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Abstract Background Aspergillus spp. are rare causes of surgical site infections (SSIs). Specifically, Aspergillus section Nigri, commonly identified as Aspergillus niger through morphological findings, has infrequently been reported as an abdominal SSI pathogen. Case presentation An 86-year-old woman with a history of hypertension, chronic kidney disease, and atrial fibrillation who was taking 6 mg of prednisolone daily for rheumatoid arthritis was admitted to our hospital because of sudden abdominal pain. She was diagnosed with sigmoid colon perforation and underwent an open Hartmann operation on the day of admission. Subsequently, a superficial abdominal SSI was detected. Through analysis of the calmodulin gene, Aspergillus welwitschiae, which is classified within the Aspergillus section Nigri, was identified as the responsible pathogen. The minimum inhibitory concentration of voriconazole (VRCZ) was 2 mg/L. Surgical removal of the infected tissue and VRCZ administration was effectively used to treat the infection. Conclusions Given the reported low susceptibility of Nigri section species to azoles, identification and drug susceptibility testing of these fungi are highly important.

Abstract Background Although quality of life (QOL) is an outcome of postoperative cardiac rehabilitation (CR), its course and related factors from postoperative hospitalization to the post-discharge period have not been adequately investigated. Additionally, the EuroQol-5Dimension-5Level (EQ-5D-5L) index score has not been characterized over the same period. We aimed to characterize QOL changes assessed by the EQ-5D-5L, over the period from hospitalization to 1 year post-discharge, in patients post-cardiac and thoracic aortic surgery, and investigate the factors associated with these temporal changes. Methodology This prospective, single-center study included 117 patients who underwent open cardiovascular surgery (median age, 72 years; men, 69%). Patients were assessed for QOL status when transferred to the general ward; at discharge; and at 6 and 12 months after discharge, using the EQ-5D-5L index score and a generalized linear mixed model with random intercepts. Patients were classified into two groups based on score changes post-discharge. Logistic regression analysis evaluated factors associated with QOL decrease post-discharge. Results The EQ-5D-5L index score significantly increased over time, except between 6 and 12 months post-discharge; “Common activities” was the most common dimension showing score improvement. In 25 patients (21%), the EQ-5D-5L index scores were lower after discharge compared to their scores at discharge. In the logistic regression analysis, Barthel Index pre-admission, preoperative hemoglobin level, and Mini-Mental State Examination-Japanese scores pre-discharge were significantly associated with QOL decline after adjusting for the European System for Cardiac Operative Risk Evaluation II score. Conclusions Most patients post-cardiac or thoracic aortic surgery experienced improved QOL from postoperative hospital stay to 1 year post-discharge. However, in patients with pre-operative basic activities of daily living, hemoglobin and post-operative cognitive decline may require ongoing comprehensive CR because of reduced QOL. Given the potential selection bias introduced by the relatively small sample size in this study, future research involving larger populations is necessary.

The menisci have a poor intrinsic healing capability. Biological augmentation is used to promote meniscal healing in conjunction with suture techniques as the result of their poor healing rate. A fibrin clot (FC) is a well-known treatment option for meniscal injuries that are difficult to heal. Several methods for delivering FCs to target sites have been reported; however, all available methods have drawbacks such as unstable delivery, low maneuverability, and/or clot sizes that are too large. We use a dedicated device to efficiently deliver FCs of a suitable size for the tear. In this method, an FC formed to a size of 5 mm is stored and delivered in a thin syringe with a built-in plunger. This method enables an accurate delivery of a suitably sized FC to the desired location and fixes FCs to the tear site when used in combination with conventional suture methods. In this report, we will succinctly describe how to make and deliver an FC using the aforementioned device with a step-by-step instructional technique and an illustrative video.

