Changes in Cerebrospinal Fluid Interleukin-6 Levels after Surgical Treatment of Subarachnoid Hemorrhage.

BACKGROUND: We measured postoperative changes in cerebrospinal fluid (CSF) interleukin (IL)-6 levels in subarachnoid hemorrhage (SAH) due to aneurysm rupture and examined factors associated with outcomes and cerebral vasospasm. We used physiologic saline or artificial CSF as the intraoperative irrigation fluid and examined the differences. METHODS: The participants were 16 men and 41 women who were transported to our facility for SAH and underwent surgical treatment during the period from February 2012 through March 2015. In terms of severity, 31 cases were World Federation of Neurological Surgeons (WFNS) grade I-III and 26 cases were grade IV-V. All cases underwent clipping. Physiologic saline and artificial CSF were used as intraoperative irrigation fluid. We placed a ventricular drainage tube intraoperatively and collected CSF daily from postoperative day (POD) 1 through 10 or until drain removal. RESULTS: IL-6 level varied from 74 pg/mL to 407,936 pg/mL and peaked on PODs 1 and 5. Patients with favorable outcomes had significantly lower postoperative IL-6 levels. POD 1 IL-6 level significantly differed in relation to the presence of cerebral vasospasm but was not associated with its timing or severity. Use of artificial CSF was associated with a significantly lower incidence of cerebral vasospasm. Age and WFNS grade were significantly associated with outcome, and use of artificial CSF had a tendency toward favorable outcomes. CONCLUSIONS: Artificial CSF is a potentially useful intervention when managing subarachnoid hemorrhage.

Treatment of Geriatric Traumatic Brain Injury: A Nationwide Cohort Study.

BACKGROUND: Because of the aging of the Japanese population, traumatic brain injuries (TBI) have increased in elderly adults. However, the effectiveness and prognosis of intensive treatment for geriatric TBI have not yet been determined. Thus, we used nationwide data from the Japan Neurotrauma Data Bank (JNTDB) projects to analyze prognostic factors for intensive and aggressive treatments. METHODS: We analyzed 1,879 geriatric TBI cases (age ≥65 years) registered in four JNTDB projects: Project 1998 (P1998) to Project 2015 (P2015). Clinical features, use of aggressive treatment, and 6-month outcomes on the Glasgow Outcome Scale (GOS) were compared among study projects. Logistic regression was used to identify prognostic factors in aggressively treated patients. RESULTS: The percentage of geriatric TBI cases significantly increased with time-P1998: 30.1%; Project 2004 (P2004): 34.6%; Project 2009 (P2009): 43.9%; P2015: 53.6%, p<0.0001). Use of aggressive treatment also significantly increased, from 67.0% in P1998 to 69.3% in P2015 (p<0.0001). Less invasive methods, such as trepanation and normothermic targeted temperature management, were more often chosen for geriatric patients. These efforts resulted in a significant decrease in the 6-month mortality rate, from 76.2% in P1998 to 63.1% in P2015 (p=0.0003), although the percentage of severely disabled patients increased, from 8.9% in P1998 to 11.1% in P2015 (p=0.0003). Intraventricular hemorrhage was the factor most strongly associated with unfavorable 6-month outcomes (OR 3.79, 95% CI 1.78-8.06, p<0.0001). CONCLUSIONS: Less invasive treatments reduced mortality in geriatric TBI but did not improve functional outcomes. Patient age was not the strongest prognostic factor; thus, physicians should consider characteristics other than age.

[Two Cases of Long-Term Control of Advanced Gastric Cancer Treated with>35 Cycles of Low-Dose Nab-Paclitaxel].

Nanoparticle albumin-bound paclitaxel(nab-PTX)is effective as second-line chemotherapy for advanced gastric cancer. Long-term administration is generally impossible because of peripheral sensory neuropathy. However, we report 2 cases that were treated with>35 cycles of nab-PTX with dose reduction to control disease progression, which appears to be the highest number cycles so far reported. Case 1 was a male patient in his 70s, with distant lymph node metastases and an advanced primary lesion(tub2). He received 6 cycles S-1/CDDP and achieved a partial response; however, the treatment was changed to second-line chemotherapy with nab-PTX because of adverse effects; the dose of nab-PTX was reduced by 60% every 3 weeks. At the time of writing, 36 cycles have been administered and disease control has been maintained, with Grade 2 peripheral sensory neuropathy. Case 2 was another male patient in his 70s, who underwent total gastrectomy for gastric cancer(mucinous adenocarcinoma). Virchow metastasis was detected 6months after surgery. He received 1 cycle S-1/CDDP and achieved a partial response; however, treatment was changed to second-line chemotherapy with nab-PTX because of adverse effects; the dose of nab-PTX was reduced by 60% every 3 weeks. At the time of writing, 41 cycles have been administered and disease control has been maintained, with Grade 2 peripheral sensory neuropathy.

