Showing papers by "Karolinska Institutet published in 2001"
TL;DR: A new membrane protein topology prediction method, TMHMM, based on a hidden Markov model is described and validated, and it is discovered that proteins with N(in)-C(in) topologies are strongly preferred in all examined organisms, except Caenorhabditis elegans, where the large number of 7TM receptors increases the counts for N(out)-C-in topologies.
11,453 citations
Mayo Clinic1, Baylor College of Medicine2, Technische Universität München3, Icahn School of Medicine at Mount Sinai4, Washington University in St. Louis5, Johns Hopkins University6, French Institute of Health and Medical Research7, University College London8, University of California, San Diego9, Karolinska Institutet10
TL;DR: A group of experts on aging and MCI from around the world in the fields of neurology, psychiatry, geriatrics, neuropsychology, neuroimaging, neuropathology, clinical trials, and ethics was convened to summarize the current state of the field of MCI.
Abstract: The field of aging and dementia is focusing on the characterization of the earliest stages of cognitive impairment. Recent research has identified a transitional state between the cognitive changes of normal aging and Alzheimer's disease (AD), known as mild cognitive impairment (MCI). Mild cognitive impairment refers to the clinical condition between normal aging and AD in which persons experience memory loss to a greater extent than one would expect for age, yet they do not meet currently accepted criteria for clinically probable AD. When these persons are observed longitudinally, they progress to clinically probable AD at a considerably accelerated rate compared with healthy age-matched individuals. Consequently, this condition has been recognized as suitable for possible therapeutic intervention, and several multicenter international treatment trials are under way. Because this is a topic of intense interest, a group of experts on aging and MCI from around the world in the fields of neurology, psychiatry, geriatrics, neuropsychology, neuroimaging, neuropathology, clinical trials, and ethics was convened to summarize the current state of the field of MCI. Participants reviewed the world scientific literature on aging and MCI and summarized the various topics with respect to available evidence on MCI. Diagnostic criteria and clinical outcomes of these subjects are available in the literature. Mild cognitive impairment is believed to be a high-risk condition for the development of clinically probable AD. Heterogeneity in the use of the term was recognized, and subclassifications were suggested. While no treatments are recommended for MCI currently, clinical trials regarding potential therapies are under way. Recommendations concerning ethical issues in the diagnosis and the management of subjects with MCI were made.
4,424 citations
TL;DR: The fear module is assumed to mediate an emotional level of fear learning that is relatively independent and dissociable from cognitive learning of stimulus relationships.
Abstract: An evolved module for fear elicitation and fear learning with 4 characteristics is proposed. (a) The fear module is preferentially activated in aversive contexts by stimuli that are fear relevant in an evolutionary perspective. (b) Its activation to such stimuli is automatic. (c) It is relatively impenetrable to cognitive control. (d) It originates in a dedicated neural circuitry, centered on the amygdala. Evidence supporting these propositions is reviewed from conditioning studies, both in humans and in monkeys; illusory correlation studies; studies using unreportable stimuli; and studies from animal neuroscience. The fear module is assumed to mediate an emotional level of fear learning that is relatively independent and dissociable from cognitive learning of stimulus relationships.
2,777 citations
TL;DR: The TrxR-catalyzed regeneration of several antioxidant compounds, including ascorbic acid (vitamin C), selenium-containing substances, lipoic acid, and ubiquinone are summarized.
2,632 citations
TL;DR: In this paper, the effects of velocity rescaling on the self-diffusion coefficient D and radial distribution functions, gOO, gOH, and gHH for all five water models were determined and compared to experimental data.
Abstract: Molecular dynamics simulations of five water models, the TIP3P (original and modified), SPC (original and refined), and SPC/E (original), were performed using the CHARMM molecular mechanics program. All simulations were carried out in the microcanonical NVE ensemble, using 901 water molecules in a cubic simulation cell furnished with periodic boundary conditions at 298 K. The SHAKE algorithm was used to keep water molecules rigid. Nanosecond trajectories were calculated with all water models for high statistical accuracy. The characteristic self-diffusion coefficients D and radial distribution functions, gOO, gOH, and gHH for all five water models were determined and compared to experimental data. The effects of velocity rescaling on the self-diffusion coefficient D were examined. All these empirical water models used in this study are similar by having three interaction sites, but the small differences in their pair potentials composed of Lennard-Jones (LJ) and Coulombic terms give significant difference...
