Multimodality imaging in connective tissue disease-related interstitial lung disease.

Interstitial lung disease is a well-recognised manifestation and a major cause of morbidity and mortality in patients with connective tissue diseases. Interstitial lung disease may arise in the context of an established connective tissue disease or be the initial manifestation of an otherwise occult autoimmune disorder. Early detection and characterisation are paramount for adequate patient management and require a multidisciplinary approach, in which imaging plays a vital role. Computed tomography is currently the imaging method of choice; however, other imaging techniques have recently been investigated, namely ultrasound, magnetic resonance imaging, and positron-emission tomography, with promising results. The aim of this review is to describe the imaging findings of connective tissue disease-related interstitial lung disease and explain the role of each imaging technique in diagnosis and disease characterisation.

Ocular involvement in systemic lupus erythematosus patients: a paradigm shift based on the experience of a tertiary referral center.

OBJECTIVE: To evaluate ocular involvement in a cohort of systemic lupus erythematosus (SLE) patients of a tertiary referral center and to compare the results with the existing literature. METHODS: Patients underwent a complete ophthalmological evaluation, including visual acuity, slit-lamp examination, fluorescein staining, Schirmer-I test, Goldmann applanation tonometry, fundoscopy, 10-2 automated threshold visual fields, fundus autofluorescence and spectral-domain optical coherence tomography to screen for hydroxychloroquine (HCQ) macular toxicity. RESULTS: A total of 161 patients (16 men and 145 women) were enrolled in this study. The mean age was 47.6 years and the mean disease duration was 11.5 years. Fifty patients (31.1%) had at least one ocular manifestation of SLE. The most frequent manifestation was dry eye syndrome (12.4%), immediately followed by cataracts (11.2%) and HCQ macular toxicity (11.2%). Among patients with HCQ maculopathy, two presented with an atypical spectral-domain optical coherence tomography pattern. Five patients (3.1%) presented with glaucoma, two patients (1.2%) presented with SLE retinopathy while only one presented with lupus choroidopathy (0.6%). CONCLUSIONS: Compared with previous studies, we conclude there has been a significant reduction in disease-related ocular complications, particularly those associated with poor systemic disease control. On the other hand, drug and age-related complications are assuming a prominent role in the ophthalmic care of these patients.

Immunodeficiency and autoimmunity coming together: a nearly missed diagnosis.

The coexistence of human immunodeficiency virus (HIV) and systemic lupus erythematosus (SLE) appears to be unusual and the prevalence of patients who carry the dual diagnosis is currently unknown. We hereby present a case of a C4 deficient HIV-1 positive Caucasian female under highly active antiretroviral therapy for the past eight years, admitted to hospital with an aggressive and potentially fatal clinical presentation of SLE. There was a favorable outcome despite a significant diagnostic delay. Despite its rarity, the case highlights that this association is remarkable and may be overlooked by clinicians familiar with either condition.

Two separate effects contribute to regulatory T cell defect in systemic lupus erythematosus patients and their unaffected relatives.

Forkhead box P3 (FoxP3)+ regulatory T cells (Tregs ) are functionally deficient in systemic lupus erythematosus (SLE), characterized by reduced surface CD25 [the interleukin (IL)-2 receptor alpha chain]. Low-dose IL-2 therapy is a promising current approach to correct this defect. To elucidate the origins of the SLE Treg phenotype, we studied its role through developmentally defined regulatory T cell (Treg ) subsets in 45 SLE patients, 103 SLE-unaffected first-degree relatives and 61 unrelated healthy control subjects, and genetic association with the CD25-encoding IL2RA locus. We identified two separate, uncorrelated effects contributing to Treg CD25. (1) SLE patients and unaffected relatives remarkably shared CD25 reduction versus controls, particularly in the developmentally earliest CD4+ FoxP3+ CD45RO- CD31+ recent thymic emigrant Tregs . This first component effect influenced the proportions of circulating CD4+ FoxP3high CD45RO+ activated Tregs . (2) In contrast, patients and unaffected relatives differed sharply in their activated Treg CD25 state: while relatives as control subjects up-regulated CD25 strongly in these cells during differentiation from naive Tregs , SLE patients specifically failed to do so. This CD25 up-regulation depended upon IL2RA genetic variation and was related functionally to the proliferation of activated Tregs , but not to their circulating numbers. Both effects were found related to T cell IL-2 production. Our results point to (1) a heritable, intrathymic mechanism responsible for reduced CD25 on early Tregs and decreased activation capacity in an extended risk population, which can be compensated by (2) functionally independent CD25 up-regulation upon peripheral Treg activation that is selectively deficient in patients. We expect that Treg -directed therapies can be monitored more effectively when taking this distinction into account.

