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The intranasal route enables direct delivery of multiple substances from the nose to the brain, through olfactory and trigeminal pathways, bypassing the blood-brain barrier and avoiding systemic absorption. Despite the potential of this route, the various administration approaches make data reproducibility and interpretation challenging, emphasizing the necessity to establish a consistent methodology. Considering this, the aim of our study was to assess and compare the distribution of two dye volumes (30 µl and 50 µl) in the nasal cavity of rat cadavers. We employed three distinct methods of intranasal delivery: nose drops, by pipette tip, or cannula inserted into the nasal cavity. The results indicated that for both volumes, using the nose drops and the pipette tip methods, the dye dispersion occurred mainly in the vestibule, respiratory and olfactory regions, without reaching the olfactory bulbs. Using the cannula method, the deposition predominantly occurred in the respiratory and olfactory regions, with the dye reaching 66.7% and 100% of the olfactory bulbs, respectively, to low and high volume. Furthermore, the results demonstrated differences between the two volumes, in the pharynx, larynx, trachea, septal window, and incisive papilla, where an increased dye presence was observed with the 50 µl instillation across all three methods. According to our results, the intranasal delivery with a cannula was the most effective method for dye deposition in the olfactory region. However, further studies in live animals will be necessary to determine and refine the administration method that consistently allows specific deposition in the olfactory system.
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Developmental toxicology is a constantly evolving research field which needs to attend to a complex underlying regulatory network. In order to ensure human health and environmental safety, new substances have to be tested for toxic effects on reproduction and development, before being commercialized. Traditional in vivo mammalian models represent the intricacy of human development and provide more adequately an assessment of the interaction of chemical compounds with the reproductive system. However, in the last years, the directives are to reduce the use of vertebrate animals, promoting their use only as a last resort. Consequently, the interest on the development and validation of alternative tests, able to cover the various aspects of the reproductive cycle, has significantly increased. Reproductive toxicity is probably the most difficult endpoint to be replaced by alternative assays, since it should provide information on mechanism interactions essential for female and male fertility and also knowledge on the animal development during the first phases of its life cycle. This complexity explains the slow progress in implementing alternative models for reproductive toxicity safety assays. Alternative test models may be based on in vitro systems and nonmammalian animal models. Many biological processes have been successfully addressed using in vitro models, opening the possibility to study the interference of teratogenic compounds. Their validation and implementation have lagged behind, in part because of difficulties in establishing their predictability. Nevertheless, the advance toward the process of validation is crucial to replace and reduce the use of living animals. Based on the present state of the art, it is not probable that such testing strategies will completely replace the need to assess reproductive toxicity in vivo in the near future, but they will contribute to reduce animal tests and will provide important information. In this chapter, the approved guidelines for standard methods and alternative methods, according to their regulatory and scientific status, are enumerated and briefly described.
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Reproducción , Teratogénesis , Animales , Humanos , Femenino , Masculino , Bioensayo , Modelos Animales , Probabilidad , MamíferosRESUMEN
Today, the use of animal models from different species continues to represent a fundamental step in teratogenic testing, despite the increase in alternative solutions that provide an important screening to the enormous quantity of new substances that aim to enter the market every year. The maintenance of these models is due to the sharing of similar development processes with humans, and in this way they represent an important contribution to the safety in the use of the compounds tested. Furthermore, the application of advances in embryology to teratology, although hampered by the complexity of reproductive processes, continues to prove the importance of sensitivity during embryonic and fetal development to detect potential toxicity, inducing mortality/abortion and malformations.In this chapter, essential periods of development in different models are outlined, highlighting the similarities and differences between species, the advantages and disadvantages of each group, and specific sensitivities for teratogenic testing. Models can be divided into invertebrate species such as earthworms of the species Eisenia fetida/Eisenia andrei, Caenorhabditis elegans, and Drosophila melanogaster, allowing for rapid results and minor ethical concerns. Vertebrate nonmammalian species Xenopus laevis and Danio rerio are important models to assess teratogenic potential later in development with fewer ethical requirements. Finally, the mammalian species Mus musculus, Rattus norvegicus, and Oryctolagus cuniculus, phylogenetically closer to humans, are essential for the assessment of complex specialized processes, occurring later in development.Regulations for the development of toxicology tests require the use of mammalian species. Although ethical concerns and costs limit their use in large-scale screening. On the other hand, invertebrate and vertebrate nonmammalian species are increasing as alternative animal models, as these organisms combine low cost, less ethical requirements, and culture conditions compatible with large-scale screening. Their main advantage is to allow high-throughput screening in a whole-animal context, in contrast to the in vitro techniques, not dependent on the prior identification of a target. Better knowledge of the development pathways of animal models will allow to maximize human translation and reduce the number of animals used, leading to a selection of compounds with an improved safety profile and reduced time to market for new drugs.