2,223 citations
TL;DR: The role of estrogen receptors in physiology and pathology has been investigated in the past decade and it was found that there was not one but two distinct and functional estrogen receptors, now called ERα and ERβ.
Abstract: Our appreciation of the physiological functions of estrogens and the mechanisms through which estrogens bring about these functions has changed during the past decade. Just as transgenic mice were produced in which estrogen receptors had been inactivated and we thought that we were about to understand the role of estrogen receptors in physiology and pathology, it was found that there was not one but two distinct and functional estrogen receptors, now called ERα and ERβ. Transgenic mice in which each of the receptors or both the receptors are inactive have revealed a much broader role for estrogens in the body than was previously thought. This decade also saw the description of a male patient who had no functional ERα and whose continued bone growth clearly revealed an important function of estrogen in men. The importance of estrogen in both males and females was also demonstrated in the laboratory in transgenic mice in which the aromatase gene was inactivated. Finally, crystal structures of the estrogen r...
1,950 citations
TL;DR: This paper found that participants specifically fearful of snakes but not spiders (or vice versa) showed facilitated search for the feared objects but did not differ from controls in search for nonfeared fear-relevant or fear-irrelevant, targets.
Abstract: Participants searched for discrepant fear-relevant pictures (snakes or spiders) in grid-pattern arrays of fear-irrelevant pictures belonging to the same category (flowers or mushrooms) and vice versa. Fear-relevant pictures were found more quickly than fear-irrelevant ones. Fear-relevant, but not fear-irrelevant, search was unaffected by the location of the target in the display and by the number of distractors, which suggests parallel search for fear-relevant targets and serial search for fear-irrelevant targets. Participants specifically fearful of snakes but not spiders (or vice versa) showed facilitated search for the feared objects but did not differ from controls in search for nonfeared fear-relevant or fear-irrelevant, targets. Thus, evolutionary relevant threatening stimuli were effective in capturing attention, and this effect was further facilitated if the stimulus was emotionally provocative.
1,919 citations
TL;DR: A new ARWMC scale applicable to both CT and MRI that has almost equal sensitivity, except for certain regions is presented, including frontal area and basal ganglia and infratentorial areas.
Abstract: Background and Purpose—MRI is more sensitive than CT for detection of age-related white matter changes (ARWMC). Most rating scales estimate the degree and distribution of ARWMC either on CT or on MRI, and they differ in many aspects. This makes it difficult to compare CT and MRI studies. To be able to study the evolution and possible effect of drug treatment on ARWMC in large patient samples, it is necessary to have a rating scale constructed for both MRI and CT. We have developed and evaluated a new scale and studied ARWMC in a large number of patients examined with both MRI and CT. Methods—Seventy-seven patients with ARWMC on either CT or MRI were recruited and a complementary examination (MRI or CT) performed. The patients came from 4 centers in Europe, and the scans were rated by 4 raters on 1 occasion with the new ARWMC rating scale. The interrater reliability was evaluated by using κ statistics. The degree and distribution of ARWMC in CT and MRI scans were compared in different brain areas. Results—...
1,571 citations
TL;DR: Threatening angry faces were more quickly and accurately detected than were other negative faces (sad or "scheming"), which suggests that the threat advantage can be attributed to threat rather than to the negative valence or the uniqueness of the target display.
Abstract: Schematic threatening, friendly, and neutral faces were used to test the hypothesis that humans preferentially orient their attention toward threat. Using a visual search paradigm, participants searched for discrepant faces in matrices of otherwise identical faces. Across 5 experiments, results consistently showed faster and more accurate detection of threatening than friendly targets. The threat advantage was obvious regardless of whether the conditions favored parallel or serial search (i.e., involved neutral or emotional distractors), and it was valid for inverted faces. Threatening angry faces were more quickly and accurately detected than were other negative faces (sad or "scheming"), which suggests that the threat advantage can be attributed to threat rather than to the negative valence or the uniqueness of the target display.
1,361 citations
TL;DR: This study led to the identification with a high degree of confidence of over a dozen novel worm-mammalian ortholog assignments that were previously undetected because of shortcomings of phylogenetic methods.
