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Background: Although GqPCR activation often leads to cell survival by activating the PI3K/AKT pathway, it was previously shown that in several cell types AKT activity is reduced and leads to JNK activation and apoptosis. The mechanism of AKT inactivation in these cells involves an IGBP1-coupled PP2Ac switch that induces the dephosphorylation and inactivation of both PI3K and AKT. However, the machinery involved in the initiation of PP2A switch is not known., Methods: We used phospho-mass spectrometry to identify the phosphorylation site of PP2Ac, and raised specific antibodies to follow the regulation of this phosphorylation. Other phosphorylations were monitored by commercial antibodies. In addition, we used coimmunoprecipitation and proximity ligation assays to follow protein-protein interactions. Apoptosis was detected by a TUNEL assay as well as PARP1 cleavage using SDS-PAGE and Western blotting., Results: We identified Ser24 as a phosphorylation site in PP2Ac. The phosphorylation is mediated mainly by classical PKCs (PKCα and PKCβ) but not by novel PKCs (PKCδ and PKCε). By replacing the phosphorylated residue with either unphosphorylatable or phosphomimetic residues (S24A and S24E), we found that this phosphorylation event is necessary and sufficient to mediate the PP2A switch, which ultimately induces AKT inactivation, and a robust JNK-dependent apoptosis., Conclusion: Our results show that the PP2A switch is induced by PKC-mediated phosphorylation of Ser24-PP2Ac and that this phosphorylation leads to apoptosis upon GqPCR induction of various cells. We propose that this mechanism may provide an unexpected way to treat some cancer types or problems in the endocrine machinery., (© 2024. The Author(s).)

AKT is a central signaling protein kinase that plays a role in the regulation of cellular survival metabolism and cell growth, as well as in pathologies such as diabetes and cancer. Human AKT consists of three isoforms (AKT1-3) that may fulfill different functions. Here, we report that distinct subcellular localization of the isoforms directly influences their activity and function. AKT1 is localized primarily in the cytoplasm, AKT2 in the nucleus, and AKT3 in the nucleus or nuclear envelope. None of the isoforms actively translocates into the nucleus upon stimulation. Interestingly, AKT3 at the nuclear envelope is constitutively phosphorylated, enabling a constant phosphorylation of TSC2 at this location. Knockdown of AKT3 induces moderate attenuation of cell proliferation of breast cancer cells. We suggest that in addition to the stimulation-induced activation of the lysosomal/cytoplasmic AKT1-TSC2 pathway, a subpopulation of TSC2 is constitutively inactivated by AKT3 at the nuclear envelope of transformed cells., Competing Interests: Declaration of interests The authors declare no competing interest., (Copyright © 2022 The Author(s). Published by Elsevier Inc. All rights reserved.)

Background: G protein-coupled receptors (GPCRs) usually regulate cellular processes via activation of intracellular signaling pathways. However, we have previously shown that in several cell lines, GqPCRs induce immediate inactivation of the AKT pathway, which leads to JNK-dependent apoptosis. This apoptosis-inducing AKT inactivation is essential for physiological functions of several GqPCRs, including those for PGF2α and GnRH., Methods: Here we used kinase activity assays of PI3K and followed phosphorylation state of proteins using specific antibodies. In addition, we used coimmunoprecipitation and proximity ligation assays to follow protein-protein interactions. Apoptosis was detected by TUNEL assay and PARP1 cleavage., Results: We identified the mechanism that allows the unique stimulated inactivation of AKT and show that the main regulator of this process is the phosphatase PP2A, operating with the non-canonical regulatory subunit IGBP1. In resting cells, an IGBP1-PP2Ac dimer binds to PI3K, dephosphorylates the inhibitory pSer608-p85 of PI3K and thus maintains its high basal activity. Upon GqPCR activation, the PP2Ac-IGBP1 dimer detaches from PI3K and thus allows the inhibitory dephosphorylation. At this stage, the free PP2Ac together with IGBP1 and PP2Aa binds to AKT, causing its dephosphorylation and inactivation., Conclusion: Our results show a stimulated shift of PP2Ac from PI3K to AKT termed "PP2A switch" that represses the PI3K/AKT pathway, providing a unique mechanism of GPCR-stimulated dephosphorylation. Video Abstract., (© 2022. The Author(s).)

