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Background: Soluble fibrin (SF) is a form of fibrinogen that is activated by thrombin and is considered to be useful for the diagnosis of the prethrombotic state or thrombosis. Methods: Plasma levels of fibrin-related markers (FRMs), such as SF, D-dimer, fibrinogen, and fibrin degradation prioduct (FDP) levels in critically ill patients, were examined for the diagnosis of disseminated intravascular coagulation (DIC), venous thromboembolism (VTE), peripheral arterial thromboembolism (PATE), acute myocardial infarction (AMI), and acute cerebral infarction (ACI). Results: FRMs showed the usefulness in diagnosing DIC and VTE and the cutoff values of D-dimer, FDP, and SF for DIC were 7.2–7.8 μg/mL, 10.0 μg/mL, and 9.5 μg/mL, respectively. The cutoff values of D-dimer and FDP for VTE were similar to the 97.5th percentile values of healthy volunteers, while the cutoff value of SF was 6.9 μg/mL. In AMI and ACI, the cutoff values of D-dimer and FDP were lower than the 97.5 percentile values of healthy volunteers. A receiver operating characteristic analysis for all thrombosis cases showed that an adequate cutoff value in only SF among FRMs was higher than the confidence interval of healthy volunteers. Only SF had high sensitivity for thrombosis, as the FDP/SF ratio was markedly low for ACI, AMI and VTE. Conclusions: FRMs, especially D-dimer and FDP, were useful for diagnosing thrombosis with hyperfibrinolysis (e.g., DIC). As SF showed high sensitivity for predominantly thrombotic diseases, including arterial thrombosis, such as ACI and AMI, a high SF value suggests the possibility of an association with thrombosis. Finally, SF is the most useful marker for raising suspicion of an association with thrombosis, especially arterial thrombosis.

The present study aimed to identify useful biomarkers to predict deterioration in patients with coronavirus disease 2019 (COVID‑19). A total of 201 COVID‑19 patients were classified according to their disease severity into non‑severe (n=125) and severe (n=76) groups, and the behavior of laboratory biomarkers was examined according to the prognosis. Neutrophil count, aspartate aminotransferase (AST), alanine aminotransferase, lactate dehydrogenase (LDH), C‑reactive protein (CRP), sialylated carbohydrate antigen KL‑6 (KL‑6), procalcitonin (PCT), presepsin (PSP) and D‑dimer levels were significantly higher, and lymphocyte count and platelet count were significantly lower in the non‑severe group compared with the severe group. In the non‑severe group, ROC analysis demonstrated that only four biomarkers, CRP, PSP, AST and LDH were useful for differentiating the prognosis between improvement and deterioration subgroups. No strong correlation was revealed for any of the markers. Multivariate analysis identified CRP as a significant prognostic factor in non‑severe cases (odds ratio, 41.45; 95% confidence interval, 4.91‑349.24; P0.001). However, there were no blood biomarkers that could predict the outcome of patients in the severe group. Overall, several blood markers changed significantly according to disease severity in the course of COVID‑19 infection. Among them, CRP, PSP, LDH and AST were the most reliable markers for predicting the patient's prognosis in non‑severe COVID‑19 cases.

Although thrombosis in coronavirus disease 2019 (COVID-19) infection has attracted attention, the mechanism underlying its development remains unclear. The relationship between platelet activation and the severity of COVID-19 infection was compared with that involving other infections. Plasma soluble C-type lectin-like receptor 2 (sCLEC-2) levels were measured in 46 patients with COVID-19 infection and in 127 patients with other infections. The plasma sCLEC-2 levels in patients with COVID-19 infection {median (25th, 75th percentile), 489 (355, 668) ng/L} were significantly higher (p < 0.001) in comparison to patients suffering from other pneumonia {276 (183, 459) ng/L}, and the plasma sCLEC-2 levels of COVID-19 patients with severe {641 (406, 781) ng/L} or critical illness {776 (627, 860) ng/L} were significantly higher (p < 0.01, respectively) in comparison to those with mild illness {375 (278, 484) ng/L}. The ratio of the sCLEC-2 levels to platelets in COVID-19 patients with critical illness of infection was significantly higher (p < 0.01, p < 0.001 and p < 0.05, respectively) in comparison to COVID-19 patients with mild, moderate or severe illness. Plasma sCLEC-2 levels were significantly higher in patients with COVID-19 infection than in those with other infections, suggesting that platelet activation is triggered and facilitated by COVID-19 infection.