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Oligoquetos , Teratogénesis , Teratología , Femenino , Embarazo , Humanos , Ratones , Animales , Conejos , Ratas , Teratógenos/toxicidad , Drosophila melanogaster , Caenorhabditis elegans , Modelos Animales , MamíferosRESUMEN
OBJECTIVES: To estimate digit circumference and the impact of sex and body mass index (BMI) for the calculation of the Leeds Dactylitis Index (LDI) in psoriatic arthritis (PsA) patients with bilateral dactylitis. METHODS: Digit circumference of the hands and the foot were measured with a dactylometer and were studied according to sex and BMI (divided in 4 weight categories) in healthy Portuguese subjects, using Student's t-test and One-way ANOVA, respectively. The effect size of sex and BMI were calculated using Cohen's d test and Eta squared, respectively. Multiple linear regression was used to calculate the effect of sex and BMI, as well as their interaction, to create a formula to predict digit circumference. RESULTS: Fifty-nine participants (33 women, 26 men) with a mean BMI of 24.8 were included. Men's mean digit circumferences were statistically higher than those of women (p<0.001), with a large sex effect size in most of the digits. Differences in the mean circumference between the four BMI categories were statistically significant (p<0.05) for all digits, with a large BMI effect size. Sex and BMI were independent variables to predict mean digit circumference (p<0.001). A new tool (based on regression analysis) allowing to estimate the circumference of digits for males and females of different BMIs is presented. CONCLUSIONS: Our data allows the calculation of digit circumference for males and females of different BMIs in the Portuguese population; and shows that BMI influences digital circumference supporting BMI inclusion in LDI references tables.
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Artritis Psoriásica , Masculino , Humanos , Femenino , Índice de Masa Corporal , Artritis Psoriásica/diagnóstico , Mano , Análisis de Regresión , Circunferencia de la CinturaRESUMEN
BACKGROUND: Ultrasound-guided quadratus lumborum block (QLB) and sacrococcygeal epidural anaesthesia (ScE) have been used for neutering cats, providing effective pain relief. OBJECTIVES: To compare the effects of the QLB with those of ScE in cats undergoing ovariectomies. METHODS: Feral cats undergoing ovariectomy were premedicated with dexmedetomidine (20 µg kg-1) and methadone (0.2 mg kg-1) intramuscularly. Anaesthesia was induced with 2-4 mg kg-1 of propofol intravenously and maintained with isoflurane in oxygen. The cats were randomly allocated to the groups QLB (bilateral QLB with 0.4 mL kg-1 of 0.25% bupivacaine) and ScE (0.3 mL kg-1 of 0.25% bupivacaine). Hemodynamic data and analgesia rescue were collected at four intraoperative periods. The pain scale and motor block were assessed in both groups during the postoperative period. RESULTS: The ScE results in increased hypotension, prolonged extubation time, and higher postoperative motor block than the QLB (p < 0.05). The QLB and ScE groups required a similar number of intraoperative rescues and presented the same postoperative pain scale classification. CONCLUSIONS: The QLB with 0.25% bupivacaine is a potential alternative to ScE with 0.25% bupivacaine in perioperative pain management in elective cat ovariectomy. The QLB promoted less hypotension and postoperative motor block when compared with the ScE group.
