Τρίτη, 12 Ιουλίου 2016

Altered intrinsic connectivity of the auditory cortex in congenital amusia

Congenital amusia, a neurodevelopmental disorder of music perception and production, has been associated with abnormal anatomical and functional connectivity in a right frontotemporal pathway. To investigate whether spontaneous connectivity in brain networks involving the auditory cortex is altered in the amusic brain, we ran a seed-based connectivity analysis, contrasting at-rest functional MRI data of amusic and matched control participants. Our results reveal reduced frontotemporal connectivity in amusia during resting state, as well as an overconnectivity between the auditory cortex and the default mode network (DMN). The findings suggest that the auditory cortex is intrinsically more engaged toward internal processes and less available to external stimuli in amusics compared with controls. Beyond amusia, our findings provide new evidence for the link between cognitive deficits in pathology and abnormalities in the connectivity between sensory areas and the DMN at rest.



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Strategies for targeting primate neural circuits with viral vectors

Understanding how the brain works requires understanding how different types of neurons contribute to circuit function and organism behavior. Progress on this front has been accelerated by optogenetics and chemogenetics, which provide an unprecedented level of control over distinct neuronal types in small animals. In primates, however, targeting specific types of neurons with these tools remains challenging. In this review, we discuss existing and emerging strategies for directing genetic manipulations to targeted neurons in the adult primate central nervous system. We review the literature on viral vectors for gene delivery to neurons, focusing on adeno-associated viral vectors and lentiviral vectors, their tropism for different cell types, and prospects for new variants with improved efficacy and selectivity. We discuss two projection targeting approaches for probing neural circuits: anterograde projection targeting and retrograde transport of viral vectors. We conclude with an analysis of cell type-specific promoters and other nucleotide sequences that can be used in viral vectors to target neuronal types at the transcriptional level.



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Integration of sensory, spinal, and volitional descending inputs in regulation of human locomotion

We reported previously that both transcutaneous electrical spinal cord stimulation and direct pressure stimulation of the plantar surfaces of the feet can elicit rhythmic involuntary step-like movements in noninjured subjects with their legs in a gravity-neutral apparatus. The present experiments investigated the convergence of spinal and plantar pressure stimulation and voluntary effort in the activation of locomotor movements in uninjured subjects under full body weight support in a vertical position. For all conditions, leg movements were analyzed using electromyographic (EMG) recordings and optical motion capture of joint kinematics. Spinal cord stimulation elicited rhythmic hip and knee flexion movements accompanied by EMG bursting activity in the hamstrings of 6/6 subjects. Similarly, plantar stimulation induced bursting EMG activity in the ankle flexor and extensor muscles in 5/6 subjects. Moreover, the combination of spinal and plantar stimulation exhibited a synergistic effect in all six subjects, eliciting greater motor responses than either modality alone. While the motor responses to spinal vs. plantar stimulation seems to activate distinct but overlapping spinal neural networks, when engaged simultaneously, the stepping responses were functionally complementary. As observed during induced (involuntary) stepping, the most significant modulation of voluntary stepping occurred in response to the combination of spinal and plantar stimulation. In light of the known automaticity and plasticity of spinal networks in absence of supraspinal input, these findings support the hypothesis that spinal and plantar stimulation may be effective tools for enhancing the recovery of motor control in individuals with neurological injuries and disorders.



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Resting-state functional connectivity differentiates anxious apprehension and anxious arousal

Abstract

Brain regions in the default mode network (DMN) display greater functional connectivity at rest or during self-referential processing than during goal-directed tasks. The present study assessed resting-state connectivity as a function of anxious apprehension and anxious arousal, independent of depressive symptoms, in order to understand how these dimensions disrupt cognition. Whole-brain, seed-based analyses indicated differences between anxious apprehension and anxious arousal in DMN functional connectivity. Lower connectivity associated with higher anxious apprehension suggests decreased adaptive, inner-focused thought processes, whereas higher connectivity at higher levels of anxious arousal may reflect elevated monitoring of physiological responses to threat. These findings further the conceptualization of anxious apprehension and anxious arousal as distinct psychological dimensions with distinct neural instantiations.



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Ictal time-irreversible intracranial EEG signals as markers of the epileptogenic zone

The aim of pre-surgical evaluation of patients suffering from pharmacoresistant epilepsies is to delineate the epileptogenic zone, which has been defined as the minimal area of cortex that must be resected to produce seizure-freedom (Luders et al., 2006). Since there is still no unique diagnostic method to precisely, directly and unequivocally identify the epileptogenic zone, it is crucial to extract as much information as possible from existing modalities. Intracranial EEG (iEEG) is currently the technology with the highest spatiotemporal resolution and the best signal-to-noise ratio to record the electric brain activity during human epileptic seizures.

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Young Investigator Paper Awards Clinical Neurophysiology



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The effects of bariatric surgeries on nonalcoholic fatty liver disease

Abstract

Non-alcoholic fatty liver disease (NAFLD) is the most common chronic liver disease and is associated with obesity. Bariatric surgery has been shown to be the most effective method for weight reduction. However, no conclusive data exists on the effects of weight reduction surgery on NAFLD. This study aimed to characterize liver histology, metabolic status, and liver function changes in patients who underwent bariatric surgery, before and after the weight-reduction procedure. This is a phase 1 report of a prospective cohort study of patients who underwent bariatric surgery. Biopsies were obtained at baseline (intraoperatively) and 3 months postoperatively. Clinical characteristics, biochemical profile, and histopathological data [steatosis, NAFLD activity score (NAS), hepatocyte ballooning, lobular inflammation, and degree of fibrosis] were obtained at each time point. Twenty-seven patients were included (9 men and 18 women), and the median age was 35 ± 8 years old. At baseline, 3 patients had dyslipidemia, 4 had diabetes, and 5 patients had hypertension, which did not change at follow-up. The average body mass index decreased from 44.6 ± 7.8 to 34.2 ± 6.3 kg/m2 at follow-up (P < 0.001). On histopathology, 12 of the 18 patients with preoperative steatosis (median score 2) had reduced steatosis scores postoperatively (P = 0.025); fibrosis (median score 1) was also reduced in 17 patients (P = 0.012), and NAS was decreased from 4 (3–5) to 2 (1–3) (P = 0.004). The changes in lobular inflammation and hepatocyte ballooning were not statistically significant on follow-up. The phase 1 results of this study described the histopathological changes following weight reduction surgery and suggested that hepatic steatosis, fibrosis, and NAFLD activity score were reduced 3 months after surgery. This clinical trial is financially supported by the National Plan for Science, Technology and Innovation Program grant number (11-MED1910-02).



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SAGES guidelines for laparoscopic ventral hernia repair



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Robot-assisted versus laparoscopic-assisted surgery for colorectal cancer: a meta-analysis

Abstract

Background and objectives

Robotic surgery is positioned at the cutting edge of minimally invasive management of colorectal cancer. We performed a meta-analysis of data from randomized controlled trials (RCTs) and non-RCTs (NRCTs) that compared the clinicopathological outcomes of robotic-assisted colorectal surgery (RACS) with those of laparoscopic-assisted colorectal surgery (LACS). Inferences on the feasibility and the relative safety and efficacy have been drawn.

Methods

A literature search for relevant studies was performed on MEDLINE, Ovid, Embase, Cochrane Library, and Web of Science databases. Inter-group differences in the standardized mean differences and relative risk were assessed. Operation times, conversion rates to open surgery, estimated blood loss (EBL), early postoperative morbidity, and length of hospital stay (LHS) were compared. Oncologic outcomes assessed were number of lymph nodes harvested and lengths of proximal and distal resection margins.

Results

Twenty-four studies (2 RCTs and 22 NRCTs [5 prospective plus 17 retrospective]) with a total of 3318 patients were included. Of these, 1466 (44.18 %) patients underwent RACS and 1852 (55.82 %) underwent LACS. Conversion rates, EBL and LHS were significantly lower, while the operation times and total costs were similar between RACS and LACS. Complication rates and oncological accuracy of resection showed no significant difference.

Conclusion

Based on this meta-analysis, RACS appears to be a promising surgical approach with its safety and efficacy comparable to that of LACS in patients undergoing colorectal surgery. Further studies are required to evaluate the long-term cost-efficiency as well as the functional and oncologic outcomes of RACS.



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Robot-assisted laparoscopic versus open middle pancreatectomy: short-term results of a randomized controlled trial

Abstract

Objective

This first prospective randomized controlled trial was performed to compare short-term outcomes of robot-assisted laparoscopic middle pancreatectomy (RA-MP) with open middle pancreatectomy (OMP).

Background

RA-MP is a novel minimally invasive surgical technique for benign or borderline tumors in the pancreatic neck or body. Its short-term effectiveness and safety remain unknown, compared to OMP.

Methods

Patients eligible for MP from August 2011 to November 2015 were randomized into the RA-MP or OMP group. The primary endpoint was length of hospital stay (LOS). Secondary endpoints were intraoperative parameters, and postoperative and recovery variables.

Results

A total of 100 patients were included into the study to analyze primary and secondary endpoints. Demographic characteristics and pathological parameters were similar in both groups. Furthermore, LOS was significantly shorter (15.6 vs. 21.7 days, P = 0.002), median operative time was reduced (160 vs. 193 min, P = 0.002), median blood loss was lower (50 vs. 200 mL, P < 0.001), rate of clinical postoperative pancreatic fistula (POPF) was lower (18 vs. 36.0 %, P = 0.043), nutritional status recovery was better, off-bed return to activity was expedited (3.1 vs. 4.6 days, P < 0.001), and resumption of bowel movement was faster (3.5 vs. 5.0 days, P < 0.001) in the RA-MP group, compared to the OMP group.

Conclusion

RA-MP was associated with significantly shorter LOS, reduced operative time, blood loss and clinical POPF rate, and expedited postoperative recovery, compared to OMP.



