4.1% before screening. Screening effects on chlamydial incidence were computed by using a population-based stochastic simulation model. Incidence data were connected with a decision analysis model to determine the health effects of the program. The net costs of the program were calculated (investment costs minus averted costs, in 1997 US$) from a societal perspective and expressed per major outcome averted (symptomatic pelvic inflammatory disease, chronic pelvic pain, ectopic pregnancy, infertility, neonatal pneumonia). RESULTS: Unlike the standard static approach, our model adequately addresses dynamic processes such as chlamydial transmission and the impact of screening programs on chlamydial incidence in the population. During the first 10 years of screening, the investigated program yields savings of US $492 or US $1,086 per major outcome averted, excluding or including indirect costs, respectively. These results depend on chlamydial prevalence and partner referral. CONCLUSIONS: The cost-effectiveness of chlamydial screening programs seems best to be determined by using dynamic modeling on a population basis. In addition to preventing negative health outcomes, the investigated screening program may save costs.

Cervical squamous intraepithelial lesions in HIV-infected women: prevalence, incidence and regression. European Study Group on Natural History of HIV Infection in Women.

OBJECTIVES: To assess the impact of HIV-related immunodeficiency and antiretroviral treatment on the occurrence and evolution of abnormal Papanicolaou tests. STUDY DESIGN: Cohort of 485 HIV-infected women with a known date of infection, enrolled during May 1993-April 1998 in 23 centres (gynaecology, infectious disease or STD clinics, or drug treatment centres) in 12 European countries; in 21 centres, follow-up was performed every 6 months (median follow-up: 2 years). METHODS: Human papillomavirus (HPV) was detected at inclusion by Southern blot and PCR. The prevalence of squamous intraepithelial lesions (SIL), the incidence of SIL and regression from low-grade SIL were studied according to CD4 count after controlling for HPV detection results. RESULTS: Compared with women with CD4 cell counts > 500 x 10(6)/l, women with CD4 cell counts < 200 x 10(6)/l had a twofold increase in both prevalence and incidence of SIL and in non-regression from untreated low-grade SIL; in addition, these women had a lower response rate to treatment of high-grade cervical intraepithelial neoplasia. The increase in SIL incidence associated with a low CD4 cell count was significant in women not receiving antiretroviral treatment (relative risk, CD4 cell count 200-499 x 10(6)/l, 1.9; CD4 cell count < 200 x 10(6)/l, 2.9; CD4 cell count > 500 x 10(6)/l, reference), whereas it was less marked and not statistically significant in treated women. CONCLUSIONS: Severe HIV-related immunodeficiency strongly increases the risk of occurrence of SIL; antiretroviral treatment may reduce this risk, probably by restoring or at least preserving immune function.