[A Case of Large-Cell Neuroendocrine Carcinoma of the Stomach with Multiple Liver Metastases That Show Complete Response to Multidisciplinary Therapy].

A 64-year-old man was diagnosed with advanced gastric cancer based on an endoscopic examination in June 2009; histological findings indicated poorly differentiated adenocarcinoma.Computed tomography revealed multiple liver metastases and bulky lymph node metastases of LN#7.The multiple liver metastases of the gastric cancer were not considered to be candidates for surgical resection, and S-1/CDDP chemotherapy was initiated in July 2009. After 6 courses of this regimen, liver and lymph node metastases showed partial response(PR), but the gastric tumor showed progressive disease(PD).Therefore, we switched this regimen to bi-weekly CPT-11/CDDP in March 2010. However, because the gastric tumor had increased in size and presented with bleeding, we performed distal gastrectomy.The pathological diagnosis based on the resected speci- men was large-cell neuroendocrine carcinoma.After surgery, CPT-11/CDDP was continued but was switched to CPT-11 in June 2011 because of induced renal dysfunction.In November 2011, the regimen was switched to weekly paclitaxel because of a progressive increase in size of a solitary liver metastatic lesion located in S4-5.Two courses of this regimen were administered, but they were ineffective; therefore, we performed partial hepatectomy.No other recurrent lesions were observed during the surgery, and the patient was estimated to have achieved complete response(CR).After the surgery, no further adjuvant chemotherapy was administered.Four years after hepatectomy, the patient was diagnosed with esophageal cancer but exhibited no recurrence of the gastric cancer.We performed esophagectomy for the esophageal cancer in May 2016.T he patient is currently well without any relapse.

A retrospective study of the effect of fibrinogen levels during fresh frozen plasma transfusion in patients with traumatic brain injury.

BACKGROUND: The association between traumatic brain injury (TBI) and coagulopathy is well established. While coagulopathy prophylaxis in TBI involves replenishing coagulation factors with fresh frozen plasma (FFP), its effectiveness is controversial. We investigated the relationship between plasma fibrinogen concentration 3 h after initiating FFP transfusion and outcomes and evaluated the correlation with D-dimer levels at admission. METHODS: We retrospectively examined data from 380 patients with severe isolated TBI with blood samples collected a maximum of 1 h following injury. Plasma fibrinogen and D-dimer concentrations were obtained at admission, and plasma fibrinogen concentration was again assessed 3-4 h following injury. The patients were divided into two groups based on whether or not they received FFP transfusion. Patients were also divided into subgroups according their fibrinogen level: ≥ 150 mg/dL (high-fibrinogen subgroup) or < 150 mg/dL (low-fibrinogen subgroup) 3 h after injury. Demographic, clinical, radiological and laboratory data were compared between these subgroups. RESULTS: Glasgow Outcome Scale (GOS) scores at discharge and 3 months after injury were significantly lower in the FFP transfusion group than in the FFP non-transfusion group. Among patients who received FFP, GOS scores at discharge and 3 months after injury were significantly higher in the high-fibrinogen subgroup than in the low-fibrinogen subgroup. Elevated admission D-dimer predicted subsequent fibrinogen decrease. CONCLUSIONS: In FFP transfusion, fibrinogen level ≥ 150 mg/dL 3 h after injury was associated with better outcomes in TBI patients. Assessing the admission D-dimer and tracking the fibrinogen are crucial for optimal coagulopathy prophylaxis in TBI patients.

Feasibility of Human Neural Stem Cell Transplantation for the Treatment of Acute Subdural Hematoma in a Rat Model: A Pilot Study.

