Garssen, J.

Sharp upturn of life expectancy in the Netherlands: effect of more health care for the elderly? (Article)

2011-11-29T00:00:00Z

During the 1980s and 1990s life expectancy at birth has risen only slowly in the Netherlands. In 2002, however, the rise in life expectancy suddenly accelerated. We studied the possible causes of this remarkable development. Mortality data by age, gender and cause of death were analyzed using life table methods and age-period-cohort modeling. Trends in determinants of mortality (including health care delivery) were compared with trends in mortality. Two-thirds of the increase in life expectancy at birth since 2002 were due to declines in mortality among those aged 65 and over. Declines in mortality reflected a period rather than a cohort effect, and were seen for a wide range of causes of death. Favorable changes in mortality determinants coinciding with the acceleration of mortality decline were mainly seen within the health care system. Health care expenditure rose rapidly after 2001, and was accompanied by a sharp rise of specialist visits, drug prescriptions, hospital admissions and surgical procedures among the elderly. A decline of deaths following non-treatment decisions suggests a change towards more active treatment of elderly patients. Our findings are consistent with the idea that the sharp upturn of life expectancy in the Netherlands was at least partly due to a sharp increase in health care for the elderly, and has been facilitated by a relaxation of budgetary constraints in the health care system.

Non-digestible oligosaccharides reduce immunoglobulin free light-chain concentrations in infants at risk for allergy (Article)

2011-08-01T00:00:00Z

Prebiotic oligosaccharides influence the intestinal microbiota and can positively modulate the infant's immune system. It was demonstrated that a special prebiotic mixture (Immunofortis®) of short-chain galacto-oligosaccharides (scGOS) and long-chain fructo-oligosaccharides (lcFOS) can reduce the cumulative incidence of atopic dermatitis (AD) in infants at risk for allergy as determined using the AD symptom score (SCORAD). Additionally, it was shown very recently that immunoglobulin free light-chain (Ig-fLC) might be involved in the pathophysiology of allergic disease. Increased Ig-fLC concentrations were found in patients suffering from AD, cow's milk allergy, allergic rhinitis, or asthma. In this study, the effect of supplementation of scGOS/lcFOS on the Ig-fLC plasma concentrations in infants at risk for allergy was assessed. The plasma kappa and lambda Ig-fLC concentrations were measured in a double-blind, placebo-controlled, randomized trial, in which infants at risk for developing allergic disease received a hypoallergenic whey formula containing 8g/l of the scGOS/lcFOS mixture (n=34) or maltodextrin as a placebo (n=40) for 6months. After intervention, plasma samples were collected, and total plasma concentrations of lambda and kappa Ig-fLC were analyzed using ELISA. Total kappa and lambda Ig-fLC plasma concentrations were higher in infants suffering from AD when compared to infants without any sign of AD. In infants receiving the prebiotic mixture, the Ig-fLC levels were significantly lower compared to the placebo-fed infants (p<0.001). Interestingly, lambda Ig-fLC concentrations were positively correlated with total IgE (p<0.05). These data demonstrate for the first time that the specific scGOS/lcFOS mixture lowered kappa and lambda Ig-fLC plasma concentrations in infants at high risk for allergies when compared to infants receiving placebo formula. Because Ig-fLC concentrations were increased in infants suffering from AD, this may have contributed, at least in part, to the reduced incidence in AD as described previously. This suggests a possible role for Ig-fLC in the pathophysiology of AD in infants at risk for allergy development.

