When You Can't Walk a Mile: Walking Limitation Prevalence and Associations Among Middle-Aged and Older US Adults with Arthritis: A Cross-Sectional, Population-Based Study.

OBJECTIVE: We examined walking limitations and associated characteristics among middle-aged and older US adults with arthritis, overall, and by sex. METHODS: Using 2005-2006 Arthritis Conditions and Health Effects Survey (ACHES) data (n = 1793), we estimated "a lot" and "any" ("a lot" or "a little" combined) walking limitation for more than 1 mile (1.6 km) among US adults 45 years or older with arthritis and examined associations (sociodemographics, arthritis symptoms and effects, psychosocial measures, and physical health) with walking limitations in unadjusted and multivariable (MV) adjusted logistic regression models using prevalence ratios (PRs) and 95% confidence intervals, accounting for the complex survey design. RESULTS: Respondents frequently reported "a lot" (48%) and "any" (72%) limitation for more than 1 mile. Women reported higher prevalence of all levels of walking limitation versus men (eg, 51% vs 42% for "a lot" overall); additionally, the gap for walking limitations between women and men widened with age. Limitation was high for both sexes at all ages, affecting 1-in-3 to 4-in-5, depending on level of walking limitation. The strongest MV associations for "a lot" of walking limitation among all respondents included substantial and modest arthritis-attributable life interference (PR = 2.5 and 1.6, respectively), age 75 years or older (PR = 1.5), and physical inactivity and fair/poor self-rated health (PR = 1.4 for both). CONCLUSION: Walking limitations among middle-aged and older adults are substantial. Existing proven interventions that improve walking ability and physical function may help this population to reduce and delay disability.

Associations of Arthritis-Attributable Interference with Routine Life Activities: A Modifiable Source of Compromised Quality-of-Life.

OBJECTIVE: Arthritis patients experience the impact of disease beyond routinely assessed clinical measures. We characterized arthritis-attributable interference in four important routine life domains: 1) recreation/leisure/hobbies; 2) household chores; 3) errands/shopping; and 4) social activities. METHODS: Participants were from the Arthritis Conditions Health Effects Survey (2005-2006), a cross-sectional survey of noninstitutionalized US adults 45 years or older with doctor-diagnosed arthritis (n = 1793). We estimated the prevalence of "a lot" of arthritis-attributable interference and quantified the associations between sociodemographic, clinical, and psychological characteristics and "a lot" of arthritis-attributable interference (vs "a little" or "none") in each domain using prevalence ratios (PRs) in multivariable (MV)-adjusted logistic regression models. RESULTS: An estimated 1 in 5 to 1 in 4 adults with arthritis reported "a lot" of arthritis-attributable interference in recreation/leisure/hobbies (27%), household chores (25%), errands/shopping (22%), and social activities (18%). The highest prevalence of "a lot" of arthritis-attributable interference was for those unable to work/disabled or reporting severe arthritis symptoms (pain, stiffness, fatigue), anxiety, depression, or no/low confidence in ability to manage arthritis, across domains. In MV-adjusted models, those unable to work/disabled, currently seeing a doctor, or reporting fair/poor self-rated health, severe joint pain, anxiety, or no/low confidence in ability to manage arthritis were more likely to report arthritis-attributable interference than their respective counterparts. Magnitudes varied by domain but were consistently strongest for those unable to work/disabled (MV PR range = 1.8-2.5) and with fair/poor health (MV PR range = 1.7-2.7). CONCLUSION: Many characteristics associated with arthritis-attributable interference in routine life activities are potentially modifiable, suggesting unmet need for use of existing evidence-based interventions that address these characteristics and reduce interferences to improve quality of life.

Employment exit and entry among U.S. adults with and without arthritis during the Great Recession. A longitudinal study: 2007-2009, NHIS/MEPS.

BACKGROUND: Negative employment consequences of arthritis are known but not fully understood. Examining transitions in and out of work can provide valuable information. OBJECTIVE: To examine associations of arthritis with employment during the Great Recession and predictors of employment transitions. METHODS: Data were for 3,277 adults ages 30-62 years with and without arthritis from the 2007 National Health Interview Survey followed in the Medical Expenditure Panel Survey 2008-2009. Employment (working vs. not working) was ascertained at baseline and five follow-ups. We estimated Kaplan Meier survival curves with 95% confidence intervals (CI) separately for time to stopping work (working at baseline) and starting work (not working at baseline) using Cox proportional hazards regression models with hazard ratios (HR). RESULTS: Arthritis was significantly associated with greater risk of stopping work (HR = 1.7, 95% CI = 1.3-2.2; adjusted HR= 1.5, 95% CI = 1.1-2.0) and significantly associated with 40% lower chance of starting work (HR = 0.6, 95% CI = 0.4-0.8), which reversed on adjustment (HR = 1.5, 95% CI = 1.0-2.2). Employment predictors were mixed by outcome. CONCLUSIONS: During the Great Recession, adults with arthritis stopped work at higher rates and started work at lower rates than those without arthritis.

