IL4 stimulated macrophages promote axon regeneration after peripheral nerve injury by secreting uPA to stimulate uPAR upregulated in injured axons.

Accumulating evidences suggest that M2 macrophages are involved with repair processes in the nervous system. However, whether M2 macrophages can promote axon regeneration by directly stimulating axons nor its precise molecular mechanism remains elusive. Here, the current study demonstrated that typical M2 macrophages, which were generated by IL4 simulation, had the capacity to stimulate axonal growth by their direct effect on axons and that the graft of IL4 stimulated macrophages into the region of Wallerian degeneration enhanced axon regeneration and improved functional recovery after PNI. Importantly, uPA (urokinase plasminogen activator)-uPA receptor (uPAR) was identified as the central axis underlying the axon regeneration effect of IL4 stimulated macrophages. IL4 stimulated macrophages secreted uPA, and its inhibition abolished their axon regeneration effect. Injured but not intact axons expressed uPAR to be sensitive to uPA. These results unveil a cellular and molecular mechanism underlying the macrophage related axon regeneration and provide a basis of a novel therapy for PNI.

Suppressive effects of morphine injected into the ventral bed nucleus of the stria terminalis on the affective, but not sensory, component of pain in rats.

Pain is a complex experience with both sensory and affective components. Clinical and preclinical studies have shown that the affective component of pain can be reduced by doses of morphine lower than those necessary to reduce the sensory component. Although the neural mechanisms underlying the effects of morphine on the sensory component of pain have been investigated extensively, those influencing the affective component remain to be elucidated. The bed nucleus of the stria terminalis (BNST) has been implicated in the regulation of various negative emotional states, including aversion, anxiety and fear. Thus, this study aimed to clarify the role of the ventral part of the BNST (vBNST) in the actions of morphine on the affective and sensory components of pain. First, the effects of intra-vBNST injections of morphine on intraplantar formalin-induced conditioned place aversion (CPA) and nociceptive behaviors were investigated. Intra-vBNST injections of morphine reduced CPA without affecting nociceptive behaviors, which suggests that intra-vBNST morphine alters the affective, but not sensory, component of pain. Next, to examine the effects of morphine on neuronal excitability in type II vBNST neurons, whole-cell patch-clamp recordings were performed in brain slices. Bath application of morphine hyperpolarized type II vBNST neurons. Thus, the suppressive effects of intra-vBNST morphine on pain-induced aversion may be due to its inhibitory effects on neuronal excitability in type II vBNST neurons. These results suggest that the vBNST is a key brain region involved in the suppressive effects of morphine on the affective component of pain.

Exocrine Pancreatic Insufficiency Possibly Related to Atypical Chronic Graft-versus-Host Disease.

We report the case of a 66-year-old woman who presented with diarrhea and weight loss approximately 14 months after unrelated allogeneic bone marrow transplantation for acute myeloid leukemia. Her early post-transplant course was notable for mild acute skin graft-versus-host disease (GVHD) and biopsy-proven upper gastrointestinal (GI) acute GVHD, both of which resolved with treatment. She then developed weight loss and diarrhea treated with prednisolone for what was thought to be GI late acute GVHD. However, her diarrhea and weight loss persisted. Colonoscopy showed a grossly intact mucosa, and stool studies only confirmed steatorrhea. However, an atrophic pancreas was found on an abdominal computed tomography (CT) scan. Exocrine pancreatic enzymes, such as lipase and pancreatic amylase, were markedly decreased, yet pancreatic endocrine function remained intact. The patient's diarrhea and weight loss improved upon treatment with pancrelipase. Therefore, we suggest that her exocrine pancreatic insufficiency was likely partly caused by atypical chronic GVHD.

Minimum Ten-Year Outcomes of Partial Ulnar Nerve Transfer for Restoration of Elbow Flexion in Patients with Upper Brachial Plexus Injury.

