Effects of voluntary exercise on synaptic plasticity and gene expression in the dentate gyrus of adult male Sprague-Dawley rats in vivo

We have previously shown that voluntary exercise produces enhanced neurogenesis and long-term potentiation (LTP) in the dentate gyrus (DG) of mice in vitro. In the present experiments we show that rats given access to a running wheel (Runners) exhibit significantly more short-term potentiation and LTP with theta-patterned conditioning stimulation in vivo than do age-matched litter mates (Controls). This increase in LTP appears to reflect an alteration in the induction threshold for synaptic plasticity that accompanies voluntary exercise. Weak theta-patterned stimulation, which did not produce LTP in control subjects, produced a robust and long-lasting LTP in Runners. LTP induction in both groups was dependent upon the activation of N-methyl-D-aspartate (NMDA) receptors, and could be blocked by the competitive antagonist [+/-]-3-[2-carboxypiperazin-4-yl] propanephosphonic acid. Consistent with these findings, we found that mRNA levels for NR2B subtype of NMDA receptor were increased specifically in the DG of Runners. In addition to changes in NR2B mRNA levels, quantitative polymerase chain reaction analysis revealed that brain-derived neurotrophic factor (BDNF) and glutamate receptor 5 mRNA levels were also significantly elevated in the DG of Runners, but not in other areas of the hippocampus. Thus, alterations in the expression of BDNF, and specific glutamate receptor subtypes, may underlie the ability of exercise to enhance neurogenesis and reduce the threshold for LTP in the DG.     

Chaperonin-mediated assembly of wild-type and mutant subunits of human propionyl-CoA carboxylase expressed in Escherichia coli

We developed a bacterial expression system for the human alpha and beta cDNAs of propionyl-CoA carboxylase (PCC). These cDNAs (less the putative mitochondrial matrix targeting presequences) were co-expressed in Escherichia coli on one plasmid vector with each cDNA having its own IPTG-inducible promoter. Only negligible amounts of active PCC were measured despite the presence of both alpha and beta subunits as indicated by Western blot analysis and the almost complete biotinylation of the alpha subunit. Co-expression of this plasmid with a second plasmid vector over-expressing the E. coli chaperonin proteins, groES and groEL, resulted in a several hundred-fold increase in PCC specific activity, to a level comparable with that found in crude human liver extracts. PCC was partially purified on monomeric avidin affinity resin and the presence of both alpha and beta subunits was demonstrated, thereby confirming the assembly of both subunits into an active enzyme. Deficiency of either alpha PCC or beta PCC results in propionic acidemia, an autosomal recessive disorder. We used this expression system to characterize one missense mutation previously described in five Japanese alleles, namely C1283T (Thr428lle) in beta PCC. This mutation, when expressed in E.coli under the same conditions as that of wild-type PCC, had null activity, despite the presence of assembled alpha PCC and beta PCC subunits. This bacterial expression system can be useful for analysis of either alpha PCC or beta PCC mutations. Our findings indicated that the groES and groEL chaperonin proteins were essential for folding and assembly of the human PCC heteromeric subunits.      

Changing acute renal failure treatment from intermittent hemodialysis to continuous hemofiltration: impact on azotemic control.