Human neural stem cells (hNSCs) transplantation in several brain injury models has established their therapeutic potential. However, the feasibility of hNSCs transplantation is still not clear for acute subdural hematoma (ASDH) brain injury that needs external decompression. Thus, the aim of this pilot study was to test feasibility using a rat ASDH decompression model with two clinically relevant transplantation methods. Two different methods, in situ stereotactic injection and hNSC-embedded matrix seating on the brain surface, were attempted. Athymic rats were randomized to uninjured or ASDH groups (F344/NJcl-rnu/rnu, n = 7-10/group). Animals in injury group were subjected to ASDH, and received decompressive craniectomy and 1-week after decompression surgery were transplanted with green fluorescent protein (GFP)-transduced hNSCs using one of two approaches. Histopathological examinations at 4 and 8 weeks showed that the GFP-positive hNSCs survived in injured brain tissue, extended neurite-like projections resembling neural dendrites. The in situ transplantation group had greater engraftment of hNSCs than matrix embedding approach. Immunohistochemistry with doublecortin, NeuN, and GFAP at 8 weeks after transplantation showed that transplanted hNSCs remained as immature neurons and did not differentiate toward to glial cell lines. Motor function was assessed with rotarod, compared to control group (n = 10). The latency to fall from the rotarod in hNSC in situ transplanted rats was significantly higher than in control rats (median, 113 s in hNSC vs. 69 s in control, P = 0.02). This study first demonstrates the robust engraftment of in situ transplanted hNSCs in a clinically-relevant ASDH decompression rat model. Further preclinical studies with longer study duration are warranted to verify the effectiveness of hNSC transplantation in amelioration of TBI induced deficits.

Quantitative pupillometry and neuron-specific enolase independently predict return of spontaneous circulation following cardiogenic out-of-hospital cardiac arrest: a prospective pilot study.

This study aimed to identify neurological and pathophysiological factors that predicted return of spontaneous circulation (ROSC) among patients with out-of-hospital cardiac arrest (OHCA). This prospective 1-year observational study evaluated patients with cardiogenic OHCA who were admitted to a tertiary medical center, Nippon Medical School Hospital. Physiological and neurological examinations were performed at admission for quantitative infrared pupillometry (measured with NPi-200, NeurOptics, CA, USA), arterial blood gas, and blood chemistry. Simultaneous blood samples were also collected to determine levels of neuron-specific enolase (NSE), S-100b, phosphorylated neurofilament heavy subunit, and interleukin-6. In-hospital standard advanced cardiac life support was performed for 30 minutes.The ROSC (n = 26) and non-ROSC (n = 26) groups were compared, which a revealed significantly higher pupillary light reflex ratio, which was defined as the percent change between maximum pupil diameter before light stimuli and minimum pupil diameter after light stimuli, in the ROSC group (median: 1.3% [interquartile range (IQR): 0.0-2.0%] vs. non-ROSC: (median: 0%), (Cut-off: 0.63%). Furthermore, NSE provided the great sensitivity and specificity for predicting ROSC, with an area under the receiver operating characteristic curve of 0.86, which was created by plotting sensitivity and 1-specificity. Multivariable logistic regression analyses revealed that the independent predictors of ROSC were maximum pupillary diameter (odds ratio: 0.25, 95% confidence interval: 0.07-0.94, P = 0.04) and NSE at admission (odds ratio: 0.96, 95% confidence interval: 0.93-0.99, P = 0.04). Pupillary diameter was also significantly correlated with NSE concentrations (r = 0.31, P = 0.027). Conclusively, the strongest predictors of ROSC among patients with OHCA were accurate pupillary diameter and a neuronal biomarker, NSE. Quantitative pupillometry may help guide the decision to terminate resuscitation in emergency departments using a neuropathological rationale. Further large-scale studies are needed.

Brain Death in Pediatric Patients in Japan: Diagnosis and Unresolved Issues.

Brain death (BD) is a physiological state defined as complete and irreversible loss of brain function. Organ transplantation from a patient with BD is controversial in Japan because there are two classifications of BD: legal BD in which the organs can be donated and general BD in which the organs cannot be donated. The significance of BD in the terminal phase remains in the realm of scientific debate. As indicated by the increasing number of organ transplants from brain-dead donors, certain clinical diagnosis for determining BD in adults is becoming established. However, regardless of whether or not organ transplantation is involved, there are many unresolved issues regarding BD in children. Here, we will discuss the historical background of BD determination in children, pediatric emergencies and BD, and unresolved issues related to pediatric BD.

