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We hypothesized that after synovial injury, collagen V (Col V) expose occult antigens, and Col V autoantibodies develop, indicating the loss of immune tolerance against this molecule, thus leading to damage to mesenchymal-derived cells as well as the extracellular matrix in experimental arthritis. Thus, the present study investigated the effects of oral administration of Col V on the synovium after the development of inflammation in mBSA/CFA-induced arthritis. After fourteen days of intraarticular administration of mBSA, 10 male Lewis rats were orally administered Col V (500 μg/300 μL) diluted in 0.01 N acetic acid (IA-Col V group). The arthritic group (IA group, n = 10) received only intraarticular mBSA. An intra-articular saline injection (20 μL) was given to the control group (CT-Col V, n = 5). IA group presented damaged synovia, the expansion of the extracellular matrix by cellular infiltrate, which was characterized by T and B lymphocytes, and fibroblastic infiltration. In contrast, after Col V oral immunotherapy IA-Col V group showed a significant reduction in synovial inflammation and intense expression of IL-10+ and FoxP3+ cells, in addition to a reduction in Col V and an increase in Col I in the synovia compared to those in the IA group. Furthermore, an increase in IL-10 production was detected after IA-Col V group spleen cell stimulation with Col V in vitro. PET imaging did not differ between the groups. The evaluation of oral treatment with Col V, after mBSA/CFA-induced arthritis in rats, protects against inflammation and reduces synovial tissue damage, through modulation of the synovial matrix, showing an immunotherapeutic potential in inhibiting synovitis., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2024 Ramos da Silveira et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Metastatic pheochromocytomas and paragangliomas (PPGLs) are frequently associated with skeletal complications. Primary objective: to describe the frequency of adverse skeletal related events (SREs) in PPGL patients with bone metastases (BMs). Secondary objectives: to 1) identify predictive and prognostic factors for SREs and 2) obtain information on the effectiveness of bone resorption inhibitors in reducing SRE risk and improving outcomes in term of survival and SREs time onset. In this retrospective multicenter, multinational study, 294 PPGL patients were enrolled. SREs occurred in 90 patients (31 %). Fifty-five patients (19 %) had bone fractures, 47 (16 %) had spinal cord compression, and 11 (4 %) had hypercalcemia. Twenty-two patients (7 %) had more than one SRE. Sixty-four patients (22 %) underwent surgery, and 136 (46 %) underwent radiotherapy. SREs occurred a median of 4.4 months after diagnosis of BM (range, 0-246.6 months). Independent factors associated with reduced risk of SREs in multivariable analysis were I-131-MIBG radionuclide therapy (hazard ratio [HR], 0.536 [95 % CI, 0.309-0.932]; P = .027) and absence of liver metastases (HR, 0.638 [95 % CI, 0.410-0.992]; P = .046). The median overall survival duration was 5.3 year. In multivariable analysis, age younger than 48 years at PPGL diagnosis (HR, 0.558 [95 % CI, 0.3877-0.806]; P = .002), absence of liver metastases (HR, 0.618 [95 % CI, 0.396-0.965]; P = .034), treatment with bisphosphonates or denosumab (HR, 0.598 [95 % CI, 0.405-0.884]; P = .010), and MIBG radionuclide therapy (HR, 0.444 [95 % CI, 0.274-0.718]; P = .001) were associated with a reduced risk of death. SREs occur frequently and early in bone-metastatic PPGL patients but do not negatively impact survival. MIBG radionuclide therapy and treatment with bone resorption inhibitors are associated with favorable outcome., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Context: The role of hormone parameters at adrenal venous sampling (AVS) in predicting clinical and biochemical outcomes remains controversial., Objective: To investigate the impact of hormone parameters at AVS under cosyntropin stimulation on lateralization and on complete biochemical and clinical outcomes., Methods: We retrospectively evaluated 150 sequential AVS under cosyntropin infusion. The bilateral successful cannulation rate was 83.3% (n = 140), 47.9% bilateral and 52.1% unilateral. The lateralization index, aldosterone/cortisol ratio (A/C) in the dominant adrenal vein (AV), and relative aldosterone secretion index (RASI = A/C in AV divided by A/C in inferior vena cava) were assessed. The contralateral suppression (CS) percentage was defined by (1 - nondominant RASI) * 100., Results: A nondominant RASI <0.5 (CS >50%) had 86.84% sensitivity and 92.96% specificity to predict contralateral lateralization. An A/C ratio in dominant AV >5.9 (74.67% sensitivity and 80% specificity) and dominant RASI >4.7 (35.21% sensitivity and 88.06% specificity) had the worst performance to predict ipsilateral lateralization. Complete biochemical and clinical cure was significantly more frequent in the patients with CS >50% [98.41% vs 42.86% (P < .001) and 41.94% vs 0% (P < .001)]. CS correlated with high aldosterone at diagnosis (P < .001) and low postoperative aldosterone levels at 1 month (P = .019). Postoperative biochemical hypoaldosteronism was more frequent in patients with CS >50% (70% vs 16.67%, P = .014). In multivariable analysis, a CS >50% was associated with complete biochemical cure [odds ratio (OR) 125, 95% confidence interval (CI) 11.904-5000; P = .001] and hypertension remission (OR 12.19, 95% CI 2.074-250; P = .023)., Conclusion: A CS >50% was an independent predictor of complete clinical and biochemical cure. Moreover, it can predict unilateral primary aldosteronism and postoperative biochemical hypoaldosteronism. Our findings underscore the usefulness of CS for clinical decision-making., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Endocrine Society. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)