BACKGROUND: Continuous renal replacement therapy is increasingly used in the management of acute renal failure in critically ill patients. The advantages of continuous renal replacement therapy (CRRT) over intermittent hemodialysis (IHD), however, are not yet fully documented. In particular, it is unknown whether continuous veno-venous hemodiafiltration (CVVHDF) provides better control of azotemia than IHD. OBJECTIVES: To study the effect on azotemic control of changing acute renal failure treatment from IHD to CVVHDF. SETTINGS: Tertiary intensive care unit. PATIENTS: Forty seven consecutive critically ill patients with multiorgan failure and acute renal failure treated with IHD and 47 similar patients treated with CVVHDF. METHODS: Analysis of daily morning urea and creatinine concentrations over the period of renal replacement therapy in the ICU. Statistical comparison of data. RESULTS: The two groups of patients were comparable for mean age (55 years for IHD vs. 60 years for CVVHDF; NS) and number of failing organs prior to therapy (mean of 4.2 for IHD vs. 3.7 for CVVHDF; NS). Severity of illness at admission as assessed by APACHE II score, however, was greater for patients receiving CVVHDF (29.4 vs 25.7; p<0.003). CVVHDF was associated with a significantly lower plasma urea (p < 0.0001) and serum creatinine (p < 0.01) level at 24 hours of treatment despite similar levels at the start of therapy Throughout the duration of therapy, mean urea levels (35.0 mmol/L for IHD vs 23.4 mmol/L for CVVHDF) and mean serum creatinine levels (513 micromoles/L for IHD and 263 micromoles/L for CVVHDF) showed significantly (p <0.0001) better control of uremia with CRRT. CONCLUSIONS: Changing the form of renal replacement therapy from intermittent hemodialysis to continuous hemofiltration is associated with improved control of azotemia. The superior adequacy of small solute clearance achieved during CVVHDF provides additional support for its preferential use in the management of acute renal failure in the ICU.     

Anionic Synthesis of Epoxy End‐Capped Polymers

The reaction of living anions of polystyrene (PS) or poly(methyl methacrylate) (PMMA) with epibromohydrin for the synthesis of well‐defined epoxy end‐functionalized polymers is reported. Polyanions were reacted with an excess of epibromohydrin in tetrahydrofuran (THF) at ?78 °C. The functionalities of the resulting polymers were analyzed by matrix‐assisted laser desorption ionization time‐of‐flight mass spectrometry (MALDI‐TOF MS), NMR, and size exclusion chromatography (SEC). The epoxy end groups were reacted with 1,1‐diphenyl‐ hexyllithium, and MALDI‐TOF MS and NMR before and after this chemical modification were used to determine the presence of the epoxy end groups. The presence of the epoxy end group was confirmed by anionically polymerizing ethylene oxide from these epoxy end group. The formation of a block copolymer due to the epoxy end groups was proved by SEC analysis. The combined MALDI‐TOF MS, ¹H NMR, and SEC results indicate that epoxy end‐capped PS was obtained in quantitative yield. The method was extended to the synthesis of epoxy end‐capped PMMA. With this polymer the extent of end‐functionalization was high but not quantitative, with non‐dimeric byproducts detected by MALDI‐TOF MS.

     

Developmental profile of slow hand movement oscillation coupling in humans

In adults, slow hand and finger movements are characterized by 6- to 12-Hz discontinuities visible in the raw records and spectra of motion signals such as acceleration. This pulsitile behavior is correlated with motor unit synchronization at 6-12 Hz as shown by significant coherence at these frequencies between pairs of motor units and between the motor units and the acceleration recorded from the limb part controlled by the muscle, suggesting that it has a central origin. In this study, we examined the correlation between this 6- to 12-Hz pulsatile behavior and muscle activity as a function of childhood development. Sixty-eight participants (ages 4-25 yr) performed static wrist extensions against gravity or slow wrist extension and flexion movements while extensor carpi radialis muscle electromyographic (EMG) and wrist acceleration signals were simultaneously recorded. Coherence between EMG and acceleration within the 6- to 12-Hz frequency band was used as an index of the strength of the relation between central drive and the motor output. The main findings of the study are 1) EMG-acceleration coherence increased with increases in age, with the age differences being greater under movement conditions and the difference between conditions increasing with age; 2) the EMG signal showed increases in normalized power with increases in age under both conditions; and 3) coherence under movement conditions was moderately positively correlated with manual dexterity. These findings indicate that the strength of the 6- to 12-Hz central oscillatory drive to the motor output increases through childhood development and may contribute to age-related improvements in motor skills.     

