The impact of rural residency on the expression and outcome of systemic lupus erythematosus: data from a multiethnic Latin American cohort.

OBJECTIVE: The objective of this paper is to examine the role of place of residency in the expression and outcomes of systemic lupus erythematosus (SLE) in a multi-ethnic Latin American cohort. PATIENTS AND METHODS: SLE patients (< two years of diagnosis) from 34 centers constitute this cohort. Residency was dichotomized into rural and urban, cut-off: 10,000 inhabitants. Socio-demographic, clinical/laboratory and mortality rates were compared between them using descriptive tests. The influence of place of residency on disease activity at diagnosis and renal disease was examined by multivariable regression analyses. RESULTS: Of 1426 patients, 122 (8.6%) were rural residents. Their median ages (onset, diagnosis) were 23.5 and 25.5 years; 85 (69.7%) patients were Mestizos, 28 (22.9%) Caucasians and 9 (7.4%) were African-Latin Americans. Rural residents were more frequently younger at diagnosis, Mestizo and uninsured; they also had fewer years of education and lower socioeconomic status, exhibited hypertension and renal disease more frequently, and had higher levels of disease activity at diagnosis; they used methotrexate, cyclophosphamide pulses and hemodialysis more frequently than urban patients. Disease activity over time, renal damage, overall damage and the proportion of deceased patients were comparable in rural and urban patients. In multivariable analyses, rural residency was associated with high levels of disease activity at diagnosis (OR 1.65, 95% CI 1.06-2.57) and renal disease occurrence (OR 1.77, 95% CI 1.00-3.11). CONCLUSIONS: Rural residency associates with Mestizo ethnicity, lower socioeconomic status and renal disease occurrence. It also plays a role in disease activity at diagnosis and kidney involvement but not on the other end-points examined.

Effectiveness of exergames for improving mobility and balance in older adults: a systematic review and meta-analysis.

BACKGROUND: Exergaming is a fun, engaging, and interactive form of exercising that may help overcome some of the traditional exercise barriers and help improve adherence on the part of older adults, providing therapeutic applications for balance recovery and functional mobility. The purpose of this systematic review is to summarize the effects of exergames on mobility and balance in older adults. METHODS: The PRISMA guidelines for systematic reviews were followed. The following databases were searched from inception to August 2019: Cochrane Central Register of Controlled Trials, MEDLINE, EMBASE, PEDro, CINAHL, and INSPEC. We selected randomized controlled trials that assessed the effects of exergames on balance or mobility of older adults without neurological conditions, in comparison to no intervention or health education. Two review authors independently screened the trials' titles and abstracts and identified trials for inclusion according to the eligibility criteria. An almost perfect agreement between the authors was observed with respect to interrater reliability of trial selection (kappa = 0.84; P < 0.001). We performed descriptive analysis of the quantitative data to summarize the evidence. Meta-analysis was carried out using RevMan. A random effects model was used to compute the pooled prevalence with 95% confidence intervals. RESULTS: After screening 822 records, 12 trials comparing exergames with no intervention were included. A total of 1520 older adults participated in the studies, with a mean age of 76 ± 6 years for the experimental group and 76 ± 5 years for the control group. Quantitative synthesis showed significant improvements in balance and mobility based on the center of pressure sway (SMD = - 0.89; 95%CI = - 1.26 to - 0.51; P = 0.0001; I2 = 58%), Berg Balance Scale (MD = 2.15; 95%CI = 1.77 to 2.56; P = 0.0001; I2 = 96%), and on Timed Up and Go test (MD = - 2.48; 95%CI = - 3.83 to - 1.12; P = 0.0003; I2 = 0). CONCLUSIONS: Exergames improved balance and mobility in older adults without neurological disorders and motivate patients to keep performing balance exercises. High quality studies with standardized assessment protocols are necessary to improve the strength of the evidence.

Friedreich's ataxia: autosomal recessive disease caused by an intronic GAA triplet repeat expansion.

