Summary Background Great heterogeneity exists in survival and the interval between onset of motor symptoms and dementia symptoms across synucleinopathies. We aimed to identify genetic and ...pathological markers that have the strongest association with these features of clinical heterogeneity in synucleinopathies. Methods In this retrospective study, we examined symptom onset, and genetic and neuropathological data from a cohort of patients with Lewy body disorders with autopsy-confirmed α synucleinopathy (as of Oct 1, 2015) who were previously included in other studies from five academic institutions in five cities in the USA. We used histopathology techniques and markers to assess the burden of tau neurofibrillary tangles, neuritic plaques, α-synuclein inclusions, and other pathological changes in cortical regions. These samples were graded on an ordinal scale and genotyped for variants associated with synucleinopathies. We assessed the interval from onset of motor symptoms to onset of dementia, and overall survival in groups with varying levels of comorbid Alzheimer's disease pathology according to US National Institute on Aging–Alzheimer's Association neuropathological criteria, and used multivariate regression to control for age at death and sex. Findings On the basis of data from 213 patients who had been followed up to autopsy and met inclusion criteria of Lewy body disorder with autopsy-confirmed α synucleinopathy, we identified 49 (23%) patients with no Alzheimer's disease neuropathology, 56 (26%) with low-level Alzheimer's disease neuropathology, 45 (21%) with intermediate-level Alzheimer's disease neuropathology, and 63 (30%) with high-level Alzheimer's disease neuropathology. As levels of Alzheimer's disease neuropathology increased, cerebral α-synuclein scores were higher, and the interval between onset of motor and dementia symptoms and disease duration was shorter (p<0·0001 for all comparisons). Multivariate regression showed independent negative associations of cerebral tau neurofibrillary tangles score with the interval between onset of motor and dementia symptoms (β −4·0, 95% CI −5·5 to −2·6; p<0·0001; R2 0·22, p<0·0001) and with survival (–2·0, −3·2 to −0·8; 0·003; 0·15, <0·0001) in models that included age at death, sex, cerebral neuritic plaque scores, cerebral α-synuclein scores, presence of cerebrovascular disease, MAPT haplotype, and APOE genotype as covariates. Interpretation Alzheimer's disease neuropathology is common in synucleinopathies and confers a worse prognosis for each increasing level of neuropathological change. Cerebral neurofibrillary tangles burden, in addition to α-synuclein pathology and amyloid plaque pathology, are the strongest pathological predictors of a shorter interval between onset of motor and dementia symptoms and survival. Diagnostic criteria based on reliable biomarkers for Alzheimer's disease neuropathology in synucleinopathies should help to identify the most appropriate patients for clinical trials of emerging therapies targeting tau, amyloid-β or α synuclein, and to stratify them by level of Alzheimer's disease neuropathology. Funding US National Institutes of Health (National Institute on Aging and National Institute of Neurological Disorders and Stroke).
Ichthyosis vulgaris (OMIM 146700) is the most common inherited disorder of keratinization and one of the most frequent single-gene disorders in humans. The most widely cited incidence figure is 1 in ...250 based on a survey of 6,051 healthy English schoolchildren. We have identified homozygous or compound heterozygous mutations R501X and 2282del4 in the gene encoding filaggrin (FLG) as the cause of moderate or severe ichthyosis vulgaris in 15 kindreds. In addition, these mutations are semidominant; heterozygotes show a very mild phenotype with incomplete penetrance. The mutations show a combined allele frequency of ∼4% in populations of European ancestry, explaining the high incidence of ichthyosis vulgaris. Profilaggrin is the major protein of keratohyalin granules in the epidermis. During terminal differentiation, it is cleaved into multiple filaggrin peptides that aggregate keratin filaments. The resultant matrix is cross-linked to form a major component of the cornified cell envelope. We find that loss or reduction of this major structural protein leads to varying degrees of impaired keratinization.
