Locomotive Syndrome: Operational Definition Based on a Questionnaire, and Exercise Interventions on Mobility Dysfunction in Elderly People.

The increasing elderly population has a great impact on public health, and it is important to understand the progression of musculoskeletal disorders seen in this population. To establish useful preventative methods for such locomotive disorders, we must detect early changes in these individuals and identify those at risk in order to implement early interventions. The purpose of this review was: (1) to introduce an operational definition of locomotion dysfunction to prevent a care-need condition, and to verify its validity through a prospective cohort study, and (2) to review the indication of exercise intervention for multiple musculoskeletal involvements from the preceding literature. We developed a measurement scale called the Geriatric Locomotive Function Scale (GLFS)-25, which clearly reflects the degree of functional deterioration. We used it in a prospective cohort study of 314 patients recruited from 5 clinics or nursing care facilities and investigated the relationship of the GLFS-25 with 46 variables covering various clinical manifestations. The results clearly revealed that the change in the GLFS-25 classification reflected a common pattern seen in those with locomotive dysfunction. Recently, several important movements regarding physical activity and its public promotion have been advocated by international health organizations and journal publishers. Though it has not been confirmed yet that complex musculoskeletal diseases can be treated using therapeutic exercise, the promotion of physical activity appears promising. The degree of activity limitation in aged individuals with locomotive disorders can be evaluated using this scale, which may be useful in predicting the effectiveness of future interventions.

Sublingual immunotherapy for allergic rhinitis: subjective versus objective tools to evaluate its success.

BACKGROUND: Biomarkers that enable objective evaluation of the clinical effects of immunotherapy for allergic rhinitis have yet to be identified. METHODS: This study included 40 patients who were enrolled in a large randomized, double-blind, placebo-controlled, multicenter study examining the efficacy of sublingual immunotherapy (SLIT) using Japanese cedar (JC) pollen extract during two consecutive pollen seasons from 2010 to 2012. Based on changes in total nasal symptom medication score, patients in the SLIT and placebo groups were subdivided into two subgroups: good responders and poor responders. The levels of JC pollen-specific IL-10+Foxp3+ cells and specific Th2 cytokine-producing cells were measured and the association with the efficacy of SLIT was analysed. RESULTS: The total nasal symptom medication score was significantly lower in the SLIT group compared with the placebo group. The number of JC pollen-specific Th2 cytokine-producing cells increased during the pollen season in the placebo group and in poor responders in the SLIT group; however, the increases were inhibited in the good responders in the SLIT group. The number of JC pollen-specific IL-10+Foxp3+ cells increased only in these good responders. CONCLUSIONS: Changes in levels of allergen-specific Th2 cytokine-producing cells and IL-10+Foxp3+ cells could be objective biomarkers for SLIT.

Soft-plastic brace for lower limb fractures in patients with spinal cord injury.

STUDY DESIGN: Retrospective study at a rehabilitation center. OBJECTIVES: Patients with spinal cord injury, even if they are wheelchair users, sometimes suffer from fractures of the lower limb bones. As their bones are too weak to have surgery, and because a precise reduction is not required for restoration, such patients are often indicated for conservative treatment. This case series study investigated the use of a hinged, soft-plastic brace as a conservative approach to treating fractures of the lower extremities of patients with spinal cord injury. SETTING: National Rehabilitation Center, Japan. METHODS: Fifteen patients (male, n=10; female, n=5; average age, 52.7 years) with 19 fractures of the femur or the tibia who were treated with a newly-developed hinged, soft-plastic brace were studied. All of them used wheelchairs. We analyzed the time taken for fracture union and for wearing orthotics, degree of malalignment, femorotibial angle and side effects. RESULTS: The fractures in this series were caused by relatively low-energy impact. The average time taken for fracture union was 80.1 (37-189) days, and the average amount of time spent wearing orthotics was 77.9 (42-197) days. On final X-ray imaging, the average femorotibial angle was 176.9° (s.d. ±8.90), and 15° of misalignment in the sagittal plane occurred in one patient. CONCLUSION: A hinged, soft-plastic brace is a useful option as a conservative approach for treating fractures of the lower extremities in patients with spinal cord injury.

