Brain natriuretic peptide is a long-term cardiovascular predictor in carotid endarterectomy.

BACKGROUND: In noncardiac surgery, several biomarkers are known to play a role in predicting long-term complications, such as major adverse cardiovascular events (MACE), myocardial infarction, or death. Carotid endarterectomy (CEA) is considered a low to medium-risk surgery for carotid stenosis aimed at preventing stroke events. Brain natriuretic peptide (BNP) is a biomarker with potential prognostic value regarding MACE. Since its role in patients undergoing CEA is unknown, this study aims to assess the potential role of BNP as a short and long-term predictor of all-cause mortality and MACE in patients undergoing CEA. METHODS: From a prospective database, patients who underwent CEA under regional anesthesia (RA) at a tertiary hospital center were enrolled, and a post hoc analysis was conducted. Patients on which BNP levels were measured up to fifteen days before surgery, and two groups based on the BNP threshold (200 pg/mL) were defined and compared. Kaplan Meier survival curves and adjusted hazard ratios (aHR) were assessed by multivariable Cox regression. The primary outcome was the incidence of long-term MACE and all-cause mortality. Secondary outcomes included the incidence of AMI and AHF. RESULTS: A total of 89 patients were evaluated. The mean age of the cohort was 71.2 ± 8.7 years, with 71 (79.8%) males, and presented a median follow-up of 30 [13.5-46.4] months. BNP > 200 pg/mL has demonstrated positive predictive value for MACE (aHR: 5.569, confidence interval (CI): 2.441-12.7, p < 0.001) and all-cause mortality (aHR: 3.469, CI: 1.315-9.150, p = 0.018). CONCLUSION: BNP has been demonstrated to independently predict long-term all-cause mortality, MACE and AMI following CEA. It serves as a low-cost, ready-to-use biomarker, although further studies are necessary.

Age-related white matter change disease predicts long-term cerebrovascular morbidity following carotid endarterectomy.

PURPOSE: Cerebrovascular diseases remain a critical focus of medical research due to their substantial impact on global health. Carotid stenosis, often associated with atherosclerosis and advancing age, profoundly affects cerebral blood supply and white matter integrity. This study aims to assess how age-related white matter changes (ARWMC) score, applied to cortex and Basal Ganglia, relates to cardiovascular and cerebrovascular events in patients who underwent carotid endarterectomy (CEA). METHODS: Ninety patients undergoing CEA with regional anesthesia were prospectively enrolled from January 2012 to January 2022, and a post hoc analysis of patients with preoperative cerebral CT scans were reviewed, stratified by ARWMC score. Survival analysis and multivariate Cox regression were employed to assess time-dependent variables and independent predictors. RESULTS: A median follow-up of 51 months (Inter-quartile range [IQR [ [38.8-63.2] months) revealed higher ARWMC grades in the basal ganglia independently associated with significantly increased stroke risk (HR=5.070, 95% CI: 1.509-17.031, P=0.009), acute heart failure (HR=19.066, 95% CI: 2.038-178.375, P=0.01), major adverse cardiovascular events (MACE) (HR=2.760, 95% CI: 1.268-6.009, P=0.011), and all-cause mortality (HR=2.497, 95% CI:1.009-6.180, P=0.048). Polyvascular disease and chronic kidney disease emerged as additional predictors of MACE. CONCLUSION: Higher grades of ARWMC score in the basal ganglia were related to a significant increase in the risk of adverse cardiovascular events, such as stroke, MACE, AHF and all-cause mortality. This study suggests that ARWMC may have potential as a possible predictor of long-term cardio- and cerebrovascular events in patients undergoing CEA.

Gupta Perioperative Risk for Myocardial Infarction or Cardiac Arrest Score is a Long-Term Cardiovascular Risk Predictor After Aortoiliac Revascularization.

