Brn3a controls the soma localization and axonal extension patterns of developing spinal dorsal horn neurons.

The spinal dorsal horn comprises heterogeneous neuronal populations, that interconnect with one another to form neural circuits modulating various types of sensory information. Decades of evidence has revealed that transcription factors expressed in each neuronal progenitor subclass play pivotal roles in the cell fate specification of spinal dorsal horn neurons. However, the development of subtypes of these neurons is not fully understood in more detail as yet and warrants the investigation of additional transcription factors. In the present study, we examined the involvement of the POU domain-containing transcription factor Brn3a in the development of spinal dorsal horn neurons. Analyses of Brn3a expression in the developing spinal dorsal horn neurons in mice demonstrated that the majority of the Brn3a-lineage neurons ceased Brn3a expression during embryonic stages (Brn3a-transient neurons), whereas a limited population of them continued to express Brn3a at high levels after E18.5 (Brn3a-persistent neurons). Loss of Brn3a disrupted the localization pattern of Brn3a-persistent neurons, indicating a critical role of this transcription factor in the development of these neurons. In contrast, Brn3a overexpression in Brn3a-transient neurons directed their localization in a manner similar to that in Brn3a-persistent neurons. Moreover, Brn3a-overexpressing neurons exhibited increased axonal extension to the ventral and ventrolateral funiculi, where the axonal tracts of Brn3a-persistent neurons reside. These results suggest that Brn3a controls the soma localization and axonal extension patterns of Brn3a-persistent spinal dorsal horn neurons.

Roles and Competencies of Doctors in Artificial Intelligence Implementation: Qualitative Analysis Through Physician Interviews.

BACKGROUND: Artificial intelligence (AI) is a term used to describe the use of computers and technology to emulate human intelligence mechanisms. Although AI is known to affect health services, the impact of information provided by AI on the patient-physician relationship in actual practice is unclear. OBJECTIVE: The purpose of this study is to investigate the effect of introducing AI functions into the medical field on the role of the physician or physician-patient relationship, as well as potential concerns in the AI era. METHODS: We conducted focus group interviews in Tokyo's suburbs with physicians recruited through snowball sampling. The interviews were conducted in accordance with the questions listed in the interview guide. A verbatim transcript recording of all interviews was qualitatively analyzed using content analysis by all authors. Similarly, extracted code was grouped into subcategories, categories, and then core categories. We continued interviewing, analyzing, and discussing until we reached data saturation. In addition, we shared the results with all interviewees and confirmed the content to ensure the credibility of the analysis results. RESULTS: A total of 9 participants who belonged to various clinical departments in the 3 groups were interviewed. The same interviewers conducted the interview as the moderator each time. The average group interview time for the 3 groups was 102 minutes. Content saturation and theme development were achieved with the 3 groups. We identified three core categories: (1) functions expected to be replaced by AI, (2) functions still expected of human physicians, and (3) concerns about the medical field in the AI era. We also summarized the roles of physicians and patients, as well as the changes in the clinical environment in the age of AI. Some of the current functions of the physician were primarily replaced by AI functions, while others were inherited as the functions of the physician. In addition, "functions extended by AI" obtained by processing massive amounts of data will emerge, and a new role for physicians will be created to deal with them. Accordingly, the importance of physician functions, such as responsibility and commitment based on values, will increase, which will simultaneously increase the expectations of the patients that physicians will perform these functions. CONCLUSIONS: We presented our findings on how the medical processes of physicians and patients will change as AI technology is fully implemented. Promoting interdisciplinary discussions on how to overcome the challenges is essential, referring to the discussions being conducted in other fields.

Involvement of Brn3a-positive spinal dorsal horn neurons in the transmission of visceral pain in inflammatory bowel disease model mice.

The spinal dorsal horn plays a crucial role in the transmission and processing of somatosensory information. Although spinal neural circuits that process several distinct types of somatic sensations have been studied extensively, those responsible for visceral pain transmission remain poorly understood. In the present study, we analyzed dextran sodium sulfate (DSS)-induced inflammatory bowel disease (IBD) mouse models to characterize the spinal dorsal horn neurons involved in visceral pain transmission. Immunostaining for c-fos, a marker of neuronal activity, demonstrated that numerous c-fos-positive cells were found bilaterally in the lumbosacral spinal dorsal horn, and their distribution was particularly abundant in the shallow dorsal horn. Characterization of these neurons by several molecular markers revealed that the percentage of the Pit1-Oct1-Unc86 domain (POU domain)-containing transcription factor Brn3a-positive neurons among the c-fos-positive neurons in the shallow dorsal horn was 30%-40% in DSS-treated mice, which was significantly higher than that in the somatic pain model mice. We further demonstrated by neuronal tracing that, within the shallow dorsal horn, Brn3a-positive neurons were more highly represented in spino-solitary projection neurons than in spino-parabrachial projection neurons. These results raise the possibility that Brn3a-positive spinal dorsal horn neurons make a large contribution to visceral pain transmission, part of which is mediated through the spino-solitary pathway.

