Transversus abdominis activation during a side-bridge exercise progression is similar in people with recurrent low back pain and healthy controls

ABSTRACT: Himes, MA, Selkow, NM, Gore, MA, Hart, JM, Saliba, SA. Transversus abdominis activation during a side-bridge exercise progression is similar in people with recurrent low back pain and healthy controls. J Strength Cond Res 26(11): 3106-3112, 2012-Low back pain (LBP) affects 70-80% of the population. The transversus abdominis (TrA) has been implicated as part of the cause of LBP. Prevention and rehabilitation of LBP often target the TrA using exercises such as the side bridge accompanied with the abdominal drawing-in maneuver (ADIM). However, it is unknown whether individuals with recurrent LBP, when they are in a period of no pain, are able to activate the TrA and healthy individuals during this exercise. The purpose of our study was to compare the activation ratio of the TrA during a 5-level side-bridge exercise progression. Twenty-three subjects with a history of recurrent, nonspecific LBP, but not experiencing an exacerbation of symptoms and 24 healthy controls volunteered. All the subjects performed the ADIM and side-bridge exercises with clinician feedback (verbal cueing). Each participant performed the side-bridge exercise progression while ultrasound images were taken. The subjects were only progressed if they successfully completed the previous level. The thickness of the TrA was measured in rested and contracted states at each exercise level to find the activation ratio (TrA contracted/TrA rest). Separate analyses of covariance did not reveal a difference in activation ratios between groups (p > 0.40) when the ratio at the lowest level was used as the covariate. The results from this study indicate that both groups were able to contract the TrA with verbal cueing during a side-bridge exercise progression. Because the TrA contracted similarly during exercise in both groups, the association of LBP with the TrA may be because of another mechanism, such as delayed activation in the feed-forward mechanism during activity or a lack of endurance of the TrA.     

Ceramide Sphingolipid Signaling Mediates Tumor Necrosis Factor (TNF)-Dependent Toxicity via Caspase Signaling in Dopaminergic Neurons

ABSTRACT: BACKGROUND: Dopaminergic (DA) neurons in the ventral midbrain selectively degenerate in Parkinsons disease (PD) in part because their oxidative environment in the substantia nigra (SN) may render them vulnerable to neuroinflammatory stimuli. Chronic inhibition of soluble Tumor Necrosis Factor (TNF) with dominant-negative TNF inhibitors protects DA neurons in rat models of parkinsonism, yet the molecular mechanisms and pathway(s) that mediate TNF toxicity remain(s) to be clearly identified. Here we investigated the contribution of ceramide sphingolipid signaling in TNF-dependent toxicity. RESULTS: Ceramide dose-dependently reduced the viability of DA neuroblastoma cells and primary DA neurons and pharmacological inhibition of sphingomyelinases (SMases) with three different inhibitors during TNF treatment afforded significant neuroprotection by attenuating increased endoplasmic reticulum (ER) stress, loss of mitochondrial membrane potential, caspase-3 activation and decreases in Akt phosphorylation. Using lipidomics mass spectrometry we confirmed that TNF treatment not only promotes generation of ceramide, but also leads to accumulation of several atypical deoxy-sphingoid bases (DSBs). Exposure of DA neuroblastoma cells to atypical DSBs in the micromolar range reduced cell viability and inhibited neurite outgrowth and branching in primary DA neurons, suggesting that TNFinduced de novo synthesis of atypical DSBs may be a secondary mechanism involved in mediating its neurotoxicity in DA neurons. CONCLUSIONS: We conclude that TNF/TNFR1-dependent activation of SMases generates ceramide and sphingolipid species that promote degeneration and caspase-dependent cell death of DA neurons. Ceramide and atypical DSBs may represent novel drug targets for development of neuroprotective strategies that can delay or attenuate the progressive loss of nigral DA neurons in patients with PD.     

