Detection and progression of chronic allograft nephropathy : A study based on protocol biopsies

Background. Kidney transplantation (KTX) is considered to be the best treatment of terminal uremia. Despite improvements in short-term graft survival, a considerable number of kidney allografts are lost due to the premature death of patients with a functional kidney and to chronic allograft nephropathy (CAN). Aim. To investigate the risk factors involved in the progression of CAN and to analyze diagnostic methods for this entity. Materials and methods. Altogether, 153 implant and 364 protocol biopsies obtained between June 1996 and April 2008 were analyzed. The biopsies were classified according to Banff ’97 and chronic allograft damage index (CADI). Immunohistochemistry for TGF-β1 was performed in 49 biopsies. Kidney function was evaluated by creatinine and/or cystatin C measurement and by various estimates of glomerular filtration rate (GFR). Demographic data of the donors and recipients were recorded after 2 years’ follow-up. Results. Most of the 3-month biopsies (73%) were nearly normal. The mean CADI score in the 6-month biopsies decreased significantly after 2001. Diastolic hypertension correlated with ΔCADI. Serum creatinine concentration at hospital discharge and glomerulosclerosis were risk factors for ΔCADI. High total and LDL cholesterol, low HDL and hypertension correlated with chronic histological changes. The mean age of the donors increased from 41 -52 years. Older donors were more often women who had died from an underlying disease. The prevalence of delayed graft function increased over the years, while acute rejections (AR) decreased significantly over the years. Sub-clinical AR was observed in 4% and it did not affect long-term allograft function or CADI. Recipients´ drug treatment was modified along the Studies, being mycophenolate mophetil, tacrolimus, statins and blockers of the renine-angiotensin-system more frequently prescribed after 2001. Patients with a higher ΔCADI had lower GFR during follow-up. CADI over 2 was best predicted by creatinine, although with modest sensitivity and specificity. Neither cystatin C nor other estimates of GFR were superior to creatinine for CADI prediction. Cyclosporine A toxicity was seldom seen. Low cyclosporin A concentration after 2 h correlated with TGF- β1 expression in interstitial inflammatory cells, and this predicted worse graft function. Conclusions. The progression of CAN has been affected by two major factors: the donors’ characteristics and the recipients’ hypertension. The increased prevalence of DGF might be a consequence of the acceptance of older donors who had died from an underlying disease. Implant biopsies proved to be of prognostic value, and they are essential for comparison with subsequent biopsies. The progression of histological damage was associated with hypertension and dyslipidemia. The augmented expression of TGF-β1 in inflammatory cells is unclear, but it may be related to low immunosuppression. Serum creatinine is the most suitable tool for monitoring kidney allograft function on every-day basis. However, protocol biopsies at 6 and 12 months predicted late kidney allograft dysfunction and affected the clinical management of the patients. Protocol biopsies are thus a suitable surrogate to be used in clinical trials and for monitoring kidney allografts.

Complement factor C4 and immunoglobulins in recurrent or chronic mucosal infections

