Clinical characteristics and drug utilisation patterns in patients with chronic cough: a retrospective cohort study using a Japanese claims database.

BACKGROUND: Although unmet medical needs for better care of patients with chronic cough exist in Japan, epidemiological information about these patients and their treatments is very limited. OBJECTIVES: To describe patient characteristics, underlying cough-related diseases and drug utilisation patterns in patients with chronic cough, and their changes over time. METHODS: This large retrospective claims database study enrolled subjects with chronic cough, identified either by a specific diagnostic cough code for chronic cough (Population 1) or by multiple cough-related diagnostic codes spanning > 8 weeks (Population 2). Within Population 2, patients with each of the three most frequent diagnostic cough codes were analysed as subgroups. Patient characteristics, underlying cough-related diseases and utilisation patterns for drugs used for cough were documented at the index date, during the 6-month pre-index period and during the 12-month post-index period. RESULTS: 6,038 subjects were enrolled in the cohort (Population 1: N = 3,500; Population 2: N = 2,538). The mean age was 43.7 ± 12.2 years and 61.8% were women. The largest cough diagnosis subgroups in Population 2 were 'other coughs' (N = 1,444), 'cough-variant asthma' (N = 1,026) and 'atopic/allergic cough' (N = 105). At the index date, the most frequent underlying cough-related diseases were allergic rhinitis/nasal inflammation (N = 3,132; 51.9%), asthma (N = 2,517; 41.7%) and gastro-esophageal reflux disease (N = 829; 13.7%). At the index date, 4,860 participants (80.5%) were prescribed at least one cough-related treatment. 194 participants (4.0% of medication users) were prescribed central antitussives alone, principally in Population 1, and 2,331 (48.0%) were prescribed expectorants. Other frequently prescribed medications were antiallergic drugs (N = 2,588; 53.3%), antimicrobials (N = 1,627; 34.4%) and inhaled corticosteroids with long-acting beta-agonists (N = 1,404; 28.9%). Over time, cough diagnoses tended to be lost, with only 470 participants in Population 1 retaining a diagnostic code for chronic cough one year later. The frequency of underlying cough-related diseases was stable over time. CONCLUSIONS: Patients in this cohort with chronic cough are most frequently identified by a diagnostic cough code for chronic cough, followed by codes for other coughs, cough-variant asthma and atopic cough. Chronic cough frequently presents with an underlying cough-related disease, most frequently allergic rhinitis/nasal inflammation, asthma or GERD. Medication prescription for the underlying cough-related diseases was generally appropriate.

Impact of refractory and unexplained chronic cough on disease burden: a qualitative study.

BACKGROUND: Chronic cough lasting for > 8 weeks is a common medical condition that burdens patients. This study aimed to qualitatively describe knowledge, awareness, experiences, and subtypes of burdens (physical, social, psychological) among Japanese patients with refractory chronic cough (refractory to treatment of underlying relevant medical conditions) and unexplained chronic cough (symptoms of unexplained origin). METHODS: This non-interventional, cross-sectional study was conducted between February and March 2021 among patients (aged ≥ 20 years) with self-reported refractory or unexplained chronic cough. Subjects with a history of comorbid respiratory conditions were excluded. Eligible subjects participated in a 60-min online semi-structured interview. Verbatim terms from interviews were qualitatively transcribed and generated into word clouds, followed by a clustering analysis in which meaningful clusters were chosen, manually coded, and utterances and burdens categorized. RESULTS: A total of 21 participants (95.2% with refractory chronic cough, mean age 53.5 years, and 76.2% being males) with Leicester Cough Questionnaire mean ± standard deviation scores of physical 4.8 ± 1.1, psychological 4.4 ± 1.3, social 4.9 ± 1.4, and total 14.1 ± 3.5 were included. The word cloud identified the most frequently used word ('cough'); etiology ('asthma'); and words associated with change in states ('influence,' 'changing,' 'change') and expressions ('tough,' 'pain,' 'hard,' 'terrible,' 'unpleasant'). The patients experienced 'mental/social burden,' 'physical burden,' 'impact on sleep and meals,' 'impact on work and housework,' 'impact on communication,' 'impact on hobbies and leisure,' and 'economic burden.' By closed coding analysis, the situations or types of burden patients experienced from the cough were ordered sequentially as emotion, working style, acquaintanceship, hobbies and leisure, and sleeping pattern. CONCLUSIONS: The present study indicated that there were two types of participant clusters, in which one showed mainly the burdens in the social communications such as work-related communication and another one showed the burdens of relationships with others. Also, some participants highlighted 'mental burden,' on social life due to the current pandemic. To relieve these burdens, disease awareness and knowledge should be improved for patients with refractory and unexplained chronic cough. Trial registration The trial was registered under UMIN-CTR as UMIN000042772, on 17/12/2020. The study was approved by the Medical Corporation Toukeikai Kitamachi Clinic (IRB registration number: 11001110).