Essential information for transition of care for frail elderly patients in Japan: A qualitative study.

BACKGROUND: Information exchange between hospitals and primary care physicians is suboptimal. Most physicians are dissatisfied with the current referral process, and poor communication leads to negative care transition outcomes. METHOD: To identify the key information needed for a successful transition of care, we conducted a qualitative study using consecutive, semistructured in-person interviews and focus group sessions. We recruited five participants engaged in clinical work for individual interviews and 16 participants for focus groups. We analyzed all data using qualitative thematic analysis. All results were returned to the participants and modified based on their feedback. RESULTS: The five individual interviews provided a general picture of the current referral process and an interview guide for the following focus group sessions. The focus group discussions were used to identify the essential information needed at admission and discharge from the hospital. Essential information on hospital admission was as follows: (1) basic medical and care information, (2) care resources available at home, (3) the purpose of admission and the goals of care during hospitalization, and (4) status of advance care planning (ACP) and patient's will in an emergency. Essential information on hospital discharge was as follows: (1) clinical course, (2) explanation of medical condition during hospitalization, (3) status of ACP and patient's will in an emergency, and (4) medical procedures to be continued at home. CONCLUSIONS: We identified the essential information needed for a successful transition of care in Japan. The clinical effectiveness of a template that contains the information identified in our study warrants further investigation.

Correction to: Stiripentol alleviates neuropathic pain in L5 spinal nerve-transected mice.

In the original publication of the article, the value "40-µm thickness" was incorrect in the legend of Figure 4. The correct value is 10-µm thickness.

Stiripentol alleviates neuropathic pain in L5 spinal nerve-transected mice.

PURPOSE: Antiepileptic drugs are used not only for the treatment of epilepsy but also for that of neuropathic pain. However, their action mechanisms have not always been well explained. Stiripentol, an effective antiepileptic drug indicated as a therapeutic for Dravet syndrome, was recently shown to act as an inhibitor of lactate dehydrogenase in astrocytes. In this present study, we examined the effect of stiripentol on neuropathic pain in L5 spinal nerve-transected mice. METHODS: We carried out behavioral tests using calibrated von Frey filaments and the immunohistochemistry of glial fibrillary acidic protein, an astrocyte marker, in L5 spinal nerve-transected mice after intrathecal administration of drugs. RESULTS: Like other anticonvulsants such as gabapentin and carbamazepine, stiripentol alleviated mechanical hyperalgesia induced by L5 spinal nerve transection in a dose-dependent manner, when intrathecally administered to mice 7, 14, and 28 days after L5 spinal nerve transection. Likewise, α-cyano-4-hydroxycinnamic acid, a broad inhibitor of monocarboxylate transporters, diminished mechanical hyperalgesia induced by L5 spinal nerve transection. Simultaneous administration of L-lactate negated the analgesic effect elicited by stiripentol, carbamazepine or α-cyano-4-hydroxycinnamic acid, but not that by gabapentin. None of the anticonvulsants affected the immunoreactivity of glial fibrillary acidic protein. CONCLUSIONS: This present study demonstrated that stiripentol was effective against neuropathic pain and suggested that the astrocyte-neuron lactate shuttle was involved in such pain.

Arctic-Eurasian climate linkage induced by tropical ocean variability.

Eurasian continent has experienced cold winters over the past two decades in contrast with Arctic warming. Previous studies have suggested that the cold Eurasian winters are associated with Arctic sea-ice loss, while others attributed them to atmospheric internal variability. However, here we show that the Arctic and Eurasian climate linkage is driven by the combination between atmospheric teleconnection originating in the tropical oceans and Arctic sea ice. Like a battery charges a capacitor, El Niño heats the tropical Atlantic, and the warmer Atlantic condition persists until early winter of El Niño-decay year. We find that the persisting tropical Atlantic warming induces anomalous Rossby wave train arching to Eurasia, leading to Arctic sea-ice increase and Eurasian warming. In La Niña phase these changes are reversed. Our results therefore suggest that the combination of recent tropical Pacific cooling and Arctic sea-ice loss have contributed to the frequent Eurasian cold winters.

Diabetic neuropathy research: from mouse models to targets for treatment.

