Synergistic antitumor activity by dual blockade of CCR1 and CXCR2 expressed on myeloid cells within the tumor microenvironment.

BACKGROUND: Chemokine signaling within the tumor microenvironment can promote tumor progression. Although CCR1 and CXCR2 on myeloid cells could be involved in tumor progression, it remains elusive what effect would be observed if both of those are blocked. METHODS: We employed two syngeneic colorectal cancer mouse models: a transplanted tumor model and a liver metastasis model. We generated double-knockout mice for CCR1 and CXCR2, and performed bone marrow (BM) transfer experiments in which sub-lethally irradiated wild-type mice were reconstituted with BM from either wild-type, Ccr1-/-, Cxcr2-/- or Ccr1-/-Cxcr2-/- mice. RESULTS: Myeloid cells that express MMP2, MMP9 and VEGF were accumulated around both types of tumors through CCR1- and CXCR2-mediated pathways. Mice reconstituted with Ccr1-/-Cxcr2-/- BM exhibited the strongest suppression of tumor growth and liver metastasis compared with other three groups. Depletion of CCR1+CXCR2+ myeloid cells led to a higher frequency of CD8+ T cells, whereas the numbers of Ly6G+ neutrophils, FOXP3+ Treg cells and CD31+ endothelial cells were significantly decreased. Furthermore, treatment with a neutralizing anti-CCR1 mAb to mice reconstituted with Cxcr2-/- BM significantly suppressed tumor growth and liver metastasis. CONCLUSION: Dual blockade of CCR1 and CXCR2 pathways in myeloid cells could be an effective therapy against colorectal cancer.

Changes in severity of pediatric suicide attempts before and after coronavirus disease 2019.

BACKGROUND: The recent coronavirus disease 2019 (COVID-19) pandemic and school closures were reported to have negatively impacted the mental health of children and adolescents. This study aimed to examine the change in the number and severity of pediatric suicide attempts before and after the COVID-19 pandemic. METHODS: This study enrolled 54 patients (26 vs. 28 patients before and after the COVID-19 pandemic, respectively) under 19 years of age who were transported to the emergency department as a result of suicide attempts between April 2017 and December 2021. The primary outcome includes the rate of serious suicide attempts (SSAs). RESULTS: The SSA rates were 19% (5/26) and 43% (12/28) before and after the COVID-19 pandemic, respectively (p = 0.62). The average number of transported suicide attempts per month almost doubled (0.72 vs. 1.33, respectively) and suicide attempts as a percentage of all ambulance transportations of individuals under 19 years old increased significantly from 0.95% (26/2729)to 1.98% (28/1414) (p = 0.006). CONCLUSIONS: The COVID-19 pandemic increased the severity of pediatric suicide attempts but not to a statistically significant degree. Social preventive support and early psychological intervention are therefore needed currently and in the future.

The impact of preclinical clerkship in general surgery on medical students' attitude to a surgical career.

PURPOSE: With the advent of a new program for postgraduate medical students in 2004, the number of applicants choosing surgical careers in Japan has been declining. We conducted this study to evaluate the impact of preclinical clerkship and how it affects students' attitudes toward a surgical career. METHODS: The subjects of our study were fifth-year medical students who participated in a clinical clerkship in general surgery in our department between April 2021 and March 2022. We conducted pre- and post-preclinical clerkship surveys to assess the perceived image of surgeons and the impact of clerkship on surgical career interest. RESULTS: Among 132 medical students (77 men and 55 women) who rotated through preclinical clerkship in our department, 125 participated in the survey and 66% expressed interest in a surgical career. In the post-clerkship survey, an increased interest in a surgical career was expressed by 79% of the students; notably, including those who initially expressed interest. Approximately 77% of students were satisfied with the practical skill training they received. CONCLUSION: Engaging medical students early in surgical experience through a preclinical clerkship for general surgery appears to promote their interest in a surgical career.

Neutrophil Extracellular Traps Promote Metastases of Colorectal Cancers through Activation of ERK Signaling by Releasing Neutrophil Elastase.