BACKGROUND: Gupta Perioperative Risk for Myocardial Infarction or Cardiac Arrest (MICA) is a validated self-explanatory score applied in cardiac or noncardiac surgeries. This study aims to assess the predictive value of the MICA score for cardiovascular events after aortoiliac revascularization. METHODS: This prospective cohort underwent elective aortoiliac revascularization between 2013 and 2021. Patients' demographic, clinical characteristics, and outcomes were registered. The patients were divided into 2 groups according to the MICA score using optimal binning. Survival analysis to test for time-dependent variables and multivariate Cox regression analysis for independent predictors were performed. RESULTS: This study included 130 patients with a median follow-up of 55 months. Preoperative MICA score was ≥6.5 in 41 patients. MICA ≥6.5 presented a statistically significant association, with long-term occurrence of acute heart failure (HR = 1.695, 95% CI 1.208-2.379, P = 0.002), major adverse cardiovascular events (HR = 1.222, 95% CI 1.086-1.376, P < 0.001), and all-cause mortality (HR = 1.256, 95% CI 1.107-1.425, P < 0.001). Multivariable Cox regression confirmed MICA as a significant independent predictor of long-term major adverse cardiovascular events (aHR = 1.145 95% CI 1.010-1.298, P = 0.034) and all-cause mortality (aHR = 1.172 95% CI 1.026-1.339, P = 0.020). CONCLUSIONS: The MICA score is a quick, easy-to-obtain, predictive tool in identifying patients with a higher risk of postaortoiliac revascularization cardiovascular events, such as acute heart failure, major adverse cardiovascular events, and all-cause mortality. Additional research for the validation of the MICA score in the context of aortoiliac revascularization and specific interventions is necessary.

A rare vascular injury in a blood donor after whole blood donation.

BACKGROUND: Blood donation is a safe process though reactions may still occur. We describe a rare vascular complication in a frequent donor, with improvements in the collection process aimed at avoiding future events. METHODS: A 63-year-old woman presented with local pain and an apparent collection in the left arm 8 days after donation. Duplex ultrasound identified a superficial liquid collection and signs of arteriovenous fistula (AVF) between the cubital vein and an arterial branch. A computed tomography (CT)-angio performed 1 day after ultrasound did not identify signs of AVF, followed by a new duplex which confirmed CT-angio findings. It was assumed that a traumatic AVF evolved with spontaneous thrombosis. In the early follow-up (18 days), a progressive regression of hematoma was observed without any sequelae. RESULTS: Investigation showed a faster whole blood bag collection time (3 min; normal: 5-9 min), and the processed packed red blood cell had a brighter red color than usual. The donor reported local bleeding after needle withdrawal, not observed in previous donations and a bruise forming on the same day. No arterial puncture (AP) was noticed by the collection staff during the procedure. The staff was retrained and actions were taken focusing on more active surveillance of late reactions, highlighting the importance of post-donation information by the donors, regardless of any adverse reaction observed, to detect late complications. CONCLUSION: We described an uncommon AP in a donor that was not identified, leading to an AVF that spontaneously thrombosed.

Catheter-Directed Thrombolysis Protocols for Deep Venous Thrombosis of the Lower Extremities-A Systematic Review and Meta-analysis.

OBJECTIVE: To summarize characteristics, complications, and success rates of different catheter-directed thrombolysis (CDT) protocols for the treatment of lower extremity deep venous thrombosis (LE-DVT). METHODS: A systematic review using electronic databases (MEDLINE, Scopus, and Web of Science) was performed to identify randomized controlled trials and observational studies related to LE-DVT treated with CDT. A random-effects model meta-analysis was performed to obtain the pooled proportions of early complications, postthrombotic syndrome (PTS), and venous patency. RESULTS: Forty-six studies met the inclusion criteria reporting 49 protocols (n = 3,028 participants). In studies that addressed the thrombus location (n = 37), LE-DVT had iliofemoral involvement in 90 ± 23% of the cases. Only four series described CDT as the sole intervention for LE-DVT, while 47% received additional thrombectomy (manual, surgical, aspiration, or pharmacomechanical), and 89% used stenting.Definition of venogram success was highly variable, being the Venous Registry Index the most used method (n = 19). Among those, the minimal thrombolysis rate (<50% lysed thrombus) was 0 to 53%, partial thrombolysis (50-90% lysis) was 10 to 71%, and complete thrombolysis (90-100%) was 0 to 88%. Pooled outcomes were 8.7% (95% confidence interval [CI]: 6.6-10.7) for minor bleeding, 1.2% (95% CI: 0.8-1.7%) for major bleeding, 1.1% (95% CI: 0.6-1.6) for pulmonary embolism, and 0.6% (95% CI: 0.3-0.9) for death. Pooled incidences of PTS and of venous patency at up to 1 year of follow-up were 17.6% (95% CI: 11.8-23.4) and 77.5% (95% CI: 68.1-86.9), respectively. CONCLUSION: Assessment of the evidence is hampered by the heterogeneity of protocols, which may be reflected in the variation of PTS rates. Despite this, CDT is a low-risk treatment for LE-DVT.