Background. The diagnostic criteria for disseminated intravascular coagulation (DIC) vary and are complicated and the cut-off values are different. Simple and quick diagnostic criteria for DIC are required in physicians for critical care. Material and methods. Platelet counts, prothrombin time–international normalized ratio (PT-INR) and D-dimer levels were examined in 1293 critical ill patients. Adequate cut-off values of these parameters were determined and a quick DIC score using these biomarkers was proposed. The quick DIC score was evaluated using a receiver operating characteristic (ROC) analysis. Results. Using the Japanese Ministry of Health, Labor and Welfare diagnostic criteria, 70 and 109 patients were diagnosed with DIC and pre-DIC, respectively. The ROC analysis of factors difference between DIC and non-DIC, revealed the following cut-off values: PT-INR, 1.20; platelet count, 12.0 × 1010/L and D-dimer, 10.0 μg/mL. Based on the above results, the quick DIC score system was proposed. All patients with DIC had a quick DIC score of 3, 4 or 5, and 85.3% of the patients with pre-DIC had a quick DIC score of ≥3 points. All patients with pre-DIC had a score of ≥2 points. In the ROC analysis, the area under the curve was 0.997 for DIC vs. non-DIC, and 0.984 for pre-DIC + DIC vs. non-DIC, and the cut-off value was 3 points for DIC and 2 points for DIC + pre-DIC. The quick DIC scores of non-survivors were significantly higher than those of survivors. Conclusions. The Quick DIC score system is a simple and useful tool that can be used for the diagnosis of DIC and pre-DIC. Further evaluation of the quick DIC score system in a large-scale study is required.

Object: Although many Japanese patients infected with coronavirus disease 2019 (COVID-19) only experience mild symptoms, in some cases a patient’s condition deteriorates, resulting in a poor outcome. This study examines the behavior of biomarkers in patients with mild to severe COVID-19. Methods: The disease severity of 152 COVID-19 patients was classified into mild, moderate I, moderate II, and severe, and the behavior of laboratory biomarkers was examined across these four disease stages. Results: The median age and male/female ratio increased with severity. The mortality rate was 12.5% in both moderate II and severe stages. Underlying diseases, which were not observed in 45% of mild stage patients, increased with severity. An ROC analysis showed that C-reactive protein (CRP), ferritin, procalcitonin (PCT), hemoglobin (Hb) A1c, albumin, and lactate dehydrogenase (LDH) levels were significantly useful for the differential diagnosis of mild/moderate I stage and moderate II/severe stage. In the severe stage, Hb levels, coagulation time, total protein, and albumin were significantly different on the day of worsening from those observed on the day of admission. The frequency of hemostatic biomarker abnormalities was high in the severe disease stage. Conclusion: The evaluation of severity is valuable, as the mortality rate was high in the moderate II and severe stages. The levels of CRP, ferritin, PCT, albumin, and LDH were useful markers of severity, and hemostatic abnormalities were frequently observed in patients in the severe disease stage.

Case Reversible cerebral vasoconstriction syndrome (RCVS) is an increasingly recognized and important cause of thunderclap headache. Delays in diagnosis may cause deterioration of symptoms and concomitant unnecessary investigations. However, the diagnosis of RCVS in the acute stage remains difficult. A 41-year-old man was admitted to the emergency department for severe, recurrent occipital headaches. The results of initial computed tomography and magnetic resonance imaging (MRI) of the brain and cerebrospinal fluid analysis were normal. Magnetic resonance angiography (MRA) showed multisegmental luminal stenosis of the basilar artery. Basi-parallel anatomical scanning (BPAS)-MRI, illustrating the outer contour of the vertebrobasilar artery, also showed multisegmental stenosis. Outcome The patient was speculated as having RCVS and was treated with oral lomerizine hydrochloride. Repeat MRA and BPAS-MRI 2 months later showed resolution, confirming RCVS. Conclusion Combined with MRA, BPAS-MRI is an effective and non-invasive imaging method for diagnosis of RCVS of the basilar artery.

Disseminated intravascular coagulation (DIC) is induced by excess activation coagulation, and activated platelets are also involved in pathogenesis. Therefore, plasma levels of soluble C-type lectin-like receptor 2 (sCLEC-2), a new marker for platelet activation, can be expected as a marker of DIC in critically ill patients. Plasma levels of sCLEC-2 and D-dimer were measured using the STACIA system. Plasma sCLEC-2 and D-dimer levels were significantly higher in patients with underlying diseases of DIC than in those with unidentified clinical syndrome (UCS). Plasma sCLEC-2 levels were significantly higher in the patients with DIC and Pre-DIC than in those without DIC or Pre-DIC. Similarly, plasma D-dimer levels were also significantly higher in patients with DIC and Pre-DIC than in those without DIC or Pre-DIC. The plasma sCLEC-2 levels in all patients and those with a DIC score ≤ 4 were significantly higher in non-survivors than survivors. The plasma D-dimer levels in all patients, those with a DIC score ≥ 5 and those with a DIC score ≤ 4, were significantly higher in non-survivors than in survivors. The plasma sCLEC-2 is expected as a marker for DIC/Pre-DIC as well as the prognostic marker in critically ill patients.