Neutrophil extracellular traps (NETs) play important roles in host immunity, as there is increasing evidence of their contribution to the progression of several types of cancers even though their role in colorectal cancers (CRCs) remains unclear. To investigate the clinical relevance of NETs in CRCs, we examined the expression of citrullinated histone H3 using immunohistochemistry and preoperative serum myeloperoxidase-DNA complexes in CRC patients using an enzyme-linked immunosorbent assay. High expression of intratumoral or systemic NETs was found to correlate with poor relapse-free survival (RFS), for which it is an independent prognostic factor. In vitro investigations of CRC cells (HCT116, HT29) revealed that NETs did not affect their proliferation but did promote the migration of CRC cells mediated by neutrophil elastase (NE) released during NETosis to increase extracellular signal-regulated kinase (ERK) activity. In vivo experiments using nude mice (KSN/slc) revealed that NE inhibition suppressed liver metastases in CRC cells, although it did not affect the growth of subcutaneously implanted tumors. Taken together, these results suggest that NET formation correlates with poor prognoses of patients with CRC and that the inhibition of NE could be a potential therapy for CRC metastases.

Superiority of OxyMaskTM with less carbon dioxide rebreathing in children.

Despite the growing importance of oxygen-delivery devices worldwide, there are only a few reports of physiological data on various oxygen masks in children. The possibility of carbon dioxide (CO2) rebreathing has been a prevalent concern with the use of oxygen-delivery devices. OxyMask KidTM (Southmedic Inc. Canada; hereafter OxyMask) is expected to reduce CO2 rebreathing even at low oxygen flow rates because of its structural features. Biological data using OxyMask in children have not been well investigated. Measured respiratory parameters of OxyMask with those of a simple oxygen mask in healthy children were compared. Ten subjects were enrolled, with a median age of 5.4 years. All subjects used both OxyMask and a simple oxygen mask. The fraction of inspiratory oxygen (FIO2), partial pressure of inspiratory CO2 (PICO2), and partial pressure of end-tidal CO2 were measured using a sidestream gas-sampling monitor in all subjects. The oxygen flow rate was set at 1, 3, 5, and 10 L/min. FIO2 levels were higher with OxyMask than those with the simple oxygen mask at 3 L/min of oxygen. PICO2 levels were significantly lower with OxyMask than those with the simple oxygen mask (1.5 mmHg vs. 3.7 mmHg at 1 L/min, P = 0.005; 1.0 mmHg vs. 2.7 mmHg at 3 L/min, P = 0.005, respectively), whereas PICO2 levels were higher at low oxygen flow rates with both masks.Conclusion: Our results showed that higher FIO2 and less CO2 rebreathing were achieved with OxyMask than those with a simple oxygen mask at low flow rates of oxygen in healthy children. What is Known: • OxyMask is expected to reduce carbon dioxide rebreathing even at low oxygen flow rates because of its structural features. • Efficacy has been demonstrated in experimental models and adult data, but clinical data on the use of the OxyMask in children are limited. What is New: • Higher fraction of inspiratory oxygen and lesser carbon dioxide rebreathing were achieved with OxyMask than with a simple oxygen mask at low flow rates of oxygen in healthy children.

Unexpected postmortem diagnoses in cases of clinically diagnosed amyotrophic lateral sclerosis.

Amyotrophic lateral sclerosis (ALS) is a motor neuron disease that is clinically and pathologically characterized by impairment of the upper and lower motor neurons. The clinical diagnosis of ALS is not always straightforward because of the lack of specific biomarkers and clinical heterogeneity. This review presents the clinical and pathological findings of four autopsied cases that had been diagnosed with ALS before death. These cases had demonstrated definite and progressive motor neuron signs and symptoms, whereas postmortem assessment revealed miscellaneous disorders, including fungal infection, paraneoplastic syndrome, and amyloidosis. Importantly, nonmotor neuron signs and symptoms, including seizures, extra-pyramidal signs, ocular movement disorders, sensory disturbance, and dysautonomia, had also been documented during the disease course of the cases in the present study. The ALS-unlike symptoms were indicative of the "true" diagnosis in each case when those symptoms were isolated from motor neuron signs/symptoms.

Laparoscopic gastrectomy with and without prophylactic drains in gastric cancer: a propensity score-matched analysis.

