Physical activity in adults with and without rheumatoid arthritis: cross-sectional results from the Survey of Health, Ageing and Retirement in Europe (SHARE).

OBJECTIVE: Studies examining habitual physical activity levels and patterns in adults with rheumatoid arthritis (RA) using raw data from modern accelerometers are lacking. We aimed (i) to examine physical activity levels and patterns in adults with RA in their familiar environment, and (ii) to investigate whether physical activity levels differ throughout the day. METHOD: Data were taken from Wave 8 of the Survey of Health, Ageing and Retirement in Europe, including N = 607 men and women who wore a triaxial accelerometer and had adequate information for RA and accelerometry data summarized as Euclidean norm minus one (ENMO, mg). Growth-curve models and simple contrast analysis were used to examine the effect of RA on daily patterns of physical activity levels, including mean total ENMO in mg, mean minutes of light-intensity physical activity (ENMO values ≥ 25 mg and ≤ 75 mg), and moderate-to-vigorous-intensity physical activity (ENMO values > 75 mg). RESULTS: Total physical activity averaged throughout the day was 25.0 and 28.6 mg for respondents with and without RA, respectively. Respondents with RA spent more time in light-intensity physical activity throughout the day (p < 0.001), but less time in moderate-to-vigorous-intensity physical activity between 4 am and 11 pm (p < 0.001) than respondents without RA. CONCLUSION: Adults with RA were less physically active than adults without RA. However, there were no diurnal differences in physical activity.

Changes in physical activity and the association between pain and physical activity - a longitudinal analysis of 17,454 patients with knee or hip osteoarthritis from the GLA:D® registry.

OBJECTIVE: Investigate change in physical activity following an 8-week education and exercise therapy program for patients with knee/hip osteoarthritis, focusing on those with low physical activity level. Furthermore, to evaluate associations between changes in pain intensity and physical activity. METHOD: Data from the Good Life with osteoArthritis in Denmark (GLA:D®) registry, at baseline, immediately after completion, and 12 months after entering the program was used. Measures of interest were UCLA activity scale (1-10) and Visual Analog Scale for pain intensity (0-100 mm). Changes in physical activity levels (low 1-4, moderate 5-6, and high 7-10) over three time points were investigated. Asymmetric fixed effects regression models were used to evaluate the association between clinically relevant change in pain (≥15 mm) and change in physical activity level from baseline to 12 months. RESULTS: 37% with low activity level at baseline (n = 4,836) and 69% of all patients (n = 17,454) reached or maintained at least a moderate physical activity level at follow-ups. Surprisingly, both an improvement (ß = 1.44, P < 0.001) and a worsening (ß = 1.18, P < 0.001) in pain intensity was associated with increased physical activity in low activity patients. For all patients a similar trend was observed (ß = 0.51, P < 0.001 and ß = 0.11, P = 0.215, respectively). CONCLUSION: In low active knee or hip OA patients, a third of patients participating in an education and exercise therapy program reached and maintained at least a moderate physical activity level for 1 year. The improvement in physical activity was not dependent on pain reduction.

Individualized predictions of changes in knee pain, quality of life and walking speed following patient education and exercise therapy in patients with knee osteoarthritis - a prognostic model study.

OBJECTIVE: To facilitate shared decision-making for patients with knee osteoarthritis (OA), we aimed at building clinically applicable models to predict the individual change in pain intensity (VAS scale 0-100), knee-related quality of life (QoL) (KOOS QoL score 0-100) and walking speed (m/sec) immediately following two educational and 12 supervised exercise therapy sessions. METHODS: We used data from patients with knee OA from the 'Good Life with osteoArthritis in Denmark' (GLA:D®) registry (n = 6,767). From 51 patient characteristics, we selected the best performing variables to predict the outcomes via random forest regression. We evaluated model performance via R2. Lastly, we validated and compared our models with the average improvements via the mean differences in an independent validation data set from the GLA:D® registry (n = 2,896) collected 1 year later than the data used to build the models. RESULTS: Validating our models including the best performing variables yielded R2s of 0.34 for pain intensity, 0.18 for knee-related QoL, and 0.07 for walking speed. The absolute mean differences between model predictions and the true outcomes were 14.65 mm, 10.32 points, and 0.14 m/s, respectively, and similar to the absolute mean differences of 17.64, 11.28 and 0.14 observed when we subtracted the average improvements from the true outcomes. CONCLUSION: Despite including 51 potential predictors, we were unable to predict changes in individuals' pain intensity, knee-related QoL and walking speed with clinically relevant greater precision than the respective group average outcomes. Therefore, average prediction values can be used to inform patients about expected outcomes.