Case Cortical blindness induced by hepatic encephalopathy is an extremely rare complication and its epidemiology has not been studied in great detail. We report a 63-year-old man with liver cirrhosis who developed sudden bilateral visual impairment. Outcome On arrival at hospital, the patient had orientation disturbance, slurred speech, and mild disturbance of consciousness with impaired vision (light sense). He had no focal neurological deficits except for bilateral blindness. Cerebral stroke was suspected, but imaging and ophthalmological examination did not reveal major abnormalities. An increased concentration of ammonia in blood suggested hepatic encephalopathy; a diagnosis of cortical blindness was proposed. His vision returned gradually with relief of hepatic encephalopathy. Conclusion Cortical blindness can be an initial symptom of hepatic encephalopathy without severe disturbance of consciousness, and can be misdiagnosed as cerebral stroke. Cortical blindness induced by hepatic encephalopathy has been reported in only 10 cases, including our patient, and merits further evaluation.

Case Aberrant right subclavian artery–esophageal fistula is a rare, but fatal, complication. A 55-year-old febrile man with a nasogastric feeding tube developed sudden massive hematemesis and shock. Outcome Upper endoscopy revealed an intragastric hematoma with no active bleeding observed except for oozing from an esophageal tear. Enhanced computed tomography scan detected aberrant right subclavian artery but was unable to determine the bleeding source. Repeat endoscopy carried out on day 2 confirmed hemostasis and the disappearance of the intragastric hematoma. However, the patient suddenly developed recurrent massive hematemesis with refractory shock on day 4 and died. Postmortem computed tomography revealed endoscopic clips in contiguity with aberrant right subclavian artery; a final diagnosis of aberrant right subclavian artery–esophageal fistula was made. Conclusion Our case demonstrates aberrant right subclavian artery–esophageal fistula may present with transient spontaneous hematemesis in a state of shock, possibly related to fever of unknown origin, and is challenging to diagnose by repeated endoscopy once hematemesis develops.

要旨 重症呼吸不全に対するextracorporeal membrane oxygenation（ECMO）の適用は普及しつつある。しかし，多発外傷に対しては出血の問題があり，その適応は確立されていない。今回我々は，小児外傷後肺損傷に対し，ECMOを用いて救命した1例を報告する。症例は5歳，男児。乗用車に轢過され救急搬送された。血気胸，肺損傷，肝損傷，骨盤骨折，大腿骨骨折が認められた。止血処置を行った後，人工呼吸器管理では対応できない呼吸不全に陥ったため，veno–venous ECMO（VV–ECMO）を導入した。ヘパリンコーティングされた回路を用い，抗凝固療法としてメシル酸ナファモスタットを用いた。次第に呼吸状態は改善し，合併症を来すことなく導入から92時間後に離脱した。人工呼吸器管理では対応しきれない小児外傷性肺損傷に対してECMOは有効と考えられる。

Case A 72-year-old man was admitted to the intensive care unit for severe pancreatitis with coagulopathy. He underwent hemodialysis catheter insertion into the internal jugular vein that subsequently leaked arterial blood; vertebral artery cannulation was suspected following a computed tomography scan. Outcome Under angiographic guidance, the catheter was removed, and an arteriovenous fistula was identified. The patient was successfully treated with endovascular embolization of the affected vertebral artery with detachable coils and N-butyl-2-cyanoacrylate. Conclusion Despite ultrasound guidance, vertebral cannulation can occur, which can result in serious complications. Prompt management is needed to prevent further sequelae. Endovascular embolization with detachable coils and N-butyl-2-cyanoacrylate appears to be an effective option for vertebral artery injury in patients with coagulopathy.

Case A 74-year-old woman underwent computed tomography-guided transthoracic needle biopsy of a small lung mass. Immediately after the procedure, she lost consciousness. After resuscitation, her brain computed tomography scan confirmed a cerebral air embolism. Outcome As hyperbaric oxygenation was unavailable, she received controlled normothermia for neuroprotection. No cerebral symptoms were observed following treatment. Conclusion Air embolisms are rare, but fatal, complications of computed tomography-guided transthoracic needle biopsy. Therefore, clinicians should be familiar with early diagnosis and prompt treatment. Preventing hyperthermia might be effective for treating hypoxic brain injury caused by cerebral air embolisms.

Surrogate and peripheral (bio)markers of neuronal injury may be of value in assessing effects of seizures on the brain or epilepsy development following trauma. The presence of 14-3-3 isoforms in cerebrospinal fluid (CSF) is a diagnostic indicator of Creutzfeldt-Jakob disease but these proteins may also be present following acute neurological insults. Here, we examined neuronal and 14-3-3 proteins in CSF from rats after seizures. Seizures induced by intra-amygdala microinjection of 0.1 microg kainic acid (KA) caused damage which was mainly restricted to the ipsilateral CA3 subfield of the hippocampus. 14-3-3zeta was detected at significant levels in CSF sampled 4 h after seizures compared with near absence in control CSF. Neuron-specific nuclear protein (NeuN) was also elevated in CSF in seizure rats. CSF 14-3-3zeta levels were significantly lower in rats treated with 0.01 microg KA. These data suggest the presence of 14-3-3zeta within CSF may be a biomarker of acute seizure damage.