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Vagus Nerve Stimulation During Rehabilitative Training Improves Forelimb Recovery After Chronic Ischemic Stroke in Rats

Background and objective. Stroke is a leading cause of long-term disability. Currently, there are no consistently effective rehabilitative treatments for chronic stroke patients. Our recent studies demonstrate that vagus nerve stimulation (VNS) paired with rehabilitative training improves recovery of function in multiple models of stroke. Here, we evaluated the ability of VNS paired with rehabilitative training to improve recovery of forelimb strength when initiated many weeks after a cortical and subcortical ischemic lesion in subjects with stable, chronic motor deficits. Methods. Rats were trained to perform an automated, quantitative measure of voluntary forelimb strength. Once proficient, rats received injections of endothelin-1 to cause a unilateral cortical and subcortical ischemic lesion. Then, 6 weeks after the lesion, rats underwent rehabilitative training paired with VNS (Paired VNS; n = 10), rehabilitative training with equivalent VNS delivered 2 hours after daily rehabilitative training (Delayed VNS; n = 10), or rehabilitative training without VNS (Rehab, n = 9). Results. VNS paired with rehabilitative training significantly improved recovery of forelimb function compared with control groups. The Paired VNS group displayed an 86% recovery of strength, the Rehab group exhibited 47% recovery, and the Delayed VNS group exhibited 42% recovery. Improvement in forelimb function was sustained in the Paired VNS group after the cessation of stimulation, potentially indicating lasting benefits. No differences in intensity of rehabilitative training, lesion size, or MAP-2 expression were observed between groups. Conclusion. VNS paired with rehabilitative training confers significantly greater recovery of forelimb function after chronic ischemic stroke in rats.



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The Effects of Stroke Type, Locus, and Extent on Long-Term Outcome of Gait Rehabilitation: The LEAPS Experience

Background. Paresis in stroke is largely a result of damage to descending corticospinal and corticobulbar pathways. Recovery of paresis predominantly reflects the impact on the neural consequences of this white matter lesion by reactive neuroplasticity (mechanisms involved in spontaneous recovery) and experience-dependent neuroplasticity, driven by therapy and daily experience. However, both theoretical considerations and empirical data suggest that type of stroke (large vessel distribution/lacunar infarction, hemorrhage), locus and extent of infarction (basal ganglia, right-hemisphere cerebral cortex), and the presence of leukoaraiosis or prior stroke might influence long-term recovery of walking ability. In this secondary analysis based on the 408 participants in the Locomotor Experience Applied Post-Stroke (LEAPS) study database, we seek to address these possibilities. Methods. Lesion type, locus, and extent were characterized by the 2 neurologists in the LEAPS trial on the basis of clinical computed tomography and magnetic resonance imaging scans. A series of regression models was used to test our hypotheses regarding the effects of lesion type, locus, extent, and laterality on 2- to 12-month change in gait speed, controlling for baseline gait speed, age, and Berg Balance Scale score. Results. Gait speed change at 1 year was significantly reduced in participants with basal ganglia involvement and prior stroke. There was a trend toward reduction of gait speed change in participants with lacunar infarctions. The presence of right-hemisphere cortical involvement had no significant impact on outcome. Conclusions. Type, locus, and extent of lesion, and the loss of substrate for neuroplastic effect as a result of prior stroke may affect long-term outcome of rehabilitation of hemiparetic gait.



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Reducing The Cost of Transport and Increasing Walking Distance After Stroke: A Randomized Controlled Trial on Fast Locomotor Training Combined With Functional Electrical Stimulation

Background. Neurorehabilitation efforts have been limited in their ability to restore walking function after stroke. Recent work has demonstrated proof-of-concept for a functional electrical stimulation (FES)–based combination therapy designed to improve poststroke walking by targeting deficits in paretic propulsion. Objectives. To determine the effects on the energy cost of walking (EC) and long-distance walking ability of locomotor training that combines fast walking with FES to the paretic ankle musculature (FastFES). Methods. Fifty participants >6 months poststroke were randomized to 12 weeks of gait training at self-selected speeds (SS), fast speeds (Fast), or FastFES. Participants' 6-minute walk test (6MWT) distance and EC at comfortable (EC-CWS) and fast (EC-Fast) walking speeds were measured pretraining, posttraining, and at a 3-month follow-up. A reduction in EC-CWS, independent of changes in speed, was the primary outcome. Group differences in the number of 6MWT responders and moderation by baseline speed were also evaluated. Results. When compared with SS and Fast, FastFES produced larger reductions in EC (Ps ≤.03). FastFES produced reductions of 24% and 19% in EC-CWS and EC-Fast (Ps <.001), respectively, whereas neither Fast nor SS influenced EC. Between-group 6MWT differences were not observed; however, 73% of FastFES and 68% of Fast participants were responders, in contrast to 35% of SS participants. Conclusions. Combining fast locomotor training with FES is an effective approach to reducing the high EC of persons poststroke. Surprisingly, differences in 6MWT gains were not observed between groups. Closer inspection of the 6MWT and EC relationship and elucidation of how reduced EC may influence walking-related disability is warranted.



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Does Poststroke Lower-Limb Spasticity Influence the Recovery of Standing Balance Control? A 2-Year Multilevel Growth Model

Background. Poststroke lower-limb spasticity (LLS) has been shown to degrade standing balance control by disrupting the temporal synchronization between individual limb centers of pressure (COPs). Time-varying changes in standing balance control associated with alterations in the extent of LLS have yet to be documented and are important to informing treatment strategies to improve such functional outcomes. Objective. The present work aimed to understand the natural recovery of standing balance control among stroke survivors with LLS using limb-specific indices of standing balance control. Furthermore, we sought to understand if time-varying changes in LLS were associated with alterations in standing balance control. Methods. A retrospective analysis of 92 participants was performed; 47 participants never exhibited LLS during the study (No_LLS), and 45 participants exhibited LLS during at least 1 testing session (LLS). Quiet standing for a duration of 30 s on 2 force platforms was recorded. Temporal synchrony and spatial symmetry of COP displacements were assessed, along with interlimb weight-bearing symmetry. Results. All variables, except spatial symmetry, indicated initial improvement followed by deceleration in the rate of balance control recovery. Limb-specific measures indicated that individuals with LLS exhibited deficits in balance control. The recovery trajectories were not different between groups, suggesting a similar rate, but reduced extent, of balance control recovery among the LLS relative to the No_LLS group. Only temporal synchrony was altered by time-varying changes in spasticity. Conclusions. The present results suggest that the reduction in spasticity may be beneficial to balance control recovery.



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Subcortical Volume Loss in the Thalamus, Putamen, and Pallidum, Induced by Traumatic Brain Injury, Is Associated With Motor Performance Deficits

Background. Traumatic brain injury (TBI) has been associated with altered microstructural organization of white matter (WM) and reduced gray matter (GM). Although disrupted WM organization has been linked to poorer motor performance, the predictive value of GM atrophy for motor impairments in TBI remains unclear. Objective. Here, we investigated TBI-induced GM volumetric abnormalities and uniquely examined their relationship with bimanual motor impairments. Methods. 22 moderate to severe TBI patients (mean age = 25.9 years, standard deviation [SD] = 4.9 years; time since injury = 4.7 years, SD = 3.7 years) and 27 age- and gender-matched controls (mean age = 23.4 years; SD = 3.8 years) completed bimanual tasks and a structural magnetic resonance imaging scan. Cortical and subcortical GM volumes were extracted and compared between groups using FreeSurfer. The association between bimanual performance and GM volumetric measures was investigated using partial correlations. Results. Relative to controls, patients performed significantly poorer on the bimanual tasks and demonstrated significantly smaller total GM as well as overall and regional subcortical GM. However, the groups did not show significant differences in regional cortical GM volume. The majority of the results remained significant even after excluding TBI patients with focal lesions, suggesting that TBI-induced volume reductions were predominantly caused by diffuse injury. Importantly, atrophy of the thalamus, putamen, and pallidum correlated significantly with poorer bimanual performance within the TBI group. Conclusions. Our results reveal that GM atrophy is associated with motor impairments in TBI, providing new insights into the etiology of motor control impairments following brain trauma.



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Compensatory Versus Noncompensatory Shoulder Movements Used for Reaching in Stroke

Background. The extent to which the upper-limb flexor synergy constrains or compensates for arm motor impairment during reaching is controversial. This synergy can be quantified with a minimal marker set describing movements of the arm-plane. Objectives. To determine whether and how (a) upper-limb flexor synergy in patients with chronic stroke contributes to reaching movements to different arm workspace locations and (b) reaching deficits can be characterized by arm-plane motion. Methods. Sixteen post-stroke and 8 healthy control subjects made unrestrained reaching movements to targets located in ipsilateral, central, and contralateral arm workspaces. Arm-plane, arm, and trunk motion, and their temporal and spatial linkages were analyzed. Results. Individuals with moderate/severe stroke used greater arm-plane movement and compensatory trunk movement compared to those with mild stroke and control subjects. Arm-plane and trunk movements were more temporally coupled in stroke compared with controls. Reaching accuracy was related to different segment and joint combinations for each target and group: arm-plane movement in controls and mild stroke subjects, and trunk and elbow movements in moderate/severe stroke subjects. Arm-plane movement increased with time since stroke and when combined with trunk rotation, discriminated between different subject groups for reaching the central and contralateral targets. Trunk movement and arm-plane angle during target reaches predicted the subject group. Conclusions. The upper-limb flexor synergy was used adaptively for reaching accuracy by patients with mild, but not moderate/severe stroke. The flexor synergy, as parameterized by the amount of arm-plane motion, can be used by clinicians to identify levels of motor recovery in patients with stroke.



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Improving Motor Corticothalamic Communication After Stroke Using Real-Time fMRI Connectivity-Based Neurofeedback

Background. Two thirds of stroke survivors experience motor impairment resulting in long-term disability. The anatomical substrate is often the disruption of cortico-subcortical pathways. It has been proposed that reestablishment of cortico-subcortical communication relates to functional recovery. Objective. In this study, we applied a novel training protocol to augment ipsilesional cortico-subcortical connectivity after stroke. Chronic stroke patients with severe motor impairment were provided online feedback of blood-oxygenation level dependent signal connectivity between cortical and subcortical regions critical for motor function using real-time functional magnetic resonance imaging neurofeedback. Results. In this proof of principle study, 3 out of 4 patients learned to voluntarily modulate cortico-subcortical connectivity as intended. Conclusions. Our results document for the first time the feasibility and safety for patients with chronic stroke and severe motor impairment to self-regulate and augment ipsilesional cortico-subcortical connectivity through neurofeedback using real-time functional magnetic resonance imaging.