Friedreich's ataxia (FRDA) is an autosomal recessive, degenerative disease that involves the central and peripheral nervous systems and the heart. A gene, X25, was identified in the critical region for the FRDA locus on chromosome 9q13. This gene encodes a 210-amino acid protein, frataxin, that has homologs in distant species such as Caenorhabditis elegans and yeast. A few FRDA patients were found to have point mutations in X25, but the majority were homozygous for an unstable GAA trinucleotide expansion in the first X25 intron.

A potent and selective p38 inhibitor protects against bone damage in murine collagen-induced arthritis: a comparison with neutralization of mouse TNFalpha.

BACKGROUND AND PURPOSE: The p38 kinase regulates the release of proinflammatory cytokines including tumour-necrosis factor-alpha (TNFalpha) and is regarded as a potential therapeutic target in rheumatoid arthritis (RA). Using the novel p38 inhibitor Org 48762-0, we investigated the therapeutic potential of p38 inhibition and compared this to anti-mouse (m)TNFalpha antibody treatment in murine collagen-induced arthritis (CIA). EXPERIMENTAL APPROACH: Pharmacological profiles of Org 48762-0 were characterized in kinase assays, cellular assays and in lipopolysaccharide (LPS)-induced inflammation in mice. The effects of Org 48762-0 and of mTNFalpha-neutralization on established arthritis were examined in murine CIA. KEY RESULTS: Org 48762-0 potently inhibited p38alpha kinase with a high degree of kinase selectivity. In cellular assays, Org 48762-0 reduced LPS-induced TNFalpha release. Oral administration of Org 48762-0 in mice showed drug-like pharmacokinetic properties and inhibited LPS-induced cytokine production. These pharmacological characteristics of Org 48762-0 prompted a comparison of therapeutic efficacy with mTNFalpha-neutralization in CIA. Org 48762-0 and anti-mTNFalpha antibody treatment equally inhibited development of arthritis when evaluated macroscopically. Radiological analyses revealed protection against bone damage for both treatments, although statistical difference was reached with Org 48762-0 treatment only. Further, micro-computed tomographical and histopathological analyses confirmed the protective effects of Org 48762-0 on joint damage. CONCLUSIONS AND IMPLICATIONS: Pharmacological targeting of p38 kinase provided good protection against joint tissue damage in CIA. In our experiments, neutralization of mTNFalpha produced less prominent suppression of bone damage. Our data suggest a therapeutic potential for selective and potent p38 inhibitors in RA.

Assessment of Injuries Caused by Anastrepha fraterculus (Wied.) (Diptera: Tephritidae) on the Incidence of Bunch Rot Diseases in Table Grape.

Anastrepha fraterculus (Wied.) is the main insect pest of table grapes (Vitis vinifera) in the Southern Region of Brazil. In this study, we aimed to investigate the effect of fruit puncturing by adult females and larval infestation by A. fraterculus on the occurrence of bunch rot disease in the grape (cultivar "Itália") by evaluating grapes (a) punctured for oviposition by females of A. fraterculus, sterilized in laboratory with novaluron (40 mg L(-1)) and further spray-inoculated separately with Botrytis cinerea (1 × 10(6) conidia mL(-1)), Glomerella cingulata (1 × 10(6) conidia mL(-1)), and bacteria and yeast that cause sour rot (1 × 10(5) cells mL(-1)), (b) grapes punctured for oviposition by non-sterilized females with pathogen spraying, (c) grapes with mechanical wounds and pathogen spraying, (d) grapes with no wounds and with pathogen spraying, (e) grapes punctured for oviposition by A. fraterculus chemically sterilized in laboratory with novaluron, (f) grapes punctured for oviposition by A. fraterculus non-sterilized in laboratory with novaluron, (g) grapes with mechanical wounds, and (h) grapes with no sterilization or pathogen spraying. Our data indicated that the mechanical and oviposition wounds caused by A. fraterculus increased the percentage of grapes infected by B. cinerea, G. cingulata, and microorganisms of acid rot. The grape puncturing by A. fraterculus and the mechanical wound allows the penetration of B. cinerea and microorganisms leading to acid rot. We conclude that the fruit fly A. fraterculus may facilitate phytopathogens penetration leading to bunch rots in the table grape Itália.