BACKGROUND: The number of patients who are undergoing laparoscopic gastrectomy for treating gastric cancer is increasing. Although prophylactic drains have been widely employed following the procedure, there are few studies reporting the efficacy of prophylactic drainage. Therefore, this study assessed the efficacy of prophylactic drains following laparoscopic gastrectomy for gastric cancer. METHODS: Data of patients who received laparoscopic gastrectomy for treating gastric cancer in our institution between April 2011 and March 2017 were reviewed, and the outcomes of patients with and without a prophylactic drainage were compared. Propensity score matching was used to minimize potential selection bias. RESULTS: A total of 779 patients who underwent surgery for gastric cancer were reviewed; of these, 628 patients who received elective laparoscopic gastrectomy were included in this study. After propensity score matching, data of 145 pairs of patients were extracted. No significant differences were noted in the incidence of postoperative complications between the drain and no-drain groups (19.3% vs 11.0%, P = 0.071). The days after the surgery until the initiation of soft diet (6.3 ± 7.4 vs 4.9 ± 2.9 days, P = 0.036) and the length of postoperative hospital stay (15.7 ± 12.9 vs 13.0 ± 6.3 days, P = 0.023) were greater in the drain group than those in the no-drain group. CONCLUSIONS: This study suggests that routinely using prophylactic drainage following laparoscopic gastrectomy for treating gastric cancer is not obligatory.

RpA1 ameliorates symptoms of mutant ataxin-1 knock-in mice and enhances DNA damage repair.

DNA damage and repair is a critical domain of many neurodegenerative diseases. In this study, we focused on RpA1, a candidate key molecule in polyQ disease pathologies, and tested the therapeutic effect of adeno-associated virus (AAV) vector expressing RpA1 on mutant Ataxin-1 knock-in (Atxn1-KI) mice. We found significant effects on motor functions, normalized DNA damage markers (γH2AX and 53BP1), and improved Purkinje cell morphology; effects that lasted for 50 weeks following AAV-RpA1 infection. In addition, we confirmed that AAV-RpA1 indirectly recovered multiple cellular functions such as RNA splicing, transcription and cell cycle as well as abnormal morphology of dendrite and dendritic spine of Purkinje cells in Atxn1-KI mice. All these results suggested a possibility of gene therapy with RpA1 for SCA1.

Targeting TEAD/YAP-transcription-dependent necrosis, TRIAD, ameliorates Huntington's disease pathology.

Neuronal cell death in neurodegenerative diseases is not fully understood. Here we report that mutant huntingtin (Htt), a causative gene product of Huntington's diseases (HD) selectively induces a new form of necrotic cell death, in which endoplasmic reticulum (ER) enlarges and cell body asymmetrically balloons and finally ruptures. Pharmacological and genetic analyses revealed that the necrotic cell death is distinct from the RIP1/3 pathway-dependent necroptosis, but mediated by a functional deficiency of TEAD/YAP-dependent transcription. In addition, we revealed that a cell cycle regulator, Plk1, switches the balance between TEAD/YAP-dependent necrosis and p73/YAP-dependent apoptosis by shifting the interaction partner of YAP from TEAD to p73 through YAP phosphorylation at Thr77. In vivo ER imaging with two-photon microscopy detects similar ER enlargement, and viral vector-mediated delivery of YAP as well as chemical inhibitors of the Hippo pathway such as S1P recover the ER instability and necrosis in HD model mice. Intriguingly S1P completely stops the decline of motor function of HD model mice even after the onset of symptom. Collectively, we suggest approaches targeting the signalling pathway of TEAD/YAP-transcription-dependent necrosis (TRIAD) could lead to a therapeutic development against HD.

Optimized optical coupling to silica-clad photonic crystal waveguides.

Silica-clad silicon photonic crystal waveguides (PCWs) are promising components for various applications because of their simple fabrication and generation of slow light. However, an optical loss higher than 4 dB occurs when they are simply coupled to input/output silicon wire waveguides. To reduce the optical loss, we proposed a junction structure in which light in the waveguide is first coupled to a high-group-velocity radiation mode at an expanded core and subsequently converted to the slow-light mode in a tapered core of the PCW. The coupling loss at a junction is calculated to be 0.28 dB at its minimum and less than 0.5 dB for the wavelength range of 12 nm. We measured a coupling loss of 0.46 dB for the device fabricated by the silicon photonics process. This low-loss junction well supports the practical use of PCWs.

