Validation of the PECARN head trauma prediction rules in Japan: A multicenter prospective study.

BACKGROUND: Head trauma in children is one of the most common causes for emergency department visits. Although most trauma cases are minor, identifying those patients who have clinically important traumatic brain injury (ciTBI) is challenging. The Pediatric Emergency Care Applied Research Network (PECARN) head trauma prediction rules identifying children who do not require cranial computed tomography (CT) were validated and are used all over the world. However, these rules have not been validated with large cohort multicenter studies in Asia. OBJECTIVES: To investigate whether the PECARN rules can be safely applied to Japanese children. METHODS: We conducted a multicenter, prospective, observational cohort study. We included children younger than 16 with minor head trauma (Glasgow Coma Scale ≥14) who presented to the six participating centers within 24 h of their injuries between June 2016 and September 2017. The primary analysis was set to calculate the negative predictive value of the patients with very low risk by the PECARN rules, compared with a preset threshold of 99.85%. RESULTS: We included 6585 children of which 463 (7.0%) had head CT scans performed and 23 (0.35%) had ciTBI. There were two patients with ciTBI who were classified as very low risk. The negative predictive value, calculated as 99.96% (95%CI: 99.86-100.00; P = .019), was significantly superior compared with the preset threshold of 99.85%. CONCLUSIONS: The PECARN head trauma prediction rules seemed to be safely applicable to Japanese children. Further studies are needed to determine safety in hospitals where physicians do not have expertise in managing children.

A SNP in the ABCC11 gene is the determinant of human earwax type.

Human earwax consists of wet and dry types. Dry earwax is frequent in East Asians, whereas wet earwax is common in other populations. Here we show that a SNP, 538G --> A (rs17822931), in the ABCC11 gene is responsible for determination of earwax type. The AA genotype corresponds to dry earwax, and GA and GG to wet type. A 27-bp deletion in ABCC11 exon 29 was also found in a few individuals of Asian ancestry. A functional assay demonstrated that cells with allele A show a lower excretory activity for cGMP than those with allele G. The allele A frequency shows a north-south and east-west downward geographical gradient; worldwide, it is highest in Chinese and Koreans, and a common dry-type haplotype is retained among various ethnic populations. These suggest that the allele A arose in northeast Asia and thereafter spread through the world. The 538G --> A SNP is the first example of DNA polymorphism determining a visible genetic trait.

Intratumoral metastasis of sigmoid colon cancer to chromophobe renal cell carcinoma: a case report.

We herein report an extremely rare case of intratumoral metastasis of colon cancer to chromophobe renal cell carcinoma. A 71-year-old woman was diagnosed with lung metastasis of sigmoid colon cancer and underwent sigmoid colon resection with D3 lymph node dissection. Preoperative contrast-enhanced computed tomography (CT) revealed a left renal tumor; however, colon resection was prioritized, and the renal tumor was placed under observation. Two years later, CT revealed enlargement of the left renal tumor, and laparoscopic partial left nephrectomy was performed 1 month later. Histopathologic examination showed that the resected renal tumor was a chromophobe renal cell carcinoma with intratumoral metastasis of colon cancer to the renal tumor center, and adjuvant chemotherapy with bevacizumab plus SOX (L-OHP + S-1) was initiated. Because of severe chemotherapy-induced fatigue and nausea, the patient was switched to bevacizumab + S-1. However, the patient's nausea did not improve after this change, and postoperative adjuvant chemotherapy was discontinued at the patient's request 4 months after the partial nephrectomy. Two months after discontinuation of chemotherapy, CT showed no renal recurrence; however, increased lung metastases and a new bone metastasis in the left sciatic bone were observed. Palliative treatment was then initiated because of severe adverse events that made it difficult to continue treatment. In patients who have multiple cancers and an increase in renal tumor size, the possibility of intratumoral metastasis to the renal tumor should be considered.

Bilateral vocal cord palsy induced by long-term use of small-bore nasogastric tube.

