MTG8 interacts with LHX6 to specify cortical interneuron subtype identity.

Cortical interneurons originating in the embryonic medial ganglionic eminence (MGE) diverge into a range of different subtypes found in the adult mouse cerebral cortex. The mechanisms underlying this divergence and the timing when subtype identity is set up remain unclear. We identify the highly conserved transcriptional co-factor MTG8 as being pivotal in the development of a large subset of MGE cortical interneurons that co-expresses Somatostatin (SST) and Neuropeptide Y (NPY). MTG8 interacts with the pan-MGE transcription factor LHX6 and together the two factors are sufficient to promote expression of critical cortical interneuron subtype identity genes. The SST-NPY cortical interneuron fate is initiated early, well before interneurons migrate into the cortex, demonstrating an early onset specification program. Our findings suggest that transcriptional co-factors and modifiers of generic lineage specification programs may hold the key to the emergence of cortical interneuron heterogeneity from the embryonic telencephalic germinal zones.

Electrically elicited quadriceps muscle torque: Comparison at three knee angles.

Background and Purpose: The effect of knee angle on electrically elicited quadriceps muscle torque has not been established. The goal of this study was to determine which knee angle allowed for the production of the greatest knee extensor maximal voluntary isometric torque (KEMVIT), the greatest electrically elicited torque, and the highest percent of KEMVIT from the knee extensor muscles. Case Description: Eighteen participants were secured in a force dynamometer with the knee positioned at 30°, 60°, and 90° flexion. Participants performed KEMVITs followed by electrically elicited contractions to their maximum tolerance. Outcomes: The mean ± SD of the peak KEMVITs was 123.7 ± 35.7 Nm, 222.6 ± 67.1 Nm, and 248.2 ± 81.1 Nm at 30°, 60°, and 90°, respectively. Significantly greater KEMVITs were produced at 60° and 90° than at 30° (p < 0.001). The mean ± SD of the maximally tolerated electrically elicited torques was 71.8 ± 18.8 Nm, 170.9 ± 70.4 Nm, and 134.6 ± 72.6 Nm at 30°, 60°, and 90°, respectively. Significantly higher torques were tolerated at 60° than at 30° (p < 0.001) and 90° (p = 0.018). The mean ± SD of the percent KEMVITs was 59.7 ± 11.7%, 78.2 ± 23.8%, and 52.6 ± 18.7% at 30°, 60°, and 90°, respectively. Significantly greater percent KEMVITs were produced at 60° than at 30° (p = 0.001) and 90° (p < 0.001). Discussion: Electrically elicited quadriceps torque production is greater at 60° as compared to 30° and 90° knee flexion.

Eyelid retraction discomfort with cotton-tipped applicator, unimanual and speculum intravitreal injection techniques: Eyelid retraction technique randomized comparison trial (Eyelid RETRACT).

Purpose: The aim of this study was to test the discomfort experienced during intravitreal injections with eyelid retraction between an eyelid speculum, cotton-tipped applicator (CTA), and unimanual eyelid retraction techniques. Methods: In total, 99 patients receiving intravitreal bevacizumab were enrolled into this prospective study. Participants were randomized to one of the three methods, given subconjunctival 2% lidocaine and then injected in the superior temporal quadrant. Immediately after the procedure, each patient was given a visual analog scale (VAS) to rate their discomfort. Results: The mean pain scores for eyelid retraction with unimanual, CTA, and speculum groups were 0.788 (standard deviation [SD] 0.70, 95% confidence interval [CI] 0.448-1.128), 0.945 (SD 1.28, 95% CI 0.600-1.291), and 1.561 (SD 1.28, 95% CI 1.210-1.912), respectively. A one-way analysis of variance (ANOVA) test revealed a significant difference between the groups (P = 0.006). Post hoc analysis also revealed a difference in mean pain scores between the speculum and both the CTA and the unimanual methods. Conclusion: Our study shows that the unimanual and CTA methods for eyelid retraction are significantly less painful for patients compared to the speculum method. Patient comfort is of the utmost importance as intravitreal injections are performed millions of times a year with most patients requiring multiple injections.

Electrically Elicited Quadriceps Muscle Torque: A Comparison of 3 Waveforms.