Context: Paragangliomas (PGLs) are rare tumors in adrenal and extra-adrenal locations. Metastasis are found in approximately 5% to 35% of PGLs, and there are no reliable predictors of metastatic disease., Objective: This work aimed to develop a prognostic score of metastatic potential in PGLs., Methods: A retrospective analysis was conducted of clinical data from a cohort with PGLs and tumor histological assessment. Patients were divided into metastatic PGL (presence of metastasis) and nonmetastatic PGL (absence of metastasis ≥96 months of follow-up) groups. Univariate and multivariable analysis were performed to identify predictors of metastatic potential. A prognostic score was developed based on coefficients of multivariable analysis. Kaplan-Meier curves were generated to estimate disease-specific survival (DSS)., Results: Out of 263 patients, 35 patients had metastatic PGL and 110 patients had nonmetastatic PGL. In multivariable analysis, 4 features were independently related to metastatic disease and composed the Prognostic Score of Paragangliomas (PSPGL): presence of central or confluent necrosis (33 points), more than 3 mitosis/10 high-power field (HPF) (28 points), extension into adipose tissue (20 points), and extra-adrenal location (19 points). A PSPGL of 24 or greater showed similar sensitivity with higher specificity than the Pheochromocytoma of the Adrenal Gland Scaled Score (PASS) and Grading System for Adrenal Pheochromocytoma and Paraganglioma (GAPP). PSPGL less than or equal to 20 was associated with a risk of metastasis of approximately 10%, whereas a PSPGL of 40 or greater was associated with approximately 80%. The presence of metastasis and Ki-67 of 3% or greater were related to lower DSS., Conclusion: The PSPGL, composed of 4 easy-to-assess parameters, demonstrated good performance in predicting metastatic potential and good ability in estimating metastasis risk., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Endocrine Society.)

Few studies demonstrated a percentage decrease in the estimated glomerular filtration rate (eGFR) at a single time and the rate of hypoaldosteronism after adrenalectomy for primary aldosteronism (PA). Our aim was to investigate the evolution of renal function and the hypoaldosteronism risk after adrenalectomy for PA. Aldosterone, renin, eGFR, and electrolyte levels were determined before and at 1 week, 1, 3 and 6 months after unilateral adrenalectomy in 94 PA patients (40 men and 54 women). The main outcome was the postoperative eGFR decline using analysis of covariance with the preoperative eGFR as a covariate. eGFR decreased during first postoperative week compared to 3 months before surgery. During the first 6 months, eGFR remained stable at similar levels to the first week after surgery. Age (p=0.001), aldosterone levels (p=0.021) and eGFR 3 months before surgery (p+<+0.0001) had a significant correlation with eGFR during first postoperative week. High aldosterone levels at diagnosis were correlated with decline in renal function in the univariate model (p=0.033). In the multivariate analysis, aldosterone levels at diagnosis had a tendency to be an independent predictor of renal function after surgery (p=0.059). Postoperative biochemical hypoaldosteronism was diagnosed in 48% of the cases after adrenalectomy, but prolonged hyperkalemia occurred in only 4 cases (4.5%). Our findings showed a decrease of eGFR after unilateral adrenalectomy for PA. Additionally, aldosterone levels at diagnosis correlated with postoperative renal function. Postoperative biochemical hypoaldosteronism occurred in almost half of the patients, but prolonged hyperkalemia with fludrocortisone replacement was less frequent., Competing Interests: The authors declare that they have no conflict of interest., (Thieme. All rights reserved.)

Background: Pulmonary atelectasis is a commonly occurs during anesthesia. In these cases, mechanical ventilation (MV) associated with alveolar recruitment maneuvers (ARMs) and positive end-expiratory pressure (PEEP) is indicated to reverse the condition, ensure adequate gas exchange and improve oxygenation. ARMs can trigger volutrauma, barotrauma, and atelectrauma. Therefore, computed tomography (CT) is the gold-standard method for monitoring lung aeration after ARM., Objective: To evaluate lung volume distribution after stepwise ARMs using computed tomography (CT)., Methods: Twelve dogs weighing 24.0 ± 6.0 kg, aged 3 ± 1 years, of both sexes and different breeds, underwent orchiectomy or ovariohysterectomy. The animals were anesthetized and ventilated in volume-controlled mode. ARMs were then initiated by positive end-expiratory pressure (PEEP) titration (5, 10, 15, and 20 cmH 2 O). CT scans, cardiovascular parameters, and ventilatory mechanics were evaluated at all time points. Data were assessed for normality using the Shapiro-Wilk test and a two-way analysis of variance, followed by a post-hoc Bonferroni test to identify differences between time points. Statistical significance was attributed to a value of p of <0.05., Results: CT demonstrated that the ARMs increased ventilation throughout the lung, including the dependent regions, with volumes that increased and decreased proportionally with PEEP titration. When they reached PEEP 10 and 5 cmH 2 O descending (d), they remained significantly higher than those in PEEP 0 cmH 2 O (baseline). Static compliance improved about 40% at PEEP 10d and PEEP 5d compared to baseline. There was an increase in heart rate (HR) from PEEP 15 increasing (i) (74.5%) to PEEP 10d (54.8%) compared to baseline. Mean arterial blood pressure (MABP) decreased approximately 9% from PEEP 15i to PEEP 15d compared to baseline., Conclusion: Lung attenuation and regional and global volumes assessed by CT showed that maximum pulmonary aeration distribution followed by PEEP titration occurred at PEEP 20 cmH 2 O, maintaining the lungs normoaerated and without hyperaeration., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Sanchez, Ambrósio, Fonseca Pinto, Pereira, Andrade, Rodrigues, de Carvalho Martins, Baroni, Ferrante and Fantoni.)

