Diagnosis and treatment of interstitial lung disease related to systemic autoimmune myopathies: a narrative review.

Systemic autoimmune myopathies (SAMs) are rare diseases that lead to muscle inflammation and may be associated with a variety of systemic manifestations. Although there is great heterogeneity in the spectrum of extra-muscular involvement in SAMs, interstitial lung disease (ILD) is the most frequent lung manifestation. SAM-related ILD (SAM-ILD) presents significant variations according to geographic location and temporal trends and is associated with increased morbidity and mortality. Several myositis autoantibodies have been discovered over the last decades, including antibodies targeting aminoacyl-tRNA synthetase enzymes, which are associated with a variable risk of developing ILD and a myriad of other clinical features. In this review, the most relevant topics regarding clinical manifestations, risk factors, diagnostic tests, autoantibodies, treatment, and prognosis of SAM-ILD are highlighted. We searched PubMed for relevant articles published in English, Portuguese, or Spanish from January 2002 to September 2022. The most common SAM-ILD patterns are nonspecific interstitial pneumonia and organizing pneumonia. The combination of clinical, functional, laboratory, and tomographic features is usually sufficient for diagnostic confirmation, without the need for additional invasive methods. Glucocorticoids remain the first-line treatment for SAM-ILD, although other traditional immunosuppressants, such as azathioprine, mycophenolate, and cyclophosphamide have demonstrated some efficacy and, therefore, have an important role as steroid-sparing agents.

COVID-19 as potential aggravating factor for the natural course of new onset-dermatomyositis.

Borges et al. have recently reported the first case of a dermatomyositis onset in close association with established coronavirus disease 2019 (COVID-19). Similarly, we report a patient who, on the contrary, had COVID-19 following early established dermatomyositis. We report prospectively the outcome of her disease.

Switching from originator recombinant growth hormone (Genotropin™) to biosimilar (CRISCY™): Results from a 6-month, multicentric, non-inferiority, extension trial.

OBJECTIVE: A previous 12-month comparative trial with Criscy™ (r-hGH Cristália), a biosimilar recombinant growth hormone, demonstrated equivalent efficacy and safety to Genotropin™. This extension trial evaluated the effects of switching patients treated with Genotropin™ to the biosimilar Criscy™ over an additional 6-month treatment period, comparing efficacy, safety, and immunogenicity parameters with patients remaining in the Criscy™ arm. DESIGN: This extension study included 11 research centers and 81 patients who participated in the CERES study (Czepielewski et al., 2019 [1]). Participants from the Genotropin™ arm (n = 39) had the drug replaced by Criscy™ and the remaining participants were kept in the Criscy™ arm (n = 42) for an additional 6-month period to evaluate immunogenicity, efficacy (growth rate, height SDS), and safety (laboratory tests, and adverse events). RESULTS: Before the switch, both Criscy™ and Genotropin groups were similar concerning demographics, and auxological measures: age, sex, height, height SDS, weight, and BMI. Height velocity (HV) after 18 months of treatment was 8.7 ± 1.56 cm/year for Criscy™ group and 8.9 ± 1.36 cm/year for Genotropin™ group in the ITT population (p = 0.43). The auxological parameters and IGF-1 and IGFBP-3 SDS were comparable between both groups of patients. No participants were excluded from the study due to adverse events. There were no clinical or statistical relevant differences between the treatment groups concerning frequency, distribution, intensity, and AEs outcome. Similarly, no new anti-r-hGH (ADA) cases among patients that switched from Genotropin™ to Criscy™ were reported. No neutralizing antibody (nAb) was detected in either group. CONCLUSIONS: This trial showed that switching from originator recombinant human growth hormone to Criscy™ had no impact on efficacy, safety, nor immunogenicity as compared to continued treatment with Criscy™. Growth rates and ADA incidence remained the same as seen before the switch.

Efficacy and safety of a biosimilar recombinant human growth hormone (r-hGH Cristalia) compared with reference r-hGH in children with growth hormone deficiency (CERES study): A randomized, multicentric, investigator-blind, phase 3 trial.