Contribution of IgE and immunoglobulin free light chain in the allergic reaction to cow's milk proteins (Article)

2010-06-01T00:00:00Z

Background: Cow's milk allergy (CMA) affects 2.5% of young infants. In previous murine studies it was observed that allergic sensitization to the major cow's milk allergens casein and whey led, respectively, to IgE-independent and IgE-dependent clinical responses. Objectives: In this study the involvement of immunoglobulin free light chains (Ig-fLCs) in the hypersensitivity response to cow's milk proteins was explored in mice, and Ig-fLC serum levels were determined in children affected by CMA or atopic dermatitis (AD). Methods: Mice were orally sham, casein, or whey sensitized. Acute allergen-specific skin responses were determined, and serum immunoglobulin and Ig-fLC concentrations were measured. Ig-fLC dependency was validated by using the Ig-fLC blocker F991 in actively and passively sensitized mice. Ig-fLC serum concentrations were measured in a cohort of infants with CMA and infants with AD. Results: After sensitization, no specific IgE was detectable in sera of casein-sensitized mice, whereas specific IgE levels were enhanced in whey-sensitized mice. Instead, Ig-fLC levels were increased in sera from casein-sensitized mice. Furthermore, blocking Ig-fLCs strongly diminished the allergic skin responses not only in casein-sensitized mice but also in mice transferred with splenocyte supernatants of casein-sensitized mice. In both patients with CMA and patients with AD, serum Ig-fLC concentrations were significantly enhanced. Conclusions: This study indicates that sensitization with cow's milk proteins can lead to both IgE-dependent and Ig-fLC-dependent allergic hypersensitivity responses. Also, in children affected with CMA or AD, serum Ig-fLC concentrations were increased, implying the relevance of Ig-fLC measurements in the diagnoses of human allergic disease.

Cyclooxygenase-2 in mucosal DC mediates induction of regulatory T cells in the intestine through suppression of IL-4 (Article)

2009-05-07T00:00:00Z

Oral intake of protein leads to tolerance through the induction of regulatory T cells (Tr cells) in mesenteric lymph nodes (MLNs). Here we show that the inhibition of cyclooxygenase-2 (COX-2) in vivo suppressed oral tolerance and was associated with enhanced differentiation of interleukin (IL)-4-producing T cells and reduced Foxp3+Tr-cell differentiation in MLN. As a result, the functional suppressive capacity of these differentiated mucosal T cells was lost. IL-4 was causally related to loss of tolerance as treatment of mice with anti-IL-4 antibodies during COX-2 inhibition restored tolerance. Dendritic cells (DCs) in the MLN differentially expressed COX-2 and reductionist experiments revealed that selective inhibition of the enzyme in these cells inhibited Foxp3+Tr-cell differentiation in vitro. Importantly, the inhibition of COX-2 in MLN-DC caused increased GATA-3 expression and enhanced IL-4 release by T cells, which was directly related to impaired Tr-cell differentiation. These data provide crucial insights into the mechanisms driving de novo Tr-cell induction and tolerance in the intestine.

A specific mixture of short-chain galacto-oligosaccharides and long-chain fructo-oligosaccharides induces a beneficial immunoglobulin profile in infants at high risk for allergy (Article)

2009-03-01T00:00:00Z

Background: It has been suggested that human breast milk oligosaccharides play a role in the development of the immune system in infants, and may consequently inhibit the onset of allergy. A specific prebiotic mixture of short-chain galacto-oligosaccharides and long-chain fructo-oligosaccharides (GOS/FOS) has been shown to reduce the incidence of atopic dermatitis (AD) at 6 months of age in infants at risk for allergy. Aim of the study: This study was aimed to analyze the effect of GOS/FOS on the immune response in these infants. Methods: In a double-blind randomized placebo-controlled study, infants received a hypoallergenic whey formula with either 8 g/l GOS/FOS in a 9 : 1 ratio (IMMUNOFORTIS™) or 8 g/l maltodextrine (placebo) for 6 months. At 3 months of age, children were vaccinated with Hexavac against a.o. diphteria, tetanus, polio (DTP). At 6 months of age, plasma samples were collected from 84 infants (verum group n = 41, placebo group n = 43). Levels of total immunoglobulins (Ig) and of cow's milk protein (CMP-) and DTP-specific Ig were measured. Results: GOS/FOS supplementation led to a significant reduction in the plasma level of total IgE, IgG1, IgG2 and IgG3, whereas no effect on IgG4 was observed. CMP-specific IgG1 was significantly decreased. DTP-specific Ig levels were not affected. Conclusions: This study shows that GOS/FOS supplementation induces a beneficial antibody profile. GOS/FOS reduces the total Ig response and modulates the immune response towards CMP, while leaving the response to vaccination intact. This suggests that oral GOS/FOS supplementation is a safe method to restrain the atopic march.