Background: Nasogastric tube syndrome is a rare but life-threatening complication of nasogastric tube placement due to acute upper airway obstruction caused by bilateral vocal cord paresis. Case Presentation: An 86-year-old woman was brought to the emergency department with acute stridor. She had been diagnosed with stroke 106 days prior, and an 8F nasogastric tube was placed on the day following the diagnosis. A laryngeal fiberscopy revealed bilateral laryngeal edema and bilateral vocal cord palsy. Nasogastric tube removal and intubation were carried out, and the stridor disappeared. Two days later, a tracheostomy was performed. Unfortunately, the patient's vocal cord function had not improved at the 1 month follow-up upon assessment with a laryngeal fiberscope. Conclusion: Long-term small-bore nasogastric tube placement can cause upper airway obstruction due to bilateral vocal cord palsy.

TIM-3 expression induces resistance to PD-1 inhibitor in G-CSF-producing lung spindle cell carcinoma: A case report.

Lung spindle cell carcinoma is an aggressive subtype of pleomorphic lung cancer resistant to cytotoxic chemotherapy. Programmed cell death-1 (PD-1) inhibitors have been reported to have clinical effects in patients with spindle cell carcinoma; however, the resistance mechanism to PD-1 inhibitors is yet to be fully elucidated. Herein, we report the case of an 88-year-old man with G-CSF-producing spindle cell carcinoma who acquired resistance to PD-1/PD-ligand 1 (L1) inhibitor in an early setting after a remarkable response. A histopathological review of the resistant specimen revealed a low count of CD8+ T cells and a predominant presence of M2 and TIM-3+ macrophages, indicating the presence of an immunosuppressive microenvironment. Our findings suggest a novel resistance mechanism to PD-1/PD-L1 inhibitors in G-CSF-producing spindle cell carcinoma.

Intravascular Catheter Accidentally Placed into the Right Lumbar Vein from the Right Femoral Vein: A Case Report.

BACKGROUND Severe hypothermia has a high mortality rate and necessitates aggressive warming to save lives. One of the most effective treatments for severe hypothermia is intravascular rewarming. Intravascular recuperative warming can be delivered by inserting a catheter through the cervical or femoral veins. Catheter insertion through the femoral vein is a commonly performed procedure with fewer complications than catheter insertion through the internal jugular vein. This procedure is commonly conducted by inserting a central venous catheter through the femoral vein. When a catheter is inserted through the femoral vein, a frontal abdominal radiograph is often used to confirm the position of the catheter tip. CASE REPORT We present the case of a 58-year-old Japanese man who had severe hypothermia. Under ultrasound guidance, a catheter was inserted through the femoral vein into the inferior vena cava for active rewarming. A frontal abdominal radiograph showed that a catheter tip appeared to be in the inferior vena cava. However, a subsequent computed tomography scan revealed that the catheter tip had been misplaced into the right ascending lumbar vein. CONCLUSIONS Catheters may stray into the right ascending lumbar vein if they are placed through the right femoral vein. Frontal abdominal radiographs may be insufficient to confirm catheter placement.

Changes in tissue inflammation, angiogenesis and apoptosis in endometriosis, adenomyosis and uterine myoma after GnRH agonist therapy.

BACKGROUND: Information is limited regarding the multifunctional role of GnRH agonist (GnRHa) therapy in reproductive diseases. We investigated the pattern of changes in inflammatory reaction, micro-vessel density and apoptosis in the tissues collected from women with endometriosis, adenomyosis and uterine myoma who were treated with or without GnRHa therapy. METHODS: Biopsy specimens were collected from lesions, myometria and corresponding endometria of 45 women with ovarian endometrioma, 35 women with adenomyosis and 56 women with uterine myoma. A fraction of these women were treated with GnRHa therapy for a variable period of 3-6 months before surgery. We performed immunohistochemical analysis of CD68, a macrophage (Mvarphi) marker and von Willebrand factor (VWF), a vessel marker, using respective antibodies. Changes in apoptosis were examined using TdT-mediated dUTP-biotin nick end-labeling assay and by the immunoexpression of activated caspase-3 in tissues after GnRHa therapy. RESULTS: The infiltration of CD68-positive Mvarphi and VWF-positive micro-vessel density were significantly decreased in the endometria of women with endometriosis, adenomyosis and uterine myoma in the GnRHa-treated group when compared with that in the non-treated group. Marked decreases in inflammatory and angiogenic responses were observed in lesions and myometria of these diseases. When compared with the non-treated group, a significant increase in apoptotic index (apoptotic cells per 10 mm(2) area) and quantitative-histogram scores of activated caspase-3 after GnRHa therapy were observed in the eutopic endometria, lesions and myometria of these diseases. CONCLUSIONS: GnRHa was able to markedly reduce the inflammatory reaction and angiogenesis and to significantly induce apoptosis in tissues derived from women with endometriosis, adenomyosis and uterine myoma. These multiple biological effects at the tissue level may be involved in the regression of these reproductive diseases.