OBJECTIVE: The CERES study was a randomized, multicenter, investigator-blind trial aimed to evaluate the efficacy and safety of a recombinant human growth hormone (r-hGH) developed by Cristalia, as a biosimilar product, with analytical, functional and pharmacokinetics similarities comparable to Genotropin™, in children with growth hormone deficiency (GHD). DESIGN: A total of 135 naïve prepubertal children with GHD were recruited, of whom 97 were randomized in 14 Brazilian sites to received either r-hGH Cristalia (n = 49) or Genotropin™ (n = 48). Efficacy was evaluated considering the height standard deviation score (SDS) and growth velocity as auxological parameters, IGF-1 and IGFBP-3 were measured as pharmacodynamic parameters during 12 months treatment time. Safety was assessed by monitoring adverse events, immunogenicity, blood count with platelets, biochemical profile and hormonal levels particularly fasting glucose, insulin and HbA1C. RESULTS: The auxological parameters and IGF-1 and IGFBP-3 levels were comparable between both groups of patients. At end of study or the 12th month treatment, the means growth velocity was 9.7 cm/year and 9.5 cm/year, for r-hGH Cristalia and Genotropin™, respectively. The ANCOVA mean difference between the groups was 0.16 cm/year to Cristalia group (CI 95% = -0.72 to 1.03 cm/year). There was no difference in adherence among the treatment groups. The safety profile was comparable between groups. CONCLUSIONS: The clinical similarity between r-hGH and Genotropin™ was demonstrated within 12 month of treatment. On the basis of comparability of quality, safety, and efficacy to the reference product, r-hGH from Cristalia can be considered a cost-effective therapeutic option for patients with growth disorders.

Predictive factors of graft-censored failure in pediatric kidney transplantation.

Kidney transplantation in children has shown steady improvement in graft survival outcome over the last decades. Using data obtained from the transplantation registry of our center between 1984 and 2012, we assessed the independent determinants of graft failure using the Cox proportional hazards regression. Altogether, 128 recipients younger than 18 years of age at the time of kidney transplantation and who had >3 months graft survival were studied. During 9.95 years of medium follow-up, 27 censored graft failures occurred. Censored graft survival rates at 5, 10, 15, and 20 years post-transplantation were 93%, 82%, 70%, and 63%, respectively. Studied factors included recipient and donor age, recipient gender, dialysis vintage, donor/recipient cytomegalovirus (CMV) serology, panel-reactive antibody percentage, human leukocyte antigen mismatching, previous transplantation number, donor type (deceased vs living donation), cold ischemia time, induction therapy with antithymocyte globulin, occurrence of acute tubular necrosis, and development of acute rejection. Using univariate analysis, the significant predictors for graft-censored failure were adult donor (P < .001), recipient age (P = .035), human leukocyte antigen mismatching (P = .025), antithymocyte globulin induction (P = .03), and development of acute rejection (P < .001). Two factors independently predicted graft-censored failure in multivariate analysis. The odds ratios for graft failure in patients with acute rejection and in children who received an organ of an adult were 3.744 and 4.962, respectively. Pediatric recipients should receive the first priority for allografts from pediatric donors and acute rejection should be meticulously prevented.

Role of ventral hippocampal nitric oxide/cGMP pathway in anxiety-related behaviors in rats submitted to the elevated T-maze.

The L-arginine/nitric oxide (NO)/cGMP pathways have been implicated in the control of a variety of physiological mechanisms and are believed to participate in the modulation of anxiety in the CNS. The aim of this study was to investigate the effects of N(G)-nitro-L-arginine-methyl-ester (L-NAME), a non-selective inhibitor of NO synthase (NOS); 7-nitroindazole (7-NI), a preferential inhibitor of neuronal NOS; and sodium nitroprusside (SNP), an NO donor, administered into the ventral hippocampus (VH) of rats submitted to the elevated T-maze (ETM). The ETM, an animal model derived from the elevated plus-maze, allows the measurement of two defensive behavioral responses in the same rat: inhibitory avoidance and escape. Results showed that L-NAME and 7-NI impaired the acquisition of inhibitory avoidance and prolonged escape latency in the ETM, suggesting an anxiolytic-like and panicolytic-like effect, respectively. SNP facilitated the acquisition of inhibitory avoidance without interfering with escape performance, suggesting an anxiogenic-like effect. Treatment with methylene blue did not alter per se any of the behavioral responses measured in the ETM, but blocked the effect promoted by SNP. Thus, altogether these results suggest that NO in the VH is critically involved in the modulation of defensive behavior of rats exposed to the ETM.