Background Extracorporeal cardiopulmonary resuscitation (ECPR) is being used increasingly in the emergency and critical care field in Japan. A major complication of ECPR is bleeding; however, the optimal initial heparin dose and activated coagulation time (ACT) remain unknown. The aim of this study was to assess the appropriateness of our initial anticoagulation protocol. Methods We retrospectively evaluated the initial heparin dose, ACT value, and incidence of bleeding and thrombotic complications in post-cardiopulmonary arrest patients who received a fixed, body weight-unadjusted loading dose of unfractionated heparin (3000 U) prior to veno-arterial extracorporeal membrane oxygenator (ECMO) between February 2011 and November 2013 at Mie University Hospital, Japan. Results ACT was evaluated within 3 h of initiation of 32 consecutive ECPR patients. The mean heparin dose per body weight was 53.6 U/kg and the mean ACT was 231.3 s. In 17 patients, ACT exceeded 200 s. Three patients experienced fatal bleeding in the chest wall within 24 h of receiving ECMO. The mean heparin dose per kilogram body weight, mean initial ACT, and mean duration of cardiopulmonary resuscitation (CPR) did not statistically differ between the patients who experienced fatal bleeding and those who did not. Conclusions Fixed-dose heparin of 3000-U bolus resulted in a mean heparin dose per kilogram body weight of 53.6 U/kg and an ACT of 231.3 s and experienced 3 out of 32 fatal bleedings. Further researches are warranted to optimize anticoagulation protocol for ECPR patients.

Seizures, particularly when prolonged, may cause neuronal loss within vulnerable brain structures such as the hippocampus, in part by activating programmed (apoptotic) cell death pathways. Experimental modeling suggests that seizures activate tumor necrosis factor receptor 1 (TNFR1) and engage downstream pro- and anti-apoptotic signaling cascades. Whether such TNFR1-mediated signaling occurs in human temporal lobe epilepsy (TLE) is unknown. Presently, we examined this pathway in hippocampus surgically obtained from refractory TLE patients and contrasted findings to matched autopsy controls. Western blotting established that total protein levels of the TNFR1 proximal signaling adaptor TNFR-associated protein with death domain (TRADD), cleaved initiator caspase-8 and apoptosis signal-regulating kinase 1 (ASK1) were higher in TLE samples than controls. Intracellular distribution analyses revealed raised cytoplasmic levels of TNFR1, TRADD and the caspase-8 recruitment adaptor Fas-associated protein with death domain (FADD), and higher levels of TRADD and cleaved caspase-8 in the microsomal fraction, in TLE samples. Immunoprecipitation studies detected TRADD-FADD binding, and fluorescence microscopy revealed TRADD co-localization with FADD in TLE hippocampus. These data suggest that TNFR1 signaling is engaged in the hippocampus of patients with refractory temporal lobe epilepsy.

Background Kudoa septempunctata is a recently identified cause of food poisoning. We report three cases of food poisoning due to ingestion of this parasite. Case Reports Among the 358 people exposed during the same catered meal, 94 (including our 3 patients) developed vomiting and diarrhea within 1–9 h after ingestion of raw muscle from contaminated aquacultured olive flounders ( Paralichthys olivaceus ). These symptoms occurred frequently but were temporary; only 1 patient was hospitalized for dehydration and was discharged 2 days later. Conclusion In Japan, cases of food poisoning due to eating olive flounder have increased during recent years. This increase should prompt heightened awareness among clinicians diagnosing food poisoning.

Restenosis or neointimal hyperplasia remains an important complication after carotid artery stenting (CAS) for carotid artery stenosis. The purpose of this study was to examine if an anti-hypertensive drug, angiotensin receptor blocker (ARB), prevents post-CAS neointimal hyperplasia during the first 1-year period after CAS, and to clarify the possible mechanisms.Hypertension had been treated with a calcium channel blocker (CCB) and/or an ARB, valsartan, by the preference of the neurosurgeon in charge in our department. At admission to perform CAS, patients were assigned to normotensive, valsartan (hypertensive patients treated with valsartan with/without any kind of CCBs), and non-valsartan (hypertensive patients treated with any kind of CCBs without ARBs) groups. Post-CAS neointimal hyperplasia was evaluated by carotid duplex ultrasound imaging in terms of intima-media thickening (IMT), which was performed at pre-CAS and at 90, 180, 270, and 360 days post-CAS. Biomarkers of oxidative stress (8-hydroxy-2'-deoxyguanosine), inflammation (C-reactive protein, tenascin-C) and endothelial cell injury (von Willebrand factor [vWF] antigen) were measured at pre-CAS and at 1, 7, and 180 days post-CAS.The non-valsartan group (n = 8) had a higher incidence of maximum in-stent IMT ≧ 1.1 mm compared with the normotensive group (n = 6). Valsartan (n = 9) significantly suppressed plasma vWF levels at 7 days post-CAS and decreased the incidence of maximum in-stent IMT ≧ 1.1 mm compared with the non-valsartan group, although clinical parameters were similar between the two groups. Other biomarkers were not significantly different among the three groups.These findings suggest that valsartan may prevent post-CAS neointimal hyperplasia possibly by suppressing endothelial cell injury.

