Sepsis is a devastating and complex syndrome and continues to be a major cause of morbidity and mortality among critically ill patients at the surgical intensive care unit setting in the United States. The occurrence of sepsis and septic shock has increased significantly over the past two decades. Despite of highly dedicated basic research and numerous clinical trials, remarkable progress has not been made in the development of novel and effective therapeutics. The sepsis-induced physiologic derangements are due largely to the host responses to the invading microorganism in contrast to the direct effects of the microorganism itself. Sepsis, the systemic inflammatory response to infection, is marked by dysregulated production of pro-inflammatory cytokines. Although pro-inflammatory cytokine production is normally indispensable to protect against pathogens and promote tissue repair, the dysregulated and prolonged production of these cytokines can trigger a systemic inflammatory cascade mediated by chemokines, vasoactive amines, the complement and coagulation system, and reactive oxygen species (ROS), amongst others. These mediators collectively lead to multiple organ failure, and ultimately to death. In this regard, the role of inflammation in the pathophysiology of sepsis, although still incompletely understood, is clearly critical. Recent findings resulting from vigorous investigations have contributed to delineate various novel directions of sepsis therapeutics. Among these, this review article is focused on new promising mechanisms and concepts that could have a key role in anti-inflammatory strategies against sepsis, including 1) "inflammasome": a multiprotein complex that activates caspase-1; 2) "the cholinergic anti-inflammatory pathway": the efferent arm of the vagus nerve-mediated, brain-to-immune reflex; 3) "stem cells": unspecialized and undifferentiated precursor cells with the capacity for self-renewal and potential to change into cells of multiple lineages; 4) "milk fat globule-EGF factor VIII (MFG-E8)": a bridging molecule between apoptotic cells and phagocytes, which promotes phagocytosis of apoptotic cells.

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Bleeding from esophageal varices (EVs) or gastric varices (GVs) is a catastrophic complication of chronic liver disease. In this paper, we review the management of bleeding EVs and GVs.
Diagnosis of EVs and GVs: The grading system for esophagogastric varices proposed by the Japan Society for Portal Hypertension classifies GVs into those involving the cardia (Lg-c), the fundus (Lg-f), and both the cardia and the fundus (Lg-cf). In this review, we divide GVs into 2 categories: Lg-c (cardiac varices: CVs) and Lg-cf or Lg-f (fundal varices: FVs).
Treatment Modalities for EVs and GVs: Treatment modalities for EVs and GVs include placement of a Sengstaken-Blakemore tube, pharmacologic therapy, surgery, interventional radiology, and endoscopic treatment.
Management of Bleeding EVs and GVs: In Japan, endoscopic treatment has recently become the therapy of choice for bleeding EVs or GVs. In other countries, especially the United States, vasoactive drugs and endoscopic treatment are routinely used to manage variceal hemorrhage.
Bleeding EVs: Endoscopic variceal ligation is useful for controlling bleeding from EVs. However, confirmation of ligation precisely at the site of bleeding is usually difficult in patients with massive variceal bleeding. The site of acute bleeding can generally be identified by means of water instillation and suction. Ligation is then performed at the bleeding point. If endoscopic hemostasis is unsuccessful, a Sengstaken-Blakemore tube is used as a temporary bridge to other treatments. Transportal obliteration is useful for blocking variceal blood flow.
Bleeding GVs: Endoscopic injection sclerotherapy with a tissue adhesive, such as N-butyl-cyanoacrylate or isobutyl-2-cyanoacrylate, is effective for acute bleeding from GVs. However, bleeding from the GV injection site and rebleeding from the rupture point have been reported in patients receiving endoscopic injection sclerotherapy. If endoscopic hemostasis is unsuccessful, a Sengstaken-Blakemore tube is used as a temporary bridge to other treatments. Balloon-occluded retrograde transvenous obliteration and transportal obliteration are useful for the treatment of uncontrolled bleeding from GVs.
Prevention of Recurrent Variceal Hemorrhage: Given the high recurrence rate, survivors of an acute variceal hemorrhage should receive treatment to prevent recurrence. Complete eradication of EVs or GVs and maintenance of low portal venous pressure are essential for preventing recurrence of variceal hemorrhage.

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Procedures of statistical analysis are reviewed to provide an overview of applications of statistics for general use. Topics that are dealt with are inference on a population, comparison of two populations with respect to means and probabilities, and multiple comparisons. This study is the second part of series in which we survey medical statistics. Arguments related to statistical associations and regressions will be made in subsequent papers.