Duration of residence was not consistently related to immigrant mortality (Article)

2007-06-01T00:00:00Z

Objective: This paper aimed to examine immigrant mortality according to duration of residence in the Netherlands and to compare duration-specific mortality levels to levels of mortality in the native Dutch population. Study Design and Setting: For the years 1995-2000, we linked the national cause of death register, that contains information on deaths of legal residents, to the municipal population register, that contains information on all legal residents. We studied mortality in relation to period of immigration by means of directly standardized mortality rates and Poisson regression. Results: All cause mortality was not related to year of immigration among Turkish and Moroccan men and women, and among Surinamese women. Among Surinamese men and among Antilleans/Aruban men and women, mortality was higher in more recent immigrants. Part of their excess mortality was due to their relatively low socioeconomic status. For most specific causes of death, no consistent relation with duration of residence was observed. Conclusion: A consistent relation between duration of residence and immigrant mortality was only observed in some immigrant groups. The results suggest that the healthy migrant effect or adaptation of health-related behaviors were no predominant determinants of immigrant mortality in the Netherlands.

Socioeconomic inequalities in mortality within ethnic groups in the Netherlands, 1995-2000 (Article)

2005-01-01T00:00:00Z

STUDY OBJECTIVE: To analyse socioeconomic inequalities in mortality in Dutch, Turkish, Moroccans, Surinamese, and Antillean/Aruban men and women living in the Netherlands and to assess the contribution of specific causes of death to these inequalities. DESIGN: Open cohort design using data from the Municipal Population Registers and cause of death registry. SETTING: the Netherlands from 1995 through 2000. PARTICIPANTS: All inhabitants of the Netherlands. MAIN OUTCOME MEASURES: This study calculated directly standardised mortality rates by mean neighbourhood income and estimated relative mortality ratios comparing the two lowest socioeconomic groups with the two highest socioeconomic groups for all and cause specific mortality by country of origin and sex. MAIN RESULTS: Socioeconomic differences in total mortality were comparatively large in Dutch, (RR = 1.49, CI = 1.46 to 1.52), Surinamese (1.32, 1.19 to 1.46), and Antillean/Aruban men (1.56, 1.29 to 1.89) and in Dutch (1.39, 135 to 1.42) and Surinamese women (1.27, 1.11 to 1.46). They were comparatively small among Turkish (1.10, 0.99 to 1.23) and Moroccan men (1.10, 0.97 to 1.26) and among Turkish (1.13, 0.97 to 1.33), Moroccan (1.12, 0.93 to 1.35) and Antillean/Aruban women (1.03, 0.80 to 1.33). The mortality differences among the Dutch were partly attributable to inequalities in mortality from cardiovascular diseases, whereas among Antillean/Aruban men external causes strongly contributed to the mortality differences. The small differences among Turkish and Moroccan men were due to a lack of inequalities for cardiovascular diseases and small inequalities for the other causes. CONCLUSIONS: The impact of socioeconomic status on mortality differed between ethnic groups living in the Netherlands. Maintaining small socioeconomic inequalities in mortality among Turkish and Moroccans men and women and among Antillean/Aruban women could prevent future increases in overall mortality in these groups.