Pain-related sensory innervation in monoiodoacetate-induced osteoarthritis in rat knees that gradually develops neuronal injury in addition to inflammatory pain.

BACKGROUND: The exact mechanism of knee osteoarthritis (OA)-associated pain is unclear, whereas mixed evidence of inflammatory pain and neuropathic pain has been noted. We aimed to investigate pain-related sensory innervation in a monoiodoacetate (MIA)-induced model of OA. METHODS: Sixty of seventy female Sprague Dawley rats of six week-old underwent intra-articular MIA and fluorogold (FG) retrograde neurotracer injection into their right (ipsilateral) knee, while their left knees were treated with FG in saline as a control (contralateral knee). Other rats were treated with FG only bilaterally, and used as controls. Rats were evaluated for tactile allodynia using von Frey hairs. Proinflammatory mediators in the knee soft tissues, including tumor necrosis factor (TNF)-α, interleukin (IL)-6, and nerve growth factor (NGF), were quantified using ELISAs to evaluate inflammation in the knee after 1, 4, 7, 14, 21, and 28 days post injection. Dorsal root ganglia (DRG) were immunostained for three molecules after 7, 14, 21, and 28 days post injection: calcitonin gene-related peptide (CGRP), a marker of inflammatory pain; and activating transcription factor-3 (ATF3) and growth associated protein-43 (GAP43), as markers for nerve injury and regenerating axons. The distribution of microglia in the spinal cord were also evaluated, because they have been reported to increase in neuropathic pain states. These evaluations were performed up to 28 days postinjection. P < 0.05 was considered significant. RESULTS: Progressive tactile allodynia and elevated cytokine concentrations were observed in ipsilateral knees. CGRP-immunoreactive (-ir) ipsilateral DRG neurons significantly increased, peaking at 14 days postinjection, while expression of FG-labeled ATF3-ir or ATF3-ir GAP43-ir DRG neurons significantly increased in a time-dependent manner. Significant proliferation of microglia were found with time in the ipsilateral dorsal horn. CONCLUSIONS: Pain-related characteristics in a MIA-induced rat OA model can originate from an inflammatory pain state induced by the local inflammation initiated by inflammatory cytokines, and that state will be followed by gradual initiation of neuronal injury, which may induce the neuropathic pain state.

Disease burden and quality of life of patients with chronic cough in Japan: a population-based cross-sectional survey.

BACKGROUND: Cough lasting 3-8 and >8 weeks are defined as subacute/prolonged cough and chronic cough (CC), respectively. Studies have revealed that CC negatively impact patients' quality of life (QoL). In Japan, there is limited data on the impact of CC on health-related quality of life (HRQoL), work productivity and activity impairment (WPAI) and healthcare resource utilisation (HRU) using validated instruments. This study aimed to estimate the burden of CC and to compare the burden among patients with CC between subgroups. METHODS: Data from two cross-sectional online surveys conducted between September and November 2019 were combined for the analysis. Eligible patients with cough were propensity score matched to non-cough respondents. Comparisons of general HRQoL, WPAI, HRU and other symptoms experienced were conducted between matched non-cough respondents and patients with cough. Among patients with CC, subgroup comparisons were performed to understand general HRQoL, WPAI, HRU, cough-related QoL (Leicester Cough Questionnaire and Hull Airway Reflux Questionnaire) between patients with CC of different severities, patients with refractory CC and patients with non-refractory CC and patients with CC whose underlying diseases were unknown and others. RESULTS: Patients with CC (n=568) in Japan reported significantly poorer HRQoL, increased WPAI, more HRU and higher proportion of psychological and sleep problems, compared with matched non-cough respondents selected from 21 415 non-cough respondents. More patients with severe CC reported significantly poorer HRQoL, increased WPAI and worse cough-related QoL. Patients with refractory CC experienced significantly greater burden measured by cough-related QoL. No significant differences were observed between patients with CC whose underlying diseases were unknown and other patients with CC in terms of general HRQoL and cough-related QoL. CONCLUSIONS: This study showed that patients with CC in Japan experienced significant burden compared with non-cough respondents. Patients with more severe cough and refractory CC experienced worse cough-related QoL. These results highlighted the unmet need for better interventions and treatments to reduce the burden among patients with CC.

