Exercise therapy including the cervical extensor muscles in individuals with neck pain: A systematic review.

OBJECTIVE: To review the use (dosage parameters and combination with other therapeutic interventions) of cervical extensor muscle exercises and their effect on pain, disability (primary outcomes), range of motion, endurance and strength (secondary outcomes) in people with neck pain. DATA SOURCES: An extensive literature search was conducted through MEDLINE (Ovid), Scopus (Elsevier) and Physiotherapy Evidence Database (PEDro) up to May 2023. The reference lists of all included studies and relevant reviews were screened for additional studies. REVIEW METHODS: Randomised controlled trials reporting the use of cervical extensor muscle exercises (alone or combined) applied to adults with idiopathic or traumatic neck pain were included. Study selection, data extraction and critical appraisal (PEDro assessment scale) were performed by two blinded reviewers. Data extraction included dosage parameters, other modalities combined with these exercises and outcomes. RESULTS: Thirty-five randomised controlled trails (eight of which were complementary analyses) with 2409 participants fulfilled the inclusion criteria. Twenty-six were of moderate to high quality. In most studies, cervical extensor muscle exercises were combined with various other therapeutic modalities and applied at different dosages. Only two studies (one high and one low quality) specifically assessed their effectiveness. The high-quality study showed significant improvements in neck pain and disability, pressure point threshold and neck mobility after both low load and high load training for 6 weeks. CONCLUSION: The results suggest cervical extensor muscle exercises may reduce neck pain and disability; however firm conclusions cannot be drawn because of the few studies that addressed this question and the heterogeneity of the dosage parameters.

Powassan Virus in a Hunter Returning from a Trip in the Adirondack Park.

Powassan virus is a rare flavivirus that may be transmitted by tick bite and is associated with encephalitis. Infections have been described in the northern United States, Canada, and Russia. We present the case of a 56-y-old man who presented to our hospital with symptoms of confusion, altered behavior, and headache. The patient developed fever and status epilepticus despite supportive care and required endotracheal intubation. Six days before presentation, the patient had returned from a hunting trip in the Adirondack region of New York State.

N-cadherin prodomain processing regulates synaptogenesis.

Classical cadherins, which are adhesion molecules functioning at the CNS synapse, are synthesized as adhesively inactive precursor proteins in the endoplasmic reticulum (ER). Signal sequence and prodomain cleavage in the ER and Golgi apparatus, respectively, activates their adhesive properties. Here, we provide the first evidence for sorting of nonadhesive precursor N-cadherin (ProN) to the neuronal surface, where it coexists with adhesively competent mature N-cadherin (N-cad), generating a spectrum of adhesive strengths. In cultured hippocampal neurons, a high ProN/N-cad ratio downregulates synapse formation. Neurons expressing genetically engineered uncleavable ProN make markedly fewer synapses. The synapse number can be rescued to normality by depleting surface ProN levels through prodomain cleavage by an exogenous protease. Finally, prodomain processing is developmentally regulated in the rat hippocampus. We conclude that it is the ProN/N-cad ratio and not mature N-cad alone that is critical for regulation of adhesion during synaptogenesis.

Cellular response to micropatterned growth promoting and inhibitory substrates.

BACKGROUND: Normal development and the response to injury both require cell growth, migration and morphological remodeling, guided by a complex local landscape of permissive and inhibitory cues. A standard approach for studying by such cues is to culture cells on uniform substrates containing known concentrations of these molecules, however this method fails to represent the molecular complexity of the natural growth environment. RESULTS: To mimic the local complexity of environmental conditions in vitro, we used a contact micropatterning technique to examine cell growth and differentiation on patterned substrates printed with the commonly studied growth permissive and inhibitory substrates, poly-L-lysine (PLL) and myelin, respectively. We show that micropatterning of PLL can be used to direct adherence and axonal outgrowth of hippocampal and cortical neurons as well as other cells with diverse morphologies like Oli-neu oligodendrocyte progenitor cell lines and fibroblast-like COS7 cells in culture. Surprisingly, COS7 cells exhibited a preference for low concentration (1 pg/mL) PLL zones over adjacent zones printed with high concentrations (1 mg/mL). We demonstrate that micropatterning is also useful for studying factors that inhibit growth as it can direct cells to grow along straight lines that are easy to quantify. Furthermore, we provide the first demonstration of microcontact printing of myelin-associated proteins and show that they impair process outgrowth from Oli-neu oligodendrocyte precursor cells. CONCLUSION: We conclude that microcontact printing is an efficient and reproducible method for patterning proteins and brain-derived myelin on glass surfaces in order to study the effects of the microenvironment on cell growth and morphogenesis.