1,196 citations
TL;DR: Although increased throughout the range of values of LDL-cholesterol, apoB and apoA-I might be of greatest value in diagnosis and treatment in men and women who have common lipid abnormalities, but have normal or low concentrations of HDL-ch cholesterol.
TL;DR: Cross-repressive interactions between class I and class II proteins appear to refine and maintain these progenitor domains, which generate a distinct class of postmitotic neurons in the ventral third of the neural tube.
TL;DR: Recommendations are given for the management of patients with acute stone colic and for active removal of stones from the ureter and kidney and the principles for risk evaluation of Patients with recurrent stone formation and appropriate recurrence preventive treatment are given.
TL;DR: The finding of increased protofibril formation and decreased Aβ plasma levels in the Arctic AD may reflect an alternative pathogenic mechanism for AD involving rapid Aβ protofibil formation leading to accelerated buildup of insoluble Aβ intra- and/or extracellularly.
Abstract: Several pathogenic Alzheimer's disease (AD) mutations have been described, all of which cause increased amyloid beta-protein (Abeta) levels. Here we present studies of a pathogenic amyloid precursor protein (APP) mutation, located within the Abeta sequence at codon 693 (E693G), that causes AD in a Swedish family. Carriers of this 'Arctic' mutation showed decreased Abeta42 and Abeta40 levels in plasma. Additionally, low levels of Abeta42 were detected in conditioned media from cells transfected with APPE693G. Fibrillization studies demonstrated no difference in fibrillization rate, but Abeta with the Arctic mutation formed protofibrils at a much higher rate and in larger quantities than wild-type (wt) Abeta. The finding of increased protofibril formation and decreased Abeta plasma levels in the Arctic AD may reflect an alternative pathogenic mechanism for AD involving rapid Abeta protofibril formation leading to accelerated buildup of insoluble Abeta intra- and/or extracellularly.
TL;DR: Differences in the composition of the gut flora between infant who will and infants who will not develop allergy are demonstrable before the development of any clinical manifestations of atopy.
Abstract: Background: The intestinal microflora is a likely source for the induction of immune deviation in infancy. Objective: The purpose of this study was to prospectively relate the intestinal microflora to allergy development in 2 countries differing with respect to the prevalence of atopic diseases. Methods: Newborn infants were followed prospectively through the first 2 years of life in Estonia (n = 24) and Sweden (n = 20). By that age, 9 Estonian and 9 Swedish infants had developed atopic dermatitis and/or positive skin prick test results. Stool samples were obtained at 5 to 6 days and at 1, 3, 6, and 12 months, and 13 groups of aerobic and anaerobic microorganisms were cultivated through use of standard methods. Results: In comparison with healthy infants, babies who developed allergy were less often colonized with enterococci during the first month of life (72% vs 96%; P < .05) and with bifidobacteria during the first year of life (17% to 39% vs 42% to 69%; P < .05). Furthermore, allergic infants had higher counts of clostridia at 3 months (median value, 10.3 vs 7.2 log10; P < .05). The prevalence of colonization with Staphylococcus aureus was also higher at 6 months (61% vs 23%; P < .05), whereas the counts of Bacteroides were lower at 12 months (9.9 vs 10.6 log10; P < .05). Conclusion: Differences in the composition of the gut flora between infants who will and infants who will not develop allergy are demonstrable before the development of any clinical manifestations of atopy. Because the observations were made in 2 countries with different standards of living, we believe that our findings could indicate a role for the intestinal microflora in the development of and protection from allergy. (J Allergy Clin Immunol 2001;108:516-20.)
TL;DR: This population-based study of patients treated in the hospital documented increased SMRs for suicide in patients with bipolar and unipolar disorder and the SMR for all natural causes of death was increased, causing about half the excess deaths.