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Imaging Predictors of Improvement From a Motor Learning-Based Intervention for Children With Unilateral Cerebral Palsy

Background. Motor-learning interventions may improve hand function in children with unilateral cerebral palsy (UCP) but with inconsistent outcomes across participants. Objective. To examine if pre-intervention brain imaging predicts benefit from bimanual intervention. Method. Twenty children with UCP with Manual Ability Classification System levels I to III, aged 7-16 years, participated in an intensive bimanual intervention. Assessments included the Assisting Hand Assessment (AHA), Jebsen Taylor Test of Hand Function (JTTHF) and Children's Hand Experience Questionnaire (CHEQ) at baseline (T1), completion (T2) and 8-10 weeks post-intervention (T3). Imaging at baseline included conventional structural (radiological score), functional (fMRI) and diffusion tensor imaging (DTI). Results. Improvements were seen across assessments; AHA (P = 0.04), JTTHF (P < .001) and CHEQ (P < 0.001). Radiological score significantly correlated with improvement at T2; AHA (r = .475) and CHEQ (r = .632), but negatively with improvement on unimanual measures at T3 (JTTFH r = –.514). fMRI showed negative correlations between contralesional brain activation when moving the affected hand and AHA improvements (T2: r = –.562, T3: r = –0.479). Fractional Anisotropy in the affected posterior limb of the internal capsule correlated negatively with increased bimanual use on CHEQ at T2 (r = –547) and AHA at T3 (r = –.656). Conclusions. Children with greater structural, functional and connective brain damage showed enhanced responses to bimanual intervention. Baseline imaging may identify parameters predicting response to intervention in children with UCP.



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Delayed Exercise Is Ineffective at Reversing Aberrant Nociceptive Afferent Plasticity or Neuropathic Pain After Spinal Cord Injury in Rats

Neuropathic pain is a debilitating consequence of spinal cord injury (SCI) that correlates with sensory fiber sprouting. Recent data indicate that exercise initiated early after SCI prevents the development of allodynia and modulated nociceptive afferent plasticity. This study determined if delaying exercise intervention until pain is detected would similarly ameliorate established SCI-induced pain. Adult, female Sprague-Dawley rats with a C5 unilateral contusion were separated into SCI allodynic and SCI non-allodynic cohorts at 14 or 28 days postinjury when half of each group began exercising on automated running wheels. Allodynia, assessed by von Frey testing, was not ameliorated by exercise. Furthermore, rats that began exercise with no allodynia developed paw hypersensitivity within 2 weeks. At the initiation of exercise, the SCI Allodynia group displayed marked overlap of peptidergic and non-peptidergic nociceptive afferents in the C7 and L5 dorsal horn, while the SCI No Allodynia group had scant overlap. At the end of 5 weeks of exercise both the SCI Allodynia and SCI No Allodynia groups had extensive overlap of the 2 c-fiber types. Our findings show that exercise therapy initiated at early stages of allodynia is ineffective at attenuating neuropathic pain, but rather that it induces allodynia-aberrant afferent plasticity in previously pain-free rats. These data, combined with our previous results, suggest that there is a critical therapeutic window when exercise therapy may be effective at treating SCI-induced allodynia and that there are postinjury periods when exercise can be deleterious.



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Psychosocial Factors and Sport Injuries: Meta-analyses for Prediction and Prevention

Abstract

Background

Several studies have suggested that psychosocial variables can increase the risk of becoming injured during sport participation.

Objectives

The main objectives of these meta-analyses were to examine (i) the effect sizes of relationships between the psychosocial variables (suggested as injury predictors in the model of stress and athletic injury) and injury rates, and (ii) the effects of psychological interventions aimed at reducing injury occurrence (prevention).

Methods

Electronic databases as well as specific sport and exercise psychology journals were searched. The literature review resulted in 48 published studies containing 161 effect sizes for injury prediction and seven effect sizes for injury prevention.

Results

The results showed that stress responses (r = 0.27, 80 % CI [0.20, 0.33]) and history of stressors (r = 0.13, 80 % CI [0.11, 0.15]) had the strongest associations with injury rates. Also, the results from the path analysis showed that the stress response mediated the relationship between history of stressors and injury rates. For injury prevention studies, all studies included (N = 7) showed decreased injury rates in the treatment groups compared to control groups.

Conclusion

The results support the model's suggestion that psychosocial variables, as well as psychologically, based interventions, can influence injury risk among athletes.



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Ischaemic preconditioning does not alter the determinants of endurance running performance in the heat

Abstract

Purpose

Ischaemic preconditioning (IP) has been shown to be ergogenic for endurance performance in normothermic conditions and alleviate physiological strain under hypoxia, potentially through haemodynamic and/or metabolic mechanisms. Exertional hyperthermia is characterised by competition for blood flow between the muscles and skin, an enhanced metabolic strain and impaired endurance performance. This study investigated the effect of IP on the determinants of endurance performance, through an incremental exercise test in the heat.

Method

Eleven males completed two graded exercise tests in the heat (32 °C, 62 % RH) until volitional exhaustion, preceded by IP (4 × 5 min 220 mmHg bilateral upper leg occlusion) or a control (CON) condition (4 × 5-min 50 mmHg bilateral).

Result

IP did not improve running speeds at fixed blood lactate concentrations of 2 and 4 mMol L−1 (p = 0.828), or affect blood glucose concentration throughout the trial [mean (±SD); CON 5.03 (0.94) mMol L−1, IP 5.47 (1.38) mMol L−1, p = 0.260). There was no difference in \(\dot{V}\) O2max [CON 55.5 (3.7) mL kg−1 min−1, IP 56.0 (2.6) mL kg−1 min−1, p = 0.436], average running economy [CON 222.3 (18.0) mL kg−1 km−1, IP 218.9 (16.5) mL kg−1 km−1, p = 0.125], or total running time during graded exercise [CON 347 (42) s, IP 379 (68) s, p = 0.166]. The IP procedure did not change muscle temperature [CON ∆ = 0.55 (0.57) °C, IP ∆ = 0.78 (0.85) °C, p = 0.568], but did reduce T CORE during exercise (~−0.1 °C, p = 0.001).

Conclusion

The novel application of IP prior to exercise in the heat does not enhance the determinants of endurance performance. For events where IP appears ergogenic, muscle warming strategies are unnecessary as IP does not influence deep muscle temperature.



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Nerve excitation using an amplitude-modulated signal with kilohertz-frequency carrier and non-zero offset

Incorporating kilohertz-frequency signals in transcutaneous electrical stimulation has been proposed as a means to overcome the impedance of the skin, thereby reaching deeper nerves. In particular, a transderm...

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Regional block: who first thought of such an approach?



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De novo assembly of A. thaliana Ler [Genetics]

Resequencing or reference-based assemblies reveal large parts of the small-scale sequence variation. However, they typically fail to separate such local variation into colinear and rearranged variation, because they usually do not recover the complement of large-scale rearrangements, including transpositions and inversions. Besides the availability of hundreds of genomes of diverse...

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Mutations in Human Interferon α2b Gene and Potential as Risk Factor Associated with Female Breast Cancer

Cancer Biotherapy & Radiopharmaceuticals , Vol. 0, No. 0.


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Mutations in Human Interferon α2b Gene and Potential as Risk Factor Associated with Female Breast Cancer

Cancer Biotherapy & Radiopharmaceuticals , Vol. 0, No. 0.


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Chronotype and academic performance of adolescents

2016-07-12T09-33-35Z
Source: National Journal of Physiology, Pharmacy and Pharmacology
Yogananda Reddy Indla, Mohammed Aleemuddin, Yamini Devulapally, Yanadi Reddy Male, Rameshwari Reddy, Rameswarudu Mummadi, Swathi Ammireddy, Srilekha Varikunta.
Background: Performance of an individual at physical and mental level depends on many factors and chronotype is one among them. Aims and Objectives: To categorize the subjects into different chronotype groups based on Horne-Ostbergs morningness-eveningness questionnaire. To illustrate the academic performance of the subjects by recording their scores obtained in the physiology internal assessment theory examination. To observe the relation between chronotype group and their academic performance. Materials and Methods: After making them to understand the methods and objectives of the study, written informed consent was obtained from 150 adolescents of aged between 17 and 19 years; both the genders were included in the study. Horne-Ostbergs morningness-eveningness questionnaire has 19 questions and points against each of them. All the points are added and then the total scores are obtained. Scores can range from 16 to 86; scores ≤41 indicate evening type and scores ≥59 indicate morning type, and scores between 42 and 58 are intermediate type. Physiology internal assessment theory examination was conducted for maximum 50 marks; obtained marks were entered. Results: Mean scores obtained in the physiology theory examination by moderate evening, intermediate, and moderate morning chronotypic groups are 23.2 (8.5), 25.2 (6.8), and 25.6 (6.3), respectively (P = 0.649). Conclusion: Academic performance of the students is independent of their chronotype.


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Motor nerve conduction parameters in patients with iron deficiency anemia

2016-07-12T09-33-35Z
Source: National Journal of Physiology, Pharmacy and Pharmacology
Anandhalakshmi Swaminathan, Subramaniyan Kumarasamy, Sundar Shanmugam, Saravanan Ayyavoo, Sundaravadivelu Velayutham.
Background: Worldwide, iron deficiency anemia (IDA) is the most common nutritional problem. Iron is very essential and has many important functions in brain energy metabolism, neurotransmitter function, and myelin formation. IDA may cause nerve dysfunctions. Aims and Objectives: The purpose of the present study was to investigate the effects of IDA on peripheral motor nerve function. Materials and Methods: A total of 40 individuals (25 females and 15 males) with IDA in the age range of 20-50 years from the Department of Medicine, SRM Medical College, as the study group and 30 participants (20 females and 10 males) without anemia as the control group were enrolled into this cross-sectional study. Patients with history of diabetes mellitus, neuromuscular, metabolic, vasculitic, or rheumatologic diseases and those taking medications that may alter central or peripheral nerve function were excluded from the study. The motor nerve conduction parameters, viz., distal latency, amplitude of compound muscle action potential (CMAP), and motor nerve conduction velocity (MNCV) were recorded bilaterally in median, ulnar, and posterior tibial nerves using standard protocols and settings. Values from patients were compared with those of controls by unpaired students t-test and one-way ANOVA. Results: The observations revealed significantly prolonged distal motor latencies, reduced CMAP amplitudes, and slowed MNCV in the peripheral nerves in IDA. Conclusion: The results indicated that the alteration in motor conduction parameters in IDA might be due to various functional and structural changes in peripheral nerves associated with iron deficiency.