Abstract This investigation examined the clinical implications of mild vertebral fractures in older community-dwelling residents. Focusing on the locomotion health of older individuals, the earlier reported Obuse study enrolled 415 randomly sampled Japanese residents aged between 50 and 89 years, 411 of whom underwent X-ray evaluations for pre-existing vertebral fractures. A blinded assessment of vertebral fractures based on Genant’s criteria was conducted on the T5-L5 spine for rating on a severity scale. Grade 1 mild fractures were not linked to age in males, but increased with aging in females. Female participants had fewer Grade 1 and 2 fractures (P = 0.003 and 0.035, respectively) but more Grade 3 fractures (P = 0.013) than did males independently of age (Grade 1, 2, and 3: 25%, 16%, and 9% in females and 40%, 22%, and 6% in males, respectively). Weak negative correlations were observed between the number of fractures and bone mineral density in females for all fracture grades (Spearman’s rho: 0.23 to 0.36, P

A large posterior tibial slope (PTS) has been widely recognized as a potential risk factor in loosening and retear after anterior cruciate ligament reconstruction. Anterior closed-wedge osteotomy is an effective surgical approach to mitigate this risk factor but presents several disadvantages. We describe in this Technical Note an original PTS correction technique called the posterior open-wedge osteotomy. The posterior surface of the proximal tibia is exposed, and 2 K-wires are inserted anteroposteriorly as osteotomy guides, and one wire is inserted mediolaterally as a hinge blocker. The osteotomy is performed from the posterior side and advanced to the anterior side using a single-bladed reciprocating saw. The slope is corrected by opening the osteotomy plane posteriorly with a spreader. The correction is maintained by inserting the harvested fibula fragments into the open space, and the fixation is completed with a locking plate to ensure firm fixation and allow early rehabilitation. This procedure can be an effective solution for patients with various risk factors for retear of the anterior cruciate ligament graft, including abnormal PTS.

Abstract SARS-CoV-2 continues to spread worldwide. Patients with COVID-19 show distinct clinical symptoms. Although many studies have reported various causes for the diversity of symptoms, the underlying mechanisms are not fully understood. Peripheral blood mononuclear cells from COVID-19 patients were collected longitudinally, and single-cell transcriptome and T cell receptor repertoire analysis was performed. Comparison of molecular features and patients’ clinical information revealed that the proportions of cells present, and gene expression profiles differed significantly between mild and severe cases; although even among severe cases, substantial differences were observed among the patients. In one severely-infected elderly patient, an effective antibody response seemed to have failed, which may have caused prolonged viral clearance. Naïve T cell depletion, low T cell receptor repertoire diversity, and aberrant hyperactivation of most immune cell subsets were observed during the acute phase in this patient. Through this study, we provided a better understanding of the diversity of immune landscapes and responses. The information obtained from this study can help medical professionals develop personalized optimal clinical treatment strategies for COVID-19.

Ultra-high molecular weight polyethylene sutures are used for repair and reconstruction of extra-articular ligaments in the knee, elbow, and ankle joints. In recent years, the use of these sutures has become popular in a suture augmentation technique and has been applied for use in the reconstruction of the anterior cruciate ligament, which is an intra-articular ligament. Although several surgical techniques have been described in Technical Notes, all reports have been for single-bundle reconstruction, and none have applied the technique to double-bundle reconstruction. This Technical Note provides a detailed description of an anatomical double-bundle anterior cruciate ligament reconstruction combined with the suture augmentation technique.

Abstract Purpose The purpose of this study is to examine 1) the degree and frequency of laterality in posterior tibial slope (PTS) with control and anterior cruciate ligament (ACL) injury groups and 2) the laterality of PTS between sides of injury and dominant legs in patients with primary ACL injuries. Methods A total of 187 consecutive patients with clinically diagnosed noncontact ACL injuries and an age‐ and sex‐matched 1:1 control group were identified. PTS was measured using three different methods (aPTS = anterior PTS, mPTS = middle PTS, pPTS = posterior PTS) on a lateral knee radiograph. PTS of the left and right sides were compared between the patients in the control and ACL‐injured groups, and between the injured and non‐injured and dominant and non‐dominant legs among the patients in the ACL‐injured group. The patients with a difference in PTS of ≥ 3° in mPTS were selected. The percentages were compared between left and right between and among both groups, and between the injured and non‐injured, and non‐dominant and dominant leg, for the ACL group. Multiple regression analysis was performed to analyze the factors influencing the degree of mPTS. Results Both control (Right vs Left: aPTS; 9.0 ± 2.5 vs 10.5 ± 3.0, mPTS; 6.6 ± 2.3 vs 8.1 ± 2.7, pPTS; 4.0 ± 2.4 vs 5.6 ± 2.8, respectively, p