Introduction: Transbronchial lung cryobiopsy (TBCB) has emerged as a diagnostic alternative to surgical lung biopsy mostly in interstitial lung disease. Despite its less invasive nature and reported higher diagnostic yield, some associated complications have been described, such as pneumothorax. Moreover, a comparison between TBCB and transbronchial forceps biopsy is seldomly made. The aim of the present study is to evaluate the incidence of pneumothorax following TBFB and TBCB and the need for pleural drainage., Methods: Retrospective study of patients who underwent transbronchial forceps biopsy or transbronchial lung cryobiopsy, specifically those who developed postoperative pneumothorax., Results: A total of 181 transbronchial lung biopsies were performed. Sixty three (35%) were TBFB and 118 (65%) were TBCB. Three patients in the TBFB group (5%) presented postoperative pneumothorax, while 16 patients (14%) presented pneumothorax in the TBCB group (p 0,051). The univariate analysis revealed a statistically significant association between the preoperative diagnosis of fibrosis and a higher risk of postoperative pneumothorax following TBCB (p 0.027), while other variables did not yield a statistical significance., Conclusion: Even though more high-volume comparative studies are needed, this paper highlights the relevance of pneumothorax following TBCB. This derives in a strong need for clearly standardized procedure protocols for TBCB and careful evaluation of its complications vs. its definitive diagnostic yields., (Universidad Nacional de Córdoba)

Pulmonary alveolar proteinosis is an unusual diffuse lung disease characterized by abnormal accumulation of pulmonary surfactant and lipoproteins in the alveolar space, which impairs gas exchange with a variable clinical course, ranging from an asymptomatic clinical presentation to severely affected respiratory failure. A 16-year-old girl with diagnosis of pulmonary alveolar proteinosis presented to our hospital for therapeutic lung lavage after a recent history of progressive dyspnea, respiratory distress, declining lung function measurements, and worsening radiographic abnormalities. We obtained baseline pulmonary function tests and laboratory measurements before and after therapeutic bilateral lung lavage., Competing Interests: None, (Sociedad Argentina de Pediatría.)

Large vessel vasculitis and particularly Temporal Arteritis are systemic diseases that may affect the aorta and its major branches, mainly involving extra cranial branches of the carotid artery. We report a 72-year-old man presenting with weight loss, fever and malaise. Positron emission computed tomography (PET CT) showed an extensive inflammation of the aorta and its major branches. Temporal artery biopsy confirmed the presence of vasculitis with granulomas. Treatment with a high dose of steroids had an excellent clinical response. This case underscores the utility of PET CT in the assessment of this disease.

The dynamic subcellular localization of ERK in resting and stimulated cells plays an important role in its regulation. In resting cells, ERK localizes in the cytoplasm, and upon stimulation, it translocates to its target substrates and organelles. ERK signaling initiated from different places in resting cells has distinct outcomes. In this review, we summarize the mechanisms of ERK1/2 translocation to the nucleus and mitochondria, and of ERK1c to the Golgi. We also show that ERK1/2 translocation to the nucleus is a useful anti cancer target. Unraveling the complex subcellular localization of ERK and its dynamic changes upon stimulation provides a better understanding of the regulation of ERK signaling and may result in the development of new strategies to combat ERK-related diseases., (Copyright © 2016 Elsevier Ltd. All rights reserved.)

