Stress response mechanisms in protein misfolding diseases: Profiling a cellular model of Huntington's disease.

Stress response pathways like the integrated stress response (ISR), the mitochondrial unfolded protein response (UPRmt) and the heat shock response (HSR) have emerged as part of the pathophysiology of neurodegenerative diseases, including Huntington's disease (HD) - a currently incurable disease caused by the production of mutant huntingtin (mut-Htt). Previous data from HD patients suggest that ISR is activated while UPRmt and HSR are impaired in HD. The study of these stress response pathways as potential therapeutic targets in HD requires cellular models that mimic the activation status found in HD patients of such pathways. PC12 cells with inducible expression of the N-terminal fragment of mut-Htt are among the most used cell lines to model HD, however the activation of stress responses remains unclear in this model. The goal of this study is to characterize the activation of ISR, UPRmt and HSR in this HD cell model and evaluate if it mimics the activation status found in HD patients. We show that PC12 HD cell model presents reduced levels of Hsp90 and mitochondrial chaperones, suggesting an impaired activation or function of HSR and UPRmt. This HD model also presents increased levels of phosphorylated eIF2α, the master regulator of the ISR, but overall similar levels of ATF4 and decreased levels of CHOP - transcription factors downstream to eIF2α - in comparison to control, suggesting an initial activation of ISR. These results show that this model mimics the ISR activation and the impaired UPRmt and HSR found in HD patients. This work suggests that the PC12 N-terminal HD model is suitable for studying the role of stress response pathways in the pathophysiology of HD and for exploratory studies investigating the therapeutic potential of drugs targeting stress responses.

Nicotinic α7 receptor-induced adenosine release from perisynaptic Schwann cells controls acetylcholine spillover from motor endplates.

Acetylcholine (ACh) spillover from motor endplates occurs after neuronal firing bursts being potentiated by cholinesterase inhibitors (e.g., neostigmine). Nicotinic α7 receptors (α7nAChR) on perisynaptic Schwann cells (PSCs) can control ACh spillover by unknown mechanisms. We hypothesized that adenosine might be the gliotransmitter underlying PSCs-nerve terminal communication. Rat isolated hemidiaphragm preparations were used to measure (1) the outflow of [3 H]ACh, (2) real-time transmitter exocytosis by video-microscopy with the FM4-64 fluorescent dye, and (3) skeletal muscle contractions during high-frequency (50 Hz) nerve stimulation bursts in the presence of a selective α7nAChR agonist, PNU 282987, or upon inhibition of cholinesterase activity with neostigmine. To confirm our prediction that α7nAChR-mediated effects require direct activation of PSCs, we used fluorescence video-microscopy in the real-time mode to measure PNU 282987-induced [Ca2+ ]i transients from Fluo-4 NW loaded PSCs in non-stimulated preparations. The α7nAChR agonist, PNU 282987, decreased nerve-evoked diaphragm tetanic contractions. PNU 282987-induced inhibition was mimicked by neostigmine and results from the reduction of ACh exocytosis measured as decreases in [3 H]ACh release and FM4-64 fluorescent dye unloading. Methyllycaconitine blockage of α7nAChR and the fluoroacetate gliotoxin both prevented inhibition of nerve-evoked ACh release and PSCs [Ca2+ ]i transients triggered by PNU 282987 and neostigmine. Adenosine deamination, inhibition of the ENT1 nucleoside outflow, and blockage of A1 receptors prevented PNU 282987-induced inhibition of transmitter release. Data suggest that α7nAChR controls tetanic-induced ACh spillover from the neuromuscular synapse by promoting adenosine outflow from PSCs via ENT1 transporters and retrograde activation of presynaptic A1 inhibitory receptors.

CAMPHOR score: patient-reported outcomes are improved by pulmonary endarterectomy in chronic thromboembolic pulmonary hypertension.