Fast and Simple UPLC-Q-TOF MS Method for Determination of Bitter Flavan-3-ols and Oligomeric Proanthocyanidins: Impact of Vegetable Protein Fining Agents on Red Wine Composition.

Wine phenolic compounds, particularly proanthocyanidins (PAs), play a significant role in wine sensory characteristics, specifically bitterness and astringency. Although not consensual, flavan-3-ols and oligomeric PAs are generally considered the primary contributors to wine bitterness. Patatin, a vegetable protein fining agent, has been explored as an alternative to animal and synthetic fining agents for reducing wine bitterness. However, contradictory results exist regarding its effectiveness in removing flavan-3-ols and oligomeric PAs in red wines. In this work, a UPLC-Q-TOF MS/MS method was optimized and validated for accurately measuring flavan-3-ols, as well as dimeric and trimeric PAs, in red wines. The MS/MS analysis of flavan-3-ols, in addition to the typical fragmentation described in the literature, revealed an intense mass fragment resulting from the loss of C3O2 and C3O2 + H2O from the parent ion. It was observed that flavan-3-ols and PAs undergo oxidation during sample preparation, which was reversed by the addition of 5 g/L of ascorbic acid. The method demonstrated good linearity range (2 mg/L to 20 mg/L), detection limit (0.3 mg/L to 0.7 mg/L), quantification limit (0.8 mg/L to 2.2 mg/L), precision (repeatability 2.2% to 7.3%), and accuracy (recovery 98.5% to 100.5%). The application of patatin at different doses (5 g/L to 30 g/L) in two different red wine matrices did not reduce the levels of monomeric, dimeric, and trimeric PAs in red wines. However, similar behaviors were observed for pea protein and gelatin. Therefore, wine fining trials and efficiency measurements of the treatments in each matrix are strongly advised.

Distinct Inflammatory and Oxidative Effects of Diabetes Mellitus and Hypothyroidism in the Lacrimal Functional Unit.

Diabetes mellitus (DM) and hypothyroidism (HT) are prevalent diseases associated with dry eye (DE). Their impact on the lacrimal functional unit (LFU) is poorly known. This work evaluates the changes in the LFU in DM and HT. Adult male Wistar rats had the disease induced as follows: (a) DM: streptozotocin and (b) HT: methimazole. The tear film (TF) and blood osmolarity were measured. Cytokine mRNA was compared in the lacrimal gland (LG), trigeminal ganglion (TG), and cornea (CO). Oxidative enzymes were evaluated in the LG. The DM group showed lower tear secretion (p = 0.02) and higher blood osmolarity (p < 0.001). The DM group presented lower mRNA expression of TRPV1 in the cornea (p = 0.03), higher Il1b mRNA expression (p = 0.03), and higher catalase activity in the LG (p < 0.001). The DM group presented higher Il6 mRNA expression in the TG (p = 0.02). The HT group showed higher TF osmolarity (p < 0.001), lower expression of Mmp9 mRNA in the CO (p < 0.001), higher catalase activity in the LG (p = 0.002), and higher expression of Il1b mRNA in the TG (p = 0.004). The findings revealed that DM and HT induce distinct compromises to the LG and the entire LFU.