The best-known etiologies of hyperinsulinemic hypoglycemia are insulinoma, non-insulinoma pancreatogenous hypoglycemic syndrome, autoimmune processes, and factitious hypoglycemia. In 2009, a disease not associated with classic genetic syndromes and characterized by the presence of multiple pancreatic lesions was described and named insulinomatosis. We present the clinical and pathologic features of four patients with the diagnosis of insulinomatosis, aggregated new clinical data, reviewed extensively the literature, and illustrated the nature and evolution of this recently recognized disease. One of our patients had isolated (without fasting hypoglycemia) postprandial hypoglycemia, an occurrence not previously reported in the literature. Furthermore, we reported the second case presenting malignant disease. All of them had persistent/recurrent hypoglycemia after the first surgery even with pathology confirming the presence of a positive insulin neuroendocrine tumor. In the literature review, 27 sporadic insulinomatosis cases were compiled. All of them had episodes of fasting hypoglycemia except one of our patients. Only two patients had malignant disease, and one of them was from our series. The suspicion of insulinomatosis can be raised before surgery in patients without genetic syndromes, with multiple tumors in the topographic investigation and in those who had persistent or recurrent hypoglycemia after surgical removal of one or more tumors. The definitive diagnosis is established by histology and immunohistochemistry and requires examination of the "macroscopically normal pancreas." Our case series reinforces the marked predominance in women, the high frequency of recurrent hypoglycemia, and consequently, a definitive poor response to the usual surgical treatment., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The author(s) declared that they were an editorial board member of Frontiers, at the time of submission. This had no impact on the peer review process and the final decision., (Copyright © 2024 Lourenço, Corrêa-Giannella, Siqueira, Nery, Ribeiro, Quedas, Rocha, Nascimento and Pereira.)

Context: Confirmatory tests represent a fundamental step in primary aldosteronism (PA) diagnosis, but they are laborious and often require a hospital environment due to the risks involved., Objective: To evaluate the efficacy of oral furosemide as a new confirmatory test for PA diagnosis., Methods: We prospectively evaluated the diagnostic performance of 80 mg of oral furosemide in 64 patients with PA and 22 with primary hypertension (controls). Direct renin concentration (DRC) was measured before, and 2 hours and 3 hours after the oral furosemide. In addition, the oral furosemide test was compared with 2 other confirmatory tests: the furosemide upright test (FUT) and saline infusion test (SIT) or captopril challenge test (CCT) in all patients with PA., Results: The cut-off of 7.6 µU/mL for DRC at 2 hours after oral furosemide had a sensitivity of 92%, specificity of 82%, and accuracy of 90% for PA diagnosis. In 5 out of 6 controls with low-renin hypertension, which might represent a PA spectrum, renin remained suppressed. Excluding these 6 controls with low-renin hypertension, the DRC cut-off of 10 µU/mL at 2 hours after oral furosemide had a sensitivity of 95.3%, specificity of 93.7% and accuracy of 95% for PA diagnosis. DRC after 3 hours of oral furosemide did not improve diagnostic performance. Using the cut-off of 10 µU/mL, the oral furosemide test and the FUT were concordant in 62 out of 64 (97%) patients with PA. Only 4 out of 64 cases with PA (6.4%) ended the oral furosemide test with potassium <3.5 mEq/L. Hypotension was not evidenced in any patient with PA during the test., Conclusion: The oral furosemide test was safe, well-tolerated and represents an effective strategy for PA investigation., (© The Author(s) 2023. Published by Oxford University Press on behalf of the Endocrine Society.)

Context: Limited information is available concerning the genetic spectrum of pheochromocytoma and paraganglioma (PPGL) patients in South America. Germline SDHB large deletions are very rare worldwide, but most of the individuals harboring the SDHB exon 1 deletion originated from the Iberian Peninsula., Objective: Our aim was to investigate the spectrum of SDHB genetic defects in a large cohort of Brazilian patients with PPGLs., Methods: Genetic investigation of 155 index PPGL patients was performed by Sanger DNA sequencing, multiplex ligation-dependent probe amplification, and/or target next-generation sequencing panel. Common ancestrality was investigated by microsatellite genotyping with haplotype reconstruction, and analysis of deletion breakpoint., Results: Among 155 index patients, heterozygous germline SDHB pathogenic or likely pathogenic variants were identified in 22 cases (14.2%). The heterozygous SDHB exon 1 complete deletion was the most frequent genetic defect in SDHB, identified in 8 out of 22 (36%) of patients. Haplotype analysis of 5 SDHB flanking microsatellite markers demonstrated a significant difference in haplotype frequencies in a case-control permutation test (P = 0.03). More precisely, 3 closer/informative microsatellites were shared by 6 out of 8 apparently unrelated cases (75%) (SDHB-GATA29A05-D1S2826-D1S2644 | SDHB-186-130-213), which was observed in only 1 chromosome (1/42) without SDHB exon 1 deletion (X2 = 29.43; P < 0.001). Moreover, all cases with SDHB exon 1 deletion had the same gene breakpoint pattern of a 15 678 bp deletion previously described in the Iberian Peninsula, indicating a common origin., Conclusion: The germline heterozygous SDHB exon 1 deletion was the most frequent genetic defect in the Brazilian PPGL cohort. Our findings demonstrated a founder effect for the SDHB exon 1 deletion in Brazilian patients with paragangliomas., (© The Author(s) 2023. Published by Oxford University Press on behalf of the Endocrine Society. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Context: Primary aldosteronism (PA) screening relies on an elevated aldosterone to renin ratio with a minimum aldosterone level, which varies from 10 to 15 ng/dL (277-415.5 pmol/L) using immunoassay., Objective: To evaluate intra-individual coefficient of variation (CV) of aldosterone and aldosterone to direct renin concentration ratio (A/DRC) and its impact on PA screening., Methods: A total of 671 aldosterone and DRC measurements were performed by the same chemiluminescence assays in a large cohort of 216 patients with confirmed PA and at least 2 screenings., Results: The median intra-individual CV of aldosterone and A/DRC was 26.8% and 26.7%. Almost 40% of the patients had at least one aldosterone level <15 ng/dL, 19.9% had at least 2 aldosterone levels <15 ng/dL, and 16.2% had mean aldosterone levels <15 ng/dL. A lower cutoff of 10 ng/dL was associated with false negative rates for PA screening of 14.3% for a single aldosterone measurement, 4.6% for 2 aldosterone measurements, and only 2.3% for mean aldosterone levels. Considering the minimum aldosterone, true positive rate of aldosterone thresholds was 85.7% for 10 ng/dL and 61.6% for 15 ng/dL. An A/DRC >2 ng/dL/µIU/mL had a true positive rate for PA diagnosis of 94.4% and 98.4% when based on 1 or 2 assessments, respectively. CV of aldosterone and A/DRC were not affected by sex, use of interfering antihypertensive medications, PA lateralization, hypokalemia, age, and number of hormone measurements., Conclusion: Aldosterone concentrations had a high CV in PA patients, which results in an elevated rate of false negatives in a single screening for PA. Therefore, PA screening should be based on at least 2 screenings with concomitant aldosterone and renin measurements., (© The Author(s) 2022. Published by Oxford University Press on behalf of the Endocrine Society. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