Study Design A controlled laboratory study, with a single-blind, block-randomization crossover design. Objectives To compare the electrically elicited knee extensor torque produced by 3 clinically available waveforms: 2500-Hz burst-modulated alternating current (BMAC), 1000-Hz BMAC, and 1000-Hz burst-modulated biphasic square-wave pulsed current (BMBPC). Background Neuromuscular electrical stimulation (NMES) is the therapeutic use of electrical current to strengthen muscle. Muscle torque produced by NMES is limited by discomfort. Methods The knee extensor maximal volitional isometric torque (KEMVIT) of 33 able-bodied participants (18 female) was measured and used to normalize the electrically elicited knee extensor torque to produce a percent of KEMVIT (%KEMVIT). Electrically elicited isometric knee extensor torque was measured in response to each of the waveforms at the participants' maximum tolerance. Results The average maximum tolerated stimulation produced 32.0 ± 16.7 %KEMVIT with 2500-Hz BMAC, 38.2 ± 18.4 %KEMVIT with 1000-Hz BMAC, and 42.2 ± 17.1 %KEMVIT with 1000-Hz BMBPC. Tukey honest significant difference (HSD) post hoc testing revealed a statistically significant difference between 2500-Hz BMAC and 1000-Hz BMAC (P = .046), and between 2500-Hz BMAC and 1000-Hz BMBPC (P<.001). No statistically significant difference was found between 1000-Hz BMAC and 1000-Hz BMBPC (P = .267). Conclusion For eliciting maximum knee extensor muscle torque, 1000-Hz BMBPC and 1000-Hz BMAC were similarly effective, and 2500-Hz BMAC was less effective. J Orthop Sports Phys Ther 2018;48(3):217-224. Epub 19 Dec 2017. doi:10.2519/jospt.2018.7601.

Descemet's Membrane Dehiscence Resulting From Misdirected Viscoelastic During Anterior Chamber Reformation.

We report a case of Descemet's membrane detachment after inadvertent intrastromal injection of hyaluronic acid. Surgical removal was attempted with minimal but slow improvement. Near-complete resolution occurred with subsequent conservative management within 6 weeks.

Successful treatment of a cardiac resynchronization therapy nonresponder by identifying lead malpositioning.

This case describes some of the commonly overlooked device-related issues in patients who have reportedly failed to respond to cardiac resynchronization therapy (CRT). The case demonstrates voltage-dependent right ventricular capture instead of right atrial capture by a subtly malpositioned right atrial lead. CRT therapy failed to improve symptoms of heart failure and the diagnosis of "CRT nonresponder" was made. With a detailed fact-finding approach, the mechanism behind this nonresponse was identified, and the outcome of CRT was significantly improved with rectification of the problems.

A Case of Streptococcus pyogenes Sepsis of Possible Oral Origin.

The importance of integrating the dental service in overall case management is highlighted in this case of infection.

Analysis of four pentacyclic triterpenoid acids in several bioactive botanicals with gas and liquid chromatography and mass spectrometry detection.

Several pentacyclic triterpenoid acids including betulinic, oleanolic, and ursolic acids were reported to have health beneficial properties such as antiviral and anti-inflammatory properties, as well as the capability to inhibit "in vitro" the development of various cancer cell types. For this reason betulinic, oleanolic, and ursolic acids are used as neutraceuticals. For the analysis of the pentacyclic triterpenoid acids in complex plant materials, an improved scheme was developed, involving a qualitative screening using silylation and gas chromatography with mass spectrometry analysis, followed by quantitation using a novel liquid chromatography with tandem mass spectrometry procedure. The use of the two methods provides more reliable information regarding the plant materials with unknown composition. Besides betulinic, oleanolic, and ursolic acids that were analyzed, by this procedure a fourth pentacyclic triterpenoid acid was identified and quantitated that was not previously reported to be present in plants. This acid has been identified as 3ß-3-hydroxy-lupa-18,20(29)-dien-28-oic acid. The newly identified acid has a structure as a derivative of lupane, although lupane with a double bond in the 18-position was not previously reported as present in plants. The new liquid chromatography with tandem mass spectrometry procedure developed for this study offers a very low limit of quantitation, excellent precision, and robustness. Rosemary was found to contain the largest levels of pentacyclic triterpenoid acids among all the analyzed botanicals.

