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Aims Elevated serum alkaline phosphatase (ALP) levels are associated with an increased risk of cerebrocardiovascular diseases. However, the associations of ALP with peripheral arterial disease (PAD) and outcomes in patients with acute ischemic stroke (AIS) are not well-known. Methods We examined the association between ALP levels and the ankle-brachial index (ABI) in 2111 consecutive patients with AIS. A poor functional outcome was defined as a modified Rankin Scale (mRS) score of 3-6 at 3 months after stroke. A low ABI was defined as a value of ≤ 0.9. Results Of the total cohort, 482 patients (22.8%) had a low ABI. ALP levels were higher in patients with a low ABI than in those without (p＜0.001). The multivariable logistic analysis revealed that quartiles of ALP levels were significantly associated with a low ABI (odds ratio [OR]: 1.20, 95% confidence interval [CI]: 1.08-1.33). Of the 1322 patients with a premorbid mRS score of 0-2, 434 patients (32.8%) had a poor outcome. The multivariable analysis revealed that elevated serum ALP levels and a low ABI were independently associated with poor stroke outcomes after adjustment for baseline characteristics (OR: 1.21, 95% CI: 1.07-1.38, and OR: 2.00, 95% CI: 1.40-2.84, respectively). Conclusions Increased serum ALP levels are significantly associated with a low ABI. These indicators are independent prognostic factors for poor stroke outcomes at 3 months.

We investigated the appropriate D-dimer cutoff value for each brain tumor type for acute or subacute deep vein thrombosis (DVT) following transcranial brain tumor surgery.In this single-center retrospective study, a cumulative total of 128 patients who underwent transcranial brain tumor surgery were enrolled and classified into the glioma group, the other intracranial malignant tumor group, and the intracranial benign tumor group. Venous ultrasonography was performed if the D-dimer plasma levels were positive (≥1 μg/mL) before surgery and on postoperative day (POD) 3 or 7.Of the 128 cases, DVT developed in 32 (25.0%). Among those, acute or subacute DVT was diagnosed in 22 cases on POD 3 and in 8 cases on POD 7. Compared with DVT-negative cases on POD 3, acute or subacute DVT-positive cases on POD 3 revealed a significant increase in the D-dimer level in all groups combined and in the benign tumor group but not in the glioma group. With regard to DVT on POD 3 in all groups, the receiver operating characteristic curve for the D-dimer level on POD 3 demonstrated a cutoff value of 3.3 μg/mL (sensitivity [0.636] and specificity [0.750]). However, if this cutoff value was used in practice, eight cases would be false-negative with a minimum D-dimer level of 1.5 μg/mL.The D-dimer cutoff value for acute or subacute DVT on POD 3 could be set to 3.3 μg/mL; however, the setting resulted in several false-negative cases. Practically, 1.5 μg/mL of the D-dimer cutoff value on POD 3 might be appropriate to avoid false-negative results.

Associated factors of the Myasthenia Gravis Activities of Daily Living (MG-ADL) score were investigated in 55 patients who had had generalized MG for more than 5 years. In multivariate analysis, correlates of the MG-ADL score at the last follow-up were the total number of fast-acting treatments (FTs) (standardized regression coefficient 0.617，P0.001) and Myasthenia Gravis Foundation of America (MGFA) classification (standardized regression coefficient 0.227，P = 0.032) (F = 32.7，P0.001). In patients with a score of 5 or more on MG-ADL at the last follow-up, tendency as follows were seen: 1) early-onset (P = 0.002), 2) longer duration (P = 0.014), 3) high frequency of MGFA classification V (P = 0.017), 4) high frequency of the total number of FTs (P0.001), and 5) higher dose of prednisolone at the last follow-up (P = 0.003). MGFA V, early-onset without depending on E-L-T classification, or difficulty of reduction for high doses of prednisolone can be the target of novel treatment for MG, and future prospective study will be expected.

Cancer-associated ischemic stroke (CAS) refers to a hypercoagulation disorder related to malignant tumors, especially adenocarcinoma. Carbohydrate antigen (CA) 125 is a mucinous serum marker that might reflect hypercoagulation status, but the association between CA 125 and CAS is unclear across various types of cancer. The aim of this study was to investigate the associations among tumor markers, coagulation markers, and clinical factors in acute ischemic stroke (AIS) patients with active cancer. Consecutive AIS patients with active cancer (a diagnosis or ongoing active therapy for cancer within 6 months) were prospectively enrolled at four hospitals. D-dimer, C-reactive protein (CRP), carcinoembryonic antigen (CEA), CA19-9, and CA 125 levels were measured. Of 120 AIS patients with active cancer, 47 were diagnosed with CAS. CA 125 had the strongest correlations with D-dimer and CRP (ρ = 0.543, p