Purpose: The aim of this study was to verify the effects of a new remnant augmentation technique with anatomical double-bundle anterior cruciate ligament (ACL) reconstruction for postoperative clinical scores, anterior stability and frequency of complications compared to remnant removal and cases with remnant defects. Methods: The 105 patients who underwent anatomical double-bundle ACL reconstruction were divided into three groups. If the remnant was a Crain I-III type, remnant-preserving bone tunnel creation was attempted. After the creation of the bone tunnel, good continuity was maintained in 34 patients (preserved group). Due to lost continuity, the remnant was resected in 26 patients (resected group). No identifiable remnant continuity remained (Crain IV) in 45 patients (absent group). The Lysholm knee score, Tegner activity scale, International Knee Documentation Committee (IKDC) subjective score, anterior stability measured using the KT-1000 arthrometer at 2 years postoperatively, and frequency of complications were compared among the three groups. Univariate and multiple linear regression analysis were performed to clarify the factors affecting postoperative anterior stability. Results: The Lysholm knee score, Tegner activity scale, IKDC subjective score, and frequency of complications were not significantly different among the groups. The mean side-to-side difference of anterior stability was significantly better in the preserved group (0.3 ± 1.6 mm) compared to the resected group (1.6 ± 2.3 mm, p = 0.003) and absent group (1.6 mm ± 1.7, p = 0.009). The multiple linear regression analysis showed remnant preservation significantly related to postoperative anterior stability. Conclusion: Although there were no differences in clinical scores, the ACL reconstruction with new preservation technique showed good anterior stability and no difference in the frequency of complications.

Recent studies on the detailed anatomy of the medial patellar stabilizer have revealed that the medial patellofemoral ligament (MPFL) not only attaches to the patella but also has fibers that attach to the quadriceps muscle, known as the medial quadriceps tendon femoral ligament (MQTFL). Reconstruction of the medial stabilizer for patellar dislocation that includes both the MPFL and MQTFL may achieve better anatomical and physiological correction. In this Technical Note, we will describe a simultaneous reconstruction technique of the MPFL and MQTFL for patellar dislocation using an artificial ligament.

Abstract Background Locomotive syndrome (LoS) is defined as the loss of mobility due to age-related impairment of motor organs. The purpose of this study was to evaluate the prevalence and severity of LoS, muscular strength and balancing ability, and prevalence of sarcopenia in relation to the presence of LoS according to sex and age groups ranging between 50 and 89 years. Methods Male and female participants between the ages of 50–89 were randomly selected in the resident registry of a cooperating town. Calls for participation continued until approximately 50 consenting participants were successfully recruited for each age group and sex. A total of 413 participants (203 male and 210 female) were enrolled for undergoing a LoS risk test and measuring their physical function. Physical function was compared to participants with or without LoS. Results A total of 312 patients (75.5%) were diagnosed as LoS, of which 144 (46.2%) were male and 168 (53.8%) were female. The severity of LoS for the 312 patients were 210 (67.3%) for stage 1 and 102 (32.7%) for stage 2. The prevalence of LoS in males were 37, 59, 91, and 100% in the 50s, 60s, 70s, and 80s age strata, respectively. The prevalence of LoS in females were 71, 62, 89, and 98% in the 50s, 60s, 70s, and 80s age strata, respectively. The prevalence of sarcopenia was significantly higher as the age strata in males grew higher. Knee extension strength was significantly lower for participants in their 50s and females in addition to females in their 60s with LoS. The 31 patients diagnosed as sarcopenia included 29 (93.5%) with LoS, 11 (35.4%) classified as LoS stage 1, and 18 (58.1%) classified as stage 2. Conclusions The prevalence of LoS was high in participants over 70 years of age. In males, the prevalence of sarcopenia was higher as the age strata grew higher. Patients with LoS exhibited lower knee extension strength. We believe that some measures to prevent or improve LoS may require exercise to increase the muscle strength of the lower limbs.