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Use of multiple choice questions during lectures helps medical students improve their performance in written formative assessment in physiology

2016-07-12T09-33-35Z
Source: National Journal of Physiology, Pharmacy and Pharmacology
Madhu Bhatt, Shelka Dua.
Background: Multiple choice questions (MCQs) play a pivotal role in various types of assessment in medical schools, due to the ease with which these can be administered and evaluated. Although primarily employed for assessment, the direct role of MCQ-assisted teaching learning (MATeL) may be explored among teachers and students as an aid to learning. Aims and Objectives: The present study endeavors to evaluate how MATeL helps students improve their performance and to explore the correlation between MCQ and short answer questions (SAQ) performance of students on a given topic of instruction in physiology. Materials and Methods: For MATeL topics, a total of 25 MCQs, based on five specific learning objectives, were discussed with 94 students of the 1st year Bachelor of Medicine and Bachelor of Surgery course, and in-depth evaluation of each of the correct choices was done during the lectures. For the non-MATeL topics, the students were advised to read up the topic before the lecture which was followed by an exhaustive discussion on the same. At the end of the lecture series, a formative written assessment was carried, and the MCQ and SAQ scores were analyzed for each of the students. Results: Mean scores for both SAQs and MCQs was significantly higher in MATeL than the non-MATeL topics (SAQs 5.31 vs. 4.36, t = 2.5; MCQs 7.18 vs. 6.68, t = 5.23). There was a good correlation between total MCQ and total SAQ scores for the students (r = 0.34, P

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Effect of acute isotonic exercise on cardiovascular functional status among adolescents with different body mass indices

2016-07-12T09-33-35Z
Source: National Journal of Physiology, Pharmacy and Pharmacology
Swathi Ammireddy, Yogananda Reddy Indla, Yanadi Reddy Male, Rameshwari Reddy, Rameswarudu Mummadi, Yamini Devulapally, Aleemuddin Mohammed, Srilekha Varikunta.
Background: Although within the physiological range, overweight and obese adolescents, who are otherwise normal, have blood pressures at the higher side, whereas underweight adolescents have lower blood pressures when compared with the normal weight individuals. Aims and Objectives: (1) To assess the functional status of the cardiovascular system by measuring the heart rate (HR) and blood pressure in adolescents with different body mass indices (BMI) at rest. (2) To illustrate the response of the cardiovascular system to acute isotonic exercise by recording the HR and blood pressure in normal weight, underweight, and overweight adolescents. Materials and Methods: A total of 44 adolescents, aged between 17 and 19 years with different BMI, are the study group. Subjects are categorized into underweight, normal weight, and overweight/obese group based on their BMI. HR and blood pressure were recorded before and immediately after the acute bicycle ergometer exercise test, with three finger test and sphygmomanometer, respectively. Results: Increase in HR, systolic blood pressure (SBP), and pulse pressure (PP) in diastolic blood pressure (DBP) were observed immediately after the exercise (P = 0.000) among all the subjects. Before the exercise, SBP, DBP, and mean arterial blood pressure (P = 0.002, 0.008, and 0.003) and after the exercise, SBP and PP (P = 0.007 and 0.037) are significant among underweight, normal weight, and overweight subjects. Conclusion: Overweight/obese adolescents are having higher blood pressure at rest. SBP and PP were increased more in overweight/ obese adolescents after the exercise than the normal weight subjects.


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Patients with Endoscopically Visible Polypoid Adenomatous Lesions Within the Extent of Ulcerative Colitis Have an Increased Risk of Colorectal Cancer Despite Endoscopic Resection

Abstract

Objectives

Ulcerative colitis (UC) is associated with an increased risk of colorectal cancer (CRC). Few studies have looked at long-term outcomes of endoscopically visible adenomatous lesions removed by endoscopic resection in these patients. We aimed to assess the risk of developing CRC in UC patients with adenomatous lesions that develop within the segment of colitis compared to the remainder of an ulcerative colitis cohort.

Methods

We identified patients with a confirmed histological diagnosis of UC from 1991 to 2004 and noted outcomes till June 2011. The Kaplan–Meier method was used to estimate cumulative probability of subsequent CRC. Factors associated with risk of CRC were assessed in a Cox proportional hazards model.

Results

Twenty-nine of 301 patients with UC had adenomatous lesions noted within the segment of colitis. The crude incidence rate of developing colon cancer in patients with UC was 2.45 (95 % CI 1.06–4.83) per 1000 PYD and in those with UC and polypoid adenomas within the extent of inflammation was 11.07 (95 % CI 3.59–25.83) per 1000 PYD. Adjusted hazards ratio of developing CRC on follow-up in UC patients with polypoid dysplastic adenomatous lesions within the extent of inflammation was 4.0 (95 % CI 1.3–12.4).

Conclusions

The risk of developing CRC is significantly higher in UC patients with polypoid adenomatous lesions, within the extent of inflammation, despite endoscopic resection. Patients and physicians should take the increased risk into consideration during follow-up of these patients.



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Recalibrating the Child–Turcotte–Pugh Score to Improve Prediction of Transplant-Free Survival in Patients with Cirrhosis

Abstract

Background

The Child–Turcotte–Pugh (CTP) score is a widely used and validated predictor of long-term survival in cirrhosis. However, the cutpoints for stratifying laboratory variables in CTP have never been validated.

Objective

The objective of this study was to identify evidence-based cutpoints for the CTP laboratory subscores to improve its predictive capacity for transplant-free survival.

Design

Retrospective observational study.

Data Source

Using a cohort of 30,897 cirrhotic US Veteran patients with at least 5 years of follow-up, we performed Cox proportional hazard survival model iterations varying the upper and lower cutpoints for INR, total bilirubin and albumin CTP subscores. Cutpoints yielding the highest Harrell's C-statistics for concordance with transplant-free survival were incorporated into a modified CTP (mCTP) score. Validation of the mCTP was performed at multiple time frames within the follow-up period of the cohort and within subsets defined by disease etiology.

Results

Modification of CTP cutpoints increased the Harrell's C-statistic for age- and gender-adjusted Cox proportional hazard models from 0.701 ± 0.002 to 0.709 ± 0.002 and the risk ratio per unit change from 1.49 (1.48–1.50) to 1.53 (1.52–1.54). The modified cutpoints showed superiority in predicting 5-year transplant-free survival in various disease etiology subgroups. A mCTP substituting serum creatinine for INR performed superiorly for predicting 5-year transplant-free survival.

Conclusion

We propose an evidence-based recalibration of CTP score cutpoints that optimizes this model's capacity to predict transplant-free survival in patients with cirrhosis. The CTP score remains the best predictor of 5-year overall and transplant-free survival in patients with cirrhosis.



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A Longitudinal Study of Adenoma Detection Rate in Gastroenterology Fellowship Training

Abstract

Background

Current guidelines suggest that a gastroenterology fellow in training needs to perform 140 colonoscopies to achieve competency. Data are limited regarding adenoma detection rate (ADR) in fellowship.

Aims

To assess how fellow ADR correlates with number of colonoscopies performed.

Methods

We performed a retrospective study examining consecutive colonoscopies performed by gastroenterology fellows. Fellow ADR before and after the 140 procedure benchmark was compared to colonoscopies performed by attending only with whom these fellows trained. A threshold for ideal procedure count was performed using ROC analysis.

Results

We analyzed 2021 average-risk colonoscopies performed by 10 gastroenterology fellows under the supervision of an attending physician. When fellows had performed <140 colonoscopies, the ADR was 27 % compared with an ADR of 36 % when fellows had performed >140 colonoscopies under attending supervision (p = 0.02). The ADR of fellows who had performed >140 colonoscopies under attending supervision was greater than that of attending-only colonoscopies (36 vs. 25 %, p < 0.0001). A threshold of >325 (male patients) and 539 (female patients) colonoscopies was determined to be ideal for achieving adequate ADR based on ROC analysis.

Conclusions

Our data suggest that ADR increases after fellows perform >140 colonoscopies under attending supervision, and thereafter surpasses the ADR of attending-only colonoscopies. Some of the differences may be driven by detection of small adenomas. The findings of this study suggest that a higher threshold for number of colonoscopies performed under attending supervision may be needed to achieve adequate ADR during fellowship prior to independent practice.



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Cloning and analysis of promoter region of mouse immunoglobulin germline γ3 transcripts

Abstract

The germline γ3 transcripts (GLTγ3) is transcribed by mouse B cells following stimulation with lipopolysaccharide (LPS). GLTγ3 transcription is a prerequisite for IgG3 class switching. However, to date, the promoter activity of GLTγ3 has not been investigated. In this study, we constructed GLTγ3 promoter reporters and tested their promoter activities following LPS stimulation in B cells. Among the reporters, pGL3-γ3(F4) had the highest basal activity and was optimally activated by LPS. Deletion of the first and second conserved sequences (CS1 and CS2) in the GLTγ3 promoter abrogated LPS-induced promoter activity. In addition, DNase I-hypersensitive site 1,2 (HS1,2) further enhanced GLTγ3 promoter activity. These findings indicate that CS1 and CS2 of the GLTγ3 promoter are essential for LPS-induced GLTγ3 transcription and that HS1,2 enhances transcription.



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A betaine aldehyde dehydrogenase gene in quinoa ( Chenopodium quinoa ): structure, phylogeny, and expression pattern

Abstract

Betaine aldehyde dehydrogenase (BADH) is widely considered as a key enzyme in glycine betaine metabolism in higher plants. Several paralogous genes encoding different isozymes of BADH have been identified and characterized in some plants; however, until now, only limited information is available about BADH genes in quinoa (Chenopodium quinoa). Here, we report the molecular cloning, structural organization, phylogenetic evolution, and expression profile of a BADH gene (CqBADH1) from quinoa. The translated putative CqBADH1 protein included five conserved features of the ALDH Family 10. Comparisons between the cDNA and genomic sequences revealed that the CqBADH1 gene contained 15 exons and 14 introns. Comparative screening of introns in homologous genes demonstrated that the number and position of the BADH introns were highly conserved among the BADH genes in Amaranthaceae plants and in other more distantly related plant species. A phylogenetic analysis showed that CqBADH1 had the closest relationship with a protein from Atriplex canescens and belonged to the ALDH10 family. Expression profile analyses indicated that CqBADH1 was expressed only in root, and showed time-dependent expression profiles under NaCl-stress condition. Moreover, in quinoa, NaCl stress led to increased levels of CqBADH1 mRNA accompanied by the accumulation of glycine betaine. This is the first study to describe a BADH gene in quinoa.