Linkage disequilibrium analysis of Friedreich's ataxia in 140 Caucasian families: positioning of the disease locus and evaluation of allelic heterogeneity.

We investigated linkage disequilibrium between Friedreich's ataxia (FRDA) and four tightly linked multi-allele markers in 140 families from France and Italy. These markers include three microsatellites (D9S111, D9S15 and D9S110) and one RFLP (D9S5). Their chromosomal order, D9S111-D9S15-D9S110-D9S5, had previously been established by physical mapping. Linkage disequilibrium was evaluated between each marker and FRDA and between markers. Extended haplotypes were obtained and their frequencies on FRDA and normal chromosomes were evaluated. We obtained evidence of strong allelic association of FRDA with D9S5 only. Analysis of linkage disequilibrium between markers revealed a significant decrease between D9S110 and D9S5, suggesting the presence of a recombination hot spot in the interval between these markers. Probably for this reason, no major FRDA-associated extended haplotype could be identified. Our data suggest the presence of a few common disease-causing mutations in the examined population, and indicate a putative localization for the FRDA gene. Transcribed sequences have been found in this candidate region.

Has spinocerebellar ataxia type 2 a distinct phenotype? Genetic and clinical study of an Italian family.

The gene for spinocerebellar ataxia type 2 (SCA2) is mapped to chromosome 12q23-24.1. Using D12S79 and D12S105, we performed linkage analysis in nine individuals including six affected members of a four-generation family in which we excluded SCA1 by direct mutation analysis. We obtained a lod score = 2.37 at theta = 0.00 for the compound haplotype. The clinical picture appeared homogeneous, showing the absence of corticospinal signs and the presence of peripheral neuropathy. The present study suggests that this SCA2 family is clinically different from most SCA1 families.

Atypical Friedreich ataxia phenotype associated with a novel missense mutation in the X25 gene.

We describe two sisters with early onset gait ataxia, rapid disease progression, absent or very mild dysarthria and upper limb dysmetria, retained knee jerks in one, slight to moderate peripheral nerve involvement, and diabetes. Molecular analysis showed that they are compound heterozygotes for GAA expansion and a novel exon 5a missense mutation (R165P). This mutation appears to be associated with an atypical but not milder Friedreich ataxia phenotype.

Broadened Friedreich's ataxia phenotype after gene cloning. Minimal GAA expansion causes late-onset spastic ataxia.

We describe three siblings from an Italian family affected by an autosomal recessive spinocerebellar degeneration. Gait ataxia, presenting between 38 and 45 years, was the first symptom in all three patients. Dysarthria, dysmetria, brisk tendon reflexes, extensor plantar response, and scoliosis were constant features. Disease progression was slow. Electrophysiologic studies demonstrated a slight reduction in sural nerve sensory action potential in only one patient. Analysis of GAA expansion within the X25 gene showed that patients were homozygous for the expansion, with the shorter expanded allele ranging from 120 to 156 triplets. The size of the GAA expansion may be smaller than we previously described. Such minimal expansions may result in atypical forms of Friedreich's ataxia.

Diphenylpropionic acids as new AT1 selective angiotensin II antagonists.

The synthesis and pharmacological evaluation of a new series of potent AT1 selective diphenylpropionic acid nonpeptide angiotensin II receptor antagonists are reported. The new compounds were evaluated for in vitro AT1 (rat liver) and AT2 (rat adrenal) binding affinity as well as for in vivo inhibition of angiotensin II-induced increase in mean arterial blood pressure in pithed rats. Unsaturation of the diphenylpropionic acids as well as substitution or replacement by alkyl groups of the pendant phenyl ring resulted in a decrease of potency. On the other hand, the presence of small alkyl groups in the alpha-position to the carboxylic acid was important for activity, with one of the resultant diastereoisomers (R*,R*) being ca. 10-fold more active than the other (R*,S*). Oral evaluation of the most active compounds in a furosemide-treated sodium-depleted rat model showed that compound 36g (UR-7198) reduced blood pressure dose dependently. This compound showed in vitro and iv potencies similar to that of the reference compound losartan but faster onset of action and somewhat greater oral activity, presumably due to its improved bioavailability.