Systems biology analysis of Drosophila in vivo screen data elucidates core networks for DNA damage repair in SCA1.

DNA damage repair is implicated in neurodegenerative diseases; however, the relative contributions of various DNA repair systems to the pathology of these diseases have not been investigated systematically. In this study, we performed a systematic in vivo screen of all available Drosophila melanogaster homolog DNA repair genes, and we tested the effect of their overexpression on lifespan and developmental viability in Spinocerebellar Ataxia Type 1 (SCA1) Drosophila models expressing human mutant Ataxin-1 (Atxn1). We identified genes previously unknown to be involved in CAG-/polyQ-related pathogenesis that function in multiple DNA damage repair systems. Beyond the significance of each repair system, systems biology analyses unraveled the core networks connecting positive genes in the gene screen that could contribute to SCA1 pathology. In particular, RpA1, which had the largest effect on lifespan in the SCA1 fly model, was located at the hub position linked to such core repair systems, including homologous recombination (HR). We revealed that Atxn1 actually interacted with RpA1 and its essential partners BRCA1/2. Furthermore, mutant but not normal Atxn1 impaired the dynamics of RpA1 in the nucleus after DNA damage. Uptake of BrdU by Purkinje cells was observed in mutant Atxn1 knockin mice, suggesting their abnormal entry to the S-phase. In addition, chemical and genetic inhibitions of Chk1 elongated lifespan and recovered eye degeneration. Collectively, we elucidated core networks for DNA damage repair in SCA1 that might include the aberrant usage of HR.

Suppression of the novel ER protein Maxer by mutant ataxin-1 in Bergman glia contributes to non-cell-autonomous toxicity.

Non-cell-autonomous effect of mutant proteins expressed in glia has been implicated in several neurodegenerative disorders, whereas molecules mediating the toxicity are currently not known. We identified a novel molecule named multiple alpha-helix protein located at ER (Maxer) downregulated by mutant ataxin-1 (Atx1) in Bergmann glia. Maxer is an endoplasmic reticulum (ER) membrane protein interacting with CDK5RAP3. Maxer anchors CDK5RAP3 to the ER and inhibits its function of Cyclin D1 transcription repression in the nucleus. The loss of Maxer eventually induces cell accumulation at G1 phase. It was also shown that mutant Atx1 represses Maxer and inhibits proliferation of Bergmann glia in vitro. Consistently, Bergmann glia are reduced in the cerebellum of mutant Atx1 knockin mice before onset. Glutamate-aspartate transporter reduction in Bergmann glia by mutant Atx1 and vulnerability of Purkinje cell to glutamate are both strengthened by Maxer knockdown in Bergmann glia, whereas Maxer overexpression rescues them. Collectively, these results suggest that the reduction of Maxer mediates functional deficiency of Bergmann glia, and might contribute to the non-cell-autonomous pathology of SCA1.

Streptococcus pulmonary empyema after varicella infection in a serologically immunocompetent boy.

Varicella zoster virus (VZV) is the etiologic agent of varicella, and it remains common among children in Japan due to low vaccination rates. It can cause a variety of serious and life-threatening complications. Generally, the most frequent complication of varicella in healthy children is bacterial superinfection, but empyema after VZV infection is a rare condition. This case report describes a previously healthy 21-month-old boy who attended nursery school with a recent varicella and group A ß-hemolytic streptococcus (GABHS) pharyngitis outbreak and who presented with a 7 day history of vesicular rash along with progressive fever. Due to continued mild cough and prolonged fever, however, chest radiography was done, which showed a right pleural effusion. Further computed tomography showed a right pulmonary empyema, and purulent material was drained and eventually grew GABHS. This report hereby describes the development of pleural empyema caused by GABHS after VZV infection in a serologically immunocompetent patient.

Prolonged incubation period in neonatal Pasteurella multocida meningitis and bacteremia.