The study assessed whether plasma concentrations of complement factors C3, C4, or immunoglobulins, serum classical pathway hemolytyic activity, or polymorphisms in the class I and II HLA genes, isotypes and gene numbers of C4, or allotypes of IgG1 and IgG3 heavy chain genes were associated with severe frequently recurring or chronic mucosal infections. According to strict clinical criteria, 188 consecutive voluntary patients without a known immunodeficiency and 198 control subjects were recruited. Frequencies of low levels in IgG1, IgG2, IgG3 and IgG4 were for the first time tested from adult general population and patients with acute rhinosinusitis. Frequently recurring intraoral herpes simplex type 1 infections, a rare form of the disease, was associated with homozygosity in HLA -A*, -B*, -C*, and -DR* genes. Frequently recurrent genital HSV-2 infections were associated with low levels of IgG1 and IgG3, present in 54% of the recruited patients. This association was partly allotype-dependent. The G3mg,G1ma/ax haplotype, together with low IgG3, was more common in patients than in control subjects who lacked antibodies against herpes simplex viruses. This is the first found immunogenetic deficiency in otherwise healthy adults that predisposes to highly frequent mucosal herpes recurrences. According to previous studies, HSV effectively evades the allotype G1ma/ax of IgG1, whereas G3mg is associated with low IgG3. Certain HLA genes were more common in patients than in control subjects. Having more than one C4A or C4B gene was associated with neuralgias caused by the virus. Low levels of IgA, IgG1, IgG2, IgG3, and IgG4 were common in the general adult population, but even more frequent in patients with chronic sinusitis. Only low IgG1 was more common chronic than in acute rhinosinusitis. Clinically, nasal polyposis and bronchial asthma were associated with complicated disease forms. The best differentiating immunologic parameters were C4A deficiency and the combination of low plasma IgG4 together with low IgG1 or IgG2, performing almost equally. The lack of C4A, IgA, and IgG4, all known to possess anti-inflammatory activity, together with a concurrently impaired immunity caused by low subclass levels, may predispose to chronic disease forms. In severe chronic adult periodontitis, any C4A or C4B deficiency combined was associated with the disease. The new quantitative analysis of C4 genes and the conventional C4 allotyping method complemented each other. Lowered levels of plasma C3 or C4 or both, and serum CH50 were found in herpes and periodontitis patients. In rhinosinusitis, there was a linear trend with the highest levels found in the order: acute > chronic rhinosinusitis > general population > blood donors with no self-reported history of rhinosinusitis. Complement is involved in the defense against the tested mucosal infections. Seemingly immunocompetent patients with chronic or recurrent mucosal infections frequently have subtle weaknesses in different arms of immunity. Their susceptibility to chronic disease forms may be caused by these. Host s subtly impaired immunity often coincides with effective immune evasion from the same arms of immunity by the disease-causing pathogens. The interpretation of low subclass levels, if no additional predisposing immunologic factors are tested, is difficult and of limited value in early diagnosis and treatment.

Brain imaging of chronic pain

Acute pain has substantial survival value because of its protective function in the everyday environment. Instead, chronic pain lacks survival and adaptive function, causes great amount of individual suffering, and consumes the resources of the society due to the treatment costs and loss of production. The treatment of chronic pain has remained challenging because of inadequate understanding of mechanisms working at different levels of the nervous system in the development, modulation, and maintenance of chronic pain. Especially in unclear chronic pain conditions the treatment may be suboptimal because it can not be targeted to the underlying mechanisms. Noninvasive neuroimaging techniques have greatly contributed to our understanding of brain activity associated with pain in healthy individuals. Many previous studies, focusing on brain activations to acute experimental pain in healthy individuals, have consistently demonstrated a widely-distributed network of brain regions that participate in the processing of acute pain. The aim of the present thesis was to employ non-invasive brain imaging to better understand the brain mechanisms in patients suffering from chronic pain. In Study I, we used magnetoencephalography (MEG) to measure cortical responses to painful laser stimulation in healthy individuals for optimization of the stimulus parameters for patient studies. In Studies II and III, we monitored with MEG the cortical processing of touch and acute pain in patients with complex regional pain syndrome (CRPS). We found persisting plastic changes in the hand representation area of the primary somatosensory (SI) cortex, suggesting that chronic pain causes cortical reorganization. Responses in the posterior parietal cortex to both tactile and painful laser stimulation were attenuated, which could be associated with neglect-like symptoms of the patients. The primary motor cortex reactivity to acute pain was reduced in patients who had stronger spontaneous pain and weaker grip strength in the painful hand. The tight coupling between spontaneous pain and motor dysfunction supports the idea that motor rehabilitation is important in CRPS. In Studies IV and V we used MEG and functional magnetic resonance imaging (fMRI) to investigate the central processing of touch and acute pain in patients who suffered from recurrent herpes simplex virus infections and from chronic widespread pain in one side of the body. With MEG, we found plastic changes in the SI cortex, suggesting that many different types of chronic pain may be associated with similar cortical reorganization. With fMRI, we found functional and morphological changes in the central pain circuitry, as an indication of central contribution for the pain. These results show that chronic pain is associated with morphological and functional changes in the brain, and that such changes can be measured with functional imaging.