This study was aimed to evaluate the source of endothelin-1 (ET-1) in cirrhotic patients. ET-1 is implicated in the pathogenesis of portal hypertension. However, the mechanism and source for increased plasma ET-1 in cirrhotic patients are still obscure. Plasma ET-1 levels in systemic (SV), superior mesenteric (SMV), and splenic venous (SPV) blood were measured in 23 patients with cirrhosis and 8 controls with normal liver. Fourteen removed spleens were immunohistochemically studied for ET-1, CD34, CD68, and CD20. In situ hybridization was done to localize ET-1 messenger RNA (mRNA). In cirrhosis, ET-1 levels in both SMV and SPV were higher than in SV. ET-1 in SV and SPV were significantly higher in cirrhotic patients than in control patients. Three groups of cells in the spleen expressed both protein and mRNA of ET-1: endothelial cells in the sinus, which were also stained for CD34; cells in the germinal center; and cells in the marginal zone of lymphoid sheaths and follicles, which were also stained for CD20 but not for CD34 and CD68. The ET-1 concentration released from the spleen was in parallel with the grade of ET-1 expression in the spleen. The spleen is one of the major sites of ET-1 release in cirrhotic patients. Endothelial cells of the splenic sinus and possibly B lymphocytes in the germinal center and marginal zone of lymphoid sheaths and follicles seem to be the sites of ET-1 production in the spleen.

The role of estrogen receptor (ER) in hepatocellular carcinoma (HCC) and the surrounding liver is not fully clarified. This study included 79 patients who had undergone curative hepatic resection between 1983 and 1991. ER concentrations were measured by a binding assay method for 79 HCCs and 49 surrounding liver tissues. The ER status in tumor and liver was retrospectively analyzed in terms of clinicopathological factors and intrahepatic recurrence (IHR) of the tumor. ERs were found in 24 (30%) of 79 HCC samples and in 26 (53%) of 49 liver samples, averaging 1.77±4.07 (range 0–25.6) and 2.51±3.57 (range 0–18.6) fmol/mgp, respectively. There were three types of changes in the tumor ER contents as compared to the surrounding liver. The tumor ER contents were unchanged in 39% (19/49) where ER was undetectable in both tumor and the surrounding liver. A decrease in the tumor ER contents was found in 45% (22/49), while the remaining 16% (8/49) had an increase in the tumor ER concentrations. There were no significant differences in the clinicopathological data between ER-positive and ERnegative HCCs. Although the patients in the last group had the poorest IHR-free survival rate, the multivariate analysis with Cox proportional hazard model could not identify ERs in HCC and the surrounding liver to be independent prognostic factors for IHR-free survival. The tumor ER contents can decrease, increase or remain unchanged. However, the majority of HCCs lack ERs. Estrogens may not be involved in tumor development in cases in which the liver has already lost ER. ERs in HCC or liver may not be a useful prognostic indicator after curative hepatic resection.

Hepatocellular carcinoma (HCC) occurs more prevalently in livers, not only with cirrhosis but chronic hepatitis due to hepatitis C virus (HCV), than in hepatitis B virus (HBV) related counterparts. This study aimed to investigate intrahepatic recurrence (IHR) and underlying mechanisms after resection of HCC associated with chronic hepatitis B and C from the viewpoint of hepatocarcinogenesis. A total of 44 patients with HCC and chronic hepatitis due to HBV in 15 patients and HCV in 29 patients were carefully followed up after curative hepatic resection. Clinical backgrounds, preoperative laboratory data, histopathologies of HCC and liver were compared between the two groups. Prognostic factors were analyzed by univariate and multivariate analyses. There were no differences in clinical backgrounds except for higher age in C hepatitis ( P =0.0048). Preoperative laboratory data were better in B hepatitis; AST ( P =0.0021, t -test), ALT ( P =0.0039), albumin ( P =0.0230), ICG test ( P =0.0043), platelet count ( P =0.0080), and plasma fibrinogen ( P =0.0224). No significant differences were found in tumor size or stage and other tumoral factors. Although the extent of hepatic fibrosis was similar, necroinflammatory activity was higher in C hepatitis ( P =0.0081). IHR rate was higher in C (65.5%) than in B hepatitis ( P =0.0145), but there was no difference in the recurrence pattern and time. The 5-year disease-free survival rate was 10.9% in C versus 84.6% in B hepatitis ( P =0.0018, log-rank test; P =0.0068, Wilcoxon test). Multivariate analysis revealed that the type of hepatitis virus and tumor size were independent factors for IHR. IHR occurs more frequently in chronic hepatitis C. Higher age and higher hepatitis activity may partly be responsible for this but further studies are necessary to elucidate the differences in carcinogenic potential and mechanism between chronic hepatitis B and C.