Ethnic inequalities in age- and cause-specific mortality in The Netherlands. (Article)

2004-10-01T00:00:00Z

BACKGROUND: By describing ethnic differences in age- and cause-specific mortality in The Netherlands we aim to identify factors that determine whether ethnic minority groups have higher or lower mortality than the native population of the host country. METHODS: We used data for 1995-2000 from the municipal population registers and cause of death registry. All inhabitants of The Netherlands were included in the study. The mortality of people who themselves or whose parent(s) were born in Turkey, Morocco, Surinam, or the Dutch Antilles/Aruba was compared with that of the native Dutch population. Mortality differences were estimated by Poisson regression analyses and by directly standardized mortality rates. RESULTS: Compared with native Dutch men, mortality was higher among Turkish (relative risk [RR] = 1.21, 95% CI: 1.16, 1.26), Surinamese (RR = 1.24, 95% CI: 1.19, 1.29), and Antillean/Aruban (RR = 1.25, 95% CI: 1.15, 1.36) males, and lower among Moroccan males (RR = 0.85, 95% CI: 0.81, 0.90). Among females, inequalities in mortality were small. In general, mortality differences were influenced by socio-economic and marital status. Most minority groups had a high mortality at young ages and low mortality at older ages, a high mortality from ill-defined conditions (which is related to mortality abroad) and external causes, and a low mortality from neoplasms. Cardiovascular disease mortality was low among Moroccan males (RR = 0.51, 95% CI: 0.44, 0.59) and high among Surinamese males (RR = 1.13, 95% CI: 1.05, 1.21) and females (RR = 1.14, 95% CI: 1.06, 1.23). Homicide mortality was elevated in all groups. CONCLUSION: Socio-economic factors and marital status were important determinants of ethnic inequalities in mortality in The Netherlands. Mortality from cardiovascular diseases, homicide, and mortality abroad were of particular importance for shifting the balance from high towards low all-cause mortality.

Association of transcription-coupled repair but not global genome repair with ultraviolet-B-induced Langerhans cell depletion and local immunosuppression. (Article)

2003-10-01T00:00:00Z

Exposure to ultraviolet-B radiation impairs cellular immune responses. This immunosuppression seems to be associated with Langerhans cell migration. DNA damage appears to play a key role because enhanced nucleotide excision repair, a pathway essential for elimination of ultraviolet-B-induced DNA lesions, strongly counteracts immunosuppression. To determine the effect of DNA repair on ultraviolet-B-induced local immunosuppression and Langerhans cell disappearance, three mouse strains carrying different defects in nucleotide excision repair were compared. XPC mice, which were defective in global genome repair, were as sensitive to ultraviolet-B-induced local suppression of contact hypersensitivity to picryl chloride as their wild-type littermates. CSB mice, defective in transcription-coupled repair, were far more sensitive for immunosuppression as were XPA mice, defective in both transcription-coupled repair and global genome repair. Only a moderate depletion of Langerhans cells was observed in XPC mice and wild-type littermates. Ultraviolet-B-induced Langerhans cell depletion was enhanced in CSB and XPA mice. Hence, the major conclusion is that local immunosuppression is only affected when transcription-coupled DNA repair is impaired. Furthermore, a defect in transcription-coupled repair was linked to enhanced ultraviolet-B-induced Langerhans cell depletion. In combination with earlier experiments, it can be concluded that Langerhans cell disappearance is related to ultraviolet-B-induced local but not to systemic immunosuppression.

Transcription-coupled and global genome repair differentially influence Ultraviolet-B induced acute skin effects and systemic immunosuppression (Article)

2000-01-01T00:00:00Z

Exposure to UV-B radiation impairs immune responses in mammals by inhibiting especially Th1-mediated contact hypersensitivity and delayed-type hypersensitivity. Immunomodulation is not restricted to the exposed skin, but is also observed at distant sites, indicating the existence of mediating factors such as products from exposed skin cells or photoactivated factors present in the superficial layers. DNA damage appears to play a key role, because enhanced nucleotide excision repair (NER) strongly counteracts immunosuppression. To determine the effects of the type and genomic location of UV-induced DNA damage on immunosuppression and acute skin reactions (edema and erythema) four congenic mouse strains carrying different defects in NER were compared: CSB and XPC mice lacking transcription-coupled or global genome NER, respectively, as well as XPA and TTD/XPD mice carrying complete or partial defects in both NER subpathways, respectively. The major conclusions are that 1) transcription-coupled DNA repair is the dominant determinant in protection against acute skin effects; 2) systemic immunomodulation is only affected when both NER subpathways are compromised; and 3) sunburn is not related to UV-B-induced immunosuppression.

