Functionalization of Morin-Loaded PLGA Nanoparticles with Phenylalanine Dipeptide Targeting the Brain.

Alzheimer's disease (AD) is the most prevalent neurodegenerative disorder, with its incidence constantly increasing. To date, there is no cure for the disease, with a need for new and effective treatments. Morin hydrate (MH) is a naturally occurring flavonoid of the Moraceae family with antioxidant and anti-inflammatory properties; however, the blood-brain barrier (BBB) prevents this flavonoid from reaching the CNS when aiming to potentially treat AD. Seeking to use the LAT-1 transporter present in the BBB, a nanoparticle (NPs) formulation loaded with MH and functionalized with phenylalanine-phenylalanine dipeptide was developed (NPphe-MH) and compared to non-functionalized NPs (NP-MH). In addition, two formulations were prepared using rhodamine B (Rh-B) as a fluorescent dye (NPphe-Rh and NP-Rh) to study their biodistribution and ability to cross the BBB. Functionalization of PLGA NPs resulted in high encapsulation efficiencies for both MH and Rh-B. Studies conducted in Wistar rats showed that the presence of phenylalanine dipeptide in the NPs modified their biodistribution profiles, making them more attractive for both liver and lungs, whereas non-functionalized NPs were predominantly distributed to the spleen. Formulation NPphe-Rh remained in the brain for at least 2 h after administration.

Celecoxib Microparticles for Inhalation in COVID-19-Related Acute Respiratory Distress Syndrome.

Inhalation therapy is gaining increasing attention for the delivery of drugs destined to treat respiratory disorders associated with cytokine storms, such as COVID-19. The pathogenesis of COVID-19 includes an inflammatory storm with the release of cytokines from macrophages, which may be treated with anti-inflammatory drugs as celecoxib (CXB). For this, CXB-loaded PLGA microparticles (MPs) for inhaled therapy and that are able to be internalized by alveolar macrophages, were developed. MPs were prepared with 5% and 10% initial percentages of CXB (MP-C1 and MP-C2). For both systems, the mean particle size was around 5 µm, which was adequate for macrophage uptake, and the mean encapsulation efficiency was >89%. The in vitro release of CXB was prolonged for more than 40 and 70 days, respectively. The uptake of fluorescein-loaded PLGA MPs by the RAW 264.7 macrophage cell line was evidenced by flow cytometry, fluorescence microscopy and confocal microscopy. CXB-loaded PLGA MPs did not produce cytotoxicity at the concentrations assayed. The anti-inflammatory activity of CXB (encapsulated and in solution) was evaluated by determining the IL-1, IL-6 and TNF-α levels at 24 h and 72 h in RAW 264.7 macrophages, resulting in a higher degree of reduction in the expression of inflammatory mediators for CXB in solution. A potent degree of gene expression reduction was obtained with the developed CXB-loaded MPs.

Temporal lobe epilepsy: Evaluation of central and systemic immune-inflammatory features associated with drug resistance.

Neuroinflammation is probably one of the factors involved in drug resistance in people with epilepsy. Finding peripheral markers reflecting the intensity of neuroinflammation could be of great help to decide for which patients anti-inflammatory treatment might be an option. In this context, peripheral cytokines levels and lymphocyte phenotypes were assessed by ELISA and flow cytometry in 3 groups of subjects: drug resistant patients with temporal lobe epilepsy (DR-TLE), non DR-TLE patients and healthy controls. The same parameters were assessed in brain tissue in the DR-TLE group. Differences in the peripheral immune-inflammatory status between the 3 groups of subjects, and correlations between the central and peripheral immune-inflammatory status in DR-TLE patients were evaluated. Forty-one patients with DR-TLE, ten with non-DR-TLE and twenty controls were included. In the periphery, decrease in regulatory cells were observed in DR-TLE patients compared to controls. In addition, significant increase of IL-6 and IL-5 was observed in patients with epilepsy (particularly DR-TLE patients). Two groups of DR-TLE patients with significant differences in several central inflammatory parameters were identified in a cluster analysis. The inflammatory cluster was associated with a peripheral increase of CD4+CD38+ cells and different significant correlations between central and systemic inflammatory parameters were observed. Although their interpretation is not immediate, they demonstrate a clear dialogue between central and peripheral inflammatory reactions. In conclusion, our results add new elements to better understand the interactions between the central and peripheral compartments in patients with DR-TLE, and to help better define treatment options in this group of patients.