Highly divergent cattle hepacivirus N in Southern Brazil.

The genus Hepacivirus includes 14 species (Hepacivirus A-N). In this study, we determined a partial genome sequence of a highly divergent bovine hepacivirus (hepacivirus N, HNV) isolate from cattle in Southern Brazil. Previously described HNV isolates have shared 80-99.7% nucleotide sequence identity in the NS3 coding region. However, the sequence determined in this study had 72.6% to 73.8% nucleotide sequence identity to known HNV NS3 sequences. This high divergence could be seen in a phylogenetic tree, suggesting that it represents a new genotype of HNV. These data expand our knowledge concerning the genetic variability and evolution of hepaciviruses.

Comprehensive evolutionary and phylogenetic analysis of Hepacivirus N (HNV).

Hepaciviruses (HVs) have been detected in several domestic and wild animals and present high genetic diversity. The actual classification divides the genus Hepacivirus into 14 species (A-N), according to their phylogenetic relationships, including the bovine hepacivirus [Hepacivirus N (HNV)]. In this study, we confirmed HNV circulation in Brazil and sequenced the whole genome of two strains. Based on the current classification of HCV, which is divided into genotypes and subtypes, we analysed all available bovine hepacivirus sequences in the GenBank database and proposed an HNV classification. All of the sequences were grouped into a single genotype, putatively named 'genotype 1'. This genotype can be clearly divided into four subtypes: A and D containing sequences from Germany and Brazil, respectively, and B and C containing Ghanaian sequences. In addition, the NS3-coding region was used to estimate the time to the most recent common ancestor (TMRCA) of each subtype, using a Bayesian approach and a relaxed molecular clock model. The analyses indicated a common origin of the virus circulating in Germany and Brazil. Ghanaian sequences seemed to have an older TMRCA, indicating a long time of circulation of these viruses in the African continent.

The UDP-N-acetylglucosamine 2-epimerase/N-acetylmannosamine kinase gene is mutated in recessive hereditary inclusion body myopathy.

Hereditary inclusion body myopathy (HIBM; OMIM 600737) is a unique group of neuromuscular disorders characterized by adult onset, slowly progressive distal and proximal weakness and a typical muscle pathology including rimmed vacuoles and filamentous inclusions. The autosomal recessive form described in Jews of Persian descent is the HIBM prototype. This myopathy affects mainly leg muscles, but with an unusual distribution that spares the quadriceps. This particular pattern of weakness distribution, termed quadriceps-sparing myopathy (QSM), was later found in Jews originating from other Middle Eastern countries as well as in non-Jews. We previously localized the gene causing HIBM in Middle Eastern Jews on chromosome 9p12-13 (ref. 5) within a genomic interval of about 700 kb (ref. 6). Haplotype analysis around the HIBM gene region of 104 affected people from 47 Middle Eastern families indicates one unique ancestral founder chromosome in this community. By contrast, single non-Jewish families from India, Georgia (USA) and the Bahamas, with QSM and linkage to the same 9p12-13 region, show three distinct haplotypes. After excluding other potential candidate genes, we eventually identified mutations in the UDP-N-acetylglucosamine-2-epimerase/N-acetylmannosamine kinase (GNE) gene in the HIBM families: all patients from Middle Eastern descent shared a single homozygous missense mutation, whereas distinct compound heterozygotes were identified in affected individuals of families of other ethnic origins. Our findings indicate that GNE is the gene responsible for recessive HIBM.