Although associations between malnutrition status at stroke admission and poor stroke outcomes have been established, the effect of nutritional intake during the acute phase remains unclear. We aimed to evaluate the associations between nutritional intake one week after admission and the outcome at three months among acute ischemic stroke (AIS) patients.Consecutive AIS patients were investigated. Nutritional status at admission was evaluated using the Controlling Nutritional Status score, calculated from the serum albumin, lymphocyte count, and total cholesterol. We retrospectively evaluated nutritional intake (energy and protein) one week after admission, and the cutoff value of each nutritional intake level for good outcome was defined as the modified Rankin Scale 0-2 at three months after stroke onset using the receiver operating characteristic curve.Of the 205 patients, 146 patients had good outcomes. Mild initial neurological symptoms and good nutritional status at admission were associated with good outcome. The cutoff value of good outcome for protein intake was 0.812 g/kg/day (sensitivity: 0.884, specificity: 0.509) and that for energy intake was 19.0 kcal/kg/day (sensitivity: 0.918, specificity: 0.424). Those nutritional intake indicators were independently associated with good outcome after adjusting for baseline confounders, including stroke severity and nutritional status at admission (protein intake: odds ratio (OR), 4.04; 95% confidence intervals (CIs), 1.14-13.1, and energy intake: OR, 5.00; 95% CIs, 1.41-17.8, respectively).Adequate nutritional intake at one week after admission was independently associated with good outcome regardless of the nutritional status at admission or stroke severity.

Necrotizing lymphadenitis (NEL) is a self-limited systemic disease exhibiting characteristic clinical features. The pathogenesis of the disease remains unclear, but it may be associated with viral infection. In lymph nodes affected by this disease, innumerable plasmacytoid dendritic cells produce interferon-α when triggered by certain viral stimuli. IFN-α presents antigens causing the transformation of CD8+ cells into immunoblasts and apoptosis of CD4+ cells. From the perspective of innate immunity, UNC93B1, an endoplasmic reticulum (ER)-resident protein, associates more strongly with TLR9 than TLR7. Homeostasis is maintained under normal conditions. However, in NEL, TLR 7 was observed more than TLR 9, possibly because mutant type UNC93B1 associates more tightly with TLR7. The inhibitory effects against TLR7 by TLR9 were reported to disappear. It is likely that more TLR7 than TLR9 is transported from the ER to endolysosomes. In conclusion, overexpression of TLR7, an innate immune sensor of microbial single-stranded RNA, is inferred. Consequently, NEL may be induced.

A 76-year-old man with renal cell carcinoma exhibited consciousness disturbance and high fever after two cycles of combination therapy with ipilimumab and nivolumab. His cerebrospinal fluid (CSF) showed a protein concentration of 385 mg/dl, a cell count of 147/mm3, an interleukin-6 concentration of 1,280 pg/ml, and an adenosine deaminase concentration of 24.8 U/l. Contrast-enhanced FLAIR images were notable for diffuse meningeal enhancement. He was diagnosed with meningoencephalitis caused by an immune-related adverse event from immune checkpoint inhibitors (ICIs). His symptoms improved after repeated intravenous methylprednisolone pulse therapy and oral prednisolone. The meningeal enhancement disappeared, and the CSF findings became almost normal. As consciousness levels improved, we observed quadriplegia and peripheral neuropathy with antiganglioside antibodies, which led to a diagnosis of polyradiculoneuropathy. This is a rare case of a patient with overlapping meningoencephalitis and polyradiculo-neuropathy induced by ICIs.

Central nervous system methotrexate-associated lymphoproliferative disorder (CNS-MTX-LPD) is rare, but its spontaneous regression has been observed in some patients after withdrawal of agents. We herein report three cases of primary CNS-MTX-LPD that received oral MTX for rheumatoid arthritis. Epstein-Barr virus and oligoclonal bands (OCBs) were positive, while proton magnetic resonance spectroscopy (

