Valproic Acid Limits Pancreatic Recovery after Pancreatitis by Inhibiting Histone Deacetylases and Preventing Acinar Redifferentiation Programs.

The mechanisms by which drugs induce pancreatitis are unknown. A definite cause of pancreatitis is due to the antiepileptic drug valproic acid (VPA). On the basis of three crucial observations-that VPA inhibits histone deacetylases (HDACs), HDACs mediate pancreas development, and aspects of pancreas development are recapitulated during recovery of the pancreas after injury-we hypothesized that VPA does not cause injury on its own, but it predisposes patients to pancreatitis by inhibiting HDACs and provoking an imbalance in pancreatic recovery. In an experimental model of pancreatic injury, we found that VPA delayed recovery of the pancreas and reduced acinar cell proliferation. In addition, pancreatic expression of class I HDACs (which are the primary VPA targets) increased in the midphase of pancreatic recovery. VPA administration inhibited pancreatic HDAC activity and led to the persistence of acinar-to-ductal metaplastic complexes, with prolonged Sox9 expression and sustained ß-catenin nuclear activation, findings that characterize a delay in regenerative reprogramming. These effects were not observed with valpromide, an analog of VPA that lacks HDAC inhibition. This is the first report, to our knowledge, that VPA shifts the balance toward pancreatic injury and pancreatitis through HDAC inhibition. The work also identifies a new paradigm for therapies that could exploit epigenetic reprogramming to enhance pancreatic recovery and disorders of pancreatic injury.

Pediatric Laryngeal Coccidioidomycosis: A Case Series in an Endemic Region.

BACKGROUND: Laryngeal coccidioidomycosis is a rare but life-threatening manifestation of coccidioidomycosis. Data in children are sparse and limited to case reports. We conducted this study to review the characteristics of laryngeal coccidioidomycosis in children. METHODS: We performed a retrospective review of patients ≤21 years of age with laryngeal coccidioidomycosis who were treated from January 2010 to December 2017. We collected demographic data, clinical and laboratory studies and patient outcomes. RESULTS: Five cases of pediatric laryngeal coccidioidomycosis were reviewed. All children were Hispanic and 3 were female. The median age was 1.8 years and the median duration of symptoms before diagnosis was 24 days. The most common symptoms included fever (100%), stridor (60%), cough (100%) and vocal changes (40%). Airway obstruction requiring tracheostomy and/or intubation for airway management was present in 80%. The most frequent location of lesions was the subglottic area. Coccidioidomycosis complement fixation titers were frequently low and culture/histopathology of laryngeal tissue was necessary to make a definitive diagnosis. All patients required surgical debridement and were treated with antifungal agents. None of the patients had recurrence during the follow-up period. CONCLUSIONS: This study suggests that laryngeal coccidioidomycosis in children presents with refractory stridor or dysphonia and severe airway obstruction. Favorable outcomes can be achieved with a comprehensive diagnostic work-up and aggressive surgical and medical management. With the rise in cases of coccidioidomycosis, physicians should have a heightened awareness regarding the possibility of laryngeal coccidioidomycosis when encountering children who have visited or reside in endemic areas with stridor or dysphonia.

Medulloepithelioma with peculiar clinical presentation, stem cell phenotype and aberrant DNA-methylation profile.

We present a 21-year-old male with a neck mass diagnosed as medulloepithelioma. Despite aggressive chemo- and radio-therapy, the tumor metastasized and proved fatal after seventeen months. The tumor demonstrated robust immunohistochemical expression of multiple markers of embryonic/neural stem cells and embryogenesis from the paraffin embedded tissue. The tumor, expressing LIN28A but negative for the 19q13.42 amplicon, also lacked the characteristic methylation profile for medulloepithelioma and other tumors with similar morphology. The expression of embryonic markers may explain its unresponsiveness to therapy and poor prognosis. Therapies targeted at embryonic cell phenotypes may hold the key for successfully treating cancers with embryonal phenotypes or tumors harboring cells with embryonal phenotypes.

Polypharmacy, age, and scheduled surgery.

STUDY OBJECTIVE: To test the hypothesis that there is a correlation between the age of patients who present for scheduled surgery and the number of drugs taken by these patients. DESIGN: Prospective clinical study. SETTING: Outpatient admissions. PATIENTS: 150 ASA physical status I, II, and III patients 40 years of age or older, scheduled for outpatient surgery. INTERVENTIONS: None. MEASUREMENTS: Age, medical history, and prescription and nonprescription medications of these patients were recorded. MAIN RESULTS: There was no significant difference among number of drugs taken by patients in different age groups [40 to 49 years: 3.2 +/- 3.1 (average number of drugs taken, standard deviation); 50 to 59 years: 3.6 +/- 3.1; 60 to 69 years: 4.0 +/- 2.9; 70 to 79 years: 4.4 +/- 2.7; 80+ years: 3.7 +/- 2.2]. CONCLUSIONS: Medical condition, which may, in part, be a function of biological age and not chronological age, is the primary determinant of the number of medications taken by patients presenting to an outpatient clinic for scheduled surgery.

A computer-based automated algorithm for assessing acinar cell loss after experimental pancreatitis.

The change in exocrine mass is an important parameter to follow in experimental models of pancreatic injury and regeneration. However, at present, the quantitative assessment of exocrine content by histology is tedious and operator-dependent, requiring manual assessment of acinar area on serial pancreatic sections. In this study, we utilized a novel computer-generated learning algorithm to construct an accurate and rapid method of quantifying acinar content. The algorithm works by learning differences in pixel characteristics from input examples provided by human experts. HE-stained pancreatic sections were obtained in mice recovering from a 2-day, hourly caerulein hyperstimulation model of experimental pancreatitis. For training data, a pathologist carefully outlined discrete regions of acinar and non-acinar tissue in 21 sections at various stages of pancreatic injury and recovery (termed the "ground truth"). After the expert defined the ground truth, the computer was able to develop a prediction rule that was then applied to a unique set of high-resolution images in order to validate the process. For baseline, non-injured pancreatic sections, the software demonstrated close agreement with the ground truth in identifying baseline acinar tissue area with only a difference of 1% ± 0.05% (p = 0.21). Within regions of injured tissue, the software reported a difference of 2.5% ± 0.04% in acinar area compared with the pathologist (p = 0.47). Surprisingly, on detailed morphological examination, the discrepancy was primarily because the software outlined acini and excluded inter-acinar and luminal white space with greater precision. The findings suggest that the software will be of great potential benefit to both clinicians and researchers in quantifying pancreatic acinar cell flux in the injured and recovering pancreas.