Comparison of clinical outcomes of osimertinib and first-generation EGFR-tyrosine kinase inhibitors (TKIs) in TKI-untreated EGFR-mutated non-small-cell lung cancer with leptomeningeal metastases.

BACKGROUND: Leptomeningeal metastases (LM) are devastating complications of epidermal growth factor receptor (EGFR)-mutated non-small-cell lung cancer (NSCLC). Although osimertinib, a third-generation EGFR-tyrosine kinase inhibitor (TKI), has better penetration into the central nervous system than first-generation EGFR-TKIs, data on the distinct activity of EGFR-TKIs in untreated advanced EGFR-mutated NSCLC with LM are lacking. PATIENTS AND METHODS: We retrospectively reviewed patients treated with EGFR-TKIs for TKI-untreated common EGFR-mutated NSCLC with LM between July 2002 and July 2021 at the National Cancer Center Hospital. The patients were divided into two groups: patients treated with osimertinib (Osi group) and those treated with gefitinib or erlotinib [first-generation (1G)-TKI group]. RESULTS: Of the 967 patients, 71 were eligible, including 29 in the Osi group and 42 in the 1G-TKI group. The median progression-free survival (PFS) and overall survival (OS) in the Osi group were better than those in the 1G-TKI group (PFS: 16.9 months versus 8.6 months, P = 0.007, and OS: 26.6 months versus 20.0 months, P = 0.158). The LM-overall response rate (ORR) and LM-PFS were significantly better in the Osi group than in the 1G-TKI group (LM-ORR: 62.5% versus 25.7%, P = 0.007; LM-PFS: 23.4 months versus 12.1 months, P = 0.021). In the subgroup analysis of EGFR mutation status, LM-PFS for patients with exon 19 deletion was significantly longer in the Osi group than in the 1G-TKI group (32.7 months versus 13.4 months, P = 0.013), whereas those with L858R mutation in exon 21 did not differ between the two groups. In the multivariate analysis, osimertinib and exon 19 deletion were significant factors for better LM-PFS and OS. CONCLUSION: Osimertinib can be more effective for untreated common EGFR-mutated NSCLC patients with LM, especially those with exon 19 deletion, compared to first-generation TKIs.

Middle meningeal artery embolization for chronic subdural hematoma with cerebrospinal fluid hypovolemia: A report of 2 cases.

BACKGROUND: Chronic subdural hematoma (CSDH) with cerebrospinal fluid hypovolemia syndrome (CHS) remains refractory to standard treatment with hematoma drainage by burr hole and irrigation and/or epidural blood patch. Previously, we reported the utility of middle meningeal artery (MMA) embolization for intractable CSDH. In this study, we present the usefulness of MMA embolization as a treatment for CSDHs with CHSs. CASES: We present two cases of CSDHs with CHSs occurring in patients, 1 treated with burr hole craniotomy and irrigation, and the other treated with the epidural blood patch. Both patients exhibited similar-appearing bilateral relatively-thin hematomas, hyperplasia, and enhanced contrast effects in the dura mater, and extradural hygroma in the cervical portion on enhanced magnetic resonance imaging scans. Also, to reviewing prior literature and imaging findings, they had already undergone conventional treatment. We added MMA embolization treatment and they followed a good course. RESULTS: Despite the known intractable outcomes of patients with CSDHs with CHSs, MMA embolization worked well in the current case series. CONCLUSION: MMA embolization might be considered as a preferred therapeutic option for CSDHs with CHSs in order to buy time before the epidural blood patch starts working.

Neuromuscular electrical stimulation: implications of the electrically evoked sensory volley.