Web-based survey to evaluate the prevalence of chronic and subacute cough and patient characteristics in Japan.

BACKGROUND: Cough lasting 3-8 weeks and more than 8 weeks are defined as subacute/prolonged cough and chronic cough, respectively. Japanese chronic cough population has not been well studied. This study aimed to describe the prevalence and characteristics of chronic cough and subacute cough patients in Japan. This study also sought to compare between chronic cough patients who were not greatly satisfied with treatment effectiveness for resolving cough and other chronic cough patients. METHODS: Data from a cross-sectional online 2019 Japan National Health and Wellness Survey and a supplemental chronic cough survey were used to understand respondents' chronic cough status and their cough-specific characteristics and experience. The prevalence, patient characteristics and cough-specific characteristics were summarised descriptively. Patients who were not greatly satisfied with treatment effectiveness and other chronic cough patients were compared for their characteristics and cough severity. RESULTS: The point prevalence of chronic cough was 2.89% and 12-month period prevalence was 4.29%. Among all chronic cough patients analysed, the average age was 56 years old, 61.1% were males and 29.4% were current smokers. Patients were most frequently told by a physician that cough was related to allergic rhinitis, asthma and cough variant asthma. Only 44.2% of chronic cough patients had spoken with a physician about their cough, and half of chronic cough patients did not use any medications. Patients who were not greatly satisfied with treatment effectiveness had significantly greater cough severity during past 2 weeks compared with other chronic cough patients (Visual Analogue Scale 45.34 vs 39.63). CONCLUSIONS: This study described the prevalence and patient characteristics information of chronic cough patients in Japan. Furthermore, the study highlighted an unmet need for better diagnosis and treatments for chronic cough patients, especially among patients who were not greatly satisfied with treatment effectiveness and reported significantly worse cough severity.

Restricted clonal expression of IL-2 by naive T cells reflects differential dynamic interactions with dendritic cells.

Limited frequencies of T cells express IL-2 in primary antigenic responses, despite activation marker expression and proliferation by most clonal members. To define the basis for restricted IL-2 expression, a videomicroscopic system and IL-2 reporter transgenic model were used to characterize dendritic cell (DC)-T cell interactions. T cells destined to produce IL-2 required prolonged interactions with DCs, whereas most T cells established only transient interactions with DCs and were activated, but did not express IL-2. Extended conjugation of T cells with DCs was not always sufficient to initiate IL-2 expression. Thus, there is intrinsic variability in clonal T cell populations that restricts IL-2 commitment, and prolonged engagement with mature DCs is necessary, but not sufficient, for IL-2 gene transcription.

Th1 cells promote neurite outgrowth from cortical neurons via a mechanism dependent on semaphorins.

The roles of T lymphocytes in the central nervous system (CNS) are diverse; their roles in the injured CNS have been reported to be both detrimental and advantageous. Hence, an investigation of the effects of specific subsets of T cells on neurons may provide an insight into the interaction between the nervous system and the immune system. In the present study, we demonstrate that a specific subset of T lymphocytes enhanced neurite outgrowth in vitro. When cultured T helper type 1 (Th1) cells were co-cultured with cortical neurons, neurite outgrowth from neurons was enhanced; however, the same was not observed when Th2 or naïve T cells were used. We observed that the promotion of neurite outgrowth by Th1 cells was completely inhibited by anti-interferon γ (IFN-γ) neutralizing antibody, but that IFN-γ did not directly promote neurite growth. Furthermore, experiments using knockout mice revealed that semaphorin 4A (Sema4A) but not Sema7A was required for the effect produced by Th1 cells. These results demonstrate that Sema4A and IFN-γ expressed in Th1 cells play a critical role in enhancing neurite outgrowth from cortical neurons.