Diabetic neuropathy is one of the most serious complications of diabetes, and its increase shows no sign of stopping. Furthermore, current clinical treatments do not yet approach the best effectiveness. Thus, the development of better strategies for treating diabetic neuropathy is an urgent matter. In this review, we first discuss the advantages and disadvantages of some major mouse models of diabetic neuropathy and then address the targets for mechanism-based treatment that have been studied. We also introduce our studies on each part. Using stem cells as a source of neurotrophic factors to target extrinsic factors of diabetic neuropathy, we found that they present a promising treatment.

Quality of primary care provided in community clinics in Japan.

BACKGROUND: Quality indicators (QIs) for primary care are used worldwide. To date, however, the use of QIs to assess the quality of primary care in Japan has not been reported besides diabetes care. Here, we used QIs to evaluate the quality of primary care services provided by local clinics in Japan. METHODS: Four primary care clinics participated in the retrospective medical chart review in 2015. To assess primary care quality, we used 18 process-oriented QIs from the Quality Indicators for Primary Care practice in Japan (QIPC-J) those we previously developed by using a modified Delphi appropriateness method, which comprises 39 QIs in five categories (Comprehensive care/Standardized care, Access, Communication, Coordination, and Understanding of patient's background). Adult subjects were selected from among patients who visited each clinic within the previous one year using medical claims data. We collected data by reviewing medical charts, and calculated the quality score for each QI and clinic. RESULTS: A cumulative total of 4330 medical charts were reviewed. The overall quality score was 31.5%. Adherence to QIs ranged from 3.2% to 85.6%. Some quality scores varied substantially between clinics but the overall quality of care among clinics varied less, from 29.2% to 34.0%. CONCLUSIONS: The quality of primary care services provided by local clinics in Japan varies by both QI and clinic. Strategies to improve the quality of care are warranted.

The association between physician's affiliation and patients' adherence to their antihypertensive medication and pharmaceutical knowledge.

BACKGROUND: The aim of this study was to examine whether or not the type of physician is associated with the knowledge of and adherence to hypertensive medication among patients. METHODS: The study was a self-administered questionnaire survey among patients who submitted their prescriptions for antihypertensive drugs to 13 pharmacies in Japan in 2006. We compared patients' knowledge of their medications and the self-reported adherence according to the type of physician. RESULTS: A total of 736 patients were surveyed, and 687 (362 from clinics and 325 from hospitals) were analyzed. In total, 51.8% of the patients correctly named their antihypertensive medicine, with no significant differences observed between clinics and hospitals (51.4% in clinics vs 52.3% in hospitals; P = 0.81, adjusted odds ratio (OR) to the hospital: 0.736, 95% confidence interval [CI]: 0.50-1.08). Significant differences were not observed in the knowledge of the frequency with which hypertensive medication was supposed to be taken (47.2% in clinics vs 46.5% in hospitals; P = 0.84, adjusted OR: 0.80, 95% CI: 0.55-1.16), nor observed in the knowledge of the side effects of the medication (53.2% in clinics vs 51.0% in hospitals; P = 0.57, adjusted OR: 1.14, 95% CI: 0.78-1.68). No significant difference was observed in self-reported adherence (75.1% in clinics vs 77.7% in hospitals; P = 0.42, adjusted OR: 0.73, 95% CI: 0.46-1.16). CONCLUSIONS: About 75% answered that they were taking their medication as instructed. No significant differences were observed in responses based on the physician's affiliation. Further studies are needed to achieve better patient's adherence and pharmaceutical knowledge.

Development and Pilot Testing of Quality Indicators for Primary Care in Japan.

INTRODUCTION: To the best of our knowledge, no quality indicators (QIs) for primary care provided by local clinics have yet been developed in Japan. We aimed to develop valid and applicable QIs to evaluate primary care in Japan. METHODS: Two focus group interviews were held to identify conceptual categories. Existing indicators for these categories were identified, and initial sets of potential QIs were developed. Using a modified Delphi appropriateness method, a multidisciplinary expert panel then developed and selected the QIs. Feasibility and applicability of these QIs were then confirmed in pilot testing at six local clinics in Hokkaido, Japan. To determine patient acceptance of these quality improvement activities, the survey asked two questions, "Do you think it is preferable that the patients of this clinic be periodically surveyed?" and "Do you think it is preferable that this clinic periodically undergo an external quality review by an independent body?" RESULTS: Seven categories emerged from the focus group discussions as key components of primary care in Japan. Thirty-nine QIs under five categories (Comprehensive care/Standardized care, Access, Communication, Co-ordination, and Understanding of patient background) were finally selected and named the QIs for Primary Care Practice in Japan. In pilot testing at six primary care clinics in 2015, 65.4% of patients answered favorably to the idea that clinics should conduct regular patient surveys, and 71.8% answered favorably to the idea that clinics should undergo periodic external quality review by an independent body. CONCLUSIONS: We developed QIs to assess primary care services provided by clinics in Japan, for the first time. Although further refinement is required, establishment of these QIs is the first step in quality improvement for primary care practices in Japan.