Variable responses of human microbiomes to dietary supplementation with resistant starch.

BACKGROUND: The fermentation of dietary fiber to various organic acids is a beneficial function provided by the microbiota in the human large intestine. In particular, butyric acid contributes to host health by facilitating maintenance of epithelial integrity, regulating inflammation, and influencing gene expression in colonocytes. We sought to increase the concentration of butyrate in 20 healthy young adults through dietary supplementation with resistant starch (unmodified potato starch-resistant starch (RS) type 2). METHODS: Fecal samples were collected from individuals to characterize butyrate concentration via liquid chromatography and composition of the microbiota via surveys of 16S rRNA-encoding gene sequences from the Illumina MiSeq platform. Random Forest and LEfSe analyses were used to associate responses in butyrate production to features of the microbiota. RESULTS: RS supplementation increased fecal butyrate concentrations in this cohort from 8 to 12 mmol/kg wet feces, but responses varied widely between individuals. Individuals could be categorized into three groups based upon butyrate concentrations before and during RS: enhanced, high, and low (n = 11, 3, and 6, respectively). Fecal butyrate increased by 67 % in the enhanced group (from 9 to 15 mmol/kg), while it remained ≥11 mmol/kg in the high group and ≤8 mmol/kg in the low group. Microbiota analyses revealed that the relative abundance of RS-degrading organisms-Bifidobacterium adolescentis or Ruminococcus bromii-increased from ~2 to 9 % in the enhanced and high groups, but remained at ~1.5 % in the low group. The lack of increase in RS-degrading bacteria in the low group may explain why there was no increase in fecal butyrate in response to RS. The microbiota of individuals in the high group were characterized by an elevated abundance of the butyrogenic microbe Eubacterium rectale (~6 % in high vs. 3 % in enhanced and low groups) throughout the study. CONCLUSIONS: We document the heterogeneous responses in butyrate concentrations upon RS supplementation and identify characteristic of the microbiota that appear to underlie this variation. This study complements and extends other studies that call for personalized approaches to manage beneficial functions provided by gut microbiomes.

Social participation restriction among US adults with arthritis: a population-based study using the International Classification of Functioning, Disability and Health.

OBJECTIVE: To examine arthritis impact among US adults with self-reported doctor-diagnosed arthritis using the International Classification of Functioning, Disability and Health (ICF) framework (including the impairments, activity limitations, environmental, and personal factors domains and social participation restriction [SPR] as the outcome) overall and among those with and without SPR, and to identify the correlates of SPR. METHODS: Cross-sectional 2009 National Health Interview Survey data were analyzed to examine the distribution of the ICF domain components. Unadjusted and multivariable-adjusted prevalence ratios (PRs) and 95% confidence intervals (95% CIs) were estimated to identify the correlates of SPR. Analyses using SAS, version 9.2 survey procedures accounted for the complex sample design. RESULTS: SPR prevalence was 11% of adults with arthritis (5.7 million). After initial multivariable adjustment by ICF domain, serious psychological distress (impairments domain; PR 2.5 [95% CI 2.0-3.2]), ≥5 medical office visits (environmental domain; PR 3.4 [95% CI 2.5-4.4]), and physical inactivity (personal domain; PR 4.8 [95% CI 3.6-6.4]) were most strongly associated with SPR. A combined measure (key limitations [walking, standing, or carrying]; PR 31.2 [95% CI 22.3-43.5]) represented the activity limitations domain. After final multivariable adjustment incorporating all ICF domains simultaneously, the strongest associations with SPR were key limitations (PR 24.3 [95% CI 16.8-35.1]), ≥9 hours of sleep (PR 1.6 [95% CI 1.3-2.0]), and income-to-poverty ratio <2.00 and severe joint pain (PR 1.4 [95% CI 1.2-1.6] for both). CONCLUSION: SPR affects 1 of 9 adults with arthritis. This study is the first to use the ICF framework in a population-based sample to identify specific functional activities, pain, sleep, and other areas as priorities for intervention to reduce negative arthritis impacts on disability, including SPR. Increased use of existing clinical and public health interventions is warranted.

Azatrioxa[8]circulenes: planar anti-aromatic cyclooctatetraenes.