Virome of crab-eating (Cerdocyon thous) and pampas foxes (Lycalopex gymnocercus) from southern Brazil and Uruguay.

Crab-eating (Cerdocyon thous) and Pampas foxes (Lycalopex gymnocercus) are wild canids distributed in South America. Domestic dogs (Canis lupus familiaris) and wild canids may share viral pathogens, including rabies virus (RABV), canine distemper virus (CDV), and canine parvovirus 2 (CPV-2). To characterize the virome of these wild canid species, the present work evaluated the spleen and mesenteric lymph node virome of 17 crab-eating and five Pampas foxes using high-throughput sequencing (HTS). Organ samples were pooled and sequenced using an Illumina MiSeq platform. Additional PCR analyses were performed to identify the frequencies and host origin for each virus detected by HTS. Sequences more closely related to the Paramyxoviridae, Parvoviridae and Anelloviridae families were detected, as well as circular Rep-encoding single-stranded (CRESS) DNA viruses. CDV was found only in crab-eating foxes, whereas CPV-2 was found in both canid species; both viruses were closely related to sequences reported in domestic dogs from southern Brazil. Moreover, the present work reported the detection of canine bocavirus (CBoV) strains that were genetically divergent from CBoV-1 and 2 lineages. Finally, we also characterized CRESS DNA viruses and anelloviruses with marked diversity. The results of this study contribute to the body of knowledge regarding wild canid viruses that can potentially be shared with domestic canids or other species.

Histone proteins in HeLa S3 cells are synthesized in a cell cycle stage specific manner.

The synthesis of histone proteins in G1 and S phase HeLa S3 cells was examined by two-dimensional electrophoretic fractionation of nuclear and total cellular proteins. Newly synthesized histones were detected only in S phase cells. Histone messenger RNA sequences, as detected by hybridization with cloned human histone genes, were present in the cytoplasm of S phase but not G1 cells.

HoBi-like is the most prevalent ruminant pestivirus in Northeastern Brazil.

The ruminant pestiviral species BVDV-1, BVDV-2 and BDV, along with the putative species HoBi-like, may cause substantial economic losses in cattle, sheep and goats. Brazil's large size, variable biomes and wide range of ruminant animal production within different geographic regions suggest that the presence and prevalence of ruminant pestivirus may differ by regions within Brazil. This study investigated the genetic diversity of ruminant pestiviruses and determined the frequency of active infections within two states of the Northeast Region of Brazil, Maranhão and Rio Grande do Norte. Serum samples from 16,621 cattle and 2,672 small ruminants from 569 different herds residing in this region were tested by RT-PCR followed by DNA sequencing. Seventeen positive cattle were detected (0.1%) from fifteen different herds (2.64%). All isolates were classified as HoBi-like pestiviruses based on phylogenetic analysis. All small ruminant samples tested negative. The findings presented herein suggest that the Northeast Region of Brazil has a uniquely high prevalence of HoBi-like viruses. The increasing reports of HoBi-like viruses detected in cattle in the field suggest that natural infection with these viruses may be more widespread than previously thought. The identification of HoBi-like viruses as the most prevalent type of ruminant pestivirus circulating in the Northeast Region of Brazil indicates the need for both continued monitoring and determination of the extent of economic losses associated with HoBi-like virus infections. In addition, it must be taken into account in the choice of diagnostic tests and in vaccine formulations.

Characterization of dog serum virome from Northeastern Brazil.

Domestic dogs share habitats with human, a fact that makes them a potential source of zoonotic viruses. Moreover, knowledge regarding possible bloodborne pathogens is important due to the increasing application of blood transfusion in dogs. In the present study, we evaluated the serum virome of 520 dogs using throughput sequencing (HTS). The serum samples were pooled and sequenced using an Illumina MiSeq platform. Our unbiased method identified prevalent canine pathogens as canine protoparvovirus 1 (canine parvovirus 2), undersearched agents as canine bocaparvovirus 1 (minute virus of canines) and canine circovirus, circular viruses closely related to viruses recently found in human samples, and new parvovirus and anelloviruses. The dog virome described in the present work furthers the knowledge concerning the viral population in domestic animals. The present data includes information regarding viral agents that are potentially transmitted through blood transfusion among dogs.

