Parameter mapping of hemiplegic shoulder electrical stimulation for motor function: A scoping review.

BACKGROUND: Electrical stimulation (ES) of the shoulder is effective in treating subluxation and shoulder pain. However, few studies have reported on ES of the hemiplegic shoulder with motor function as an outcome; thus, the method remains unclear. OBJECTIVE: We aimed to map the existing evidence and identify the parameters for ES of the hemiplegic shoulder for motor function in stroke patients. METHODS: A literature search was performed through PubMed and Scopus to retrieve original articles from 1975 to March 2023 using the terms "stroke", "shoulder", and "electricity". We selected studies in which ES was performed on hemiplegic shoulders after stroke, parameters were described, and upper extremity motor functional assessment was included as an outcome. The extracted data included study design, phase, sample size, electrode position, parameters, intervention period, evaluation frequency, outcomes, and results. RESULTS: Of the 449 titles identified, 25 fulfilled the inclusion and exclusion criteria. Nineteen were randomized controlled trials. The most common electrode positions and parameters (frequency and pulse width) were over the posterior deltoid and the supraspinatus (upper trapezius) muscles, 30 Hz, and 250µs, respectively. The intervention period was 30-60 minutes per day, 5-7 days per week, for 4-5 weeks in over half of the studies. CONCLUSION: Stimulation positions and parameters for electrical stimulation of the hemiplegic shoulder are inconsistent. Whether ES represents a significant treatment option remains unclear. Establishing universal ES methods is necessary to improve the motor function of hemiplegic shoulders.

Maiden voyage: induced pluripotent stem cell-based drug screening for amyotrophic lateral sclerosis.

Using patient-derived induced pluripotent stem cells, neurodegenerative disease phenotypes have been recapitulated and their pathogenesis analysed leading to significant progress in drug screening. In amyotrophic lateral sclerosis, high-throughput screening using induced pluripotent stem cells-derived motor neurons has identified candidate drugs. Owing to induced pluripotent stem cell-based drug evaluation/screening, three compounds, retigabine, ropinirole and bosutinib, have progressed to clinical trials. Retigabine blocks hyperexcitability and improves survival in amyotrophic lateral sclerosis patient-derived motor neurons. In a randomized clinical trial (n = 65), treatment with retigabine reduced neuronal excitability after 8 weeks. Ropinirole, identified in a high-throughput screening, attenuates pathological phenotypes in patient-derived motor neurons. In a trial limited by a small sample size (n = 20), ropinirole was tolerable and had clinical benefits on function and survival. A phase 1 study of bosutinib has reported safety and tolerability for 12 weeks. Thus, these clinical trials show safety and positive effects and confirm the reliability of stem cell-based drug discovery. This novel strategy leads to reduced costs and time when compared to animal testing and opens new avenues for therapy in intractable diseases.

Synergistic effect of bodyweight resistance exercise and protein supplementation on skeletal muscle in sarcopenic or dynapenic older adults.

AIM: The objective of this trial was to investigate the synergistic effects of bodyweight resistance exercise and a protein supplement with vitamin D on skeletal muscle in sarcopenic or dynapenic older adults. METHODS: This was a four-arm randomized controlled trial. Sarcopenic or dynapenic older adults were recruited for this trial. After screening, a total of 112 older adults were randomly allocated among four groups; 28 older adults each were enrolled in the combined resistance exercise and nutritional supplementation group, the exercise alone group, the nutritional supplementation alone group, and the control group. Participants in the combined group and exercise alone groups took part in a bodyweight resistance exercise program for 12 weeks. Protein and vitamin D supplements were provided every day for 12 weeks for the participants in the combined group and nutritional supplementation alone groups. We assessed the echo intensity of participants' thigh muscle using ultrasonography, measured their appendicular muscle mass using a bioelectrical impedance data acquisition system, and tested their knee extension strength and physical function. RESULTS: Participants in the combined group had a significantly greater improvement in rectus femoris echo intensity and knee extension torque than those in the other groups (P < 0.05). Furthermore, the combined program increased appendicular muscle mass in sarcopenic older adults (P < 0.05), but not in older adults with low physical function with normal muscle mass. CONCLUSIONS: The present study confirmed the synergistic effect of bodyweight resistance exercise and protein supplement with vitamin D on muscle quality and muscle strength in sarcopenic or dynapenic older adults. Geriatr Gerontol Int 2019; 19: 429-437.

Increased Ca++ uptake by erythrocytes infected with malaria parasites: Evidence for exported proteins and novel inhibitors.