Sulfasalazine Microparticles Targeting Macrophages for the Treatment of Inflammatory Diseases Affecting the Synovial Cavity.

Rheumatoid arthritis (RA) is a chronic inflammatory disease with sulfasalazine (SSZ) extensively used for long-term treatment of both juvenile and adult RA. Its use is associated with adverse effects and toxicity due to its non-selective biodistribution. Macrophages play an important role in inflammatory processes. In order to target SSZ to macrophages in this work two microparticulate systems (MPs) are developed: SSZ-loaded PLGA MPs without and with α-tocopherol, with particle sizes lower than 5 µm and encapsulation efficiencies of 81.07 ± 11% and 63.50 ± 6.62%, respectively. Release of SSZ from MPs prepared with α-tocopherol was prolonged for 20 days. In RAW 264.7 cell macrophages MPs prepared with α-tocopherol were captured faster. Cell viability studies confirmed that SSZ-loaded MPs prepared without and with α-tocopherol did not produce cytotoxicity at the concentrations assayed. The anti-inflammatory activity of SSZ-loaded MPs was studied by quantifying interleukins IL-1, IL-6 and TNF-α in macrophages. All formulations produced a significant reduction of cytokine concentrations after 24 and 72 h, indicating that release of SSZ from the MPs was able to inhibit the inflammatory response induced by lipopolysaccharide (LPS). Gene expression of IL-1, IL-6 and TNF-α was decreased by SSZ-loaded MPs. SSZ-loaded MPs prepared with α-tocopherol will potentially allow increasing the residence time of SSZ in the synovial cavity, prolonging its duration of action, and reducing the adverse effects associated with its non-selective biodistribution.

Prognosis of Patients With Severe Aortic Stenosis After the Decision to Perform an Intervention.

INTRODUCTION AND OBJECTIVES: Current therapeutic options for severe aortic stenosis (AS) include transcatheter aortic valve implantation (TAVI) and surgical aortic valve replacement (SAVR). Our aim was to describe the prognosis of patients with severe AS after the decision to perform an intervention, to study the variables influencing their prognosis, and to describe the determinants of waiting time > 2 months. METHODS: Subanalysis of the IDEAS (Influence of the Severe Aortic Stenosis Diagnosis) registry in patients indicated for TAVI or SAVR. RESULTS: Of 726 patients with severe AS diagnosed in January 2014, the decision to perform an intervention was made in 300, who were included in the present study. The mean age was 74.0 ± 9.7 years. A total of 258 (86.0%) underwent an intervention: 59 TAVI and 199 SAVR. At the end of the year, 42 patients (14.0%) with an indication for an intervention did not receive it, either because they remained on the waiting list (34 patients) or died while waiting for the procedure (8 patients). Of the patients who died while on the waiting list, half did so in the first 100 days. The mean waiting time was 2.9 ± 1.6 for TAVI and 3.5 ± 0.2 months for SAVR (P = .03). The independent predictors of mortality were male sex (HR, 2.6; 95%CI, 1.1-6.0), moderate-severe mitral regurgitation (HR, 2.6; 95%CI, 1.5-4.5), reduced mobility (HR, 4.6; 95%CI, 1.7-12.6), and nonintervention (HR, 2.3; 95%CI, 1.02-5.03). CONCLUSIONS: Patients with severe aortic stenosis awaiting therapeutic procedures have a high mortality risk. Some clinical indicators predict a worse prognosis and suggest the need for early intervention.

Conjunctival leiomyosarcoma: A case report and review of literature.

Leiomyosarcoma is a malignant mesenchymal tumor that is very uncommon in the conjunctiva. Nevertheless, we describe here the clinical manifestations, management, and prognosis of a rare case of leiomyosarcoma in this location. An 81-year-old male presented at a tertiary hospital with a rapidly growing mass. After performing biopsy, histopathological examination revealed the existence of a conjunctival leiomyosarcoma. On this diagnosis, a thorough metastatic screening was performed showing no enlarged lymph nodes or metastatic deposits anywhere in the body. To treat the condition, we performed an evisceration with clear margins and subsequent radiotherapy.

A Probabilistic Model for Cushing's Syndrome Screening in At-Risk Populations: A Prospective Multicenter Study.