Outcome and Refractory Factor of Intensive Treatment for Geriatric Traumatic Brain Injury: Analysis of 1165 Cases Registered in the Japan Neurotrauma Data Bank.

OBJECTIVE: With the increase in the aged population, geriatric traumatic brain injury (gTBI) is also rapidly increasing in Japan. There is thus a need to review the effect of intensive treatments for gTBIs. The aim of this study was 1) to assess how intensive treatments influenced patient outcome and 2) to identify the refractory factor against these intensive treatments in gTBI, from the Japan Neurotrauma Data Bank (JNTDB). METHODS: Of all 3194 patients in the JNTDB, 1165 (≥ 65 years old) with severe gTBIs were enrolled in this study. The clinical features and their outcomes based on the Glasgow Outcome Scale on discharge and 6 months after injury were compared. RESULTS: Intensive treatments were administered to 71.4% of all patients with severe gTBI showing a significant increase over 15 years. Accordingly, mortality decreased significantly (from 62.7% to 51.1%, P = 0.001). On the other hand, severely disabled dependent survivors, who need daily help from others for living, increased accordingly (from 63.2% to 68.4%). The existence of intraventricular hemorrhage (IVH) rather than the patient's age was identified as the strongest refractory factor (odds ratio, 5.762; 95% confidence interval, 1.317-25.216) against intensive treatment. CONCLUSIONS: This study clarified that 1) intensive treatments are associated with higher survival rates (however, they also increase the incidence of severely disabled survivors) and 2) the strongest refractory factor for intensive treatment in cases of severe gTBI was not age but the existence of IVH. These results warrant further establishment of a seamless strategy for both the acute and the chronic phase of gTBI.

The Effects of Xanthine Oxidoreductase Inhibitors on Oxidative Stress Markers following Global Brain Ischemia Reperfusion Injury in C57BL/6 Mice.

We demonstrated that 3-nitrotyrosine and 4-hydroxy-2-nonenal levels in mouse brain were elevated from 1 h until 8 h after global brain ischemia for 14 min induced with the 3-vessel occlusion model; this result indicates that ischemia reperfusion injury generated oxidative stress. Reactive oxygen species production was observed not only in the hippocampal region, but also in the cortical region. We further evaluated the neuroprotective effect of xanthine oxidoreductase inhibitors in the mouse 3-vessel occlusion model by analyzing changes in the expression of genes regulated by the transcription factor nuclear factor-kappa B (including pro-inflammatory cytokines interleukin-1ß (IL-1ß) and tumor necrosis factor-α (TNF-α), matrix metalloproteinase-9 and intercellular adhesion molecules-1). Administration of allopurinol resulted in a statistically significant decrease in IL-1ß and TNF-α mRNA expression, whereas febuxostat had no significant effect on expression of these genes; nevertheless, both inhibitors effectively reduced serum uric acid concentration. It is suggested that the neuroprotective effect of allopurinol is derived not from inhibition of reactive oxygen species production by xanthine oxidoreductase, but rather from a direct free-radical-scavenging effect.

Pathophysiology of microwave-induced traumatic brain injury.

Microwave technology has been widely used in numerous applications; however, excessive microwave exposure causes adverse effects, particularly in the brain. The present study aimed to evaluate the change in the number of neural cells and presence of apoptotic cells in rats for one month after exposure to excessive microwave radiation. The rats were exposed to 3.0 kW of microwaves for 0.1 sec and were sacrificed after 24 h (n=3), or 3 (n=3), 7 (n=3), 14 (n=3) or 28 days (n=4) of exposure. The neural cells were counted in the motor cortex and hippocampus [cornu ammonis 1 (CA1) and CA2] and the percentage of positive cells stained with terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate nick-end labeling (TUNEL) were also measured, which detected apoptotic cell death in the choroid plexus in the lateral ventricle, motor cortex and hippocampus. In the CA1, the number of neural cells decreased significantly by day 28 compared with that in the control (60.7 vs. 50.6, P=0.0358), but did not decrease before day 28. There were no significant differences on any day in the CA2 and the motor cortex. The number of cells showed a significant increase on day 7 compared to the control in the choroid plexus (2.1±1.1 vs. 21.8±19.1%, P=0.0318). There were no significant differences from the controls in the percentage of TUNEL-positive cells in the motor cortex and hippocampus. The effects of microwave exposure on the brain remain unclear; however, microwave-induced neurotrauma shows the same pathological changes as blast traumatic brain injury.