First Japanese patient treated with parathyroid hormone peptide immunization for refractory hypercalcemia caused by metastatic parathyroid carcinoma.

Patients with unresectable parathyroid carcinoma develop severe hypercalcemia, bone fractures and renal failure, and become unresponsive to conventional treatments. It has been shown that successful induction of anti-parathyroid hormone (PTH) antibodies, using PTH peptide fragments for immunisation, normalized serum levels of calcium as well as improved clinical symptoms. Here, we report our experience of PTH immunization in a Japanese female suffering from refractory hypercalcemia and renal failure caused by unresectable metastatic parathyroid carcinoma. Upon immunization, there were apparent clinical responses including reduction of serum levels of Ca along with anti-PTH antibodies induction. Therefore, we concluded that PTH immunization was an effective treatment against hypercalcemia caused by metastatic parathyroid carcinomas that are unresponsive to conventional treatments.

Reversible cerebral vasoconstriction syndrome: the importance of follow-up imaging within 2 weeks.

AIM: In patients with thunderclap headaches, reversible cerebral vasoconstriction syndrome (RCVS) should be considered as a differential diagnosis. However, RCVS diagnosis in the emergency department (ED) remains challenging. This report describes the clinical features and factors related to RCVS diagnosis and suggests diagnostic strategies for its management. METHODS: We retrospectively reviewed the medical records of eight patients diagnosed with RCVS from January 2010 to March 2019 (aged 18-69 years, 5 women). RESULTS: The median duration from the ED visit to RCVS diagnosis was 6 days (range, 1-11 days). Of the eight patients, seven were middle-aged, six had apparent triggers, six had subarachnoid hemorrhage (SAH), five had high systolic blood pressure, and none had any specific abnormality observed upon physical examination. At the initial visit, RCVS was diagnosed in only one patient who had a history of RCVS. Of the other patients, SAH was diagnosed in two, and primary headache was diagnosed in four patients with negative computed tomography (CT) findings. Based on follow-up angiography (e.g., magnetic resonance angiography), seven of eight patients with convexal SAH were diagnosed with RCVS (as the cause of SAH). CONCLUSION: Reversible cerebral vasoconstriction syndrome with negative CT findings at the ED visit was likely to be misdiagnosed as a primary headache. In patients with thunderclap headache and negative CT findings, physicians should consider RCVS as a differential diagnosis, inform patients of the risk of RCVS, and undertake follow-up imaging within 2 weeks.

Impact of non-pharmaceutical interventions for the COVID-19 pandemic on emergency department patient trends in Japan: a retrospective analysis.