CONTEXT: Cushing's syndrome (CS) is challenging to diagnose. Increased prevalence of CS in specific patient populations has been reported, but routine screening for CS remains questionable. To decrease the diagnostic delay and improve disease outcomes, simple new screening methods for CS in at-risk populations are needed. OBJECTIVE: To develop and validate a simple scoring system to predict CS based on clinical signs and an easy-to-use biochemical test. DESIGN: Observational, prospective, multicenter. SETTING: Referral hospital. PATIENTS: A cohort of 353 patients attending endocrinology units for outpatient visits. INTERVENTIONS: All patients were evaluated with late-night salivary cortisol (LNSC) and a low-dose dexamethasone suppression test for CS. MAIN OUTCOME MEASURES: Diagnosis or exclusion of CS. RESULTS: Twenty-six cases of CS were diagnosed in the cohort. A risk scoring system was developed by logistic regression analysis, and cutoff values were derived from a receiver operating characteristic curve. This risk score included clinical signs and symptoms (muscular atrophy, osteoporosis, and dorsocervical fat pad) and LNSC levels. The estimated area under the receiver operating characteristic curve was 0.93, with a sensitivity of 96.2% and specificity of 82.9%. CONCLUSIONS: We developed a risk score to predict CS in an at-risk population. This score may help to identify at-risk patients in non-endocrinological settings such as primary care, but external validation is warranted.

Comparison of 1-Year Outcome in Patients With Severe Aorta Stenosis Treated Conservatively or by Aortic Valve Replacement or by Percutaneous Transcatheter Aortic Valve Implantation (Data from a Multicenter Spanish Registry).

The factors that influence decision making in severe aortic stenosis (AS) are unknown. Our aim was to assess, in patients with severe AS, the determinants of management and prognosis in a multicenter registry that enrolled all consecutive adults with severe AS during a 1-month period. One-year follow-up was obtained in all patients and included vital status and aortic valve intervention (aortic valve replacement [AVR] and transcatheter aortic valve implantation [TAVI]). A total of 726 patients were included, mean age was 77.3 ± 10.6 years, and 377 were women (51.8%). The most common management was conservative therapy in 468 (64.5%) followed by AVR in 199 (27.4%) and TAVI in 59 (8.1%). The strongest association with aortic valve intervention was patient management in a tertiary hospital with cardiac surgery (odds ratio 2.7, 95% confidence interval 1.8 to 4.1, p <0.001). The 2 main reasons to choose conservative management were the absence of significant symptoms (136% to 29.1%) and the presence of co-morbidity (128% to 27.4%). During 1-year follow-up, 132 patients died (18.2%). The main causes of death were heart failure (60% to 45.5%) and noncardiac diseases (46% to 34.9%). One-year survival for patients treated conservatively, with TAVI, and with AVR was 76.3%, 94.9%, and 92.5%, respectively, p <0.001. One-year survival of patients treated conservatively in the absence of significant symptoms was 97.1%. In conclusion, most patients with severe AS are treated conservatively. The outcome in asymptomatic patients managed conservatively was acceptable. Management in tertiary hospitals is associated with valve intervention. One-year survival was similar with both interventional strategies.

Acquired vulvar lymphangioma: a case series with emphasis on expanding clinical contexts.

Vulvar lymphangioma circumscriptum (LC) is an unusual benign condition, congenital or acquired, related to interference in the lymph drainage. Acquired cases are usually related to oncological surgical procedures. We report 6 cases of vulvar LC: 3 have been caused by surgery and radiotherapy for gynecologic cancer, whereas the other 3 have originated under benign conditions--Crohn disease, recurring episodes of cellulits, and lower limb lymphedema. In 3 of them, the initial clinical diagnosis was genital wart. Surgical exeresis was performed as the treatment of choice in 5 patients and there were 3 cases of recurrences. Diagnosis of this unusual condition is not always easy even after histopathologic examination. The possibility of vulvar LC should be taken into account as a possible diagnosis in patients with previous oncological surgery or genital warts refractory to the conventional treatment. In these cases, a biopsy of not only the epidermis but also the superficial dermis is recommendable to rule out inflammatory or tumoral processes. Knowledge on the features of this lesion can avoid unnecessary clinical and therapeutic procedures.

Perioperative complications and surgical oncology outcomes in an initial study from 84 patients submitted to laparoscopic radical cystectomy.