Neuromuscular electrical stimulation (NMES) generates contractions by depolarising axons beneath the stimulating electrodes. The depolarisation of motor axons produces contractions by signals travelling from the stimulation location to the muscle (peripheral pathway), with no involvement of the central nervous system (CNS). The concomitant depolarisation of sensory axons sends a large volley into the CNS and this can contribute to contractions by signals travelling through the spinal cord (central pathway) which may have advantages when NMES is used to restore movement or reduce muscle atrophy. In addition, the electrically evoked sensory volley increases activity in CNS circuits that control movement and this can also enhance neuromuscular function after CNS damage. The first part of this review provides an overview of how peripheral and central pathways contribute to contractions evoked by NMES and describes how differences in NMES parameters affect the balance between transmission along these two pathways. The second part of this review describes how NMES location (i.e. over the nerve trunk or muscle belly) affects transmission along peripheral and central pathways and describes some implications for motor unit recruitment during NMES. The third part of this review summarises some of the effects that the electrically evoked sensory volley has on CNS circuits, and highlights the need to identify optimal stimulation parameters for eliciting plasticity in the CNS. A goal of this work is to identify the best way to utilize the electrically evoked sensory volley generated during NMES to exploit mechanisms inherent to the neuromuscular system and enhance neuromuscular function for rehabilitation.

Reflex pathways connect receptors in the human lower leg to the erector spinae muscles of the lower back.

Reflex pathways connect all four limbs in humans. Presently, we tested the hypothesis that reflexes also link sensory receptors in the lower leg with muscles of the lower back (erector spinae; ES). Taps were applied to the right Achilles' tendon and electromyographic activity was recorded from the right soleus and bilaterally from ES. Reflexes were compared between sitting and standing and between standing with the eyes open versus closed. Reflexes were evoked bilaterally in ES and consisted of an early latency excitation, a medium latency inhibition, and a longer latency excitation. During sitting but not standing, the early excitation was larger in the ES muscle ipsilateral to the stimulation (iES) than in the contralateral ES (cES). During standing but not sitting, the longer latency excitation in cES was larger than in iES. This response in cES was also larger during standing compared to sitting. Responses were not significantly different between the eyes open and eyes closed conditions. Taps applied to the lateral calcaneus (heel taps) evoked responses in ES that were not significantly different in amplitude or latency than those evoked by tendon taps, despite a 75-94% reduction in the amplitude of the soleus stretch reflex evoked by the heel taps. Electrical stimulation of the sural nerve, a purely cutaneous nerve at the ankle, evoked ES reflexes that were not significantly different in amplitude but had significantly longer latencies than those evoked by the tendon and heel taps. These results support the hypothesis that reflex pathways connect receptors in the lower leg with muscles of the lower back and show that that the amplitude of these reflexes is modulated by task. Responses evoked by stimulation of the sural nerve establish that reflex pathways connect the ES muscles with cutaneous receptors of the foot. In contrast, the large volley in muscle spindle afferents induced by the tendon taps compared to the heel taps did not alter the ES responses, suggesting that the reflex connection between triceps surae muscle spindles and the ES muscles may be relatively weak. These heteronymous reflexes may play a role in stabilizing the trunk for maintaining posture and balance.

Perspective on immune oncology with liquid biopsy, peripheral blood mononuclear cells, and microbiome with non-invasive biomarkers in cancer patients.

Antibodies against immune checkpoint inhibitors such as anti-programmed cell death protein 1 (PD-1) and anti-programmed death ligand 1 (PD-L1) play a key role in the treatment of advanced lung cancer. To examine the clinical benefits of these agents, preclinical and clinical studies have been conducted to identify definitive biomarkers associated with cancer status. Analysis of the blood and feces of tumor patients has attracted attention in recent studies attempting to identify non-invasive biomarkers such as cytokines, soluble PD-L1, peripheral blood mononuclear cells, and gut microbiota. These factors are believed to interact with each other to produce synergistic effects and contribute to the formation of the tumor immune microenvironment through the seven steps of the cancer immunity cycle. The immunogram was first introduced as a novel indicator to define the immunity status of cancer patients. In this review, we discuss the progress in the identification of predictive biomarkers as well as future prospects for anti-PD-1/PD-L1 therapy.