EULAR recommendations for women's health and the management of family planning, assisted reproduction, pregnancy and menopause in patients with systemic lupus erythematosus and/or antiphospholipid syndrome.

OBJECTIVES: Develop recommendations for women's health issues and family planning in systemic lupus erythematosus (SLE) and/or antiphospholipid syndrome (APS). METHODS: Systematic review of evidence followed by modified Delphi method to compile questions, elicit expert opinions and reach consensus. RESULTS: Family planning should be discussed as early as possible after diagnosis. Most women can have successful pregnancies and measures can be taken to reduce the risks of adverse maternal or fetal outcomes. Risk stratification includes disease activity, autoantibody profile, previous vascular and pregnancy morbidity, hypertension and the use of drugs (emphasis on benefits from hydroxychloroquine and antiplatelets/anticoagulants). Hormonal contraception and menopause replacement therapy can be used in patients with stable/inactive disease and low risk of thrombosis. Fertility preservation with gonadotropin-releasing hormone analogues should be considered prior to the use of alkylating agents. Assisted reproduction techniques can be safely used in patients with stable/inactive disease; patients with positive antiphospholipid antibodies/APS should receive anticoagulation and/or low-dose aspirin. Assessment of disease activity, renal function and serological markers is important for diagnosing disease flares and monitoring for obstetrical adverse outcomes. Fetal monitoring includes Doppler ultrasonography and fetal biometry, particularly in the third trimester, to screen for placental insufficiency and small for gestational age fetuses. Screening for gynaecological malignancies is similar to the general population, with increased vigilance for cervical premalignant lesions if exposed to immunosuppressive drugs. Human papillomavirus immunisation can be used in women with stable/inactive disease. CONCLUSIONS: Recommendations for women's health issues in SLE and/or APS were developed using an evidence-based approach followed by expert consensus.

Technical note: Mammary gland ultrasonography to evaluate mammary parenchymal composition in prepubertal heifers.

Bovine mammary gland development studies are often terminal or involve invasive biopsy procedures. Therefore, noninvasive means of assessing mammary development should be considered as alternative methods in live animals. The objective was to test if mammary ultrasonography can be used as a noninvasive way to estimate mammary parenchyma (PAR) composition in prepubertal dairy heifers with different average daily body weight gains. In the 84 d preceding, the ultrasound exam heifers were maintained in 1 of 3 treatment groups. Individual heifers were fed a high gain (1 kg/d; n = 6), low gain (0.5 kg/d, n = 6), or maintenance (n = 6) treatment diet. To achieve desired body weight gains, heifers were fed differing amounts of the same silage-based diet. Mammary glands of 18 crossbred heifers Holstein:Gyr underwent a single mammary ultrasound exam immediately before heifer slaughter, which took place when heifers weighed 142.0 ± 8.0 kg and were 200 d old. The 4 mammary glands of each heifer were evaluated using a real-time B-mode ultrasound machine equipped with a 6.5-MHz micro-convex transducer. Digital images (8-bit) of glands were obtained and PAR was identified within gland. Average pixel values per unit of PAR area were determined for each gland and analyzed at the level of heifer. Pixel results were interpreted on the basis that lower average pixel values reflect PAR with relatively high amounts of protein as opposed to fat. To help validate that the pixel value within PAR is associated with composition of PAR, pixel findings were compared with histological [number of adipocytes in PAR (Nad) and epithelial area in PAR (Ep)] and biochemical [percent crude protein in PAR (%CP), percent ether extract in PAR (%EE), PAR weight (WPAR), and mammary fat pad weight (WFAT)] composition of PAR in these same heifers. Within PAR, %EE and WFAT were positively correlated with pixel values, whereas %CP, Ep, and Nad were negatively correlated. Parenchyma weight did not correlate with pixel values. Regression analyses (fixed effect log-pixel value; random effect treatment) were used to estimate Nad, Ep, %CP, %EE, WPAR, and WFAT. Sensitivity analysis of regression equations revealed that accuracy of tested equations ranged from 0.77 to 0.93 and precision ranged from 0.56 to 0.82. Concordance correlation coefficients of the equations ranged from 0.41 to 0.76. In conclusion, ultrasonography of PAR can accurately measure and predict PAR composition in prepubertal dairy heifers growing at various rates of gain.

Comparative case-control study of homocysteine, vitamin B12, and folic acid levels in patients with epilepsy. / Estudio comparativo de los niveles plasmáticos de homocisteína, vitamina B12 y ácido fólico en pacientes epilépticos frente a controles.