BACKGROUND: Pulmonary endarterectomy (PEA) is the recommended treatment for eligible patients with chronic thromboembolic pulmonary hypertension (CTEPH). The Cambridge Pulmonary Hypertension Outcome Review (CAMPHOR) score is an internationally validated patient-reported outcome (PRO) measure for CTEPH. It assesses three domains: activity, quality of life (QoL) and symptoms. We assessed PROs in patients with CTEPH undergoing PEA. METHODS: This retrospective observational study of consecutive CTEPH patients undergoing PEA at the UK national PEA centre between 2006 and 2017 assessed change in CAMPHOR score from baseline (pre-PEA) until up to 5 years post-PEA. CAMPHOR scores were compared between 1) those with and without clinically significant residual pulmonary hypertension and 2) those undergoing PEA and propensity-matched CTEPH patients who were not operated on. The minimally clinically important difference (MCID) was calculated using an anchor-based method. RESULTS: Out of 1324 CTEPH patients who underwent PEA, 1053 (80%) had a CAMPHOR score recorded pre-PEA, 934 (71%) had a score recorded within a year of PEA and 784 (60%) had both. There were significant improvements between pre- and post-PEA in all three CAMPHOR domains (median±interquartile range activity -5±7, QoL -4±8, symptoms -7±8; all p<0.0001). Improvements in CAMPHOR score were greater and more sustained in those without clinically significant residual pulmonary hypertension. CTEPH patients undergoing PEA had better CAMPHOR scores than those not operated on. The MCID in CAMPHOR score was -3±5 for activity, -4±7 for QoL and -6±7 for symptoms. CONCLUSIONS: PROs are markedly improved by PEA in patients with CTEPH, more so in those without clinically significant residual pulmonary hypertension.

PERK inhibition in zebrafish mimics human Wolcott-Rallison syndrome phenotypes.

Wolcott-Rallison Syndrome (WRS) is the most common cause of permanent neonatal diabetes mellitus among consanguineous families. The diabetes associated with WRS is non-autoimmune, insulin-requiring and associated with skeletal dysplasia and growth retardation. The therapeutic options for WRS patients rely on permanent insulin pumping or on invasive transplants of liver and pancreas. WRS has a well identified genetic cause: loss-of-function mutations in the gene coding for an endoplasmic reticulum kinase named PERK (protein kinase R-like ER kinase). Currently, WRS research is facilitated by cellular and rodent models with PERK ablation. While these models have unique strengths, cellular models incompletely replicate the organ/system-level complexity of WRS, and rodents have limited scalability for efficiently screening potential therapeutics. To address these challenges, we developed a new in vivo model of WRS by pharmacologically inhibiting PERK in zebrafish. This small vertebrate displays high fecundity, rapid development of organ systems and is amenable to highly efficient in vivo drug testing. PERK inhibition in zebrafish produced typical WRS phenotypes such as glucose dysregulation, skeletal defects, and impaired development. PERK inhibition in zebrafish also produced broad-spectrum WRS phenotypes such as impaired neuromuscular function, compromised cardiac function and muscular integrity. These results show that zebrafish holds potential as a versatile model to study WRS mechanisms and contribute to the identification of promising therapeutic options for WRS.

Balloon pulmonary angioplasty outcomes in patients previously treated by pulmonary endarterectomy surgery are inferior to those of inoperable patients.

Pulmonary endarterectomy (PEA) may not achieve full clearance of vascular obstructions in patients with more distal chronic thromboembolic pulmonary hypertension (CTEPH). Balloon pulmonary angioplasty (BPA) may be indicated to treat these residual vascular lesions. We compared whether patients post-PEA (PP) treated by BPA derived similar benefit to those who had inoperable CTEPH (IC), and assessed predictors of BPA response after surgery. We treated 109 patients with BPA-89 with IC and 20 PP. Serial right heart catheterization performed at baseline (immediately before BPA) and 3 months after completing BPA, compared pulmonary vascular resistance (PVR), mean pulmonary artery pressure (mPAP) as well as change in WHO functional class and 6-minute walk distance. We also assessed the impact of total thrombus tail length (TTTL) from photographed PEA surgical specimens and PP computed tomography pulmonary angiography (CTPA)-quantified residual disease burden on BPA response. PP and IC groups did not differ significantly in terms of demographics, baseline hemodynamics or procedural characteristics. However, IC derived greater hemodynamic benefit from BPA: ΔPVR (-27.9 ± 20.2% vs. -13.9 ± 23.9%, p < 0.05) and ΔmPAP (-17.1 ± 14.4% vs. -8.5 ± 18.0%, p < 0.05). There was a negative correlation between pre-BPA PVR and TTTL (r = -0.47, p < 0.05) which persisted post-BPA. PVR, mPAP, WHO FC and 6MWD were not improved significantly post-BPA in PP patients. BPA response was not related to TTTL terciles or CTPA-quantified residual disease burden. Patients PP experienced inferior response to BPA, despite similar baseline and procedural characteristics to IC. BPA does not abolish the relationship between TTTL and postsurgical PVR in PP patients, suggesting that BPA is less effective in treating residual PH after surgery in an experienced surgical center.

