Modulation of level response areas and stimulus selectivity of neurons in cat primary auditory cortex

Sounds commonly occur in sequences, such as in speech. It is therefore important to understand how the occurrence of one sound affects the response to a subsequent sound. We approached this question by determining how a conditioning stimulus alters the response areas of single neurons in the primary auditory cortex (AI) of barbiturate-anesthetized cats. The response areas consisted of responses to stimuli that varied in level at the two ears and delivered at the characteristic frequency of each cell. A binaural conditioning stimulus was then presented > or =50 ms before each of the stimuli comprising the level response area. An effective preceding stimulus alters the shape and severely reduces the size and response magnitude of the level response area. This ability of the preceding stimulus depends on its proximity in the level domain to the level response area, not on its absolute level or on the size of the response it evokes. Preceding stimuli evoke a nonlinear inhibition across the level response area that results in an increased selectivity of a cortical neuron for its preferred binaural stimuli. The selectivity of AI neurons during the processing of a stream of acoustic stimuli is likely to be restricted to a portion of their level response areas apparent in the tone-alone condition. Thus rather than being static, level response areas are fluid; they can vary greatly in extent, shape and response magnitude. The dynamic modulation of the level response area and level selectivity of AI neurons might be related to several tasks confronting the central auditory system.     

A functional three-dimensional microphysiological human model of myeloma bone disease

Human myeloma bone disease (MBD) occurs when malignant plasma cells migrate to the bone marrow and commence inimical interactions with stromal cells, disrupting the skeletal remodeling process. The myeloma cells simultaneously suppress osteoblastic bone formation while promoting excessive osteoclastic resorption. This bone metabolism imbalance produces osteolytic lesions that cause chronic bone pain and reduce trabecular and cortical bone structural integrity, and often culminate in pathological fractures. Few bone models exist that enable scientists to study MBD and the effect therapies have on restoring the bone metabolism imbalance. The purpose of this research was to develop a well characterized three-dimensional (3D) bone organoid that could be used to study MBD and current or potential treatment options. First, bone marrow stromal cell–derived osteoblasts (OBs) mineralized an endosteal-like extracellular matrix (ECM) over 21 days. Multiple analyses confirmed the generation of hydroxyapatite (HA)-rich bone-like tissue fragments that were abundant in alkaline phosphatase, calcium, and markers of osteoblastic gene expression. On day 22, bone marrow macrophage (BMM)–derived osteoclasts (OCs) were introduced to enhance the resorptive capability of the model and recapitulate the balanced homeostatic nature of skeletal remodeling. Tartrate-resistant acid phosphatase 5b (TRAcP-5b), type I collagen C-telopeptide (CTX-1), and gene expression analysis confirmed OC activity in the normal 3D organoid (3D in vitro model of normal bonelike fragments [3D-NBF]). On day 30, a human multiple myeloma (MM)–derived plasmacytoma cell line was introduced to the 3D-NBF to generate the 3D-myeloma bone disease organoid (3D-MBD). After 12 days, the 3D-MBD had significantly reduced total HA, increased TRAcP-5b levels, increases levels of CTX-1, and decreased expression of osteoblastic genes. Therapeutic intervention with pharmaceutical agents including an immunomodulatory drug, a bisphosphonate, and monoclonal restored HA content and reduced free CTX-1 in a dose-dependent manner. This osteogenically functional model of MBD provides a novel tool to study biological mechanisms guiding the disease and to screen potential therapeutics. © 2021 American Society for Bone and Mineral Research (ASBMR).     

Partial nephrectomy should be classified as an inpatient procedure: Results from a statewide quality improvement collaborative

ObjectivesTo examine length of stay (LOS) and readmission rates for all minimally-invasive partial nephrectomy (MIPN) and MI radical nephrectomy (MIRN) performed for localized renal masses ≤7 cm in size (cT1RM) within 12 Michigan urology practices. Both RN and PN are commonly performed in treating cT1RM. Although technically more complex and associated with higher complication rates, Centers for Medicare & Medicaid Services considers MIPN an outpatient procedure and MIRN is inpatient.MethodsWe collected data for renal surgeries for cT1RM at MUSIC-KIDNEY practices between May 2017–February 2020. Data abstractors recorded clinical, radiographic, pathologic, surgical, and short-term follow-up data into the registry for cT1RM patients.ResultsWithin MUSIC-KIDNEY, 807 patients underwent MI renal surgery at 12 practices. Median LOS for cT1RM patients after MIPN (n = 531, 66%) was 2 days and after MIRN (n = 276, 34%) was also 2 days. Among patients undergoing laparoscopic or robotic PN, 171 (32%), 230 (43%), and 130 (24%) stayed ≤1, 2, ≥3 days. Among patients undergoing laparoscopic or robotic RN, 81 (29%), 112 (41%), and 83 (30%) stayed ≤1, 2, ≥3 days. No significant difference was observed between MIPN and MIRN on LOS commensurate with outpatient surgery (≤1-day, OR = 0.97, P = 0.87).ConclusionsLess than one-third of patients had a LOS ≤1-day and LOS was comparable for MIPN and MIRN. Centers for Medicare & Medicaid Services should be advised that MIPN is a more complex surgery than MIRN, most patients receiving a MIPN will require a ≥2-day hospital stay and it would be more appropriate to classify MIPN an inpatient procedure with MIRN.     