INTRODUCTION: Increased blood homocysteine levels are a known cardiovascular risk factor. Epileptic patients on long-term treatment with antiepileptic drugs may present higher homocysteine levels and, consequently, a potential increase in cardiovascular risk. MATERIAL AND METHODS: We conducted an observational case-control study to compare plasma levels of homocysteine, folic acid, and vitamin B12. RESULTS: Our study included a total of 88 subjects: 52 patients with epilepsy and 36 controls. Epileptic patients showed higher homocysteine levels (P=.084) and lower levels of folic acid (P<.05). CONCLUSION: Homocysteine levels should be monitored in epileptic patients on long-term treatment with antiepileptic drugs. We suggest starting specific treatment in patients with high homocysteine levels.

Mucopolysaccharidosis type II: identification of 30 novel mutations among Latin American patients.

In this study, 103 unrelated South-American patients with mucopolysaccharidosis type II (MPS II) were investigated aiming at the identification of iduronate-2-sulfatase (IDS) disease causing mutations and the possibility of some insights on the genotype-phenotype correlation The strategy used for genotyping involved the identification of the previously reported inversion/disruption of the IDS gene by PCR and screening for other mutations by PCR/SSCP. The exons with altered mobility on SSCP were sequenced, as well as all the exons of patients with no SSCP alteration. By using this strategy, we were able to find the pathogenic mutation in all patients. Alterations such as inversion/disruption and partial/total deletions of the IDS gene were found in 20/103 (19%) patients. Small insertions/deletions/indels (<22 bp) and point mutations were identified in 83/103 (88%) patients, including 30 novel mutations; except for a higher frequency of small duplications in relation to small deletions, the frequencies of major and minor alterations found in our sample are in accordance with those described in the literature.

Neuropsychiatric questionnaires in systemic lupus erythematosus.

Patients with systemic lupus erythematosus (SLE) can be affected by a multitude of neurologic and psychiatric symptoms with a wide range of prevalence and severity. Irrespectively from attribution to SLE or other causes, neuropsychiatric (NP) symptoms strongly impact short-term and long-term outcomes, thus NP evaluation during routine clinical practice in SLE should be undertaken regularly. The assessment of NP involvement in SLE patients is challenging and the available diagnostic tools fail to guarantee optimal diagnostic accuracy, sensitivity to changes as well as feasibility in routine clinical care. Standardised questionnaires (both physician-administered and self-reported) can offer valuable help to the treating physician to capture all possible NP syndromes; few SLE-specific NP questionnaire have been developed but validation in large cohort or cross-cultural adaptations are still pending. On the other hand, general instruments have been largely applied to SLE patients. Both kinds of questionnaires can address all possible NP manifestations either globally or, more frequently, focus on specific NP symptoms. These latter have been mainly used in SLE to detect and classify mild and subtle symptoms, more likely to be overlooked during routine clinical assessment such as headache, cognitive impairment and psychiatric manifestations. In conclusion, this literature review highlights a clear case for validation studies in this area and the wider implementation of questionnaires to assess NP involvement is still warranted. The broader use of such instruments could have important consequences; first of all, by standardising symptom assessment, a better definition of the prevalence of NP manifestation across different centres could be achieved. Secondly, prospective studies could allow for the evaluation of clinical significance of mild symptoms and their impact on the patient's function and quality of life.

A derivative of ascorbic acid modulates cAMP production.

We reported, in previous experiments, that AA is a global regulator of cAMP pools. In this study, we demonstrate that K873, an analog of AA we synthesized and presenting antiproliferative properties, has also an impact on cAMP production. However, K873 has no antioxidant activity, at the contrary of AA. It definitively demonstrates that action of AA on the cAMP production is not linked to antioxidant activity. These data suggest that AA, and derivatives of this molecule, could be promising drug acting on biological processes that are under the control of cAMP dependent pathway.

Phylogenetic diversity of Aeromonas from "alheira," a traditional Portuguese meat product.

"Alheira" is a traditional smoked meat sausage produced in the north of Portugal, representing an important economic resource for the region. This meat product has been subjected to research studies with the aim of detecting the presence of common foodborne pathogens, but, to our knowledge, isolation of emerging foodborne Aeromonas from alheira has never been previously described. Present work attempts to evaluate the Aeromonas species diversity of 84 isolates of Aeromonas spp. collected from 32 alheira samples. All presumptive Aeromonas isolates were subjected to genotyping by enterobacterial repetitive intergenic consensus-polymerase chain reaction analysis. The isolates presenting a different pattern were subjected to gyrB gene sequencing for species classification, and the species A. hydrophila, A. salmonicida, A. caviae, A. media, and A. allosaccharophila were identified. The Aeromonas species diversity found has not been previously described in any other meat product evaluated in previous studies. It is also important to highlight the presence of A. hydrophila and A. caviae because they were previously associated with illness in humans, including gastroenteritis.