As in other tumors, the assessment of microvessel density (MVD) in hepatocellular carcinoma (HCC) may be essential to perform an effective anti-angiogenic therapy for this tumor. The relationship between vascular endothelial growth factor (VEGF) and MVD of HCC as well as the surrounding liver remains to be elucidated. In 71 patients who had undergone curative hepatic resection for HCC, MVD and VEGF expressions were evaluated for HCC and the liver by quantitative reverse-transcription polymerase chain reaction (RT-PCR) and/or immunostaining. The intensity and extent of VEGF immunoreactivity were evaluated using a computer image analyzer-cell analysis system (CAS). Angiographic data were re-evaluated and compared with MVD in 50 tumors. Tumoral MVD was significantly correlated with tumor capsule formation (t test, P = .0016). Small HCCs (< or = 2 cm) had a significantly lower MVD compared with moderate-sized HCCs (2-5 cm) (t test, P = .016), and the MVD of large HCCs was relatively lower than that of moderate tumors. Tumor vascularity on angiography was not correlated with the MVD. Neither VEGF mRNA levels nor protein expression in HCC were correlated with the tumoral MVD or any histopathological features of the tumor. However, cirrhotic livers had significantly higher MVD and VEGF expressions compared with noncirrhotic livers (t test, P = .0015 and P = .047, respectively). Only the MVD of tumor was significantly correlated with intrahepatic recurrence (t test, P = .0048) and disease-free survival (DFS) rates (log rank test, P = .0035). Moreover, the MVD was an independent predictor for DFS by multivariate analysis (chi2 test, P = .03). In conclusion, the MVD in HCC may be involved in the dismal prognosis of this tumor, and VEGF may be associated with the angiogenic process of the cirrhotic liver, but not with the angiogenesis of HCC.

Strongyloidiasis is a parasitic infection that occurs in tropical regions. Hyperinfection, which is an accelerated autoinfection, is often associated with an immunosuppressive state, such as HTLV-1 infection or steroid use. Immunosuppression can also lead to reactivation of tuberculosis infection. These infections may have interacted as a result of impaired cellular immunity. A 28-year-old Nepali male was referred to our hospital for slight abdominal pain and high fever. An abdominal CT scan showed ascites and intestinal swelling. He was admitted with suspected gastroenteritis. Results of stool microscopy on the third day of hospitalization revealed abundant strongylid larvae. We diagnosed a Strongyloides hyperinfection and prescribed ivermectin. Although the numbers of strongylid organisms in the patient’s stool soon diminished, his temperature remained high. After receiving a second dose of ivermectin on day 17, he was transferred to a nearby hospital for observation, where he was noted to have massive pleural effusion. He returned to our hospital where his pleural effusion was found to be positive for adenosine deaminase (ADA), and he was diagnosed with a tuberculosis infection. Strongyloides hyperinfection can occur in a non-endemic region. It can be associated with tuberculosis infection possibly due to impaired cellular immunity. It is important to consider other possible infections when treating a patient with an infection associated with impaired cellular immunity.

Treatment of infections caused by multidrug-resistant Pseudomonas species is difficult because few antibiotics active against such organisms are available. Arbekacin, a relatively new aminoglycoside, is effective against Pseudomonas spp. in vitro. However, no clinical report on arbekacin treatment of a human infection with a multidrug-resistant Pseudomonas has appeared to date. We encountered a case of pneumonia caused by a Pseudomonas strain producing a metallo-beta-lactamase; the patient was successfully treated with arbekacin. A 69-year-old male presented to our hospital experiencing cardiac arrest after rescue from water. Spontaneous circulation had earlier resumed after brief application of cardiopulmonary resuscitation. The patient was subjected to induced hypothermia. He experienced severe acute respiratory distress syndrome. The patient regained consciousness on day 8 post-admission. Episodes of ventilator-associated pneumonia were recorded on days 5 and 12. The causative organism was a strain of Pseudomonas putida that produced a metallo-beta-lactamase. Combination therapy with arbekacin and levofloxacin successfully resolved the pneumonia. The patient was transferred to another hospital on day 37 to undergo further rehabilitation. Strains of P. putida producing metallo-beta-lactamases have become more widespread in recent years. Colistin is traditionally the drug of last resort to treat infections with multidrug-resistant Pseudomonas. However, colistin use is associated with a very high frequency of adverse effects, and the costs of such therapy are not covered by the Japanese health insurance system. Our results indicate that arbekacin is an efficient alternative to multidrug-resistant Pseudomonas.