Chronic inflammatory demyelinating polyneuropathy sera inhibit axonal growth of mouse dorsal root ganglion neurons by activation of Rho-kinase.

Clinical course and prognosis are variable among patients with chronic inflammatory demyelinating polyneuropathy (CIDP), whereas the extent of axonal degeneration is the major prognostic factor. We studied the effects of sera from CIDP patients on axonal growth in cultured mouse dorsal root ganglion neurons. Compared with control sera, CIDP sera prominently suppressed axonal outgrowth of dorsal root ganglion neurons and shortened axonal length. The inhibitory activity was abolished by adding Y27632, a Rho-kinase inhibitor. These findings suggest that CIDP sera inhibit axonal elongation by Rho-kinase activation, and some serum factors may be responsible for development of axonal degeneration in CIDP.

Regulation of axonal elongation and pathfinding from the entorhinal cortex to the dentate gyrus in the hippocampus by the chemokine stromal cell-derived factor 1 alpha.

During the early developmental stage, a neural circuit is established between the entorhinal cortex (EC) and the hippocampal dentate gyrus (DG) via the perforant pathway. However, the manner in which the perforant fibers are navigated has mostly remained a mystery. Here, we analyzed the functional role of a chemokine, namely, stromal cell-derived factor 1alpha (SDF-1alpha), in the navigation of the perforant fibers. SDF-1alpha was observed to promote neurite growth, which is dependent on mDia1, in cultured entorhinal cortical neurons obtained from rats at postnatal day 0. We then used entorhino-hippocampal cocultures comprising green fluorescence-labeled EC and DG slices to assess the projection of the perforant fibers from the EC. Although the specific laminar termination of the entorhinal axons was observed with this system, the number of appropriately terminating entorhinal axons decreased significantly when the SDF-1alpha signaling pathway was blocked by a neutralizing antibody against SDF-1alpha or by the specific SDF-1alpha receptor antagonist AMD3100 (1,1'-[1,4-phenylenebis(methylene)]bis-1,4,8,11-tetra-azacyclotetradecane octahydrochloride). Furthermore, inhibition of the SDF-1alpha signaling pathway resulted in a decrease in the immunoreactivity for PSD-95 (postsynaptic density protein-95) in the DG, possibly because of a reduction in the number of projecting perforant fibers. These results demonstrate that SDF-1alpha plays a critical role in promoting the growth of perforant fibers from the EC to the DG.

[Adherence to Oral Antihyperglycemic Agents (Dipeptidyl Peptidase-4 Inhibitors and Biguanides) and Its Associated Factors in Patients with Type 2 Diabetes].

To investigate medication adherence to oral antihyperglycemic agents and its associated factors in Japanese type 2 diabetic patients, a questionnaire survey was conducted in 983 adult patients receiving once-daily (QD) or twice-daily (BID) dipeptidyl peptidase-4 inhibitors (DPP-4 inhibitor) or BID biguanides (BG) as monotherapy at 502 pharmacies in Japan. The percentage of patients with good adherence (the proportion of days in which patients took all pills as prescribed in the past 7 days ≥80%) was high (≥90%) in any dosing regimen with no significant difference among the groups. The following factors were identified as associating with good adherence: the longer duration of type 2 diabetes (≥1 year) (p=0.002), "Feeling your disease gets worse if you don't take medications" (p=0.031), "Not forgetting to bring along your medicine when you leave home" (p=0.007), "Feeling anxiety on taking medications for long period of time" (p=0.042), "Neither feeling nor not feeling anxiety on taking medications for a long period of time" (p=0.004), "Never run out of your medicine because you get a refill on time" (p=0.035), and the lower MMAS-4 score (p<0.001). Subgroup analyses revealed that adherence of younger patients (<65 years) with BG (BID) was lower than those with DPP-4 inhibitor (QD) (p=0.021). Additionally, around 60% of patients currently prescribed with QD preferred QD regimen, and ≥80% patients prescribed with BID equally preferred once-weekly or QD regimen, suggesting a large discrepancy exists between their preference and the actual regimen in patients on BID.