Objective Onco-cardiology services are expanding rapidly in Japan. To provide a better service, it is important to consider the needs of oncologists. However, little is known regarding specific needs for which oncologists should consult cardiologists to manage cardiovascular problems of their patients. We analysed cardiology consultations sought by oncologists to evaluate the role of cardiologists in cancer treatment. Method We retrospectively investigated consecutive 2064 cardiology consultations of cancer patients in the University of Tsukuba Hospital, Tsukuba, Japan, between January 2014 and December 2018. Results The most common timing of cardiology consultation was before the commencement of cancer treatment (n = 1355; 65.7%), followed by after the commencement of cancer treatment (n = 686; 33.2%). Among the 361 consultations before the administration of anticancer drugs, 235 (65.1%) were for anthracycline-based regimens. There were 506 (24.5%) consultations for the management of cardiovascular emergencies developing after the commencement of cancer treatment; venous thromboembolism was the most frequent (n = 125; 24.7%), followed by atrial fibrillation (n = 110; 21.7%) and heart failure (n = 74; 14.6%). There were marked differences in the types of cardiovascular emergencies depending on the type of cancer. Conclusions This survey revealed the various cardiovascular problems for which oncologists sought interventions by cardiologists. A multidisciplinary approach in an onco-cardiology service is essential to achieve optimal long-term outcomes.

Although hypercoagulability using D-dimer levels may be a useful marker for predicting outcomes in ischemic stroke patients with cancer, other biological markers for predicting outcomes are unclear. We aimed to investigate the associations between several biological markers and short-term or long-term outcomes among ischemic stroke patients with cancer.Consecutive acute ischemic stroke patients with cancer (n = 309) were registered. Biological markers such as hemoglobin, albumin, C-reactive protein and D-dimer levels were assessed. Stroke outcomes, namely, a 3-month modified Rankin Scale score indicating poor functional outcome (mRS score of 3-6) and 1-year survival, were assessed.Of the 277 patients who could be assessed for 3 months outcome, 131 patients (47.3%) had a poor outcome at 3 months. Multivariable analysis revealed that increased D-dimer levels and decreased albumin levels were independently associated with poor stroke outcomes (adjusted odds ratio [aOR]: 1.04, 95% confidence interval [CI]: 1.00-1.08, and aOR: 0.50, 95% CI: 0.31-0.80, respectively). Of 309 patients, 70 patients (22.7%) died during the follow-up period (median, 241 days). Multivariate Cox proportional hazard analyses showed that high D-dimer levels and hypoalbuminemia were independently associated with mortality (adjusted hazard ratio [aHR]: 2.65, 95% CI: 1.37-5.12, and aHR: 2.29, 95% CI: 1.21-4.49, respectively). The effect of each biological marker on mortality was notably observed among patients with active cancer but not among those with nonactive cancer.Low albumin levels were independently associated with short- and long-term outcomes, as were D-dimer levels, in acute ischemic stroke patients with cancer.

A 36-year-old man experienced severely impaired consciousness twice after drinking because of hyperammonemia. No abnormal blood tests were found other than ammonia levels. However, magnetic resonance imaging (MRI) showed atrophy of the brain parenchyma. One the second occasion, the patient suffered severe impairment of consciousness, and because of seizures and glossoptosis, mechanical ventilation was started. Urea cycle disorders (UCDs) were assumed to be involved. Genetic testing revealed a monoallelic mutation of the carbamoyl phosphate synthase 1 (CPS1) gene. When transient hyperammonemia of unknown cause occurs repeatedly in adults, an active investigation for UCDs should be conducted.

The mainstay of treatment for idiopathic normal-pressure hydrocephalus (iNPH) is spinal fluid shunting. A tap test (TT) is recommended as an indication of shunting. Patients with iNPH are often elderly and have multiple comorbidities affecting the shunting outcome. We investigated the factors affecting TT in patients with iNPH.Seventy-five patients with iNPH were admitted to our department for a TT from April 2010 to May 2021. The patients were divided into a responsive group and an unresponsive group according to the clinical outcomes after TT on the Timed Up and Go Test (TUG), Mini-Mental State Examination (MMSE), or iNPH grading scale. Factors affecting the TT were compared between the responders and nonresponders.There were 38 patients (50.7%) in the TT responder group, and the prevalence of improvement was 82.9% in the TUG, 27.6% in the MMSE, and 76.3% in the iNPH grading scale. There were no significant differences in the vascular risk factors between the two groups. The prevalence of lumbar spondylosis, compression fracture, severe periventricular hyperintensity, deep and subcortical white matter hyperintensity (DSWMH), and old cerebral infarcts was significantly higher among the TT nonresponders. The logistic regression analysis showed that severe DSWMH and lumbar spondylosis were associated with a TT nonresponse (p 0.001 and p = 0.003, respectively). Shunting was performed in 22 patients, 19 of whom were TT responders.Severe DSWMH and lumbar spondylosis were associated with a poor response to the TT in iNPH patients. We should consider risk factors when selecting candidates for shunt surgery.