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Anterior decompression and fusion of the cervical spine is a widely accepted treatment for cervical canal disease. The Williams-Isu method involves cervical anterior fusion with autologous bone grafts from cervical vertebral bodies. Its advantages are a wide operative field, excellent graft fusion, the absence of problems related to the iliac donor site, and direct visualization of the nerve root. For detailed decompression of the cervical root, an ultrasonic bone curette (SONOPET, Stryker Japan K.K., Tokyo) may be useful. To prevent graft extrusion, bioabsorbable screws featuring a head are placed in 4 corners of the bone graft and are fixed with a tap on a part of the graft. The screws are visualized on postoperative X-ray, computed tomography, and magnetic resonance imaging studies. In 69 patients reported elsewhere there were no complications attributable to screw insertion, screw or graft extrusion, or surgery-related infections. When adequate bone cannot be harvested, a piece of ceramic hydroxyapatite is placed between the bone grafts. This sandwich method reinforces the graft, and radiological evidence suggests that it yields better results with respect to the angle and height of the fused segment. For the surgical treatment of cervical ossification of the posterior longitudinal ligament, a large vertebral bone window and a large bone graft are needed; this may result in postoperative radiological worsening. Radiological studies have shown that cervical ossification of the posterior longitudinal ligament can, as can cervical spondylosis, be addressed with the Williams-Isu method. Detailed radiological studies in patients treated with the Williams-Isu method have demonstrated that the range of motion and the disc height of the fused segment must be considered to prevent worsening in that segment after anterior fusion. The Williams-Isu method cannot completely correct cervical alignment, and great caution must be exercised in patients with preoperative malalignment. To reduce the levels to be fused in patients with multilevel lesions due to cervical disease, the Williams-Isu method can be combined with the transvertebral approach. The transvertebral approach facilitated by the wide Williams-Isu window allows the root bifurcation area to be confirmed during the early stage of surgery and possible decompression along the root. Radiological examination has shown that the combination of the Williams-Isu method and transvertebral approach does not affect the fusion level compared with the Williams-Isu method alone and produces better results than does the transvertebral approach alone.

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Myofibroblasts play a critical role in tissue fibrosis. However, the intracellular signaling pathways in myofibroblast differentiation are poorly understood. Here, we studied the relationship between transforming growth factor-β (TGF-β)/Smad pathway activation and myofibroblast differentiation in both in vivo and in vitro experiments. In murine bleomycin-induced pulmonary fibrosis, nuclear localization of phosphorylated Smad2/3 (p-Smad2/3) was observed in pulmonary fibrotic lesions 7 days after bleomycin injection, whereas α-smooth muscle actin (ASMA)-positive myofibroblasts appeared in the lesions at 14 days, when the cytoplasmic localization of p-Smad2/3 was observed. We also compared the effects of TGF-β1 on myofibroblast differentiation and on type I collagen expression in a murine lung fibroblast cell line (MLg2908). TGF-β1 induced rapid expression of p-Smad2/3 in nuclei, after which ASMA organization in the cytoplasm of fibroblasts was observed. However, TGF-β1 produced no effect on the quantity of ASMA, either in mRNA levels or protein levels, even after the phosphorylation of Smad2/3. In contrast, TGF-β1 upregulated the expression of type I collagen mRNA. These findings suggest that in pulmonary fibrosis the molecular mechanism of myofibroblast differentiation is complex and that the difference between ASMA expression and type I collagen expression is mediated by the TGF-β/Smad pathway.

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Aim: Intrapartum management guidelines based on fetal heart rate classification comprising a 5-tier system (Levels 1-5) was proposed by the Perinatology Committee of the Japan Society of Obstetrics and Gynecology (JSOG). This study aimed to assess the reproducibility and clinical usefulness of this classification.
Methods: For assessing intraobserver and interobserver reproducibility in the interpretation of fetal heart rate tracing, 2 obstetricians reviewed 247 fetal heart rate tracings using the JSOG classification (Level 1, normal; Level 2, benign variant; Level 3, mild variant; Level 4, moderate variant; and Level 5, severe variant) and a subjective 3-tier classification (normal, equivocal, and ominous). In a separate series, we investigated whether the JSOG classification is related to early neonatal outcome and the delivery mode in 96 deliveries.
Results: Weighted kappa coefficients of intraobserver and interobserver reproducibility in the interpretation of fetal heart rate tracings based on the JSOG classification were 0.73 to 0.77 and 0.70, respectively. In the subjective classification, these values were 0.69 to 0.72 and 0.59. There was a progressive increase in the rate of instrumental or cesarean deliveries across the 5 levels of the JSOG classification (P<0.001). Although, level 5 of the JSOG classification had a lower Apgar score and umbilical artery pH than did the other 4 levels (p<0.05), there were no significant differences among the other levels in regard to early neonatal outcome.
Conclusions: This study demonstrated that both intraobserver reproducibility and interobserver reproducibility of the JSOG classification for interpreting FHR tracings were clinically acceptable. The results also suggest that the intervention according to the JSOG classification is useful for avoiding worsening early neonatal outcomes.