Two isoforms of cyclic GMP-dependent kinase-I exhibit distinct expression patterns in the adult mouse dorsal root ganglion.

cGMP-dependent kinase-I (cGKI) is known to regulate spinal pain processing. This enzyme consists of two isoforms (cGKIα and cGKIß) that show distinct substrate specificity and tissue distribution. It has long been believed that the α isoform is exclusively expressed in the adult dorsal root ganglion. The aim of the present study was to reexamine the expression of cGKI isoforms in the adult mouse dorsal root ganglion using isoform-specific cGKI antibodies whose specificities had been validated in the previous studies. Immunoblot and immunohistochemical analyses revealed the presence of both isoforms in the dorsal root ganglion. Moreover, cGKIα was found to be mainly expressed within the cytoplasm of small- to medium-sized peptidergic and nonpeptidegic C-fibers, whereas cGKIß was located within the nuclei of a wide range of dorsal root ganglion neurons. In addition, glutamine synthetase-positive satellite glial cells expressed both isoforms to varying degrees. Finally, using an experimental model for neuropathic pain produced by L5 spinal nerve transection, we found that cGKIα expression was downregulated in the injured, but not in the uninjured, dorsal root ganglion. In contrast, cGKIß expression was upregulated in both the injured and uninjured dorsal root ganglions. Also, injury-induced cGKIß upregulation was found to occur in small-to-medium-diameter dorsal root ganglion neurons. These data thus demonstrate the existence of two differently distributed cGKI isoforms in the dorsal root ganglion, and may provide insight into the cellular and molecular mechanisms of pain.

Tomojiro Nagai, founder of the Association of the Medical Practitioners (Jicchi ika no tame no kai) in Japan.

Obituary: Tomojiro Nagai, founder of the Association of the Medical Practitioners (Jicchi-ika no tame no kai) in Japan.

Recovery from a depressive episode during postgraduate residency training is associated with senior doctors' support.

Background: Depression among doctors in residency training can have significant impacts on the health of the residents and on patient safety. This study aimed to investigate factors associated with recovery from a depressive episode experienced during postgraduate residency training. Methods: A questionnaire was administered to 2935 first-year residents at the beginning of residency training in 2011; follow-up surveys were conducted after 3 months and at the end of the training in 2013. The questionnaire included the Center for Epidemiologic Studies Depression Scale and the Senior Doctor's Support Scale (SDSS). Logistic regression was used to identify associations between factors that may have been related to recovery from depressive episodes. Results: A total 182 residents experienced a depressive episode in the 3 months after starting residency training. When reassessed at the end of the 2-year training, 102 (56%) residents had recovered from the episode and 80 (44%) had not. Increased odds of recovery were associated with a middle or high score on the SDSS (middle score odds ratios [OR] 4.45, 95% confidence interval [CI] 1.0-18.0, P = .04; and high score OR 5.70, 95% CI 1.4-23.4, P = .02). Conclusions: Support from senior doctors should be enhanced to optimize recovery from depressive episodes experienced after the start of residency training.

Impaired peripheral nerve regeneration in type-2 diabetic mouse model.

Peripheral neuropathy is one of the most common and serious complications of type-2 diabetes. Diabetic neuropathy is characterized by a distal symmetrical sensorimotor polyneuropathy, and its incidence increases in patients 40 years of age or older. In spite of extensive research over decades, there are few effective treatments for diabetic neuropathy besides glucose control and improved lifestyle. The earliest changes in diabetic neuropathy occur in sensory nerve fibers, with initial degeneration and regeneration resulting in pain. To seek its effective treatment, here we prepared a type-2 diabetic mouse model by giving mice 2 injections of streptozotocin and nicotinamide and examining the ability for nerve regeneration by using a sciatic nerve transection-regeneration model previously established by us. Seventeen weeks after the last injection, the mice exhibited symptoms of type-2 diabetes, that is, impaired glucose tolerance, decreased insulin level, mechanical hyperalgesia, and impaired sensory nerve fibers in the plantar skin. These mice showed delayed functional recovery and nerve regeneration by 2 weeks compared with young healthy mice and by 1 week compared with age-matched non-diabetic mice after axotomy. Furthermore, type-2 diabetic mice displayed increased expression of PTEN in their DRG neurons. Administration of a PTEN inhibitor at the cutting site of the nerve for 4 weeks promoted the axonal transport and functional recovery remarkably. This study demonstrates that peripheral nerve regeneration was impaired in type-2 diabetic model and that its combination with sciatic nerve transection is suitable for the study of the pathogenesis and treatment of early diabetic neuropathy.