The objective of this study was to compare the hemodynamic effects of dobutamine and ephedrine during the management of anesthesia-related hypotension in healthy horses. Thirteen horses underwent general anesthesia with isoflurane and were randomly divided into two different groups, one of which received a dobutamine constant rate infusion (CRI) (1 µg/kg bwt/min) and the other received an ephedrine CRI (20 µg/kg bwt/min) when hypotension (<60 mmHg) was identified, following up to 15 min after the blood pressure reached 70 mmHg. All horses were equipped with a pulmonary artery catheter and a peripheral artery catheter, and multiparameter monitoring commenced as soon as they were under mechanical ventilation. Hemodynamic parameters were recorded, while tissue perfusion markers (peripheral oxygen saturation, arterial oxygen partial pressure, arterial carbon dioxide partial pressure, arterial pH, arterial plasma bicarbonate concentration, arterial oxygen saturation, mixed venous oxygen saturation, mixed venous oxygen content, arterial oxygen content, arteriovenous oxygen difference, oxygen delivery index, oxygen consumption index, and oxygen extraction ratio), serum lactate concentration, and troponin I concentrations were analyzed before the start of infusions (T0), when the blood pressure reached 70 mmHg (T1), and 15 min after T1 (T2). The time to restore the arterial pressure was similar in both groups ( p > 0.05); however, the heart rate was higher in the ephedrine group ( p = 0.0098), and sinus bradyarrhythmia occurred in the dobutamine group. Furthermore, both experimental protocols increased cardiac output ( p = 0.0012), cardiac index ( p = 0.0013), systemic vascular resistance ( p = 0.008), systemic vascular resistance index ( p < 0.001), and ameliorated perfusion markers. In the dobutamine group, the pulmonary artery wedge pressure ( p < 0.001) and systolic index ( p = 0.003) were elevated, while the arteriovenous oxygen difference was reduced in the ephedrine group ( p = 0.02). Troponin I was used as a myocardial injury indicator, and did not differ between moments or between groups ( p > 0.05). We concluded that both drugs were effective and safe to treat anesthetic hypotension under the conditions of this study.

Background: Electrical impedance tomography (EIT) has been an essential tool for assessing pulmonary ventilation in several situations, such as the alveolar recruitment maneuver (ARM) in PEEP titration to maintain the lungs open after atelectasis reversion. In the same way as in humans and dogs, in horses, this tool has been widely used to assess pulmonary aeration undergoing anesthesia, mechanical ventilation, recruitment maneuver, standing horses, or specific procedures., Objectives: The present study aimed to evaluate the distribution of regional ventilation during ARM based on lung monitoring assessment by EIT, with a focus on better recruitment associated with less or no overdistention., Methods: Fourteen horses of 306 ± 21 kg undergoing isoflurane anesthesia in dorsal recumbency were used. The animals were mechanically ventilated with a tidal volume of 14 ml kg -1 and a respiratory rate of 7-9. An alveolar recruitment maneuver was instituted, increasing the PEEP by five cmH 2 O every 5 min until 32 cmH 2 O and decreasing it by five cmH 2 O every 5 min to 7 cmH 2 O. At each step of PEEP, arterial blood samples were collected for blood gas analysis, EIT images, hemodynamic, and respiratory mechanics., Results: Associated with the CoV-DV increase, there was a significant decrease in the DSS during the ARM and a significant increase in the NSS when PEEP was applied above 12 cmH 2 O compared to baseline. The Compl ROI showed a significant increase in the dependent area and a significant decrease in the non-dependent area during ARM, and both were compared to their baseline values. The driving pressure decreased significantly during the ARM, and Cst, PaO 2 , and PaO 2 /FiO 2 ratio increased significantly. The V D /V T decreased significantly at DEPEEP17 and DEPEEP12. There was an HR increase at INPEEP27, INPEEP 32, and DEPEEP17 ( p < 0.0001; p < 0.0001; and p < 0.05, respectively), those values being above the normal reference range for the species. The SAP, MAP, DAP, CI, and DO 2 I significantly decreased INPEEP32 ( p < 0.05)., Conclusion: The ARM by PEEP titration applied in the present study showed better ventilation distribution associated with better aeration in the dependent lung areas, with minimal overdistention between PEEP 17 and 12 cmH 2 O decreasing step. Those changes were also followed by improvements in static and regional compliance associated with increased oxygenation and pulmonary ventilation. ARM promoted a transitory decrease in arterial blood pressure and depression in CI with a concomitant drop in oxygen delivery, which should be best investigated before its routine use in clinical cases., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Andrade, Ambrósio, Rodrigues, Faccó, Gonçalves, Garcia Filho, dos Santos, Rossetto, Pereira and Fantoni.)