Electrically Elicited Muscle Torque: Comparison Between 2500-Hz Burst-Modulated Alternating Current and Monophasic Pulsed Current.

STUDY DESIGN: Single-blind, block-randomization crossover design. OBJECTIVE: To compare the knee extensor muscle torque production elicited with 2500-Hz burst-modulated alternating current (BMAC) and with a monophasic pulsed current (MPC) at the maximum tolerated stimulation intensity. BACKGROUND: Neuromuscular electrical stimulation (NMES) is often used for strengthening the quadriceps following knee surgery. Strength gains are dependent on muscle torque production, which is primarily limited by discomfort. Burst-modulated alternating current stimulation is a clinically popular waveform for NMES. Prior research has established that MPC with a relatively long pulse duration is effective for high muscle torque production. METHODS: Participants in this study were 20 adults with no history of knee injury. A crossover design was used to randomize the order in which each participant's dominant or nondominant lower extremity received NMES and the waveform (MPC or BMAC) this limb received. Stimulation intensity was incrementally increased until participants reached their maximum tolerance. The torque produced was converted to a percentage of each participant's maximum volitional isometric contraction of the respective limb. RESULTS: A general linear model for a 2-treatment, 2-period crossover design was utilized to analyze the results. The mean ± SD electrically induced percent maximum volitional isometric contraction at maximal participant tolerance was 49.5% ± 19.6% for MPC and 29.8% ± 12.4% for BMAC. This difference was statistically significant (P = .002) after accounting for treatment order and limb, which had no effect on torque production. CONCLUSION: Neuromuscular stimulation using MPC may be more efficacious than using BMAC to achieve a high torque output in patients with quadriceps weakness.

Atrial Fibrillation Monitoring in Cryptogenic Stroke: the Gaps Between Evidence and Practice.

Identifying occult paroxysmal atrial fibrillation as the etiology of cryptogenic stroke has been a top research priority in the past decade. This is because prompt initiation of anticoagulation has significantly decreased subsequent stroke risk. Available evidence suggests that prolonged cardiac monitoring after stroke increases the likelihood of detecting atrial fibrillation. However, further research is required to fill in the gaps in regard to the optimal period of monitoring, candidates for monitoring, etc. Here, we review the current evidence supporting the use of prolonged monitoring for cryptogenic stroke patients and discuss the directions of future research.

Analysis of small carbohydrates in several bioactive botanicals by gas chromatography with mass spectrometry and liquid chromatography with tandem mass spectrometry.

Bioactive botanicals contain natural compounds with specific biological activity, such as antibacterial, antioxidant, immune stimulating, and taste improving. A full characterization of the chemical composition of these botanicals is frequently necessary. A study of small carbohydrates from the plant materials of 18 bioactive botanicals is further described. The study presents the identification of the carbohydrate using a gas chromatographic-mass spectrometric analysis that allows detection of molecules as large as maltotetraose, after changing them into trimethylsilyl derivatives. A number of carbohydrates in the plant (fructose, glucose, mannose, sucrose, maltose, xylose, sorbitol, and myo-, chiro-, and scyllo-inositols) were quantitated using a novel liquid chromatography with tandem mass spectrometric technique. Both techniques involved new method developments. The gas chromatography with mass spectrometric analysis involved derivatization and separation on a Rxi(®)-5Sil MS column with H2 as a carrier gas. The liquid chromatographic separation was obtained using a hydrophilic interaction type column, YMC-PAC Polyamine II. The tandem mass spectrometer used an electrospray ionization source in multiple reaction monitoring positive ion mode with the detection of the adducts of the carbohydrates with Cs(+) ions. The validated quantitative procedure showed excellent precision and accuracy allowing the analysis in a wide range of concentrations of the analytes.

Neuromuscular electrical stimulation pulse duration and maximum tolerated muscle torque.