Protons have been discovered to play a role in neuronal signaling, but current methods to measure pH in the brain of animal models are limited. Here the authors develop a miniaturized proton image sensor that fits into a living mouse brain and can measure pH changes at micrometer and millisecond resolution scales.

Aim This study compared the clinical outcomes of critically ill patients with coronavirus disease (COVID‐19) pneumonia treated with high‐dose methylprednisolone and other steroids. Methods This retrospective observational study included critically ill COVID‐19 pneumonia adult patients with tracheal intubation treated between April 1, 2020, and September 15, 2021. Of the 46 patients who met the inclusion criteria, 36 received steroid pulse therapy (Group P) and 10 received steroids without pulse therapy (Group NP). Subgroup analyses in Group P by methylprednisolone dose of 1000 or 500 mg for 3 days during intensive care unit stay were carried out. The primary and secondary outcomes were 28‐day mortality and steroid‐associated complications, respectively. Results In the Kaplan–Meier curve analysis, there was no difference in the 28‐day survival between P and NP groups (log–rank P = 0.046). Univariate Cox proportional hazard model also showed that Group P had a decreased 28‐day mortality (hazard ratio 0.30; [95% confidence interval, 0.20–0.44]; P

Abstract By combining video laryngoscopy and fiberoptic bronchoscopy, awake intubation can be performed more safely.

BackgroundEarly rehabilitation allows patients to better perform the activities of daily living after hospital discharge. A specialized physical therapist has been assigned as part of the early rehabilitation, but the effectiveness of the program remains unclear. We investigated how early rehabilitation provided by a specialized physical therapist affects ADL in patients with sepsis.MethodsThis was a retrospective cohort study. This study's subjects were sepsis patients who entered the advanced emergency critical care center of Shinshu University Hospital between April 2014 and March 2020. Electronic medical records were reviewed to obtain information on demographic characteristics, severity score, primary source of infection, therapeutic medication, the number of days after hospital admittance until rehabilitation begins, length of hospital stay, discharge to home, and an assessment of daily living activities for each patient. The patients were divided into two groups based on whether they were treated before or after a specialized physical therapist had been hired by the advanced emergency critical care center.ResultsAssigning a physical therapist to a patient significantly shortened the number of days until rehabilitation began. In a multivariable model, the strongest predictors of return to independent living after hospital discharge were (1) assigning a specialized physical therapist (odds ratio = 2.40; 95% confidence interval = 1.09-5.79; P = 0.050) and (2) the number of days until rehabilitation started (odds ratio = 0.24; 95% confidence interval = 0.08-0.76; P = 0.014).ConclusionsAssigning a specialized physical therapist to sepsis patients at an advanced emergency critical care center significantly shortened the number of days until a patient can begin rehabilitation after hospital admittance and improved activities of daily living after hospital discharge.Trial registrationTrial registration [University Hospital Medical Information Network Clinical Trials Registry, number UMIN000040570 (2020/5/28).].

Extensive activation of glial cells during a latent period has been well documented in various animal models of epilepsy. However, it remains unclear whether activated glial cells contribute to epileptogenesis, i.e., the chronically persistent process leading to epilepsy. Particularly, it is not clear whether interglial communication between different types of glial cells contributes to epileptogenesis, because past literature has mainly focused on one type of glial cell. Here, we show that temporally distinct activation profiles of microglia and astrocytes collaboratively contributed to epileptogenesis in a drug-induced status epilepticus model. We found that reactive microglia appeared first, followed by reactive astrocytes and increased susceptibility to seizures. Reactive astrocytes exhibited larger Ca2+ signals mediated by IP3R2, whereas deletion of this type of Ca2+ signaling reduced seizure susceptibility after status epilepticus. Immediate, but not late, pharmacological inhibition of microglial activation prevented subsequent reactive astrocytes, aberrant astrocyte Ca2+ signaling, and the enhanced seizure susceptibility. These findings indicate that the sequential activation of glial cells constituted a cause of epileptogenesis after status epilepticus. Thus, our findings suggest that the therapeutic target to prevent epilepsy after status epilepticus should be shifted from microglia (early phase) to astrocytes (late phase).