Abstract: Background: Selected groups of patients with bipolar and unipolar disorder have an increased mortality rate from suicide and natural causes of death. However, there has been no population-based study of mortality of patients followed up from the onset of the illness. Methods: All patients with a hospital diagnosis of bipolar (n=15386) or unipolar (n=39182) disorder in Sweden from 1973 to 1995 were identified from the inpatient register and linked with the national cause-ofdeath register to determine the date and cause of death. Overall and cause-specific standardized mortality ratios (SMRs) and numbers of excess deaths were calculated by 5-year age classes and 5-year calendar periods. Results: The SMRs for suicide were 15.0 for males and 22.4 for females with bipolar disorder, and 20.9 and 27.0, respectively, for unipolar disorder. For all natural causes of death, SMRs were 1.9 for males and 2.1 for females with bipolar disorder, and 1.5 and 1.6, respectively, for unipolar disorder. For bipolar disorder, most excess deaths were from natural causes, whereas for unipolar disorder, most excess deaths were from unnatural causes. The SMR for suicide was especially high for younger patients during the first years after the first diagnosis. Increasing SMR for suicide during the period of study was found for female patients with unipolar disorder. Conclusions: This population-based study of patients treated in the hospital documented increased SMRs for suicide in patients with bipolar and unipolar disorder. The SMR for all natural causes of death was also increased, causing about half the excess deaths. Arch Gen Psychiatry. 2001;58:844-850
TL;DR: HPV-16 infection may be a risk factor for squamous-cell carcinoma of the head and neck in subjects who were seropositive for HPV-16, and no increased risk was observed for other HPV types.
Abstract: Background Oncogenic human papillomaviruses (HPVs), especially HPV type 16 (HPV-16), cause anogenital epithelial cancers and are suspected of causing epithelial cancers of the head and neck. Methods To examine the relation between head and neck cancers and HPVs, we performed a nested case–control study within a joint Nordic cohort in which serum samples were collected from almost 900,000 subjects. Samples collected at enrollment from 292 persons in whom squamous-cell carcinoma of the head and neck developed, on average, 9.4 years after enrollment and from 1568 matched controls were analyzed for antibodies against HPV-16, HPV-18, HPV-33, and HPV-73 and for cotinine levels as a marker of smoking habits. Polymerase-chain-reaction (PCR) analyses for HPV DNA were performed in tumor tissue from 160 of the study patients with cancer. Results After adjustment for cotinine levels, the odds ratio for squamous-cell carcinoma of the head and neck in subjects who were seropositive for HPV-16 was 2.2 (95 percent confid...
TL;DR: By using antimicrobial agents that do not disturb colonisation resistance, the risk of emergence and spread of resistant strains between patients and dissemination of resistant determinants between microorganisms is reduced.
Abstract: The normal microflora acts as a barrier against colonisation of potentially pathogenic microorganisms and against overgrowth of already present opportunistic microorganisms. Control of growth of opportunistic microorganisms is termed colonisation resistance. Administration of antimicrobial agents, therapeutically or as prophylaxis, causes disturbances in the ecological balance between the host and the normal microflora. Most studies on the impact of antimicrobial agents on normal microflora have been carried out on the intestinal flora. Less is known on the effects on oropharyngeal, skin, and vaginal microflora. Disturbances in the microflora depend on the properties of the agents as well as of the absorption, route of elimination, and possible enzymatic inactivation and/or binding to faecal material of the agents. The clinically most common disturbances in the intestinal microflora are diarrhoea and fungal infections that usually cease after the end of treatment. A well-balanced microflora prevents establishment of resistant microbial strains. By using antimicrobial agents that do not disturb colonisation resistance, the risk of emergence and spread of resistant strains between patients and dissemination of resistant determinants between microorganisms is reduced. In this article, the potential ecological effects of administration of antimicrobial agents on the intestinal, oropharyngeal, and vaginal microflora are summarised. The review is based on clinical studies published during the past 10 years.
TL;DR: RASSF1A is a potential tumor suppressor gene that undergoes epigenetic inactivation in lung and breast cancers through hypermethylation of its promoter region and is associated with impaired patient survival.