Retrospective analysis of medical costs and resource utilization for severe hypoglycemic events in patients with type 2 diabetes in Japan.

AIMS/INTRODUCTION: The present study aimed to describe hospital utilization and examine actual medical costs for severe hypoglycemic events in patients with type 2 diabetes mellitus in Japan. MATERIALS AND METHODS: Medical resource utilization associated with severe hypoglycemia was evaluated using a receipt database of acute-care hospitals in Japan. Patients with type 2 diabetes treated with antihyperglycemic agents were included. Severe hypoglycemic events were identified and divided into two groups: with or without hospitalization. Total and attributable medical costs per event were calculated based on the actual medical treatment after severe hypoglycemic events. Attributable costs were estimated from the receipt codes directly associated with the treatment of severe hypoglycemia. RESULTS: In the hospitalized patients, the median length of hospital stay was 11 days, and the median total and attributable medical costs were ¥402,081 and ¥302,341, respectively. The majority of the hospitalized patients underwent a radiographic examination and general blood tests. Apart from the hospitalization costs, the costs associated with diagnosis accounted for 29.6% of the total medical costs. In the outpatients, 60.6% visited hospitals only once for the severe hypoglycemic event, whereas 11.4% visited hospitals daily for a week after the severe hypoglycemic event. The mean number of hospital visits of the outpatient after a severe hypoglycemic event was 2.7 ± 2.6 days. The median total and attributable medical costs were ¥265,432 and ¥4,628, respectively. CONCLUSIONS: Significant medical resources are used for the treatment of severe hypoglycemic events of patients with type 2 diabetes in Japan.

Association between sleep disturbance in Alzheimer's disease patients and burden on and health status of their caregivers.

BACKGROUND: Sleep disturbance in Alzheimer's disease (AD) patients may have a negative impact not only on patients themselves but also on the physical and mental health of their caregivers. Detailed analysis of these issues is lacking. OBJECTIVE: This study investigated the association between sleep disturbance in AD patients and the burden on, and health status of, their caregivers in Japan. METHODS: We conducted a cross-sectional web-based questionnaire survey among caregivers of AD patients with insomnia symptoms in Japan. Demographic data and Sleep Disorders Inventory (SDI) scores for patients, caregiver burden (Burden Index of Caregivers-11 [BIC-11]) and health status, including Pittsburgh Sleep Quality Index, Patient Health Questionnaire-9, and 12-Item Short Form Health Survey v2, were collected. Multivariate analysis was used to examine the association between the burden and health status of caregivers and sleep disturbance in their care recipients with AD. RESULTS: A total of 496 caregivers of AD patients with insomnia symptoms were examined in this study. We found that the BIC-11 total score increased as the SDI score increased, indicating a significant positive association, even after adjusting for confounding factors. We also found an association between sleep disturbances of AD patients and health of caregivers (sleep quality, depression, and physical/mental quality of life). CONCLUSION: This study demonstrated that sleep disturbance in AD patients was associated with an increased burden and poorer health status of caregivers. Our findings highlight the importance of sleep management in AD patients.

Factors associated with reluctance to initiate or continue oral antihyperglycemic agent (OAHA) treatments in type 2 diabetes mellitus patients in Japan: An observational patient-reported study.

BACKGROUND: Type 2 Diabetes Mellitus (T2DM) is undertreated in Japan. We sought to understand the potential factors associated with reluctance to initiate/continue oral antihyperglycemic agents (OAHA) treatment in Japan. METHODS: A two-phase study was conducted which included cognitive interviews in the first phase (N = 12) to ensure retrieval from memory of relevant information to respond to questions. The second phase included recruitment of respondents from an internet re-contact survey (N = 560) using NHWS or other Lightspeed panels. Patients' self-reported measures were collected to identify the potential barriers to T2DM treatment initiation or continuation. All measured variables were summarized descriptively using means and standard deviations for continuous variables, and frequencies and percentages for categorical variables. RESULTS: A total of 560 respondents were assessed. Of those who were drug-naïve and ever been recommended prescription medication, only 17.3% were satisfied with how physicians presented the treatment options compared to current users or those who discontinued treatment (47.2% and 47.6% respectively). More than 50% of respondents did not realize neuropathic pain and end organ damage as potential consequences of untreated T2DM. 34.8% and 47.6% of drug-naïve and T2DM respondents who discontinued treatment were likely to start/restart treatment after realizing potential complications. Among those who discontinued treatment, 23.1% were extremely dissatisfied with their dosing frequency and less than 15% reported that their physicians discussed the importance of staying on medication long-term. CONCLUSION: The potential barriers addressed in this study should be considered when planning intervention strategies targeted at T2DM patients to promote their treatment in Japan.