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Interaction between irbesartan, peroxisome proliferator-activated receptor (PPAR-γ), and adiponectin in the regulation of blood pressure and renal function in spontaneously hypertensive rats

Abstract

Adiponectin exerts vasodilatory effects. Irbesartan, an angiotensin receptor blocker, possesses partial peroxisome proliferator-activated receptor gamma (PPAR-γ) agonist activity and increases circulating adiponectin. This study explored the effect of irbesartan alone and in combination with adiponectin on blood pressure, renal hemodynamic excretory function, and vasoactive responses to angiotensin II and adrenergic agonists in spontaneously hypertensive rat (SHR). Irbesartan was given orally (30 mg/kg/day) for 28 days and adiponectin intraperitoneally (2.5 μg/kg/day) for last 7 days. Groups of SHR received either irbesartan or adiponectin or in combination. A group of Wistar Kyoto rats (WKY) served as controls. Metabolic data and plasma samples were taken on days 0, 21, and 28. In acute studies, the renal vasoconstrictor actions of angiotensin II (ANGII), noradrenaline (NA), phenylephrine (PE), and methoxamine (ME) were determined. SHR control rats had a higher mean blood pressure than the WKY (132 ± 7 vs. 98 ± 2 mmHg), lower plasma and urinary adiponectin, creatinine clearance, urine flow rate and sodium excretion, and oxidative stress markers compared to WKY (all P < 0.05) which were progressively normalized by the individual drug treatments and to a greater extent by combined treatment. Responses to intrarenal administration of NA, PE, ME, and ANGII were larger in SHR (P < 0.05) than WKY by 20–25 %. Irbesartan enhanced (P < 0.05) responses to NA and PE, while adiponectin blunted responses to all vasoconstrictors (all P < 0.05). Combined treatment in SHR further decreased the renal vascular responses to ANGII. These findings suggest that an interactive relationship may exist between PPAR-γ, alpha adrenoceptors, and ANGII in the renal vasculature of the SHR.



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Correlation of foot length and gestational maturity in neonates

2016-07-12T07-40-08Z
Source: International Journal of Contemporary Pediatrics
Sunil Gavhane, Anjali Kale, Akshay Golawankar, Avinash Sangle.
Background: Accurate assessment of gestation maturity is not possible in all newborn infants specially when they are sick and need intensive care support. The aim was to study correlation of foot length (FL) with gestational age and other anthropometric measures at birth among preterm, term and post-term neonates. Methods: Prospective observational study was done. 800 babies born at MGM Medical College Aurangabad from December 2012 to November 2014 were enrolled. FL at birth was measured from the center of the back of the heel to the tip of the big toe. Gestational assessment was done using modified Ballards scoring on day one. Based on gestational age, babies were grouped as preterm, term and post term babies. All the three groups of babies were categorised into small for gestational age (SGA), appropriate for gestational age (AGA) and large for gestational age (LGA) groups using lubchenco intrauterine growth curves. Linear regression analysis was done to investigate the relation of FL to gestational age, birth weight (BW), head circumference (HC) and crown heel length (CHL). Results: There were 52.5% males and 47.5% females. Of the 800 newborns, preterm babies were 124 (15.5%), term babies were 604 (75.5%) and post-term babies were 72 (9%). The mean foot length was 7.42 cm with a range of 4.5-8.8 cm. Foot length correlated significantly (p


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A cross-sectional study of prevalence and determinants of depression among stroke patients

2016-07-12T07-36-43Z
Source: International Journal of Advances in Medicine
Jim Litton, Lokesh S..
Background: The association between depression and stroke is well known. Few studies show that lesion side and site are associated with post-stroke depression (PSD), but there exists a vast discrepancy in the results among various studies. The prevalence of post stroke depression also varies widely. In India there is paucity in the amount of literature in this context. Early detection of depression is of prime importance for better outcomes. The study was mainly intended to find out these variations. Methods: To study the prevalence of post stroke depression, the neuroanatomical correlation of post stroke depression and impact of comorbid conditions in post stroke depression. This cross sectional study was designed at medicine department of MGMCRI, Puducherry, India. All adult patients with stroke (>40 years) presenting to the emergency medical services (EMS) and department of medicine were enrolled. Patients fulfilling the inclusion criteria were taken up for the study after obtaining consent. Data about pre-existing comorbid illness such as diabetes, hypertension, ischaemic heart disease and substance abuse like smoking, alcohol use were collected. Complete physical examination and CNS examination were performed. The findings of CT brain were documented including the site of lesion. Depression was assessed on the 14th day after stroke using PHQ-9 questionnaire. Chi square and regression analysis were employed for statistical analysis. Results: The mean age of subjects in this study was found to be 63.84±11.40 years. The prevalence of severe depression in this study was 47%. Milder form of depression was found in 53% of the subjects. Of the total population studied, statistically significant severe depression was associated with patients who had lesion on left hemisphere. Conclusions: Post stroke depression is more associated primarily with left sided hemispheric lesions. The prevalence of significant post stroke depression in present study was 47%. This study highlights the importance of screening stroke patients for depression. Early intervention of post stroke depression can lead to better outcomes.


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The effects of respiratory sinus arrhythmia on anger reactivity and persistence in major depression

Abstract

The experience of anger during a depressive episode has recently been identified as a poor prognostic indicator of illness course. Given the clinical implications of anger in major depressive disorder (MDD), understanding the mechanisms involved in anger reactivity and persistence is critical for improved intervention. Biological processes involved in emotion regulation during stress, such as respiratory sinus arrhythmia (RSA), may play a role in maintaining negative moods. Clinically depressed (MDD; n = 49) and nondepressed (non-MDD; n = 50) individuals were challenged with a stressful computer task shown to increase anger, while RSA (high frequency range 0.15–0.4 Hz) was collected. RSA predicted future anger, but was unrelated to current anger. That is, across participants, low baseline RSA predicted anger reactivity during the task, and in depressed individuals, those with low RSA during the task had a greater likelihood of anger persistence during a recovery period. These results suggest that low RSA may be a psychophysiological process involved in anger regulation in depression. Low RSA may contribute to sustained illness course by diminishing the repair of angry moods.



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Examining habituation of the startle reflex with the reinforcement sensitivity theory of personality

Abstract

The habituation of the acoustic startle reflex (ASR) was examined concerning individual differences in sensitivity to punishment (PUN) and sensitivity to reward (REW), within the general framework of the reinforcement sensitivity theory (RST) of personality. Two hypotheses derived from the RST were evaluated: the separable subsystems hypothesis and the joint subsystems hypothesis. In addition, we examined the direction of the relationship of PUN and REW with the habituation of the ASR. A habituation segment of electromyography recordings of the orbicularis oculi was assessed with an unconditional latent curve model. In accordance with the RST hypotheses, the relationship of PUN and REW on the habituation process was assessed with two conditional latent curve models. There was higher support for the separable subsystems hypothesis. In addition, PUN and REW related with the habituation trajectory of the ASR in the expected directions. Higher levels of PUN and lower levels of REW related with a slower habituation of the ASR, whereas lower levels of PUN and higher levels of REW related with a faster habituation of the ASR.



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Role of self help groups in women empowerment and health

2016-07-12T04-48-45Z
Source: International Journal of Community Medicine and Public Health
Narasimha B.C., Anand P., Ravish K.S., Navya S. S., Ranganath T. S..
Background: Self-help groups (SHGs) are small voluntary association of people from the same socio-economic background with a purpose of solving their common problems through self-help and mutual help. Since Women empowerment and health are interrelated -women's empowerment cannot be achieved by ignoring issues related to health of women. There have been fewer attempts to address the issue of women's health so as to have an impact on their total wellbeing. Hence the present study intends to explore the extent to which self-help groups are involved in health and also identify other possible methods to increase their involvement in health related matters. Methods: A Community based cross sectional study was conducted in urban field practice area of Bangalore Medical College and Research Institute. Banglore, India. 95 women who were involved in SHG for 1 year were interviewed by a pre- validated questionnaire. Results: Out of 98 women 95 were interviewed, 62.1% were literates, 65.26% received economic help through this programme, 26.3% got importance in family as well as community, 21% had improvement in personal health, 68.4% of individuals self decides to seek medical care for health related issues. Conclusions: Self-help group is a useful platform to enhance women's health through increased knowledge and awareness on health issues, and financial security during health emergencies etc. its very active in providing income generating activities. However there is no much significant improvement in health behaviour or knowledge about health related issues.


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Perioperative management of pediatric en-bloc combined heart–liver transplants: a case series review

Summary

Background

Combined heart and liver transplantation (CHLT) in the pediatric population involves a complex group of patients, many of whom have palliated congenital heart disease (CHD) involving single ventricle physiology.

Objective

The purpose of this study was to describe the perioperative management of pediatric patients undergoing CHLT at a single institution and to identify management strategies that may be used to optimize perioperative care.

Methods

We did a retrospective database review of all patients receiving CHLT at a children's hospital between 2006 and 2014. Information collected included preoperative characteristics, intraoperative management, blood transfusions, and postoperative morbidity and mortality.

Results

Five pediatric CHLTs were performed over an 8-year period. All patients had a history of complex CHD with multiple sternotomies, three of whom had failing Fontan physiology. Patient age ranged from 7 to 23 years and weight from 29.5 to 68.5 kg. All CHLTs were performed using an en-bloc technique where both the donor heart and liver were implanted together on cardiopulmonary bypass (CPB). The median operating room time was 14.25 h, median CPB time was 3.58 h, and median donor ischemia time was 4.13 h. Patients separated from CPB on dopamine, epinephrine, and milrinone infusions and two required inhaled nitric oxide. All patients received a massive intraoperative blood transfusion post CPB with amounts ranging from one to three times the patient's estimated blood volume. The patient who required the most transfusions was in decompensated heart and liver failure preoperatively. Four of the five patients received an antifibrinolytic agent as well as a procoagulant (prothrombin complex concentrate or recombinant activated Factor VII) to assist with hemostasis. There were no 30-day thromboembolic events detected. Postoperatively the median length of mechanical ventilation, ICU stay and stay to hospital discharge was 4, 8, and 37 days, respectively. All patients are alive and free from allograft rejection at this time.