Abstract: Background: The recently identified RASSF1 locus is located within a 120-kilobase region of chromosome 3p21.3 that frequently undergoes allele loss in lung and breast cancers. We explored the hypothesis that RASSF1 encodes a tumor suppressor gene for lung and breast cancers. Methods: We assessed expression of two RASSF1 gene products, RASSF1A and RASSF1C, and the methylation status of their respective promoters in 27 non-small-cell lung cancer (NSCLC) cell lines, in 107 resected NSCLCs, in 47 small-cell lung cancer (SCLC) cell lines, in 22 breast cancer cell lines, in 39 resected breast cancers, in 104 nonmalignant lung samples, and in three breast and lung epithelial cultures. We also transfected a lung cancer cell line that lacks RASSF1A expression with vectors containing RASSF1A complementary DNA to determine whether exogenous expression of RASSF1A would affect in vitro growth and in vivo tumorigenicity of this cell line. All statistical tests were two-sided. Results: RASSF1A messenger RNA was expressed in nonmalignant epithelial cultures but not in 100% of the SCLC, in 65% of the NSCLC, or in 60% of the breast cancer lines. By contrast, RASSF1C was expressed in all nonmalignant cell cultures and in nearly all cancer cell lines. RASSF1A promoter hypermethylation was detected in 100% of SCLC, in 63% of NSCLC, in 64% of breast cancer lines, in 30% of primary NSCLCs, and in 49% of primary breast tumors but in none of the nonmalignant lung tissues. RASSF1A promoter hypermethylation in resected NSCLCs was associated with impaired patient survival (P = .046). Exogenous expression of RASSF1A in a cell line lacking expression decreased in vitro colony formation and in vivo tumorigenicity. Conclusion: RASSF1A is a potential tumor suppressor gene that undergoes epigenetic inactivation in lung and breast cancers through hypermethylation of its promoter region.
TL;DR: Excess body mass accounts for 5% of all cancers in the European Union, 3% in men and 6% in women, corresponding to 27,000 male and 45,000 female cancer cases yearly, and can be avoided by halving the prevalence of overweight and obese people in Europe.
Abstract: There is growing evidence that excess body weight increases the risk of cancer at several sites, including kidney, endometrium, colon, prostate, gallbladder and breast in post-menopausal women. The proportion of all cancers attributable to overweight has, however, never been systematically estimated. We reviewed the epidemiological literature and quantitatively summarised, by meta-analysis, the relationship between excess weight and the risk of developing cancer at the 6 sites listed above. Estimates were then combined with sex-specific estimates of the prevalence of overweight [body mass index (BMI) 25-29 kg/m(2)] and obesity (BMI > or = 30 kg/m(2)) in each country in the European Union to obtain the proportion of cancers attributable to excess weight. Overall, excess body mass accounts for 5% of all cancers in the European Union, 3% in men and 6% in women, corresponding to 27,000 male and 45,000 female cancer cases yearly. The attributable proportion varied, in men, between 2.1% for Greece and 4.9% for Germany and, in women, between 3.9% for Denmark and 8.8% for Spain. The highest attributable proportions were obtained for cancers of the endometrium (39%), kidney (25% in both sexes) and gallbladder (25% in men and 24% in women). The largest number of attributable cases was for colon cancer (21,500 annual cases), followed by endometrium (14,000 cases) and breast (12,800 cases). Some 36,000 cases could be avoided by halving the prevalence of overweight and obese people in Europe.
TL;DR: The results suggest that poor self rated health is a strong predictor of subsequent mortality in all subgroups studied, and thatSelf rated health therefore may be a useful outcome measure.
Abstract: STUDY OBJECTIVE—To analyse the predictive power of self rated health for mortality in different socioeconomic groups.
DESIGN, SETTING, PARTICIPANTS—Analysis of mortality rates and risk ratios of death during follow up among 170 223 respondents aged 16 years and above in the Swedish Survey of Living Conditions 1975-1997, in relation to self rated health stated at the interview, by age, sex, socioeconomic group, chronic illness and over time.
MAIN RESULTS—There was a strong relation between poor self rated health and mortality, greater at younger ages, similar among men and women and among persons with and without a chronic illness. The relative relation between self rated health and subsequent death was stronger in higher than in lower socioeconomic groups, possibly because of the lower base mortality of these groups. However, the absolute mortality risk differences between persons reporting poor and good self rated health were similar across socioeconomic groups within each sex. The mortality risk difference between persons reporting poor and good self rated health was considerably higher among persons with a chronic illness than among persons without a chronic illness. The mortality risk among persons reporting poor health was increased for shorter (<2 years) as well as longer (10+ years) periods of follow up.