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INTRODUCTION: Psoriatic arthritis (PsA) is a chronic, progressive inflammatory joint disease that is associated with higher prevalence of depression. There is limited literature about the impact of depression, particularly regarding the response to therapy. METHODS: A retrospective cohort study with PsA patients that started their first biologic disease-modifying antirheumatic drugs (bDMARD) was conducted. In the majority of cases, a cutoff score of ≥ 8 in Hospital Anxiety and Depression Scale (HADS) was used to define cases of depression. In cases where patients did not complete the questionnaire, a previous diagnosis made by a psychiatrist was used to establish the presence of depression. Response to therapy 12 months after the start of bDMARD was evaluated and the switch rate to another bDMARD due to inefficacy was assessed at month 12. RESULTS: A total of 129 patients (66 females, 51.2%; mean age of 47.7 ± 11.0 years and mean disease duration of 10.0 ± 7.7 years) with PsA were included. Thirty-two (24.8%) patients had depression. Patients with depression and peripheral involvement had a significantly lower ACR20/50/70 responses (p = 0.001, p = 0.002, and p = 0.001 respectively) after 12 months of therapy and a significantly worse EULAR response (p = 0.002). Furthermore, patients with depression and axial involvement had a significantly worse response based on ASDAS response criteria (p = 0.031). Switch due to ineffectiveness in the first 12 months was significantly higher in patients with depression (p = 0.002). CONCLUSION: Depression in PsA is a frequent yet often understudied comorbidity. The causal relationship between depression and PsA is difficult to decrypt and further research is needed. Recognition of depressive symptoms is crucial and a multidisciplinary approach should be provided to individuals with this comorbidity. Key Points ⢠Depression in PsA is a frequent yet often understudied comorbidity. In our study, the prevalence of depression was 24.8%. ⢠Depression in PsA seems to be associated to lower response to therapy and higher discontinuation rates of bDMARD. ⢠Recognition of depressive symptoms is crucial and a multidisciplinary approach should be provided to individuals with this comorbidity.
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Antirreumáticos , Artritis Psoriásica , Productos Biológicos , Femenino , Humanos , Adulto , Persona de Mediana Edad , Artritis Psoriásica/complicaciones , Artritis Psoriásica/tratamiento farmacológico , Artritis Psoriásica/diagnóstico , Estudios Retrospectivos , Depresión/complicaciones , Depresión/epidemiología , Productos Biológicos/uso terapéutico , Antirreumáticos/uso terapéuticoRESUMEN
Ultrasound (US) has emerged as one of the most applied imaging tools to diagnose musculoskeletal disorders and assist in guided intra-articular administrations. Nevertheless, in evaluating the rabbit hip joint, there is a need for an ultrasonographic approach. Therefore, this study aimed to describe the hip sonoanatomy, develop and validate a US-guided protocol to assess the hip joint in rabbits and apply this protocol in vivo. This study was carried out in three phases, phase I: a pilot cadaveric study, to assess the applicability of different US approaches in the hip of rabbits and, consequently, develop a detailed US-guided protocol (2 rabbit cadavers, n = 4 hips); phase II: validation of the established US-guided protocol through a numerical scoring system in healthy joints (11 rabbit cadavers, n = 22 hips), and, lastly, phase III: application of the US-guided protocol in vivo in osteoarthritic joints (5 rabbits, n = 5 hips). A total of six planes were validated, two in the ventral approach and four in the dorsal approach. The ventral transverse plane was deemed more informative regarding the hip joint sonoanatomy, enabling the identification of a greater number of structures when compared to the other planes. Nevertheless, this study suggested that the isolated application of a plane was deemed insufficient for a complete and detailed evaluation of the hip joint anatomy, rendering it necessary to employ other planes complementarily. Furthermore, the established US-guided protocol allowed a definitive diagnosis of OA, and osteophytes and capsular hypertrophy were among the defects most frequently detected. This novel study provided US anatomical landmarks for forthcoming therapeutic research and monitoring of OA development, granting the accurate identification of osseous and cartilaginous defects.