Background This multicenter retrospective study aimed to determine whether elective neck dissection (END) can be performed for T1-2N0M0 tongue cancer. Methods Patients with T1-2N0M0 tongue squamous cell carcinoma who received treatment between January 2000 and December 2012 were enrolled at 14 multicenter study sites. The 5-year overall survival (OS) and 5-year disease-specific survival (DSS) were compared between the propensity score-matched END and observation (OBS) groups. Results The results showed that the OS rates among the 1234 enrolled patients were 85.5% in the END group and 90.2% in the OBS group (P = 0.182). The DSS rates were 87.0% in the END group and 94.3% in the OBS group (P = 0.003). Among the matched patients, the OS rates were 87.1% in the END group and 76.2% in the OBS group (P = 0.0051), and the respective DSS rates were 89.2% and 82.2% (P = 0.0335). Conclusion This study showed that END is beneficial for T1-2N0M0 tongue cancer. However, END should be performed for patients with a tumor depth of 4–5 mm or more, which is the depth associated with a high rate of lymph node metastasis. The use of END should be carefully considered for both elderly and young patients.

Background: There is an unmet need for treatment options for generalised myasthenia gravis that are effective, targeted, well tolerated, and can be used in a broad population of patients. We aimed to assess the safety and efficacy of efgartigimod (ARGX-113), a human IgG1 antibody Fc fragment engineered to reduce pathogenic IgG autoantibody levels, in patients with generalised myasthenia gravis. Methods: ADAPT was a randomised, double-blind, placebo-controlled, phase 3 trial done at 56 neuromuscular academic and community centres in 15 countries in North America, Europe, and Japan. Patients aged at least 18 years with generalised myasthenia gravis were eligible to participate in the study, regardless of anti-acetylcholine receptor antibody status, if they had a Myasthenia Gravis Activities of Daily Living (MG-ADL) score of at least 5 (>50% non-ocular), and were on a stable dose of at least one treatment for generalised myasthenia gravis. Patients were randomly assigned by interactive response technology (1:1) to efgartigimod (10 mg/kg) or matching placebo, administered as four infusions per cycle (one infusion per week), repeated as needed depending on clinical response no sooner than 8 weeks after initiation of the previous cycle. Patients, investigators, and clinical site staff were all masked to treatment allocation. The primary endpoint was proportion of acetylcholine receptor antibody-positive patients who were MG-ADL responders (≥2-point MG-ADL improvement sustained for ≥4 weeks) in the first treatment cycle. The primary analysis was done in the modified intention-to-treat population of all acetylcholine receptor antibody-positive patients who had a valid baseline MG-ADL assessment and at least one post-baseline MG-ADL assessment. The safety analysis included all randomly assigned patients who received at least one dose or part dose of efgartigimod or placebo. This trial is registered at ClinicalTrials.gov (NCT03669588); an open-label extension is ongoing (ADAPT+, NCT03770403). Findings: Between Sept 5, 2018, and Nov 26, 2019, 167 patients (84 in the efgartigimod group and 83 in the placebo group) were enrolled, randomly assigned, and treated. 129 (77%) were acetylcholine receptor antibody-positive. Of these patients, more of those in the efgartigimod group were MG-ADL responders (44 [68%] of 65) in cycle 1 than in the placebo group (19 [30%] of 64), with an odds ratio of 4·95 (95% CI 2·21–11·53, p

Aim The prediction of functional outcome is essential in the management of acute ischemic stroke patients. We aimed to explore the various prognostic factors with multivariate linear discriminant analysis or neural network analysis and evaluate the associations between candidate factors, baseline characteristics, and outcome. Methods Acute ischemic stroke patients (n=1,916) with premorbid modified Rankin Scale (mRS) scores of 0-2 were analyzed. The prediction models with multivariate linear discriminant analysis (quantification theory type II) and neural network analysis (log-linearized Gaussian mixture network) were used to predict poor functional outcome (mRS 3-6 at 3 months) with various prognostic factors added to age, sex, and initial neurological severity at admission. Results Both models revealed that several nutritional statuses and serum alkaline phosphatase (ALP) levels at admission improved the predictive ability. Of the 1,484 patients without missing data, 560 patients (37.7%) had poor outcomes. The patients with poor outcomes had higher ALP levels than those without (294.3±259.5 vs. 246.3±92.5 U/l, P＜0.001). Multivariable logistic analyses revealed that higher ALP levels (1-SD increase) were independently associated with poor stroke outcomes after adjusting for several confounding factors, including the neurological severity, malnutrition status, and inflammation (odds ratio 1.21, 95% confidence interval 1.02- 1.49). Several nutritional indicators extracted from prediction models were also associated with poor outcome. Conclusion Both the multivariate linear discriminant and neural network analyses identified the same indicators, such as nutritional status and serum ALP levels. These indicators were independently associated with functional stroke outcome.