Intraspecific C-value variation and the outcomes in Psidium cattleyanum Sabine essential oil.

Polyploidy, a numerical alteration of the karyotype, is one of the most important mechanisms in plant speciation and diversification, but could also be detected among populations, the cytotypes. For example, Psidium cattleyanum, a polyploid complex, has chromosome numbers ranging from 2n=3x=33 to 2n=12x=132. Polyploidization causes an increase in DNA content, and both modifications may cause alteration in plant growth, physiology, and epigenetics. Based on this possibility, here we aim to verify the influence of the polyploidization on the production of P. cattleyanum essential oil chemotypes. Differences in the DNA contents, as a proxy to different ploidies, were observed and three distinct chemotypes were identified through the chromatographic profile analysis. The Psidium cattleyanum DNA content and qualitative and quantitative characteristics of the essential oils presented a positive relationship. Plants with higher DNA contents presented higher levels of oil production, which was mostly composed of hydrogenated sesquiterpenes, while plants with lower DNA contents produced lower amount of oil, which was mostly composed of hydrogenated monoterpenes. Based on the importance of essential oils, polyploid plants, which present higher DNA content, are recommended as possible matrices for the propagation of new plants with the potential to produce major compounds of agronomic and pharmacological interest.

Phytotoxicity and cytogenetic action mechanism of leaf extracts of Psidium cattleyanum Sabine in plant bioassays.

The search for more environmental friendly herbicides, aiming at the control of agricultural pests, combinated with less harmfulness to human health and the environment has grown. An alternative used by researchers is the application of products of secondary plant metabolism, which are investigated due to their potential bioactivities. Thus, species belonging to the Myrtaceae family are potential in these studies, since this family is recognized for having high biological activity. A species belonging to this genus is Psidium cattleyanum, which has a medicinal effect and its fruits are used in human food. Thus, the objective of this research was to evaluate and compare the phyto-cyto-genotoxicity of aqueous and ethanolic leaf extracts of the specie P. cattleyanum, from plant bioassays, as well as to identify the main classes of compounds present in the extracts. For this, the extracts were prepared, characterized and biological tests were carried out by evaluating, in seeds and seedlings of lettuce and sorghum, the variables: percentage of germination, germination speed index, root growth and aerial growth; and in meristematic lettuce cells the variables: mitotic phases, mitotic index, nuclear alterations and chromosomal alterations. Flavones, flavonones, flavonols, flavononols, flavonoids, alkaloids, resins, xanthones and anthraquinone glycoside were characterized in the ethanolic extract. Both evaluated extracts, in the highest concentration, inhibited the initial plant development. All treatments caused alterations in the mitotic phases and inhibited mitotic index. In addition, the treatments promoted an increase in nuclear and chromosomal alterations. The mechanism of action presented was aneugenic, clastogenic and determined in epigenetic alterations. The ethanolic extract was more cytotoxic, since it had a more expressive effect at a lower concentration. Despite the cytotoxicity of the extracts under study, they promoted alterations at lower levels than the glyphosate positive control.

Levels of endogenous ß-glucanase activity in barley affect the efficacy of exogenous enzymes used to supplement barley-based diets for poultry.

To improve the nutritive value of barley-based diet for broilers, 2 experiments using 2 different barley lots were performed to evaluate the capacity of a mesophilic cellulase when fused to a ß-glucan specific family 11 carbohydrate-binding module. The data revealed that the recombinant ß-glucanase derivatives were not appropriate for feed supplementation because of a lack of stability at acidic pH levels. However, under the same experimental conditions, a commercial enzyme mixture improved the nutritive value of 1 of the cereal lots used. Analysis of the nutritive value of the 2 barleys revealed intrinsic differences in the levels of endogenous ß-glucanase activity. These differences were extensively evident when the studies were expanded to a range of 64 barley lots. Thus, to clarify the effect of endogenous cellulases on the efficacy of exogenous ß-glucanases used to supplement barley-based diets for poultry, 2 barley lots presenting low and high levels of endogenous plant cell wall-degrading enzymes were selected. These lots were used to prepare 2 barley-based diets, which were supplemented with or without a commercial enzyme product and fed to broiler chicks. The data revealed that the exogenous enzymes were effective when the basal diet presented low levels of endogenous ß-glucanases but were unable to improve the nutritive value of the barley lot displaying higher ß-glucanase activity. Thus, these studies suggest that levels of endogenous ß-glucanases may affect the efficacy of exogenous enzymes used to improve the nutritive value of barley-based diets for broilers. The development of a quick ß-glucanase assay that could be applied for cereal-based feeds may help identify those barley-based diets that are more responsive to the action of feed enzymes.