Regulated production of activin A and inhibin B throughout the cycle of the seminiferous epithelium in the rat.

Production and regulation of activin A and inhibin B during the cycle of the seminiferous epithelium were investigated in adult rats. Immunohistochemistry localised the activin beta(A)-subunit to the Sertoli cell cytoplasm, with much weaker expression in spermatocytes and spermatids. Both activin A and inhibin B, measured by ELISA were secreted by, seminiferous tubule fragments over 72 h in culture. Activin A was secreted in a cyclic manner with peak secretion from tubules isolated at stage VIII. Tubules collected during stage VI produced the least activin A. Inhibin B secretion was highest from stage IX-I tubules and lowest from stage VII tubules. Addition of interleukin-1beta (IL-1beta) had relatively little effect on activin A or inhibin B secretion in culture. In contrast, the peak secretion of activin A by stage VIII tubules was blocked by co-incubation with an excess of human recombinant IL-1 receptor antagonist, whereas inhibin B secretion increased slightly. Dibutyryl cAMP stimulated activin A secretion by late stage VII and VIII tubules and stimulated inhibin B across all stages. These data indicate that activin A and inhibin B are cyclically regulated within the seminiferous epithelium, with endogenous IL-1 (presumably IL-1alpha produced by the Sertoli cells), responsible for a peak of activin A production subsequent to sperm release at stage VIII. These data provide direct evidence that production of activin A and inhibin B by the Sertoli cell is locally modulated by IL-1alpha , in addition to FSH/cAMP, under the influence of the developing spermatogenic cells.

Possible involvement of cytochrome c release and sequential activation of caspases in ceramide-induced apoptosis in SK-N-MC cells.

Ceramide is characterized as a second messenger of apoptosis induced by various agents such as tumor necrosis factor (TNF-alpha), Fas ligand, hydrogen peroxide, heat shock and ionizing radiation. In this study, we investigated the mechanism of ceramide-induced apoptosis using a human neuroblastoma cell line, SK-N-MC. N-Acetyl-sphingosine (C2-ceramide), a cell-permeable ceramide analogue, was able to induce apoptosis in SK-N-MC cells as estimated by DNA fragmentation and chromatin condensation. C2-ceramide-induced DNA fragmentation was blocked by caspase inhibitor (Z-Asp-CH(2)-DCB). An increase in caspase-3 (CPP32)-like protease activity was evident during C2-ceramide-induced apoptosis, suggesting that caspases are involved in this apoptosis. Moreover, enzymatic cleavage of VDVAD-AFC and LEHD-AFC (specific substrates for caspase-2 and -9, respectively) was increased by treatment with C2-ceramide. To elucidate which types of caspase are activated in C2-ceramide-treated cells, we performed Western blot analysis using antibodies against each isoform. Both proforms of caspase-2 and -3 were decreased in response to C2-ceramide in a time-dependent manner. Mitochondrial cytochrome c is also time-dependently released into the cytosol in response to treatment with C2-ceramide. Addition of cytochrome c into the S-100 fractions prepared from SK-N-MC cells could activate caspase-2 in cell-free systems. These results suggest the possibility that cytochrome c released to the cytosol can activate caspases (caspase-9, -3, and -2) during C2-ceramide-induced apoptosis of SK-N-MC cells.

Regulation of activin A and inhibin B secretion by inflammatory mediators in adult rat Sertoli cell cultures.