The hTH-GFP Reporter Rat Model for the Study of Parkinson's Disease

Parkinson disease (PD) is the second leading neurodegenerative disease in the US. As there is no known cause or cure for PD, researchers continue to investigate disease mechanisms and potential new therapies in cell culture and in animal models of PD. In PD, one of the most profoundly affected neuronal populations is the tyrosine hydroxylase (TH)-expressing dopaminergic (DA) neurons of the substantia nigra pars compacta (SNpc). These DA-producing neurons undergo degeneration while neighboring DA-producing cells of the ventral tegmental area (VTA) are largely spared. To aid in these studies, The Michael J. Fox Foundation (MJFF) partnered with Thomas Jefferson University and Taconic Inc. to generate new transgenic rat lines carrying the human TH gene promoter driving EGFP using a 11 kb construct used previously to create a hTH-GFP mouse reporter line. Of the five rat founder lines that were generated, three exhibited high level specific GFP fluorescence in DA brain structures (ie. SN, VTA, striatum, olfactory bulb, hypothalamus). As with the hTH-GFP mouse, none of the rat lines exhibit reporter expression in adrenergic structures like the adrenal gland. Line 12141, with its high levels of GFP in adult DA brain structures and minimal ectopic GFP expression in non-DA structures, was characterized in detail. We show here that this line allows for anatomical visualization and microdissection of the rat midbrain into SNpc and/or VTA, enabling detailed analysis of midbrain DA neurons and axonal projections after toxin treatment in vivo. Moreover, we further show that embryonic SNpc and/or VTA neurons, enriched by microdissection or FACS, can be used in culture or transplant studies of PD. Thus, the hTH-GFP reporter rat should be a valuable tool for Parkinson''s disease research.     

The Real World Mental Health Needs of Heart Failure Patients Are Not Reflected by the Depression Randomized Controlled Trial Evidence

Introduction

International depression screening guidelines in heart failure (HF) are partly based on depression treatment efficacy from randomized controlled trials (RCTs). Our aim was to test the external validity of depression RCT criteria in a sample of real-world HF patients.

Methods

HF patients admitted to 3 hospitals in South Australia were referred to a HF psychologist if not already receiving current psychiatric management by psychologist or psychiatrist elsewhere. Screening and referral protocol consisted of the following; (a). Patient Health Questionnaire ≥10; (b). Generalized Anxiety Disorder Questionnaire ≥7); (c). positive response to 1 item panic attack screener; (d). evidence of suicidality. Patients were evaluated against the most common RCT exclusion criteria personality disorder, high suicide risk, cognitive impairment, psychosis, alcohol or substance abuse or dependency, bi-polar depression.

Results

Total 81 HF patients were referred from 404 HF admissions, and 73 were assessed (age 60.6±13.4, 47.9% female). Nearly half (47%) met at least 1 RCT exclusion criterion, most commonly personality disorder (28.5%), alcohol/substance abuse (17.8%) and high suicide risk (11.0%). RCT ineligibility criteria was more frequent among patients with major depression (76.5% vs. 46.2%, p<.01) and dysthymia (26.5% vs. 7.7%, p = .03) but not significantly associated with anxiety disorders. RCT ineligible patients reported greater severity of depression (M = 16.6±5.0 vs. M = 12.9±7.2, p = .02) and were higher consumers of HF psychotherapy services (M = 11.5±4.7 vs. M = 8.5±4.8, p = .01).

Conclusion

In this real-world sample comparable in size to recent RCT intervention arms, patients with depression disorders presented with complex psychiatric needs including comorbid personality disorders, alcohol/substance use and suicide risk. These findings suggest external validity of depression screening and RCTs could serve as a basis for level A guideline recommendations in cardiovascular diseases.     

The enumeration of minimal phylograms

We consider the problem of finding a minimal tree to a set of nodes (of species represented byd characters) in a space ofd-dimensions subject to the hypothesis that evolution is nonconvergent and irreversible. A solution to this problem is formulated, using integer linear programming techniques.     

The effect of cold water immersion on 48-hour performance testing in collegiate soccer players