Myosin IIA is required for neurite outgrowth inhibition produced by repulsive guidance molecule.

Although myelin-associated neurite outgrowth inhibitors express their effects through RhoA/Rho-kinase, the downstream targets of Rho-kinase remain unknown. We examined the involvement of myosin II, which is one of the downstream targets of Rho-kinase, by using blebbistatin - a specific myosin II inhibitor - and small interfering RNA targeting two myosin II isoforms, namely, MIIA and MIIB. We found that neurite outgrowth inhibition by repulsive guidance molecule (RGMa) was mediated via myosin II, particularly MIIA, in cerebellar granule neurons. RGMa induced myosin light chain (MLC) phosphorylation by a Rho-kinase-dependent mechanism. After spinal cord injury in rats, phosphorylated MLC in axons around the lesion site was up-regulated, and this effect depends on Rho-kinase activity. Further, RGMa-induced F-actin reduction in growth cones and growth cone collapse were mediated by MIIA. We conclude that Rho-kinase-dependent activation of MIIA via MLC phosphorylation induces F-actin reduction and growth cone collapse and the subsequent neurite retraction/outgrowth inhibition triggered by RGMa.

Inhibition of branching and spine maturation by repulsive guidance molecule in cultured cortical neurons.

Repulsive guidance molecule (RGM) is a membrane-bound protein that was originally identified as an axon guidance molecule in the visual system. Functional studies in Xenopus and chick embryos revealed the roles of RGM in axon guidance and laminar patterning, while those in mouse embryos demonstrated its function in regulating cephalic neural tube closure. Moreover, RGM inhibition enhanced the growth of injured axons and promoted functional recovery after spinal cord injury in rats. Here, we demonstrate in vitro that RGMa, an RGM homolog, inhibits neurite growth and cortical neuron branching on mouse embryonic day 16. Further, exposure of cultured neurons to RGMa significantly reduced the number of colocalized immunoreactive clusters of synapsin 1 and PSD-95 in the spines. This RGMa-mediated inhibition of the assembly of presynaptic and postsynaptic components suggests a role of RGMa in inhibiting mature synapse formation. Thus, RGMa may negatively regulate neuronal network formation in cortical neurons.

Peptides derived from repulsive guidance molecule act as antagonists.

Repulsive guidance molecule (RGM) is a membrane-bound protein that was originally identified as an axon guidance molecule in the visual system [T. Yamashita, B.K. Mueller, K. Hata, Neogenin and RGM signaling in the central nervous system, Curr. Opin. Neurobiol. 17 (2007) 29-34]. Functional studies in Xenopus and chick embryos have revealed the roles of RGM in axon guidance and laminar patterning, while those in mouse embryos have demonstrated its function in regulating the cephalic neural tube closure. Importantly, RGM inhibition enhanced the growth of injured axons and promoted functional recovery after spinal cord injury in rats. Here, we identified two RGMa-derived peptides that functioned as antagonists against RGMa. The peptides studied in vitro dose-dependently suppressed the neurite growth inhibition and growth cone collapse induced by RGMa. Thus, these peptides are promising reagents to treat injuries of the central nervous system.

Incidence rate and patient characteristics of severe hypoglycemia in treated type 2 diabetes mellitus patients in Japan: Retrospective Diagnosis Procedure Combination database analysis.