CONCLUSIONS—The results suggest that poor self rated health is a strong predictor of subsequent mortality in all subgroups studied, and that self rated health therefore may be a useful outcome measure.
Keywords: self rated health; mortality
TL;DR: An inhibitory PAS (Per/Arnt/Sim) domain protein, IPAS, which is a basic helix-loop-helix (bHLH)/PAS protein structurally related to HIFs, is described, which demonstrates dominant negative regulation of HIF-mediated control of gene expression.
Abstract: Alteration of gene expression is a crucial component of adaptive responses to hypoxia. These responses are mediated by hypoxia-inducible transcription factors (HIFs)1,2. Here we describe an inhibitory PAS (Per/Arnt/Sim) domain protein, IPAS, which is a basic helix-loop-helix (bHLH)/PAS protein structurally related to HIFs. IPAS contains no endogenous transactivation function but demonstrates dominant negative regulation of HIF-mediated control of gene expression. Ectopic expression of IPAS in hepatoma cells selectively impairs induction of genes involved in adaptation to a hypoxic environment, notably the vascular endothelial growth factor (VEGF) gene, and results in retarded tumour growth and tumour vascular density in vivo. In mice, IPAS was predominantly expressed in Purkinje cells of the cerebellum and in corneal epithelium of the eye. Expression of IPAS in the cornea correlates with low levels of expression of the VEGF gene under hypoxic conditions. Application of an IPAS antisense oligonucleotide to the mouse cornea induced angiogenesis under normal oxygen conditions, and demonstrated hypoxia-dependent induction of VEGF gene expression in hypoxic corneal cells. These results indicate a previously unknown mechanism for negative regulation of angiogenesis and maintenance of an avascular phenotype.
TL;DR: The aim was to examine the effect of glucagon-like peptide-1 on subsequent energy intake using a data set composed of subject data from previous studies and from two as yet unpublished studies, and investigate whether the effect on energy intake is dose dependent and differs between lean and overweight subjects.
Abstract: Seven studies have now been published pertaining to the acute effect of iv administration of glucagon-like peptide-1 (7-36) amide on ad libitum energy intake. In four of these studies energy intake was significantly reduced following the glucagon-like peptide-1 infusion compared with saline. In the remaining studies, no significant effect of glucagon-like peptide-1 could be shown. Lack of statistical power or low glucagon-like peptide-1 infusion rate may explain these conflicting results. Our aim was to examine the effect of glucagon-like peptide-1 on subsequent energy intake using a data set composed of subject data from previous studies and from two as yet unpublished studies. Secondly, we investigated whether the effect on energy intake is dose dependent and differs between lean and overweight subjects. Raw subject data on body mass index and ad libitum energy intake were collected into a common data set (n = 115), together with study characteristics such as infusion rate, duration of infusion, etc. From four studies with comparable protocol the following subject data were included if available: plasma concentrations of glucagon-like peptide-1, subjective appetite measures, well-being, and gastric emptying rate of a meal served at the start of the glucagon-like peptide-1 infusion. Energy intake was reduced by 727 kJ (95% confidence interval, 548-908 kJ) or 11.7% during glucagon-like peptide-1 infusion. Although the absolute reduction in energy intake was higher in lean (863 kJ) (634-1091 kJ) compared with overweight subjects (487 kJ) (209-764 kJ) (P = 0.05), the relative reduction did not differ between the two groups (13.2% and 9.3%, respectively). Stepwise regression analysis showed that the glucagon-like peptide-1 infusion rate was the only independent predictor of the reduction in energy intake during glucagon-like peptide-1 (7-36) amide infusion (r = 0.4, P < 0.001). Differences in mean plasma glucagon-like peptide-1 concentration on the glucagon-like peptide-1 and placebo day (n = 43) were related to differences in feelings of prospective consumption (r = 0.40, P < 0.01), fullness (r = 0.38, P < 0.05), and hunger (r = 0.26, P = 0.09), but not to differences in ad libitum energy intake. Gastric emptying rate was significantly lower during glucagon-like peptide-1 infusion compared with saline. Finally, well-being was not influenced by the glucagon-like peptide-1 infusion. Glucagon-like peptide-1 infusion reduces energy intake dose dependently in both lean and overweight subjects. A reduced gastric emptying rate may contribute to the increased satiety induced by glucagon-like peptide-1.