Celotno besedilo
Dostopno za:
DOBA, IJS, IZUM, KILJ, NUK, PILJ, PNG, SAZU, UILJ, UKNU, UL, UM, UPUK
We provide an updated version of the Compendium of Physical Activities, a coding scheme that classifies specific physical activity (PA) by rate of energy expenditure. It was developed to enhance the ...comparability of results across studies using self-reports of PA. The Compendium coding scheme links a five-digit code that describes physical activities by major headings (e.g., occupation, transportation, etc.) and specific activities within each major heading with its intensity, defined as the ratio of work metabolic rate to a standard resting metabolic rate (MET). Energy expenditure in MET-minutes, MET-hours, kcal, or kcal per kilogram body weight can be estimated for specific activities by type or MET intensity. Additions to the Compendium were obtained from studies describing daily PA patterns of adults and studies measuring the energy cost of specific physical activities in field settings. The updated version includes two new major headings of volunteer and religious activities, extends the number of specific activities from 477 to 605, and provides updated MET intensity levels for selected activities.
Hyperglycemia and Adverse Pregnancy Outcomes Metzger, Boyd E; Lowe, Lynn P; Dyer, Alan R ...
The New England journal of medicine,
05/2008, Letnik:
358, Številka:
19
Journal Article
Recenzirano
Odprti dostop
In this large, multinational study, glucose levels that were increased during pregnancy but were below levels diagnostic of diabetes were significantly associated with increased risks of birth weight ...above the 90th percentile and C-peptide levels above the 90th percentile, as well as with other adverse pregnancy outcomes. These results indicate the need to reconsider current thresholds for diagnosing and treating hyperglycemia during pregnancy.
Glucose levels that were increased during pregnancy but were below levels diagnostic of diabetes were significantly associated with increased risks of birth weight above the 90th percentile and C-peptide levels above the 90th percentile, as well as with other adverse pregnancy outcomes.
Gestational diabetes mellitus, defined as “glucose intolerance with onset or first recognition during pregnancy,”
1
,
2
has been the subject of considerable controversy. Criteria for the diagnosis were initially established more than 40 years ago
3
and, with minor modifications, remain in use today. These criteria are not designed to identify pregnant women who are at increased risk for adverse perinatal outcomes but rather women who are at high risk for the development of diabetes after pregnancy,
3
,
4
or they are the criteria used for the general population.
5
Overt diabetes mellitus during pregnancy is associated with significantly increased risks of adverse perinatal . . .
Various methods are used by epidemiologists to estimate the energy cost of physical activity; these include physical activity records and recalls. However, there is limited validation of these ...methods against the doubly labeled water technique for determining energy expenditure (EE).
We compared EE as estimated by indirect methods (physical activity records and recall questionnaires) used in epidemiologic studies with EE obtained from doubly labeled water (EE(DLW)) in free-living men.
We determined EE(DLW), energy intake at weight maintenance, and EE from 7-d physical activity records (EE(Record)) and a 7-d physical activity recall questionnaire (EE(Recall)) in 24 men aged 41 plus minus 2.0 y ( plus minus SEM) with a body mass index (in kg/m(2)) of 25.1 plus minus 0.5.
There was excellent agreement between EE(DLW) (13.27 plus minus 0.35 MJ/d) and energy intake (13.19 plus minus 0.36 MJ/d), with a difference of 0.5 plus minus 1.0% ( plus minus SE). The indirect measures of physical activity and EE were 14.17 plus minus 0.37 MJ/d for EE(Record) (difference from EE(DLW): 7.9 plus minus 3.2%) and 17.40 plus minus 1.45 MJ/d for EE(Recall) (difference from EE(DLW): 30.6 plus minus 9.9%).
Seven-day physical activity records provide an acceptable estimate of EE in free-living adults compared with EE(DLW), but 7-d physical activity recalls have limited application to estimate daily EE. For optimal validity, the 7-d physical activity records require good subject compliance and the provision of careful instructions for their use.