Lipidome and proteome map of myelin membranes.

To understand the molecular anatomy of myelin membranes, we performed a large-scale, liquid chromatography-coupled tandem mass spectrometry (LC-MS/MS)-based lipidome and proteome screen on freshly purified human and murine myelin fractions. We identified more than 700 lipid moieties and above 1,000 proteins in the two species, including 284 common lipids and 257 common proteins. This study establishes the first comprehensive map of myelin membrane components in human and mice. Although this study demonstrates many similarities between human and murine myelin, several components have been identified exclusively in each species. Future quantitative validation studies focused on interspecies differences will authenticate the myelin membrane anatomy. The combined lipidome and proteome map presented here can nevertheless be used as a reference library for myelin health and disease.

Implication of perturbed axoglial apparatus in early pediatric multiple sclerosis.

Cerebrospinal fluid samples collected from children during initial presentation of central nervous system inflammation, who may or may not subsequently be diagnosed as having multiple sclerosis (MS), were subjected to large-scale proteomics screening. Unexpectedly, major compact myelin membrane proteins typically implicated in MS were not detected. However, multiple molecules that localize to the node of Ranvier and the surrounding axoglial apparatus membrane were implicated, indicating perturbed axon-glial interactions in those children destined for diagnosis of MS.

Septin 7: actin cross-organization is required for axonal association of Schwann cells.

Myelin sheaths present two distinct domains: compacted myelin spirals and flanking non-compacted cytoplasmic channels, where lipid and protein segregation is established by unknown mechanisms. Septins, a conserved family of membrane and cytoskeletal interacting GTPases, form intracellular diffusion barriers during cell division and neurite extension and are expressed in myelinating cells. Septins, particularly septin 7 (Sept7), the central constituent of septin polymers, are associated with the cytoplasmic channels of myelinating cells. Here we show that Schwann cells deprived of Sept7 fail to wrap around axons from dorsal root ganglion neurons and exhibit disorganization of the actin cytoskeleton. Likewise, Sept7 distribution is dependent on microfilament but not microtubule organization.

Atomic force microscopy reveals important differences in axonal resistance to injury.

Axonal degeneration after traumatic brain injury and nerve compression is considered a common underlying cause of temporary as well as permanent disability. Because a proper functioning of neural network requires phase coherence of all components, even subtle changes in circuitry may lead to network failure. However, it is still not possible to determine which axons will recover or degenerate after injury. Several groups have studied the pressure threshold for axonal injury within a nerve, but difficulty accessing the injured region; insufficient imaging methods and the extremely small dimensions involved have prevented the evaluation of the response of individual axons to injury. We combined microfluidics with atomic force microscopy and in vivo imaging to estimate the threshold force required to 1), uncouple axonal transport without impairing axonal survival, and 2), compromise axonal survival in both individual and bundled axons. We found that rat hippocampal axons completely recover axonal transport with no detectable axonal loss when compressed with pressures up to 65 ± 30 Pa for 10 min, while dorsal root ganglia axons can resist to pressures up to 540 ± 220 Pa. We investigated the reasons for the differential susceptibility of hippocampal and DRG axons to mechanical injury and estimated the elasticity of live axons. We found that dorsal root ganglia axons have a 20% lower elastic modulus than hippocampal axons. Our results emphasize the importance of the integrity of the axonal cytoskeleton in deciding the axonal fate after damage and open up new avenues to improve injury diagnosis and to identify ways to protect axons.