Quantitation and characterization of glutathionyl haemoglobin as an oxidative stress marker in chronic renal failure by mass spectrometry

Objectives: Glutathionyl haemoglobin (GS-Hb) belonging to the class of glutathionylated proteins has been investigated as a possible marker of oxidative stress in different chronic diseases. The purpose of this study was to examine whether glutathionyl haemoglobin can serve as an oxidative stress marker in non-diabetic chronic renal failure patients on different renal replacement therapies (RRT) through its quantitation, and characterization of the specific binding site of glutathione in haemoglobin molecule by mass spectrometric analysis. Design and methods: The study group consisted of non-diabetic chronic renal failure patients on renal replacement therapy (RRT): hemodialysis (HD), continuous ambulatory peritoneal dialysis (CAPD) and renal allograft transplant (Txp) patients. Haemoglobin samples of these subjects were analyzed by liquid chromatography electrospray ionization mass spectrometry for GS-Hb quantitation. Characterization of GS-Hb was done by tandem mass spectrometry. Levels of erythrocyte glutathione (GSH) and lipid peroxidation (as thiobarbituric acid reacting substances) were measured spectrophotometrically, while glycated baernoglobin (HbA1c) was measured by HPLC. Results: GS-Hb levels were markedly elevated in the dialysis group and marginally in the transplant group as compared to the controls. GS-Hb levels correlated positively with lipid peroxidation and negatively with the erythrocyte glutathione levels in RRT groups indicating enhanced oxidative stress. De novo sequencing of the chymotryptic fragment of GS-Hb established that glutathione is attached to Cys-93 of the beta globin chain. Mass spectrometric quantitation of total glycated haemoglobin showed good agreement with HbA1c estimation by conventional HPLC method. Conclusions: Glutathionyl haemoglobin can serve as a clinical marker of oxidative stress in chronic debilitating therapies like RRT. Mass spectrometry provides a reliable analytical tool for quantitation and residue level characterization of different post-translational modifications of haemoglobin. (c) 2007 The Canadian Society of Clinical Chemists. Published by Elsevier Inc. All rights reserved.

Evaluating the effectiveness of a self-management exercise intervention on wound healing, functional ability and health-related quality of life outcomes in adults with venous leg ulcers: a randomised controlled trial

Exercise that targets ankle joint mobility may lead to improvement in calf muscle pump function and subsequent healing. The objectives of this research were to assess the impact of an exercise intervention in addition to routine evidence-based care on the healing rates, functional ability and health-related quality of life for adults with venous leg ulcers (VLUs). This study included 63 patients with VLUs. Patients were randomised to receive either a 12-week exercise intervention with a telephone coaching component or usual care plus telephone calls at the same timepoints. The primary outcome evaluated the effectiveness of the intervention in relation to wound healing. The secondary outcomes evaluated physical activity, functional ability and health-related quality of life measures between groups at the end of the 12 weeks. A per protocol analysis complemented the effectiveness (intention-to-treat) analysis to highlight the importance of adherence to an exercise intervention. Intention-to-treat analyses for the primary outcome showed 77% of those in the intervention group healed by 12 weeks compared to 53% of those in the usual care group. Although this difference was not statistically significant due to a smaller than expected sample size, a 24% difference in healing rates could be considered clinically significant. The per protocol analysis for wound healing, however, showed that those in the intervention group who adhered to the exercise protocol 75% or more of the time were significantly more likely to heal and showed higher rates for wound healing than the control group (P = 0·01), that is, 95% of those who adhered in the intervention group healed in 12 weeks. The secondary outcomes of physical activity, functional ability and health-related quality of life were not significantly altered by the intervention. Among the secondary outcomes (physical activity, functional ability and health-related quality of life), intention-to-treat analyses did not support the effectiveness of the intervention. However, per protocol analyses revealed encouraging results with those participants who adhered more than 75% of the time (n = 19) showing significantly improved Range of Ankle Motion from the self-management exercise programme (P = 0·045). This study has shown that those participants who adhere to the exercise programme as an adjunctive treatment to standard care are more likely to heal and have better functional outcomes than those who do not adhere to the exercises in conjunction with usual care.