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Lagomorpha , Osteoartritis de la Cadera , Animales , Conejos , Osteoartritis de la Cadera/diagnóstico por imagen , Articulación de la Cadera/diagnóstico por imagen , Cadáver , Ultrasonografía IntervencionalRESUMEN
INTRODUCTION: Immune-mediated skin lesions (IMSL) can be very disabling leading to treatment discontinuation. Although these lesions have rarely been previously described, the true incidence is unknown. OBJECTIVE: To explore the cumulative incidence, management and outcomes of IMSL related to bDMARD in a large cohort of patients with chronic inflammatory rheumatic diseases. To explore possible associations and risk factors for IMSL development. METHODS: A retrospective single-center study of patients with rheumatoid arthritis (RA), spondylarthritis (SpA) and psoriatic arthritis (PsA) that had been treated with at least one bDMARD for at least 6 months was conducted. IMSL related to bDMARD characteristics and outcomes were collected. RESULTS: A total of 989 patients with RA, SpA and PsA were included. Twenty-seven patients (2.7%) presented IMSL potentially related to bDMARD, being psoriasis the most common IMSL (n=12, 44.4%), followed by drug-induced lupus erythematosus (n=6), alopecia areata (n=3) and leukocytoclastic vasculitis (n=2). IMSL led to withdrawal of bDMARD in 18 of the 27 patients (66.7%). Patients with IMSL had younger age at diagnosis (p=0.038), longer disease duration (p=0.018), longer duration of bDMARD treatment (p=0.008), and higher number of previous bDMARDs (p < 0.001) than patients without IMSL. In the group of patients with IMSL there was a significantly higher percentage of patients treated with adalimumab (p < 0.001). In multivariate regression model, the number of previous bDMARDs (OR 2.13, 95%CI 1.47-3.10, p < 0.001) and treatment with adalimumab (OR 4.60, 95%CI 1.96-10.80 , p < 0.001) were statistically significant predictive factors for IMSL development. CONCLUSION: In our study, IMSL related to bDMARDs had an estimated cumulative incidence of 2.7%. Younger age at diagnosis, longer disease duration, longer duration of bDMARD treatment, higher number of previous bDMARDs and treatment with adalimumab were independently associated with an increased risk of IMSL development.
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Macrophage activation syndrome (MAS) is a potentially life-threatening complication of rheumatic diseases. We report a unique case of a previously healthy 20-year-old female presenting with MAS as first presentation of systemic lupus erythematosus. Remission was achieved with hydroxychloroquine, intravenous methylprednisolone pulse followed by oral prednisolone and cyclosporine. However, the management of MAS is still challenging, and the mortality rate remains high.
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Lupus Eritematoso Sistémico , Síndrome de Activación Macrofágica , Femenino , Humanos , Adulto Joven , Adulto , Lupus Eritematoso Sistémico/complicaciones , Lupus Eritematoso Sistémico/diagnóstico , Lupus Eritematoso Sistémico/tratamiento farmacológico , Ciclosporina/uso terapéutico , Metilprednisolona/uso terapéutico , Síndrome de Activación Macrofágica/complicaciones , Hidroxicloroquina/uso terapéuticoRESUMEN
Macrophage activation syndrome (MAS) is a potentially life-threatening complication of rheumatic diseases. We report a unique case of a previously healthy 20-year-old female presenting with MAS as first presentation of systemic lupus erythematosus. Remission was achieved with hydroxychloroquine, intravenous methylprednisolone pulse followed by oral prednisolone and cyclosporine. However, the management of MAS is still challenging, and the mortality rate remains high.(AU)
El síndrome de activación macrofágica (SAM) es una complicación potencialmente letal de algunas enfermedades reumáticas. Presentamos un caso único de una mujer de 20 años previamente sana que se presentó con SAM como primera manifestación de lupus eritematoso sistémico. Se logró una remisión completa con hidroxicloroquina, pulsos intravenosos de metilprednisolona seguido de prednisolona oral y ciclosporina. Sin embargo, el manejo del SAM sigue siendo un desafío y la tasa de mortalidad sigue siendo alta.(AU)
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Humanos , Femenino , Adulto Joven , Lupus Eritematoso Sistémico/complicaciones , Lupus Eritematoso Sistémico/mortalidad , Síndrome de Activación Macrofágica , Ciclosporina , Reumatología , Enfermedades Reumáticas/complicaciones , Pacientes Internos , Examen FísicoRESUMEN
The alteration in the shape of the femoral neck is an important radiographic sign for scoring canine hip dysplasia (CHD). Previous studies have reported that the femoral neck thickness (FNT) is greater in dogs with hip joint dysplasia, becoming progressively thicker with disease severity. The main objective of this work was to describe a femoral neck thickness index (FNTi) to quantify FNT and to study its association with the degree of CHD using the Fédération Cynologique Internationale (FCI) scheme. A total of 53 dogs (106 hips) were randomly selected for this study. Two examiners performed FNTi estimation to study intra- and inter-examiner reliability and agreement. The paired t-test, the Bland-Altman plots, and the intraclass correlation coefficient showed excellent agreement and reliability between the measurements of the two examiners and the examiners' sessions. All joints were scored in five categories by an experienced examiner according to FCI criteria. The results from examiner 1 were compared between FCI categories. Hips that were assigned an FCI grade of A (n = 19), B (n = 23), C (n = 24), D (n = 24), and E (n = 16) had a mean ± standard deviation FNTi of 0.809 ± 0.024, 0.835 ± 0.044, 0.868 ± 0.022, 0.903 ± 0.033, and 0.923 ± 0.068, respectively (ANOVA, p < 0.05). Therefore, these results show that FNTi is a parameter capable of evaluating proximal femur bone modeling and that it has the potential to enrich conventional CHD scoring criteria if incorporated into a computer-aided diagnosis capable of detecting CHD.