Neuromuscular electrical stimulation (NMES) is a physical therapy intervention used to treat muscle weakness. NMES-elicited forces during therapy are correlated with strength gains. Patient discomfort limits NMES-elicited forces potentially compromising strength gains and the efficacy of this invention. The purpose of this study was to determine if NMES containing two different electrical stimulation pulse durations (200 or 500 µs) affected the knee extensor muscle torques subjects tolerated. Other NMES characteristics were identical in the two conditions: monophasic square-wave pulses; 75 pulses per second; and electrical stimulation train duration of one second. The primary dependent variable of interest was the percentage of maximum voluntary isometric contraction (MVIC) tolerated. The two pulse duration conditions were tested during a single session on the opposing lower extremities of 15 subjects. Subjects tolerated 49.3 ± 18.7% of MVIC torques in the 500-µs condition versus 44.5 ± 17.9% of MVIC torques in the 200-µs condition, which was a statistically significant difference (p = 0.02). Further research is needed to explore if the differences observed in this study would lead to clinically significant differences in strength gains and to see if the findings of this study can be generalized to other forms of NMES that contain other types of wave forms.

Paradoxical contractile properties in the knee extensors of HIV-infected men treated with antiretroviral therapy.

We assessed contractile properties in the knee extensors of 18 men with the human immunodeficiency virus (HIV+) being treated with antiretroviral therapy (ART), and 9 healthy controls matched for age and body mass index. We found significant, divergent differences between groups with regard to force relaxation. Half-times of twitch relaxation were shorter (62.6 ± 5.4 ms vs. 48.9 ± 3.0 ms; p = 0.045) and maximum rates of torque relaxation were slower (0.47% ± 0.04%(s-)1 vs. 1.32% ± 0.10%(s-)1; p < 0.001) in HIV+ individuals. These preliminary findings suggest potential intramuscular impairments in HIV+ individuals on ART, perhaps because of interactions between calcium handling and mitochondrial dysfunction.

Sarcopenia--mechanisms and treatments.

BACKGROUND: Sarcopenia is a consequence of aging. This atrophic event is responsible for decrease in strength and associated functional deficits seen in the aging adult. PURPOSE: This paper reviews: (1) the mechanisms contributing to sarcopenia, (2) the impact of age-related changes in muscle composition on 3 processes integral to muscle function, (3) the efficacy of pharmaceuticals and over-the-counter nutritional supplements in the management of sarcopenia, (4) experimental use of pharmaceutical regulation of myostatin to increase muscle mass and strength in animal models, and (5) efficacy of resistance training as a means of maintaining or recovering muscle mass and strength. METHODS: PubMed was searched for relevant research articles using the following descriptors: sarcopenia, aging, muscle mass, muscle performance, muscle strength, myostatin, testosterone, growth hormone, dehydroepiandrosterone, hormone replacement, nutrition, resistance training, and endurance training. RESULTS: Sarcopenia is mediated by multiple mechanisms, including alpha-motor neuron death, altered hormone concentrations, increased inflammation, and altered nutritional status. Age-related changes within muscle likely affect processes integral to muscle function. These changes negatively influence muscle performance directly or by contributing to sarcopenia. Pharmaceutical or supplement interventions to treat sarcopenia have not proved encouraging to date, either lacking or providing limited efficacy, along with the potential for negative health consequences. In contrast, resistance training has proven safe and highly effective for increasing muscle mass and strength in aging adults. CONCLUSION: Sarcopenia is a multifactorial consequence of aging that will affect many adults. Resistance training is the most effective and safe intervention to attenuate or recover some of the loss of muscle mass and strength that accompanies aging.

Prediction of cardiorespiratory fitness in older men infected with the human immunodeficiency virus: clinical factors and value of the six-minute walk distance.

OBJECTIVES: To investigate factors related to cardiorespiratory fitness in older human immunodeficiency virus (HIV)-infected patients and to explore the utility of 6-minute walk distance (6-MWD) in measuring fitness. DESIGN: Cross-sectional study in clinic-based cohort. SETTING: Veterans Affairs Medical Center, Baltimore, Maryland. PARTICIPANTS: Forty-three HIV-infected men, median age 57 (range 50-82), without recent acquired immunodeficiency syndrome-related illness and receiving antiretroviral (ARV) therapy. MEASUREMENTS: Peak oxygen utilization (VO(2)peak) according to treadmill graded exercise testing, 6-MWD, grip strength, quadriceps maximum voluntary isometric contraction, cross-sectional area, muscle quality, and muscle adiposity. RESULTS: There was a moderate correlation between VO(2)peak (mean +/- SD; 18.4 +/- 5.6 mL/kg per minute) and 6-MWD (514 +/- 91 m) (r=0.60, P<.001). VO(2)peak was lower in subjects with hypertension (16%, P<.01) and moderate anemia (hemoglobin 10-13 gm/dL; 15%, P=.09) than in subjects without these conditions. CD4 cell count (median 356 cells/mL, range 20-1,401) and HIV-1 viral load (84% nondetectable) were not related to VO(2)peak. Among muscle parameters, only grip strength was an independent predictor of VO(2)peak. Estimation of VO(2)peak using linear regression, including age, 6-MWD, grip strength, and hypertension as independent variables, explained 61% of the variance in VO(2)peak. CONCLUSION: Non-AIDS-related comorbidity predicts cardiorespiratory fitness in older HIV-infected men receiving ARV therapy. The 6-MWD is a valuable measure of fitness in this patient population, but a larger study with diverse subjects is needed.