Backgrounds Vascular compression of the rostral ventrolateral medulla (RVLM) has been associated with hypertension or blood pressure (BP) variability. For acute ischemic stroke patients, increased BP variability may cause poor functional outcomes. We tested the hypothesis that RVLM compression was associated with increased BP variability or stroke outcome in acute ischemic stroke patients. Methods Acute ischemic stroke patients (n = 622) with 24-h ambulatory BP monitoring during the subacute phase of stroke (median 9 days from onset) were retrospectively studied. Variability in BP was evaluated with the SD and coefficient of variation of SBP and DBP. The morning surge was also evaluated. The presence of RVLM compression was evaluated using time-of-flight three-dimensional MRI. A poor outcome was defined as a modified Rankin Scale score of 3-6 at 3 months. Results Patients with RVLM compression (n = 213) had significantly higher 24-h SBP mean, 24-h SBP SD, 24-h SBP coefficient of variation, 24-h DBP mean, 24-h DBP SD, and 24-h DBP coefficient of variation values and a higher prevalence of morning surge than those without (n = 409). Multiple regression analysis revealed that RVLM compression was associated with increased SBP variability, DBP variability, and morning surge. Despite the significant association between RVLM compression and BP variability, RVLM compression was not associated with poor stroke outcome. Conclusion Although RVLM compression was closely associated with BP variability in the subacute ischemic stroke phase, an effect of RVLM compression on stroke outcome was not observed.

Clear cell carcinoma is an extremely rare low-grade malignancies occurring in less than 1% of salivary gland tumors. We report a case of clear cell carcinoma of the hard palate in a 15-year-old adolescent patient. She first noticed a palatal tumor at age 9, but the tumor was left untreated for 6 years. We performed incisional biopsy, but no definitive diagnosis was obtained. Excisional biopsy was then performed, and the histopathological diagnosis was clear cell carcinoma of the salivary gland. However, the tumor was exposed at the margin of the surgical specimen; thus, additional excision was performed. Five years after the treatment, no local recurrence or metastasis has been observed.

Introduction The association of malnutrition on stroke subtypes has not been well established. We investigated the relationship between malnutrition and functional outcome according to stroke subtypes. Methods Acute consecutive ischemic stroke patients (n = 1915, 73 ± 12 years) were analysed. The nutritional status was evaluated using the Controlling Nutritional Status (CONUT) score, which was calculated from the serum albumin level, lymphocyte count, and total cholesterol level; malnutrition was defined as a CONUT score of 5 to 12. A poor outcome was defined as a modified Rankin Scale score ≥ 3 at 3 months. Results Of the 1518 patients, 113 (7.4%) had malnutrition, and 533 (33.1%) had a poor outcome. Among the patients with cardioembolic stroke and stroke of other etiologies, those with malnutrition had higher rates of poor outcomes than those without. After adjusting for age, sex, and baseline stroke severity, malnutrition was independently associated with poor outcomes in patients with cardioembolic stroke and other stroke etiologies (odds ratio 3.25, 95% confidence interval 1.02–10.4, p = .044; 6.22, 2.71–14.3, p Conclusions Considering stroke subtype, malnutrition determined using the CONUT score was independently associated with poor outcomes in the patients with cardioembolic stroke or stroke of other etiologies.

Background Malnutrition is an independent risk factor for poor outcomes in patients with acute ischemic stroke. However, the indicator of malnutrition has not yet been established. We investigated the relationship between the Controlling Nutritional Status score, a useful prognostic measure of malnutrition in patients with cardiovascular diseases and malignant tumors, and functional outcomes in patients with acute ischemic stroke. Methods Patients with acute ischemic stroke (n = 264, 71 ± 12 y old) were consecutively evaluated within 7 d of stroke onset. The Controlling Nutritional Status score was calculated from the serum albumin, total peripheral lymphocyte count, and total cholesterol; a Controlling Nutritional Status score of 5 to 12 was defined as malnutrition. Poor functional outcome was defined as a modified Rankin Scale score of 3 to 6 at 3 mo. Results Of the total cohort, 230 patients (87.1%) were assessed. The patients with poor functional outcome (n = 85) were older; had a lower body mass index; had a higher frequency of atrial fibrillation, chronic heart failure, and anemia; and had a lower frequency of dyslipidemia and a current smoking status. In addition, the Controlling Nutritional Status score and National Institutes of Health Stroke Scale score at admission were significantly higher for the patients with poor functional outcome. After multivariate analysis, adjusted for baseline characteristics, a Controlling Nutritional Status score of 5 to 12 was found to be independently associated with poor outcome (odds ratio: 4.15, 95% confidence interval: 1.52–11.67, P = 0.005). Conclusions The Controlling Nutritional Status score at admission could be a useful prognostic marker of 3-mo functional outcomes in patients with acute ischemic stroke.