Nitric oxide involvement and neural substrates of the conditioned and innate fear as evaluated in the T-maze test in rats.

The L-arginine/nitric oxide (NO) pathways are widely distributed in the central nervous system (CNS) and have been implicated in the modulation of anxiety. The elevated plus-maze (ETM) is an animal test pharmacologically validated for the study of experimental anxiety in rats, designed to evaluate inhibitory avoidance (AVOID) learning and one-way escape (ESC) from open arms, thought to represent learned (conditioned) and innate (unconditioned) fear, respectively. The aim of the present study was to evaluate the effect of prior treatment with the NO-synthase inhibitor N omega-nitro-L-arginine methyl ester (L-NAME) on both AVOID and ESC behavior of rats in the ETM, when applied to different cerebral regions associated with defensive behaviors. Central treatment with L-NAME (50, 100, 400 and 800 nmol) did not impair the AVOID response through the trials and had no effect on the ESC behavior. Nevertheless, animals treated with L-NAME at 200 nmol into the lateral ventricle (LV), basolateral amygdala (BLA), dorsolateral periaqueductal gray (dlPAG) matter, lateral septal nucleus (LSN), but not in the bed nucleus of stria terminalis (BNST), displayed impaired AVOID2 in comparison to the control group. Thus, our results suggest that NO may underlie learned fear in the ETM via BLA, dlPAG and LSN, but not BNST. These results are compatible with the proposal that NO exerts a positive modulatory role on defensive reactions in rats, exerting among them an anxiogenic-like effect as evaluated in rats submitted to ETM.

Inespecificidade parasitária em Argas (Persicargas) miniatus Koch, 1844 (Acari: Argasidae) / Nonspecificity of parasitism on Argas (Persicargas) miniatus Koch, 1844 (Acari: Argasidae)

Foram coletados 665 espécimes de Argas miniatus em dois municípios dos estados da Bahia e Minas Gerais. Destes, 596 (89,6 por cento) tinham se alimentado, sendo que 489 (82 por cento) reagiram para um único tipo de sangue, distribuídos entre aves (46,8 por cento), roedores (30,9 por cento), gambás (14,5 por cento), bovinos (4,3 por cento) e eqüinos (3,5 por cento). Nesse tipo de reação, o sangue de mamíferos foi detectado em 53,2 por cento (260/489) dos argasídios. As reações múltiplas foram observadas em 107 (17,9 por cento) carrapatos, com sangue de aves presente em 84,1 por cento (90/107), enquanto, o sangue de mamíferos reagiu em 100 por cento (107/107). Os resultados apontam para a inespecificidade parasitária

Six hundred and sixty-five specimens of Argas miniatus were collected in two municipalities of Bahia and Minas Gerais states, Brazil. Five hundred and ninety-six (89.6 percent) of them had fed and 489 (82 percent) of them reacted to only one type of blood, including birds (46.8 percent), rodents (30.9 percent), opossuns (14.5 percent), bovines (4.3 percent) and horses (3.5 percent). In that reaction, the type of mammal blood was detected in 53.2 percent (260/489) of the ticks. Multiple reactions were observed in 107 (17.9 percent) ticks, with blood of birds present in 84.1 percent (90/107), while the blood of mammals was detected in 100 percent (107/107). The results point for the nonspecificity of parasitism

The role of nitric oxide in the emotional learning of rats in the plus-maze.

The present study evaluated the role of nitric oxide (NO) in the transfer latency (TL) paradigm in the elevated plus-maze. Male Wistar rats received i.p. injections of either 0.9% Saline, N(omega) Nitro-L-arginine-methyl-ester (L-NAME, an inhibitor of NO synthesis), d-NAME (inert isomer), scopolamine (SCO, antagonist of muscarinic receptors), or MK-801 (antagonist of NMDA receptors) and, after 30 min, were submitted to TL procedure. In an independent experiment, the ability of the same L-NAME treatments in changing the arterial pressure and blood glucose level (BGL) was evaluated in conscious rats. The treatment with SCO (1 mg kg(-1)), MK-801 (0.15 mg kg(-1)) and L-NAME (10 and 50 mg kg(-1)), but not with D-NAME, impaired the TL learning. The L-NAME-induced TL deficit was counteracted by L-ARG (100 and 200 mg kg(-1)), while the co-administration of sub-effective doses of L-NAME and MK-801 failed to impair the TL learning. The L-NAME (50 mg kg(-1)) treatment failed to alter the BGL. All treatments with L-NAME induced hypertension, but the rats treated with L-NAME (5 mg kg(-1)) were still able to learn the TL task. The data indicate that the TL deficit induced by L-NAME (10 and 50 mg kg(-1)) is not due to either hypertension or changes in the BGL. It is also possible to establish that NO production is important for emotional learning underlying the TL procedure in rats.