Complementary DNA probes for the Duchenne muscular dystrophy locus demonstrate a previously undetectable deletion in a patient with dystrophic myopathy, glycerol kinase deficiency, and congenital adrenal hypoplasia.

Genomic DNA from a patient with dystrophic myopathy, glycerol kinase deficiency, and congenital adrenal hypoplasia was investigated using cDNA probes for the Duchenne muscular dystrophy (DMD) locus. Genomic probes had not detected a deletion in this patient. Southern analysis of Hind III-digested genomic DNA from this patient identified a deletion when the three distal Hinc II DMD cDNA fragments were used as probes. The deletion began in the genomic region corresponding to the 1.05-kb Hinc II cDNA fragment and extended through the 3' end of the DMD gene. This represents a centromeric breakpoint that corresponds to a position approximately 10.2-10.6 kb from the 5' end of the 14-kb DMD cDNA. These investigations demonstrate the value of the DMD cDNA probes for improved diagnoses in patients with molecular lesions involving the DMD locus. Furthermore, this novel deletion involving the coding portion of the 3' end of the DMD gene assists in the ordering of exons in this region and will provide insight into the functional role of the carboxy terminus of the DMD gene product, dystrophin.

Growth hormone receptor mutations in children with idiopathic short stature.

Homozygous or compound heterozygous mutations in the GH receptor (GHR) gene result in GH insensitivity syndrome. Previous reports have shown that some heterozygous mutations may induce a partial insensitivity to GH, but others appear to have limited effect on growth. To investigate further these observations, we analyzed the GHR gene in 17 subjects with idiopathic short stature (ISS). All subjects had a height 2 SD or more below the mean and/or abnormal growth velocity. In addition, serum GH levels were 10 ng/mL or more and insulin-like growth factor I levels were normal or low. A novel heterozygous mutation resulting in a valine to isoleucine change (V144I) in exon 6 in the extracellular domain was found in one subject. His mother and one brother had significant short stature and also had the identical mutation. Affected family members also had a polymorphism in exon 6 of the GHR gene, which has been present in other subjects who had short stature and heterozygous mutations of the GHR gene. The other subjects with ISS had normal GHR genes. However, eight subjects had neutral polymorphisms distributed throughout the GHR locus. Accumulating evidence suggests that GHR gene mutations account for up to 5% of all ISS patients. These mutations should be considered when other causes of short stature have been eliminated.

Clinical, biochemical, and molecular investigations of a genetic isolate of growth hormone insensitivity (Laron's syndrome).

We have characterized the GH receptor mutation that is responsible for extreme short stature and GH insensitivity in a Bahamian genetic isolate. Heights of affected individuals ranged from -4.0 to -6.3 SD. Like others with Laron's syndrome, they had normal to high serum GH concentrations and low serum insulin-like growth factor I concentrations. Circulating levels of GH-binding protein activity were below limits of detection. Amplification of exons 2-7 and screening with single strand conformational polymorphism analysis located an abnormality in exon 7. Sequencing identified homozygosity for a C to T transition in the third position of codon 236. Reverse transcription and PCR amplification of complementary DNA from lymphocytes showed that this same sense mutation generated a new splice donor site 63 bp 5' to the normal exon 7 splice site. This novel site was used to the exclusion of the normal site in homozygotes. Both normal and variant messenger ribonucleic acid species were detected in heterozygotes. The predicted protein lacks 21 amino acids, including those defining the WS-like motif of the GH receptor extracellular domain. The high frequency of Laron's syndrome in this isolated island population probably reflects the introduction of the G236 splice mutation by a settler early in the 300-yr history of English settlement.

Clinical and biochemical phenotype of familial anterior hypopituitarism from mutation of the PROP1 gene.

