All-Aqueous, Surfactant-Free, and pH-Driven Nanoformulation Methods of Dual-Responsive Polymer Nanoparticles and their Potential use as Nanocarriers of pH-Sensitive Drugs.

All-aqueous, surfactant-free, and pH-driven nanoformulation methods to generate pH- and temperature-responsive polymer nanoparticles (NPs) are described. Copolymers comprising a poly(methyl methacrylate) (PMMA) backbone with a few units of 2-(dimethylamino)ethyl methacrylate (DMAEMA) are solubilized in acidic buffer (pH 2.0) to produce pH-sensitive NPs. Copolymers of different molar mass (2.3-11.5 kg mol-1 ) and DMAEMA composition (7.3-14.2 mol%) are evaluated using a "conventional" pH-driven nanoformulation method (i.e., adding an aqueous polymer solution (acidic buffer) into an aqueous non-solvent (basic buffer)) and a robotized method for pH adjustment of polymer dispersions. Dynamic light scattering, zeta-potential (ζ), and sedimentation-diffusion analyses suggest the formation of dual-responsive NPs of tunable size (from 20 to 110 nm) being stable for at least 28 days in the pH and temperature intervals from 2.0 to 6.0 and 25 to 50 °C, respectively. Ultraviolet-visible spectroscopic experiments show that these NPs can act as nanocarriers for the pH-sensitive dipyridamole drug, expanding its bioavailability and potential controlled release as a function of pH and temperature. These approaches offer alternative strategies to prepare stimuli-responsive NPs, avoiding the use of harmful solvents and complex purification steps, and improving the availability of biocompatible polymer nanoformulations for specific controlled release of pH-sensitive cargos.

Asthma Exacerbations: The Genes Behind the Scenes.

The clinical and socioeconomic burden of asthma exacerbations (AEs) constitutes a major public health problem. In the last 4 years, there has been an increase in ethnic diversity in candidate-gene and genome-wide association studies of AEs, which in the latter case led to the identification of novel genes and underlying pathobiological processes. Pharmacogenomics, admixture mapping analyses, and the combination of multiple "omics" layers have helped to prioritize genomic regions of interest and/or facilitated our understanding of the functional consequences of genetic variation. Nevertheless, the field still lags behind the genomics of asthma, where a vast compendium of genetic approaches has been used (eg, gene-environment nteractions, next-generation sequencing, and polygenic risk scores). Furthermore, the roles of the DNA methylome and histone modifications in AEs have received little attention, and microRNA findings remain to be validated in independent studies. Likewise, the most recent transcriptomic studies highlight the importance of the host-airway microbiome interaction in the modulation of risk of AEs. Leveraging -omics and deep-phenotyping data from subtypes or homogenous subgroups of patients will be crucial if we are to overcome the inherent heterogeneity of AEs, boost the identification of potential therapeutic targets, and implement precision medicine approaches to AEs in clinical practice.

Asthma Exacerbations: The Genes Behind the Scenes

The clinical and socioeconomic burden of asthma exacerbations (AEs) constitutes a major public health problem. In the last 4 years, there has been an increase in ethnic diversity in candidate-gene and genome-wide association studies of AEs, which in the latter case led to the identification of novel genes and underlying pathobiological processes. Pharmacogenomics, admixture mapping analyses, and the combination of multiple “omics” layers have helped to prioritize genomic regions of interest and/or facilitated our understanding of the functional consequences of genetic variation. Nevertheless, the field still lags behind the genomics of asthma, where a vast compendium of genetic approaches has been used (eg, gene–environment interactions, next-generation sequencing, and polygenic risk scores). Furthermore, the roles of the DNA methylome and histone modifications in AEs have received little attention, and microRNA findings remain to be validated in independent studies. Likewise, the most recent transcriptomic studies highlight the importance of the host–airway microbiome interaction in the modulation of risk of AEs. Leveraging -omics and deep-phenotyping data from subtypes or homogenous subgroups of patients will be crucial if we are to overcome the inherent heterogeneity of AEs, boost the identification of potential therapeutic targets, and implement precision medicine approaches to AEs in clinical practice (AU)