We describe herein the first synthesis of a new class of anti-aromatic planar cyclooctatetraenes: the azatrioxa[8]circulenes. This was achieved by treating a suitably functionalised 3,6-dihydroxycarbazole with 1,4-benzoquinones or a 1,4-naphthoquinone. We fully characterised the azatrioxa[8]circulenes by using optical, electrochemical and computational techniques as well as by single-crystal X-ray crystallography. The results of a computational study (NICS) suggest that the central planar cyclooctatetraene is anti-aromatic when the molecules are in neutral or oxidised states (2+), and that the corresponding dianions are aromatic. We discuss the aromatic/anti-aromatic nature of the planar cyclooctatetraenes and compare them with the isoelectronic tetraoxa[8]circulenes.

Crystal structure and deletion analysis show that the accessory subunit of mammalian DNA polymerase gamma, Pol gamma B, functions as a homodimer.

Polymerase gamma, which replicates and repairs mitochondrial DNA, requires the Pol gamma B subunit for processivity. We determined the crystal structure of mouse Pol gamma B, a core component of the mitochondrial replication machinery. Pol gamma B shows high similarity to glycyl-tRNA synthetase and dimerizes through an unusual intermolecular four-helix bundle. A human Pol gamma B mutant lacking the four-helix bundle failed to dimerize in solution or to stimulate the catalytic subunit Pol gamma A, but retained the ability to bind with Pol gamma A to a primer-template construct, indicating that the functional holoenzyme contains two Pol gamma B molecules. Other mutants retained stimulatory activity but lost the ability to bind folded ssDNA. These results suggest that the Pol gamma B dimer contains distinct sites for Pol gamma A binding, dimerization, and DNA binding.

The nucleotide excision repair protein UvrB, a helicase-like enzyme with a catch.

Nucleotide excision repair (NER) is a universal DNA repair mechanism found in all three kingdoms of life. Its ability to repair a broad range of DNA lesions sets NER apart from other repair mechanisms. NER systems recognize the damaged DNA strand and cleave it 3', then 5' to the lesion. After the oligonucleotide containing the lesion is removed, repair synthesis fills the resulting gap. UvrB is the central component of bacterial NER. It is directly involved in distinguishing damaged from undamaged DNA and guides the DNA from recognition to repair synthesis. Recently solved structures of UvrB from different organisms represent the first high-resolution view into bacterial NER. The structures provide detailed insight into the domain architecture of UvrB and, through comparison, suggest possible domain movements. The structure of UvrB consists of five domains. Domains 1a and 3 bind ATP at the inter-domain interface and share high structural similarity to helicases of superfamilies I and II. Not related to helicase structures, domains 2 and 4 are involved in interactions with either UvrA or UvrC, whereas domain 1b was implicated for DNA binding. The structures indicate that ATP binding and hydrolysis is associated with domain motions. UvrB's ATPase activity, however, is not coupled to the separation of long DNA duplexes as in helicases, but rather leads to the formation of the preincision complex with the damaged DNA substrate. The location of conserved residues and structural comparisons with helicase-DNA structures suggest how UvrB might bind to DNA. A model of the UvrB-DNA interaction in which a beta-hairpin of UvrB inserts between the DNA double strand has been proposed recently. This padlock model is developed further to suggest two distinct consequences of domain motion: in the UvrA(2)B-DNA complex, domain motions lead to translocation along the DNA, whereas in the tight UvrB-DNA pre-incision complex, they lead to distortion of the 3' incision site.

Crystal structure of UvrB, a DNA helicase adapted for nucleotide excision repair.

Nucleotide excision repair (NER) is a highly conserved DNA repair mechanism. NER systems recognize the damaged DNA strand, cleave it on both sides of the lesion, remove and newly synthesize the fragment. UvrB is a central component of the bacterial NER system participating in damage recognition, strand excision and repair synthesis. We have solved the crystal structure of UvrB in the apo and the ATP-bound forms. UvrB contains two domains related in structure to helicases, and two additional domains unique to repair proteins. The structure contains all elements of an intact helicase, and is evidence that UvrB utilizes ATP hydrolysis to move along the DNA to probe for damage. The location of conserved residues and structural comparisons allow us to predict the path of the DNA and suggest that the tight pre-incision complex of UvrB and the damaged DNA is formed by insertion of a flexible beta-hairpin between the two DNA strands.

Crystal structure of human arylsulfatase A: the aldehyde function and the metal ion at the active site suggest a novel mechanism for sulfate ester hydrolysis.