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We performed a cross-sectional survey to investigate actual clinical practices regarding blood-pressure control in patients with hypertension. From October 16 to 31, 2008, postal questionnaires regarding the care of patients with hypertension were sent to members of the Kanagawa Physicians Association in Kanagawa, Japan. Data of 675 patients (mean age: 70.1 ± 10.6 years, 301 men and 374 women) were returned. The overall mean systolic blood pressure (BP) in these patients was 134.6 ± 10.6 mm Hg, and diastolic BP was 76.2 ± 8.3 mm Hg. According to the 2009 guidelines of the Japanese Society of Hypertension for the management of patients with hypertension, the target office BP was achieved by 53.9% of all subjects; 29.7% of patients with diabetes mellitus, chronic kidney disease, or a history of myocardial infarction; 72.0% of elderly patients; 23.6% of nonelderly patients (younger than 65 years); and 75.4% of patients with cerebrovascular disease. Cross-sectional analysis showed that factors significantly associated with an increased likelihood of achieving the target office BP were: 1) usage of a larger number of antihypertensive agents in nonelderly patienys and in patients with diabetes mellitus, chronic kidney disease, or a history of myocardial infarction and: 2) usage of a smaller number of antihypertensive agents in elderly patients and patients with cerebrovascular disease. Further follow-up surveys are necessary to provide a full assessment.

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Avulsion of the flexor digitorum profundus tendon with fracture of the distal phalanx is rare. Moreover, enchondroma is less frequent in the distal phalanx. We report two unusual cases of avulsion of the flexor digitorum profundus tendon at its insertion in combination with pathological fracture of the distal phalanx due to enchondroma. Curettage and bone grafting were performed for an enchondroma of the distal phalanx. The flexor digitorum profundus tendon and the avulsed bone fragment were reinserted through the bone graft into the distal phalanx using the pull-out technique. With Strickland's criteria, the clinical results were evaluated as excellent in both cases. At the final follow-up examinations, there were no symptoms and no recurrence of the bone tumor. In the present cases, three-dimensional computed tomography imaging was useful for diagnosing the flexor tendon avulsion, determining the preoperative identification the location of a ruptured tendon stump, and planning the operation to minimize the surgical wound. The recommended treatment for avulsion of the FDP tendon due to enchondroma is curettage, bone grafting of the resultant cavity, and reattachment of the tendon to ensure sufficient structural strength to permit secure fixation and early mobilization and, especially, to prevent flexion contracture of the finger because the stump of the flexor digitorum profundus is buried in the cavity of the distal phalanx.

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Background and Objective: Aspirin, clopidogrel, cilostazol, and statins are thought to reduce the risk of cerebral infarction in patients with intracranial arterial stenosis. We present a case of multiple intracranial arterial stenoses in which increased cerebral blood flow (CBF) was demonstrated after long-term medical therapy.
Case Presentation: A 68-year-old man with a history of cerebral infarction showed complete occlusion of the left internal carotid artery with severe stenoses in the A1 segment of the left anterior cerebral artery (ACA) and the left posterior communicating artery resulting in poor visualization of the left middle cerebral artery (MCA) on magnetic resonance angiography (MRA). Administration of aspirin and clopidogrel prevented ischemia from recurring for 1 year; however, the stenoses never improved. Technetium-99m-L, L-ethylcysteinate dimer single-photon emission computed tomography (SPECT) demonstrated a significant decrease in CBF in the territory of the left MCA. Anastomosis between the superficial temporal artery and the MCA was recommended to the patient because no supplementary blood supply was expected through either the left A1 or posterior communicating artery. However, the patient refused surgery because of the associated risks. To enhance vasodilation, clopidogrel was replaced by cilostazol. One year later, the stenoses had partially improved. Further treatment with aspirin, cilostazol, simvastatin, and nateglinide contributed to the significant increase in CBF with normal hemodynamics, as shown with acetazolamide-loading SPECT.
Conclusion: The goal of treatment for intracranial arterial stenosis is to supply sufficient blood flow to the brain rather than to completely dilate the stenotic artery. Long-term treatment with aspirin, cilostazol, simvastatin, and nateglinide might help increase CBF in some patients with intracranial arterial stenosis.

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