R2CHA2DS2-VA Predictsthe Cardiovascular Risk after Carotid Endarterectomy.

BACKGROUND: R2CHA2DS2-VA score has been used to predict short and long-term outcomes in many cardiovascular diseases. This study aims to validate the R2CHA2DS2-VA score as a long-term major adverse cardiovascular events (MACE) predictor after carotid endarterectomy (CEA). Secondary outcomes were also assessed regarding the incidence of all-cause mortality, acute myocardial infarction (AMI), major adverse limb events (MALE), and acute heart failure (AHF). METHODS: From January 2012 to December 2021, patients (n = 205) from a Portuguese tertiary care and referral center that underwent CEA with regional anesthesia (RA) for carotid stenosis (CS) were selected from a previously collected prospective database, and a posthoc analysis was performed. Demographics and comorbidities were registered. Clinical adverse events were assessed 30 days after the procedure and in the subsequent long-term surveillance period. Statistical analysis was performed by the Kaplan-Meier method and Cox proportional hazards regression. RESULTS: Of the patients enrolled, 78.5% were males with a mean age of 70.44 ± 8.9 years. Higher scores of R2CHA2DS2-VA were associated with long-term MACE (adjusted hazard ratio (aHR) 1.390; 95% confidence interval (CI) 1.173-1.647); and mortality (aHR 1.295; 95% CI 1.08-1.545). CONCLUSIONS: This study demonstrated the potential of the R2CHA2DS2-VA score to predict long-term outcomes, such as AMI, AHF, MACE, and all-cause mortality, in a population of patients submitted to carotid endarterectomy.

Molecular profile of patients with myelofibrosis: a 10-year experience.

OBJECTIVE: To analyze the karyotype test and myeloid panel with next-generation sequencing findings in patients with myelofibrosis, and to compare transplant characteristics in patients referred for bone marrow transplantation. METHODS: Retrospective, single-center study with patients diagnosed with myelofibrosis treated at Hospital Israelita Albert Einstein between 2010 and 2020. RESULTS: A total of 104 patients with myelofibrosis were examined. Patients who had not been submitted to tests in our service were excluded. The final sample comprised 69 patients. Of these 69, 56 were submitted to karyotyping and 22 to myeloid panel with next-generation sequencing. Karyotype was normal in 60% of the patients and altered in 40%. The prevalence of high-risk molecular mutations was higher in patients referred for bone marrow transplantation (100% versus 50%). The median follow-up of transplant patients was 2.4 years and the overall survival at 2 years was 80% (95%CI: 62-100%). CONCLUSION: The molecular analysis enables estimating the patient's risk and thus instituting more aggressive treatment such as bone marrow transplant for patients at higher risk, being a relevant tool to guide therapy. Given the significance of molecular analysis for therapeutic decision-making in myelofibrosis, collection and disclosure of data on the prevalence of cytogenetic changes and findings of next-generation sequencing in affected patients is important.

Pediatric inflammatory multisystemic syndrome in Brazil: sociodemographic characteristics and risk factors to death

Abstract Objective: To determine the incidence of MIS-C in Brazil, describe the clinical and sociodemographic characteristics of the pediatric population affected by MIS-C and compare mortality and lethality outcomes with isolated Covid-19 and MIS-C cases. Methods: Observational and retrospective cohort study of cases of MIS-C associated with Covid-19 in the Brazilian population between 04/01/2020 and 04/17/2021. Data from the Ministry of Health's epidemiological bulletin up to the 15th epidemiological week of 2021, were used. The analyzes were descriptive through absolute and relative frequencies. The significance level is 5% in Stata 16.0 package. Results: Between 04/01/2020 and 04/07/2021, 903 cases of MIS-C associated with Covid-19 were notified in Brazil, of which, the largest part (55.26%) were male, between 0 and 4 years old (45.29%), from the Southeast region (38.76%). The deaths (61; 6.7%) were higher in the female gender, between 0 and 4 years old (47.54%) and in the Southeast region (34.43%). It was identified that the risk of death by MIS-C related to Covid-19 is 5.29 (CI = 2.83; 9.87 and P-value = <0.001) times higher in adolescents from 15-19 years old than in other age groups when compared to 0-4 years old children. Also, the residency in North region was as risk factor to death (RR = 3.72, IC = 1.29; 10.74 e P-value = 0.008). Conclusion: In this study, despite the numbers showing more deaths from zero to 4 years old, the risk for teenagers is notably higher. In addition, Brazil's Northern region is a risk factor that reaffirms social inequality and poor access to health.