Superconducting quantum critical point in CeCoIn(5-x)Sn(x).

We report a combined pressure-doping study in the nearly two-dimensional heavy fermion superconductor CeCoIn5 as its superconducting phase is driven to the normal state by Sn doping and/or applied pressure. Temperature-pressure-dependent electrical resistivity measurements were performed at the vicinity of a superconducting quantum critical point where Tc→0. A universal plot of the concentration- and pressure-dependent phase diagram suggests that for the concentrations studied a single mechanism is responsible for reducing Tc and bringing the system to the superconducting quantum critical point. A two-band model with hybridization controlled by pressure and doping provides a consistent description of the phase diagram and the suppression of the d-wave superconductivity in this material.

Ventromedial medullary pathway mediating cardiac responses evoked from periaqueductal gray.

Periaqueductal gray (PAG) is a midbrain region that projects to areas controlling behavioral and autonomic outputs and is involved in the behavioral and physiological components of defense reactions. Since Raphe Pallidus (RPa) is a medial medullary region comprising sympathetic premotor neurons governing heart function, it is worth considering the PAG-RPa path. We assessed: i) whether PAG projects to RPa; ii) the amplitude of cardiac responses evoked from PAG; iii) whether cardiovascular responses evoked from PAG rely on RPa. Experiments conducted in Wistar rats (±300 g) were approved by Ethics Committee CEUA-UFG (092/18). Firstly, (n = 3), monosynaptic retrograde tracer Retrobeads was injected into RPa; PAG slices were analyzed. Other two groups (n = 6 each) were anesthetized with urethane (1.4 g/kg) and chloralose (120 mg/kg) and underwent craniotomy, tracheostomy, catheterization of femoral artery and vein and of cardiac left ventricle. In one group, we injected the GABAA receptor antagonist, bicuculline methiodide (BMI - 40 pmol/100 nL) into lateral/dorsolateral PAG. Another group was injected (100 nL) with the GABAA receptor agonist muscimol (20 mM) into RPa, 20 min before BMI into PAG. The results were: i) retrogradely labelled neurons were found in PAG; ii) PAG activation by BMI caused positive chronotropism and inotropism, which were accompanied by afterload increases; iii) RPa inhibition with Muscimol reduced heart rate, arterial and ventricular pressures; iv) the subsequent PAG activation still increased arterial pressure, cardiac chronotropy and inotropy, but these responses were significantly attenuated. In conclusion, PAG activation increases cardiac chronotropy and inotropy, and these responses seem to rely on a direct pathway reaching ventromedial medullary RPa neurons.

Adherence rate to inhaled corticosteroids and their impact on asthma control.

BACKGROUND: Poor asthma control is associated to high morbidity. The objective of this study was to assess the association between adherence rates to beclomethasone dipropionate (BDP) and the degree of asthma control. METHODS: A cohort concurrent study was carried out for 12 months with 122 asthmatic patients, aged 3-12 years, randomly selected in a pediatric pulmonology outpatient clinic, who received BDP free of charge. Adherence rates were verified by pharmacy records. Clinical control was assessed through a scoring system comprised four variables (nocturnal and morning symptoms, limitation of physical activities and exacerbations). Total score was 16 points. Patients whose score was below or equal to two were considered controlled (group 1), and patients whose score was above or equal to three were considered uncontrolled (group 2). For patients able to perform spirometry, we considered as controlled the patients with forced expiratory volume in 1 s (FEV(1)) equal to or above 80% of the predicted value, and as uncontrolled the patients with FEV(1) below 80%. RESULTS: Fewer than half (40.3% maximum) of the 122 patients maintained asthma control. Median adherence rate of groups 1 and 2 were 85.5% and 33.8%, (P < 0.001) in the 4th month, 90.0% and 48.0% (P < 0.001) in the 8th month and 84.4% and 47.0% in the 12th month (P < 0.001), respectively. CONCLUSION: In all periods, there were statistically significant differences in adherence rates for maintaining or not maintaining the asthma control. Optimal asthma control entailed adherence rate higher than 80%. Strategies for reducing asthma morbidity should include a regular monitoring of adherence to inhaled steroids.