Transcription-coupled and global genome repair differentially influence UV-B-induced acute skin effects and systemic immunosuppression (Article)

2000-01-01T00:00:00Z

Mouse model for the DNA repair/basal transcription disorder Trichothiodystrophy reveals cancer predisposition. (Article)

1999-01-01T00:00:00Z

Patients with the nucleotide excision repair (NER) disorder xeroderma pigmentosum (XP) are highly predisposed to develop sunlight-induced skin cancer, in remarkable contrast to photosensitive NER-deficient trichothiodystrophy (TTD) patients carrying mutations in the same XPD gene. XPD encodes a helicase subunit of the dually functional DNA repair/basal transcription complex TFIIH. The pleiotropic disease phenotype is hypothesized to be, in part, derived from a repair defect causing UV sensitivity and, in part, from a subtle, viable basal transcription deficiency accounting for the cutaneous, developmental, and the typical brittle hair features of TTD. To understand the relationship between deficient NER and tumor susceptibility, we used a mouse model for TTD that mimics an XPD point mutation of a TTD patient in the mouse germline. Like the fibroblasts from the patient, mouse cells exhibit a partial NER defect, evident from the reduced UV-induced DNA repair synthesis (residual repair capacity approximately 25%), limited recovery of RNA synthesis after UV exposure, and a relatively mild hypersensitivity to cell killing by UV or 7,12-dimethylbenz[a]anthracene. In accordance with the cellular studies, TTD mice exhibit a modestly increased sensitivity to UV-induced inflammation and hyperplasia of the skin. In striking contrast to the human syndrome, TTD mice manifest a dear susceptibility to UV- and 7,12-dimethylbenz[a]anthracene-induced skin carcinogenesis, albeit not as pronounced as the totally NER-deficient XPA mice. These findings open up the possibility that TTD is associated with a so far unnoticed cancer predisposition and support the notion that a NER deficiency enhances cancer susceptibility. These findings have important implications for the etiology of the human disorder and for the impact of NER on carcinogenesis.

Mouse model for the DNA repair/basal transcription disorder trichothiodystrophy reveals cancer predisposition (Article)

1999-01-01T00:00:00Z

A rat cytomegalovirus infection model as a tool for immunotoxicity testing. (Article)

1995-03-22T00:00:00Z

A rat cytomegalovirus infection model for use in immunotoxicity testing has been developed. In resistance against viruses, natural killer cells and cytotoxic T-cells play an important role. Therefore, this model complements other rat host resistance models for immunotoxicity testing, i.e. existing bacterial and parasitic infection models in which cytotoxic T-cells and natural killer cells play a minor role. Host resistance against cytomegalovirus infections in the rat was determined by titrating infectious virus levels in organs after cytomegalovirus infection in an in vitro infectivity test denoted as the Plaque Forming Unit (PFU) Test. In this test, homogenates of different organs were investigated for infectious virus titers on rat embryonic cell monolayers. We demonstrated that in the salivary gland, the major target organ for rat cytomegalovirus, virus was detectable from 8 days onward after intraperitoneal infection. To show that this model is suitable for the detection of immunotoxicity four different methods for immunosuppression were investigated: 1. gamma-irradiation, 2. congenitally athymic rats, 3. chemically induced immunosuppression, 4. ultraviolet-B (UVB) irradiation. Rat cytomegalovirus titers in the salivary glands of irradiated (500 rad 1 day prior to infection) or congenitally athymic rats were significantly increased as compared to non-irradiated rats and euthymic control rats respectively. In TOX-Wistar rats, given 20 or 80 mg bis(tri-n-butyltin)oxide (TBTO) per kg food beginning 6 weeks before cytomegalovirus infection, a regimen known to have immunotoxic effects, cytomegalovirus titers in the salivary glands were significantly increased as compared to non-TBTO-treated cytomegalovirus infected rats.(ABSTRACT TRUNCATED AT 250 WORDS)