Pediatric inflammatory multisystemic syndrome in Brazil: sociodemographic characteristics and risk factors to death.

OBJECTIVE: To determine the incidence of MIS-C in Brazil, describe the clinical and sociodemographic characteristics of the pediatric population affected by MIS-C and compare mortality and lethality outcomes with isolated Covid-19 and MIS-C cases. METHODS: Observational and retrospective cohort study of cases of MIS-C associated with Covid-19 in the Brazilian population between 04/01/2020 and 04/17/2021. Data from the Ministry of Health's epidemiological bulletin up to the 15th epidemiological week of 2021, were used. The analyzes were descriptive through absolute and relative frequencies. The significance level is 5% in Stata 16.0 package. RESULTS: Between 04/01/2020 and 04/07/2021, 903 cases of MIS-C associated with Covid-19 were notified in Brazil, of which, the largest part (55.26%) were male, between 0 and 4 years old (45.29%), from the Southeast region (38.76%). The deaths (61; 6.7%) were higher in the female gender, between 0 and 4 years old (47.54%) and in the Southeast region (34.43%). It was identified that the risk of death by MIS-C related to Covid-19 is 5.29 (CI = 2.83; 9.87 and P-value = <0.001) times higher in adolescents from 15-19 years old than in other age groups when compared to 0-4 years old children. Also, the residency in North region was as risk factor to death (RR = 3.72, IC = 1.29; 10.74 e P-value = 0.008). CONCLUSION: In this study, despite the numbers showing more deaths from zero to 4 years old, the risk for teenagers is notably higher. In addition, Brazil's Northern region is a risk factor that reaffirms social inequality and poor access to health.

Molecular profile of patients with myelofibrosis: a 10-year experience

ABSTRACT Objective To analyze the karyotype test and myeloid panel with next-generation sequencing findings in patients with myelofibrosis, and to compare transplant characteristics in patients referred for bone marrow transplantation. Methods Retrospective, single-center study with patients diagnosed with myelofibrosis treated at Hospital Israelita Albert Einstein between 2010 and 2020. Results A total of 104 patients with myelofibrosis were examined. Patients who had not been submitted to tests in our service were excluded. The final sample comprised 69 patients. Of these 69, 56 were submitted to karyotyping and 22 to myeloid panel with next-generation sequencing. Karyotype was normal in 60% of the patients and altered in 40%. The prevalence of high-risk molecular mutations was higher in patients referred for bone marrow transplantation (100% versus 50%). The median follow-up of transplant patients was 2.4 years and the overall survival at 2 years was 80% (95%CI: 62-100%). Conclusion The molecular analysis enables estimating the patient's risk and thus instituting more aggressive treatment such as bone marrow transplant for patients at higher risk, being a relevant tool to guide therapy. Given the significance of molecular analysis for therapeutic decision-making in myelofibrosis, collection and disclosure of data on the prevalence of cytogenetic changes and findings of next-generation sequencing in affected patients is important.