The PERKs of mitochondria protection during stress: insights for PERK modulation in neurodegenerative and metabolic diseases.

Protein kinase RNA-like ER kinase (PERK) is an endoplasmic reticulum (ER) stress sensor that responds to the accumulation of misfolded proteins. Once activated, PERK initiates signalling pathways that halt general protein production, increase the efficiency of ER quality control, and maintain redox homeostasis. PERK activation also protects mitochondrial homeostasis during stress. The location of PERK at the contact sites between the ER and the mitochondria creates a PERK-mitochondria axis that allows PERK to detect stress in both organelles, adapt their functions and prevent apoptosis. During ER stress, PERK activation triggers mitochondrial hyperfusion, preventing premature apoptotic fragmentation of the mitochondria. PERK activation also increases the formation of mitochondrial cristae and the assembly of respiratory supercomplexes, enhancing cellular ATP-generating capacity. PERK strengthens mitochondrial quality control during stress by promoting the expression of mitochondrial chaperones and proteases and by increasing mitochondrial biogenesis and mitophagy, resulting in renewal of the mitochondrial network. But how does PERK mediate all these changes in mitochondrial homeostasis? In addition to the classic PERK-eukaryotic translation initiation factor 2α (eIF2α)-activating transcription factor 4 (ATF4) pathway, PERK can activate other protective pathways - PERK-O-linked N-acetyl-glucosamine transferase (OGT), PERK-transcription factor EB (TFEB), and PERK-nuclear factor erythroid 2-related factor 2 (NRF2) - contributing to broader regulation of mitochondrial dynamics, metabolism, and quality control. The pharmacological activation of PERK is protective in models of neurodegenerative and metabolic diseases, such as Huntington's disease, progressive supranuclear palsy and obesity, while the inhibition of PERK was protective in models of Parkinson's and prion diseases and diabetes. In this review, we address the molecular mechanisms by which PERK regulates mitochondrial dynamics, metabolism and quality control, and discuss the therapeutic potential of targeting PERK in neurodegenerative and metabolic diseases.

Acute lung injury after balloon pulmonary angioplasty results in a similar haemodynamic response and possible clinical advantage at follow-up.

Acute lung injury (ALI) is a common but poorly defined and understood complication of balloon pulmonary angioplasty (BPA) for chronic thromboembolic pulmonary hypertension (CTEPH). Little data are available on the medium term clinical outcomes of BPA complicated by ALI. We analyzed per-procedure data from 282 procedures in 109 patients and per-patient data from 85 patients. Serial right heart catheterization at baseline, after each BPA and at 3-month follow-up measured pulmonary vascular resistance (PVR), mean pulmonary artery pressure (mPAP), and cardiac output (CO). ALI (ALI+) was identified by chest radiography alone (ALIr+) or in association with hypoxia clinically (ALIcr+). Procedural predictors of ALI and patient outcomes at 3-months were compared no ALI (ALI-). ALI+ occurred in 17/282 (6.0%) procedures (ALIcr+: 2.5%, ALIr+: 3.5%). Prevailing haemodynamics (PVR: p < 0.01; mPAP: p < 0.05) at a procedural and patient level, as well as number of BPA sessions (p < 0.01), total number of vessels (p < 0.05), and occlusions (p < 0.05) treated at a patient level predicted ALI+. Those with ALI had greater percentage improvement in ΔCAMPHOR symptoms score (ALI+: -63.5 ± 35.7% (p < 0.05); ALIcr+: -84.4 ± 14.5% (p < 0.01); ALI-: -27.2 ± 74.2%) and ΔNT-proBNP (ALIcr+: -78.4 ± 11.9% (p < 0.01); ALI-: -42.9 ± 36.0%) at follow-up. There was no net significant difference in haemodynamic changes in ALI+ versus ALI- at follow-up. ALI is predicted by haemodynamic severity, number of vessels treated, number of BPA sessions, and treating occlusive disease. ALI in this cohort was associated with a clinical advantage at follow-up.

The role of weight stigmatization in cumulative risk for binge eating.