La carga clínica y socioeconómica de las exacerbaciones asmáticas (EA) representa un importante problema de salud pública. En los últimos cuatro años, ha aumentado la diversidad étnica en los estudios de asociación de genes candidatos y del genoma completo (GWAS) de las EA, lo que, en este último caso, ha llevado a la identificación de nuevos genes y procesos fisiopatológicos subyacentes. La farmacogenómica, los análisis de mapeo por mezcla y la combinación de múltiples capas "ómicas" han contribuido a priorizar regiones genómicas de interés y/o comprender las consecuencias funcionales de la variación genética. A pesar de esto, el campo todavía está en desarrollo en comparación con la genómica del asma, donde se ha utilizado un amplio compendio de enfoques genéticos (por ejemplo: interacciones gen-ambiente, secuenciación de nueva generación o puntuaciones de riesgo poligénico). Además, el papel de la metilación del ADN y las modificaciones de las histonas en las EA se ha explorado escasamente, y los hallazgos relacionados con los microARNs aún no se han validado en estudios independientes. Asimismo, los estudios transcriptómicos más recientes destacan la importancia de la interacción entre el microbioma de las vías respiratorias y el huésped en la modulación del riesgo de las EA. La integración de datos ómicos y de fenotipado profundo de subtipos o subgrupos homogéneos de pacientes será crucial para superar la heterogeneidad inherente de las EA e impulsar la identificación de dianas terapéuticas potenciales y la implementación de la medicina de precisión para las EA en la práctica clínica (AU)

Colitis actínica de localización cecal. Serie de casos / Actinic colitis of cecal location. Number of cases

Resumen Por definición, la colitis actínica incluye cambios inflamatorios de la mucosa colorrectal secundarios a radioterapia en cercanía a la región tratada. La localización más frecuente es el recto y la indicación más común de radioterapia corresponde a neoplasias de la región pélvica incluidos el recto, la próstata y el cérvix. Se estima que hasta la mitad de los pacientes que reciben radiación pélvica llega a desarrollar síntomas gastrointestinales asociados. Se presentan dos pacientes con metástasis óseas sacroilíacas y pélvicas secundarias a adenocarcinoma de próstata que recibieron radiación en la región lumbosacra y pélvica, ambos pacientes presentaron episodios de deposiciones con sangre que iniciaron tempranamente posterior a la radioterapia. La colonoscopia mostró eritema y ulceración. En el estudio histopatológico se observó un patrón de colitis isquémica, con núcleo y citomegalia, estroma fibroso con cambios reactivos y abundante infiltrado inflamatorio neutrofílico. Estos hallazgos son característicos de la colitis actínica aguda; sin embargo, la localización cecal no ha sido frecuentemente reportada. Aunque al ser el ciego y el íleon terminal móviles de localización pélvica, se convierten en un factor de riesgo para que estos segmentos anatómicos sean susceptibles al impacto directo de la radioterapia. Esta condición, en la fase aguda, es autolimitada y se suele resolver con medidas de soporte. Es indispensable que el personal involucrado en el manejo de estos pacientes conozca esta entidad y los posibles diagnósticos diferenciales.

Abstract By definition, actinic colitis includes inflammatory changes of the colorectal mucosa secondary to radiation therapy of nearby tissue. The most frequent location is the rectum, and the most common indication for radiation therapy is a pelvic region neoplasm in the rectum, prostate or cervix. It is estimated that up to half of patients receiving pelvic radiation go on to develop associated gastrointestinal symptoms. We present two patients with sacroiliac and pelvic bone metastases secondary to prostate adenocarcinoma who received radiation in the lumbosacral and pelvic region. Both patients developed bloody stools soon after radiation therapy. Colonoscopy showed erythema and ulceration, and histopathology found a pattern of ischemic colitis with nucleus and cytomegalovirus infection, fibrous stroma with reactive changes and abundant inflammatory infiltration of neutrophils. These findings are characteristic of acute actinic colitis, but the cecal location has not been reported frequently. Nevertheless, the pelvic location of the cecum and the terminal ileum puts these anatomical segments at risk from the direct impact of radiation therapy. In the acute phase, this condition, is self-limiting and usually resolves with support measures. It is essential that the personnel involved in the management of these patients be aware of this entity and its possible differential diagnoses.

Merkel Cell Carcinoma and Diagnostic Experience in a Reference Hospital: A Case Series.

Merkel cell carcinoma (MCC) is a rare poorly differentiated neuroendocrine tumor, usually located in sun-exposed skin, with aggressive behavior and with high recurrence risk and metastatic disease. In Latin America, case series have been published, and it does not exceed 32 patients in 10 years, and in Colombia, there are case reports. We present a descriptive retrospective cross-sectional study in patients diagnosed with MCC in the Department of Pathology and Laboratories at the University Hospital Fundación Santa Fe de Bogotá(FSFB) between January 2003 and December 2018. We present the demographic, clinical, and pathological variables of these patients, as well as a literature review.

Accuracy and interobserver agreement of retroareolar frozen sections in nipple-sparing mastectomies.