Lack of midazolam-induced anxiolysis in the plus-maze Trial 2 is dependent on the length of Trial 1.

The influence of the first exposure length upon the effect of midazolam (MDZ) administration prior to the second exposure in the elevated plus-maze (EPM) was investigated. Drug-free rats were assigned to freely explore the EPM for 1, 2 or 5 min (Trial 1). Twenty-four hours later, each group was subdivided in two further groups, which were retested in the EPM for 5 min, 30 min after either saline or MDZ (1.5 mg kg(-1)) administration (Trial 2). The data showed that during Trial 2, the percentage of entries (%Open arm entries) and time spent in the open arms (%Open arm time) were decreased if rats were pre-exposed to the EPM for 2- or 5-min Trial 1, while the group submitted to 1-min Trial 1 length displayed decreased %Open arm time only. The anxiolytic effect of MDZ prior to Trial 2 was present in the group submitted to 1-min, impaired in the group submitted to 2-min and absent in the group submitted to 5-min Trial 1 length. Data are analyzed taking into account the emotional learning which underlies the exploratory behavior during the EPM Trial 2.

Nitric oxide may underlie learned fear in the elevated T-maze.

The present study evaluated the role of nitric oxide (NO) in learned and innate fear in rats submitted to the elevated T-maze (ETM). Learned and innate fear were evaluated through the inhibitory avoidance and escape behaviour from the open arms, respectively. Rats treated with the inhibitor of NO synthesis N(omega)-nitro-L-Arginine methyl ester (L-NAME; 5, 10, and 50 mg. kg(-1)) were able to learn the inhibitory avoidance. However, L-NAME (50 mg. kg(-1)), but not its inert isomer N(omega)-nitro-D-arginine methyl ester (D-NAME, 50 mg. kg(-1)), impaired the inhibitory avoidance 2 with no change in the baseline values, thus suggesting an anxiolytic-like effect without locomotor impairment. All treatments with L-NAME were able to induce increased mean arterial pressure (MAP), measured indirectly through the animal's tail. The treatment with L-NAME (5 and 10 mg. kg(-1)) failed to induce anxiolysis but significantly increased the MAP of the animals, which indicates that hypertension per se, did not underlie anxiolysis induced by L-NAME. L-Arginine, the precursor molecule for NO synthesis, facilitated the inhibitory avoidance and counteracted the L-NAME (50 mg. kg(-1))-induced anxiolysis. Neither previous treatment was able to change the escape behaviour. The results indicate that NO may underlie learned, but not innate, fear in the ETM.

Temporal analysis of the rat's behavior in the plus-maze: effect of midazolam.

The aim of the present study was to carry out a temporal analysis of the midazolam (MDZ)-induced anxiolysis in rats submitted to the elevated plus-maze (EPM) test. Male Wistar rats received either MDZ (0.5, 1.0 and 1.5 mg.kg(-1)) or saline (0.9%) and were submitted to the EPM test. Temporal analysis revealed that the group receiving MDZ (1.5 mg.kg(-1)), as well as the group treated with saline, displayed low %Open arm entries, which suggests increased anxiety over the test period. Motor activity, evaluated by the enclosed arm entries, was also decreased in both experimental groups, thus suggesting locomotor habituation. The treatment with MDZ (1.5 mg. kg(-1)) induced a clear anxiolysis during the first 3 min, but not at the end of the test, since only the %Open arm time remained increased. The data are discussed with reference to the lack of the test's sensitivity to alterations in the level of anxiety over time and with respect to a qualitative shift in the experimental anxiety at the end of the session.