Background: In medicine, the transversus abdominis plane (TAP) block has been shown as an effective method of analgesia in several surgical procedures. In this context, this prospective, randomized, blinded study aimed to evaluate the analgesic efficacy of TAP block, guided by ultrasound in female dogs submitted to ovariectomy., Methods: Therefore, 32 animals randomly assigned in two groups ( n = 16) were used. Groups consisted of TAP block control (TBC) which received water injection (0.2 ml kg -1 point), and TAP block bupivacaine (TBB) which received bupivacaine (0.2 ml kg -1 point at 0.25%); both groups were submitted to four-point approach. Animals were pre-medicated with acepromazine (0.03 mg kg -1 ) and meperidine (2 mg kg -1 ) IM, propofol was used as anesthetic induction (3-5 mg kg -1 ) IV, and isoflurane was used to maintain. To standardize groups, the animals received a continuous infusion of remifentanil (0.2μg kg -1 min) and rocuronium (0.6 mg kg -1 ) IV in the intraoperative period. Variables measured were the heart and respiratory rates, blood pressure, temperature, peripheral oxyhemoglobin saturation, exhaled carbon dioxide concentration, exhaled isoflurane concentration, serum cortisol, analgesia, and sedation. Before the pre-anesthetic medication (Baseline) and 1, 2, 4, 6, and 8 h after extubation, pain and sedation were assessed using a numeric rating scale (NRS), Glasgow composite measure pain scale (GCMPS-SF), and sedation scale. Moreover, serum cortisol was measured at different moments., Results: The results show that in the intraoperative period, there was no significant difference between groups. After surgery, in TBC, 13 out of 16 animals required analgesic rescue, whereas, in TBB, this occurred only in one animal. Regarding the measurement of serum cortisol, the TBC group showed a significant difference when compared to the baseline time in the traction of the first ovary ( p < 0.0001), 2 h ( p = 0.0441), and 8 h ( p = 0.0384) after extubation. In TBB, cortisol showed a significant increase only in the traction of the first ovary and 2 h after extubation ( p < 0.0001)., Conclusion: The technique using ultrasound-guided TAP block in two points approach by hemiabdomen with 0.2 ml kg -1 bupivacaine 0.25% was effective in providing post-operative analgesia in dogs undergoing ovariectomy., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Cavaco, Otero, Ambrósio, Neves, Perencin, Pereira, Matera and Fantoni.)

Several analgesics are suggested for pain management in mice. Nonsteroidal antiinflammatories (NSAIDs), such as meloxicam can be administered for the treatment of inflammation and acute pain; however, several side effects can occur which include gastrointestinal ulceration and renal and hepatic toxicity. We previously performed a pilot study to test the antinociceptive activity of meloxicam in mice, but we observed behavioral changes in unoperated control mice. These observations spurred further investigation. One hypothesis for the result was potential differences in formulation between commercial brands of meloxicam. Thus, this current study aimed to evaluate the effects of 3 different commercial brands of meloxicam (20 mg/kg) in the general activity of mice using the open field test. Our results showed that meloxicam had several effects on mouse behavior and caused the formation of skin lesions at the injection site, depending on the brand of the drug. The most significant adverse effect observed was decreased exploratory activity. Grooming frequency was reduced in all groups. These adverse effects might be related to the quality of the drugs because meloxicam formulations can contain crystal polymorphisms that affect drug quality and efficacy. This study points out the importance of drug quality variation that can affect the outcome of behavioral studies in mice.

Background: During protective mechanical ventilation, electrical impedance tomography (EIT) is used to monitor alveolar recruitment maneuvers as well as the distribution of regional ventilation. This technique can infer atelectasis and lung overdistention during mechanical ventilation in anesthetized patients or in the ICU. Changes in lung tissue stretching are evaluated by monitoring the electrical impedance of lung tissue with each respiratory cycle., Objective: This study aimed to evaluate the distribution of regional ventilation during recruitment maneuvers based on the variables obtained in pulmonary electrical impedance tomography during protective mechanical ventilation, focusing on better lung recruitment associated with less or no overdistention., Methods: Prospective clinical study using seven adult client-owned healthy dogs, weighing 25 ± 6 kg, undergoing elective ovariohysterectomy or orchiectomy. The animals were anesthetized and ventilated in volume-controlled mode (7 ml.kg -1 ) with stepwise PEEP increases from 0 to 20 cmH 2 O in steps of 5 cmH 2 O every 5 min and then a stepwise decrease. EIT, respiratory mechanics, oxygenation, and hemodynamic variables were recorded for each PEEP step., Results: The results show that the regional compliance of the dependent lung significantly increased in the PEEP 10 cmH 2 O decrease step when compared with baseline ( p < 0.027), and for the nondependent lung, there was a decrease in compliance at PEEP 20 cmH 2 O ( p = 0.039) compared with baseline. A higher level of PEEP was associated with a significant increase in silent space of the nondependent regions from the PEEP 10 cmH 2 O increase step ( p = 0.048) until the PEEP 15 cmH 2 O (0.019) decrease step with the highest values at PEEP 20 cmH 2 0 ( p = 0.016), returning to baseline values thereafter. Silent space of the dependent regions did not show any significant changes. Drive pressure decreased significantly in the PEEP 10 and 5 cmH 2 O decrease steps ( p = 0.032) accompanied by increased respiratory static compliance in the same PEEP step ( p = 0.035 and 0.018, respectively)., Conclusions: The regional ventilation distribution assessed by EIT showed that the best PEEP value for recruitment maintenance, capable of decreasing areas of pulmonary atelectasis in dependent regions promoting less overinflation in nondependent areas, was from 10 to 5 cmH 2 O decreased steps., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Ambrósio, Sanchez, Pereira, Andrade, Rodrigues, Vitorasso, Moriya and Fantoni.)

Objective: Few and conflicting reports have characterized the genetics of paediatric pheochromocytomas and paragangliomas (PPGLs). This study aimed to investigate the clinical and genetic features of Brazilian children with PPGL., Patients and Methods: This study included 25 children (52% girls) with PPGL. The median age at diagnosis was 15 years (4-19). The median time of follow-up was 145 months. The genetic investigation was performed by Sanger DNA sequencing, multiplex ligation-dependent probe amplification and/or target next-generation sequencing panel., Results: Of the 25 children with PPGL, 11 (44%), 4 (16%), 2 (8%), 1 (4%) and 7 (28%) had germline VHL pathogenic variants, SDHB, SDHD, RET and negative genetic investigation, respectively. Children with germline VHL missense pathogenic variants were younger than those with SDHB or SDHD genetic defects [median (range), 12 (4-16) vs. 15.5 (14-19) years; P = .027]. Moreover, 10 of 11 cases with VHL pathogenic variants had bilateral pheochromocytoma (six asynchronous and four synchronous). All children with germline SDHB pathogenic variants presented with abdominal paraganglioma (one of them malignant). The two cases with SDHD pathogenic variants presented with head and neck paraganglioma. Among the cases without a genetic diagnosis, 6 and 2 had pheochromocytoma and paraganglioma, respectively. Furthermore, metastatic PPGL was diagnosed in four (16%) of 25 PPGL., Conclusions: Most of the paediatric PPGL were hereditary and multifocal. The majority of the affected genes belong to pseudohypoxic cluster 1, with VHL being the most frequently mutated. Therefore, our findings impact surgical management and surveillance of children with PPGL., (© 2021 John Wiley & Sons Ltd.)