Evaluation of neuronal protective effects of xanthine oxidoreductase inhibitors on severe whole-brain ischemia in mouse model and analysis of xanthine oxidoreductase activity in the mouse brain.

Global cerebral ischemia and reperfusion (I/R) often result in high mortality. Free radicals play an important role in global cerebral I/R. Xanthine oxidoreductase (XOR) inhibitors, such as allopurinol, have been reported to protect tissues from damage caused by reactive oxygen species (ROS) by inhibiting its production through XOR inhibition. The recently introduced XOR inhibitor febuxostat, which is a more potent inhibitor than allopurinol, is expected to decrease free radical production more effectively. Here, we analyzed the effects of allopurinol and febuxostat in decreasing global severe cerebral I/R damage in mice. Mice were divided into three groups: a placebo group, an allopurinol group, and a febuxostat group. Pathological examinations, which were performed in each group in the CA1 and CA2 regions of the hippocampus 4 days after I/R surgery, revealed that there was a decrease in the number of neuronal cells in the 14-min occlusion model in both regions and that drugs that were administered to prevent this damage were not effective. The enzymatic activity was extremely low in the mouse brain, and XOR could not be detected in the nonischemic and ischemic mice brains with western blot analyses. Thus, one of the reasons for the decreased effectiveness of XOR inhibitors in controlling severe whole-brain ischemia in a mouse model was the low levels of expression of XOR in the mouse brain.

Association between serum lactate levels and early neurogenic pulmonary edema after nontraumatic subarachnoid hemorrhage.

BACKGROUND AND PURPOSE: Few studies have described the risk factors associated with the development of neurological pulmonary edema (NPE) after subarachnoid hemorrhage (SAH). We have hypothesized that acute-phase increases in serum lactate levels are associated with the early development of NPE following SAH. The aim of this study was to clarify the association between lactic acidosis and NPE in patients with nontraumatic SAH. METHODS: We retrospectively evaluated 140 patients with nontraumatic SAH who were directly transported to the Nippon Medical School Hospital emergency room by the emergency medical services. We compared patients in whom NPE developed (NPE group) and those in whom it did not (non-NPE group). RESULTS: The median (quartiles 1-3) arrival time at the hospital was 32 minutes (28-38 minutes) after the emergency call was received. Although the characteristics of the NPE and non-NPE groups, including mean arterial pressure (121.3 [109.0-144.5] and 124.6 [108.7-142.6] mm Hg, respectively; P=0.96), were similar, the median pH and the bicarbonate ion (HCO3(-)) concentrations were significantly lower in the NPE group than in the non-NPE group (pH, 7.33 [7.28-7.37] vs. 7.39 [7.35-7.43]); P=0.002; HCO3(-), 20.8 [18.6-22.6] vs. 22.8 [20.9-24.7] mmol/L; P=0.01). The lactate concentration was significantly higher in the NPE group (54.0 [40.3-61.0] mg/dL) than in the non-NPE group (28.0 [17.0-37.5] mg/dL; P<0.001). Multivariable regression analysis indicated that younger age and higher glucose and lactate levels were significantly associated with the early onset of NPE in patients with SAH. CONCLUSION: The present findings indicate that an increased serum lactate level, occurring within 1 hour of the ictus, is an independent factor associated with the early onset of NPE. Multicenter prospective studies are required to confirm our results.

GATA-dependent regulation of TPO-induced c-mpl gene expression during megakaryopoiesis.

Thrombopoietin (TPO) and its receptor, c-Mpl, play the crucial role during megakaryocytopoiesis. Previously, we have shown that the promoter activity of c-mpl induced by TPO is modulated by transcription through a PKC-dependent pathway and that GATA(-77) is involved as a positive regulatory element in TPO-induced c-mpl gene expression in the megakaryoblastic CMK cells. In this research, to examine participating possibility of GATA promoter element in TPO- induced c-mpl gene expression through a PKC-independent pathway, the promoter activity of site-directed mutagenesis and the effect of potein kinase C modulator were measured by a transient transfection assay system. Together with our previous results on the TPO-induced c-mpl promoter, this study indicates destruction of -77GATA in c-mpl promoter decreased the activity by 47.3% under existence of GF109203. These results suggest that GATA promoter element plays significant role in TPO-induced c-mpl gene expression through a PKC-independent pathway.