2,2-Dialkylnaphthalen-1-ones as new potassium channel activators.

A new series of 2,2-dialkylnaphthalen-1-one potassium channel activators has been prepared, and their in vitro relaxant activities in isolated rat portal vein and guinea pig tracheal spirals as well as their oral antihypertensive effect in spontaneously hypertensive rats have been evaluated. The group of 1,2-dihydro-4-(1,2-dihydro-2-oxo-1-pyridyl)-2,2-dimethylnaphthalen -1- ones with an electron-withdrawing substituent at the 6-position contain the most active compounds and 1,2-dihydro-4-(1,2-dihydro-2-oxo-1-pyridyl)-2,2-dimethyl-1-oxonaphtha lene-6- carbonitrile, 17f (UR-8225), has been selected for further pharmacological development.

Synthesis and structure-activity relationship of a new series of potent AT1 selective angiotensin II receptor antagonists: 5-(biphenyl-4-ylmethyl)pyrazoles.

The synthesis and pharmacological activity of a new series of 5-(biphenyl-4-ylmethyl)pyrazoles as potent angiotensin II antagonists both in vitro (binding of [3H]AII) and in vivo (iv, inhibition of AII-induced increase in blood pressure, pithed rats; po, furosemide-treated sodium-depleted rats) are reported. The various substituents of the pyrazole ring have been modified taking into account the receptor's requirements derived from related structure-activity relationship studies. A propyl or butyl group at position 1 as well as a carboxylic acid group at position 4 were shown to be essential for high affinity. Different groups at position 3 (H, small alkyl, phenyl, benzyl) provided good binding affinity, but oral activity was highly discriminating: bulky alkyl groups provided the highest potencies. Among the acidic isosteres tested in the biphenyl moiety, the tetrazole group proved to be the best. Compound 14n (3-tert-butyl-1-propyl-5-[[2'-(1H-tetrazol-5-yl)-1,1'-biphenyl-4-y l] methyl]-1H-pyrazole-4-carboxylic acid, UR-7280) shows high potency both in vitro (IC50 = 3 nM) and in vivo (iv, 61.2 +/- 10% decrease in blood pressure at 0.3 mg/kg; po, 30 mmHg fall in blood pressure at 0.3 mg/kg), in comparison to losartan (IC50 = 59 nM; iv, 62.5 +/- 8.9% decrease in blood pressure at 1 mg/kg; po, 13 mmHg fall in blood pressure at 3 mg/kg). These data, together with the good pharmacokinetic profile of 14n in different species, have led to its selection for clinical evaluation as an antihypertensive agent.

Synthesis and SAR of a new series of COX-2-selective inhibitors: pyrazolo[1,5-a]pyrimidines.

The synthesis and pharmacological activity of a series of bicyclic pyrazolo[1,5-a]pyrimidines as potent and selective cyclooxygenase-2 (COX-2) inhibitors are described. The new compounds were evaluated both in vitro (COX-1 and COX-2 inhibition in human whole blood) and in vivo (carrageenan-induced paw edema and air-pouch model). Modification of the pyrimidine substituents showed that 6,7-disubstitution provided the best activity and led to the identification of 3-(4-fluorophenyl)-6,7-dimethyl-2-(4-methylsulfonylphenyl)pyrazolo[1,5-a]pyrimidine (10f) as one of the most potent and selective COX-2 inhibitor in this series.

Intrafamilial phenotype variation in Friedreich's disease: possible exceptions to diagnostic criteria.