The ability of human immunodeficiency virus (HIV-1) to persist and cause AIDS is dependent on its avoidance of antibody-mediated neutralization. The virus elicits abundant, envelope-directed ...antibodies that have little neutralization capacity. This lack of neutralization is paradoxical, given the functional conservation and exposure of receptor-binding sites on the gp120 envelope glycoprotein, which are larger than the typical antibody footprint and should therefore be accessible for antibody binding. Because gp120-receptor interactions involve conformational reorganization, we measured the entropies of binding for 20 gp120-reactive antibodies. Here we show that recognition by receptor-binding-site antibodies induces conformational change. Correlation with neutralization potency and analysis of receptor-antibody thermodynamic cycles suggested a receptor-binding-site 'conformational masking' mechanism of neutralization escape. To understand how such an escape mechanism would be compatible with virus-receptor interactions, we tested a soluble dodecameric receptor molecule and found that it neutralized primary HIV-1 isolates with great potency, showing that simultaneous binding of viral envelope glycoproteins by multiple receptors creates sufficient avidity to compensate for such masking. Because this solution is available for cell-surface receptors but not for most antibodies, conformational masking enables HIV-1 to maintain receptor binding and simultaneously to resist neutralization.
Celotno besedilo
Dostopno za:
DOBA, IJS, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Cytokine-mobilized peripheral blood is increasingly used instead of bone marrow as the source of cells for allogeneic transplantation. Although cells lead to faster hematologic recovery, their ...effects on graft-versus-host disease, relapse, and survival are less certain. Between January 1996 and February 2000, 228 patients with chronic myeloid leukemia, acute myeloid leukemia, or myelodysplasia were randomized to receive either bone marrow or peripheral blood allografts from HLA-matched siblings. All patients received busulfan and cyclophosphamide as conditioning chemotherapy and cyclosporine and methotrexate as graft-versus-host disease prophylaxis. We compared the times to neutrophil and platelet recovery, acute and chronic graft-versus-host disease, relapse, and overall survival between the groups. The median times to neutrophil recovery were 19 days and 23 days and the times to platelet recovery were 16 days and 22 days in the peripheral blood and bone marrow groups, respectively (P < .0001 for both comparisons). The cumulative incidence of grades II to IV acute graft-versus-host disease 100 days after transplantation was 44% in both groups (hazard ratio, 0.99; 95% confidence interval, 0.66-1.49; P > .9), and the incidence of extensive chronic graft-versus-host disease at 30 months after transplantation was 40% with peripheral blood and 30% with bone marrow (hazard ratio, 1.23; 95% confidence interval, 0.78-1.96; P = .37). There was no statistically significant difference in the probability of relapse of the underlying disease between the groups. The probabilities of survival at 30 months after transplantation were 68% and 60% in the peripheral blood and bone marrow groups, respectively (hazard ratio, 0.62; 95% confidence interval, 0.39-0.97; P = .04). In patients with chronic myeloid leukemia, acute myeloid leukemia, and myelodysplasia undergoing allogeneic transplantation from matched siblings, the use of peripheral blood instead of bone marrow leads to faster hematologic recovery, similar risk of graft-versus-host disease, and improved survival.
In psychoacoustic studies there is often a need to assess performance indices quickly and reliably. The aim of this study was to establish a quick and reliable procedure for evaluating thresholds in ...backward masking and frequency discrimination tasks. Based on simulations, four procedures likely to produce the best results were selected, and data collected from 20 naive adult listeners on each. Each procedure used one of two adaptive methods (staircase or maximum-likelihood estimation, each targeting the 79% correct point on the psychometric function) and two response paradigms (3-interval, 2-alternative forced-choice AXB or 3-interval; 3-alternative forced-choice oddball). All procedures yielded statistically equivalent threshold estimates in both backward masking and frequency discrimination, with a trend to lower thresholds for oddball procedures in frequency discrimination. Oddball procedures were both more efficient and more reliable (test-retest) in backward masking, but all four procedures were equally efficient and reliable in frequency discrimination. Fitted psychometric functions yielded similar thresholds to averaging over reversals in staircase procedures. Learning was observed across threshold-assessment blocks and experimental sessions. In four additional groups, each of ten listeners, trained on the different procedures, no differences in performance improvement or rate of learning were observed, suggesting that learning is independent of procedure.