Phosphorylation of Thr(1495) of nestin in a mouse model of cerebral ischemia and reperfusion damage.

Nestin, a class VI intermediate filament protein, is expressed by neuronal progenitor cells in the subventricular zone (SVZ). In the present study, we analyzed the nestin expression and phosphorylation levels in nerve cells in a mouse model of cerebral ischemia and reperfusion. C57BL/6 mice were subjected to three-vessel occlusion for 14 min, and were killed either 1 or 4 days after the procedure. The percentages of cells in the SVZ that were positive for nestin, Thr(1495)-phosphorylated nestin or Ki67 did not significantly differ between the ischemic reperfusion and sham groups. Conversely, in the striatum and cornu ammonis 2 (CA2) regions, the mice at 4 days after ischemic reperfusion showed significantly higher numbers and percentages of nerve cells that were positive for nestin, Thr(1495)-phosphorylated nestin and Ki67 compared to results from the other groups. To our knowledge, this is the first description of phosphorylated nestin expression in neural progenitor cells in the SVZ of adult mice. In this cerebral ischemia and reperfusion mouse model, cells positive for Thr(1495)-phosphorylated nestin were increased in the striatum and CA2 field of the hippocampus; suggesting that nestin phosphorylation may play an important role in mitotically active neuronal progenitor cells.

Traumatic cerebrovascular injury following severe head injury: proper diagnostic timetable and examination methods.

Traumatic cerebrovascular injury (TCVI) is a serious complication of severe head injury, with a high mortality rate. To establish a proper treatment strategy for TCVI, we investigated patients with a high risk of TCVI according to the Guidelines for the Management of Severe Head Injury (hereafter "the Guidelines") to elucidate the validity of the criteria for TCVI in the Guidelines and the appropriate screening timing and methods. Of those transported to our facility between December 2008 and June 2012, 67 individuals with a high risk of TCVI were evaluated to reveal the proper timing and methods of vascular evaluation. Of the 67 patients, 21 had a diagnosis of TCVI based on cerebral angiography, three-dimensional computed tomography angiography (3DCTA), or magnetic resonance imaging (MRI), accounting for 6.4% of all patients with severe head injury and as high as 31.3% of patients with a high risk of TCVI according to the Guidelines. In addition, according to the Glasgow Outcome Scale (GOS), outcomes were three deaths due to primary brain injury, six cases of persistent vegetative state, five cases of severe disability, three cases of moderate disability, and four cases of good recovery. Although 3DCTA is a simple and convenient diagnostic method, cerebral angiography is necessary to evaluate dissecting lesions. If patients have any signs or symptoms of TCVI, as described in the Guidelines, cerebral angiography or 3DCTA should be performed as an initial screening method within 72 hours of admission, followed by cerebral angiography on postadmission Day 14 ± 2 to prevent failed diagnosis.

Role of promoter element in c-mpl gene expression induced by TPO.

Thrombopoietin (TPO) and its receptor, c-Mpl, play the crucial role for the development of megakaryocyte and considered to regulate megakaryocytopoiesis. Previously we reported that TPO increased the c-mpl promoter activity determined by a transient expression system using a vector containing the luciferase gene as a reporter and the expression of the c-mpl gene is modulated by transcription through a protein kinase C (PKC)-dependent pathway in the megakaryoblastic cells. In this research, to elucidate the required elements in c-mpl promoter, the promoter activity of the deletion constructs and site-directed mutagenesis were measured by a transient transfection assay system. Destruction of -77GATA in c-mpl promoter decreased the activity by 22.8%. Our study elucidated that -77GATA involved in TPO-induced c-mpl gene expression in a human megakaryoblastic cell line, CMK.

Countermeasures against chemical terrorism in Japan.

Japan has experienced numerous incidents of chemical disasters and terrorist attacks. Here we review the history of changes in countermeasures against such incidents. Since 2004, the Civil Protection Law, more formally known as the "Law Concerning the Measures for Protection of the People in Armed Attack Situations etc" was enacted to fully prepare the nation for chemical terrorism. According to this law, the Japanese government must carry out Civil Protection Exercises on an annual basis to gauge response. Problem areas that remain are chosen and addressed one by one until they are judged to be resolved in subsequent exercises.