Three families are described which include members with "typical" Friedreich's disease (FD) and others who are ataxic but do not satisfy all the diagnostic criteria for that disease. In family A two patients have an early-onset, rapidly progressive FD, while two others have a late-onset, more benign form. In families B and C one member has "typical" FD, and another has a similar ataxic syndrome, except for preservation of knee jerks. Laboratory evaluation is consistent with the diagnosis of FD in all cases. FD diagnosis appears justified in secondary cases with late onset or preserved tendon reflexes, provided that the index case fulfils all diagnostic criteria. Whether the diagnosis of FD is tenable in sporadic "atypical" cases remains to be seen. Echocardiographic and neurophysiological examination may be valuable in classifying such cases.

Evidence of a genetic marker associated with early onset in Friedreich's ataxia.

We evaluated the association between age at onset of Friedreich's ataxia and alleles of two restriction fragment length polymorphisms (RFLP) at D9S15 and D9S5 in the 9q13-9q21.1 region. We studied 65 Italian patients from 49 families. Age at onset was not normally distributed in our patients, suggesting allelic heterogeneity. Patients homozygous for allele 1 of MspI RFLP detected by probe MCT112 at D9S15 (M1) had an earlier onset (mean 9.3, SD 3.4 years) than patients homozygous for allele 2 (M2; mean 12.1, SD 4.3). Heterozygotes had an onset age similar to that of the M2 homozygotes. These findings suggest that the M1 allele might be a marker of one allelic early-onset Friedreich's ataxia mutation.

Determinants of onset age in Friedreich's ataxia.

We studied the factors that might influence onset age in Friedreich's ataxia in 41 cases (20 male, 21 female) homozygous for GAA expansion on the first intron of X25 gene. Patients came from 18 multiplex families (13 couples, 5 triplets). Mean age (SD) was 18.1 (8.9) years and did not differ by gender. Onset age and the sizes of the smaller (GAA1) and the larger (GAA2) allele in each pair showed high intrafamily correlation. We found an inverse correlation between age at onset and GAA1 size, but not between age at onset and GAA2 size. Stepwise multiple regression of onset age on GAA1 size, sibling onset age, and GAA2 size showed that GAA1 accounts for 73% of onset age variance, and sibling onset age for an additional 13%. The study demonstrates that, in addition to GAA expansion size, other environmental or genetic familial factors influence disease expression.

Why do some Friedreich's ataxia patients retain tendon reflexes? A clinical, neurophysiological and molecular study.

Among 101 patients homozygous for GAA expansion within the X25 gene, 11 from 8 families had Friedreich's ataxia with retained reflexes in the lower limbs (FARR). These patients had a lower occurrence of decreased vibration sense, pes cavus, and echocardiographic signs of left ventricular hypertrophy than the 90 FA patients with areflexia. The mean age at onset was significantly later (26.6+/-11.4 vs. 14.2+/-6.9 years), and the mean size of the smaller allele was significantly less (408+/-252 vs. 719+/-184 GAA triplets) in FARR patients. The neurophysiological findings were consistent with milder peripheral neuropathy and milder impairment of the somatosensory pathways in FARR patients.

In vitro pharmacological characterization of a new selective angiotensin AT1 receptor antagonist, UR-7280.

UR-7280 (3-tert-butyl-1-propyl-5-[[2'-(1H-tetrazol-5-yl)-1,1'-biphenyl-4-y l]methyl]-1H-pyrazole-4-carboxylic acid) is a new and potent angiotensin AT1-selective receptor antagonist. Binding studies in rat liver membranes showed that UR-7280 is an apparently competitive antagonist. However, in rabbit aorta this compound antagonized the angiotensin II-induced contractile response in an insurmountable way, causing a significant reduction of the maximal response. Additional binding studies evidenced that UR-7280 has a slowly reversible binding profile, consistent with its functional properties in rabbit aorta. The results obtained with a series of structural analogues of UR-7280 demonstrated a relationship between the size of the pyrazole 3-substituent and the surmountable or insurmountable mode of antagonism, indicating that this position may play a key role in the interaction between the antagonist and the angiotensin AT1 receptor.