“Well this is it. Just get on with it”: Pain willingness and activity engagement in people with chronic pain

Pain is recognised as a problem of significant concern worldwide and in the latest Global Burden of Disease Study, low back pain was identified as the biggest contributor worldwide to Years Lived with Disability. There is evidence to suggest that people who accept their chronic pain have a higher quality of life, lower levels of disability and distress, and function better emotionally, socially and physically. Findings on the specific pathways linking pain acceptance to quality of life outcomes are less clear. the two widely accepted pain acceptance factors, pain willingness and activity engagement, have not been well explored in qualitative studies on acceptance of chronic pain. To address this deficit in the literature, the current study has two related aims: 1) to explore pain willingness and activity engagement in the lives of people with chronic pain, and ; 2) to find out what people believe helps them to successfully get on with life in spite of chronic pain.

A neuro-adaptive augmented optimal dynamic inversion approach for effective and efficient treatment of chronic myelogenous leukemia

Combining the advanced techniques of optimal dynamic inversion and model-following neuro-adaptive control design, an efficient technique is presented for effective treatment of chronic myelogenous leukemia (CML). A recently developed nonlinear mathematical model for cell dynamics is used for the control (medication) synthesis. First, taking a set of nominal parameters, a nominal controller is designed based on the principle of optimal dynamic inversion. This controller can treat nominal patients (patients having same nominal parameters as used for the control design) effectively. However, since the parameters of an actual patient can be different from that of the ideal patient, to make the treatment strategy more effective and efficient, a model-following neuro-adaptive controller is augmented to the nominal controller. In this approach, a neural network trained online (based on Lyapunov stability theory) facilitates a new adaptive controller, computed online. From the simulation studies, this adaptive control design approach (treatment strategy) is found to be very effective to treat the CML disease for actual patients. Sufficient generality is retained in the theoretical developments in this paper, so that the techniques presented can be applied to other similar problem as well. Note that the technique presented is computationally non-intensive and all computations can be carried out online.