This randomized, controlled, laboratory study was designed to examine the effect of cold water immersion (CWI) as a recovery modality on repeat performance on the yo-yo intermittent recovery test (YIRT), a widely accepted tool for the evaluation of physical performance in soccer, separated by 48 hours. Twenty-two healthy Division I collegiate soccer players (13 men and 9 women; age, 19.8 ± 1.1 years; height, 174.0 ± 9.0 cm; mass, 72.1 ± 9.1 kg) volunteered as participants during the noncompetitive season. The YIRT was used to induce volitional fatigue and was administered at baseline and again 48 hours later. Athletes progressively increased sprint speed between markers set 20 m apart until pace was failed. Countermovement vertical jump (CMVJ) was used to assess anaerobic power and was measured before YIRT, immediately post-YIRT, and 24 and 48 hours post-YIRT. A 10-cm horizontal visual analog scale was administered immediately, 24 hours and 48 hours post-YIRT to assess perceived fatigue (PF) in the legs. Participants were randomly placed into the CWI or control group. The CWI condition consisted of immersion to the umbilicus in a 12°C pool for 15 minutes, whereas the control group sat quietly for 15 minutes. There were no significant differences between intervention conditions on YIRT performance (control, 4,900 ± 884 m; CWI, 5,288 ± 1,000 m; p = 0.35) or PF (control, 9.4 ± 0.5 cm; CWI, 9.3 ± 0.6 cm; p = 0.65) at 48 hours post-YIRT. There was a main time effect for CMVJ over 48 hours, but no group differences (pre-YIRT, 64.6 ± 11.0 cm; post-YIRT, 66.4 ± 10.9 cm; 24 hours post-YIRT, 63.4 ± 9.9 cm; 48 hours post-YIRT, 63.1 ± 9.4 cm; p = 0.02). This study demonstrated that in collegiate soccer players, CWI performed immediately and 24 hours after induced volitional fatigue did not affect subsequent physical performance estimates.     

Rab29 activation of the Parkinson's disease‐associated LRRK2 kinase

Parkinson's disease predisposing LRRK2 kinase phosphorylates a group of Rab GTPase proteins including Rab29, within the effector‐binding switch II motif. Previous work indicated that Rab29, located within the PARK16 locus mutated in Parkinson's patients, operates in a common pathway with LRRK2. Here, we show that Rab29 recruits LRRK2 to the trans‐Golgi network and greatly stimulates its kinase activity. Pathogenic LRRK2 R1441G/C and Y1699C mutants that promote GTP binding are more readily recruited to the Golgi and activated by Rab29 than wild‐type LRRK2. We identify conserved residues within the LRRK2 ankyrin domain that are required for Rab29‐mediated Golgi recruitment and kinase activation. Consistent with these findings, knockout of Rab29 in A549 cells reduces endogenous LRRK2‐mediated phosphorylation of Rab10. We show that mutations that prevent LRRK2 from interacting with either Rab29 or GTP strikingly inhibit phosphorylation of a cluster of highly studied biomarker phosphorylation sites (Ser910, Ser935, Ser955 and Ser973). Our data reveal that Rab29 is a master regulator of LRRK2, controlling its activation, localization, and potentially biomarker phosphorylation.     

Ceramide sphingolipid signaling mediates Tumor Necrosis Factor (TNF)-dependent toxicity via caspase signaling in dopaminergic neurons

Background

The A?? peptide that accumulates in Alzheimer??s disease (AD) is derived from amyloid precursor protein (APP) following proteolysis by ??- and ??-secretases. Substantial evidence indicates that alterations in APP trafficking within the secretory and endocytic pathways directly impact the interaction of APP with these secretases and subsequent A?? production. Various members of the low-density lipoprotein receptor (LDLR) family have been reported to play a role in APP trafficking and processing and are important risk factors in AD. We recently characterized a distinct member of the LDLR family called LDLR-related protein 10 (LRP10) that shuttles between the trans-Golgi Network (TGN), plasma membrane (PM), and endosomes. Here we investigated whether LRP10 participates in APP intracellular trafficking and A?? production.

Results

In this report, we provide evidence that LRP10 is a functional APP receptor involved in APP trafficking and processing. LRP10 interacts directly with the ectodomain of APP and colocalizes with APP at the TGN. Increased expression of LRP10 in human neuroblastoma SH-SY5Y cells induces the accumulation of mature APP in the Golgi and reduces its presence at the cell surface and its processing into A??, while knockdown of LRP10 expression increases A?? production. Mutations of key motifs responsible for the recycling of LRP10 to the TGN results in the aberrant redistribution of APP with LRP10 to early endosomes and a concomitant increase in APP ??-cleavage into A??. Furthermore, expression of LRP10 is significantly lower in the post-mortem brain tissues of AD patients, supporting a possible role for LRP10 in AD.

Conclusions

The present study identified LRP10 as a novel APP sorting receptor that protects APP from amyloidogenic processing, suggesting that a decrease in LRP10 function may contribute to the pathogenesis of Alzheimer??s disease.