OBJECTIVES: The Gold Standard treatment for a non-metastatic, invasive bladder cancer is an open radical cystoprostatectomy (ORCP). Laparoscopic radical cystoprostatectomy (LRCP) is still an experimental technique in evaluation. We describe our perioperative results defined as surgical and safety oncology variables. METHODS: Every patient who underwent a LRCP between January 2007 and July 2011 in the urology department of the University Public Hospital was evaluated. We perform a descriptive retrospective analysis. RESULTS: We evaluated 84 patients, 72 males and 12 females, with a mean age of 68 (44-79). A Bricker diversion was performed in 80 patients, a Camey II bladder replacement was performed in 3 patients, and a Studer bladder replacement was performed in 1 patient. Seventeen patients (20.23%) presented with previous abdominal surgery, and 6 patients (7.14%) presented a medical history of urological surgery. The mean surgery time was 257.57 minutes (180-420). The mean hospital stay was 11.875 days (standard deviation (SD): 6.28). The onset of tolerance to surgery occurred after 3.7 days (SD: 2.21).The transfusion rate after surgical intervention was 20.2%. The mean number of nodes removed, by means of ilio-obturator lymphadenectomy, was 17 (13-19). There were no intraoperative complications. Early complications (less than 1 month after the intervention) occurred in 28 patients (33.3% ).There were no post-operative deaths. There were late complications (starting one month after the intervention) in 7 patients (8.3% ). CONCLUSIONS: Our study demonstrated that LRCP is safe and reproducible and represents a minimally invasive option for patients with infiltrative bladder cancer.

Oligodendrogliomas in relation to astrocytes differentiation. Clinicopathologic and immunohistochemical study.

Oligodendroglioma usually arise in adults and rarely in children. The objective of the current study was to evaluate the immunoexpression of glial fibrillary acidic protein (GFAP) and heat shock proteins (HSP70), endothelial vascular growth factor (EVGF), and endothilial vascular growth factor receptor type II (EFGF-R) expression in relation to the proliferation labeling index (proliferating cell nuclear antigen [PCNA]) and vascular density in patients with oligodendroglioma. We studied 28 cases of oligodendrogliomas--20 (71.4%) were oliodendrogliomas (grade II), and 8 (28.6%) cases were anaplastic oligodendroglioma (grade II according to World Health Organization classification). Eleven cases were male (39.28%) and 9 (32.14%) cases were female. Mitosis were found in grade II (0.35 +/- 1.14) and grade III (3.88 +/- 1.81) (P = .0001*) and pleomorphism in grade II (4.40 +/- 0.99) and grade III (9.50 +/- 9.20) (P = .028). The GFAP was positive in grade II (1.45 +/- 0.60) and grade III (2.63 +/- 0.52) (P = .000); HSP70 was immunoreactive in grade II (1.35 +/- 0.59) and grade III (2.50 +/- 0.53) (P = .001); and EVGF was immunoreactive in grade II (22.70 +/- 6.10) and grade III (36 +/- 1.63) (P = .043). The EVGF-RII was immunoreactive in grade II, 18.30 +/- 6.11 and 31.63 +/- 4.93 (P = .045). The microvascular density labeling index rates were 20.70 +/- 4.34 (grade II) and 33.38 +/- 5.29 (P = .000), and the PCNA labeling index rates were 32.95 +/- 5.89 (grade II) and 56.88 +/- 5.62 (grade III) (P = .045). We observed astrocyte differentiation in oligodendrogliomas grade III. We found a higher PGAF, HSP70, EVGF, and EFGF-R expression in relation with the PCNA and vascular density (CD34) in patients with oligodendroglioma grade III than in oligodendroglioma grade II. There was a significant relationship between mitosis, glial fibrillary acidic protein (GFAP), HSP70, EVGF, EVGF-receptor II expression, and the histologic grade and size of the tumor. For that reason, we suggest that the correlation between GFAP and HSP70 could have a relationship with the protection mechanism of the tumor itself.

A case report of a pyogenic liver abscess caused by Fusobacterium nucleatum in a patient with autosomal dominant polycystic kidney disease undergoing hemodialysis.