Myofibroblastic tumor (MIT) is characterized by the infiltration of different organs, most commonly the lungs, with nodular lesions composed of myofibroblasts and inflammatory cells, which can be identified by specific patterns in the immunohistochemical studies. When it involves the peritoneum it is difficult to eradicate, tends to relapse and it has an invasive behavior, requiring its differentiation from peritoneal carcinomatosis. Treatment may be surgical excision, the use of non-steroidal anti-inflammatory drugs (NSAIDs) and glucocorticoids. We report a 30 years old female with an unremarkable medical history, presenting with abdominal pain and progressive abdominal distention. A CT scan revealed multiple peritoneal nodular lesions. A surgical biopsy was reported as a myofibroblast and inflammatory cell infiltrate. Immunohistochemical staining was consistent with MIT. Given the extensive involvement of the peritoneum surgical therapy was not considered appropriate and treatment with NSAID and glucocorticoids was started. No response was observed after 6 months, therefore infliximab therapy was started. After 10 months of follow-up the patient is well, returned to normal life, ascites improved and resolved and CT scan showed partial regression or stabilization of the lesions.

Parvovirus B19 infection is highly prevalent in children and the most common manifestation is a facial rash. In adults, acute polyarthritis and skin rash are often the presenting features. We report three patients with the disease. A 40-year-old female presenting with fever, myalgias and painful swelling of elbows, knees, wrists and feet, with functional limitation, after having a respiratory infection. Additionally, an erythematous skin rash appeared in both extremities. IgM antibodies against Parvovirus B19 were positive. The skin biopsy disclosed a leukocytoclastic vasculitis. The patient was treated with anti-inflammatory drugs and antihistaminics. A 40-year-old female, presenting with skin rash and pain in wrists and hands. IgM antibodies against parvovirus were positive. The patient was treated successfully with acetaminophen. A 38-year-old male with psoriasis, presenting with generalized and progressive polyarthralgia. A Parvovirus viral load determination found 239000 copies of the virus and IgM antibodies were positive. He was successfully treated with non-steroidal anti-inflammatory drugs.

Making a diagnosis in medicine is a complex process in which many cognitive and psychological issues are involved. After the first encounter with the patient, an unconscious process ensues to suspect the presence of a particular disease. Usually, complementary tests are requested to confirm the clinical suspicion. The interpretation of requested tests can be biased by the clinical diagnosis that was considered in the first encounter with the patient. The awareness of these sources of error is essential in the interpretation of the findings that will eventually lead to a final diagnosis. This article discusses some aspects of the heuristics involved in the adjudication of priory probabilities and provides a brief review of current concepts of the reasoning process.

Objective: To investigate the effect of adalimumab treatment on anti-cyclic citrullinated peptide antibodies (anti-CCP) in patients with rheumatoid arthritis (RA)., Methods: 70 RA patients who failed treatment with disease modifying antirheumatic drugs (DMARDs) received 40 mg adalimumab subcutaneously every other week during 24 weeks. Serum samples were collected at baseline and at weeks 8, 16 and 24 before the corresponding adalimumab dose. The serum anti-CCP levels were tested by enzyme linked immunosorbent assay., Results: At baseline, 52 of the 70 patients (74.3%) were positive for anti-CCP antibodies. 60 % of the anti CCP positive patients and 44.4% of the anti CCP negative patients were ACR 20 responders at week 24 (p<0.049). The serum levels of anti-CCP antibodies decreased significantly after 24 weeks of adalimumab treatment only in those patients who met ACR 20 response criteria at week 24 (p<0.00044). Differences between baseline anti-CCP titers and those at 8, 16 and 24 weeks were all statistically significant (p<0.014, 0.003 and 0.019 respectively). No statistically significant changes in the anti-CCP levels were observed in patients who did not meet the ACR 20 response criteria., Conclusion: Basal anti-CCP antibodies levels correlate with clinical response to adalimumab. A decrease in anti-CCP levels on time was observed in patients showing also clinical improvement, suggesting that serum anti-CCP antibodies determination may be useful in assessing treatment efficacy in RA patients.