Comparison of maximum tolerated muscle torques produced by 2 pulse durations.

BACKGROUND: Neuromuscular electrical stimulation (NMES) is an effective therapeutic technique for strengthening weak muscles. A positive dose-response relationship exists between the elicited muscle forces during training and strength (force-generating capacity) gains. Patient discomfort limits NMES muscle forces, potentially compromising efficacy. OBJECTIVE: The purpose of this study was to compare the NMES muscle torques produced by stimulation trains consisting of 2 different pulse durations. DESIGN: During a single testing session, the 2 pulse duration conditions (50 and 200 microseconds) were tested on the opposite lower extremities of the participants. METHODS: The study participants were 10 adults without remarkable medical histories. The maximum tolerated isometric knee extensor torque was the primary dependent variable. The peak currents and phase charges that produced the maximally tolerated torques, as well as the sensory, motor, and pain thresholds for the 2 pulse conditions, were compared. RESULTS: The 200-microsecond pulse duration condition resulted in participants tolerating significantly greater muscle torques; it was associated with significantly greater phase charges but significantly lower peak currents. LIMITATIONS: This study only compared muscle torques in response to stimulation trains consisting of pulses with short (50-microsecond) or medium (200-microsecond) durations and did not examine long ( approximately 400- to 600-microsecond) durations. Furthermore, the result of this study may not apply to NMES that uses stimulation patterns other than monophasic, square-wave pulsed current. CONCLUSIONS: It has been suggested that short pulse durations are most appropriate for NMES because they are less likely to recruit nociceptors. The results of this study, however, support the use of a medium pulse duration rather than a short pulse duration when the goal is to produce a maximum torque response from a muscle. These observations may be related to the currents and phase charges for the pain thresholds for the 2 pulse duration conditions.

Optical coherence tomography and histologic measurements of nerve fiber layer thickness in normal and glaucomatous monkey eyes.

PURPOSE: To investigate optical coherence tomography (OCT) measurements of retinal nerve fiber layer (RNFL) thickness change associated with elevated intraocular pressure (IOP) over a period of time, and to compare in vivo OCT RNFL thickness measurements with morphologic measurements of the same tissues. METHODS: One eye of each of 12 cynomolgus monkeys was treated with argon laser to the anterior chamber angle to induce elevated IOP. OCT measurements were made weekly in the treated and the contralateral eyes of each monkey for 14 weeks after the laser insult. The monkeys were killed at the conclusion of the experiment, and comparisons were made between the terminal OCT RNFL measurements and quantitative histomorphometric assessments in the same eyes. Effects of exposure to elevated IOP on RNFL were characterized by a mixed-effects model. Linear mixed-effects models provided unbiased analysis of balanced and unbalanced repeated-measures data, detection of group effects (fixed effects), and individual subject effects (random effects), thereby making the best use of all available data. RESULTS: Increased IOP was achieved in 10 eyes. Exposure to high IOP was associated with the loss of mean RNFL thickness at a median rate of 3.77 +/- 0.08 microm/wk. On average, OCT RNFL thickness measurements were higher than histomorphologic measurements by 5.7 microm (95% confidence interval, 3.6-7.8; P = 0.003). CONCLUSIONS: Thinning of the RNFL associated with elevated IOP was demonstrated with OCT in a group of experimentally glaucomatous monkey eyes over a period. OCT measurements corresponded with histomorphometric measurements of the same tissues.

Central activation, muscle performance, and physical function in men infected with human immunodeficiency virus.