Evaluation of cDNA libraries from different developmental stages of Schistosoma mansoni for production of expressed sequence tags (ESTs).

A comparative study of the gene expression profile in different developmental stages of Schistosoma mansoni has been initiated based on the expressed sequence tag (EST) approach. A total of 1401 ESTs were generated from seven different cDNA libraries constructed from four distinct stages of the parasite life cycle. The libraries were first evaluated for their quality for a large-scale cDNA sequencing program. Most of them were shown to have less than 20% useless clones and more than 50% new genes. The redundancy of each library was also analyzed, showing that one adult worm cDNA library was composed of a small number of highly frequent genes. When comparing ESTs from distinct libraries, we could detect that most genes were present only in a single library, but others were expressed in more than one developmental stage and may represent housekeeping genes in the parasite. When considering only once the genes present in more than one library, a total of 466 unique genes were obtained, corresponding to 427 new S. mansoni genes. From the total of unique genes, 20.2% were identified based on homology with genes from other organisms, 8.3% matched S. mansoni characterized genes and 71.5% represent unknown genes.

Acute inhibition of nitric oxide synthesis induces anxiolysis in the plus maze test.

The involvement of nitric oxide (NO) in anxiety was investigated in rats, using the elevated plus maze test. Acute, but not chronic, systemic treatment with N omega-nitro-L-arginine methyl ester (L-NAME, 10 and 60 mg.kg-1), an inhibitor of NO synthase, increased the time spent by the rats in the open arms. Both the acute and chronic treatments with L-NAME inhibited NO synthase in endothelial cells and in the central nervous system, as shown by the increase in mean arterial pressure and decreased NO synthase activity in brain tissue. Chronic treatment with L-NAME also decreased the serum nitrate levels. The anxiolysis induced by acute L-NAME treatment is unlikely to be due to hypertension, since two-kidney one-clip hypertension in non-L-NAME-treated rats failed to significantly change exploratory behaviour in the elevated plus maze. These results indicate that acute inhibition of NO synthesis decreases anxiety in rats.

Assessment of renal dopaminergic system activity during the recovery of renal function in human kidney transplant recipients.

BACKGROUND: The urinary excretion of free dopamine has been used as an index of the renal synthesis of amine. However, it is now well recognized that in the kidney, newly-formed dopamine is significantly inactivated through deamination to 3,4-dihydroxyphenylacetic acid (DOPAC) by monoamine oxidase (MAO). The aim of the present study was to assess the renal dopaminergic system activity during the recovery of renal function in kidney transplant recipients and to assess which parameters are appropriate for the evaluation of renal amine synthesis under these conditions. METHODS: Twenty-four-hour urinary excretion of L-DOPA, dopamine and its metabolites (DOPAC; 3-MT; HVA) were continuously monitored in 19 renal transplant recipients from the first day of surgery until the twelfth day post-transplantation. RESULTS: In 11 patients (Group 1), renal function consistently recovered throughout the study (plasma creatinine levels decreased from 6.2 +/- 0.4 to 2.1 +/- 0.1 mg/dl). Eight patients presented with acute tubular necrosis (Group 2) and minimal renal function was maintained until the twelfth post-operative day. The urinary excretion of L-DOPA did not differ throughout the study between the two groups of patients. In contrast, the 24-h urinary levels of dopamine, DOPAC and HVA were significantly higher throughout the study in patients of Group 1: dopamine (Group 1, 179 +/- 26 to 422 +/- 51 nmol/24 h; Group 2, 25 +/- 3 to 57 +/- 13 nmol/ 24 h), DOPAC (Group 1, 698 +/- 57 to 3487 +/- 414 nmol/ 24 h; Group 2, 158 +/- 22 to 1014 +/- 193 nmol/24 h) and HVA (Group 1, 13,058 +/- 1199 to 20,387 +/- 1559 nmol/ 24 h; Group 2, 4140 +/- 848 to 15,219 +/- 1037 nmol/24 h). CONCLUSIONS: The recovery of renal function in renal transplant recipients is accompanied by an enhanced ability to synthesize dopamine and inactivate it to DOPAC and HVA. It is suggested that the urinary levels of DOPAC may be a useful parameter for the assessment of dopamine formation in renal tissues.