In the last decades, surgical treatment of breast cancer has enormously changed. As a result, nipple-sparing mastectomy (NSM) has evolved as an oncologically safe and cosmetic approach. NSM includes a subareolar frozen section to evaluate malignancy. We determined the accuracy of subareolar frozen section diagnosis, analyzed the discrepancy factor, and estimated the interobserver agreement of frozen section in NSM. A retrospective review of all NSMs at our institution from 2009 to 2015 was performed. Frozen sections were compared to the final diagnoses to analyze the accuracy of subareolar frozen sections. Discordant results were rigorously evaluated to identify discrepancy factors. Some cases were randomly chosen to assess the interobserver agreement (kappa) among pathologists. The agreement results were evaluated with and without knowledge of the tumor morphology. Among 34 NSMs, the frozen section false-negative and false-positive rate was 5.9% and 8.8%, respectively. The sensitivity and specificity was 77.8% and 88.0%, respectively. Sampling errors and diathermy artifacts explained our false-negative diagnoses. Freezing artifacts and an intraductal papilloma explained our false-positive diagnoses. The interobserver agreement between breast and general pathologists was 0.87 (p<0.0001) and 0.31 (p=0.0001), respectively. The interobserver agreement increased to 0.35 (p<0.0001) in general pathologists with knowledge of the tumor morphology. Subareolar frozen section showed to be a specific test with moderate sensitivity. Papillary lesions can mimic atypical cells and influence the frozen section interpretation. Frozen section in NSM had a better performance in breast pathologists (almost perfect) versus general pathologists (fair). Interobserver agreement may improve with knowledge of tumor morphology.

Endometriosis mimicking glandular atypia in a cervical cytology.

Endometriosis involving the uterine cervix is a rare condition that can lead to diagnostic errors in the interpretation of Pap smear. We report the case of a 41-year-old patient in whom the initial Pap smear revealed three-dimensional clusters of glandular cells with elongated nuclei, occasional mitosis, and atypia, which was interpreted as atypical glandular cells, not otherwise specified (NOS). The patient was taken to colposcopy and endocervical biopsy. Colposcopy was normal and the biopsy presented glands with elongated nuclei and surrounded by endometrial stroma admixed with normal endocervical glands. Immunohistochemical studies were reactive for CD10 in the stromal cells and vimentin in endometrioid glands. The findings were consistent with cervical endometriosis. Endometriosis in the cervix is an uncommon pathology that mimics malignancy and may be interpreted as atypical or glandular neoplasia in the cytology.

Intraperitoneal Granulomas Unexpectedly Found during a Cesarean Delivery: A Late Complication of Dropped Gallstones.

Laparoscopic cholecystectomy is the treatment of choice for patients with symptomatic cholelithiasis. Spillage of gallstones into the abdominal cavity during laparoscopic cholecystectomy occurs in approximately one-third of cases. Although retained gallstones remain asymptomatic, few cases may develop complications. We report the case of a 29-year-old nulliparous woman presenting with several hard nodules in the omentum, raising the possibility of a metastatic disease. Histological examination demonstrated a bile-stained material and a foreign body-type granulomatous response without neoplastic tissue. Our case demonstrates an example of a complication resulting two years after a laparoscopic cholecystectomy that was unexpectedly found during a cesarean delivery. Pathologists should be aware of this entity to avoid interpretation errors.

Time-polarization multiplexing for increased output power of semiconductor optical amplifiers in the pulsed regime.

We present a setup capable of overcoming the saturation output power of semiconductor optical amplifiers operating in the pulsed regime. The concept is to couple different time delays to orthogonal polarization modes, amplify the pulses multiplexed in time, and use the polarization information to recombine them into a single high-power optical pulse. Making use of a single amplifier and two polarizing beam splitters, we were able to amplify pulses with as much as 1.9 dB above the saturation output power of the device. We also show that the method is scalable if any number of polarizing beam splitters is available, where each extra device contributes roughly 1.9 dB to the overall above-saturation amplification factor.

Optical path length and trajectory stability in rotationally asymmetric multipass cells.

We describe the behavior of optical trajectories in multipass rotationally asymmetric cavities (RACs) using a phase-space motivated approach. Emphasis is placed on generating long optical paths. A trajectory with an optical path length of 18 m is generated within a 68 cm3 volume. This path length to volume ratio (26.6 cm-2) is large compared to current state of the art multipass cells such as the cylindrical multipass cell (6.6 cm-2) and astigmatic Herriott cell (9 cm-2). Additionally, the effect of small changes to the input conditions on the path length is studied and compared to the astigmatic Herriott cell. This work simplifies the process of designing RACs with long optical path lengths and could lead to broader implementation of these multipass cells.

Unusual morphology of desmoplastic small round cell tumor from an ascitic fluid in the postchemotherapy setting.