Background: Partial ulnar nerve transfer to the biceps motor branch of the musculocutaneous nerve (Oberlin's transfer) is a successful approach to restore elbow flexion in patients with upper brachial plexus injury (BPI). However, there is no report on more than 10 years subjective and objective outcomes. The purpose of this study was to clarify the long-term outcomes of Oberlin's transfer based on the objective evaluation of elbow flexion strength and subjective functional evaluation of patients. Methods: Six patients with BPI who underwent Oberlin's transfer were reviewed retrospectively by their medical records. The mean age at surgery was 29.5 years, and the mean follow-up duration was 13 years. The objective functional outcomes were evaluated by biceps muscle strength using the Medical Research Council (MRC) grade at preoperative, postoperative, and final follow-up. The patient-derived subjective functional outcomes were evaluated using the Quick Disability of the Arm, Shoulder, and Hand (QuickDASH) questionnaire at final follow-up. Results: All patients had MRC grade 0 (M0) or 1 (M1) elbow flexion strength before operation. Four patients gained M4 postoperatively and maintained or increased muscle strength at the final follow-up. One patient gained M3 postoperatively and at the final follow-up. Although one patient achieved M4 postoperatively, the strength was reduced to M2 due to additional disorder. The mean score of QuickDASH was 36.5 (range, 7-71). Patients were divided into two groups; three patients had lower scores and the other three patients had higher scores of QuickDASH. Conclusions: Oberlin's transfer is effective in the restoration of elbow flexion and can maintain the strength for more than 10 years. Patients with upper BPI with restored elbow flexion strength and no complicated nerve disorders have over ten-year subjective satisfaction.

Venipuncture Nerve Injuries in the Upper Extremity From More Than 1 Million Procedures.

OBJECTIVES: The purpose of this study was to investigate the nerve injury rate for 1 million venipunctures and the efficacy of attempts to avoid severe nerve injury. METHODS: We collected data for outpatients from whom a venipuncture blood sample was obtained in our hospital from 2005 to 2014. Every venipuncture procedure for outpatients was performed by a trained nurse or clinical technologist at the center for blood sampling in our hospital. In addition, a series of lectures by a specialist is held in our hospital at various times. All complaints related to venipuncture blood sampling were reported to our division of hospital safety management and were followed up using the guidelines for injuries related to the venipuncture. RESULTS: The number of venipuncture-related complications was 293 (0.027%, 1/3700) of 1,082,053 during the 10 years. A total of 40 of the 1,082,053 venipunctures were referred to the department of orthopedic surgery, and 16 (0.0015%, 1/67,000) were diagnosed with obvious nerve injuries. The average duration of the treatment was 46.4 days (range, 1-126 days); 69% of the patients recovered within 5 weeks, and all patients recovered within 18 weeks. CONCLUSIONS: Although it is impossible to completely prevent venipuncture-related complications, appropriate venipuncture skills and risk management decrease the incidence of chronic or permanent nerve injury risk after venipuncture.

A novel mouse model of adult T-cell leukemia cell invasion into the spinal cord.

Adult T-cell leukemia (ATL) is a mature T-cell malignancy caused by human T-cell leukemia virus type I infection, and 10%-25% of patients show central nervous system (CNS) involvement. CNS involvement significantly reduces survival and there are no effective treatments for CNS involvement. Therefore, an appropriate animal model is required to evaluate the inhibitory effects of novel drugs on the progression of ATL with CNS involvement. Here, we established a mouse model of ATL with CNS involvement using NOD.Cg-PrkdcscidIl2rgtm1Wjl/SzJ mice inoculated with ATL cells intramuscularly in the postauricular region, and these mice showed paraparesis. Of the 10 mice inoculated with ATL cells intramuscularly (I.M.) at 5 weeks of age, 8 (80%) showed paraparesis, whereas none of the 10 mice inoculated with ATL cells subcutaneously (S.C.) showed paraparesis. In the I.M. group, PCR detected HTLV-1-specific genes in the thoracic and lumbar vertebrae; however, in the S.C. group, the vertebrae were negative for HTLV-1 genes. Histological analysis revealed a particularly high incidence of tumors, characterized by accumulation of the injected cells, in the thoracic vertebrae of mice in the I.M. group. Tumor cell infiltration was relatively high in the bone marrow. Spinal cord compression caused by invasion of the tumor mass outside the pia mater was observed in the thoracic vertebrae of the spinal cord. In conclusion, we have reported a mouse model of tumor growth with paraparesis that may be used to assess novel therapeutic agents for ATL with CNS involvement.