Comparison of the effects of corneal and lacrimal gland denervation on the lacrimal functional unit of rats / Comparação dos efeitos da denervação da córnea e da glândula lacrimal na unidade funcional lacrimal de ratos

ABSTRACT Purpose: This study aimed to compare the changes in the lacrimal functional unit in the following two models of neurogenic dry eye syndrome: sensory denervation of the cornea versus autonomic denervation of the lacrimal gland. Methods: The neural network supports the lacrimal functional unit. It can be divided into afferent (sensory) and efferent (autonomic) pathways and is affected by severe diseases that compromise the lacrimal functional unit. Male Wistar, 8-week-old rats were divided into the following three groups: 1) control naïve (n=16 animals); 2) autonomic denervation: where rats were subjected to right lacrimal gland nerve ablation and evaluated after 1 and 2 months (1M and 2M) after the procedure (n=7 animals per subgroup, autonomic denervation 1M and autonomic denervation 2M, respectively); 3) sensory denervation induced by 0.2% benzalkonium chloride eye drops, twice a day for 7 days in the right eye (n=10 animals). The corneal sensitivity was measured using the eye wipe test with capsaicin (10 µM). The quantitative real-time PCR was performed to compare the mRNA expressions of proinflammatory cytokines, such as Il-1β, Il-6, Tnf, Mmp9, in the cornea, trigeminal ganglion, and lacrimal gland. In addition, the mRNA of the promitotic factors in the lacrimal gland, such as Bmp7, Runx1, Runx3, Fgf10, and Smad1, was compared. Results: Sensory denervation induced corneal hyperalgesia (p=0.001). Sensory denervation and autonomic denervation increased the mRNA of proinflammatory cytokines in the cornea and lacrimal gland (p<0.05), but only sensory denervation increased the mRNA levels of Il-1β and Tnf in the trigeminal ganglion (p<0.05) compared with the control naïve. Conclusions: Autonomic denervation and sensory denervation models can have common features, such as inflammation of different parts of the lacrimal functional unit. However, hyperesthesia and inflammatory markers in the trigeminal ganglion because of sensory denervation and the expression of regenerative mediators in the lacrimal gland owing to autonomic denervation are the distinguishing features of these diseases that can be explored in future studies assessing dry eye syndrome secondary to neural damage of the lacrimal functional unit.

RESUMO Objetivo: O nosso objetivo neste estudo foi comparar as alterações na unidade funcional lacrimal em dois modelos de síndrome do olho seco neurogênica: desnervação sensorial da córnea versus desnervação autonômica da glândula lacrimal. Métodos: A rede neural é um importante suporte para a unidade funcional lacrimal. Pode ser dividido em vias aferentes (sensoriais) e eferentes (autonômicas), sujeitas a doenças graves que comprometem a unidade funcional lacrimal. Ratos Wistar machos, com 8 semanas de idade, foram divididos em três grupos: 1) Controle naïve (n=16 animais); 2) Desnervação autonômica: onde os ratos foram submetidos à ablação do nervo da glândula lacrimal direita e avaliados após um e dois meses (1 M a 2 M) do procedimento (n=7 animais por subgrupo, desnervação autonômica 1M e desnervação autonômica 2M, respectivamente); 3) Desnervação sensorial induzida por colírio a 0,2% de cloreto de benzalcônio, duas vezes ao dia por 7 dias no olho direito (n=10 animais). A sensibilidade da córnea foi medida pelo teste de movimento pata-olho com capsaicina (10 µM). A PCR quantitativa em tempo real foi aplicada para comparar a expressão relativa de mRNA de citocinas pró-inflamatórias: Il1b, Il6, Tnf, Mmp9, na córnea, gânglio trigêmio e glândula lacrimal. O mRNA dos agentes pró-mitóticos Bmp7, Runx1, Runx3, Fgf10 e Smad1 foram comparados na glândula lacrimal. Resultados: A desnervação sensorial induziu hiperalgesia da córnea (p=0,001). Desnervação sensorial e desnervação autonômica aumentaram o mRNA de citocinas pró-inflamatórias no córnea e glândula lacrimal (p<0,05), mas apenas desnervação sensorial aumentou o mRNA de Il1b e Tnf no gânglio trigêmio (p<0,05) quando comparado ao controle naïve. Conclusões: Os modelos de desnervação autonômica e desnervação sensorial podem ter características comuns, como inflamação de diferentes partes da unidade funcional lacrimal. No entanto, a hiperestesia e os marcadores inflamatórios no gânglio trigêmio de desnervação sensorial e a expressão de mediadores regenerativos na glândula lacrimal na desnervação autonômica são características que distinguem essas doenças, podendo ser investigadas em estudos futuros que abordam o olho seco secundário ao dano neural da unidade funcional lacrimal.