Malaria parasites export many proteins into their host erythrocytes and increase membrane permeability to diverse solutes. Although most solutes use a broad-selectivity channel known as the plasmodial surface anion channel, increased Ca++ uptake is mediated by a distinct, poorly characterised mechanism that appears to be essential for the intracellular parasite. Here, we examined infected cell Ca++ uptake with a kinetic fluorescence assay and the virulent human pathogen, Plasmodium falciparum. Cell surface labelling with N-hydroxysulfosuccinimide esters revealed differing effects on transport into infected and uninfected cells, indicating that Ca++ uptake at the infected cell surface is mediated by new or altered proteins at the host membrane. Conditional knockdown of PTEX, a translocon for export of parasite proteins into the host cell, significantly reduced infected cell Ca++ permeability, suggesting involvement of parasite-encoded proteins trafficked to the host membrane. A high-throughput chemical screen identified the first Ca++ transport inhibitors active against Plasmodium-infected cells. These novel chemical scaffolds inhibit both uptake and parasite growth; improved in vitro potency at reduced free [Ca++ ] is consistent with parasite killing specifically via action on one or more Ca++ transporters. These inhibitors should provide mechanistic insights into malaria parasite Ca++ transport and may be starting points for new antimalarial drugs.

Constitutive activation of alternative nuclear factor kappa B pathway in canine diffuse large B-cell lymphoma contributes to tumor cell survival and is a target of new adjuvant therapies.

Activation of the classical nuclear factor kappa-light-chain-enhancer of activated B cells (NFκB) pathway is a common molecular event observed in both human and canine diffuse large B-cell lymphoma (DLBCL). Although the oncogenic potential of the alternative NFκB pathway (ANFκBP) has also been recently identified in DLBCL, its precise role in tumor pathogenesis and potential as a treatment target is understudied. We hypothesized that up-regulation of the ANFκBP plays an important role in the proliferation and survival of canine DLBCL cells, and we demonstrate that the ANFκBP is constitutively active in primary canine DLBCL samples and a cell line (CLBL1). We further demonstrate that a small interfering RNA inhibits the activation of the NFκB pathway and induces apoptosis in canine DLBCL cells. In conclusion, the ANFκBP facilitates survival of canine DLBCL cells, and thus, dogs with spontaneous DLBCL can provide a useful large animal model to study therapies targeting the ANFκBP.

Randomized double-blind placebo-controlled multicenter trial of Yokukansan for neuropsychiatric symptoms in Alzheimer's disease.

AIM: Yokukansan (YKS), a traditional herbal medicine, has been used to treat behavioral and psychological symptoms of dementia (BPSD). The present study is the first double-blind, randomized, placebo-controlled trial to determine the efficacy and safety of YKS for the treatment of BPSD in Alzheimer's disease (AD). METHODS: A total of 22 sites consisting of clinics, hospitals and nursing homes participated. A total of 145 patients with AD were randomized. Active YKS (7.5 g/day) and placebo were supplied to 75 and 70 participants, respectively. The primary outcome measure was the 4-week change in total score of the Neuropsychiatric Inventory Brief Questionnaire Form (NPI-Q), an instrument that evaluates BPSD. Secondary outcome measures included 12-week changes in NPI-Q scores, changes in NPI-Q subcategory scores and total scores of the Mini-Mental-State Examination. RESULTS: Four-week changes in NPI-Q total scores did not differ significantly between the treatment and placebo groups. There were also no significant differences between groups in 12-week changes in total NPI-Q scores, NPI-Q subcategory scores or total Mini-Mental-State Examination scores. However, a subgroup with fewer than 20 points on the Mini-Mental-State Examination at baseline showed a greater decrease in "agitation/aggression" score in the YKS group than in the placebo group (P = 0.007). No serious adverse effects were observed during the study. CONCLUSIONS: Our data did not reach statistical significance regarding the efficacy of YKS against BPSD; however, YKS improves some symptoms including "agitation/aggression" and "hallucinations" with low frequencies of adverse events. Geriatr Gerontol Int 2017; 17: 211-218.

Preclinical evaluation of the novel, orally bioavailable Selective Inhibitor of Nuclear Export (SINE) KPT-335 in spontaneous canine cancer: results of a phase I study.