Human lysosomal arylsulfatase A (ASA) is a prototype member of the sulfatase family. These enzymes require the posttranslational oxidation of the -CH2SH group of a conserved cysteine to an aldehyde, yielding a formylglycine. Without this modification sulfatases are catalytically inactive, as revealed by a lysosomal storage disorder known as multiple sulfatase deficiency. The 2.1 A resolution X-ray crystal structure shows an ASA homooctamer composed of a tetramer of dimers, (alpha 2)4. The alpha/beta fold of the monomer has significant structural analogy to another hydrolytic enzyme, the alkaline phosphatase, and superposition of these two structures shows that the active centers are located in largely identical positions. The functionally essential formylglycine is located in a positively charged pocket and acts as ligand to an octahedrally coordinated metal ion interpreted as Mg2+. The electron density at the formylglycine suggests the presence of a 2-fold disordered aldehyde group with the possible contribution of an aldehyde hydrate, -CH(OH)2, with gem-hydroxyl groups. In the proposed catalytic mechanism, the aldehyde accepts a water molecule to form a hydrate. One of the two hydroxyl groups hydrolyzes the substrate sulfate ester via a transesterification step, resulting in a covalent intermediate. The second hydroxyl serves to eliminate sulfate under inversion of configuration through C-O cleavage and reformation of the aldehyde. This study provides the structural basis for understanding a novel mechanism of ester hydrolysis and explains the functional importance of the unusually modified amino acid.

Determination of backbone nitrogen-nitrogen J correlations in proteins.

Recently, a quantitative J correlation technique has been presented which makes use of homonuclear Hartmann-Hahn cross-polarization (TOCSY) to measure (3)J(C)'(C)' in proteins isotopically enriched with (13)C [Grzesiek, S. and Bax, A. (1997) J. Biomol. NMR, 9, 207-211]. Since homonuclear Hartmann-Hahn is twice as fast as conventional COSY transfer, this method is much less sensitive to transverse relaxation, which is the principal limiting factor in achieving long-range J-coupling correlations in macromolecules. Here we describe a similar experiment which is used to measure(3) J(NN) coupling constants between sequential amide(15) N nuclei in the backbone of ubiquitin. As expected from the low magnetic moment of (15)N, the (3)J(NN) coupling constants are exceedingly small, with values between 0.14 and 0.36 Hz for residues in ß-conformations and values below 0.15 Hz for residues in α-conformations. In contrast to what is expected from a Karplus-type dependence on the backbone angle ψ, large differences in the values of(3) J(NN) are observed for a number of residues with very similar backbone ψ angles. A quantitative description of statistical and systematic errors, in particular of relaxation effects during the TOCSY transfer, shows that these differences are highly significant.

High-altitude pulmonary edema at a ski resort.

Medical records of 150 patients with high-altitude pulmonary edema seen over a 39-month period in a Colorado Rocky Mountain ski area at 2,928 m (9,600 ft) (mean age 34.4 years; 84% male) were reviewed. The mean time to the onset of symptoms was 3 +/- 1.3 days after arrival. Common symptoms were dyspnea, cough, headache, chest congestion, nausea, fever, and weakness. Orthopnea, hemoptysis, and vomiting were rare, occurring in 7%, 6%, and 16%, respectively. Symptoms of cerebral edema occurred in 14%. A temperature exceeding 100 degrees F occurred in 20%, and 17% had a systolic blood pressure of 150 mm of mercury or higher. Blood pressures were higher in patients older than 50 years (142 mm of mercury). Rales were present in 85%, and a pulmonary infiltrate was present in 88%; both were most commonly bilateral or on the right side. The amount of infiltrate was mild. Men appeared to be more susceptible than women to high-altitude pulmonary edema. Pulse oximetry in 45 patients showed a mean oxygen saturation of 74% (38% to 93%). Treatment methods depended on severity and included a return to quarters for portable nasal oxygen, an overnight stay in the clinic for continuing oxygen, or a descent to Denver for recovery or admission to a hospital. All patients received oxygen for 2 to 4 hours in the clinic. There were no deaths or complications.

The uteroglobin promoter contains a noncanonical estrogen responsive element.

Uteroglobin is expressed in various tissues of the rabbit under complex hormonal control. In the endometrium the uteroglobin gene is transcribed only in epithelial cells after administration of ovarian hormones. In this paper we demonstrate that within the promoter region of the rabbit uteroglobin gene, there is a functional estrogen-responsive element (ERE) located between -265 and -252. Hybrid constructions containing sequences of the uteroglobin promoter up to -299, linked to the chloramphenicol acetyltransferase gene of E. coli respond to estrogens in gene transfer experiments, whereas a deletion that removes half of the ERE does not. A synthetic oligonucleotide corresponding to the putative ERE is able to confer estrogen inducibility to an otherwise unresponsive promoter. Binding experiments with purified estrogen receptor from calf uterus reveal a DNase-I footprint over the ERE. Within this protected region six guanine residues that have been shown to be contacted by the receptor in other EREs are protected against methylation by dimethylsulfate in the presence of the estrogen receptor. We compare this ERE with the vitellogenin A2 ERE from Xenopus and find that the relative affinity of the uteroglobin ERE is slightly lower than that of the vitellogenin ERE. Thus, this uteroglobin ERE could be involved in physiological regulation of uteroglobin expression in the genital tract.