A multi-modal intervention for managing the fatigue-sleep disturbance-depressed mood symptom cluster in breast cancer patients undergoing chemotherapy: A pilot study.

Objective: To examine the feasibility and acceptability of a multi-modal intervention for managing the cancer-related fatigue-sleep disturbance-depressed mood (F-S-D) symptom cluster in patients with breast cancer (BC) and receiving chemotherapy in Hong Kong, and the preliminary effects of such intervention on the occurrence of the F-S-D symptom cluster in these patients. Methods: This study was a single-blind randomized controlled trial. Patients with BC scheduled for chemotherapy were recruited. Intervention participants received a weekly nurse-led multi-modal intervention lasting 7 weeks. The feasibility parameters and adverse events were assessed using logbook records. Acceptability was evaluated using a program evaluation questionnaire. F-S-D symptoms and quality of life (QOL) were measured at baseline (T0), upon intervention completion (T1), and 3 months after intervention completion (T2). Generalized estimating equation analyses were used. Results: Fifty participants were enrolled. The eligibility and enrollment rates were 11% and 87.7%, respectively. The rate of adherence to the intervention was 96%. No adverse events were reported. All participants were satisfied with the intervention, which had significant effects in terms of reducing the occurrence of the F-S-D symptom cluster at T2 (P â€‹= â€‹0.035) and improving QOL at T1 and T2 (T1: P â€‹= â€‹0.035; T2: P â€‹= â€‹0.012). Conclusions: The multi-modal intervention is a feasible, acceptable, and safe intervention that demonstrated preliminary positive effects in managing the F-S-D symptom cluster and improving QOL in patients with BC and receiving chemotherapy in Hong Kong. This study provides key insights into F-S-D symptom cluster management in patients with BC. Trial registration: ChiCTR2100047819 (Chinese Clinical Trial Register).

Superstorm Sandy exposure in utero is associated with neurobehavioral phenotypes and brain structure alterations in childhood: A machine learning approach.

Introduction: Prenatal maternal stress (PNMS), including exposure to natural disasters, has been shown to serve as a risk factor for future child psychopathology and suboptimal brain development, particularly among brain regions shown to be sensitive to stress and trauma exposure. However, statistical approaches deployed in most studies are usually constrained by a limited number of variables for the sake of statistical power. Explainable machine learning, on the other hand, enables the study of high data dimension and offers novel insights into the prominent subset of behavioral phenotypes and brain regions most susceptible to PNMS. In the present study, we aimed to identify the most important child neurobehavioral and brain features associated with in utero exposure to Superstorm Sandy (SS). Methods: By leveraging an explainable machine learning technique, the Shapley additive explanations method, we tested the marginal feature effect on SS exposures and examined the individual variable effects on disaster exposure. Results: Results show that certain brain regions are especially sensitive to in utero exposure to SS. Specifically, in utero SS exposure was associated with larger gray matter volume (GMV) in the right caudate, right hippocampus, and left amygdala and smaller GMV in the right parahippocampal gyrus. Additionally, higher aggression scores at age 5 distinctly correlated with SS exposure. Discussion: These findings suggest in utero SS exposure may be associated with greater aggression and suboptimal developmental alterations among various limbic and basal ganglia brain regions.

Effectiveness of Pharmacological and Nonpharmacological Interventions for Managing the Fatigue-Sleep Disturbance-Depression Symptom Cluster in Breast Cancer Patients Undergoing Chemotherapy: A Systematic Review.