Loss of muscle mass and limitations in activity have been reported in persons infected with human immunodeficiency virus (HIV), even those who are otherwise asymptomatic. The extent to which factors other than muscle atrophy impair muscle performance has not been addressed in depth. The purpose of this study was to determine the extent of neuromuscular activation of the knee extensors and ankle dorsiflexors of 27 men infected with HIV receiving antiretroviral therapy and its relationship to muscle performance. The central activation ratio (CAR) was determined using superimposed electrical stimulation during maximum voluntary contractions. In addition to force and power measurements, muscle cross-sectional area and composition was evaluated using computed tomography. Aerobic capacity was determined from treadmill exercise testing. Eleven of the subjects had an impaired ability to activate the knee extensors (CAR = 0.72 +/- 0.12) that was associated with weakness and decreased specific force. The reduced central activation was not associated with muscle area, body composition, aerobic capacity, CD4 count, or medication regimen. Those individuals with low central activation had higher HIV-1 viral loads and were more likely to have a history of AIDS-defining illness. These results suggest the possibility of a different mechanism contributing to muscle impairment in the current treatment era that is associated with impairment of central motor function rather than atrophy. Further investigation is warranted in a larger, more diverse population before more definitive claims are made.

Effect of electrical stimulation pattern on the force responses of paralyzed human quadriceps muscles.

Most studies examining the effect of electrical stimulation pattern on the force response of muscle have been done in able-bodied persons. The purpose of this study was to examine the electrically elicited force responses of the paralyzed quadriceps femoris muscles of persons with spinal cord injuries (SCI) to see whether stimulation patterns that increase the force response in non-paralyzed muscle will do so in paralyzed muscle. Thirteen subjects ranging in age from 11 to 24 years old with motor-complete SCI were studied. Isometric muscle performance was tested using 6-pulse constant-frequency trains (CFTs), variable-frequency trains (VFTs), and doublet-frequency trains (DFTs) delivered at mean frequencies of 10, 20, 33, 50, and 100 HZ. In the non-fatigued and fatigued condition, the VFT and DFT peak forces were greater than the CFT peak forces at 10 HZ. In addition, in the fatigued condition the 20-HZ VFT peak forces were greater than the CFT peak forces, and there was a trend for the DFT peak forces to be greater than the CFT peak forces. In the non-fatigued condition, the 33-HZ and 50-HZ DFT force-time integrals were greater than both the CFT and VFT force-time integrals. In the fatigued condition, there was no significant effect of train-type on the force-time integrals. These results differ from those previously reported from studies using able-bodied persons and indicate that findings from studies of the electrically elicited force responses of the muscles of able-bodied persons do not apply to the paralyzed muscles of persons with SCI.

Contractile properties and the force-frequency relationship of the paralyzed human quadriceps femoris muscle.

BACKGROUND AND PURPOSE: Following spinal cord injury (SCI), paralyzed muscles undergo physiological changes that alter their force responses to electrical stimulation. The purpose of this study was to investigate the effects of SCI on the contractile properties and force-frequency relationship (FFR) of the paralyzed human quadriceps femoris muscle of adolescents and young adults. SUBJECTS: Thirteen subjects (11 male, 2 female; age range=11-24 years) with motor complete SCIs and 13 matched control subjects (11 male, 2 female; age range=9-23 years) without SCI participated in the study. METHODS: Both groups of subjects underwent the same testing protocol using similar equipment. RESULTS: The paralyzed muscles of the subjects with SCI produced 62% of the peak twitch force and had a fatigue ratio that was 65% of that of the control subjects. The paralyzed muscles contracted 14% and 25% faster and relaxed 38% and 46% faster than the nonparalyzed muscles in nonfatigued and fatigued conditions, respectively. Compared with the control subjects, the subjects with SCI had twitch-to-tetanus ratios that were 84% and 127% greater in nonfatigued and fatigued conditions, respectively. Relative to the control subjects, the FFR of the subjects with SCI was shifted to the left in the fatigued condition. Relative to their respective nonfatigued conditions, the FFR of both groups of subjects shifted to the right with fatigue. DISCUSSION AND CONCLUSION: These findings may have important implications for designing stimulation strategies to reduce the rapid fatigue that limits the clinical efficacy of functional electrical stimulation.