Bioactive Triterpenes from the Root of Salvia miltiorrhiza Bunge

Danshen (Salvia miltiorrhiza) is a well‐known medicinal herb in the oriental medicine. The current study on bioactive triterpenoid in the root of S. miltiorrhiza led to the isolation of a new highly hydroxylated ursane‐type triterpene, urs‐12‐ene‐2α,3β,7β,16α‐tetraol (1) and five known ones including 2β‐hydroxypomolic acid (2), maslinic acid (3), asiatic acid (4), ursolic acid (5), and oleanolic acid (6). Their structures were elucidated on the basis of extensive spectroscopic analyses and comparison with literature data. The antiproliferative testing against HL‐60 cells revealed that the new compound 1 and ursolic acid (5) showed weak and moderate activities with IC₅₀ values of 42.2 and 11.7 μM. In addition, compounds 1–3 showed inhibitory effect on ghrelin activity. Copyright © 2017 John Wiley & Sons, Ltd.     

GFAP-expressing progenitors are the principal source of constitutive neurogenesis in adult mouse forebrain

Establishing the cellular identity in vivo of adult multipotent neural progenitors is fundamental to understanding their biology. We used two transgenic strategies to determine the relative contribution of glial fibrillary acidic protein (GFAP)-expressing progenitors to constitutive neurogenesis in the adult forebrain. Transgenically targeted ablation of dividing GFAP-expressing cells in the adult mouse subependymal and subgranular zones stopped the generation of immunohistochemically identified neuroblasts and new neurons in the olfactory bulb and the hippocampal dentate gyrus. Transgenically targeted cell fate mapping showed that essentially all neuroblasts and neurons newly generated in the adult mouse forebrain in vivo, and in adult multipotent neurospheres in vitro, derived from progenitors that expressed GFAP. Constitutively dividing GFAP-expressing progenitors showed predominantly bipolar or unipolar morphologies with significantly fewer processes than non-neurogenic multipolar astrocytes. These findings identify morphologically distinctive GFAP-expressing progenitor cells as the predominant sources of constitutive adult neurogenesis, and provide new methods for manipulating and investigating these cells.     

Sensitivity to simulated directional sound motion in the rat primary auditory cortex.

Sensitivity to simulated directional sound motion in the rat primary auditory cortex. This paper examines neuron responses in rat primary auditory cortex (AI) during sound stimulation of the two ears designed to simulate sound motion in the horizontal plane. The simulated sound motion was synthesized from mathematical equations that generated dynamic changes in interaural phase, intensity, and Doppler shifts at the two ears. The simulated sounds were based on moving sources in the right frontal horizontal quadrant. Stimuli consisted of three circumferential segments between 0 and 30 degrees, 30 and 60 degrees, and 60 and 90 degrees and four radial segments at 0, 30, 60, and 90 degrees. The constant velocity portion of each segment was 0.84 m long. The circumferential segments and center of the radial segments were calculated to simulate a distance of 2 m from the head. Each segment had two trajectories that simulated motion in both directions, and each trajectory was presented at two velocities. Young adult rats were anesthetized, the left primary auditory cortex was exposed, and microelectrode recordings were obtained from sound responsive cells in AI. All testing took place at a tonal frequency that most closely approximated the best frequency of the unit at a level 20 dB above the tuning curve threshold. The results were presented on polar plots that emphasized the two directions of simulated motion for each segment rather than the location of sound in space. The trajectory exhibiting a "maximum motion response" could be identified from these plots. "Neuron discharge profiles" within these trajectories were used to demonstrate neuron activity for the two motion directions. Cells were identified that clearly responded to simulated uni- or multidirectional sound motion (39%), that were sensitive to sound location only (19%), or that were sound driven but insensitive to our location or sound motion stimuli (42%). The results demonstrated the capacity of neurons in rat auditory cortex to selectively process dynamic stimulus conditions representing simulated motion on the horizontal plane. Our data further show that some cells were responsive to location along the horizontal plane but not sensitive to motion. Cells sensitive to motion, however, also responded best to the moving sound at a particular location within the trajectory. It would seem that the mechanisms underlying sensitivity to sound location as well as direction of motion converge on the same cell.     

Implementation of a novel population panel management curriculum among interprofessional health care trainees

Background

Gaps in chronic disease management have led to calls for novel methods of interprofessional, team-based care. Population panel management (PPM), the process of continuous quality improvement across groups of patients, is rarely included in health professions training for physicians, nurses, or pharmacists. The feasibility and acceptance of such training across different healthcare professions is unknown. We developed and implemented a novel, interprofessional PPM curriculum targeted to diverse health professions trainees.

Methods

The curriculum was implemented annually among internal medicine residents, nurse practitioner students and residents, and pharmacy residents co-located in a large, academic primary care site. Small groups of interprofessional trainees participated in supervised quarterly seminars focusing on chronic disease management (e.g., diabetes mellitus, hypertension, or chronic obstructive pulmonary disease) or processes of care (e.g., emergency department utilization for nonacute conditions or chronic opioid management). Following brief didactic presentations, trainees self-assessed their clinic performance using patient-level chart review, presented individual cases to interprofessional staff and faculty, and implemented subsequent feedback with their clinic team. We report data from 2011 to 2015. Program evaluation included post-session participant surveys regarding attitudes, knowledge and confidence towards PPM, ability to identify patients for referral to interprofessional team members, and major learning points from the session. Directed content analysis was performed on an open-ended survey question.