BACKGROUND: The symptom cluster of cancer-related fatigue-sleep disturbance-depression (F-S-D) is common among breast cancer (BC) patients undergoing chemotherapy. Given the coexisting nature and synergistic effect of this symptom cluster, interventions for managing it are expected to benefit patient outcomes. OBJECTIVES: The aims of this study were to examine the effectiveness and identify the essential components of interventions used to manage the F-S-D and quality of life (QOL) in BC patients undergoing chemotherapy. METHODS: A systematic review was performed in March 2020 through 7 electronic databases. Relevant studies were assessed using the inclusion criteria. The level of evidence was assessed using the Cochrane risk-of-bias tool. The results were summarized and synthesized in narrative forms. RESULTS: Sixteen randomized controlled trials were included. Results showed that bright light therapy, acupressure, and psychological nursing interventions were useful in managing F-S-D in BC patients. Exercise and diet counseling alleviated F-D, whereas stress management and a health promotion program alleviated S-D. Bright light therapy, exercise, diet counseling, and psychological nursing interventions enhanced the QOL of these patients. CONCLUSION: Interventions that could alleviate F-S, F-D, S-D, and F-S-D in BC patients and enhance their QOL were identified. Future studies should investigate the effects of evidence-based multimodal interventions that integrate psychological support, education on the management of chemotherapy side effects, and diet counseling and exercise on F-S-D in and reduced QOL of BC patients undergoing chemotherapy. IMPLICATIONS FOR PRACTICE: Nurses act as patient advocates, and the development of evidence-based interventions for managing F-S-D and QOL is significant to nursing practice.

Effects of rhythmic auditory stimulation on upper-limb movement speed in patients with schizophrenia spectrum disorders.

Movement slowness, linked to dysfunctional basal ganglia and cerebellum, is prevalent but lacks effective therapy in patients with schizophrenia spectrum disorders. This study was to examine immediate effects of rhythmic auditory stimulation (RAS) on upper-limb movement speed in patients. Thirty patients and 30 psychiatrically healthy people executed the right-hand task and the both-hand task of the Purdue Pegboard Test when listening to RAS with two tempi: normal (equal to the fastest movement tempo for each participant without RAS) and fast (120% of the normal tempo). The testing order of the RAS tempi for each participant was randomized. Patients had lower scores of right-hand and both-hand tasks than did psychiatrically healthy people. Scores of right-hand and both-hand tasks were higher in the fast-RAS condition than the normal-RAS condition in participants. This is the first study to explore the possibility of applying RAS to movement therapy for patients with schizophrenia spectrum disorders. The results demonstrated that faster RAS was effective in inducing faster upper-limb movements in patients and psychiatrically healthy people, suggesting that manipulating RAS may be a feasible therapeutic strategy utilized to regulate movement speed. The RAS may involve alternative neural pathways to modulate movement speed and thus to compensate for impaired function of basal ganglia and cerebellum in patients.

Author Correction: Next generation histology methods for three-dimensional imaging of fresh and archival human brain tissues.

In the original version of this Article, the concentration of boric acid buffer for the SDS clearing solution was given incorrectly as '1 M sodium borate' and should have read '0.2 M boric acid'. Also, the composition of PBST incorrectly read '1% Triton X-100 (vol/vol) and 0.1% sodium azide (wt/vol)' and should have read '0.1% Triton X-100 (vol/vol) and 0.01% sodium azide (wt/vol)'. Further, the pH of the OPTIClear solution was not stated, and should have read 'with a pH between 7 to 8 adjusted with hydrochloric acid'. These errors have been corrected in both the PDF and HTML versions of the Article.

Next generation histology methods for three-dimensional imaging of fresh and archival human brain tissues.

Modern clearing techniques for the three-dimensional (3D) visualisation of neural tissue microstructure have been very effective when used on rodent brain but very few studies have utilised them on human brain material, mainly due to the inherent difficulties in processing post-mortem tissue. Here we develop a tissue clearing solution, OPTIClear, optimised for fresh and archival human brain tissue, including formalin-fixed paraffin-embedded material. In light of practical challenges with immunostaining in tissue clearing, we adapt the use of cresyl violet for visualisation of neurons in cleared tissue, with the potential for 3D quantification in regions of interest. Furthermore, we use lipophilic tracers for tracing of neuronal processes in post-mortem tissue, enabling the study of the morphology of human dendritic spines in 3D. The development of these different strategies for human tissue clearing has wide applicability and, we hope, will provide a baseline for further technique development.

Combination Treatment With Exogenous GDNF and Fetal Spinal Cord Cells Results in Better Motoneuron Survival and Functional Recovery After Avulsion Injury With Delayed Root Reimplantation.