We have investigated the largest family with PROP1 deficiency reported to date. Eight patients, aged 17-40 yr, in two sibships with possibly related mothers but no parental consanguinity were 109-137 cm in height (-8.8 to [minus]5.9 SD score) and sexually immature. None had received hormonal therapy. Affected individuals had similarities to and significant differences from patients with insulin-like growth factor I (IGF-I) deficiency due to GH receptor deficiency (GHRD) and normal thyroid function and sexual maturation. The differences from patients with GHRD include normal hand and foot length in seven of eight, normal arm span with relatively long legs, and persistence of extremely low levels of IGF-I into adulthood; similarities include the degree of growth failure, frequent but not uniform increased body weight for height or body mass index, and the presence of limited elbow extensibility and blue scleras in six of eight. Three patients had markedly increased sella turcica area for height age and bone age, determined from lateral skull films. The degree of sellar enlargement is variable in these two sibships. Serum GH concentrations were 0.1 ng/mL or less after clonidine ingestion. Other results were: IGF-I, 3-11 ng/mL (normal, 114-492); IGF-II, 185-299 ng/mL (normal, 358-854); IGF-binding protein-1 (IGFBP-1), 12-200 ng/mL (normal, 13-73); IGFBP-2, 60-384 ng/mL (normal, 55-480); and IGFBP-3, 400-600 ng/mL (normal, 2000-4000). The very low IGF-I and normal IGFBP-1 and -2 levels differ from findings in adults with GHRD. The GH-binding protein concentration was 58-799 pmol/L, with two patients above the normal range of 66-306. LH and FSH levels were very low, with no sex differences between serum levels of estradiol (3-6 pg/mL) and testosterone (3-10 ng/dL). PRL levels all were below normal. Serum concentrations of cortisol were normal. Serum T4 levels were uniformly low (<0.2-0.5; normal, 0.8-2.7 ng/dL), free T3 values were less than normal in seven of eight subjects, and total T3 concentrations were below normal in five of eight, but TSH levels were normal (0.58-2.18; normal, 0.4-4.2 mU/L). DNA specimens from affected individuals in each sibship were homozygous for a 2-bp deletion in exon 2 of the PROPI (Prophet of Pit-I) gene, which causes a shift of reading frames and results in a translational stop signal at codon 109. The mutant protein, when expressed in vivo lacks DNA-binding and transcriptional activation functions. The consequences of the PROPI abnormality in this and other kindreds include gonadotropin deficiency as well as the expected deficiencies in products of Pit-I-dependent somatotrophs, lactotrophs, and thyrotrophs. The severity of the hormone deficiency phenotype is compatible with the complete loss of PROP1 activity.

Requirement of protein synthesis for the coupling of histone mRNA levels and DNA replication.

H1 and core histone mRNA levels have been examined in the presence of protein synthesis inhibitors with different mechanisms of action. Total HeLa cell RNAs were analyzed by Northern Blot hybridization using cloned human histone genes as probes. Inhibition of DNA replication resulted in a rapid decline in histone mRNA levels. However, in the presence of cycloheximide or puromycin, H1 and core mRNAs did not decrease in parallel with DNA synthesis, but were stabilized and accumulated. Inhibition of DNA synthesis with hydroxyurea after the inhibition of protein synthesis did not lead to a decline in histone mRNA levels. These results suggest that synthesis of a protein(s)--perhaps a histone protein(s)--is required for the coordination of DNA synthesis and histone mRNA levels.

Molecular and clinical correlations of deletions leading to Duchenne and Becker muscular dystrophies.

Human DMD cDNA probes have been used to delineate possible deletions in 160 affected males. Approximately 56% of these individuals had detectable deletions, 29% of which mapped to a region centered around 500 kb from the 5' end of the gene whereas 69% mapped to a region located centrally 1,200 kb from the 5' end. We have observed no correlation between the extent of a deletion, its location, and clinical severity of the associated disease. For some cases with deletions in the two high-frequency deletion regions, the predicted effect upon translational reading frame of the resultant dystrophin mRNA did not correlate with the associated disease phenotype.

Familial inclusion body myositis: evidence for autosomal dominant inheritance.