TL;DR: The results show that the HRQoL varies greatly between socio-economic and disease groups, and after controlling for age, sex and disease, HRZoL is lower in manual than in non-manual groups.
Abstract: Health-related quality of life (HRQoL) measured on population level may be useful to guide policies for health. This study aims to describe the HRQoL; in EQ-5D dimensions, mean rating scale (RS) scores and mean EQ-5D index values, in the general population, by certain disease and socio-economic groups, in Stockholm County 1998. The EQ-5D self-classifier and a RS were included in the 1998 cross-sectional postal Stockholm County public health survey to a representative sample (n = 4950, 20-88 years), 63% response rate. Mean RS score ranged from 0.90 (20-29 years) to 0.69 (80-88 years), mean EQ-5D index value ranged from 0.89 (20-29 years) to 0.74 (80-88 years). For different diseases mean RS scores ranged from 0.80 (asthma) to 0.69 (angina pectoris), mean EQ-5D index values ranged from 0.79 (asthma) to 0.66 (low back pain). The mean health state scores (RS and EQ-5D index) were 0.06 lower in the unskilled manual group than in the higher non-manual group after controlling for age and sex (p < 0.0001). This difference was 0.03 after controlling also for different diseases (p < 0.0001). In conclusion, our results show that the HRQoL varies greatly between socio-economic and disease groups. Furthermore, after controlling for age, sex and disease, HRQoL is lower in manual than in non-manual groups.
TL;DR: It remains puzzling to me why the investigators restricted the entry criteria and consequently selected a population that was not representative of general clinical practice when excluding patients with frequently coexisting medical conditions such as diabetes, chronic obstructive pulmonary disease, and endocrine diseases.
Abstract: To the Editor:
In their recently published, 1-year prospective, double blind, placebo-controlled study, Winblad et al.1 examined the long-term clinical efficacy and safety of donepezil in mild to moderate AD. I congratulate the investigators for their effort. Unfortunately, it remains puzzling to me why the investigators restricted the entry criteria and consequently selected a population that was not representative of general clinical practice. By excluding patients with frequently coexisting medical conditions such as diabetes, chronic obstructive pulmonary disease, and endocrine diseases, the demonstrable effect of the treatment is not obscured by comorbid conditions and is therefore probably the greatest possible effect that can be observed. One clinical trial revealed that including patients with significant comorbidity reduced the beneficial effect of donepezil by almost 50% of that observed in trials with more rigorous entry criteria.2 In addition, the strict lack of any significant effect at the end point (last observation carried forward; LOCF) on the primary efficacy parameter raises questions. Furthermore, it is questionable whether the magnitude of change taken at its highest value (week 52 [6.2 units or 9.6%]) is detectable by the physician and caregivers. …
TL;DR: The HPV16 L1 VLP vaccine is well tolerated and is highly immunogenic even without adjuvant, with the majority of the recipients achieving serum antibody titers that were approximately 40-fold higher than what is observed in natural infection.
Abstract: Background Studies in animal models have shown that systemic immunization with a papillomavirus virus-like particle (VLP) vaccine composed of L1, a major structural viral protein, can confer protection against subsequent experimental challenge with the homologous virus. Here we report results of a double-blind, placebo-controlled, dose-escalation trial to evaluate the safety and immunogenicity of a human papillomavirus (HPV) type 16 (HPV16) L1 VLP vaccine in healthy adults. Methods Volunteers were given intramuscular injections with placebo or with 10- or 50-microg doses of HPV16 L1 VLP vaccine given without adjuvant or with alum or MF59 as adjuvants at 0, 1, and 4 months. All vaccine recipients were monitored for clinical signs and symptoms for 7 days after each inoculation. Immune responses were measured by an HPV16 L1 VLP-based enzyme-linked immunosorbent assay (ELISA) and by an HPV16 pseudovirion neutralization assay. The antibody titers were given as the reciprocals of the highest dilution showing positive reactivity in each assay. All statistical tests were two-sided. Results The prevaccination geometric mean ELISA titer for six seropositive individuals was 202 (range, 40--640). All vaccine formulations were well tolerated, and all subjects receiving vaccine seroconverted. Serum antibody responses at 1 month after the third injection were dose dependent in recipients of vaccine without adjuvant or with MF59 but were similar at both doses when alum was the adjuvant. With the higher dose, the geometric means of serum ELISA antibody titers (95% confidence intervals) to purified VLP 1 month after the third injection were as follows: 10,240 (1499 to 69 938) without adjuvant, 10,240 (1114 to 94 145) with MF59, and 2190 (838 to 5723) with alum. Responses of subjects within each group were similar. Neutralizing and ELISA antibody titers were highly correlated (Spearman correlation =.85), confirming that ELISA titers are valid proxies for neutralizing antibodies. Conclusions The HPV16 L1 VLP vaccine is well tolerated and is highly immunogenic even without adjuvant, with the majority of the recipients achieving serum antibody titers that were approximately 40-fold higher than what is observed in natural infection.