When spinal roots are torn off from the spinal cord, both the peripheral and central nervous system get damaged. As the motoneurons lose their axons, they start to die rapidly, whereas target muscles atrophy due to the denervation. In this kind of complicated injury, different processes need to be targeted in the search for the best treatment strategy. In this study, we tested glial cell-derived neurotrophic factor (GDNF) treatment and fetal lumbar cell transplantation for their effectiveness to prevent motoneuron death and muscle atrophy after the spinal root avulsion and delayed reimplantation. Application of exogenous GDNF to injured spinal cord greatly prevented the motoneuron death and enhanced the regeneration and axonal sprouting, whereas no effect was seen on the functional recovery. In contrast, cell transplantation into the distal nerve did not affect the host motoneurons but instead mitigated the muscle atrophy. The combination of GDNF and cell graft reunited the positive effects resulting in better functional recovery and could therefore be considered as a promising strategy for nerve and spinal cord injuries that involve the avulsion of spinal roots.

Transplantation of Embryonic Spinal Cord Derived Cells Helps to Prevent Muscle Atrophy after Peripheral Nerve Injury.

Injuries to peripheral nerves are frequent in serious traumas and spinal cord injuries. In addition to surgical approaches, other interventions, such as cell transplantation, should be considered to keep the muscles in good condition until the axons regenerate. In this study, E14.5 rat embryonic spinal cord fetal cells and cultured neural progenitor cells from different spinal cord segments were injected into transected musculocutaneous nerve of 200-300 g female Sprague Dawley (SD) rats, and atrophy in biceps brachii was assessed. Both kinds of cells were able to survive, extend their axons towards the muscle and form neuromuscular junctions that were functional in electromyographic studies. As a result, muscle endplates were preserved and atrophy was reduced. Furthermore, we observed that the fetal cells had a better effect in reducing the muscle atrophy compared to the pure neural progenitor cells, whereas lumbar cells were more beneficial compared to thoracic and cervical cells. In addition, fetal lumbar cells were used to supplement six weeks delayed surgical repair after the nerve transection. Cell transplantation helped to preserve the muscle endplates, which in turn lead to earlier functional recovery seen in behavioral test and electromyography. In conclusion, we were able to show that embryonic spinal cord derived cells, especially the lumbar fetal cells, are beneficial in the treatment of peripheral nerve injuries due to their ability to prevent the muscle atrophy.

Functional self-assembling peptide nanofiber hydrogel for peripheral nerve regeneration.

Peripheral nerves are fragile and easily damaged, usually resulting in nervous tissue loss, motor and sensory function loss. Advances in neuroscience and engineering have been significantly contributing to bridge the damage nerve and create permissive environment for axonal regrowth across lesions. We have successfully designed two self-assembling peptides by modifying RADA 16-I with two functional motifs IKVAV and RGD. Nanofiber hydrogel formed when combing the two neutral solutions together, defined as RADA 16-Mix that overcomes the main drawback of RADA16-I associated with low pH. In the present study, we transplanted the RADA 16-Mix hydrogel into the transected rat sciatic nerve gap and effect on axonal regeneration was examined and compared with the traditional RADA16-I hydrogel. The regenerated nerves were found to grow along the walls of the large cavities formed in the graft of RADA16-I hydrogel, while the nerves grew into the RADA 16-Mix hydrogel toward distal position. RADA 16-Mix hydrogel induced more axons regeneration and Schwann cells immigration than RADA16-I hydrogel, resulting in better functional recovery as determined by the gait-stance duration percentage and the formation of new neuromuscular junction structures. Therefore, our results indicated that the functional SAP RADA16-Mix nanofibrous hydrogel provided a better environment for peripheral nerve regeneration than RADA16-I hydrogel and could be potentially used in peripheral nerve injury repair.

Transplantation of embryonic spinal cord neurons to the injured distal nerve promotes axonal regeneration after delayed nerve repair.