Results

Trainees (n?=?168) completed 122 evaluation assessments. Trainees overwhelmingly reported increased confidence in using PPM and increased knowledge about managing their patient panel. Trainees reported improved ability to identify patients who would benefit from multidisciplinary care or referral to another team member. Directed content analysis revealed that trainees viewed team members as important system resources (n?=?82).

Conclusions

Structured interprofessional training in PPM is both feasible and acceptable to trainees across multiple professions. Curriculum participants reported improved panel management skills, increased confidence in using PPM, and increased confidence in identifying candidates for interprofessional care. The curriculum could be readily exported to other programs and contexts.

     

The preterm gut microbiota: changes associated with necrotizing enterocolitis and infection

Aim: To describe gut colonization in preterm infants using standard culture and 16S gene rRNA profiling, exploring differences in healthy infants and those who developed NEC/late onset sepsis (LOS). Methods: Ninety‐nine stools from 38 infants of median 27‐week gestation were cultured; 44 stools from 27 infants had their microbial profiles determined by 16S. Ordination analyses explored effects of patient variables on gut communities. Results: Standard microbiological culture identified a mean of two organisms (range 0–7), DGGE 12 (range 3–18) per patient. Enterococcus faecalis and coagulase negative staphylococci (CONS) were most common by culture (40% and 39% of specimens). Meconium was not sterile. No fungi were cultured. Bacterial community structures in infants with NEC and LOS differed from healthy infants. Infants who developed NEC carried more CONS (45% vs 30%) and less Enterococcus faecalis (31% vs 57%). 16S identified Enterobacter and Staphylococcus presence associated with NEC/LOS, respectively. Conclusions: Important differences were found in the gut microbiota of preterm infants who develop NEC/LOS. The relationship of these changes to current practices in neonatal intensive care requires further exploration.     

Divalent metal transporter 1 (DMT1) regulation by Ndfip1 prevents metal toxicity in human neurons

The regulation of metal ion transport within neurons is critical for normal brain function. Of particular importance is the regulation of redox metals such as iron (Fe), where excess levels can contribute to oxidative stress and protein aggregation, leading to neuronal death. The divalent metal transporter 1 (DMT1) plays a central role in the regulation of Fe as well as other metals; hence, failure of DMT1 regulation is linked to human brain pathology. However, it remains unclear how DMT1 is regulated in the brain. Here, we show that DMT1 is regulated by Ndfip1 (Nedd4 family-interacting protein 1), an adaptor protein that recruits E3 ligases to ubiquitinate target proteins. Using human neurons we show the Ndfip1 is upregulated and binds to DMT1 in response to Fe and cobalt (Co) exposure. This interaction results in the ubiquitination and degradation of DMT1, resulting in reduced metal entry. Induction of Ndfip1 expression protects neurons from metal toxicity, and removal of Ndfip1 by shRNAi results in hypersensitivity to metals. We identify Nedd4–2 as an E3 ligase recruited by Ndfip1 for the ubiquitination of DMT1 within human neurons. Comparison of brains from Ndfip1^−/− with Ndfip1^+/+ mice exposed to Fe reveals that Ndfip1^−/− brains accumulate Fe within neurons. Together, this evidence suggests a critical role for Ndfip1 in regulating metal transport in human neurons.     

Laryngeal papillomas: the epidemiology in a Danish subpopulation 1965–1984

The incidence rate of laryngeal papillomas in a Danish subpopulation (approximately 2.8 million inhabitants) was 3.84 × 10^-6 per year in the period 1968–1984. For juvenile papillomas the incidence rate was 3.62 × 10^-6, compared with 3.94 × 10^-6 for laryngeal papillomas of adult onset. When comparing different time periods a significantly low incidence was found in the time 1965–1968, while the incidence remained constant in 1969–1984. The low incidence rate in the early period may be real, but selectional bias may have played a part. It is in general anticipated that maternal genital HPV-infections may serve as an HPV-reservoir, and that juvenile laryngeal papilloma is a result of HPV transmission from the mother to the child during birth. In the period in question cervical HPV-infections have been recorded with increasing frequency in younger women, indicating that the prevalence is rising. However, this is not reflected in the incidence of laryngeal papillomas.     

Liver transplantation in tyrosinaemia type 1: the dilemma of timing the operation

Four children with tyrosinaemia type 1 received liver transplants. The metabolic disorder was corrected and all four had normal liver function on an unrestricted diet. Two children, transplanted at age five and seven years, proved to have occult hepatocellular carcinoma and both subsequently developed pulmonary metastases. One child was well 32 months after removal of a single pulmonary metastasis but the other child died with multiple metastases. The two younger children, transplanted at age 19 and 21 months, were well 28 and 44 months after operation, one after a second liver transplant. Our experience confirms the high risk of hepatocellular carcinoma in this disease and the potential value of early liver transplantation.     

Neurological crisis in hereditary tyrosinaemia and complete reversal after liver transplantation

A 19 month old Indian girl with tyrosinaemia developed a severe generalised neuropathy involving both phrenic nerves. Treatment with haemarginate failed to improve her condition. After liver transplantation the raised concentrations of the neurotoxin delta amino-laevulinic acid returned to normal and gradual but complete neurological recovery occurred over a period of 13 months.