Communicating non-steroidal anti-inflammatory drug risks: verbal counseling, written medicine information, and patients' risk awareness

Objective

To assess potential associations among physician counseling, pharmacist counseling, written medicine information (WMI) and patient awareness of non-steroidal anti-inflammatory drug (NSAID) risks.

Methods

Three-hundred and eighty-two older, white and African American patients prescribed NSAIDs were surveyed regarding their NSAID risk awareness defined as an index score ranging from zero to four correctly identified risks (i.e., gastrointestinal bleeding, heart attack, hypertension, and kidney disease). Associations among NSAID risk awareness and patient-reported physician counseling, pharmacist counseling, and reading of WMI were evaluated in multivariable ordered logistic regression models and confirmed using path analysis.

Results

Physician counseling was positively associated with reading WMI (p < 0.001) and NSAID risk awareness (p < 0.001). Pharmacist counseling was not associated with reading WMI (p = 0.622) and neither pharmacist counseling (p = 0.366) nor reading WMI (p = 0.916) was associated with NSAID risk awareness.

Conclusions

Physicians play a prominent role in facilitating NSAID risk awareness whereas pharmacist counseling and WMI may have limited impact.

Practice implications

The lack of significant associations among pharmacist counseling and reading WMI with NSAID risk awareness suggests a missed opportunity to improve patient understanding. There is a need for coordinated and effective strategies to communicate risk information among physicians and pharmacists and to better integrate WMI into this process.     

Computational Fluid Dynamics Reveals a Unique Net Unidirectional Pattern of Pulmonary Airflow in the Savannah Monitor Lizard (Varanus exanthematicus)

This report models pulmonary airflow in the savannah monitor (Varanus exanthematicus) using computational fluid dynamics simulations, which are based on computed tomography data. Simulations were validated by visualizing the flow of aerosolized lipids in excised lungs with good but not perfect agreement. The lung of this lizard has numerous successive bronchi branching off a long intrapulmonary bronchus, which are interconnected by intercameral perforations. Unidirectional flow has been documented in the lateral secondary bronchi of the savannah monitor, but patterns of airflow in the rest of the lung remain unknown, hindering our understanding of the evolution of pulmonary patterns of airflow in tetrapods. These results indicate that the lung contains a unique net unidirectional flow, where the overall flow scheme is similar during expiration and late inspiration, but dissimilar during early inspiration. Air is transported net caudally through the intrapulmonary bronchus and net craniad through secondary bronchi, much like the pattern of flow in birds. The simulations show that many chambers feature flow in multiple directions during parts of the respiratory cycle, but some regions also show robust unidirectional airflow. Air moves craniad through secondary bronchi and between adjacent secondary bronchi through intercameral perforations. The first secondary bronchus, the hilar-cranial bronchus, contains tidal flow that may improve ventilation of the central and dorsal lung parenchyma. These results expand our understanding of flow patterns in varanid lungs and suggest lungs with net unidirectional flow as an evolutionary pathway between tidal flow and complete unidirectional flow in multicameral lungs. Anat Rec, 2020. © 2019 American Association for Anatomy Anat Rec, 303:1768–1791, 2020. © 2019 American Association for Anatomy     

Overview and update on molecular testing in non-small cell lung carcinoma utilizing endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA) samples

Lung carcinoma remains one of the most frequent and aggressive human neoplasms. Fortunately, in the last decades, the increasing knowledge of the molecular mechanisms leading to cancer development has allowed the use of targeted therapies with improvement of prognosis in many patients. Clinical management has also changed after the introduction of endobronchialultrasonographic bronchoscopy that allows a conservative staging of lung tumors, avoiding the need of mediastinoscopy for lymph node staging. Lung pathologists and cytopathologists are facing the challenge of giving the more comprehensive prognostic and predictive information with ever smaller tissue or cytological samples. The aim of this review is to summarize the molecular testing for non-small cell lung carcinoma and how pathologists can contribute to the patient's outcome with a conscious management of biological samples.