Misalignment of PLP/DM20 transmembrane domains determines protein misfolding in Pelizaeus-Merzbacher disease.

A large number of genetic diseases have been associated with truncated or misfolded membrane proteins trapped in the endoplasmic reticulum (ER). In the ER, they activate the unfolded protein response, which can trigger cell death. Hence, a better understanding of protein misfolding features might help in developing novel therapies. Here, we have studied the molecular basis of Pelizaeus-Merzbacher disease, a leukodystrophy defined by mutations of the PLP1 gene and ER retention of two encoded tetraspan myelin proteins, PLP and DM20. In mouse oligodendroglial cells, mutant isoforms of PLP/DM20 with fewer than all four transmembrane (TM) domains are fully ER retained. Surprisingly, a truncated PLP with only two N-terminal TM domains shows normal cell-surface expression when coexpressed with a second truncated PLP harboring the two C-terminal TM domains. This striking ability to properly self-align the TM domains is disease relevant, as shown for the smaller splice isoform DM20. Here, the increased length of TM domain 3 allows for compensation of the effect of several PLP1 point mutations that impose a conformational constraint onto the adjacent extracellular loop region. We conclude that an important determinant in the quality control of polytopic membrane proteins is the free alignment of their TM domains.

Reliability and difference in neck extensor muscles strength measured by a portable dynamometer in individuals with and without chronic neck pain.

OBJECTIVE: There are limited reports about the reliability of measuring neck extensor muscle strength using a portable dynamometer in neck pain patients. The aims of the current study were 1) to investigate intra- and inter-rater reliability of neck extensor isometric strength measurement using a portable dynamometer in patients with chronic nonspecific neck pain (CNSNP) and 2) to compare neck extensor isometric strength in participants with and without CNSNP. METHODS: Guidelines for Reporting Reliability and Agreement Studies (GRRAS) were followed. Two examiners received a 15-minute training before enrollment. Inter-rater reliability was assessed with a 10-minute interval between measurements, and intra-rater reliability was assessed with a 10-day interval. Three trials were assessed and examiners were blind to the strength values (in Newtons) from other sessions of 20 individuals with CNSNP (mean±SD= 37.9 ± 9.8y; Neck Disability Index 29.2 ± 7.4%) and 20 individuals with other musculoskeletal disorders (mean ± SD = 32.8 ± 46.2y). RESULTS: Intra-rater reliability was excellent with intraclass correlation coefficient (ICC)(3,1) of 0.95 (CI:0.90-0.97) and inter-rater reliability was good to excellent with ICC(2,1) of 0.88 (CI:0.77-0.94) in CNSNP. No significant difference of neck extensor strength was found between CNSNP (93.27N±31.94) and Individuals without CNSNP (111.43N±40.11) (p > 0.05). CONCLUSION: A portable dynamometer is a reliable tool for measuring maximal isometric neck extension strength in individuals with CNSNP. Slightly but no significant differences of neck extensor strength values between individuals with and without CNSNP. Future studies are needed to assess the generalizability of the findings in patients with other muscle deconditioning.

A role for Nr-CAM in the patterning of binocular visual pathways.

Retinal ganglion cell (RGC) axons diverge within the optic chiasm to project to opposite sides of the brain. In mouse, contralateral RGCs are distributed throughout the retina, whereas ipsilateral RGCs are restricted to the ventrotemporal crescent (VTC). While repulsive guidance mechanisms play a major role in the formation of the ipsilateral projection, little is known about the contribution of growth-promoting interactions to the formation of binocular visual projections. Here, we show that the cell adhesion molecule Nr-CAM is expressed by RGCs that project contralaterally and is critical for the guidance of late-born RGCs within the VTC. Blocking Nr-CAM function causes an increase in the size of the ipsilateral projection and reduces neurite outgrowth on chiasm cells in an age- and region-specific manner. Finally, we demonstrate that EphB1/ephrin-B2-mediated repulsion and Nr-CAM-mediated attraction comprise distinct molecular programs that each contributes to the proper formation of binocular visual pathways.