BACKGROUND: The purpose of this study was to evaluate the activity of Selective Inhibitors of Nuclear Export (SINE) compounds that inhibit the function of the nuclear export protein Exportin 1 (XPO1/CRM1) against canine tumor cell lines and perform a Phase I clinical trial of KPT-335 in dogs with spontaneous cancer to provide a preliminary assessment of biologic activity and tolerability. METHODS AND FINDINGS: Canine tumor cell lines derived from non-Hodgkin lymphoma (NHL), mast cell tumor, melanoma and osteosarcoma exhibited growth inhibition and apoptosis in response to nanomolar concentrations of SINE compounds; NHL cells were particularly sensitive with IC50 concentrations ranging from 2-42 nM. A Phase I clinical trial of KPT-335 was performed in 17 dogs with NHL (naive or relapsed), mast cell tumor or osteosarcoma. The maximum tolerated dose was 1.75 mg/kg given orally twice/week (Monday/Thursday) although biologic activity was observed at 1 mg/kg. Clinical benefit (CB) including partial response to therapy (PR, n = 2) and stable disease (SD, n = 7) was observed in 9/14 dogs with NHL with a median time to progression (TTP) for responders of 66 days (range 35-256 days). A dose expansion study was performed in 6 dogs with NHL given 1.5 mg/kg KPT-335 Monday/Wednesday/Friday; CB was observed in 4/6 dogs with a median TTP for responders of 83 days (range 35-354 days). Toxicities were primarily gastrointestinal consisting of anorexia, weight loss, vomiting and diarrhea and were manageable with supportive care, dose modulation and administration of low dose prednisone; hepatotoxicity, anorexia and weight loss were the dose limiting toxicities. CONCLUSIONS: This study provides evidence that the novel orally bioavailable XPO1 inhibitor KPT-335 is safe and exhibits activity in a relevant, spontaneous large animal model of cancer. Data from this study provides critical new information that lays the groundwork for evaluation of SINE compounds in human cancer.

Multiple thalamo-cortical disconnections in anterior thalamic infarction: implications for thalamic mechanisms of memory and language.

Amnesia and linguistic deficits that are associated with thalamic damage have attracted the attention of researchers interested in identifying the neural networks involved in memory and language. The Papez circuit, which is composed of the hippocampus, mammillary body and anterior thalamic nuclei, was first proposed to be critical for memory. However, subsequently, the roles of the neural circuit consisting of the rhinal/parahippocampal cortices and the mediodorsal thalamic nuclei became evident. The ventral lateral nuclei or its adjacent structures have been found to be involved in semantic processing, but the specific neural circuits dedicated to language functions have not been identified. Anterior thalamic infarcts, which affect very circumscribed regions of the ventral anterior portion of the thalamus, often cause paradoxically prominent memory and language deficits. We conducted tractography analyses in 6 patients with left anterior thalamic infarcts to identify neural connections or circuits in which disruptions are associated with memory and language deficits in this condition. The current study demonstrated that the mammillothalamic tract, which connects the mammillary body with the anterior thalamic nuclei, and the anterior and inferior thalamic peduncles, which contain neural fibers that extend from several thalamic nuclei to the anterior temporal, medial temporal and frontal cortices, are disrupted in anterior thalamic infarction. These extensive thalamo-cortical disconnections appear to be due to the dissection of the neural fibers that penetrate the ventral anterior nucleus of the thalamus. Our results suggest the following: (1) amnesia that is associated with anterior thalamic infarction is best interpreted in the context of dual/multiple-system theories of memory/amnesia that posit that multiple neural circuits connecting the anterior and mediodorsal thalamic nuclei with the hippocampus and rhinal/parahippocampal cortices work in concert to support memory function; and (2) the semantic deficits observed in this syndrome may be associated with thalamo-anterior temporal and thalamo-lateral frontal disconnections.

Neuroanatomical characterisation of the expression of the lipodystrophy and motor-neuropathy gene Bscl2 in adult mouse brain.

The endoplasmic reticulum localised protein seipin, encoded by the gene Berardinelli-Seip congenital lipodystrophy type 2 (BSCL2), serves a critical but poorly defined function in the physiology of both adipose and neural tissue. In humans, BSCL2 loss-of-function mutations cause a severe form of lipodystrophy, whilst a distinct set of gain-of-toxic-function mutations are associated with a heterogeneous group of neuropathies. However, despite the importance of seipin dysfunction to the pathophysiology of these conditions, little is known about its physiological role in adipocytes or neurons. BSCL2 mRNA has previously been identified in human and mouse brain, yet no definitive assessment of its expression has been undertaken. Here we comprehensively characterised the neuroanatomical distribution of mouse Bscl2 using complementary in situ hybridisation histochemistry and immunohistochemistry techniques. Whilst Bscl2 was broadly expressed throughout the rostral-caudal extent of the mouse brain, it exhibited a discrete neuroanatomical profile. Bscl2 was most abundantly expressed in the hypothalamus and in particular regions associated with the regulation of energy balance including, the paraventricular, ventromedial, arcuate and dorsomedial nuclei. Bscl2 expression was also identified within the brainstem dorsal vagal complex, which together with the paraventricular nucleus of the hypothalamus represented the site of highest expression. Further neurochemical profiling of these two nuclei revealed Bscl2/seipin expression within energy balance related neuronal populations. Specifically, seipin was detected in oxytocin neurons of the paraventricular nucleus of the hypothalamus and in catecholamine neurons of the dorsal vagal complex. These data raise the possibility that in addition to its role in adipose tissue development, seipin may also be involved in the central regulation of energy balance.