Management of Vertebral Artery (VA) dissections remains controversial. The clinical and angiographic variables of VA dissections were evaluated to demonstrate the safety and efficacy of endovascular intervention in treatment of VA dissecting aneurysms.25 patients with 27 VAdissecting aneurysms were treated with endovascular intervention during the last 10 years.17 patients were admitted with subarachnoid hemorrhage. 23 aneurysms treated using destructive endovascular trapping, while reconstructive techniques were used in 3 aneurysms treated with stent-assisted coiling and one aneurysm treated with false lumen embolization.The right VA was involved in 14 patients, the left VA in 9 patients, while 2 patients had bilateral VA dissection. The pearl and string sign was the commonest angiographic sign in 12 aneurysms. Perioperative complications included; rebleeding in one patient, symptomatic brain stem infarction in two patients and silent cerebellar ischemic lesion in one patient. Afavorable outcome was evident more in patients with unruptured VA dissection (100%) versus (76.5%) in patients presented with SAH.The endovascular technique should be individualized according to the clinical status of the patient, angiographic variables, condition of the posterior circulation and the available supplies.

Distal embolism is an important periprocedural technical complication with carotid angioplasty and carotid artery stenting (CAS). We evaluated the safety and efficacy of protection devices used during CAS by detecting new cerebral ischemic lesions using diffusion-weighted magnetic resonance imaging in 95 patients who underwent 98 CAS procedures: 34 using single PercuSurge GuardWire, 31 using double balloon protection, 15 using proximal flow reverse protection devices, 14 using Naviballoon, and 4 using filter anti-embolic devices. Diffusion-weighted imaging was performed preoperatively and postoperatively to evaluate the presence of any new embolic cerebral lesions. Postoperative diffusion-weighted imaging revealed 117 new ischemic lesions. Three patients had new ischemic stroke, two minor and one major, all ipsilateral to the treated carotid artery. The remaining patients had clinically silent ischemia. The incidence of new embolic lesions was lower using the proximal flow reverse protection device than with the double balloon protection (33% vs. 48.4%), but the volume of ipsilateral new ischemic lesions per patient was 136.6 mm(3) vs. 86.9 mm(3), respectively. Neuroprotection with Naviballoon yielded ipsilateral lesions of large volume (86.6 mm(3)) and higher number (5.7 lesions per patient) than using the filter anti-embolic device (34.8 mm(3) and 1 lesion per patient). New cerebral ischemic lesions after neuroprotected CAS are usually silent. The lower incidence of distal ischemia using proximal flow reverse and double balloon protection devices is limited by the larger volume and higher number of ischemic lesions.

Experimentally evoked seizures can activate the intrinsic mitochondrial cell death pathway, components of which are modulated in the hippocampus of patients with temporal lobe epilepsy. Bcl-2 family proteins are critical regulators of mitochondrial dysfunction, but their significance in this setting remains primarily untested. Presently, we investigated the mitochondrial pathway and role of anti-apoptotic Bcl-2 proteins using a mouse model of seizure-induced neuronal death. Status epilepticus was evoked in mice by intra-amygdala kainic acid, causing cytochrome c release, processing of caspases 9 and 7, and death of ipsilateral hippocampal pyramidal neurons. Seizures caused a rapid decline in hippocampal Bcl-w levels not seen for either Bcl-2 or Bcl-xl. To test whether endogenous Bcl-w was functionally significant for neuronal survival, we investigated hippocampal injury after seizures in Bcl-w-deficient mice. Seizures induced significantly more hippocampal CA3 neuronal loss and DNA fragmentation in Bcl-w-deficient mice compared with wild-type mice. Quantitative electroencephalography analysis also revealed that Bcl-w-deficient mice display a neurophysiological phenotype whereby there was earlier polyspike seizure onset. Finally, we detected higher levels of Bcl-w in hippocampus from temporal lobe epilepsy patients compared with autopsy controls. These data identify Bcl-w as an endogenous neuroprotectant that may have seizure-suppressive functions.

Apoptosis signaling pathways are implicated in the pathogenesis of temporal lobe epilepsy (TLE), but the role of endoplasmic reticulum (ER) stress and ER-localized apoptosis signaling components remains largely unexplored. Presently, we investigated ER stress and ER localization of proapoptotic Bcl-2 family members and initiator and effector caspases in resected hippocampus from patients with intractable TLE and compared findings with autopsy controls. Hippocampal immunoreactivity for KDEL (Lys-Asp-Glu-Leu), a motif in ER stress chaperones glucose-regulated proteins 78 and 94, and calnexin, was significantly higher in TLE hippocampus compared with controls. The ER-containing microsomal fraction in control brain contained Bid, Bim, and caspase 3, whereas Bad and caspases 6, 7, and 9 were very low or absent. In contrast, caspases 6, 7, and 9 were present within the microsomal fraction of TLE brain. Furthermore, cleaved caspases 7 and 9 were detected in TLE samples but not controls, and KDEL-expressing neurons coexpressed cleaved caspase 9. Potentially adaptive changes were also detected, including lowered Bim levels in this fraction, and binding of caspase 7 to the X-linked inhibitor of apoptosis protein. These data suggest seizures may induce ER stress and trigger proapoptotic signaling pathways in the ER that are counteracted by antiapoptotic signals in chronic human TLE.