Conclusion

Combined heart and liver transplantation in the pediatric population involves a complex group of patients with unique perioperative challenges. Successful management starts with thorough preoperative planning and communication and involves strategies to deal with massive intraoperative hemorrhage and coagulopathy in addition to protecting and supporting the transplanted heart and liver and meticulous surgical technique. An integrated multidisciplinary team approach is the cornerstone for successful outcomes.

Thumbnail image of graphical abstract

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Sources of Error in Mammalian Genetic Screens

Genetic screens are invaluable tools for dissection of biological phenomena. Optimization of such screens to enhance discovery of candidate genes and minimize false positives is thus a critical aim. Here we report several sources of error common to pooled genetic screening techniques used in mammalian cell culture systems and demonstrate methods to eliminate these errors. We find that reverse transcriptase-mediated recombination during retroviral replication can lead to uncoupling of molecular tags such as DNA barcodes from their associated library elements, leading to chimeric proviral genomes in which barcodes are paired to incorrect ORFs, shRNAs, etc. This effect depends on the length of homologous sequence between unique elements and can be minimized with careful vector design. Furthermore, we report that residual plasmid DNA from viral packaging procedures can contaminate transduced cells. These plasmids serve as additional copies of the PCR template during library amplification, resulting in substantial inaccuracies in measurement of initial reference populations for screen normalization. The over-abundance of template in some samples causes an imbalance between PCR cycles of contaminated and uncontaminated samples which results in a systemic artifactual depletion of GC-rich library elements. Elimination of contaminating plasmid DNA using the bacterial endonuclease Benzonase can restore faithful measurements of template abundance and minimize GC bias.



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A Split-Ubiquitin Based Strategy Selecting for Protein Complex-Interfering Mutations

Understanding the topologies and functions of protein interaction networks requires the selective removal of single interactions. We introduce a selection strategy that enriches among a random library of alleles for mutations that impair the binding to a given partner protein. The selection makes use of a Split-Ubiquitin based protein interaction assay. This assay provides yeast cells that carry protein complex disturbing mutations with the advantage to survive on uracil-lacking media. Applied to the exemplary interaction between the PB domains of the yeast proteins Bem1 and Cdc24, we performed two independent selections. The selections were either analyzed by Sanger sequencing of isolated clones or by Next Generation Sequencing (NGS) of pools of clones. Both screens enriched for the same mutation in position 833 of Cdc24. Biochemical analysis confirmed that this mutation disturbs the interaction with Bem1 but not the fold of the protein. The larger data set obtained by NGS achieved a more complete representation of the bipartite interaction interface of Cdc24.



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Canopy Temperature and Vegetation Indices from High-Throughput Phenotyping Improve Accuracy of Pedigree and Genomic Selection for Grain Yield in Wheat

Genomic selection can be applied prior to phenotyping, enabling shorter breeding cycles and greater rates of genetic gain relative to phenotypic selection. Traits measured using high-throughput phenotyping based on proximal or remote sensing could be useful for improving pedigree and genomic prediction model accuracies for traits not yet possible to phenotype directly. We tested if using aerial measurements of canopy temperature and green and red normalized difference vegetation index as secondary traits in pedigree and genomic best linear unbiased prediction models could increase accuracy for grain yield in wheat, Triticum aestivum L., using 557 lines in five environments. Secondary traits on training and test sets, and grain yield on the training set were modeled as multivariate and compared to univariate models with grain yield on the training set only. Cross validation accuracies were estimated within and across-environment, with and without replication, and with and without correcting for days to 34 heading. We observed that within environment, with unreplicated secondary trait data, and without correcting for days to heading, secondary traits increased accuracies for grain yield by 56% in pedigree and 70% in genomic prediction models on average. Secondary traits increased accuracy slightly more when replicated and considerably less when models corrected for days to heading. In across-environment prediction, trends were similar but less consistent. These results show that secondary traits measured in high-throughput could be used in pedigree and genomic prediction to improve accuracy. This approach could improve selection in wheat during early stages if validated in early-generation breeding plots.



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ChloroSeq, an Optimized Chloroplast RNA-Seq Bioinformatic Pipeline, Reveals Remodeling of the Organellar Transcriptome Under Heat Stress

Although RNA-Seq has revolutionized transcript analysis, organellar transcriptomes are rarely assessed even when present in published datasets. Here we describe the development and application of a rapid and convenient method, ChloroSeq, to delineate qualitative and quantitative features of chloroplast RNA metabolism from strand-specific RNA-Seq datasets, including processing, editing, splicing, and relative transcript abundance. The use of a single experiment to analyze systematically chloroplast transcript maturation and abundance is of particular interest due to frequent pleiotropic effects observed in mutants that affect chloroplast gene expression and/or photosynthesis. To illustrate its utility, ChloroSeq was applied to published RNA-Seq datasets derived from Arabidopsis thaliana grown under control and abiotic stress conditions, where the organellar transcriptome had not been examined. The most appreciable effects were found for heat stress, which induces a global reduction in splicing and editing efficiency, and leads to increased abundance of chloroplast transcripts, including genic, intergenic and antisense transcripts. Moreover, by concomitantly analyzing nuclear transcripts that encode chloroplast gene expression regulators from the same libraries, we demonstrate the possibility of achieving a holistic understanding of the nucleus-organelle system. ChloroSeq thus represents a unique method for streamlining RNA-Seq data interpretation of the chloroplast transcriptome and its regulators.



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Genomic Signatures of North American Soybean Improvement Inform Diversity Enrichment Strategies and Clarify the Impact of Hybridization

Crop improvement represents a long-running experiment in artificial selection on a complex trait, namely yield. How such selection relates to natural populations is unclear, but the analysis of domesticated populations could offer insights into the relative role of selection, drift, and recombination in all species facing major shifts in selective regimes. Because of the extreme autogamy exhibited by soybean (Glycine max), many "immortalized" genotypes of elite varieties spanning the last century have been preserved and characterized using ~50,000 single-nucleotide polymorphic (SNP) markers. Also due to autogamy, the history of North American soybean breeding can be roughly divided into pre- and post-hybridization eras, allowing for direct interrogation of the role of recombination in improvement and selection. Here we report on genome-wide characterization of the structure and history of North American soybean populations and the signature of selection in these populations. Supporting previous work, we find that maturity defines population structure. Though the diversity of North American ancestors is comparable to available landraces, pre-hybridization line selections resulted in a clonal structure that dominated early breeding and explain many of the reductions in diversity found in the initial generations of soybean hybridization. The rate of allele frequency change does not deviate sharply from neutral expectation, yet some regions bare hallmarks of strong selection, suggesting a highly variable range of selection strengths biased toward weak effects. We also discuss the importance of haplotypes as units of analysis when complex traits fall under novel selection regimes.



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Covariance Between Genotypic Effects and its Use for Genomic Inference in Half-Sib Families

In livestock, current statistical approaches utilize extensive molecular data, e.g., single nucleotide polymorphisms (SNPs), to improve the genetic evaluation of individuals. The number of model parameters increases with the number of SNPs, so the multicollinearity between covariates can affect the results obtained using whole genome regression methods. In this study, dependencies between SNPs due to linkage and linkage disequilibrium among the chromosome segments were explicitly considered in methods used to estimate the effects of SNPs. The population structure affects the extent of such dependencies, so the covariance among SNP genotypes was derived for half-sib families, which are typical in livestock populations. Conditional on the SNP haplotypes of the common parent (sire), the theoretical covariance was determined using the haplotype frequencies of the population from which the individual parent (dam) was derived. The resulting covariance matrix was included in a statistical model for a trait of interest, and this covariance matrix was then used to specify prior assumptions for SNP effects in a Bayesian framework. The approach was applied to one family in simulated scenarios (few and many quantitative trait loci) and using semi-real data obtained from dairy cattle to identify genome segments that affect performance traits, as well as to investigate the impact on predictive ability. Compared with a method that does not explicitly consider any of the relationship among predictor variables, the accuracy of genetic value prediction was improved by 10 to 22%. The results show that the inclusion of dependence is particularly important for genomic inference based on small sample sizes.



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Microsporidia Intracellular Development Relies on Myc Interaction Network Transcription Factors in the Host

Microsporidia are ubiquitous parasites that infect a wide range of animal hosts, and these fungal-related microbes undergo their entire replicative lifecycle inside of host cells. Despite being widespread in the environment and causing medical and agricultural harm, virtually nothing is known about the host factors important to facilitate their growth and development inside of host cells. Here we perform a genetic screen to identify host transcription factors important for development of the microsporidian pathogen N. parisii inside intestinal cells of its natural host, the nematode C. elegans. Through this screen we identified the C. elegans Myc family of transcription factors as key host regulators of microsporidia growth and development. The Mad-like transcription factor MDL-1, and the Max-like transcription factors MXL-1 and MXL-2 promote pathogen levels, while the Myc-Mondo-like transcription factor MML-1 inhibits pathogen levels. We used epistasis analysis to show that MDL-1 and MXL-1, which are thought to function as a heterodimer, appear to be acting canonically. In contrast, MXL-2 and MML-1, which are also thought to function as a heterodimer, appear to be acting in separate pathways (non-canonically) in the context of pathogen infection. We also found that both MDL-1::GFP and MML-1::GFP are expressed in intestinal cells during infection. These findings provide novel insight into the host transcription factors that regulate microsporidia development.



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A Comparative Analysis of 5-Azacytidine and Zebularine induced DNA Demethylation

The non-methylable cytosine analogs, 5-azacytidine and zebularine, are widely used to inhibit DNA methyltransferase activity and reduce genomic DNA methylation. In this study, whole-genome bisulfite sequencing is used to construct maps of DNA methylation with single base pair resolution in Arabidopsis thaliana seedlings treated with each demethylating agent. We find that both inhibitor treatments result in nearly indistinguishable patterns of genome-wide DNA methylation and that 5-azacytidine had a slightly greater demethylating effect at higher concentrations across the genome. Transcriptome analyses revealed a substantial number of up-regulated genes, with an overrepresentation of transposable element genes, in particular CACTA-like elements. This demonstrates that chemical demethylating agents have a disproportionately large effect on loci that are otherwise silenced by DNA methylation.