Interleukin-19 (IL-19) acts as a negative-feedback regulator to limit proinflammatory response of macrophages and microglia in autocrine/paracrine manners in various inflammatory diseases. Multiple sclerosis (MS) is a major neuroinflammatory disease in the central nervous system (CNS), but it remains uncertain how IL-19 contributes to MS pathogenesis. Here, we demonstrate that IL-19 deficiency aggravates experimental autoimmune encephalomyelitis (EAE), a mouse model of MS, by promoting IL-17-producing helper T cell (Th17 cell) infiltration into the CNS. In addition, IL-19-deficient splenic macrophages expressed elevated levels of major histocompatibility complex (MHC) class II, co-stimulatory molecules, and Th17 cell differentiation-associated cytokines such as IL-1β, IL-6, IL-23, TGF-β1, and TNF-α. These observations indicated that IL-19 plays a critical role in suppression of MS pathogenesis by inhibiting macrophage antigen presentation, Th17 cell expansion, and subsequent inflammatory responses. Furthermore, treatment with IL-19 significantly abrogated EAE. Our data suggest that IL-19 could provide significant therapeutic benefits in patients with MS.

BackgroundThis study aimed to clarify how SARS-CoV-2 RNAemia is related to COVID-19 critical condition development and mortality in comparison with other predictive markers and scoring systems.MethodsThis is a retrospective cohort study conducted at Yokohama Municipal Citizen's Hospital and National Institute of Infectious Diseases. We recruited adult patients with COVID-19 admitted between March 2020 and January 2021. We compared RNAemia with clinical status on admission including scoring systems such as the 4C Mortality, CURB-65, and A-DROP, as well as the Ct value of the nasopharyngeal PCR, in predicting COVID-19 mortality and critical condition development.ResultsOf the 92 recruited patients (median age, 58; interquartile range, 45-71 years), 14 (14.9%) had RNAemia. These patients had an older age (median, 68 years vs. 55.5 years; p = 0.011), higher values of lactated dehydrogenase (median, 381 U/L vs. 256.5 U/L, p < 0.001), C-reactive protein (median, 10.9 mg/dL vs. 3.8 mg/dL; p < 0.001), D-dimer (median, 2.07 μg/mL vs. 1.28 μg/mL; p = 0.015), lower values of lymphocyte (median, 802/μL vs. 1007/μL, p = 0.025) and Ct of the nasopharyngeal PCR assay (median, 20.59 vs. 25.54; p = 0.021) than those without RNAemia. Univariate analysis showed RNAemia was associated with mortality (odds ratio [OR], 18.75; 95% confidence interval [CI], 3.92-89.76; area under the receiver operating characteristic curve [AUC], 0.7851; p = 0.002) and critical condition (OR, 72.00; 95% CI, 12.98-399.29; AUC, 0.8198; p < 0.001). Plus, multivariate analysis also revealed the association of RNAemia with critical condition (adjusted OR, 125.71; 95% CI, 11.47-1377.32; p < 0.001).ConclusionOn-admission SARS-CoV-2 RNAemia is a potent predictive marker of COVID-19 critical condition and mortality. The adjusted OR for critical condition was as high as 125.71.

Anterior cruciate ligament (ACL) remnant preservation techniques have been recently introduced for covering the graft with remnant to improve the clinical results of ACL reconstruction. Several theoretical advantages exist for this technique; however, clinical results remain inconsistent and controversial. We have focused on the biomechanical function of the remnant and have been performing a new remnant-preserving reconstruction procedure that augments the graft with residual remnant. Preserving the structure and continuity of good-quality remnants may help maintain the early postoperative stress on the tendon graft, thereby providing a positive effect on remodeling. Although our concept is significantly different from previously reported remnant preservation techniques and has several pitfalls, the surgical technique that we outline in this report is simple and does not require specialized equipment. The procedure will also work more advantageously in preserving the residual mechanoreceptors in the remnant. We believe that this method can be a procedure with better results for patients with remnants that are in good condition.