Excimer laser refractive surgery : corneal wound healing and clinical results

Although the first procedure in a seeing human eye using excimer laser was reported in 1988 (McDonald et al. 1989, O'Connor et al. 2006) just three studies (Kymionis et al. 2007, O'Connor et al. 2006, Rajan et al. 2004) with a follow-up over ten years had been published when this thesis was started. The present thesis aims to investigate 1) the long-term outcomes of excimer laser refractive surgery performed for myopia and/or astigmatism by photorefractive keratectomy (PRK) and laser-in situ- keratomileusis (LASIK), 2) the possible differences in postoperative outcomes and complications when moderate-to-high astigmatism is treated with PRK or LASIK, 3) the presence of irregular astigmatism that depend exclusively on the corneal epithelium, and 4) the role of corneal nerve recovery in corneal wound healing in PRK enhancement. Our results revealed that in long-term the number of eyes that achieved uncorrected visual acuity (UCVA)≤0.0 and ≤0.5 (logMAR) was higher after PRK than after LASIK. Postoperative stability was slightly better after PRK than after LASIK. In LASIK treated eyes the incidence of myopic regression was more pronounced when the intended correction was over >6.0 D and in patients aged <30 years.Yet the intended corrections in our study were higher for LASIK than for PRK eyes. No differences were found in percentages of eyes with best corrected visual acuity (BCVA) or loss of two or more lines of visual acuity between PRK and LASIK in the long-term. The postoperative long-term outcomes of PRK with two different delivery systems broad beam and scanning laser were compared and revealed no differences. Postoperative outcomes of moderate-to-high astigmatism yielded better results in terms of UCVA and less compromise or loss of two more lines of BCVA after LASIK that after PRK.Similar stability for both procedures was revealed. Vector analysis showed that LASIK outcomes tended to be more accurate than PRK outcomes, yet no statistically differences were found. Irregular astigmatism secondary to recurrent corneal erosion due to map-dot-fingerprint was successfully treated with phototherapeutic keratectomy (PTK). Preoperative videokeratographies (VK) showed irregular astigmatism. However, postoperatively, all eyes showed a regular pattern. No correlation was found between pre- and postoperative VK patterns. Postoperative outcomes of late PRK in eyes originally subjected to LASIK showed that all (7/7) eyes achieved UCVA ≤0.5 at last follow-up (range 3 — 11 months), and no eye lost lines of BCVA. Postoperatively all eyes developed and initial mild haze (0.5 — 1) into the first month. Yet, at last follow-up 5/7 eyes showed a haze of 0.5 and this was no longer evident in 2/7 eyes. Based on these results, we demonstrated that the long-term outcomes after PRK and LASIK were safe and efficient, with similar stability for both procedures. The PRK outcomes were similar when treated by broad-beam or scanning slit laser. LASIK was better than PRK to correct moderate-to-high astigmatism, yet both procedures showed a tendency of undercorrection. Irregular astigmatism was proven to be able to depend exclusively from the corneal epithelium. If this kind of astigmatism is present in the cornea and a customized PRK/LASIK correction is done based on wavefront measurements an irregular astigmatism may be produced rather than treated. Corneal sensory nerve recovery should have an important role in the modulation of the corneal wound healing and post-operative anterior stromal scarring. PRK enhancement may be an option in eyes with previous LASIK after a sufficient time interval that in at least 2 years.

Occupational chronic solvent encephalopathy in Finland 1995 - 2007 : incidence and diagnostic methods

The occurrence of occupational chronic solvent encephalopathy (CSE) seems to decrease, but still every year reveals new cases. To prevent CSE and early retirement of solvent-exposed workers, actions should focus on early CSE detection and diagnosis. Identifying the work tasks and solvent exposure associated with high risk for CSE is crucial. Clinical and exposure data of all the 128 cases diagnosed with CSE as an occupational disease in Finland during 1995-2007 was collected from the patient records at the Finnish Institute of Occupational Health (FIOH) in Helsinki. The data on the number of exposed workers in Finland were gathered from the Finnish Job-exposure Matrix (FINJEM) and the number of employed from the national workforce survey. We analyzed the work tasks and solvent exposure of CSE patients and the findings in brain magnetic resonance imaging (MRI), quantitative electroencephalography (QEEG), and event-related potentials (ERP). The annual number of new cases diminished from 18 to 3, and the incidence of CSE decreased from 8.6 to 1.2 / million employed per year. The highest incidence of CSE was in workers with their main exposure to aromatic hydrocarbons; during 1995-2006 the incidence decreased from 1.2 to 0.3 / 1 000 exposed workers per year. The work tasks with the highest incidence of CSE were floor layers and lacquerers, wooden surface finishers, and industrial, metal, or car painters. Among 71 CSE patients, brain MRI revealed atrophy or white matter hyperintensities or both in 38% of the cases. Atrophy which was associated with duration of exposure was most frequently located in the cerebellum and in the frontal or parietal brain areas. QEEG in a group of 47 patients revealed increased power of the theta band in the frontal brain area. In a group of 86 patients, the P300 amplitude of auditory ERP was decreased, but at individual level, all the amplitude values were classified as normal. In 11 CSE patients and 13 age-matched controls, ERP elicited by a multimodal paradigm including an auditory, a visual detection, and a recognition memory task under single and dual-task conditions corroborated the decrease of auditory P300 amplitude in CSE patients in single-task condition. In dual-task conditions, the auditory P300 component was, more often in patients than in controls, unrecognizable. Due to the paucity and non-specificity of the findings, brain MRI serves mainly for differential diagnostics in CSE. QEEG and auditory P300 are insensitive at individual level and not useful in the clinical diagnostics of CSE. A multimodal ERP paradigm may, however, provide a more sensitive method to diagnose slight cognitive disturbances such as CSE.