AIM: The coronavirus disease (COVID-19) pandemic massively impacted emergency department (ED) visits. The unavailability of specific therapies or vaccines has made non-pharmaceutical interventions (NPIs) an alternative strategy for COVID-19. We assessed the impact of NPIs (nationwide school closures and state of emergency) on ED visits during the COVID-19 pandemic in Japan. METHODS: This retrospective study compared the trends in ED visits from 1 January to 25 May, 2020 (during the pandemic) with the average during 2015-2019 (before the pandemic). The primary end-point was the change in the number of ED visits during the COVID-19 pandemic with those from before the pandemic, with the NPI application stratified across four periods in 2020: Period 0 (1-15 January), no COVID-19 cases detected in Japan; Period I (16 January-1 March), initial COVID-19 outbreak; Period II (2 March-15 April), nationwide school closures; Period III (16 April-25 May), state of emergency. RESULTS: Compared with before the pandemic, the number of walk-in ED visits significantly decreased by 23.1%, 12.4%, and 24.0% (4,047 versus 3,111; 3,211 versus 2,813; and 3,384 versus 2,573; P < 0.001 for all) in Periods I, II, and III, respectively. The number of ambulance ED visits during the pandemic significantly increased by 8.3% in Period I (1,814 versus 1,964, P = 0.002), whereas there was no significant change in Periods II and III with 2.7% and -3.1% (1,547 versus 1,589 and 1,389 versus 1,346; P = 0.335 and P = 0.284, respectively). CONCLUSIONS: The application of an NPI during the COVID-19 pandemic could have significantly reduced patient attendance in the ED.

Protective effects of a cystine and theanine mixture against acute radiation injury in rats.

This study aims to examine the effects of cystine and theanine (CT), which increases glutathione biosynthesis, on the survival rate and acute radiation injury of the small intestine and bone marrow using a rat model. CT pre-treatment (280 mg/kg for 5 days) significantly improved weight loss and survival rate of rats as compared with the control group after 5 Gy. CT pre-treatment significantly increased the rate of mucosa and crypt length, and decreased the number of apoptotic cells, TUNEL and cleaved caspase-3 positive cells, while increasing the number of mitotic cells and Ki-67 positive cells in jejunal crypts and villi compared to control rats post-irradiation. CT also suppressed bone marrow cell loss and reduced the number of apoptotic cells in bone marrow. These results suggest a protective effect of CT pre-treatment for acute injury after irradiation through apoptosis inhibition and increased proliferative activity in jejunal crypt cells and bone marrow cells.

Growth of persistent foci of DNA damage checkpoint factors is essential for amplification of G1 checkpoint signaling.

Several DNA damage checkpoint factors form nuclear foci in response to ionizing radiation (IR). Although the number of the initial foci decreases concomitantly with DNA double-strand break repair, some fraction of foci persists. To date, the physiological role of the persistent foci has been poorly understood. Here we examined foci of Ser1981-phosphorylated ATM in normal human diploid cells exposed to 1Gy of X-rays. While the initial foci size was approximately 0.6microm, the one or two of persistent focus (foci) grew, whose diameter reached 1.6microm or more in diameter at 24h after IR. All of the grown persistent foci of phosphorylated ATM colocalized with the persistent foci of Ser139-phosphorylated histone H2AX, MDC1, 53BP1, and NBS1, which also grew similarly. When G0-synchronized normal human cells were released immediately after 1Gy of X-rays and incubated for 24h, the grown large phosphorylated ATM foci (> or =1.6microm) were rarely (av. 0.9%) observed in S phase cells, while smaller foci (<1.6microm) were frequently (av. 45.9%) found. We observed significant phosphorylation of p53 at Ser15 in cells with a single grown phosphorylated ATM focus. Furthermore, persistent inhibition of foci growth of phosphorylated ATM by an ATM inhibitor, KU55933, completely abrogated p53 phosphorylation. Defective growth of the persistent IR-induced foci was observed in primary fibroblasts derived from ataxia-telangiectasia (AT) and Nijmegen breakage syndrome (NBS) patients, which were abnormal in IR-induced G1 checkpoint. These results indicate that the growth of the persistent foci of the DNA damage checkpoint factors plays a pivotal role in G1 arrest, which amplifies G1 checkpoint signals sufficiently for phosphorylating p53 in cells with a limited number of remaining foci.

Association of cellular localization of glycogen synthase kinase 3beta in the digestive tract with cancer development.