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Adequate radiographic positioning on the X-ray table is paramount for canine hip dysplasia (HD) screening. The aims of this study were to evaluate femoral parallelism on normal ventrodorsal hip extended (VDHE) view and the effect of femoral angulation (FA) on Norberg Angle (NA) and Hip Congruency Index (HCI). The femoral parallelism was evaluated comparing the alignment of the long femoral axis with the long body axis in normal VDHE views and the effect of FA on NA and HCI on repeated VDHE views with different levels of FA. The femoral long axis in normal VDHE views showed a ranged of FA from -4.85° to 5.85°, mean ± standard deviation (SD) of -0.06 ± 2.41°, 95% CI [-4.88, 4.76°]. In the paired views, the mean ± SD femur adduction of 3.69 ± 1.96° led to a statistically significant decrease NA, and HCI, and femur abduction of 2.89 ± 2.12 led to a statistically significant increase in NA and HCI (p < 0.05). The FA differences were also significantly correlated with both NA differences (r = 0.83) and HCI differences (r = 0.44) (p < 0.001). This work describes a methodology that allows evaluation of femoral parallelism in VDHE views and the results suggest that femur abduction yielded more desirable NA and HCI values and adduction impaired NA and HCI values. The positive linear association of FA with NA and HCI allows the use of regression equations to create corrections, to reduce the influence of poor femoral parallelism in the HD scoring.
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INTRODUCTION: Anti-tumor necrosis factor α (anti-TNFα) agents can potentially induce the anti-nuclear antibodies (ANA) development over time. Evidence of the real impact of these autoantibodies on clinical response to treatment in rheumatic patients is still scarce. OBJECTIVES: To explore the impact of ANA seroconversion induced by anti-TNFα therapy on clinical outcomes in biologic-naïve patients with Rheumatoid arthritis (RA), axial spondylarthritis (axSpA) and psoriatic arthritis (PsA). METHODS: An observational retrospective cohort study enrolling biologic-naïve patients with RA, axSpA and PsA who started their first anti-TNFα agent was conducted for 24 months(M). Sociodemographic data, laboratory findings, disease activity and physical function scores were collected at baseline, 12M and 24M. To examine the differences between the groups with and without ANA seroconversion, independent samples t-tests, Mann-Whitney U-tests and chi-square tests were performed. Linear and logistic regression models were used to assess the effects of ANA seroconversion on the clinical response to treatment. RESULTS: A total of 432 patients with RA (N=185), axSpA (N=171) and PsA (N=66) were included. ANA seroconversion rate at 24M was 34.6%, 64.3% and 63.6% for RA, axSpA and PsA, respectively. Regarding sociodemographic and clinical data in RA and PsA patients, no statistically significant differences between groups with and without ANA seroconversion were found. In axSpA patients, ANA seroconversion was more frequent in patients with higher body mass index (p=0.017) and significantly less frequent in patients treated with etanercept (p=0.01). Regarding disease activity, DAS28 for RA patients and ASDAS-CRP for axSpA patients were significantly higher in ANA seroconversion group at 12M (p=0.017 and p=0.009, respectively). For PsA patients, CDAI was significantly higher in ANA seroconversion group at 24M (p=0.043). Overall switching rate of biologic disease-modifying antirheumatic drugs (bDMARD) was significantly higher in the ANA seroconversion group over time (p=0.025). For RA patients, ANA seroconversion predicted DAS28 (ß=-0.21, 95%CI[-1.86;-0.18], p=0.017) at 12M. CONCLUSIONS: ANA seroconversion induced by anti-TNFα agents could interfere in clinical response of patients with rheumatic diseases. The presence of these autoantibodies can be considered as a potential predictor of poor treatment response and higher need for bDMARD switching over time.