Adverse reactions and adherence to capecitabine: A prospective study in patients with gastrointestinal cancer.

INTRODUCTION: Capecitabine is an oral anticancer drug which can cause some adverse reactions and the great challenge for its use is to ensure the medication adherence. The aim of this study was to analyze adverse reactions and adherence to capecitabine in patients with gastrointestinal cancer. METHODS: A prospective study was performed in a tertiary teaching hospital in Brazil. Outpatients undergoing capecitabine treatment for colorectal or gastric cancer were followed for three cycles of treatment. Patient demographic and clinical characteristics data were collected. Adverse reactions were analyzed using Common Terminology Criteria for Adverse Events (CTCAE) v.4. Adherence to capecitabine were evaluated using Morisky-Green and MedTake tests. Statistical analysis was conducted using Chi-square, Fisher's exact and McNemer tests. RESULTS: One hundred and four patients were enrolled in this study, with a mean age was 58.5 ± 10.9 years; 51.0% were men and 51.0% Caucasian. Nausea and diarrhea were the most frequently reported adverse reactions (82.7% and 62.5%, respectively), followed by vomiting (54.8%), fatigue (54.8%), and hand-foot syndrome (53.9%). Nausea and diarrhea were also the most severe adverse reactions. Most patients were adherent to capecitabine in all cycles of treatment using the Morisky-Green test. Adherence increased significantly between cycle 1 and cycle 2 by MedTake test (p < 0.001). Some demographic and clinical characteristics were associated with adverse reactions (e.g., age and nausea, gender and nausea and vomiting) and capecitabine adherence (e.g., marital status and educational level) as well as some adverse reactions were associated with capecitabine adherence (hand-foot syndrome and nausea). CONCLUSIONS: Clinical oncology pharmacists must provide patient information on the correct use of capecitabine, manage adverse reactions, and monitor adherence to treatment. Strategies to prevent non-adherence to capecitabine must be adopted to ensure the success of pharmacotherapy.

Comparison of the effects of corneal and lacrimal gland denervation on the lacrimal functional unit of rats.

PURPOSE: This study aimed to compare the changes in the lacrimal functional unit in the following two models of neurogenic dry eye syndrome: sensory denervation of the cornea versus autonomic denervation of the lacrimal gland. METHODS: The neural network supports the lacrimal functional unit. It can be divided into afferent (sensory) and efferent (autonomic) pathways and is affected by severe diseases that compromise the lacrimal functional unit. Male Wistar, 8-week-old rats were divided into the following three groups: 1) control naïve (n=16 animals); 2) autonomic denervation: where rats were subjected to right lacrimal gland nerve ablation and evaluated after 1 and 2 months (1M and 2M) after the procedure (n=7 animals per subgroup, autonomic denervation 1M and autonomic denervation 2M, respectively); 3) sensory denervation induced by 0.2% benzalkonium chloride eye drops, twice a day for 7 days in the right eye (n=10 animals). The corneal sensitivity was measured using the eye wipe test with capsaicin (10 µM). The quantitative real-time PCR was performed to compare the mRNA expressions of proinflammatory cytokines, such as Il-1ß, Il-6, Tnf, Mmp9, in the cornea, trigeminal ganglion, and lacrimal gland. In addition, the mRNA of the promitotic factors in the lacrimal gland, such as Bmp7, Runx1, Runx3, Fgf10, and Smad1, was compared. RESULTS: Sensory denervation induced corneal hyperalgesia (p=0.001). Sensory denervation and autonomic denervation increased the mRNA of proinflammatory cytokines in the cornea and lacrimal gland (p<0.05), but only sensory denervation increased the mRNA levels of Il-1ß and Tnf in the trigeminal ganglion (p<0.05) compared with the control naïve. CONCLUSIONS: Autonomic denervation and sensory denervation models can have common features, such as inflammation of different parts of the lacrimal functional unit. However, hyperesthesia and inflammatory markers in the trigeminal ganglion because of sensory denervation and the expression of regenerative mediators in the lacrimal gland owing to autonomic denervation are the distinguishing features of these diseases that can be explored in future studies assessing dry eye syndrome secondary to neural damage of the lacrimal functional unit.