We report a kindred manifesting clinical features and muscle biopsy findings of inclusion body myositis (IBM). In this family, multiple members were affected in two generations with direct male-to-male and female-to-male transmission. This is the first reported instance of autosomal dominant inheritance in IBM, which usually occurs sporadically or, rarely, may be transmitted as an autosomal recessive disorder.

Tumor promoter-stimulated synthesis of Mason-:Pfizer monkey virus.

The tumor promoter 12-0-tetradecanoyl-phorbol-14-acetate (TPA) increases by severalfold the synthesis of Mason-Pfizer monkey virus (MPMV), a type D retrovirus, when the virus is growing in human embryo kidney (HEK) cells. The effect is transient and paralleled by a striking morphological alteration of the cells. The optimal TPA concentration for stimulation is 5 ng. ml-1. Contrary to infected HEK cells, TPA induces at similar concentrations neither stimulation of MPMV synthesis nor altered morphology in persistently MPMV-infected cells of the continuous human tumor cell line A 204.

Isolated glomeruli in vitro: an approach to the macula-densa-mediated renin release.

The introduction of an assay for adenylate kinase into the study of renin release from isolated glomeruli is a useful tool in determining the specificity of the release process. Interestingly, even the absolute values of AK activity yield information that might be of value in understanding the effects on net renin output in media of grossly unphysiological composition. In qualitative terms, though, the AK measurements provide evidence against an unspecific loss of cytoplasmatic proteins as the cause of increased release of renin after removal of calcium or sodium bicarbonate. This renin release must have come from a compartment other than the cytoplasma of the juxtaglomerular cells. The in vivo position of the juxtaglomerular cells remaining in the present preparation, situated at the polkissen only few microns from the only hypoosmotic area in the body, suggests that the extreme osmosensitivity of renin release from isolated glomeruli represents a physiologic phenomenon. Because urea and sodium chloride are the predominant solutes in the tubular fluid at the macula densa, available data from isolated glomeruli are consistent with a macula densa feedback mechanism if it is accepted that a decrease in tubular sodium chloride concentration (and osmolality) increases the release of renin.

Changes in cardiac muscle mass and function in hemodialysis patients during growth hormone treatment.

BACKGROUND: Adult patients with chronic renal failure (CRF) often show symptoms as fatigue, wasting, and reduced working capacity with concomitant findings of reduced cardiac performance and muscle mass. This state may in part be caused by an imbalance in the somatostatin/somatomedine axis resulting in increased catabolism. During an attempt to correct this catabolic state by administration of exogenous growth hormone, cardiac muscle mass and performance were studied. METHODS: In a double-blind, placebo-controlled 6-month study comprising 20 adult enfeebled hemodialysis patients, 9 patients were treated with a single daily subcutaneous injection of recombinant human growth hormone (rhGH) 4 IU/m2 and 11 with placebo injections. Left ventricular muscle mass (LVM) and ejection fraction (EF) were evaluated by echocardiography and the maximal working capacity (MWC) was measured by a bicycle exercise test performed before and after the treatment period. Supplementary electrocardiography (ECG) was performed before and after 6-month treatment. RESULTS: Median LVM increased significantly from 172 to 220 g (p = 0.03) in the rhGH-treated group, while an insignificant decrease was observed in the placebo group from 281 to 200 g (p = 0.3). The EF showed no significant changes in the two groups. MWC showed a slight, insignificant decrease in both groups. From ECG no significant ST deviations were found and no significant changes regarding B-Hb, blood pressure or pulse were observed in the two groups. Irregular heart rhythm aggravated in one patient during the first month of treatment with rhGH, but was overcome by a -blocking agent. CONCLUSION: The treatment with rhGH of adult chronic hemodialysis patients for 6 months increased the left ventricular mass significantly, but without any effect on ejection fraction or maximal working capacity. No electrocardiographic signs of ischemia were associated with the increasing muscle mass and only one patient developed symptoms that might relate to ischemia. No changes in B-Hb, blood pressure or pulse were observed during the treatment period.