Objective: Comprehend the profile and prevalence of non-suicidal self-injury (NSSI) in adolescents and its association with impulsiveness and loneliness., Methods: Cross-sectional study carried out in 2017 in Maceió-Alagoas, Northeast Brazil, in the households of 505 adolescents aged 12-17 years, using a sample stratified and randomized by gender and neighborhood. The following instruments were used: a sociodemographic questionnaire, Brazilian version of Functional Assessment of Self-Mutilation (FASM), the Brazilian Barratt Impulsiveness Scale (BIS-11), and the Brazilian Loneliness Scale (UCLA-BR)., Results: A prevalence of 6.53% was found for non-suicidal self-injury disorder (DSM-5). Significant differences ( p ≤ 0.05) were observed regarding: the most frequently used forms of NSSI were the items "cut oneself" and "scratch oneself"; engaging in three or more different forms of self-injurious behavior (66.67%) and, reporting as reasons, "to relieve feelings of emptiness or indifference" and "to stop bad feelings/sensations." Significance was also related to the sociodemographic profile: 72.73% were females and 63.54% had family income below one minimum wage. Individuals with self-injurious behavior also had higher impulsiveness and loneliness scores (p ≤ 0.05)., Conclusions: The study identified a direct association between NSSI and impulsiveness and loneliness among adolescents, being more prevalent in females and in young individuals with socioeconomic vulnerability. The data provide support for improving public health policies, aimed at education, prevention, and treatment of adolescents with NSSI., (Copyright © 2020 Sociedade Brasileira de Pediatria. Published by Elsevier Editora Ltda. All rights reserved.)

Familial primary aldosteronism (PA) is rare and mostly diagnosed in early-onset hypertension (HT). However, 'sporadic' bilateral adrenal hyperplasia (BAH) is the most frequent cause of PA and remains without genetic etiology in most cases. Our aim was to investigate new genetic defects associated with BAH and PA. We performed whole-exome sequencing (paired blood and adrenal tissue) in six patients with PA caused by BAH that underwent unilateral adrenalectomy. Additionally, we conducted functional studies in adrenal hyperplastic tissue and transfected cells to confirm the pathogenicity of the identified genetic variants. Rare germline variants in phosphodiesterase 2A (PDE2A) and 3B (PDE3B) genes were identified in three patients. The PDE2A heterozygous variant (p.Ile629Val) was identified in a patient with BAH and early-onset HT at 13 years of age. Two PDE3B heterozygous variants (p.Arg217Gln and p.Gly392Val) were identified in patients with BAH and HT diagnosed at 18 and 33 years of age, respectively. A strong PDE2A staining was found in all cases of BAH in zona glomerulosa and/or micronodules (that were also positive for CYP11B2). PKA activity in frozen tissue was significantly higher in BAH from patients harboring PDE2A and PDE3B variants. PDE2A and PDE3B variants significantly reduced protein expression in mutant transfected cells compared to WT. Interestingly, PDE2A and PDE3B variants increased SGK1 and SCNN1G/ENaCg at mRNA or protein levels. In conclusion, PDE2A and PDE3B variants were associated with PA caused by BAH. These novel genetic findings expand the spectrum of genetic etiologies of PA.

Objective: Germline ARMC5 mutations are considered to be the main genetic cause of primary macronodular adrenal hyperplasia (PMAH). PMAH is associated with high variability of cortisol secretion caused from subclinical hypercortisolism to overt Cushing's syndrome (CS), in general due to bilateral adrenal nodules and rarely could also be due to non-synchronic unilateral adrenal nodules. The frequency of adrenal incidentalomas (AI) associated with PMAH is unknown. This study evaluated germline allelic variants of ARMC5 in patients with bilateral and unilateral AI and in patients with overt CS associated with bilateral adrenal nodules. Methods: We performed a retrospective multicenter study involving 123 patients with AI (64 bilateral; 59 unilateral). We also analyzed 20 patients with ACTH pituitary independent overt CS associated with bilateral adrenal nodules. All patients underwent germline genotyping analysis of ARMC5 ; abdominal CT and were classified as normal, possible or autonomous cortisol secretion, according to the low doses of dexamethasone suppression test. Results: We identified only one pathogenic allelic variant among the patients with bilateral AI. We did not identify any pathogenic allelic variants of ARMC5 in patients with unilateral AI. Thirteen out of 20 patients (65%) with overt CS and bilateral adrenal nodules were carriers of pathogenic germline ARMC5 allelic variants, all previously described. The germline ARMC5 mutation was observed in only one patient with bilateral AI; it was associated with autonomous cortisol secretion and showed to be a familial form. Conclusion: The rarity of germline ARMC5 mutations in AI points to other molecular mechanisms involved in this common adrenal disorder and should be investigated. In contrast, patients with overt Cushing's syndrome and bilateral adrenal nodules had the presence of ARMC5 mutations that were with high prevalence and similar to the literature. Therefore, we recommend the genetic analysis of ARMC5 for patients with established Cushing's syndrome and bilateral adrenal nodules rather than patients with unilateral AI., (Copyright © 2020 Mariani, Nishi, Wanichi, Brondani, Lacombe, Charchar, Pereira, Srougi, Tanno, Ceccato, Regazzo, Barbot, Occhi, Albiger, Vieira-Corrêa, Kater, Scaroni, Chambô, Zerbini, Mendonca, Almeida and Fragoso.)