Previous research supports a positive association between weight stigmatization experiences and binge eating. However, the extent to which weight stigmatization accounts for binge eating in the context of other risk factors requires further investigation. Using a cumulative risk model, we examine previously studied risk factors (environmental stress, psychological functioning, negative coping, body dissatisfaction) as well as weight stigmatization as predictors of binge eating bariatric patients and undergraduate students. Results show a unique contribution of weight stigmatization. Analyses by sample indicated that this was only the case for the undergraduate student sample. Results support weight stigmatization as a meaningful predictor of binge eating and highlight the need for further work investigating how these experiences work to promote eating pathology.

Allosteric activation of Hsp70 reduces mutant huntingtin levels, the clustering of N-terminal fragments, and their nuclear accumulation.

AIMS: Huntington's disease (HD) is caused by a mutant huntingtin protein that misfolds, yields toxic N-terminal fragments, aggregates, and disrupts proteostasis. The Hsp70 chaperone is a potential therapeutic target as it prevents proteotoxicity by favouring protein folding, disaggregation, or degradation. We tested the hypothesis that allosteric Hsp70 activation with a pharmacological mimetic of the Hsp70 co-chaperone Hip, YM-1, could modulate huntingtin proteostasis. MAIN METHODS: We used HD cell models expressing either N-terminal or full-length huntingtin. Using single-cell analysis we studied huntingtin aggregation in different cellular compartments by fluorescence microscopy. Protein interaction was evaluated by immunoprecipitation, while protein levels were quantified by immunofluorescence and western-blot. KEY FINDINGS: N-terminal huntingtin interacted with Hsp70 and increased its levels. Treatment with YM-1 reduced N-terminal huntingtin clustering and nuclear aggregation. Full-length mutant huntingtin also interacted with Hsp70, and treatment with YM-1 reduced huntingtin levels when combined with Hsp70 induction by heat shock. Mechanistically, YM-1 increases the Hsp70 affinity for substrates, promoting their proteasomal degradation. Consistently, YM-1 reduced the levels of ubiquitinated proteins. Interestingly, YM-1 accumulated in mitochondria, interfered with its Hsp70 isoform involved in protein import, and increased NRF1 levels, a regulator of proteasome genes. We thus suggest that YM-1 may trigger the coordination of mitochondrial and cytosolic proteostasis, enhancing protein degradation. SIGNIFICANCE: Our findings show that the strategy of allosteric Hsp70 activation holds potential for HD. While drug efficacy may be limited to tissues with elevated Hsp70, combined therapies with Hsp70 elevating strategies could harness the full potential of allosteric Hsp70 activators for HD.

[Type II Quadratus Lumborum block for a sub-total gastrectomy in a septic patient]. / Bloqueio do quadrado lombar tipo II para uma gastrectomia subtotal em um paciente séptico.

INTRODUCTION AND OBJECTIVES: Quadratus Lumborum block was recently described and has already shown good results as an analgesic technique in abdominal surgeries, having the potential to significantly reduce opioids consumption and be a valid alternative to epidural catheter. We performed a type II Quadratus Lumborum block for analgesia in a septic patient having a sub-total gastrectomy. CASE REPORT: An 80 year-old, ASA III, male patient, weighting 50kg, with a history of arterial hypertension and hypercholesterolemia, diagnosed with sepsis due to purulent peritonitis was submitted to an open laparotomy. Bilateral ultrasound-guided type II Quadratus Lumborum block was performed before surgery, using 10mL of levobupivacaine 0.25% and 5mL of mepivacaine 1%, per side. Pain relief was achieved 5minutes after injection and the patient referred no pain in the immediate postoperative period. DISCUSSION: Type II Quadratus Lumborum block may be considered a valid alternative for postoperative analgesia in a septic patient undergoing major abdominal surgery with some relative contraindications to epidural catheter placement. It allowed us to achieve excellent pain management avoiding opioids usage. However, more reports are still needed to properly access its usefulness.

[Sphenopalatine ganglion block for postdural puncture headache in ambulatory setting]. / Bloqueio do gânglio esfenopalatino para cefaleia pós­punção dural em contexto de ambulatório.