Pulmonary Arterial Hypertension includes a heterogeneous group of disorders with a common genetic, pathological and hemodinamyc origin. It is characterized by a high pulmonary artery pressure due to a primary vascular disease, as a consequence of genetic and environmental factors. The common pathway is a vascular imbalance towards vasoconstriction and proliferation inside the small vessels. According to the World Health Organization, 2003, Pulmonary Arterial Hypertension is classified as idiopathic, familiar or associated to connective tissue diseases, HIV, drugs, porto-pulmonary hypertension, congenital intracardiac shunts and others. The diagnosis is based in hemodynamics. Echocardiogram is a non invasive and right ventricular catheterization is an invasive diagnostic tool. Follow up is based on a clinical and functional assessment through functional class classification, dyspnea scores and 6-minute walking test. The prognosis is historically devastating but new therapies are changing the natural history of the disease. New treatments have demonstrated improvement in symptoms, hemodynamic profiles and survival. Intravenous, subcutaneous or inhaled prostanoids such as Epoprostenol, Treprostinil or Iloprost respectively have been approved for Pulmonary Arterial Hypertension treatment as well as oral endothelial receptor blockers. They are all considered first line treatments for arterial pulmonary hypertensive patients with even better benefits than lung transplantation. Phosphodiesterase inhibitors (Sildenafil), have been recently approved for the treatment of pulmonary arterial hypertension.

Background: Pulmonary Arterial Hypertension is a rare, progressive and devastating disease with severe consequences in quality of life and survival., Aim: A clinical, functional and hemodynamic assessment of patients with pulmonary arterial hypertension and categorization according to severity., Material and Methods: Prospective registry of patients with arterial pulmonary hypertension, hemodynamically defined. Clinical evaluation was performed using World Health Organization functional score (I to IV) and Borg dyspnea scale. Six minute walking test, echocardiography and right heart catheterization were used for functional and hemodynamic assessment. Intravenous Adenosine was used to assess vascular reactivity during the hemodynamic evaluation., Results: Twenty nine patients were included (25 women, age range 16-72 years). Pulmonary hypertension was idiopathic in 11, associated to connective tissue disease in seven, associated to congenital heart disease in nine and associated to chronic thromboembolism in two. The mean lapse of symptoms before assessment was 2.9 years and 100% had dyspnea (Borg 5.1). Functional class I, II, III and IV was observed in 0, 5, 21 and 3 patients respectively. Six minutes walking test was 378+/-113 m. Mean pulmonary pressure was 59.4+/-12.2 mmHg, cardiac index was 2.57+/-0.88 and pulmonary vascular resistance index: 1798.4+/-855 (dyne.sec)/cm5. Nine patients had a mean pulmonary arterial pressure >55 mmHg and a cardiac index <2.1, considered as bad prognosis criteria. Adenosine test was positive in 17%., Conclusions: This group of patients with Pulmonary Arterial Hypertension was mainly conformed by young females, with a moderate to severe disease.

Background: Systemic vasculitis are a group of heterogeneous diseases characterized by inflammation and necrosis of blood vessel walls. The etiology is not known, but geographic and environmental factors are implicated., Aim: To describe the clinical features of microscopic polyangiitis (MPA) and Wegener's granulomatosis (WG) in a Chilean cohort of patients., Patients and Methods: Retrospective review of the medical records of 123 patients with the diagnosis of systemic vasculitis (65 MPA and 58 WG), seen from 1990 to 2001. The diagnosis were made based on the American College of Rheumatology and Chapel Hill criteria., Results: The mean follow-up for MPA was 15 months (1-120) and for WG, 20 months (1-120). The median age (years) at diagnosis for MPA was 61 (19-82) and WG 50 (20-82). Gender distribution was similar in both groups (male: 68% and 57% respectively). The main clinical features in the MPA group were renal involvement (68%), peripheral nervous system involvement (57%), pulmonary hemorrhage (28%), and skin disease (32%). In the WG group were alveolar hemorrhage (62%), renal involvement (78%), paranasal sinus involvement (57%), and ocular disease (26%). In both, creatinine levels above 2.0 mg/dl were associated with a higher mortality (p< 0.01). ANCA by immunofluorescence was performed in 56 MPA patients (75% had pANCA, 4% had cANCA and 21% were ANCA negative) and in 55 WG patients (17% had pANCA, 79% had cANCA and 4% were ANCA negative). Global mortality was 18% and 17% respectively, and the most common causes of death were infections., Conclusions: The clinical features of our patients are similar to other published data. In our WG and MPA patients the main predictor for death was a serum creatinine above 2 mg/dl.