We report an extremely rare case of inner head displacement from the stem of a bipolar hip prosthesis (BHP). An 88-year-old woman underwent BHP implantation for right femoral neck fracture. However, severe right hip joint pain occurred 12 days after surgery. A plain radiogram film revealed displacement of the inner head from the neck of the stem, accompanied by sinking of the stem. At reoperation, the inner head was disassembled from the stem, and Vancouver type A1 fracture was confirmed. Disassembly may have been caused by the pumping phenomenon or micromovement of the stem due to periprosthetic fracture. To our knowledge, this is the first report about disassembly of the BHP inner head, probably due to periprosthetic fracture. Keywords: Bipolar hip prosthesis, Disassembly, Inner head displacement, Periprosthetic fracture

Case. We report a rare case of prefemoral fat pad impingement syndrome that was caused by a hyperplasia of the normal suprapatellar fat pad. Pain and catching were observed in the proximal-lateral patellofemoral joint, and MRI imaging confirmed a hyperplasic mass in the same area. Although conservative treatment showed no signs of improvement, symptoms improved after an arthroscopic excision of the mass. Conclusion. Prefemoral fat pad impingement syndrome is related to patellar motion and should be considered as one of the underlying causes of anterior knee pain (AKP). Surgeons should recognize that a small hyperplasia composed of normal adipose tissue can cause AKP.

Health care workers (HCWs) may transmit respiratory infection to patients. We assessed evidence for the effectiveness of vaccinating HCWs to provide indirect protection for patients at risk for severe or complicated disease after acute respiratory infection. We searched electronic health care databases and sources of gray literature by using a predefined strategy. Risk for bias was assessed by using validated tools, and results were synthesized by using a narrative approach. Seventeen of the 12,352 identified citations met the full inclusion criteria, and 3 additional articles were identified from reference or citation tracking. All considered influenza vaccination of HCWs, and most were conducted in long-term residential care settings. Consistency in the direction of effect was observed across several different outcome measures, suggesting a likely protective effect for patients in residential care settings. However, evidence was insufficient for us to confidently extrapolate this to other at-risk patient groups.

Activated microglia can exert either neurotoxic or neuroprotective effects, and they play pivotal roles in the pathogenesis and progression of various neurological diseases. In this study, we used cDNA microarrays to show that interleukin-19 (IL-19), an IL-10 family cytokine, is markedly upregulated in activated microglia. Furthermore, we found that microglia are the only cells in the nervous system that express the IL-19 receptor, a heterodimer of the IL-20Rα and IL-20Rβ subunits. IL-19 deficiency increased the production of such pro-inflammatory cytokines as IL-6 and tumor necrosis factor-α in activated microglia, and IL-19 treatment suppressed this effect. Moreover, in a mouse model of Alzheimer's disease, we observed upregulation of IL-19 in affected areas in association with disease progression. Our findings demonstrate that IL-19 is an anti-inflammatory cytokine, produced by activated microglia, that acts negatively on microglia in an autocrine manner. Thus, microglia may self-limit their inflammatory response by producing the negative regulator IL-19.

The blood-brain barrier (BBB) is composed of capillary endothelial cells, pericytes, and perivascular astrocytes, which regulate central nervous system homeostasis. Sonic hedgehog (SHH) released from astrocytes plays an important role in the maintenance of BBB integrity. BBB disruption and microglial activation are common pathological features of various neurologic diseases such as multiple sclerosis, Parkinson's disease, amyotrophic lateral sclerosis, and Alzheimer's disease. Interleukin-1β (IL-1β), a major pro-inflammatory cytokine released from activated microglia, increases BBB permeability. Here we show that IL-1β abolishes the protective effect of astrocytes on BBB integrity by suppressing astrocytic SHH production. Astrocyte conditioned media, SHH, or SHH signal agonist strengthened BBB integrity by upregulating tight junction proteins, whereas SHH signal inhibitor abrogated these effects. Moreover, IL-1β increased astrocytic production of pro-inflammatory chemokines such as CCL2, CCL20, and CXCL2, which induce immune cell migration and exacerbate BBB disruption and neuroinflammation. Our findings suggest that astrocytic SHH is a potential therapeutic target that could be used to restore disrupted BBB in patients with neurologic diseases.