BACKGROUND AND OBJECTIVES: Postdural puncture headache (PDPH) is a common complication following subarachnoid blockade and its incidence varies with the size of the needle used and the needle design. Supportive therapy is the usual initial approach. Epidural blood patch (EBP) is the gold-standard when supportive therapy fails but has significant risks associated. Sphenopalatine ganglion block (SPGB) may be a safer alternative. CASE REPORT: We observed a 41 year-old female patient presenting with PDPH after a subarachnoid blockade a week before. We administrated 1l of crystalloids, Dexamethasone 4mg, parecoxib 40mg, acetaminophen 1g and caffeine 500mg without significant relief after 2hours. We performed a bilateral SPGB with a cotton-tipped applicator saturated with 0.5% Levobupivacaine under standard ASA monitoring. Symptoms relief was reported 5minutes after the block. The patient was monitored for an hour after which she was discharged and prescribed acetaminophen 1g and ibuprofen 400mg every 8hours for the following 2 days. She was contacted on the next day and again after a week reporting no pain in both situations. CONCLUSIONS: SPGB may attenuate cerebral vasodilation induced by parasympathetic stimulation transmitted through neurons that have synapses in the sphenopalatine ganglion. This would be in agreement with the Monro-Kellie concept and would explain why caffeine and sumatriptan can have some effect in the treatment of PDPH. Apparently, SPGB has a faster onset than EBP with better safety profile. We suggest that patients presenting with PDPH should be considered primarily for SPGB. Patients may have a rescue EBP if needed.

Type II Quadratus Lumborum block for a sub-total gastrectomy in a septic patient / Bloqueio do quadrado lombar tipo II para uma gastrectomia subtotal em um paciente séptico

Abstract Introduction and objectives: Quadratus Lumborum block was recently described and has already shown good results as an analgesic technique in abdominal surgeries, having the potential to significantly reduce opioids consumption and be a valid alternative to epidural catheter. We performed a type II Quadratus Lumborum block for analgesia in a septic patient having a sub-total gastrectomy. Case report: An 80 year-old, ASA III, male patient, weighting 50 kg, with a history of arterial hypertension and hypercholesterolemia, diagnosed with sepsis due to purulent peritonitis was submitted to an open laparotomy. Bilateral ultrasound-guided type II Quadratus Lumborum block was performed before surgery, using 10 mL of levobupivacaine 0.25% and 5 mL of mepivacaine 1%, per side. Pain relief was achieved 5 minutes after injection and the patient referred no pain in the immediate postoperative period. Discussion: Type II Quadratus Lumborum block may be considered a valid alternative for postoperative analgesia in a septic patient undergoing major abdominal surgery with some relative contraindications to epidural catheter placement. It allowed us to achieve excellent pain management avoiding opioids usage. However, more reports are still needed to properly access its usefulness.

Resumo Introdução e objetivo: O bloqueio do quadrado lombar (QL) foi descrito recentemente e já mostrou bons resultados como técnica analgésica em cirurgias abdominais, com potencial para reduzir significativamente o consumo de opioides e ser uma opção válida ao cateter peridural. Fizemos um bloqueio do QL tipo II para analgesia em um paciente séptico para gastrectomia subtotal. Relato de caso: Paciente do sexo masculino, 80 anos de, ASA III, 50 kg, com história de hipertensão arterial e hipercolesterolemia, diagnosticado com sepsis devido a peritonite purulenta, foi submetido a uma laparotomia aberta. O bloqueio bilateral do QL tipo II guiado por ultrassom foi feito antes da cirurgia com 10 mL de levobupivacaína a 0,25% e 5 mL de mepivacaína a 1%, por lado. O alívio da dor foi obtido em 5 minutos após a injeção e o paciente não referiu dor no pós-operatório imediato. Discussão: O bloqueio do quadrado lombar (QL) tipo II pode ser considerado uma opção válida para analgesia no pós-operatório em um paciente séptico submetido a cirurgia abdominal de grande porte, com algumas contraindicações relativas à colocação do cateter peridural. Permitiu-nos obter um excelente manejo da dor e evitar o uso de opioides. Contudo, mais relatos ainda são necessários para avaliar corretamente a sua utilidade.

Prevalence of environmental and other military exposure concerns in Operation Enduring Freedom and Operation Iraqi Freedom veterans.