✓ The authors present the case of a 62-year-old man with a 4-month history of progressive left-sided C-5 radiculopathy and dizziness. Neuroimaging studies revealed a looped vertebral artery (VA) that had migrated into the widened left C4–5 intervertebral foramen. The patient underwent vascular reconstruction of the VA loop, in which there was minimal manipulation of the C-5 nerve root, via a left-sided anterolateral approach after a balloon occlusion test. Postoperatively the patient's symptoms improved immediately, and there were no signs of recurrence within the 2-year follow-up period. This excellent outcome supports the belief that a proper surgical reconstruction of the compressive, tortuous VA should be the therapeutic option of choice, which carries a lower risk of the nerve root injury and improves the hemodynamics in the posterior circulation.

We report here the case of a 35-year-old man who presented with inferior vena cava thrombosis (IVCT) after blunt hepatic trauma. The IVCT was incidentally detected by computed tomography (CT) 35 days after deep parenchymal suturing and suture approximation for liver lacerations. The patient denied any symptoms of thrombophlebitis. However, he had presented with significantly elevated values of FDP-D-dimer and a modest increase in plasminogen concentration, which indicated that he had been in a hypercoagulable and hypofibrinolytic state after the operation. He had not undergone any prophylactic anticoagulant therapy because of his concomitant subarachnoid hemorrhage and huge hepatic hematoma. The patient was treated with an emercy thrombectomy. Posttraumatic IVCT is extremely rare phenomenon. We should consider IVCT in patients with a severe hepatic injury, particularly if their coagulation system change into hypercoagulable and hypofibrinolytic state. Additionally, this case made us reflect on the treatment of traumatic liver injury.

Background/Aims: Angiogenesis plays an important role in tumor growth and metastasis. It is regulated by angiogenic factors. Thymidine phosphorylase (platelet-derived endothelial cell growth factor) is one such factor. Although the significance of platelet-derived endothelial cell growth factor has been studied for several types of tumor, the expression of platelet-derived endothelial cell growth factor and its correlation with microvessel density or clinicopathological factors in hepatocellular carcinoma are unknown. We evaluated microvessel density and platelet-derived endothelial cell growth factor expression in hepatocellular carcinoma to determine whether microvessel density and platelet-derived endothelial cell growth factor expression are correlated with the clinicopathological factors of hepatocellular carcinoma. Methods: Using immunohistochemical staining with anti-platelet-derived endothelial cell growth factor antibody and the ELISA method, we evaluated the correlation among platelet-derived endothelial cell growth factor expression, microvessel density and clinicopathological factors in 84 hepatocellular carcinoma patients. Microvessels were stained with anti-human von Willebrand factor (anti-Factor VIII) and anti-CD34. Results: In the surrounding liver, there was a significant correlation between microvessel density and platelet-derived endothelial cell growth factor expression ( p =0.002), and hepatitis C virus-positive livers had higher microvessel densities than otherwise ( p =0.003). However, this correlation was not found for hepatocellular carcinoma, but hepatitis C virus-positive tumors had higher expression of platelet-derived endothelial cell growth factor ( p =0.018). Microvessel density in hepatocellular carcinoma obtained by Factor VIII staining inversely affected the recurrence-free survival rate ( p =0.0416), but the microvessel density by CD34 staining was not a significant predictor. Conclusion: This study indicates that platelet-derived endothelial cell growth factor may not be a major regulator of angiogenesis of hepatocellular carcinoma, but this enzyme may play an important role in hepatocarcinogenesis cooperating with hepatitis C virus. Also, the density, not of sinusoid-like vessels, but of larger vessels in hepatocellular carcinoma could be a prognostic factor for hepatocellular carcinoma.

BACKGROUND Squamous cell carcinoma (SCC) of the esophagus is among the most malignant of neoplasms and is associated with a dismal prognosis. Although tumor microvessel density (MVD) is an important prognostic factor in several carcinomas, its role in SCC of the esophagus is still controversial. Also, the role of thymidine phosphorylase (dThdPase), a key angiogenic growth factor, is yet to be delineated in this disease. METHODS Immunohistochemical staining using monoclonal antibodies was used to quantify microvessel and dThdPase expression in archival tissue specimens from 93 patients with SCC of the esophagus. RESULTS High dThdPase expression and high MVD were associated with tumor progression (size and stage) and lymph node metastasis, but only MVD was a predictor of survival. dThdPase expression was significantly correlated with depth of tumor invasion (P = 0.015). In multivariate analysis, MVD was an independent predictor of survival in the lymph node negative cases. A significant correlation was noted between MVD and dThdPase expression, with a correlation coefficient of 0.083 (P = 0.002). CONCLUSIONS MVD is an independent factor in determining the prognoses of lymph node negative patients with SCC of the esophagus. dThdPase could be a key factor in the angiogenesis of this disease and may be responsible for its aggressive behavior. Cancer 1998;82:1225-32. © 1998 American Cancer Society.

Extracorporeal cardiopulmonary resuscitation (ECPR) is increasingly being used in emergency and critical care medicine in Japan. Although a major complication of this procedure is bleeding, the optimal heparin dose and activated coagulation time (ACT) remain unknown.