Autologous Osteochondral Mosaicplasty for Centrally and Laterally Located, Advanced Capitellar Osteochondritis Dissecans in Teenage Athletes: Clinical Outcomes, Radiography, and Magnetic Resonance Imaging Findings.

BACKGROUND: Autologous osteochondral mosaicplasty (ie, mosaicplasty) results in satisfactory clinical outcomes and reliable return to play for patients with large or unstable lesions due to osteochondritis dissecans (OCD) of the humeral capitellum. However, the association between the healing of the reconstructed cartilage and clinical outcomes remains unclear. PURPOSE: To evaluate the efficacy of mosaicplasty in teenage athletes through use of clinical scores and imaging. The secondary purpose was to compare the clinical outcomes with images of centrally and laterally located lesions. STUDY DESIGN: Case series; Level of evidence, 4. METHODS: This study analyzed 22 elbows (all male patients; mean age, 13.5 ± 1.2 years) with capitellar OCD managed with mosaicplasty. Patients were divided into 2 groups according to the location of the lesions: central (10 patients) and lateral (12 patients). Evaluation was performed through use of the clinical rating system of Timmerman and Andrews, plain radiographs, and magnetic resonance imaging (MRI; the cartilage repair monitoring system of Roberts). The mean follow-up period was 27.5 months (range, 24-48 months). RESULTS: Lateral lesions were significantly larger than central lesions (147.1 ± 51.9 mm2 vs 95.5 ± 27.4 mm2, P = .01). No other significant differences were found between central and lateral lesions. Timmerman and Andrews scores for both central and lateral lesions improved significantly from 125.0 ± 30.1 points and 138.3 ± 34.5 points preoperatively to 193.5 ± 11.3 points and 186.7 ± 18.1 points, respectively, at final follow-up ( P < .0001, P < .0001). Radiography identified complete graft incorporation in all cases and the absence of severe osteoarthritic changes or displaced osteochondral fragments. In the lateral group, the radial head ratio at final follow-up (1.83 ± 0.23) was significantly larger than the preoperative findings (1.75 ± 0.14, P = .049). The quality of joint surface reconstruction was found to be acceptable for central and lateral lesions on MRI evaluation. CONCLUSION: Mosaicplasty resulted in satisfactory clinical outcomes and smooth cartilage surface integrity in teenage athletes with OCD on their return to competition-level sports activities irrespective of lesion location.

Demonstration of pollinator-mediated competition between two native Impatiens species, Impatiens noli-tangere and I. textori (Balsaminaceae).

Plant-plant interspecific competition via pollinators occurs when the flowering seasons of two or more plant species overlap and the pollinator fauna is shared. Negative sexual interactions between species (reproductive interference) through improper heterospecific pollen transfer have recently been reported between native and invasive species demonstrating pollination-driven competition. We focused on two native Impatiens species (I. noli-tangere and I. textori) found in Japan and examined whether pollinator-mediated plant competition occurs between them. We demonstrate that I. noli-tangere and I. textori share the same pollination niche (i.e., flowering season, pollinator fauna, and position of pollen on the pollinator's body). In addition, heterospecific pollen grains were deposited on most stigmas of both I. noli-tangere and I. textori flowers that were situated within 2 m of flowers of the other species resulting in depressed fruit set. Further, by hand-pollination experiments, we show that when as few as 10% of the pollen grains are heterospecific, fruit set is decreased to less than half in both species. These results show that intensive pollinator-mediated competition occurs between I. noli-tangere and I. textori. This study suggests that intensive pollinator-mediated competition occurs in the wild even when interacting species are both native and not invasive.