The regulation of Sertoli cell activin A and inhibin B secretion during inflammation was investigated in vitro. Adult rat Sertoli cells were incubated with the inflammatory mediators, lipopolysaccharide (LPS), interleukin-1beta (IL-1beta), IL-6 and the IL-1 receptor antagonist (IL-1ra) over 48 h in culture. Activin A, inhibin B and IL-1alpha were measured in the culture medium by specific two-site ELISAs. Both IL-1beta- and LPS-stimulated activin A and inhibited inhibin B secretion. LPS also stimulated the production of IL-1alpha in the cultures. In contrast to IL-1beta, IL-6 had no effect on activin A, although it did have a significant inhibitory effect on inhibin B secretion. Ovine follicle-stimulating hormone (FSH) and the cAMP analogue dibutyryl cAMP opposed the actions of IL-1 and LPS by suppressing activin A and IL-1alpha secretion and by stimulating inhibin B. Blocking IL-1 activity in the cultures by addition of an excess of IL-1ra completely prevented the response of activin A to exogenous IL-1beta, and reduced the response to LPS by 50%. In the presence of IL-1ra, basal secretion of inhibin B was increased, but IL-1ra was unable to reverse the suppression of inhibin B by LPS. These data indicate the importance of both IL-1 isoforms in regulating secretion of activin A and inhibin B by mature Sertoli cells during inflammation. The data also establish that inflammation exerts its effects on activin A and inhibin B secretion via other pathways in addition to those mediated by IL-1, and that hormonal stimulation by FSH and cAMP moderates the Sertoli cell response to inflammation. Interference with the complex interactions between these cytokines and hormones may contribute to the disruption of reproductive function that can accompany infection and illness in men.

Reciprocal regulation of activin A and inhibin B by interleukin-1 (IL-1) and follicle-stimulating hormone (FSH) in rat Sertoli cells in vitro.

In several biological systems, the inhibin beta(A) homodimer activin A is stimulated by, and in turn, inhibits the action of interleukin (IL)-1 (both IL-1alpha and IL-1beta) and IL-6. The possibility that a similar regulatory relationship operates within the testis was investigated. Sertoli cells from immature (20-day-old) rats were cultured with human IL-1alpha or IL-1beta, human IL-6 and/or ovine FSH or dibutyryl cAMP. Activin A and the inhibin dimers, inhibin A and inhibin B, were measured by specific ELISA. Immunoreactive inhibin (ir-inhibin) was measured by RIA. Activin/inhibin subunit mRNA expression was measured by quantitative real-time PCR. Both IL-1 isoforms, but not IL-6, stimulated activin A secretion through increased synthesis of beta(A)-subunit mRNA. IL-1 also stimulated activin A secretion by testicular peritubular cells. In contrast to the effect on activin A, IL-1 suppressed inhibin beta(B)-subunit and, to a lesser extent, alpha-subunit mRNA expression, thereby reducing basal and FSH-stimulated inhibin B secretion by the Sertoli cells. Conversely, FSH inhibited basal activin A secretion and antagonised the stimulatory effects of IL-1. Dibutyryl cAMP partially inhibited the action of IL-1 on activin A secretion, but had no significant effect on basal activin A secretion. Secretion of inhibin A was low in all treatment groups. These data demonstrate that IL-1 and FSH/cAMP exert a reciprocal regulation of activin A and inhibin B synthesis and release by the Sertoli cell, and suggest a role for activin A as a potential feedback regulator of IL-1 and IL-6 activity in the testis during normal spermatogenesis and in inflammation.

Age-related defects in lifespan and learning ability in SAMP8 mice.

Pertinent animal models of age-related learning deficiencies are required to elucidate the mechanism of age-related learning deficiencies and to develop novel therapeutic drugs for age-related diseases such as learning defects. Among many strains of accelerated senescence prone, senescence-accelerated mouse (SAM), SAMP8 mice have age-related defects in learning and cognitive abilities. We review recent findings on alterations in SAMP8 brain in neurochemical parameters related to neurotransmission and synaptic plasticity compared to those in SAMR1 brain as the control. In addition, we report the preventive effects of drugs on learning deficiencies in SAMP8 and discuss the usefulness of SAMP8 as an animal model of age-related learning deficiencies.

Learning deficiency and alterations in acetylcholine receptors and protein kinase C in the brain of senescence-accelerated mouse (SAM)-P10.