Rapid assembly of functional presynaptic boutons triggered by adhesive contacts.

CNS synapse assembly typically follows after stable contacts between "appropriate" axonal and dendritic membranes are made. We show that presynaptic boutons selectively form de novo following neuronal fiber adhesion to beads coated with poly-d-lysine (PDL), an artificial cationic polypeptide. As demonstrated by atomic force and live confocal microscopy, functional presynaptic boutons self-assemble as rapidly as 1 h after bead contact, and are found to contain a variety of proteins characteristic of presynaptic endings. Interestingly, presynaptic compartment assembly does not depend on the presence of a biological postsynaptic membrane surface. Rather, heparan sulfate proteoglycans, including syndecan-2, as well as others possibly adsorbed onto the bead matrix or expressed on the axon surface, are required for assembly to proceed by a mechanism dependent on the dynamic reorganization of F-actin. Our results indicate that certain (but not all) nonspecific cationic molecules like PDL, with presumably electrostatically mediated adhesive properties, can effectively bypass cognate and natural postsynaptic ligands to trigger presynaptic assembly in the absence of specific target recognition. In contrast, we find that postsynaptic compartment assembly depends on the prior presence of a mature presynaptic ending.

A proteome map of axoglial specializations isolated and purified from human central nervous system.

Compact myelin, the paranode, and the juxtaparanode are discrete domains that are formed on myelinated axons. In humans, neurological disorders associated with loss of myelin, including Multiple Sclerosis, often also result in disassembly of the node of Ranvier. Despite the importance of these domains in the proper functioning of the CNS, their molecular composition and assembly mechanism remains largely unknown. We therefore performed a large-scale proteomics MudPIT screen for the identification of proteins in human myelin and axogliasomal fractions. We identified over 1,000 proteins in these fractions. Since even minor perturbations in neuron-glial interactions can uncouple the glial support of axons, the proteome map presented here can be used as a reference library for "myelin health" and disease states, including white matter disorders such as leukodystrophies and multiple sclerosis.

Spatiotemporal distribution and function of N-cadherin in postnatal Schwann cells: A matter of adhesion?

During embryonic development of the peripheral nervous system (PNS), the adhesion molecule neuronal cadherin (N-cadherin) is expressed by Schwann cell precursors and associated with axonal growth cones. N-cadherin expression levels decrease as precursors differentiate into Schwann cells. In this study, we investigated the distribution of N-cadherin in the developing postnatal and adult rat peripheral nervous system. N-cadherin was found primarily in ensheathing glia throughout development, concentrated at neuron-glial or glial-glial contacts of the sciatic nerve, dorsal root ganglia (DRG), and myenteric plexi. In the sciatic nerve, N-cadherin decreases with age and progress of myelination. In adult animals, N-cadherin was found exclusively in nonmyelinating Schwann cells. The distribution of N-cadherin in developing E17 DRG primary cultures is similar to what was observed in vivo. Functional studies of N-cadherin in these cultures, using the antagonist peptide INPISGQ, show a disruption of the attachment between Schwann cells, but no interference in the initial or long-term contact between Schwann cells and axons. We suggest that N-cadherin acts primarily in the adhesion between glial cells during postnatal development. It may form adherents/junctions between nonmyelinating glia, which contribute to the stable tubular structure encapsulating thin caliber axons and thus stabilize the nerve structure as a whole.

Kinesiotaping for scapular dyskinesis: The influence on scapular kinematics and on the activity of scapular stabilizing muscles.