Context: Primary aldosteronism (PA) is the most common cause of endocrine hypertension (HT). HT remission (defined as blood pressure <140/90 mm Hg without antihypertensive drugs) has been reported in approximately 50% of patients with unilateral PA after adrenalectomy. HT duration and severity are predictors of blood pressure response, but the prognostic role of somatic KCNJ5 mutations is unclear., Objective: To determine clinical and molecular features associated with HT remission after adrenalectomy in patients with unilateral PA., Methods: We retrospectively evaluated 100 patients with PA (60 women; median age at diagnosis 48 years with a median follow-up of 26 months). Anatomopathological analysis revealed 90 aldosterone-producing adenomas, 1 carcinoma, and 9 unilateral adrenal hyperplasias. All patients had biochemical cure after unilateral adrenalectomy. KCNJ5 gene was sequenced in 76 cases., Results: KCNJ5 mutations were identified in 33 of 76 (43.4%) tumors: p.Gly151Arg (n = 17), p.Leu168Arg (n = 15), and p.Glu145Gln (n = 1). HT remission was reported in 37 of 100 (37%) patients. Among patients with HT remission, 73% were women (P = 0.04), 48.6% used more than three antihypertensive medications (P = 0.0001), and 64.9% had HT duration <10 years (P = 0.0015) compared with those without HT remission. Somatic KCNJ5 mutations were associated with female sex (P = 0.004), larger nodules (P = 0.001), and HT remission (P = 0.0001). In multivariate analysis, only a somatic KCNJ5 mutation was an independent predictor of HT remission after adrenalectomy (P = 0.004)., Conclusion: The presence of a KCNJ5 somatic mutation is an independent predictor of HT remission after unilateral adrenalectomy in patients with unilateral PA., (Copyright © 2019 Endocrine Society.)

Context: Von Hippel-Lindau (VHL) disease is an autosomal dominant syndrome caused by germline mutations in the VHL gene. Guidelines recommend pheochromocytoma (PHEO) biochemical screening should start at age 5 years., Objective: Genotype-phenotype correlations in VHL, focusing on PHEO penetrance in children, were studied., Design: We retrospectively evaluated 31 individuals (median age at diagnosis was 26 years) with diagnosed VHL disease., Results: PHEO was diagnosed in six children with VHL. A large PHEO (5 cm) was detected in a 4-year-old boy with p.Gly114Ser mutation. PHEO penetrance was 55% starting at age 4 years. VHL missense mutations were identified in 11 of 22 families (50%), frameshift mutations in four (18.2%), stop codon in three (13.6%), splicing site in two (9.1%), and large gene deletion in two (9.1%). The codon 167 (n = 10) was a hotspot for VHL mutations and was significantly associated with PHEO (90% vs. 38%; P = 0.007). PHEOs and pancreatic neuroendocrine tumors (PNETs) were strongly associated with VHL missense mutations compared with other mutations (89.5% vs. 0% and 73.7% vs. 16.7%; P = 0.0001 and 0.002, respectively). In contrast, pancreatic cysts (91.7% vs. 26.3%; P = 0.0001), renal cysts (66.7% vs. 26.3%; P = 0.027), and central nervous system hemangioblastomas (91.7% vs. 47.3%; P = 0.012) were more frequent in VHL with nonmissense mutations., Conclusion: VHL missense mutations were highly associated with PHEO and PNETs. Our data support that in children with VHL harboring missense mutations, biochemical screening for PHEO should be initiated at diagnosis., Competing Interests: Disclosure Summary: The authors have nothing to disclose.Data sharing is not applicable to this article because no data sets were generated or analyzed during the current study.

Background: Surgical sterilization of cats is one of the most commonly performed procedures in veterinary practice and it can be accomplished by two different techniques: ovariohysterectomy (OVH) or ovariectomy (OVE). Although there is an apparent preference for OVH in United States and Canada, OVE seems to be the standard of care in many European countries due to its advantages, such as a smaller surgical incision and potentially less complications associated with surgical manipulation of the uterus. The aim of this randomized, blind, prospective study was to compare postoperative pain and short-term complications in cats undergoing ovariohysterectomy or ovariectomy., Methods: Twenty female cats were randomly assigned into two groups (OVH, n = 10 and OVE, n = 10). Pain was assessed prior to surgery (baseline) and 1, 2, 4, 8 12 and 24 h after the procedure using pain and sedation scales, physiologic parameters and blood glucose levels. Short-term complications were evaluated in the early postoperative period and reassessed at day 7 and day 10., Results: Changes in cardiovascular parameters were not clinically relevant, however cats in OVH group had higher heart rates at T1 h compared with baseline (p = 0.0184). Blood glucose levels in OVH group were also higher at T1 h compared with baseline (p = 0.0135) and with OVE group (p = 0.0218). Surgical time was higher in OVH group (p = 0.0115). Even though no significant differences in pain scores were observed between groups or time points, cats in OVH group had greater need for rescue analgesia compared with OVE (2/10 and 0/10, respectively). Complications were not observed in any cat during surgery, at days 7 and 10 postoperatively or at discharge., Conclusions: Both surgical techniques promoted similar intensity of postoperative pain in cats and there were no short-term complications throughout the study's evaluation period. Therefore, both techniques may be indicated for surgical sterilization of cats, according to the surgeon's preference and expertise. Cats that underwent ovariectomy did not require rescue analgesia and surgical time was shorter in that group.

Pancreatic neuroendocrine tumors (PanNETs) are rare in von Hippel-Lindau disease (VHL) but cause serious morbidity and mortality. Management guidelines for VHL-PanNETs continue to be based on limited evidence, and survival data to guide surgical management are lacking. We established the European-American-Asian-VHL-PanNET-Registry to assess data for risks for metastases, survival and long-term outcomes to provide best management recommendations. Of 2330 VHL patients, 273 had a total of 484 PanNETs. Median age at diagnosis of PanNET was 35 years (range 10-75). Fifty-five (20%) patients had metastatic PanNETs. Metastatic PanNETs were significantly larger (median size 5 vs 2 cm; P  < 0.001) and tumor volume doubling time (TVDT) was faster (22 vs 126 months; P  = 0.001). All metastatic tumors were ≥2.8 cm. Codons 161 and 167 were hotspots for VHL germline mutations with enhanced risk for metastatic PanNETs. Multivariate prediction modeling disclosed maximum tumor diameter and TVDT as significant predictors for metastatic disease (positive and negative predictive values of 51% and 100% for diameter cut-off ≥2.8 cm, 44% and 91% for TVDT cut-off of ≤24 months). In 117 of 273 patients, PanNETs >1.5 cm in diameter were operated. Ten-year survival was significantly longer in operated vs non-operated patients, in particular for PanNETs <2.8 cm vs ≥2.8 cm (94% vs 85% by 10 years; P  = 0.020; 80% vs 50% at 10 years; P  = 0.030). This study demonstrates that patients with PanNET approaching the cut-off diameter of 2.8 cm should be operated. Mutations in exon 3, especially of codons 161/167 are at enhanced risk for metastatic PanNETs. Survival is significantly longer in operated non-metastatic VHL-PanNETs., (© 2018 Society for Endocrinology.)