Background: Polymorphisms of Fc receptors for IgG (Fc gamma R) have been proposed as a genetic factor that influences susceptibility for systemic lupus erythematosus (SLE). Human Fc gamma RIIa has 2 codominantly expressed alleles, H131 and R131, which differ at amino acid position 131 in the second extracellular domain (histidine or arginine respectively) and differ substantially in their ability to bind human IgG2. The H131 allele binds IgG2 efficiently, whereas R131 binds it poorly. Because IgG2 is a poor activator of the classical complement pathway, the H131 is essential for the disposal of IgG2 immune complexes., Aim: To determine the distribution of Fc gamma RIIA genes in a cohort of Chilean SLE patients, with or without a history of lupus nephritis., Patients and Methods: We studied 52 Chilean SLE patients fulfilling the 1982 American College of Rheumatology (ACR) criteria, 20 of whom had a history of nephritis, and 44 ethnically matched disease-free controls. Fc gamma RIIa allotypes were genotyped by PCR., Results: No significant association was observed between the low affinity Fc gamma RII receptor (FcgRIIa-R131) and the presence of SLE or lupus nephritis. However, genotype frequencies in SLE patients but not in controls, departed from the proportions predicted by the Hardy-Weinberg equilibrium, suggesting this locus might be related to the disease., Conclusions: Our results suggest that in Chilean patients with SLE, as well as in many other populations, the R131 allotype is not a major factor predisposing to the development of SLE or lupus nephritis.

Several disease have been associated with hepatitis C virus infections, including rheumatologic, hematologic and neoplastic disorders. We report two women, aged 57 and 39 years old whom the initial presentation of hepatitis C virus infection was an arthritis resembling rheumatoid arthritis. Laboratory work up revealed abnormal liver function tests, stimulating the search for hepatitis C virus infection, having both patients positive ELISA tests. Detection of this agent is extremely important when selecting a therapy for the articular disease, since several drugs used in the treatment of rheumatic disorders are potentially hepatotoxic and immunosuppression is risky in the setting of a viral hepatitis.

Fcgamma receptors (FcgammaRs) are potent initiators of proinflammatory reactions and tissue injury programs through the oxidative burst, degranulation and the production of a variety of proinflammatory cytokines. Direct experimental evidence indicates that translocation of ANCA target from intracellular granules to the neutrophil membrane and subsequent binding of ANCA enables FcgammaR-mediated neutrophil activation. In the presence of ANCA, these data provide a framework from which to understand the importance of ANCA class, subclass, and titer in Wegener's granulomatosis and other ANCA-positive vasculitides. The well-characterized and functionally important alleles of neutrophil FcgammaR (FcgammaRIIa-H131/R131 and FcgammaRIIIb-NA1/NA2) are possible inheritable genetic elements that may alter disease severity and/or phenotype.