Desmoplastic small round cell tumor (DSRCT) is a malignant neoplasm that most often presents in male adolescents as an abdominal mass. Cytological features have been previously described, but only two reports noted post chemotherapy changes on effusions. We report a case of a 15-year-old male with DSRCT status postchemotherapy that presented with ascitis. Unusual morphology was seen: Numerous malignant large and single cells with prominent nucleoli and abundant cytoplasm in a background without the stroma, occasional mitosis, and the abundant apoptosis. Cell block immunocytochemistry was confirmatory. Awareness of the postchemotherapy changes in this tumor will allow us to diagnose recurrence.

Hepatocellular carcinoma with both fibrolamellar and classical components: an unusual morphological pattern.

Fibrolamellar carcinoma (FLC) is an uncommon form of primary liver malignancy with unique clinical, histological, and biological characteristics. It is usually seen in young adults without underlying liver disease. Histologically, it shows large cells with abundant eosinophilic cytoplasm, large vesicular nuclei, prominent nucleoli, and lamellar type fibrosis. In contrast, classical hepatocellular carcinoma (HCC) is typically present in elderly male patients with cirrhosis. It is the most common histological subtype, and it is characterized by its resemblance to the normal liver, both in its growth pattern and its cytology. The unusual case of a liver carcinoma that presented with histological features of both FLC and classical HCC is herein reported. This was the case of a 37-year-old female complaining of diffuse abdominal discomfort and epigastric pain for two months. She was referred to us for further management after she was diagnosed with HCC in a noncirrhotic liver. She underwent a left-sided hepatectomy. A yellow nodular mass with well-defined borders and a necrotic center was present in the resection specimen. The morphological features and immunohistochemical studies were consistent with a diagnosis of FLC mixed with classical HCC. The patient was followed up for five months, and no signs of recurrence were evident.

Necrotizing encephalitis caused by disseminated Aspergillus infection after orthotopic liver transplantation.

Liver transplantation is the only available treatment for some patients with end-stage liver disease. Despite reduction in mortality rates due to advances related to surgical techniques, intensive medical management and immunosuppressive therapy, invasive fungal infections remain a serious complication in orthotopic liver transplantation. We report the case of an 18-year-old male diagnosed with autoimmune cirrhosis in 2009 who was assessed and listed for liver transplantation for massive variceal hemorrhage. One year after listing a successful orthotopic liver transplantation was performed. Uneventful early recovery was achieved; however, he developed pulmonary and neurological Aspergillus infection 23 and 40 days after surgery, respectively. Antibiotic therapy with voriconazole and amphotericin was started early, with no major response. Neuroimaging revealed multiple right frontal and right parietal lesions with perilesional edema; surgical management of the brain abscesses was performed. A biopsy with periodic acid-Schiff and Gomori stains revealed areas with mycotic microorganisms morphologically consistent with Aspergillus, later confirmed by culture. The patient developed necrotizing encephalitis secondary to aspergillosis and died. Necrotizing encephalitis as a clinical presentation of Aspergillus infection in an orthotopic liver transplant is not common, and even with adequate management, early diagnosis and prompt antifungal treatment, mortality rates remain high.

Human immunodeficiency virus-infected subjects have no altered myocardial perfusion.

We assessed myocardial perfusion (blinded interpretation of a single-photon emission computed tomography) and known risk factors for atherosclerosis in 105 randomly selected human immunodeficiency virus (HIV)-infected patients in a clinic in Mexico City and in a community sample of 105 age and gender-matched infection-free subjects. An abnormal scan was obtained in 4.8% of the infected and in 7.6% of the non-infected subjects. Severity of scintigraphic abnormalities was similar in both groups. In these Mexican HIV-infected patients, despite a long time of infection and of exposure to combined antiretroviral therapy and to other classical risk factors for atherosclerosis, there was no evidence of increased risk for abnormal myocardial perfusion. Dissimilar magnitude in the hazard of coronary heart disease may occur among infected populations with different frequencies of traditional predisposing factors for cardiovascular illness.

Analgesia pedidural post-cesarea / Post-cesarea septions peridural analgesia

Se estudiaron 50 pacientes sometidas a cesárea electiva o de emergencia bajo anestesia peridural en el Hospital Universitario de Caracas; divididas en cinco grupos de diez pacientes cada uno, administrándose por vía epidural, uno de los siguientes fármacos para analgesia post-operatoria: ketamina: 30 mgs, bupivacaína: 25 mgs, fantanyl: 150 mcg, meperidina: 50 mgs y morfina: 4 mgs.Se evaluó intensidad del dolor inicio de la analgesia, duración del efecto, cambios de tensión arterial, frecuencia cardíaca, frecuencia respiratoria y complicaciones con cada uno de los diferentes fármacos. Los resultados confirman las ventajas de la analgesia epidural post-operatoria