Peripheral nerve injury (PNI) usually results in poor functional recovery. Nerve repair is the common clinical treatment for PNI but is always obstructed by the chronic degeneration of the distal stump and muscle. Cell transplantation can alleviate the muscle atrophy after PNI, but the subsequent recovery of the locomotive function is seldom described. In this study, we combined cell transplantation and nerve repair to investigate whether the transplantation of embryonic spinal cord cells could benefit the delayed nerve repair. The experiment consisted of 3 stages: transection of the tibial nerve to induce 'pre-degeneration', a second surgery performed 2 weeks later for transplantation of E14 embryonic spinal cord cells or vehicle (culture medium) at the distal end of the injured nerve, and, 3 months later, the removal of the grafted cells and the cross-suturing of the residual distal end to the proximal end of a freshly cut ipsilateral common peroneal (CP) nerve. Cell survival and fate after the transplantation were investigated, and the functional recovery after the cross-suturing was compared between the groups. The grafted cells could survive and generate motor neurons, extending axons that were subsequently myelinated and forming synapses with the muscle. After the cross-suturing, the axonal regeneration from the proximal stump of the injured CP nerve and the functional recovery of the denervated gastrocnemius muscle were significantly promoted in the group receiving the cells. Our study presents a new perspective indicating that the transplantation of embryonic spinal cord neurons may be a valuable therapeutic strategy for PNI.

Lithium accelerates functional motor recovery by improving remyelination of regenerating axons following ventral root avulsion and reimplantation.

Brachial plexus injury (BPI) often involves the complete or partial avulsion of one or more of the cervical nerve roots, which leads to permanent paralysis of the innervated muscles. Reimplantation surgery has been attempted as a clinical treatment for brachial plexus root avulsion but has failed to achieve complete functional recovery. Lithium is a mood stabilizer drug that is used to treat bipolar disorder; however, its effects on spinal cord or peripheral nerve injuries have also been reported. The purpose of this study was to investigate whether lithium can improve functional motor recovery after ventral root avulsion and reimplantation in a rat model of BPI. The results showed that systemic treatment with a clinical dose of lithium promoted motor neuron outgrowth and increased the efficiency of motor unit regeneration through enhanced remyelination. An analysis of myelin-associated genes showed that the effects of lithium started during the early phase of remyelination and persisted through the late stage of the process. Efficient remyelination of the regenerated axons in the lithium-treated rats led to an earlier functional recovery. Therefore, we demonstrated that lithium might be a potential clinical treatment for BPI in combination with reimplantation surgery.

Gastroesophageal Reflux Disease: Cross-Sectional Study Demonstrating Rising Prevalence in a Chinese Population.

BACKGROUND AND AIMS: The prevalence of gastroesophageal reflux disease (GERD) is consistently lower in the Chinese than in white populations. Population-based data tracking the time trend of GERD prevalence in Chinese subjects is conflicting. This study examines the population prevalence, risk factors, and time trend associated with GERD in a Chinese population. METHODS: A population-based cross-sectional study utilizing a validated GERD questionnaire administered by a telephone survey was performed on 3360 Chinese subjects from Hong Kong. GERD prevalence rates in 2011 were compared with prevalence rates in 2002 and 2006. Multiple logistic regressions were performed to determine the risk factors associated with weekly GERD. RESULTS: A total of 2074 subjects (mean age, 48.1±18.2 y; range 18 to 94; 63.1% female) completed the survey (response rate 61.7%). The prevalence of GERD as defined by the Montreal definition was 3.8%. The prevalence of weekly GERD had increased by 1.3% between 2002 and 2011, which represents an at least 50% relative increase (P<0.0005). A diagnosis of weekly GERD was associated with noncardiac chest pain [odds ratio (OR), 1.7; 95% confidence interval (CI), 1.034-2.9; P=0.037], dyspepsia (OR, 5.1; 95% CI, 3.0-8.8; P<0.005), and an acid feeling in the stomach (OR, 3.0; 95% CI, 1.8-5.1). CONCLUSIONS: GERD rates in the ethnic Chinese have risen over the last decade. Despite this, variables associated with a survey diagnosis of GERD remain ostensibly unchanged. GERD research in East Asia should focus on the factors driving the rapid rise in prevalence rates and the association with more atypical symptoms of GERD.

A self-assembling nanomaterial reduces acute brain injury and enhances functional recovery in a rat model of intracerebral hemorrhage.