Glycogen synthase kinase 3beta (GSK-3beta) is a multifunctional serine/threonine kinase involved in several signaling pathways. Recently, we reported the polarized localization of GSK-3beta on the apical membrane of normal colon epithelium. To investigate the functions of this molecule, we studied stomach and colorectal cancer tissues. In normal simple columnar epithelium, GSK-3beta was localized with tight junction-associated protein ZO-1 in a single line at the apical cell border. GSK-3beta and ZO-1 were localized in the apical regions of tubular adenocarcinoma, similar to their localization in normal epithelium; however, their localization was different at the invasive front of the cancer and was found to be associated with lymphatic invasion. In signet-ring cell carcinoma of the stomach, the expression of these proteins was reduced and dot-like expression was observed in each cell of the signet-ring cell carcinoma. We speculated that GSK-3beta is involved in glandular structure formation and that the non-apical localization of membrane-localized GSK-3beta in tubular adenocarcinoma is associated with cancer development.

Expression patterns of angiopoietin-1, -2, and tie-2 receptor in ulcerative colitis support involvement of the angiopoietin/tie pathway in the progression of ulcerative colitis.

The active stage of ulcerative colitis (UC) involves transmigration of polymorphonuclear (PMN) cells to colonic epithelia. The angiopoietin (Ang) pathway plays a role as the regulator of PMN transmigration. To clarify the role of the Ang/Tie pathway in the activation of UC, especially in cypt abscess formation, 67 tissue samples were obtained from patients with UC and ten controls without UC for immunohistochemical analysis for the expression of Ang-1, -2, or Tie-2. The epithelia of crypt abscess was strongly positive for Ang-1 and -2 for all 57 samples derived from patients with active UC, though the colorectal epithelium without crypt abscess showed minimal expression of Ang-1, -2, and Tie-2. Numerous transepithelial migrating PMN cells in crypt abscesses also expressed Tie-2. The specimens of UC patients in remission showed significantly less immunoreactivity for Ang-1, -2, or Tie-2. These findings suggest that the Ang/Tie pathway may play a role in the progression of UC.

Toll-like receptors in innate immunity: role of bacterial endotoxin and toll-like receptor 4 in endometrium and endometriosis.

Macrophages, dendritic cells, and Toll-like receptors (TLRs) are integral components of the innate immune system. This rapidly reactive system responds immediately to infectious or other non-self agents, thereby inducing an inflammatory response to protect the host until the activation of the slower adaptive immune system. The fundamentals of the innate immune system, functional characteristics of TLRs, and signaling pathways of TLR4 are discussed for the easy understanding by readers. Studies showed that the growth and progression of endometriosis continue even in ovariectomized animals. This indicates that besides ovarian steroid hormones, the growth of endometriosis can be regulated by the innate immune system in the pelvic environment. As a component of the innate immune system, increased infiltration of macrophages has been described in the intact tissue and peritoneal fluid of women with endometriosis. In this review article, we discuss the role of bacterial endotoxin and TLR4 in endometrium and endometriosis and outline the involvement of endotoxin in causing adverse reproductive outcome.

Paraplesia after surfing in a young female novice surfer: a case report on surfer's myelopathy.

BACKGROUND: Surfer's myelopathy is a non-traumatic spinal cord injury that was first described in a publication in 2004. However, most emergency physicians are not familiar with this rare disease. CASE PRESENTATION: The patient was a 19-year-old female novice surfer. She had experienced back discomfort without trauma during her surfing lessons. The discomfort turned to dysesthesia of both legs. She could not walk after 1 h and was brought to our hospital. Physical examination revealed weakness and dysesthesia of both legs, absent deep tendon reflexes, bilaterally positive Babinski reflex, and bladder and rectal disturbance. Spine magnetic resonance imaging revealed T2 prolongation from T7 to the medullary cone. She was diagnosed with surfer's myelopathy and treated conservatively. She recovered well and was discharged on day 28. CONCLUSION: Emergency physicians must be better informed about surfer's myelopathy. Novice surfers and instructors should be educated on the early signs and symptoms of this condition.

Gastric mucormycosis complicated by a gastropleural fistula: A case report and review of the literature.