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Steatotic hepatocellular carcinoma: A variant associated with metabolic factors and late tumor relapse

Histopathology

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Risk factors for clinical anastomotic leakage after right hemicolectomy

International Journal of Colorectal Disease

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Cost-effectiveness analysis of anal cancer screening in women with cervical neoplasia in British Columbia, Canada

BMC Health Services Research

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Transcutaneous bilirubin levels during the first month of life in term and late-preterm newborns

Journal of Tropical Pediatrics

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Primary sigmoidectomy and appendicostomy for chronic idiopathic constipation

Pediatric Surgery International

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Recovery of gastric ileus following laparoscopic ventral rectopexy within an enhanced recovery protocol

Surgery Today

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Littoral cell angioma of the spleen: A study of 25 cases with confirmation of frequent association with visceral malignancies

Histopathology

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Activation of autonomic thermoeffectors preceding the decision to behaviorally thermoregulate in resting humans

We tested the hypothesis that acute increases in metabolic heat production and sweating precede the initiation of thermoregulatory behavior in resting humans exposed to cool and warm environments. Twelve healthy young subjects passively moved between 17 °C and 40 °C rooms when they felt 'too cool' (C[RIGHTWARDS ARROW]W) or 'too warm' (W[RIGHTWARDS ARROW]C). Skin and internal (intestinal) temperatures, metabolic heat production, local sweat rate (forearm, chest), and cutaneous vascular conductance (CVC; forearm, fingertip) were measured continually. Compared to pre-test Baseline (31.8 ± 0.3 °C), skin temperature was higher at C[RIGHTWARDS ARROW]W (32.0 ± 0.7 °C, P = 0.01) and W[RIGHTWARDS ARROW]C (34.5 ± 0.5 °C, P < 0.01). Internal temperature did not differ (P = 0.12) between Baseline (37.2 ± 0.3 °C), C[RIGHTWARDS ARROW]W (37.2 ± 0.3 °C) or W[RIGHTWARDS ARROW]C (37.0 ± 0.3 °C). Metabolic heat production was not different from Baseline (40 ± 9 W/m2) at C[RIGHTWARDS ARROW]W (39 ± 7 W/m2, P = 0.50). Forearm (0.06 ± 0.01 mg/cm2/min) and chest (0.04 ± 0.02 mg/cm2/min) sweat rate at W[RIGHTWARDS ARROW]C did not differ from Baseline (forearm: 0.05 ± 0.02 mg/cm2/min, chest: 0.04 ± 0.02 mg/cm2/min, P ≥ 0.23). Forearm CVC was not different from Baseline (0.30 ± 0.21 PU/mmHg) at C[RIGHTWARDS ARROW]W (0.24 ± 0.11, P = 0.17), but was higher at W[RIGHTWARDS ARROW]C (0.65 ± 0.33 PU/mmHg, P < 0.01). Fingertip CVC was different from Baseline (2.6 ± 2.0 PU/mmHg) at C[RIGHTWARDS ARROW]W (0.70 ± 0.42 PU/mmHg, P < 0.01) and W[RIGHTWARDS ARROW]C (4.49 ± 1.66 PU/mmHg, P < 0.01). Thermoregulatory behavior at rest in cool and warm environments is preceded by changes in vasomotor tone in glabrous and non-glabrous skin, but not by acute increases in metabolic heat production or sweat rate.

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Simultaneous Detection of Cocaine and Heroin Use: The First Reported Speedball Case in Turkey

2016-07-12T02-08-28Z
Source: European Journal of Forensic Sciences
Zeynep Turkmen, Selda Mercan, Isil Bavunoglu, Munevver Acikkol.
Objective: The speedball is a street language term and refers to multiple drug intakes which generally define the simultaneous use of cocaine and heroin. Recently, speedball abuse listed in international drug reports is increasing not only among the famous people but also in the community and it is difficult to distinguish the speedball abusers from the others. In this study, a speedball case in a serum sample has been demonstrated with the toxicological findings for the first time in Turkey. Case report: A married 33 years old woman was admitted to the Emergency Room at the Cerrahpasa Medical Faculty, with various complaints. There were no obvious signs of an acute intoxication, which may caused by a sympathomimetic agent. After the clinical examination, toxicological analysis was requested from the Forensic Toxicology Laboratory at the Institute of Forensic Sciences. Serum analyses was performed by Gas Chromatography-Mass Spectrometry (GC-MS) and the concentrations at the time of administration were determined as 330,0 ng/mL and 11,23 ng/mL for cocaine and heroin, respectively, along with qualitatively determined 6-Monoacetylmorphine (6-MAM), one of the active metabolites of heroin. Conclusion: Since it is known that the combined drug abuse may increase the effect of each other and cause fatal consequences, it is intended to draw attention to approach during emergency treatments. Multidisciplinary approach between clinicians and toxicology experts will be in the patient's best interest in the case of speedball abuse.


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Integrating Standard Methods of Age Estimation in Western Saudi Childhood and Adolescent.

2016-07-12T02-08-28Z
Source: European Journal of Forensic Sciences
Amin Alshihri, Estie Kruger, Marc Tennant.
The aim of this study was to determine the accuracy of three methods of age estimation, using developing teeth in Western Saudi Arabian children and young adults (4-23 years old). Panoramic radiographs were examined; according to: the London Atlas of Tooth Development (n=241); Demirjians dental maturity scale (n=198); and the stage of third molar development by Mincers method (n=130). All three methods tended to under-estimate age. The London Atlas method underestimated chronological age by 1.6 (±15.0) months; Demirjians method, underestimated by 0.02 (±14.5) months, and Mincer's method, by 6.7 (±26.5) months. Overall the Demirjians method was the most accurate of the three methods. It was concluded that specific dental age methods are applicable for the different ethnic groups in Western Saudi Arabia, and accuracy varies according to age group.


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The Effect of 1-Year of Alagebrium and Moderate-Intensity Exercise Training on Left Ventricular Function during Exercise in Seniors

edentary aging leads to left ventricular (LV) and vascular stiffening due in part to advanced glycation end-products (AGEs) crosslinking of extracellular matrix proteins. Vigorous lifelong exercise ameliorates age-related cardiovascular (CV) stiffening and enhances exercise LV function, though this effect is limited when exercise is initiated later in life. We hypothesized that exercise training might be more effective at improving the impact of age-related CV stiffening during exercise when combined with an AGE cross-link breaker (Alagebrium). Methods: Sixty-two seniors (≥60 yrs) were randomized into four groups: sedentary+placebo, sedentary+Alagebrium, exercise+placebo and exercise+Alagebrium for 1-year. Moderate-intensity aerobic exercise was performed 3-4 sessions/week; controls underwent similar frequency of yoga/balance training. Twenty-four, similarly-aged lifelong exercisers (4-5 sessions/week) served as a comparator for the effect of lifelong exercise on exercising LV function. Oxygen uptake (VO2; Douglas bags), stroke index (SI; acetylene rebreathing) and effective arterial elastance (Ea) were collected at rest, submaximal and maximal exercise. Results: VO2max (23±5 to 25±6 ml/kg/min) increased while SI (35±11 to 39±12 ml/m2) and Ea (4.0±1.1 to 3.7±1.2 mmHg/ml/m2) were improved across all conditions with exercise but remained unchanged in controls (exercise x time, P≤0.018). SI or Ea were not affected by Alagebrium (medication x time, P≥0.468) or its combination with exercise (interaction P≥0.252). After a year of exercise plus Alagebrium, exercise SI and Ea remained substantially below lifelong exercisers (15-24% and 9-22% respectively, P≤0.415). Conclusion: Alagebrium plus exercise had no synergistic effect on exercise LV function and failed to achieve levels associated with lifelong exercise despite a similar exercise frequency.



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Effect of betamethasone, surfactant and positive end-expiratory pressures on lung aeration at birth in preterm rabbits

Antenatal glucocorticoids, exogenous surfactant and positive end-expiratory pressure (PEEP) ventilation are commonly provided to preterm infants to enhance respiratory function after birth. It is unclear how these treatments interact to improve the transition to air-breathing at birth. We investigated the relative contribution of antenatal betamethasone, prophylactic surfactant and PEEP (3 cmH2O) on functional residual capacity (FRC) and dynamic lung compliance (CDL) in preterm (28d GA) rabbit kittens at birth. Kittens were delivered by caesarean section and mechanically ventilated. FRC was calculated from X-ray images and CDL was measured using plethysmography. Without betamethasone, PEEP increased FRC recruitment and CDL. Surfactant did not further increase FRC, but significantly increased CDL. Betamethasone abolished the benefit of PEEP on FRC, but surfactant counteracted this effect of betamethasone. These findings indicate that low PEEP levels are insufficient to establish FRC at birth following betamethasone treatment. However, surfactant reversed the effect of betamethasone and when combined, these two treatments enhanced FRC recruitment irrespective of PEEP level.



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Intermittent hypoxia promotes recovery of respiratory motor function in spinal cord injured mice depleted of serotonin in the central nervous system

We examined the effect of repeated daily exposure to intermittent hypoxia (IH) on the recovery of respiratory and limb motor function in mice genetically depleted of central nervous system serotonin. Electroencephalography, diaphragm activity, ventilation, core body temperature and limb mobility were measured in spontaneously breathing wild type (Tph2+/+) and tryptophan hydroxylase 2 knockout (Tph2-/-) mice. Following a C2 hemisection the mice were exposed daily to IH (i.e. twelve 4-min episodes of 10% oxygen interspersed with 4-min normoxic periods followed by a 90-min end recovery period) or normoxia (i.e. sham protocol - 21% oxygen) for 10 consecutive days. Diaphragm activity recovered to pre-hemisection levels in the Tph2+/+ and Tph2-/- mice following exposure to IH but not normoxia (Tph2+/+ 1.3 ± 0.2 vs. 0.3 ± 0.2; Tph2-/- 1.06 ± 0.1 vs. 0.3 ± 0.1, standardized to pre-hemisection values, p < 0.01). Likewise, recovery of tidal volume and breathing frequency was evident, although breathing frequency values did not return to pre-hemisection levels within the time frame of the protocol. Partial recovery of limb motor function was also evident two weeks after spinal cord hemisection. However, recovery was not dependent on IH or the presence of serotonin in the central nervous system. We conclude that IH promotes recovery of respiratory function but not basic motor tasks. Moreover, we conclude that spontaneous or treatment induced recovery of respiratory and motor limb function is not dependent on serotonin in the central nervous system in a mouse model of spinal cord injury.