There is no effective treatment for intracerebral hemorrhage (ICH). Intracerebral delivery of nanomaterials into the hemorrhagic lesion may be a new therapeutic strategy. In a rat model of ICH plus ultra-early hematoma aspiration, we found that locally delivered self-assembling peptide nanofiber scaffold (SAPNS) replaced the hematoma, reduced acute brain injury and brain cavity formation, and improved sensorimotor functional recovery. SAPNS serves as biocompatible material in the hemorrhagic brain cavity. Local delivery of this nanomaterial may facilitate the repair of ICH related brain injury and functional recovery. From the clinical editor: In a rat model of intracranial hemorrhage, these authors demonstrate that following ultra-early hematoma aspiration, local delivery of a self-assembling peptide nanofiber scaffold replaces the hematoma, reduces brain cavity formation, and improves sensorimotor functional recovery. Similar approaches would be welcome additions to the clinical treatment of this often devastating condition.

Lithium enhances axonal regeneration in peripheral nerve by inhibiting glycogen synthase kinase 3ß activation.

Brachial plexus injury often involves traumatic root avulsion resulting in permanent paralysis of the innervated muscles. The lack of sufficient regeneration from spinal motoneurons to the peripheral nerve (PN) is considered to be one of the major causes of the unsatisfactory outcome of various surgical interventions for repair of the devastating injury. The present study was undertaken to investigate potential inhibitory signals which influence axonal regeneration after root avulsion injury. The results of the study showed that root avulsion triggered GSK-3ß activation in the injured motoneurons and remaining axons in the ventral funiculus. Systemic application of a clinical dose of lithium suppressed activated GSK-3ß in the lesioned spinal cord to the normal level and induced extensive axonal regeneration into replanted ventral roots. Our study suggests that GSK-3ß activity is involved in negative regulation for axonal elongation and regeneration and lithium, the specific GSK-3ß inhibitor, enhances motoneuron regeneration from CNS to PNS.

Ventral root re-implantation is better than peripheral nerve transplantation for motoneuron survival and regeneration after spinal root avulsion injury.

BACKGROUND: Peripheral nerve (PN) transplantation and ventral root implantation are the two common types of recovery operations to restore the connection between motoneurons and their target muscles after brachial plexus injury. Despite experience accumulated over the past decade, fundamental knowledge is still lacking concerning the efficacy of the two microsurgical interventions. METHODS: Thirty-eight adult female Sprague-Dawley rats were divided into 5 groups. Immediately following root avulsion, animals in the first group (n = 8) and the second group (n = 8) received PN graft and ventral root implantation respectively. The third group (n = 8) and the fourth group (n = 8) received PN graft and ventral root implantation respectively at one week after root avulsion. The fifth group received root avulsion only as control (n = 6). The survival and axonal regeneration of severed motoneurons were investigated at 6 weeks post-implantation. RESULTS: Re-implantation of ventral roots, both immediately after root avulsion and in delay, significantly increased the survival and regeneration of motoneurons in the avulsed segment of the spinal cord as compared with PN graft transplantation. CONCLUSIONS: The ventral root re-implantation is a better surgical repairing procedure than PN graft transplantation for brachial plexus injury because of its easier manipulation for re-implanting avulsed ventral roots to the preferred site, less possibility of causing additional damage and better effects on motoneuron survival and axonal regeneration.

Essential role of NK cells in IgG therapy for experimental autoimmune encephalomyelitis.

Intravenous immunoglobulin has long been used in treating autoimmune diseases, although mechanisms remain uncertain. Activating Fcγ receptors are receptors of IgG and reported to be essential in intravenous immunoglobulin (IVIG) therapy. Therefore, we hypothesized natural killer (NK) cells, which express abundant activating Fcγ receptors, are the potential cellular target. In experimental autoimmune encephalomyelitis (EAE), we demonstrated that IgG suppressed disease development in intact, but not in NK cell depleted mice. Adoptive transfer of IgG-treated NK cell could protect mice against EAE, and suppressed interferon γ and interleukin 17 production. The percentage of CD4(+)Foxp3(+) regulatory T cells was significantly increased. The increase of regulatory T cells was also observed in IgG-treated EAE mice but not in NK cell depleted mice. In vitro experiments confirmed that IgG-treated NK cells enhanced regulatory T cell induction from naïve CD4(+) T cells. Interestingly, cells from draining lymph nodes produced more interleukin 2 after the adoptive transfer of IgG-treated NK cells. We neutralized interleukin 2 and the induction of CD4(+)Foxp3(+) T cells by IgG-treated NK cells was significantly reduced. To our knowledge, we identified for the first time the critical role of NK cells in the mechanism of IgG-induced induction of Treg cells in treatment of autoimmunity.