Background: The prevalence of Lyme disease in Chile is unknown., Aim: To study the existence and epidemiology of Lyme disease in Chile., Patients and Methods: One hundred eighteen patients with signs or symptoms suggestive of Lyme disease were studied. Antibodies against Borrelia burgdorferi were measured using ELISA and indirect immunofluorescence screening tests. Positive cases were confirmed with ELISA using a purified antigen and Western Blot analysis. Human biological samples and ticks were cultured in BSK-H medium., Results: Five patients, three with dermatological manifestations and two with facial palsy and other neurological symptoms, had antibodies against Borrelia, measured by ELISA and indirect immunofluorescence. However the presence of IgM antibodies by ELISA using purified antigen, was confirmed in only one case. All sera and cerebrospinal fluids were negative on Western Blot Analysis. No plasma, skin, CSF or thick culture yielded Borrelia, Conclusions: We could not confirm the existence of Lyme disease in Chile. Positive screening with negative confirmatory test suggests false positive non-specific reactivity or that local Borrelia are antigenically different compared to North American strains.

We report a 67 years old diabetic female that received ciprofloxacin for an acute pyelonephritis. Twelve days after starting this treatment, a hand and forearm tenosynovitis appeared, that subsided after the discontinuation of ciprofloxacin. Literature review disclosed other reports of tenosynovitis associated with the use of this antimicrobial.

We report a 49 years old woman with systemic lupus erythematosus and a WHO type IV nephropathy, treated with prednisone 1 mg/kg/day po and cyclophosphamide 1 g/month iv. After two months in this treatment schedule, she presented with an acute pneumonia; broncoalveolar lavage and lung biopsy disclosed the presence of Pneumocystis carinii. She was treated with trimethoprim-sulfamethoxazole 960 mg tid with a favorable response. Opportunistic infections are frequent in lupus erythematosus and Pneumocystis carinii pneumonia has been recently reported in this disease. The changes in immune response and the adverse effects of drugs used in its treatment may explain the increased susceptibility of these patients to infections by Pneumocystis carinii.

We report a 63 year old woman with a rapidly progressive renal failure and fever of unknown origin. Laboratory tests showed anemia, increased ESR and a urine analysis compatible with a glomerular disease. Antineutrophil cytoplasmic autoantibodies were positive with a perinuclear pattern. Kidney biopsy showed an autoimmune crescenteric glomerulonephritis. The patient had a bad evolution, dying after a massive hemoptysis. The necropsy showed a disseminated arteritis without compromise of bronchial vessels. The oligosymptomatic presentation of this patient, bearing in mind the anatomo-pathological findings, is noteworthy and emphasizes the usefulness of serological markers as antineutrophil cytoplasmic autoantibodies in the differential diagnosis.

Three patients seen at the Medicine Department of Del Salvador Hospital between 1986 and 1990 are reported. All had a history of purulent or bloody nasal discharge and recurrent sinusitis, before the appearance of progressive and painful destructive phenomena that affected the rhino faucial region. The diagnosis was made with the histopathological study that disclosed and angiocentric polymorphic infiltrates and perivascular necrosis. The three patients received similar treatment consistent in prednisone 1 mg/kg/day per os, cyclophosphamide 2 mg/kg/day per os and local radiotherapy. The response to therapy was bad and survival was less than three months. It is concluded that although this entity is infrequent, its severity requires and aggressive workup and management by a multidisciplinary team. Notwithstanding the mortality remains to be high.

Five adult patients presenting with clinical and laboratory manifestations of an acute hepatitis in the course of a hitherto undiagnosed infectious mononucleosis (IM) are reviewed. Chief complaints were intense malaise and prolonged fever (7 to 15 days prior to diagnosis). Serum aminotransferases were moderately raised in all patients; three patients had mild jaundice with a direct-reacting hyperbilirubinemia; 4 patients had an enlarged and tender liver. When making the differential diagnosis of causes of acute hepatitis, blood smear examination was crucial, showing atypical lymphocytes (Downey). The diagnosis of IM was confirmed by the demonstration of high serum titers of antibodies against Epstein-Barr virus, IgM class (4 patients) or heterophil antibodies (1 patient), plus peripheral lymph node enlargement (3 patients), splenomegaly (4 patients) and the time course of the disease. The relevance of blood smear examination as a practical tool in the diagnosis of causes of acute hepatitis is stressed.