Context: Persistent disease after surgery is common in medullary thyroid cancer (MTC), requiring lifelong radiological surveillance. Staging workup includes imaging of neck, chest, abdomen, and bones. A study integrating all sites would be ideal. Despite the established use of gallium-68 (68Ga) positron emission tomography (PET)/CT with somatostatin analogues in most neuroendocrine tumors, its efficacy is controversial in MTC., Objective: Evaluate the efficacy of 68Ga PET/CT in detecting MTC lesions and evaluate tumor expression of somatostatin receptors (SSTRs) associated with 68Ga PET/CT findings., Methods: Prospective study evaluating 30 patients with MTC [group 1 (n = 16), biochemical disease; group 2 (n = 14), metastatic disease]. Patients underwent 68Ga PET/CT, bone scan, CT and ultrasound of the neck, CT of the chest, CT/MRI of the abdomen, and MRI of the spine. 68Ga PET/CT findings were analyzed by disease site as positive or negative and as concordant or discordant with conventional studies. Sensitivity and specificity were calculated using pathological or cytological analysis or unequivocal identification by standard imaging studies. Immunohistochemical analysis of SSTRs was compared with 68Ga PET/CT findings., Results: In both groups, 68Ga PET/CT was inferior to currently used imaging studies except for bone scan. In group 2, 68Ga PET/CT sensitivities were 56%, 57%, and 9% for detecting neck lymph nodes, lung metastases, and liver metastases, respectively, and 100% for bone metastases, superior to the bone scan (44%). Expression of SSTRs, observed in 44% of tumors, was not associated with 68Ga-DOTATATE uptake., Conclusions: 68Ga PET/CT does not provide optimal whole-body imaging as a single procedure in patients with MTC. However, it is highly sensitive in detecting bone lesions and could be a substitute for a bone scan and MRI.

Context: Acquired generalized lipodystrophy (AGL), a rare disorder characterized by loss of subcutaneous adipose tissue, is estimated to occur in association with autoimmune diseases in ~25% of the cases. Common variable immunodeficiency (CVI) is a condition known for its strong association with autoimmune diseases often occurring with negative autoantibodies. To the best of our knowledge, we describe the first known case of AGL in a patient with CVI., Case Description: A 24-year-old man was referred to our center with hyperglycemia, hypertriglyceridemia, hepatomegaly, and a clear pattern of generalized fat loss. AGL had been diagnosed on the basis of the clinical and laboratory findings. Because of the presence of associated hypogammaglobulinemia, a diagnosis of CVI was subsequently established., Conclusions: We propose that AGL be added to the list of possible diseases associated with CVI and, owing to the similar clinical presentation with type 1 diabetes mellitus, be included in the differential diagnosis of this condition, which is present in 1.5% of patients with CVI.

Background/objectives: Insulinoma is a rare pancreatic tumor and, usually, a benign disease but can be a malignant one and, sometimes, a highly aggressive disease. The aim of this study was to determine differences between benign and malignant tumors., Methods: Retrospective study of 103 patients with insulinoma treated in a tertiary center. It was analyzed demographic, clinical, laboratory, localization and histologic analysis of tumor and follow up data of subjects in order to identify differences between individuals benign and malignant disease., Results: Almost all patients (87%) had a benign tumor and survival rates of 100% following pancreatic tumor surgery. Those with malignant tumors (13%) have a poor prognosis, 77% insulinoma-related deaths over a period of 1-300 months after the diagnosis with a survival rate of 24% in five years. The following factors are associated with an increased risk of malignant disease: duration of symptoms < 24 months, fasting time for the occurrence of hypoglycemia < 8 h, blood plasma insulin concentration ≥ 28 μU/mL and C-peptide ≥ 4.0 ng/mL at the glycemic nadir and tumor size ≥ 2.5 cm., Conclusions: Our data help to base the literature about these tumors, reinforcing that although insulinoma is usually a single benign and surgically treated neoplasia, the malignant one is difficult to treat. We highlight the data that help predict a malignancy behavior of tumor and suggest a long follow up after diagnosis in these cases., (Copyright © 2018 IAP and EPC. Published by Elsevier B.V. All rights reserved.)

Massage therapy is becoming increasingly popular in human and animal physiotherapy and rehabilitation. Wider application of the technique led to research efforts aimed at providing scientific support to anecdotal beneficial effects, particularly pain relief. Recent studies have shown that massage therapy alters dopamine and serotonin levels, decreases noradrenaline levels, and modulates the immune system. Psychological effects such as reduction of stress and anxiety, with improvement of depressive patients, have been reported in humans. This article set out to review the major aspects of massage therapy based on recent publications on the topic, and to extrapolate concepts and practical aspects described in human physiotherapy to the veterinary patient, particularly the applicability of different techniques in Small Animal Medicine. Indications of massage therapy in small animals include pain relief, orthopedic rehabilitation, Canine Sports Medicine, intensive care, and management of nonspecific edema. Techniques described in this article were originally intended for use in humans and scientific data supporting anecdotal, beneficial effects in domestic animals are still lacking; this fruitful area for research is therefore open to veterinary professionals., (Copyright © 2017 Elsevier Inc. All rights reserved.)