Pyogenic liver abscess (PLA) is a process with significant morbidity and mortality and is a rare complication in an aisled way in patients with autosomal dominant polycystic kidney disease (ADPKD). In addition to hepatic cyst infection, intracystic hemorrhage is another complication seen in ADPKD patients; however, the liver parenchyma itself remains normal. A PLA located in normal liver tissue in these kinds of patients has not been previously reported. Fusobacterium nucleatum is an anaerobic bacterium with rare involvement other than in periodontal infections. A 58-year-old Caucasian male, who was on hemodialysis treatment from July 2004 due to end-stage renal disease secondary to ADPKD, was admitted with fever, rigor, chills, weakness, and abdominal pain of 10 days duration. During that time, ciprofloxacin 500 mg, twice daily, gentamycin 80 mg/48 h, and vancomycin 1 g/week, were prescribed, but treatment was interrupted by hospitalization. Physical examination on admission revealed that the patient had a fever of 39.8 degrees C, pallor, chills, right upper quadrant abdominal pain, and hepatosplenomegaly. Abdominal ultrasound revealed a 5.3 cm diameter collection with irregular configuration located in the caudate lobe. Abdominal computed tomography (CT) showed a large multiloculated hepatic collection. The PLA was managed with antibiotics (metronidazole) and continuous catheter drainage (8Fr drainage catheters [Abocath-T, Abbott, Sligo, Ireland]) into the abscess. Fluid culture was positive for F. nucleatum. Complete remission was obtained after 12 days without complications. We describe a PLA by F. nucleatum, in a very rare location in an ADPKD patient undergoing hemodialysis without complicated cysts, managed with antibiotics and percutaneous drainage with satisfactory resolution.

Ultrapure dialysate and inflammatory response in haemodialysis evaluated by darbepoetin requirements--a randomized study.

BACKGROUND: Dialysate quality has been suggested to influence inflammation status in patients subject to haemodialysis (HD). The aim of this study was to compare ultrapure dialysate (UPD) vs conventional dialysate (CD) with respect to darbepoetin requirements and other inflammation markers. METHODS: A controlled prospective randomized study was carried out on 78 patients from two HD units who were treated with low-flux polyamide dialysers. Patients were assigned to two groups by using different sized blocks per unit and dialysis session. One group received CD treatment while the other was treated with UPD over 12 months. From the groups, 37 patients started treatment with CD and 41 with UPD while 31 patients ended with CD and 30 with UPD. The main variables analysed were haemoglobin (Hb) and darbepoetin dose; other variables studied were C-reactive protein (CRP), albumin, interleukin-6 (IL-6) and interleukin-1 receptor antagonist (IL-1Ra). RESULTS: No significant differences were observed between the two groups for the variables analysed. At the beginning of the study the following values of CD and UPD were assessed: Hb 11.3 and 11.3 (g/dl); darbepoetin dose: 0.49 and 0.44 (microg/kg/week); CRP: 13 and 24 (mg/l); albumin: 3.8 and 3.7 (g/dl); IL-6: 5.94 and 4.18; and IL-1Ra: 345 and 420 (ng/l), respectively. At the end of the study the values of CD and UPD were: Hb 12 and 11.9 (g/dl); darbepoetin dose: 0.47 and 0.48 (microg/kg/week); CRP: 14 and 14 (mg/l); albumin: 3.8 and 3.7 (g/dl); IL-6: 14.03 and 12.93 and IL-1Ra: 322 and 340 (ng/l). CONCLUSIONS: UPD does not improve the inflammatory status evaluated by darbepoetin requirements in conventional HD patients treated with low-flux polyamide dialyser. Further controlled studies are required to evaluate the clinical influence of UPD in HD with other low- and high-flux membranes.

Psicoterapia de grupo: revisión histórica / Group psychotherapy: historical revision

Se hace una revisión de los movimientos o modelos más relevantes para el desarrollo de la psicoterapia de grupo en el mundo, entre ellos el modelo médico, el modelo psicodinámico, el sociodinámico, y las corrientes contemporáneas, y con ellos las principales figuras que han contribuido a su desarrollo

Psicoterapia de grupo en Cuba: antecedentes y actualidad / Group psychoterapy in Cuba: antecedents and present time

Se hace un resumen sobre la historia de la Psicoterapia de Grupo en Cuba, exponiendo ante todo los antecedentes en la Europa del Este, y también las influencias en el tema proveniente de Norteamérica, Europa, y Argentina. Se mencionan las figuras pioneras y relevantes de la psicoterapia de grupo en Cuba, y a la vez se ofrece un panorama de actualidad del tema en el país