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Intermuscular Adipose Tissue and Thigh Muscle Area Dynamics during an 18-Month Randomized Weight Loss Trial

It remains unclear whether intermuscular adipose tissue (IMAT) has any metabolic influence or whether it is merely a marker of abnormalities, as well as what are the effects of specific lifestyle strategies for weight loss on the dynamics of both IMAT and thigh muscle area (TMA). We followed the trajectory of IMAT and TMA during 18-month lifestyle intervention among 278 sedentary participants with abdominal obesity, using magnetic resonance imaging. We measured the resting metabolic rate (RMR) by an indirect calorimeter. Among 273 eligible participants (47.8±9.3 years of age), the mean IMAT was 9.6±4.6 cm2. Baseline IMAT levels were directly correlated with waist circumference, abdominal sub-depots, C-reactive protein and leptin, and inversely correlated with baseline TMA and creatinine (p<0.05 for all). After 18 months (86.3% adherence), both IMAT [-1.6%] and TMA [-3.3%] significantly decreased (p<0.01 vs. baseline). The changes in both IMAT and TMA were similar across the lifestyle intervention groups and directly corresponded with moderate weight loss (p<0.001). IMAT change did not remain independently associated with decreased abdominal sub-depots or improved cardiometabolic parameters after adjustments for age, sex, and 18-month weight loss. In similar models, 18-month TMA loss remained associated with decreased RMR, decreased activity, and with increased fasting glucose levels and IMAT (p<0.05 for all). Unlike other fat depots, IMAT may not represent a unique or specific adipose tissue, instead largely reflecting body weight change per se. Moderate weight loss induced a significant decrease in thigh muscle area, suggesting the importance of resistance training to accompany weight loss programs.



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Predicting metabolic rate during level and uphill outdoor walking using a low-cost GPS receiver

The objective of this study was to assess the accuracy of using speed and grade data obtained from a low-cost global positioning system (GPS) receiver to estimate metabolic rate (MR) during level and uphill outdoor walking. Thirty young, healthy adults performed randomized outdoor walking for 6-min periods at 2.0, 3.5 and 5.0 km⋅h-1 and on three different grades: i) level walking; ii) uphill walking on a 3.7% mean grade; and iii) uphill walking on a 10.8% mean grade. The reference MR (METs and VO2) values were obtained using a portable metabolic system. The speed and grade were obtained using a low-cost GPS receiver (1-Hz recording). The GPS grade ( altitude/distance walked) was calculated using both uncorrected GPS altitude data and GPS altitude data corrected with map projection software. The accuracy of predictions using reference speed and grade (actual[SPEED/GRADE]) data was high (R2=0.85, root-mean-square error [RMSE]=0.68 MET). The accuracy decreased when GPS speed and uncorrected grade (GPS[UNCORRECTED]) data were used, although it remained substantial (R2=0.66, RMSE=1.00 MET). The accuracy was greatly improved when the GPS speed and corrected grade (GPS[CORRECTED]) data were used (R2=0.82, RMSE=0.79 MET). Published predictive equations for walking MR were also cross-validated using actual or GPS speed and grade data when appropriate. The prediction accuracy was very close when either actual[SPEED/GRADE] values or GPS[CORRECTED] values (for level and uphill combined) or GPS speed values (for level walking only) were used. These results offer promising research and clinical applications related to the assessment of energy expenditure during free-living walking.



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Evaluating the control: Mini-pump implantation and breathing behavior in the neonatal rat

We evaluated genioglossus (GG) gross motoneuron morphology, electromyographic (EMG) activities and respiratory patterning in rat pups allowed to develop without interference (unexposed) and pups born to dams subjected to osmotic mini-pump implantation in utero (saline exposed). In experiment one, forty eight Sprague-Dawley rat pups (Charles-River Laboratories) ages post-natal day 7 (P7) through post-natal day 10 (P10) were drawn from two experimental groups: saline-exposed (N=24) and unexposed (N=24) and studied on post-natal day P7, P8, P9, or P10. Pups in both groups were sedated (Inactin hydrate, 70 mg kg-1) and fine-wire electrodes inserted into the genioglossus (GG) muscle of the tongue and intercostal muscles to record EMG activities during breathing in air and at three levels of normoxic hypercapnia (FICO2: 0.03, 0.06, 0.09). Using this approach, we assessed breathing frequency, heart rate, apnea type, respiratory event types and respiratory stability. In experiment two, sixteen rat pups were drawn from the same experimental groups: saline exposed (N=9) and unexposed (N=7) and used in motoneuron labelling studies. In these pups a retrograde dye was injected into the GG muscle, and the brainstems subsequently harvested and sliced. Labeled GG motoneurons were identified with microscopy, and impaled and filled with Lucifer yellow. Double-labeled motoneurons were reconstructed and the number of primary projections and soma volumes calculated. Whereas pups in each group exhibited the same number (p=0.226) and duration (p=0.093) of respiratory event types and comparable motoneuron morphologies, pups in the implant group exhibited more central apneas and respiratory instability relative to pups allowed to develop without interference.



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Correcting the Dynamic Response of a Commercial Oesophageal Balloon-catheter

It is generally recommended that an oesophageal balloon-catheter possess an adequate frequency response up to 15 Hz, such that parameters of respiratory mechanics may be quantified with precision. In our experience, however, we have observed that some commercially-available systems do not display an ideal frequency response (<8-10 Hz). We therefore investigated whether the poor frequency response of a commercially-available oesophageal catheter may be adequately compensated using two numerical techniques: 1) an exponential model correction; and 2) Wiener deconvolution. These two numerical techniques were performed on a commercial balloon-catheter interfaced with 0, 1 and 2 lengths of extension tubing (90 cm each), referred to as configurations L0, L90 and L180, respectively. The frequency response of the balloon-catheter in these configurations was assessed by empirical transfer function analysis, and its "working" range was defined as the frequency beyond which more than 5% amplitude and/or phase distortion was observed. The working frequency range of the uncorrected balloon-catheter extended up to only 10 Hz for L0, and progressively worsened with additional tubing length (L90 = 3 Hz; L180 = 2 Hz). While both numerical methods of correction adequately enhanced the working frequency range of the balloon-catheter to beyond 25 Hz for all length configurations (L0, L90 and L180), Wiener deconvolution consistently provided more accurate corrections. Our data indicate that Wiener deconvolution provides a superior correction of the balloon-catheter's dynamic response, and is more robust to extensions in catheter tube length compared with the exponential correction method.



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Measurement of intraindividual airway tone heterogeneity and its importance in asthma

While airways have some degree of baseline tone, the level and variability of this tone is not known. It is also unclear whether there is a difference in airway tone or in the variability of airway tone between asthmatic and healthy individuals. This study examined airway tone and intraindividual airway tone heterogeneity (variance of airway tone) in vivo in 19 individuals with asthma compared with 9 healthy adults. All participants underwent spirometry, body plethysmography, and high-resolution computed tomography at baseline and after maximum bronchodilation with albuterol. Airway tone was defined as the percent difference in airway diameter after albuterol at total lung capacity compared with baseline. The amount of airway tone in each airway varied both within and between subjects. The average airway tone did not differ significantly between the two groups (P = 0.09), but the intraindividual airway tone heterogeneity did (P = 0.016). Intraindividual airway tone heterogeneity was strongly correlated with airway tone (r = 0.78, P < 0.0001). Also, it was negatively correlated with the magnitude of the distension of the airways from functional residual capacity to total lung capacity at both baseline (r = –0.49, P = 0.03) and after maximum bronchodilation (r = –0.51, P = 0.02) in the asthma, but not the healthy group. However, we did not find any relationship between intraindividual airway tone heterogeneity and conventional lung function outcomes. Intraindividual airway tone heterogeneity appears to be an important characteristic of airway pathophysiology in asthma.



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Invited Editorial on "Measurement of intraindividual airway tone heterogeneity and its importance in asthma": How does an airway and subsequently the lung become hyperresponsive?



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Exercise training reverses myocardial dysfunction induced by CaMKII{delta}C overexpression by restoring Ca2+ homeostasis

Several conditions of heart disease, including heart failure and diabetic cardiomyopathy, are associated with upregulation of cytosolic Ca2+/calmodulin-dependent protein kinase II (CaMKIIC) activity. In the heart, CaMKIIC isoform targets several proteins involved in intracellular Ca2+ homeostasis. We hypothesized that high-intensity endurance training activates mechanisms that enable a rescue of dysfunctional cardiomyocyte Ca2+ handling and thereby ameliorate cardiac dysfunction despite continuous and chronic elevated levels of CaMKIIC. CaMKIIC transgenic (TG) and wild-type (WT) mice performed aerobic interval exercise training over 6 wk. Cardiac function was measured by echocardiography in vivo, and cardiomyocyte shortening and intracellular Ca2+ handling were measured in vitro. TG mice had reduced global cardiac function, cardiomyocyte shortening (47% reduced compared with WT, P < 0.01), and impaired Ca2+ homeostasis. Despite no change in the chronic elevated levels of CaMKIIC, exercise improved global cardiac function, restored cardiomyocyte shortening, and reestablished Ca2+ homeostasis to values not different from WT. The key features to explain restored Ca2+ homeostasis after exercise training were increased L-type Ca2+ current density and flux by 79 and 85%, respectively (P < 0.01), increased sarcoplasmic reticulum (SR) Ca2+-ATPase (SERCA2a) function by 50% (P < 0.01), and reduced diastolic SR Ca2+ leak by 73% (P < 0.01), compared with sedentary TG mice. In conclusion, exercise training improves global cardiac function as well as cardiomyocyte function in the presence of a maintained high CaMKII activity. The main mechanisms of exercise-induced improvements in TG CaMKIIC mice are mediated via increased L-type Ca2+ channel currents and improved SR Ca2+ handling by restoration of SERCA2a function in addition to reduced diastolic SR Ca2+ leak.



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