Mechanisms of azole resistance and carcinogenic acetaldehyde production in chronic mucosal candidosis

Autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED, APS1) is an autoimmune disease caused by a loss-of function mutation in the autoregulator gene (AIRE). Patients with APECED suffer from chronic mucocutaneous candidosis (CMC) of the oral cavity and oesophagus often since early childhood. The patients are mainly colonized with Candida albicans and decades of exposure to antifungal agents have lead to the development of clinical and microbiological resistance in the treatment of CMC in the APECED patient population in Finland. A high incidence of oral squamous cell carcinoma is associated with oral CMC lesions in the APECED patients over the age of 25. The overall aim of this study was firstly, to investigate the effect of long-term azole exposure on the metabolism of oral C. albicans isolates from APECED patients with CMC and secondly, to analyse the specific molecular mechanisms that are responsible for these changes. The aim of the first study was to examine C. albicans strains from APECED patients and the level of cross-resistance to miconazole, the recommended topical compound for the treatment of oral candidosis. A total of 16% of the strains had decreased susceptibility to miconazole and all of these isolates had decreased susceptibility to fluconazole. Miconazole MICs also correlated with MICs to voriconazole and posaconazole. A significant positive correlation between the years of miconazole exposure and the MICs to azole antifungal agents was also found. These included azoles the patients had not been exposed to. The aim of our second study was to determine if the APECED patients are continuously colonized with the same C. albicans strains despite extensive antifungal treatment and to gain a deeper insight into the genetic changes leading to azole resistance. The strains were typed using MLST and our results confirmed that all patients were persistently colonized with the same or a genetically related strain despite antifungal treatment between isolations. No epidemic strains were found. mRNA expression was analysed by Northern blotting, protein level by western blotting, and TAC1 and ERG11 genes were sequenced. The main molecular mechanisms resulting in azole resistance were gain-of-function mutations in TAC1 leading to over expression of CDR1 and CDR2, genes linked to azole resistance. Several strains had also developed point mutations in ERG11, another gene linked to azole resistance. In the third study we used gas chromatography to test whether the level of carcinogenic acetaldehyde produced by C. albicans strains isolated from APECED patients were different from the levels produced by strains isolated from healthy controls and oral carcinoma patients. Acetaldehyde is a carcinogenic product of alcohol fermentation and metabolism in microbes associated with cancers of the upper digestive tract. In yeast, acetaldehyde is a by-product of the pyruvate bypass that converts pyruvate into acetyl-CoA during fermentation. Our results showed that strains isolated from APECED patients produced mutagenic levels of acetaldehyde in the presence of glucose (100mM, 18g/l) and the levels produced were significantly higher than those from strains isolated from controls and oral carcinoma patients. All strains in the study, however, were found to produce mutagenic levels of acetaldehyde in the presence of ethanol (11mM). The glucose and ethanol levels used in this study are equivalent to those found in food and beverages and our results highlight the role of dietary sugars and ethanol on carcinogenesis. The aims of our fourth study were to research the effect of growth conditions in the levels of acetaldehyde produced by C. albicans and to gain deeper insight into the role of different genes in the pyruvate-bypass in the production of high acetaldehyde levels. Acetaldehyde production in the presence of glucose increased by 17-fold under moderately hypoxic conditions compared to the levels produced under normoxic conditions. Under moderately hypoxic conditions acetaldehyde levels did not correlate with the expression of ADH1 and ADH2, genes catalyzing the oxidation of ethanol to acetaldehyde, or PDC11, the gene catalyzing the oxidation of pyruvate to acetaldehyde but correlated with the expression of down-stream genes ALD6 and ACS1. Our results highlight a problem where indiscriminate use of azoles may influence azole susceptibility and lead to the development of cross-resistance. Despite clinically successful treatment leading to relief of symptoms, colonization by C. albicans strains is persistent within APECED patients. Microevolution and point mutations that occur in strains may lead to the development of azole-resistant isolates and metabolic changes leading to increased production of carcinogenic acetaldehyde.