Chromosome abnormalities clustering and its implications for pathogenesis and prognosis in myeloma.

The nonrandom recurrent nature of chromosome abnormalities in myeloma suggests a role for them in disease pathogenesis. We performed a careful cytogenetic analysis of patients with abnormal karyotypes (n = 254), to discern patterns of association, search for novel abnormalities and elucidate clinical implications. Patients with karyotypic abnormalities suggestive of myelodysplasia/acute leukemia were excluded. In this study we compared survival by abnormality only between patients with abnormal karyotypes. Patients with abnormalities were more likely to have features of aggressive disease as compared to all other patients without abnormalities entered into the myeloma database (lower hemoglobin, higher beta(2)-microglobulin, labeling-index and plasmocytosis; all P < 0.0001). Several groups of patients could be readily identified; hypodiploid (22%), pseudodiploid (36%), hyperdiploid (31%) and near-tetraploid (11%). Clustering associations were seen among several trisomies and monosomy of chromosome 13 and 14. Several monosomies (-2, -3, -13, -14 and -19), 1p translocations/ deletions, and hypodiploidy were associated with a significantly shorter survival. Trisomy of chromosome 13 was rare ( <2%). Even among patients with abnormal karyotypes, specific chromosome abnormalities can impart biologic variability in myeloma, including several monosomies, hypodiploidy and abnormalities of 1p.     

An indirect treatment comparison of the efficacy of patisiran and tafamidis for the treatment of hereditary transthyretin-mediated amyloidosis with polyneuropathy

Background: Hereditary transthyretin-mediated amyloidosis (hATTR amyloidosis) is a progressive, life-threatening disease. Until recently, tafamidis was the only approved pharmacotherapy. Patisiran significantly improved polyneuropathy and quality of life (QoL) in the phase III APOLLO trial. In the absence of direct comparisons, this analysis aimed to evaluate the comparative efficacy of tafamidis and patisiran in hATTR amyloidosis with polyneuropathy.

Research design and methods: Randomized controlled trial evidence for tafamidis was identified by systematic literature review. Indirect treatment comparisons were performed using the standard pairwise Bucher method for endpoints used in both APOLLO and the tafamidis Fx-005 trial: change from baseline in Neuropathy Impairment Score-lower limbs (NIS-LL), Norfolk QoL-Diabetic Neuropathy questionnaire (QoL-DN), NIS-LL response, and mBMI vs. placebo. Inter-trial population differences were assessed by sensitivity analysis.

Results: The base-case analysis (FAP Stage 1 APOLLO patients vs. intent-to-treat Fx-005 population) suggested patisiran had a greater treatment effect vs. tafamidis for all endpoints, with significant improvements in mean change in NIS-LL (–5.49) and QoL-DN (–13.10) from baseline to Month 18. Similar trends were observed in all sensitivity analyses.

Conclusions: In the absence of direct comparisons, this analysis suggests patisiran has a greater treatment effect than tafamidis in patients with hATTR amyloidosis with polyneuropathy.     

Focus group interviews: how aromatherapists feel about changing their practice through undertaking a randomised controlled trial?

In 2003/2007 a randomised controlled trial (RCT) was undertaken into the efficacy of aromatherapy in reducing levels of anxiety amongst palliative care patients. In the study patients were randomised into one of three treatment groups. The participating aromatherapists treated patients according to a strict research protocol. As the trial commenced, the therapists indicated a concern about a potential loss of their holistic principles while undertaking the trial. These genuine concerns formed the impetus to undertake a qualitative study to illuminate the aromatherapists' experience of changing their practice. Findings and discussions are through the themes that emerged. It appears that participating in a RCT does impact on aromatherapists' holistic practice but equally important is their commitment to undertake the research.     

Elevated L-lactate Promotes Major Cellular Pathologies Associated with Neurodegenerative Diseases

Dear Editor,Small,short-chain fatty acids(SCFAs)(acetic acid,propionic acid,and butyric acid:conjugate bases,acetate,propionate,and butyrate)as well as the alpha-hydroxy acid,L-lactic acid(conjugate base,L-lactate)are important energy substrates and signaling molecules in the central nervous system(CNS)[1,2].L-lactic acid is produced by glycolysis[3]and gut microbes[4]and is released in large quantities during exercise[5].