Serotonin 3A Receptor Subtype as an Early and Protracted Marker of Cortical Interneuron Subpopulations

To identify neocortical neurons expressing the type 3 serotonergic receptor, here we used transgenic mice expressing the enhanced green fluorescent protein (GFP) under the control of the 5-HT3A promoter (5-HT3A:GFP mice). By means of whole-cell patch-clamp recordings, biocytin labeling, and single-cell reversed-transcriptase polymerase chain reaction on acute brain slices of 5-HT3A:GFP mice, we identified 2 populations of 5-HT3A-expressing interneurons within the somatosensory cortex. The first population was characterized by the frequent expression of the vasoactive intestinal peptide and a typical bipolar/bitufted morphology, whereas the second population expressed predominantly the neuropeptide Y and exhibited more complex dendritic arborizations. Most interneurons of this second group appeared very similar to neurogliaform cells according to their electrophysiological, molecular, and morphological properties. The combination of 5-bromo-2-deoxyuridine injections with 5-HT3A mRNA detection showed that cortical 5-HT3A interneurons are generated around embryonic day 14.5. Although at this stage the 5-HT3A receptor subunit is expressed in both the caudal ganglionic eminence and the entopeduncular area, homochronic in utero grafts experiments revealed that cortical 5-HT3A interneurons are mainly generated in the caudal ganglionic eminence. This protracted expression of the 5-HT3A subunit allowed us to study specific cortical interneuron populations from their birth to their final functional phenotype

Recurrent loss of heterozygosity correlates with clinical outcome in pancreatic neuroendocrine cancer

Pancreatic neuroendocrine tumors (pNETs) are uncommon cancers arising from pancreatic islet cells. Here we report the analysis of gene mutation, copy number, and RNA expression of 57 sporadic well-differentiated pNETs. pNET genomes are dominated by aneuploidy, leading to concordant changes in RNA expression at the level of whole chromosomes and chromosome segments. We observed two distinct patterns of somatic pNET aneuploidy that are associated with tumor pathology and patient prognosis. Approximately 26% of the patients in this series had pNETs with genomes characterized by recurrent loss of heterozygosity (LoH) of 10 specific chromosomes, accompanied by bi-allelic MEN1 inactivation and generally poor clinical outcome. Another ~40% of patients had pNETs that lacked this recurrent LoH pattern but had chromosome 11 LoH, bi-allelic MEN1 inactivation, and universally good clinical outcome. The somatic aneuploidy allowed pathogenic germline variants (e.g., ATM) to be expressed unopposed, with RNA expression patterns showing inactivation of downstream tumor suppressor pathways. No prognostic associations were found with tumor morphology, single gene mutation, or expression of RNAs reflecting the activity of immune, differentiation, proliferative or tumor suppressor pathways. In pNETs, single gene mutations appear to be less important than aneuploidy, with MEN1 the only statistically significant recurrently mutated driver gene. In addition, only one pNET in the series had clearly actionable single nucleotide variants (SNVs) (in PTEN and FLCN) confirmed by corroborating RNA expression changes. The two clinically relevant patterns of LoH described here define a novel oncogenic mechanism and a plausible route to genomic precision oncology for this tumor type.fals

Essential Components of Melanoma Histopathological Reporting: The Surgical Oncologist’s Perspective

Histopathological reporting plays a critical role in guiding the surgical oncologist’s management plan in treatment of primary cutaneous melanoma. The International Collaboration on Cancer Reporting (ICCR) espouses various components of structured histopathological reporting as “essential” or “recommended.” From a surgical oncologist’s perspective, we discuss the clinical relevance of each essential component, as well as prognostic and treatment implications with regard to treatment planning

Essential Components of Melanoma Histopathological Reporting: The Surgical Oncologist’s Perspective

Histopathological reporting plays a critical role in guiding the surgical oncologist’s management plan in treatment of primary cutaneous melanoma. The International Collaboration on Cancer Reporting (ICCR) espouses various components of structured histopathological reporting as “essential” or “recommended.” From a surgical oncologist’s perspective, we discuss the clinical relevance of each essential component, as well as prognostic and treatment implications with regard to treatment planning

Efficacy of a trunk orthosis with joints providing resistive force on low back load during level walking in elderly persons

Junji Katsuhira,1,2 Ko Matsudaira,2 Hiroyuki Oka,2 Shinno Iijima,3 Akihiro Ito,3 Tadashi Yasui,4 Arito Yozu5 1Faculty of Medical Technology, Department of Prosthetics and Orthotics and Assistive Technology, Niigata University of Health and Welfare, Niigata, 2Department of Medical Research and Management for Musculoskeletal Pain, 22nd Century Medical and Research Center, The University of Tokyo, Tokyo, 3International University of Health and Welfare Hospital, Tochigi, 4Kawamura-Gishi Company, Ltd., Osaka, 5Department of Rehabilitation Medicine, The University of Tokyo Hospital, Tokyo, Japan Purpose: The effects of lumbosacral and spinal orthoses on low back pain and gait are not exactly clear. We previously developed a trunk orthosis with joints providing resistive force on low back load to decrease such load, and confirmed its positive effects during level walking in healthy young adults. Therefore, we aimed to determine the efficacy of this trunk orthosis during level walking in healthy elderly subjects.Methods: Fifteen community-dwelling elderly subjects performed level walking at a self-selected speed without an orthosis, with our orthosis, and with a lumbosacral orthosis. Kinematic and kinetic data were recorded using a three-dimensional motion analysis system, and erector spinae activity was recorded by electromyography.Results: When comparing the three conditions, our orthosis showed the following effects: it decreased the peak extension moment, increased the peak flexion moment, decreased the lateral bending angle, increased the peak thoracic extension angle, and had significantly lower erector spinae activity and significantly larger peak pelvic forward tilt angles.Conclusion: Our orthosis with joints providing resistive force decreased low back load and modified trunk and pelvis alignments during level walking in healthy elderly people. Keywords: biomechanics, orthosis, gait, low back pain, joint moment, motion analysi

Can early aortic root surgery prevent further aortic dissection in Marfan syndrome?

We reviewed 50 patients with Marfan syndrome who underwent surgery for aortic root pathologies comprising a root aneurysm without (n = 25; group A) and with (n = 25; group B) dissection. Aortic root repair included Bentall (n = 37) and valve-sparing (n = 13) procedures. Hospital mortality was 4.0%. Twenty-two patients required 36 repeat surgeries on the distal aorta. The main indication for re-intervention was the dilation of the false lumen. In group A, the distal aorta was stable for up to 7 years, but new dissection developed in 5 (33.3%) of the 15 patients who were followed up for >7 years after the root repair. Actuarial survival including operative mortality was 88.1 and 65.0% at 10 and 20 years, respectively; groups A and B did not significantly differ. Rates of freedom from all-cause death, new dissection or repeated aortic surgery were 60.1, 44.5 and 26.0% at 5, 10 and 15 years, respectively. Group A was significantly better than group B. Prophylactic aortic root repair apparently reduces the likelihood of overall adverse events, but it cannot guarantee the prevention of further aortic dissection. A multidisciplinary approach is needed for patients with Marfan syndrome