OBJECTIVE: This study examined the prevalence of self-reported exposures in returning Operation Enduring Freedom (OEF)/Operation Iraqi Freedom (OIF) veterans and the relationship of exposure reports to current physical symptoms. METHODS: Using self-reports obtained immediately after return from deployment in a cohort of 760 enlisted Army reserve component military personnel, we assessed prevalence rates of environmental and other exposures and the association of these exposures to severity of physical symptoms. RESULTS: Reporting of environmental exposures was relatively low in veterans of OEF/OIF, but reporting more environmental and other exposures, in particular screening positive for a traumatic brain injury, was related to greater physical symptom severity immediately after deployment. CONCLUSIONS: Non-treatment-seeking, enlisted Army reserve component personnel reported relatively few exposures immediately after return from deployment; however, more exposures was modestly associated with greater severity of physical symptoms when controlling for predeployment symptoms, gender, and other deployment-related exposures.

Sphenopalatine ganglion block for postdural puncture headache in ambulatory setting / Bloqueio do gânglio esfenopalatino para cefaleia pós-punção dural em contexto de ambulatório

Abstract Background and objectives: Postdural puncture headache (PDPH) is a common complication following subarachnoid blockade and its incidence varies with the size of the needle used and the needle design. Suportive therapy is the usual initial approach. Epidural blood patch (EBP) is the gold-standard when supportive therapy fails but has significant risks associated. Sphenopalatine ganglion block (SPGB) may be a safer alternative. Case report: We observed a 41 year-old female patient presenting with PDPH after a subarachnoid blockade a week before. We administrated 1 l of crystalloids, Dexamethasone 4 mg, parecoxib 40 mg, acetaminophen 1 g and caffeine 500 mg without significant relief after 2 hours. We performed a bilateral SPGB with a cotton-tipped applicator saturated with 0.5% Levobupivacaine under standard ASA monitoring. Symptoms relief was reported 5 minutes after the block. The patient was monitored for an hour after which she was discharged and prescribed acetaminophen 1 g and ibuprofen 400 mg every 8 hours for the following 2 days. She was contacted on the next day and again after a week reporting no pain in both situation. Conclusions: SPGB may attenuate cerebral vasodilation induced by parasympathetic stimulation transmitted through neurons that have synapses in the sphenopalatine ganglion. This would be in agreement with the Monro-Kellie concept and would explain why caffeine and sumatriptan can have some effect in the treatment of PDPH. Apparently, SPGB has a faster onset than EBP with better safety profile. We suggest that patients presenting with PDPH should be considered primarily for SPGB. Patients may have a rescue EBP if needed.

Resumo Justificativa e objetivos: Cefaleia pós-punção dural (CPPD) é uma complicação comum após bloqueio subaracnoideo e sua incidência varia de acordo com o tamanho e desenho da agulha usada. Geralmente, a terapia de apoio é a abordagem inicial. O tampão sanguíneo peridural (TSP) é o padrão de terapia quando a terapia de apoio falha, mas tem riscos significativos associados. O bloqueio do gânglio esfenopalatino (BGEP) pode ser uma opção mais segura. Relato de caso: Atendemos uma paciente de 41 anos, com CPPD após bloqueio subaracnoideo uma semana antes. Administramos cristaloides (1 L), dexametasona (4 mg), parecoxib (40 mg), acetaminofeno (1 g) e cafeína (500 mg), sem alívio significativo após 2 horas. Fizemos um bloqueio bilateral do gânglio esfenopalatino, com um aplicador com ponta de algodão saturada com levobupivacaína a 0,5% sob monitoração padrão ASA. O alívio dos sintomas foi relatado 5 minutos após o bloqueio. A paciente foi monitorada por uma hora e depois recebeu alta com prescrição de acetaminofeno (1 g) e ibuprofeno (400 mg) a cada 8 horas para os dois dias seguintes. A paciente foi contatada no dia seguinte e novamente após uma semana e, em ambos os contatos, relatou não sentir dor. Conclusões: O BGEP pode ter atenuado a vasodilatação cerebral induzida pelo estímulo parassimpático transmitido através dos neurônios que têm sinapses no gânglio esfenopalatino. Esse mecanismo estaria de acordo com o conceito de Monro-Kellie e explicaria por que a cafeína e o sumatriptano podem ter algum efeito no tratamento da CPPD. Aparentemente, o BGEP tem um início mais rápido do que o do TSP, com um melhor perfil de segurança. Sugerimos que os pacientes que se apresentam com CPPD devam ser considerados primeiro para BGEP. Os pacientes podem ser submetidos a um TSP de resgate, caso necessário.