Transplanted motoneurons derived from human induced pluripotent stem cells form functional connections with target muscle.

Induced pluripotent stem cells (iPSCs) hold promise for the treatment of motoneuron diseases because of their distinct features including pluripotency, self-derivation and potential ability to differentiate into motoneurons. However, it is still unknown whether human iPSC-derived motoneurons can functionally innervate target muscles in vivo, which is the definitive sign of successful cell therapy for motoneuron diseases. In the present study, we demonstrated that human iPSCs derived from mesenchymal cells of the umbilical cord possessed a high yield in neural differentiation. Using a chemically-defined in vitro system, human iPSCs efficiently differentiated into motoneurons which displayed typical morphology, expressed specific molecules, and generated repetitive trains of action potentials. When transplanted into the injured musculocutaneous nerve of rats, they survived robustly, extended axons along the nerve, and formed functional connections with the target muscle (biceps brachii), thereby protecting the muscle from atrophy. Our study provides evidence for the first time that human iPSC-derived motoneurons are truly functional not only in vitro but also in vivo, and they have potential for stem cell-based therapies for motoneuron diseases.

Kif5b controls the localization of myofibril components for their assembly and linkage to the myotendinous junctions.

Controlled delivery of myofibril components to the appropriate sites of assembly is crucial for myofibrillogenesis. Here, we show that kinesin-1 heavy chain Kif5b plays important roles in anterograde transport of α-sarcomeric actin, non-muscle myosin IIB, together with intermediate filament proteins desmin and nestin to the growing tips of the elongating myotubes. Mice with Kif5b conditionally knocked out in myogenic cells showed aggregation of actin filaments and intermediate filament proteins in the differentiating skeletal muscle cells, which further affected myofibril assembly and their linkage to the myotendinous junctions. The expression of Kif5b in mutant myotubes rescued the localization of the affected proteins. Functional mapping of Kif5b revealed a 64-amino acid α-helix domain in the tail region, which directly interacted with desmin and might be responsible for the transportation of these proteins in a complex.

Nanofiber scaffolds facilitate functional regeneration of peripheral nerve injury.

Peripheral nerve injury still remains a refractory challenge for both clinical and basic researchers. A novel nanofiber conduit made of blood vessel and filled with amphiphilic hydrogel of self-assembling nanofiber scaffold (SAPNS) was implanted to repair a 10 mm nerve gap after sciatic nerve transection. Empty blood vessel conduit was implanted serving as control. Results showed that this novel nanofiber conduit enabled the peripheral axons to regenerate across and beyond the 10 mm gap. Motoneuron protection, axonal regeneration and remyelination were significantly enhanced with SAPNS scaffold treatments. The target reinnervation and functional recovery induced by the regenerative nerve conduit suggest that SAPNS-based conduit is highly promising application in the treatment of peripheral nerve defect. FROM THE CLINICAL EDITOR: In this paper by Zhan et al, a novel self-assembling nanofiber scaffold is reported to promote regeneration of peripheral nerves in a sciatic nerve injury model. The promising results and the obvious medical need raises hope for a clinical translation of this approach hopefully in the near future.

Neural progenitor cells generate motoneuron-like cells to form functional connections with target muscles after transplantation into the musculocutaneous nerve.

Neural progenitor cells (NPCs) are suggested to be a valuable source of cell transplant in treatment of various neurological diseases because of their distinct attributes. They can be expanded and induced to differentiate in vitro. However, it remains uncertain whether in vitro expanded NPCs have the capacity to give rise to functional motoneurons after transplantation in vivo. Here, we showed that in vitro expanded NPCs, when transplanted into the musculocutaneous nerve, generated motoneuron-like cells that exhibited typical morphology with large cell bodies, expressed specific molecules, and extended axons to form functional connections with the target muscle. In contrast, transplanted NPCs failed to yield motoneurons in the injured ventral horn of the spinal cord. The results of the study demonstrate that NPCs have the potential to generate functional motoneurons in an appropriate environment. The distinct differentiating fate of NPCs in the musculocutaneous nerve and the injured ventral horn suggests the importance and necessity of modifying the host microenvironment in use of NPCs for cell replacement therapies for motoneuron diseases.