TL;DR: Obesity is associated with more forms of cancer than previously reported and the association of obesity with risk of breast, prostate and pancreas cancers was modified by age.
Abstract: Objective: We evaluated the relation between obesity and the risks for various forms of cancer.
TL;DR: It is concluded that the TVT procedure seems to fulfil the expectations of high long-term cure rates, as suggested in previous short-term reports.
Abstract: In a prospective long-term Nordic multicenter study, 90 consecutive patients who had a tension-free vaginal tape (TVT) operation performed because of stress urinary incontinence were evaluated according to a strict protocol after approximately 5 years (range 48–70 months). Eighty-five patients could be evaluated according to the protocol. Another 5 elderly patients had to be interviewed by telephone at the final check-up after 5 years. The study protocol involved pre- and postoperative objective and subjective evaluation. The median follow-up time was 56 months. Seventy-two of the 85 patients who were fully evaluated (84.7%) were both objectively and subjectively completely cured. Another 9 patients (10.6%) were significantly improved and 4 (4.7%) were regarded as failures. No patient complained of long-term voiding difficulties and there were no signs of defective healing or rejection of the tape material. All patients had suffered from primary stress incontinence, and 25 also had preoperative complaints of urge. In 14 of these (56%) the urge symptoms were relieved postoperatively. We conclude that the TVT procedure seems to fulfil the expectations of high long-term cure rates, as suggested in previous short-term reports.
TL;DR: Individuals who consume very low amounts of fruit and vegetables have the greatest risk of colorectal cancer, and the dose-response effect was more evident among individuals who consumed the lowest amounts of Fruit and vegetables.
Abstract: Background: Several recent large prospective cohort studies have failed to demonstrate the presumed protective effect of fruit, vegetable, and dietary fiber consumption on colorectal cancer risk. To further explore this issue, we have examined these associations in a population that consumes relatively low amounts of fruit and vegetables and high amounts of cereals. Methods: We examined data obtained from a foodfrequency questionnaire used in a population-based prospective mammography screening study of women in central Sweden. Women with colorectal cancer diagnosed through December 31, 1998, were identified by linkage to regional cancer registries. Cox proportional hazards models were used to estimate relative risks. All statistical tests were twosided. Results: During an average 9.6 years of follow-up of 61 463 women, we observed 460 incident cases of colorectal cancer (291 colon cancers, 159 rectal cancers, and 10 cancers at both sites). In the entire study population, total fruit and vegetable consumption was inversely associated with colorectal cancer risk. Subanalyses showed that this association was due largely to fruit consumption. The association was stronger, however, and the dose–response effect was more evident among individuals who consumed the lowest amounts of fruit and vegetables. Individuals who consumed less than 1.5 servings of fruit and vegetables per day had a relative risk for developing colorectal cancer of 1.65 (95% confidence interval = 1.23 to 2.20; Ptrend = .001) compared with individuals who consumed more than 2.5 servings. We observed no association between colorectal cancer risk and the consumption of cereal fiber, even at amounts substantially greater than previously examined, or of non-cereal fiber. Conclusions: Individuals who consume very low amounts of fruit and vegetables have the greatest risk of colorectal cancer. Relatively high consumption of cereal fiber does not appear to lower the risk of colorectal cancer. [J Natl Cancer Inst 2001;93:525–33]
TL;DR: Cathelicidins are well suited to provide defense against infections due to group A Streptococcus, and represent an important element of cutaneous innate immunity.