RATIONALE: Mucormycosis is a rare opportunistic fungal infection with poor prognosis. The incidence of mucormycosis has been increasing, and it is a threat to immunocompromised hosts. We present a case of gastric mucormycosis complicated by a gastropleural fistula during immunosuppressive treatment for adult-onset Still disease (AOSD). PATIENT CONCERNS: An 82-year-old woman diagnosed with AOSD who developed gastric ulcers during the administration of an immunosuppressive therapy with corticosteroids, cyclosporine, and tocilizumab complained of melena and epigastralgia. Esophagogastroduodenoscopy showed multiple ulcers covered with grayish or greenish exudates. DIAGNOSES: The patient diagnosed with mucormycosis based on culture and biopsy of the ulcers, which showed nonseptate hyphae branching at wide angles. Mucor indicus was identified using polymerase chain reaction. INTERVENTIONS AND OUTCOMES: Although liposomal amphotericin B was administered, gastric mucormycosis was found to be complicated by a gastropleural fistula. The patient died because of pneumonia due to cytomegalovirus infection, and autopsy revealed the presence of Mucorales around the fistula connecting the stomach and diaphragm. LESSONS: Gastric mucormycosis is refractory to treatment and fatal. Surgical resection, if possible, along with antifungal drugs can result in better outcomes.

Foci formation of P53-binding protein 1 in thyroid tumors: activation of genomic instability during thyroid carcinogenesis.

Defective DNA damage response (DDR) can result in genomic instability (GIN) and lead to the transformation into cancer. P53-binding protein 1 (53BP1) belongs to a family of evolutionarily conserved DDR proteins. Because 53BP1 molecules localize at the sites of DNA double strand breaks (DSBs) and rapidly form nuclear foci, the presence of 53BP1 foci can be considered as a cytologic marker for endogenous DSBs reflecting GIN. Although it has been proposed that GIN has a crucial role in the progression of thyroid neoplasms, the significance of GIN during thyroid tumorigenesis remains unclear, particularly in patients. We analyzed, therefore, the level of GIN, as detected with immunofluorescence of 53BP1, in 40 cases of resected thyroid tissues. This study demonstrated a number of nuclear 53BP1 foci in thyroid cancers, suggesting a constitutive activation of DDR in thyroid cancer cells. Because follicular adenoma also showed a few 53BP1 nuclear foci, GIN might be induced at a precancerous stage of thyroid tumorigenesis. Furthermore, high-grade thyroid cancers prominently exhibited an intense and heterogeneous nuclear staining of 53BP1 immunoreactivity, which was also observed in radiation-associated cancers and in mouse colonic crypts as a delayed response to a high dose ionizing radiation, suggesting increased GIN with progression of cancer. Thus, the present study demonstrated a difference in the staining pattern of 53BP1 during thyroid carcinogenesis. We propose that immunofluorescence analysis of 53BP1 expression can be a useful tool to estimate the level of GIN and, simultaneously, the malignant potency of human thyroid tumors.

Incidence of multiple primary cancers in Nagasaki atomic bomb survivors: association with radiation exposure.

To assess the effects of atomic bomb radiation on the incidence of multiple primary cancers (MPC), we analyzed the association between the incidence of second primary cancers in survivors of the atomic bombing of Nagasaki, and exposure distance. The incidence rate (IR) of a second primary cancer was calculated and stratified by the distance from the hypocenter and age at the time of bombing for the years 1968 through 1999. The IR of the first primary cancer was also calculated and compared with the second primary cancer to determine whether atomic bomb radiation was associated with the multiplicity of tumors. There were 511 confirmed cases of MPC in the 7572 cancer-bearing survivors. The crude IR was 27.6 per 100,000 person-years. The IR of second primaries decreased significantly with increasing distance from the hypocenter: relative risk, 0.89 per 1.0 km; 95% confidence interval, 0.84-0.94. A significant decrease was also noted for those of older ages at the time of the bombing, based on the attained age of the second primary cancer: relative risk, 0.91 per 1 year; 95% confidence interval, 0.90-0.92. These findings suggest that the radiation has affected the incidence of MPC. Furthermore, when compared with the first primary cancer, a stronger distance effect was suggested on the occurrence of a second primary cancer in the survivors. The present study suggests the significance of atomic bomb radiation on MPC in the survivors. These results on the incidence of MPC in the tumor-bearing survivors and its correlations with the atomic bombing of 62 years ago are described for the first time in this report.