Scapular dyskinesis is observed in 61% of overhead athletes (Burn et al., 2016). For most of them, it remains asymptomatic. However, scapular dyskinesis is considered a risk factor for shoulder injury by some authors (Clarsen et al., 2014). The aim of this study is to explore the effectiveness of kinesiotaping in modifying scapular kinematics and peri-scapular muscle activity in dyskinetic athletes. The 3-dimensional position and orientation of the scapula as well as the activation of upper trapezius, lower trapezius and serratus anterior were recorded in twenty asymptomatic athletes during shoulder movements (flexion and abduction), in loaded and unloaded conditions and in three circumstances (standard, kinesiotaping 1, kinesiotaping 2). A significant decrease between 9 and 12% in upper trapezius activity was observed with kinesiotaping 1 and 2. Lower trapezius activity was slightly increased with kinesiotaping 1 while it was significantly decreased about 15-20% with kinesiotaping 2. No change was observed in serratus anterior activity, for either kinesiotaping 1 or 2. Considering scapular kinematics, both kinesiotaping 1 and 2 significantly increased posterior tilt and upward rotation. External rotation was decreased with kinesiotaping 2, in comparison to standard condition. Kinesiotaping, and especially taping 1, seems to be an effective method for changing periscapular muscle activity and scapular kinematics.

Disposition of axonal caspr with respect to glial cell membranes: Implications for the process of myelination.

Neurofascin-155 (NF155) and caspr are transmembrane proteins found at discrete locations early during development of the nervous system. NF155 is present in the oligodendrocyte cell body and processes, whereas caspr is on the axonal surface. In mature nerves, these proteins are clustered at paranodes, flanking the node of Ranvier. To understand how NF155 and caspr become localized to the paranodal regions of myelinated nerves, we have studied their distribution over time in myelinating cultures. Our observations indicate that these two proteins are recruited to the cell surface at the contact zone between axons and oligodendrocytes, where they trans-interact. This association explains the early pattern of caspr distribution, a helical coil that winds around the axon, resembling the turns of the myelin sheath. Caspr, an axonal membrane protein, therefore seems to move in register with the overlying myelinating cell via its interactions with myelin proteins. We suggest that NF155 is the glial cell membrane protein responsible for caspr distribution. The pair act as interacting partners on either side of the axoglial contact area. Most likely, there are other proteins on the axonal surface whose distribution is equally influenced by interaction with the nascent myelin sheath. The fact that caspr follows the movement of the spiraling membrane has a direct affect on the interpretation of the way in which myelin is formed.

N-cadherin mediates interaction between precursor cells in the subventricular zone and regulates further differentiation.

Neurogenesis and cell differentiation in the brain continues throughout life. In the subventricular zone and rostral migratory stream, precursor cells contact each other. Cell-cell interactions mediated via adhesion molecules are no doubt involved in establishing and maintaining the neurogenic ability of these cells. Here, we demonstrate that N-cadherin plays important roles in forming cell clusters and in regulating cell differentiation. N-cadherin is abundantly expressed in chain migrating cells in the subventricular zone and rostral migratory stream but is down-regulated after cells exit these regions. We also show that neurosphere formation is inhibited via suppression of N-cadherin function and that N-cadherin expression is decreased after induction of neurosphere differentiation. Furthermore, we demonstrate that functional blockade of N-cadherin can enhance glial cell differentiation in explant cultures of precursors from the subventricular zone.

Cadherin activity is required for activity-induced spine remodeling.

Neural activity induces the remodeling of pre- and postsynaptic membranes, which maintain their apposition through cell adhesion molecules. Among them, N-cadherin is redistributed, undergoes activity-dependent conformational changes, and is required for synaptic plasticity. Here, we show that depolarization induces the enlargement of the width of spine head, and that cadherin activity is essential for this synaptic rearrangement. Dendritic spines visualized with green fluorescent protein in hippocampal neurons showed an expansion by the activation of AMPA receptor, so that the synaptic apposition zone may be expanded. N-cadherin-venus fusion protein laterally dispersed along the expanding spine head. Overexpression of dominant-negative forms of N-cadherin resulted in the abrogation of the spine expansion. Inhibition of actin polymerization with cytochalasin D abolished the spine expansion. Together, our data suggest that cadherin-based adhesion machinery coupled with the actin-cytoskeleton is critical for the remodeling of synaptic apposition zone.

TMEM10 Promotes Oligodendrocyte Differentiation and is Expressed by Oligodendrocytes in Human Remyelinating Multiple Sclerosis Plaques.