Background The risk of complications from thromboembolism is increased for patients with malignancy. Cancer-associated stroke is also a serious issue with regard to the management of patients with cancer because stroke incidence often causes disabilities that affect daily life and cancer treatment strategy. Methods Between March 2011 and September 2017, 328 patients with acute ischemic stroke were registered to our hospital. Results Of these patients, 26 (7.9%) had a cancer-associated stroke diagnosis, namely, Trousseau syndrome. After ischemic stroke onset, malignancy treatment was changed to palliative treatment for 11 patients. Eighteen patients died 1 year after ischemic stroke onset, and 15 of these patients underwent cancer treatment according to the best supportive care policy. Of those who died, 8 underwent anticoagulation therapy. We described the clinical courses of 3 cases among 26 cases with Trousseau syndrome. Two cases took direct oral anticoagulants (DOACs) due to cancer-associated venous thromboembolism before stroke onset, and there has been no stroke recurrence with subcutaneous unfractionated heparin. In the third case, when cancer activity was suppressed, we changed DOACs from subcutaneous unfractionated heparin and continued DOACs without thromboembolic events. Conclusions There is insufficient evidence regarding cases for which DOACs would be suitable for the prevention of thromboembolism and regarding its long-term efficacy and safety in patients with cancer. As it stands, heparin treatment, which has multifaceted antithrombotic actions, may be suitable for cancer-associated stroke prevention.

Histone acetyltransferases (HATs) play a crucial role in post-translational modification. Among them, overexpression, mutation, or hyperfunction of EP300/CBP has been associated with various cancers. In this study, we identified the novel compound 2-chloro-5-[5-[(E)-[1-(3-chlorophenyl)-3-methyl-5-oxo-pyrazol-4-ylidene]methyl]-2-furyl]benzoic acid (1) as an EP300 HAT inhibitor via virtual screening. Further research has been focused on the design, synthesis, and in vitro biological evaluation of virtual hit derivatives. The studies revealed that 4-pyridone-3-carboxylic acid derivatives exhibited bioisosterism of benzoic acid. Replacement proved effective, providing compounds with similar EP300 HAT-inhibitory activity and improved cell growth-inhibitory activity compared to the benzoic acid analogs. Through these studies, we identified a potent and selective EP300/CBP HAT inhibitor.

AIM This study aimed to evaluate the associations of blood pressure (BP) variability in patients with ischemic stroke during the subacute phase using ambulatory blood pressure monitoring and the ankle-brachial index (ABI). METHODS We retrospectively examined 831 consecutive patients (women 44.8%, mean age 76 ± 12 years) with acute ischemic stroke who underwent 24-h ambulatory blood pressure monitoring during the subacute phase of stroke (median 9 days from onset) and an ABI examination. BP variability was evaluated by assessing the standard deviation and coefficient of variation of systolic BP and diastolic BP. A low ABI was defined as an ABI

Mucinous adenocarcinoma (MAC) rarely occurs in the salivary glands, especially in the labial gland. MACs arising from the salivary glands are characterized by an aggressive behavior due to high invasiveness and a high rate of regional lymph node metastasis. Here, we report a case of MAC arising from the lower lip, shown to have elevated serum carcinoembryonic antigen (CEA) levels by the medical checkup. The tumor showed aggressive behavior and serum CEA levels increased with repeated recurrence. CEA has been shown to have surprisingly diverse functions in cell adhesion, intracellular and intercellular signaling, and complex biological processes such as cancer progression, inflammation, angiogenesis, and metastasis. A MAC arising from the salivary glands may have a poor prognosis because CEA is highly expressed. Generally, serum CEA levels have not been used as tumor markers for salivary gland malignancies; however, it may be useful for MAC arising from salivary glands. We recommend prospective research to determine whether serum CEA estimation is useful as a component of routine pre-treatment workup for MACs arising from the salivary glands.