Preterm birth and risk factors for chronic disease : Helsinki Study of Very Low Birth Weight Adults

Background: The improved prognosis of early preterm birth has created a generation of surviving very low birth weight (< 1500 g, VLBW) infants whose health risks in adulthood are poorly known. Of every 1000 live-born infants in Finland, about 8 are born at VLBW. Variation in birth weight, even within the normal range, relates to considerable variation in the risk for several common adult disorders, including cardiovascular disease and osteoporosis. Small preterm infants frequently exhibit severe postnatal or prenatal growth retardation, or both. Much reason for concern thus exists, regarding adverse health effects in surviving small preterm infants later lives. We studied young adults, aiming at exploring whether VLBW birth and postnatal events after such a birth are associated with higher levels of risk factors for cardiovascular disease or osteoporosis. Subjects and Methods: A follow-up study for VLBW infants began in 1978; by the end of 1985, 335 VLBW survivors at Helsinki University Central Hospital participated in the follow-up. Their gestational ages ranged from 24 to 35 weeks, mean 29.2 and standard deviation 2.2 weeks. In 2004, we invited for a clinic visit 255 subjects, aged 18 to 27, who still lived in the greater Helsinki area. From the same birth hospitals, we also invited 314 term-born controls of similar age and sex. These two study groups underwent measurements of body size and composition, function of brachial arterial endothelium (flow-mediated dilatation, FMD) and carotid artery intima-media thickness (cIMT) by ultrasound. In addition, we measured plasma lipid concentrations, ambulatory blood pressure, fasting insulin, glucose tolerance and, by dual-energy x-ray densitometry, bone-mineral density. Results: 172 control and 166 VLBW participants underwent lipid measurements and a glucose tolerance test. VLBW adults fasting insulin (adjusted for body mass index) was 12.6% (95% confidence interval, 0.8 to 25.8) higher than that of the controls. The glucose and insulin concentrations 120 minutes after 75 g glucose ingestion showed similar differences (N=332) (I). VLBW adults had 3.9 mmHg (1.3 to 6.4) higher office systolic blood pressure, 3.5 mmHg (1.7 to 5.2) higher office diastolic blood pressure (I), and, when adjusted for body mass index and height, 3.1 mmHg (0.5 to 5.5) higher 24-hour mean systolic blood pressure (N=238) (II). VLBW birth was associated neither with HDL- or total cholesterol nor triglyceride concentrations (N=332) (I), nor was it associated with a low FMD or a high cIMT (N=160) (III). VLBW adults had 0.51-unit (0.28 to 0.75) lower lumbar spine Z scores and 0.56-unit (0.34 to 0.78) lower femoral neck Z scores (N=283). Adjustments for size attenuated the differences, but only partially (IV). Conclusions: These results imply that those born at VLBW, although mostly healthy as young adults, already bear several risk factors for chronic adult disease. The significantly higher fasting insulin level in adults with VLBW suggests increased insulin resistance. The higher blood pressure in young adults born at VLBW may indicate they later are at risk for hypertension, although their unaffected endothelial function may be evidence for some form of protection from cardiovascular disease. Lower bone mineral density around the age of peak bone mass may suggest increased risk for later osteoporotic fractures. Because cardiovascular disease and osteoporosis are frequent, and their prevention is relatively cheap and safe, one should focus on prevention now. When initiated early, preventive measures are likely to have sufficient time to be effective in preventing or postponing the onset of chronic disease.