AIMS/INTRODUCTION: To evaluate the incidence rate of and identify factors associated with severe hypoglycemic episodes in patients with treated type 2 diabetes mellitus. MATERIALS AND METHODS: Using Diagnosis Procedure Combination hospital-based medical database, we carried out a retrospective cohort study to assess the incidence rate of severe hypoglycemia in treated type 2 diabetes mellitus patients. We evaluated the associations between severe hypoglycemia and age, sex, complications, and current use of insulin or sulfonylurea (SU) in a nested case-control study. RESULTS: Of 166,806 eligible patients, 1,242 had episodes of severe hypoglycemia during the observational period. The incidence rate of the first hypoglycemic events was 3.70/1,000 patient years. Based on the nested case-control analysis, age was associated with hypoglycemic events with adjusted odds ratios (ORs) of 1.64 or 65-74-year-old patients and 3.79 for ≥75-year-old patients in comparison with 20-64-year-old patients. Comorbidities, such as cognitive impairment, cancer, macrovascular disease and diabetic complications (retinopathy, nephropathy and neuropathy), were associated with severe hypoglycemia, with adjusted ORs ranging from 1.25 to 3.80. Severe hypoglycemic events also increased in patients with current use of both SU and insulin, either SU or insulin, with adjusted ORs of 18.36, 6.31 or 14.07, respectively, compared with patients with other antihyperglycemic agents. In patients with an SU glimepiride, adjusted ORs increased dose-dependently from 3.65 (≤1 mg) to 13.34 (>2 mg). CONCLUSIONS: The incidence rate of severe hypoglycemia in this cohort was 3.70/1,000 patient years. Age, cognitive impairment, cancer, diabetic complications, current use of insulin + SU and SU dosage were identified as risk factors for severe hypoglycemia.

Repulsion of cerebellar granule neurons by chondroitin sulfate proteoglycans is mediated by MAPK pathway.

Inhibitory molecules associated with myelin and glial scar formation inhibit axon regeneration after an injury to the central nervous system (CNS). Chondroitin sulfate proteoglycans (CSPGs) that are expressed in the scar contribute to the non-permissive properties of the CNS environment. Here, we employed a spot substrate assay and demonstrated that CSPGs have a repulsive effect on cell bodies as well as neurites of the postnatal cerebellar granule neurons (CGNs) in vitro. Through a brief inhibitor screen, we observed that the effects of CSPGs were abolished in the presence of mitogen-activated protein kinase (MAPK) inhibitor or epidermal growth factor receptor (EGFR) inhibitor. The MAPK pathway was activated in the neurons treated with CSPGs, and this activation was dependent on EGFR. Thus, CSPGs triggered the inhibition of CGNs through the activation of the EGFR-mediated MAPK pathway.

Induction of repulsive guidance molecule in neurons following sciatic nerve injury.

Repulsive guidance molecule (RGM) is a protein implicated in both axonal guidance and neural tube closure. We examined the expression of RGMa in the spinal cord after the sciatic nerve crush by immunohistochemistry. Although there was no RGMa immunoreactivity under naïve conditions in the dorsal horn, a weak signal for RGMa was found at 24 h after the nerve crush, and this signal was progressively increased in the NeuN-positive neurons in the ipsilateral dorsal horn from superficial to deep layers at 10 days after surgery. In the neurons of the ipsilateral ventral horn, RGMa was also induced at 10 days after surgery, whereas no RGMa signal could be observed in naïve conditions or at 24 h after surgery. Thus, RGMa expression is upregulated both in the ipsilateral dorsal and ventral horns in response to the sciatic nerve injury. We next examined the effects of complete Freund's adjuvant (CFA)-induced inflammation on RGMa expression in the spinal cord. However, no RGMa expression was observed at 24 h and 10 days after the CFA injection in the dorsal horn, suggesting that RGMa is not involved in inflammation-induced gyperalgesia. Our present study demonstrates that induction of RGMa is associated with the peripheral nerve injury.

[Therapeutic strategy to promote regeneration of the injured central nervous system].

Spontaneous regeneration of lesioned fibers is limited in the adult central nervous system due to an unfavorable environment. Several myelin-derived proteins have been identified to inhibit neurite outgrowth in vitro. These proteins induce activation of Rho in some neurons. Inhibition of Rho or Rho-kinase, downstream effector of Rho, promotes axon regeneration in vivo. Recent reports suggest that several other proteins are axon growth inhibitors. Therapeutic strategy to block the multiple axon growth inhibitors may provide efficient tools that produce functional regeneration following injuries to the central nervous system. In addition, it is noted that synaptic plasticity in pre-existing pathways and the formation of new circuits through collateral sprouting of lesioned and unlesioned fibers are important components of the recovery process.