Soluble oligomeric amyloid β (oAβ) causes synaptic dysfunction and neuronal cell death, which are involved in the pathogenesis of Alzheimer's disease (AD). The hematopoietic growth factor granulocyte-colony stimulating factor (G-CSF) is expressed in the central nervous system (CNS) and drives neurogenesis. Here we show that G-CSF attenuated oAβ neurotoxicity through the enhancement of the enzymatic activity of Aβ-degrading enzyme neprilysin (NEP) in neurons, while the NEP inhibitor thiorphan abolished the neuroprotection. Inhibition of MEK5/ERK5, a major downstream effector of G-CSF signaling, also ablated neuroprotective effect of G-CSF. Furthermore, intracerebroventricular administration of G-CSF enhanced NEP enzymatic activity and clearance of Aβ in APP/PS1 transgenic mice. Thus, we propose that G-CSF may be a possible therapeutic strategy against AD.

Interleukin-34 (IL-34) is a newly discovered cytokine as an additional ligand for colony stimulating factor-1 receptor (CSF1R), and its functions are expected to overlap with colony stimulating factor-1/macrophage-colony stimulating factor. We have previously shown that the IL-34 is primarily produced by neurons in the central nervous system (CNS) and induces proliferation and neuroprotective properties of microglia which express CSF1R. However, the functions of IL-34 in the CNS are still elucidative. Here we show that CNS capillary endothelial cells also express CSF1R. IL-34 protected blood-brain barrier integrity by restored expression levels of tight junction proteins, which were downregulated by pro-inflammatory cytokines. The novel function of IL-34 on the blood-brain barrier may give us a clue for new therapeutic strategies in neuroinflammatory and neurodegenerative diseases such as multiple sclerosis and Alzheimer's disease.

The neurodegenerative processes that underlie Alzheimer's disease are mediated, in part, by soluble oligomeric amyloid β, a neurotoxic protein that inhibits hippocampal long-term potentiation, disrupts synaptic plasticity, and induces the production of reactive oxygen species. Here we show that the sphingosine-1-phosphate (S1P) receptor (S1PR) agonist fingolimod phosphate (FTY720-P)-a new oral drug for multiple sclerosis-protects neurons against oligomeric amyloid β-induced neurotoxicity. We confirmed that primary mouse cortical neurons express all of the S1P receptor subtypes and FTY720-P directly affects the neurons. Treatment with FTY720-P enhanced the expression of brain-derived neurotrophic factor (BDNF) in neurons. Moreover, blocking BDNF-TrkB signaling with a BDNF scavenger, TrkB inhibitor, or ERK1/2 inhibitor almost completely ablated these neuroprotective effects. These results suggested that the neuroprotective effects of FTY720-P are mediated by upregulated neuronal BDNF levels. Therefore, FTY720-P may be a promising therapeutic agent for neurodegenerative diseases, such as Alzheimer's disease.

BackgroundImmunocompromised patients are vulnerable to severe or complicated influenza infection. Vaccination is widely recommended for this group. This systematic review and meta-analysis assesses influenza vaccination for immunocompromised patients in terms of preventing influenza-like illness and laboratory confirmed influenza, serological response and adverse events.Methodology/principal findingsElectronic databases and grey literature were searched and records were screened against eligibility criteria. Data extraction and risk of bias assessments were performed in duplicate. Results were synthesised narratively and meta-analyses were conducted where feasible. Heterogeneity was assessed using I(2) and publication bias was assessed using Begg's funnel plot and Egger's regression test. Many of the 209 eligible studies included an unclear or high risk of bias. Meta-analyses showed a significant effect of preventing influenza-like illness (odds ratio [OR]=0.23; 95% confidence interval [CI]=0.16-0.34; pConclusions/significanceInfection prevention and control strategies should recommend vaccinating immunocompromised patients. Potential for bias and confounding and the presence of heterogeneity mean the evidence reviewed is generally weak, although the directions of effects are consistent. Areas for further research are identified.