Oligodendrocyte precursor cells (OPCs) differentiate during postnatal development into myelin-forming oligodendrocytes, in a process distinguished by substantial changes in morphology and the onset of myelin gene expression. A mammalian-specific CNS myelin gene, tmem10, also called Opalin, encodes a type 1 transmembrane protein that is highly upregulated during early stages of OPC differentiation; however, a function for TMEM10 has not yet been identified. Here, consistent with previous studies, we detect TMEM10 protein in mouse brain beginning at ~P10 and show that protein levels continue to increase as oligodendrocytes differentiate and myelinate axons in vivo. We show that constitutive TMEM10 overexpression in the Oli-neu oligodendroglial cell line promotes the expression of the myelin-associated genes MAG, CNP and CGT, whereas TMEM10 knock down in primary OPCs reduces CNP mRNA expression and decreases the percentage of MBP-positive oligodendrocytes that differentiate in vitro. Ectopic TMEM10 expression evokes an increase in process extension and branching, and blocking endogenous TMEM10 expression results in oligodendrocytes with abnormal cell morphology. These findings may have implications for human demyelinating disorders, as oligodendrocytes expressing TMEM10 are detected in human remyelinating multiple sclerosis lesions. Together, our findings provide evidence that TMEM10 promotes oligodendrocyte terminal differentiation and may represent a novel target to promote remyelination in demyelinating disorders.

Minimally invasive versus standard approach for excision of atrial masses.

BACKGROUND: Minimally invasive cardiac surgical procedures have become ubiquitous over the past decade. In many cases, these techniques have been associated with decreased morbidity, shorter length of stay, decreased pain, faster recovery, and superior cosmetic results. The purpose of this study was to compare outcomes using a minimally invasive (mini-thoracotomy) versus standard (sternotomy) approach to the surgical resection of atrial masses. METHODS: Analysis was based on 34 consecutive patients who underwent atrial mass resection at the New York-Presbyterian Hospital/Columbia Presbyterian Medical Center in New York, NY. The reference (REF) group included 18 patients who underwent excision of an atrial mass via a standard approach (sternotomy). The minimally invasive (MI) group included 16 patients who underwent excision of an atrial mass via a mini-thoracotomy. RESULTS: There were no statistically significant differences between the REF and MI groups based on demographic or preoperative characteristics. Tissue diagnosis of the masses resected included myxoma (n = 24), fibroblastoma (n = 3), B-cell lymphoma (n = 1), and other benign masses (n = 6). Cardiopulmonary bypass (70.5 versus 76.5 minutes; P = .57) and aortic cross-clamp times (32.7 versus 47.3 minutes; P = .14) did not differ significantly between the REF and MI groups, nor did intraoperative transfusion of packed red blood cells (0.35 versus 0.38 units; P = .93). As assessed by intraoperative trans-esophageal echocardiogram, there were no moderate to severe valvular abnormalities observed following chest closure. Intensive care unit length of stay (46.1 versus 26.2 hours; P = .15), overall hospital length of stay (6.39 versus 5.06 days; P= .18), and time to extubation (0.78 versus 0.44 days; P = .44) all trended toward shorter duration in the MI group compared with the REF group-although none of these differences achieved statistical significance. Postoperative transthoracic echocardiograms were obtained in 14 of 34 (41.2%) patients; none revealed any new or significant abnormalities. All patients survived to hospital discharge; one patient in the REF group expired during the follow-up period. Among the 34 patients, 26 patients (76.4%) were at least 2 years postoperative from their resection; 25 of the 26 (96.1%) were alive at 2-year follow-up, and the remaining 8 were alive at 1-year follow-up. All patients were free of recurrence at last follow-up. CONCLUSIONS. Minimally invasive atrial mass excisions can be accomplished reliably without compromising complete tumor resection and without significant increases in operative times or serious adverse events. In addition, measures of recovery time in this study suggest faster recovery among the MI group, which is consistent with the proposed advantages by proponents of minimally invasive surgery.