In myasthenia gravis (MG) patients on intravenous methylprednisolone (IVMP) therapy, initial deterioration should be carefully monitored because it may cause myasthenic crisis. The aim of this study was to investigate the onset, duration and related factors of initial deterioration from the first IVMP in MG patients.A total dose of IVMP in the first cycle of 750 mg or less, over 750 to 1500 mg, and over 1500 to 3000 mg was used in the analysis. Initial deterioration was evaluated in qualitative and quantitative evaluation and was defined as an increase of 2 or more points on the The Myasthenia Gravis Activities of Daily Living (MG-ADL) scale after the start of IVMP therapy in the quantitative evaluation.We enrolled 51 mainly mild MG patients. The mode of onset of initial deterioration from the first IVMP treatment was day 4 in the qualitative and quantitative evaluation. In addition, the mode of duration was 3 days. In multiple logistic regression analysis, factors related to initial deterioration were MGFA classification with overall disease duration up to just before IVMP and thymectomy before IVMP in both the qualitative and the quantitative evaluation (p .001). One to four cycles of IVMP improved the MG-ADL score at hospital discharge from that at the start of IVMP (p .001).Disease severity and thymectomy before IVMP are related to initial deterioration in MG patients. IVMP can be repeated after initial deterioration weekly in most patients.

We report on the findings of the first antimicrobial susceptibility surveillance study in Japan of isolates recovered from odontogenic infections. Of the 38 facilities where patients representing the 4 groups of odontogenic infections were seen, 102 samples were collected from cases of periodontitis (group 1), 6 samples from pericoronitis (group 2), 84 samples from jaw inflammation (group 3) and 54 samples from phlegmon of the jaw bone area (group 4) for a total of 246 samples. The positivity rates of bacterial growth on culture were 85.3%, 100%, 84% and 88.9%, respectively, for groups 1, 2, 3 and 4. Streptococcus spp. isolation rates according to odontogenic infection group were 22% (group 1), 17.7% (group 3) and 20.7% (group 4). Anaerobic isolation rates were 66.9% (group 1), 71.8% (group 3) and 68.2% (group 4). Drug susceptibility tests were performed on 726 strains excluding 121 strains that were undergrown. The breakdown of the strains subjected to testing was 186 Streptococcus spp., 179 anaerobic gram-positive cocci, 246 Prevotella spp., 27 Porphyromonas spp., and 88 Fusobacterium spp. The isolates were tested against 30 antimicrobial agents. Sensitivities to penicillins and cephems were good except for Prevotella spp. The low sensitivities of Prevotella spp is due to β-lactamase production. Prevotella strains resistant to macrolides, quinolones, and clindamycin were found. No strains resistant to carbapenems or penems were found among all strains tested. No anaerobic bacterial strain was resistant to metronidazole. Antimicrobial susceptibility testing performed on the S. anginosus group and anaerobic bacteria, which are the major pathogens associated with odontogenic infections, showed low MIC90 values to the penicillins which are the first-line antimicrobial agents for odontogenic infections; however, for Prevotella spp., penicillins combined with β-lactamase inhibitor showed low MIC90 values.

Thus far, it is well known that increased blood pressure variability may exacerbate stroke outcomes. Blood pressure in the acute phase would be influenced by both reactive hypertension to stroke and intrinsic blood pressure reactivity. Thus, we aimed to evaluate the association between blood pressure variability and outcomes at 3 months using ambulatory blood pressure monitoring in ischemic stroke patients in the subacute phase after reactive hypertension subsided. We retrospectively examined 626 consecutive patients with acute ischemic stroke who underwent 24-hour ambulatory blood pressure monitoring during the subacute phase of stroke (median, 9 days from onset). The variability in blood pressure was evaluated by assessing the standard deviation and coefficient of variation of systolic and diastolic blood pressure. The primary outcome was functional status at 3 months. A poor outcome was defined as a modified Rankin scale score of 3 or more and a good outcome as 2 or less. We assessed the functional outcome at 3 months in 497 patients (79.4%). The mean systolic and diastolic blood pressure levels were not associated with functional outcome. The multivariable analysis revealed that increases in the standard deviations of systolic and diastolic blood pressure, coefficient of variation of diastolic blood pressure, and morning blood pressure surge were associated with poor outcome. Blood pressure variability during the subacute phase of ischemic stroke can be a useful prognostic indicator of poor functional outcome at 3 months in patients with acute ischemic stroke.