Pasteurella multocida, often found as part of the human oral flora and in finger/toenails, also exists in many animals, especially cats, dogs, and pigs. Although rare, pasteurella infection in neonates can cause serious systemic disease, such as meningitis. In this article, a 23-day-old girl presented with decreased appetite and irritability for >2 days. Eighteen days previously her pet cat had jumped onto the left side of her head while she was sleeping. On laboratory data C-reactive protein was high, and on cerebrospinal fluid (CSF) analysis leukocyte count was extremely high, with low glucose and high protein. P. multocida grew out of the blood and CSF cultures, and she was successfully treated with antibiotics for 3 weeks. Although pasteurellosis rarely occurs, it can sometimes lead to life-threatening situations, so parents should exercise caution when having pets around their children.

[Clinical features and predictive factors of recurrent fever observed during the treatment of bacterial meningitis in children].

Recurrent fever often occurs during the treatment of bacterial meningitis in children. Few studies have focused on the difference between the patients with and without recurrent fever. The pathogenesis and clinical significance of recurrent fever remain to be elucidated. The objectives of this study were to clarify the clinical features of the patients with recurrent fever, and to identify the predictive factors for recurrent fever in childhood bacterial meningitis. We conducted a hospital-based retrospective chart review and confirmed 52 cases of bacterial meningitis. Recurrent fever was observed in 27 of 52 (52%) patients overall, and 27 of 47 (57%) patients with dexamethasone (DEX) therapy. All patients with recurrent fever received DEX therapy. The mean date of recurrent fever occurrence was 6.2 +/- 2.0 days after admission. The median duration of recurrent fever was 5 days (range 1-19 days). The proportion of patients < 2 years of age was higher in patients with recurrent fever than those without recurrent fever (p = 0.041). Initial peripheral white blood cell count was lower in patients with recurrent fever (p = 0.008). Of the 52 children, 10 (19%) showed neurological sequelae. Neurological sequelae were more frequent in patients with recurrent fever than those without recurrent fever, although this was not statistically significant (p = 0.078). Univariate and multivariate logistic regression analysis showed that the most powerful predictive factor for recurrent fever in patients with DEX therapy was young age (< 2 years) (adjusted odds ratio, 5.1; 95% confidence interval, 1.3-20.7). These results suggest that recurrent fever is related to the two known factors for sequelae, low peripheral white blood cell count and young age. Recurrent fever should be recognized as a possible risk factor for neurological sequelae.

Neurological Resilience in Patients With Anorexia Nervosa Following Prolonged Cardiopulmonary Resuscitation.

Anorexia nervosa (AN) is a psychiatric disorder with metabolic abnormalities. Prolonged cardiopulmonary resuscitation (CPR) is predicted to result in death and poor neurological outcomes. This report describes the case of a patient with AN who had an unexpectedly favorable outcome after prolonged CPR. A 12-year-old female with AN presented to the emergency department, requiring intubation due to worsening consciousness and respiratory distress. Refractory hypotension led to cardiac arrest. After 135 minutes of CPR, venoarterial extracorporeal membrane oxygenation (EMCO) was started, and the patient was treated for post-resuscitation management, refeeding syndrome, and sepsis. The cardiac function gradually improved, the patient was weaned from EMCO eight days after admission, and the patient was extubated 30 days after admission. The patient maintained a good central nervous system function. AN patients tend to be youngsters and have a lower metabolism, which may be associated with a favorable neurological prognosis after prolonged CPR.

[A case of recurrent Campylobacter fetus meningitis, occurring two months after the |initial infection was successfully treated].

A 43-year-old man was admitted to our department due to fever and headache. The cerebrospinal fluid analysis confirmed bacterial meningitis. Campylobacter species were isolated from blood cultures on the third day of admission. The patient was treated with meropenem (MEPM) and discharged on the 17th day. However, he experienced a recurrence of meningitis and was readmitted on the 68th day, initiating MEPM therapy. Campylobacter fetus was isolated from cerebrospinal fluid cultures on the 74th day. MEPM was continued until the 81st day, followed by one month of minocycline (MINO) therapy. The patient had an uneventful recovery without further recurrence. This case highlights the potential for recurrence of Campylobacter fetus meningitis approximately two months after the resolution of the initial infection. In addition to carbapenem therapy for at least two weeks, the adjunctive administration of MINO may be beneficial.