The senescence-accelerated mouse (SAM) is known to be a murine model for accelerated aging. A novel inbred SAMP10 has shown age-related brain atrophy and learning deficiency. In the present study, we investigated the changes in learning ability and in ligand binding with muscarinic acetylcholine (mACh) receptors, alpha adrenoceptors and protein kinase C in SAMP10. In Morris's water maze task, in a control strain of SAMR1 at 9 months, the escape latency and path length decreased with increasing trial days, in contrast, escape latency and path length did not decrease in SAMP10. These results indicate that SAMP10 exhibits learning deficiency. The ligand binding activity of mACh receptors decreased in the hippocampus of SAMP10 and the protein kinase C level in the hippocampus of SAMP10 was lower than that of SAMR1. On the other hand, there was no significant difference between SAMR1 and SAMP10 regarding ligand binding activity of alpha(1) and alpha(2) adrenoceptors. Thus, a reduction of mACh receptors and protein kinase C in the brain seems to underlie dysfunction of learning and memory in SAMP10.

Thromboxane A2 is involved in the nitric oxide-induced central activation of adrenomedullary outflow in rats.

The central effect of 3-morpholinosydnonimine, a nitric oxide donor, on the sympatho-adrenomedullary system was investigated in urethane-anesthetized rats. Intracerebroventricular administration of 3-morpholinosydnonimine (100, 250 and 500 microg/animal) induced a marked elevation of adrenaline levels and a slight elevation of noradrenaline levels in the plasma. These 3-morpholinosydnonimine (250 microg/animal)-induced elevations of catecholamines were abolished by intracerebroventricular treatments with 2-(4-carboxyphenyl)-4,4,5,5-tetramethylimidazoline-l-oxyl 3-oxide (750 microg/animal), a nitric oxide scavenger, and indomethacin (500 microg/animal), a cyclo-oxygenase inhibitor, but not with superoxide dismutase (250 units/animal), a superoxide anion scavenger. Furthermore, the 3-morpholinosydnonimine (250 microg/animal)-induced elevation of plasma adrenaline levels was abolished by intracerebroventricular treatments with thromboxane A2 synthase inhibitors [furegrelate (100, 250 and 1000 microg/animal) and carboxyheptyl imidazole (500 microg/animal)], and also with thromboxane A2 receptor blockers [(+)-S-145 (100, 250 and 1000microg/animal) and SQ29548 (8microg/animal)]. The elevation of noradrenaline levels was, however, not attenuated by these thromboxane A2-related test agents. The present results indicate that nitric oxide but not peroxynitrite markedly activates central adrenomedullary outflow. Thromboxane A2 in the brain is probably involved in this central activation of adrenomedullary outflow.

Glial cell line-derived neurotrophic factor protects against delayed neuronal death after transient forebrain ischemia in rats.

Glial cell line-derived neurotrophic factor, a member of the transforming growth factor-beta superfamily, is a potent neurotrophic factor, which has a variety of biological activities that affect several types of neurons in both the central and peripheral nervous systems. In this study, we examined the effects of glial cell line-derived neurotrophic factor on delayed neuronal death in the hippocampal CA1 region of rats after transient forebrain ischemia. In the control rats pretreated with the vehicle, transient forebrain ischemia-induced delayed neuronal death in the hippocampal CA1 region was observed seven days after reperfusion. Pretreatment with glial cell line-derived neurotrophic factor (1.0 microg), which was directly microinjected into the right hippocampal CA1 region, gave significant protection against the delayed hippocampal neuronal death. On the contralateral side of the hippocampus, which was not injected with glial cell line-derived neurotrophic factor, delayed neuronal death similar to that seen in vehicle-treated control animals was observed. Intracerebroventricular glial cell line-derived neurotrophic factor (2.5 microg) injection also protected against delayed neuronal death. In addition, pretreatment with glial cell line-derived neurotrophic factor gave significant protection against apoptotic cell death induced by brain ischemia in the hippocampal CA1 region, as determined by in situ staining for DNA fragmentation. These findings suggest that glial cell line-derived neurotrophic factor plays an important role in delayed neuronal death induced by brain ischemia.