Limitations and advances in new treatments and future perspectives of corneal blindness / Limitações e avanços em novos tratamentos e perspectivas futuras na cegueira corneal

ABSTRACT This review is intended to describe the therapeutic approaches for corneal blindness, detailing the steps and elements involved in corneal wound healing. It also presents the limitations of the actual surgical and pharmacological strategies used to restore and maintain corneal transparency in terms of long-term survival and geographic coverage. In addition, we critically review the perspectives of anabolic agents, including vitamin A, hormones, growth factors, and novel promitotic and anti-inflammatory modulators, to assist corneal wound healing. We discuss the studies involving nanotechnology, gene therapy, and tissue reengineering as potential future strategies to work solely or in combination with corneal surgery to prevent or revert corneal blindness.(AU)

RESUMO O presente trabalho traz uma revisão das abordagens terapêuticas para a cegueira da córnea. O estudo detalha as etapas e os elementos envolvidos na cicatrização da córnea. Ele mostra as limitações das estratégias cirúrgicas e farmacológicas usadas para restaurar e manter a transparência da córnea em termos de sobrevida a longo prazo e alcance geográfico. As perspectivas dos agentes anabólicos, incluindo vitamina A, hormônios, fatores de crescimento e novos moduladores pró-mitóticos e anti-inflamatórios para auxiliar a cicatrização da ferida na córnea, são revisadas criticamente. Aqui, apresentamos estudos envolvendo nanotecnologia, terapia gênica e reengenharia de tecidos como possíveis estratégias futuras para atuar de maneira isolada ou combinada com a cirurgia da córnea para prevenir ou reverter a cegueira corneana.(AU)

Lacrimal Gland as a Target Organ for Adenovirus Gene Therapy Encoding Erythropoietin for Dry Eye Induced by Benzalkonium Chloride.

Purpose: The aims of this work were a) to describe the histology of the lacrimal gland (LG) and cornea induced by an adenovirus (Ad) vector encoding the human erythropoietin (Epo) gene delivered to the LG and b) to evaluate the therapeutic potential of this strategy to prevent benzalkonium chloride (BAK) corneal toxicity.Methods: Structure and function of male Wistar rats LG were compared in the groups: 1) naïve control and 2) Ad-hEpo in the right LG (RLG). The protective response against BAK eye drops was compared among the groups 1) naïve control, 2) BAK in the right eye, 3) Ad-hEpo RLG + BAK and 4) Ad-hEpo in the right salivary gland (RSG)+BAK. Ad-hEpo groups received an injection of AdLTR2EF1a-hEPO (25 ul, 1010 particles/ml) in the right LG or SG (positive control). The BAK groups received 0.2% BAK in the right cornea twice a day. The tests applied after 7 days, included tear secretion, hEPO mRNA detection by qRT-PCR, LG and cornea histology, LG ELISA for cytokines and hematocrit.Results: hEPO mRNA was present in the Ad-hEpo RLG and RSG, but not kidney or liver samples (negative controls). TNF-α and IL-1ß increased in the LG exposed to Ad-hEpo compared to naïve control (p = .0115 and p = .0397, respectively). BAK reduced tear secretion, but this reduction was prevented by Ad-hEpo RLG+BAK and Ad-hEpo RSG+BAK (p = .017). The corneal epithelia were thinner in the BAK-treated groups independent of Ad-hEpo (p = .0009). Hematocrit increased only in the Ad-hEpo RSG group (p = .01).Conclusions: Ad-hEpo infection of rat LG and SG induces local, but only the SG infection induced systemic changes in rats. Importantly, Ad-hEpo attenuated the BAK-mediated toxic reduction in tear flow. Future studies must consider viral vector tissue tropism, biodistribution and effective therapeutic gene products for ocular surface diseases.