Relapsed B-cell lymphomas are incurable with conventional chemotherapy and radiation therapy, although a fraction of patients can be cured with high-dose chemoradiotherapy and autologous stem-cell ...transplantation (ASCT). We conducted a phase I/II trial to estimate the maximum tolerated dose (MTD) of iodine 131 (131I)–tositumomab (anti-CD20 antibody) that could be combined with etoposide and cyclophosphamide followed by ASCT in patients with relapsed B-cell lymphomas. Fifty-two patients received a trace-labeled infusion of 1.7 mg/kg 131I-tositumomab (185-370 MBq) followed by serial quantitative gamma-camera imaging and estimation of absorbed doses of radiation to tumor sites and normal organs. Ten days later, patients received a therapeutic infusion of 1.7 mg/kg tositumomab labeled with an amount of131I calculated to deliver the target dose of radiation (20-27 Gy) to critical normal organs (liver, kidneys, and lungs). Patients were maintained in radiation isolation until their total-body radioactivity was less than 0.07 mSv/h at 1 m. They were then given etoposide and cyclophosphamide followed by ASCT. The MTD of131I-tositumomab that could be safely combined with 60 mg/kg etoposide and 100 mg/kg cyclophosphamide delivered 25 Gy to critical normal organs. The estimated overall survival (OS) and progression-free survival (PFS) of all treated patients at 2 years was 83% and 68%, respectively. These findings compare favorably with those in a nonrandomized control group of patients who underwent transplantation, external-beam total-body irradiation, and etoposide and cyclophosphamide therapy during the same period (OS of 53% and PFS of 36% at 2 years), even after adjustment for confounding variables in a multivariable analysis.
IGFBP-1 is elevated in fetuses with long-term, chronic hypoxia and intrauterine growth restriction. We investigated the hypothesis that hypoxia regulates IGFBP-1 in the human fetus in vivo and ...IGFBP-1 gene expression and protein in vitro. Umbilical artery IGFBP-1 levels (mean ± SEM) from term babies with respiratory acidosis (acute hypoxia), normal babies, and those with mixed respiratory/metabolic acidosis (more profound and prolonged hypoxia) were measured using an immunoradiometric assay. IGFBP-1 levels were similar in normal (n = 12) and acutely hypoxic (n = 6) babies (189.1 ± 71.8 vs. 175.8 ± 45.9 ng /ml, respectively, P = 0.789). However, with more profound and prolonged hypoxia (n = 19), IGFBP-1 levels were markedly elevated (470.6 ± 80.0 ng/ml, P = 0.044). To investigate IGFBP-1 regulation by hypoxia in vitro, HepG2 cells were incubated under hypoxia (pO2= 2%) and normoxia (pO2= 20%). IGFBP-1 protein and mRNA increased 8- and 12-fold, respectively, under hypoxic conditions. Hypoxia did not affect protein or mRNA levels of IGFBP-2 or -4. IGFBP-5 and -6 mRNAs, undetectable in control cells, were not induced by hypoxia, whereas minimally expressed IGFBP-3 mRNA increased twofold. Investigation into IGFBP-1 gene structure revealed three potential consensus sequences for the hypoxia response element (HRE) in the first intron. To investigate functionality, a 372-bp fragment of IGFBP-1 intron 1, containing putative HREs, was placed 5′to a heterologous hsp70 promoter in a plasmid using luciferase as a reporter gene. Under hypoxia, reporter gene activity increased up to 30-fold. Mutations in the middle HRE abolished reporter activity in response to hypoxia, suggesting that this HRE is functional in the IGFBP-1 hypoxia response. Cotransfection of HRE reporter genes with a constitutively expressing hypoxia-inducible factor 1 plasmid in HepG2 cells resulted in a fourfold induction of reporter activity, suggesting a role for hypoxia-inducible factor 1 in hypoxia induction of IGFBP-1 gene expression. These data support the hypothesis that hypoxia regulation of IGFBP-1 may be a mechanism operating in the human fetus to restrict insulin-like growth factor-mediated growth in utero under conditions of chronic hypoxia and limited substrate availability.
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