Corticotropin-releasing factor enhances inhibitory synaptic transmission to type III neurons in the bed nucleus of the stria terminalis.

We previously reported that corticotropin-releasing factor (CRF) increased neuronal excitability specifically in type II neurons of the dorsolateral part of the bed nucleus of the stria terminalis (dlBNST). Because the majority of type II dlBNST neurons are thought to be GABAergic interneurons, at least a portion of which are considered to regulate type III dlBNST neurons, it is possible that CRF increases inhibitory input to type III neurons through the activation of type II neurons in the dlBNST. To test this possibility, we examined the effect of CRF on type III dlBNST neurons using whole-cell voltage-clamp recordings of inhibitory postsynaptic currents (IPSCs) from rat BNST slices in the presence of kynurenic acid. Spontaneous IPSCs (sIPSCs) and miniature IPSCs (mIPSCs) were recorded in the absence and presence of tetrodotoxin, respectively. Bath application of CRF significantly increased the frequency of sIPSCs, indicating that CRF enhances the inhibitory input to type III neurons. CRF application failed to increase the frequency of mIPSCs, suggesting that CRF-induced increases in sIPSCs are dependent on action potentials. Combined with our previous finding that CRF specifically depolarizes type II dlBNST neurons, these results suggest that CRF may attenuate type III neuron excitation by augmenting the inhibitory influence of type II neurons in the dlBNST.

Congruence of microsatellite and mitochondrial DNA variation in acrobat ants (Crematogaster subgenus Decacrema, Formicidae: Myrmicinae) inhabiting Macaranga (Euphorbiaceae) myrmecophytes.

A previously reported mitochondrial DNA (mtDNA) phylogeny of Crematogaster (subgenus Decacrema) ants inhabiting Macaranga myrmecophytes indicated that the partners diversified synchronously and their specific association has been maintained for 20 million years. However, the mtDNA clades did not exactly match morphological species, probably owing to introgressive hybridization among younger species. In this study, we determined the congruence between nuclear simple sequence repeat (SSR, also called microsatellite) genotyping and mtDNA phylogeny to confirm the suitability of the mtDNA phylogeny for inferring the evolutionary history of Decacrema ants. Analyses of ant samples from Lambir Hills National park, northeastern Borneo, showed overall congruence between the SSR and mtDNA groupings, indicating that mtDNA markers are useful for delimiting species, at least at the local level. We also found overall high host-plant specificity of the SSR genotypes of Decacrema ants, consistent with the specificity based on the mtDNA phylogeny. Further, we detected cryptic genetic assemblages exhibiting high specificity toward particular plant species within a single mtDNA clade. This finding, which may be evidence for rapid ecological and genetic differentiation following a host shift, is a new insight into the previously suggested long-term codiversification of Decacrema ants and Macaranga plants.

Changes in pollinator fauna affect altitudinal variation of floral size in a bumblebee-pollinated herb.

Geographic trait variations are often caused by locally different selection regimes. As a steep environmental cline along altitude strongly influences adaptive traits, mountain ecosystems are ideal for exploring adaptive differentiation over short distances. We investigated altitudinal floral size variation of Campanula punctata var. hondoensis in 12 populations in three mountain regions of central Japan to test whether the altitudinal floral size variation was correlated with the size of the local bumblebee pollinator and to assess whether floral size was selected for by pollinator size. We found apparent geographic variations in pollinator assemblages along altitude, which consequently produced a geographic change in pollinator size. Similarly, we found altitudinal changes in floral size, which proved to be correlated with the local pollinator size, but not with altitude itself. Furthermore, pollen removal from flower styles onto bees (plant's male fitness) was strongly influenced by the size match between flower style length and pollinator mouthpart length. These results strongly suggest that C. punctata floral size is under pollinator-mediated selection and that a geographic mosaic of locally adapted C. punctata exists at fine spatial scale.