Na+ /K+ -ATPase coupled to endothelin receptor type B stimulates peripheral nerve regeneration via lactate signalling.

We have recently demonstrated that endothelin (ET) is functionally coupled to Nax , a Na+ concentration-sensitive Na+ channel for lactate release via ET receptor type B (ETB R) and is involved in peripheral nerve regeneration in a sciatic nerve transection-regeneration mouse model. Nax is known to interact directly with Na+ /K+ -ATPase, leading to lactate production in the brain. To investigate the role of Na+ /K+ -ATPase in peripheral nerve regeneration, in this study, we applied ouabain, a Na+ /K+ -ATPase inhibitor, to the cut site for 4 weeks with an osmotic pump. While functional recovery and nerve reinnervation to the toe started at 5 weeks after axotomy and were completed by 7 weeks, ouabain delayed them by 2 weeks. The delay by ouabain was improved by lactate, and its effect was blocked by α-cyano-4-hydroxy-cinnamic acid (CIN), a broad monocarboxylate transporter (MCT) inhibitor. In primary cultures of dorsal root ganglia, neurite outgrowth of neurons and lactate release into the culture medium was inhibited by ouabain. Conversely, lactate enhanced the neurite outgrowth, which was blocked by CIN, but not by AR-C155858, a MCT1/2-selective inhibitor. ET-1 and ET-3 increased neurite outgrowth of neurons, which was attenuated by an ETB R antagonist, ouabain and 2 protein kinase C inhibitors. Taken together with the finding that ETB R was expressed in Schwann cells, these results demonstrate that ET enhanced neurite outgrowth of neurons mediated by Na+ /K+ -ATPase via ETB R in Schwann cells. This study suggests that Na+ /K+ -ATPase coupled to the ET-ETB R system plays a critical role in peripheral nerve regeneration via lactate signalling.

RNA editing enzyme ADAR2 is a mediator of neuropathic pain after peripheral nerve injury.

Transcriptional and post-translational regulations are important in peripheral nerve injury-induced neuropathic pain, but little is known about the role of post-transcriptional modification. Our objective was to determine the possible effect of adenosine deaminase acting on RNA (ADAR) enzymes, which catalyze post-transcriptional RNA editing, in tactile allodynia, a hallmark of neuropathic pain. Seven days after L5 spinal nerve transection (SNT) in adult mice, we found an increase in ADAR2 expression and a decrease in ADAR3 expression in the injured, but not in the uninjured, dorsal root ganglions (DRGs). These changes were accompanied by elevated levels of editing at the D site of the serotonin (5-hydroxytryptamine) 2C receptor (5-HT2CR), at the I/V site of coatomer protein complex subunit α (COPA), and at the R/G site of AMPA receptor subunit GluA2 in the injured DRG. Compared to Adar2+/+/Gria2R/R littermate controls, Adar2-/-/Gria2R/R mice completely lacked the increased editing of 5-HT2CR, COPA, and GluA2 transcripts in the injured DRG and showed attenuated tactile allodynia after SNT. Furthermore, the antidepressant fluoxetine inhibited neuropathic allodynia after injury and reduced the COPA I/V site editing in the injured DRG. These findings suggest that ADAR2 is a mediator of injury-induced tactile allodynia and thus a potential therapeutic target for the treatment of neuropathic pain.-Uchida, H., Matsumura, S., Okada, S., Suzuki, T., Minami, T., Ito, S. RNA editing enzyme ADAR2 is a mediator of neuropathic pain after peripheral nerve injury.

Pacific Ocean decadal forcing of long-term changes in the western Pacific subtropical high.

The western Pacific subtropical high (WPSH) has a significant effect on droughts, heat waves, and tropical cyclone tracks over East Asia and the northwest Pacific. The WPSH has intensified during the past three decades, but its causes are not yet well understood. Here we show that the Pacific Decadal Oscillation (PDO) is responsible for the long-term changes in the WPSH through the meridional shift of the subtropical jet, based on comprehensive data analysis and model results. El Niño-Southern Oscillation (ENSO) is the leading forcing of WPSH variability over interannual timescales, whereas the PDO accounts for its low-frequency variability, resulting in it being independent of ENSO with regard to WPSH variability. The PDO in summer can be interpreted as a coupling with the WPSH. Our results provide useful information for projecting long-term changes in the WPSH.