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Introduction: Cranial nerve involvement in polyarteritis nodosa(PAN) is underrecognized and rarely reported. The aim of this article is to review the available literature and present an example of oculomotor nerve palsy in the course of PAN. Material and methods: Evaluation of texts describing the analyzed problem using the terms "polyarteritis nodosa", "nerve", "oculomotor", "cranial nerve" and "cranial neuropathy" for searching the PubMed database was done. Only full-text articles in English language with titles and abstracts were included in the analysis. As a guideline for the analysis of articles, the methodology described in the Principles of Individual Patient Data systematic reviews (PRISMA-IPD) was used. Results: After screening articles only 16 reported cases of PAN with cranial neuropathy were included in the analysis. In 10 the cranial neuropathy was reported as the initial manifestation of PAN with optic nerve involvement as the most frequent (62.5%); among these cases the oculomotor nerve was involved in 3 cases. Treatment with glucocorticosteroids and cyclophosphamide was the most common. Conclusions: Although cranial neuropathy, especially oculomotor nerve palsy is a rare first neurological manifestation of PAN, this clinical problem should be considered in the differential diagnosis.Especially patients with peripheral neuropathy, general symptoms, skin lesions and hepatitis B virus infection should be evaluated for cranial nerve involvement in the course of vasculitis.In the case of unclear involvement of the cranial nerves, PAN should also be considered in the differential diagnosis as the cause of symptoms and the first manifestation of the disease.
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INTRODUCTION: Immune-mediated necrotizing myopathy (IMNM) is characterized by acute or subacute, severe proximal muscle weakness and myofiber necrosis with minimal inflammatory cell infiltrate observed on muscle biopsy. On the other hand, sarcoidosis is characterised by the presence of non-caseating granulomas that can develop in several organs. CASE REPORT: We present the unique case of a 49-year-old woman, with no previous medical history, who had a rare concomitant occurrence of IMNM and pulmonary sarcoidosis. This condition was successfully treated with a combination of corticosteroids and rituximab along with rehabilitation program. DISCUSSION: This association has been reported in only two previous case reports. This highlights the importance of further research on the connection between sarcoidosis and other forms of inflammatory myopathies.
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Enfermedades Autoinmunes , Miositis , Sarcoidosis Pulmonar , Sarcoidosis , Traumatismos de los Tejidos Blandos , Femenino , Humanos , Persona de Mediana Edad , Sarcoidosis Pulmonar/complicaciones , Miositis/complicaciones , Enfermedades Autoinmunes/patología , Sarcoidosis/patología , Debilidad MuscularRESUMEN
X-ray bone semantic segmentation is one crucial task in medical imaging. Due to deep learning's emergence, it was possible to build high-precision models. However, these models require a large quantity of annotated data. Furthermore, semantic segmentation requires pixel-wise labeling, thus being a highly time-consuming task. In the case of hip joints, there is still a need for increased anatomic knowledge due to the intrinsic nature of the femur and acetabulum. Active learning aims to maximize the model's performance with the least possible amount of data. In this work, we propose and compare the use of different queries, including uncertainty and diversity-based queries. Our results show that the proposed methods permit state-of-the-art performance using only 81.02% of the data, with O ( 1 ) time complexity.
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We describe a case of a 57-year-old white woman treated for rheumatoid arthritis (RA) with tofacitinib 10mg daily (started one year ago) and prednisolone 5mg daily. She presented to the emergency department with a tight squeezing chest pain and shortness of breath for 7h and the clinical evaluation revealed regional systolic dysfunction of the left ventricle, mimicking a myocardial infarction, in the absence of angiographic evidence of obstructive coronary artery disease or acute plaque rupture. All changes were transient and resolved completely within 4 days. The diagnosis of Takotsubo cardiomyopathy (TKM) was established. This is, as far as we know, the first report of a case of TKM in a RA patient taking tofacitinib. Although the association has not been previously described and the precise cause cannot be identified in this patient, the association with tofacitinib should be considered given the etiopathogenic rationale and the absence of any other identifiable cause.