Tooth loss, closely associated with malnutrition, increases the risk for cardiovascular disease. The aim of this study was to examine the link between tooth loss, nutritional status, and stroke outcomes.We retrospectively analyzed 195 consecutive patients with acute ischemic stroke who were evaluated for tooth loss. Tooth loss was classified as mild or severe. Nutritional status was evaluated using the Controlling Nutritional Status (CONUT) score. A poor neurologic outcome was defined as a score of 3 to 6 on the modified Rankin Scale at 3 mo post-stroke onset; a score of 0 to 2 was defined as a good outcome.A significant correlation was observed between tooth loss and the CONUT score at admission (ρ = 0.156; P = 0.034). Patients with poor outcomes had higher CONUT scores (P0.001) and a greater frequency of severe tooth loss (P = 0.025). On multivariate analysis, severe tooth loss (odds ratio [OR], 3.93; 95% confidence interval [CI], 1.31-11.8) and the CONUT score (OR, 1.33; 95% CI, 1.02-1.74) were independently associated with poor stroke outcomes.Nutritional status was associated with tooth loss among patients with acute ischemic stroke. Severe tooth loss and a higher CONUT score were independently associated with poor stroke outcomes.

Antibody-drug conjugates deliver anticancer agents selectively and efficiently to tumor tissue and have significant antitumor efficacy with a wide therapeutic window. DS-8201a is a human epidermal growth factor receptor 2 (HER2)-targeting antibody-drug conjugate prepared using a novel linker-payload system with a potent topoisomerase I inhibitor, exatecan derivative (DX-8951 derivative, DXd). It was effective against trastuzumab emtansine (T-DM1)-insensitive patient-derived xenograft models with both high and low HER2 expression. In this study, the bystander killing effect of DS-8201a was evaluated and compared with that of T-DM1. We confirmed that the payload of DS-8201a, DXd (1), was highly membrane-permeable whereas that of T-DM1, Lys-SMCC-DM1, had a low level of permeability. Under a coculture condition of HER2-positive KPL-4 cells and negative MDA-MB-468 cells in vitro, DS-8201a killed both cells, whereas T-DM1 and an antibody-drug conjugate with a low permeable payload, anti-HER2-DXd (2), did not. In vivo evaluation was carried out using mice inoculated with a mixture of HER2-positive NCI-N87 cells and HER2-negative MDA-MB-468-Luc cells by using an in vivo imaging system. In vivo, DS-8201a reduced the luciferase signal of the mice, indicating suppression of the MDA-MB-468-Luc population; however, T-DM1 and anti-HER2-DXd (2) did not. Furthermore, it was confirmed that DS-8201a was not effective against MDA-MB-468-Luc tumors inoculated at the opposite side of the NCI-N87 tumor, suggesting that the bystander killing effect of DS-8201a is observed only in cells neighboring HER2-positive cells, indicating low concern in terms of systemic toxicity. These results indicated that DS-8201a has a potent bystander effect due to a highly membrane-permeable payload and is beneficial in treating tumors with HER2 heterogeneity that are unresponsive to T-DM1.

Background Few studies have examined the prevalence of peripheral arterial disease (PAD) with the use of computed tomography angiography (CTA) in patients with acute ischemic stroke (AIS), although several reports have examined its prevalence using an ankle brachial index (ABI). We aimed to determine the prevalence of PAD indicated by CTA in patients with AIS and to clarify the prevalence of PAD in each clinical ischemic stroke subtype. Methods We included 199 consecutive patients with AIS admitted to our hospital and divided them into PAD and non-PAD groups according to the CTA findings. Results Of the 199 patients, 40 (20.1%) had PAD; 27 (67.5%) of the PAD patients were asymptomatic. The prevalence of abnormal ABI (≤.9) was 12.2%. Patients with PAD were older (78.3 ± 10.2 versus 71.5 ± 10.9, P .001) and had a significantly lower ABI value (.89 ± .24 versus 1.15 ± .09, P .001) and higher prevalence of diabetes mellitus (50.0% versus 31.4%, P = .028), atrial fibrillation (40.0% versus 16.4%, P = .001), coronary artery disease (32.5% versus 8.2%, P .001), and intracranial arterial stenosis (47.5% versus 28.9%, P = .025) than patients without PAD. The prevalence of cerebral microbleeds was not different between patients with PAD and those without PAD (25.6% versus 25.4%, P = .985). The prevalence of PAD among ischemic stroke subtypes was highest in patients with cardioembolic infarction (40.5%). Conclusions Almost one fourth of the AIS patients examined had PAD on CTA. Cardioembolic infarction patients showed the highest prevalence of PAD among the clinical ischemic subtypes, suggesting the coexistence of atheromatous diseases and atrial fibrillation.

Trastuzumab conjugates consisting of exatecan derivatives were prepared and their biological activities and physicochemical properties were evaluated. The ADCs showed strong efficacy and a low aggregation rate. The exatecan derivatives were covalently connected via a peptidyl spacer (Gly-Gly-Phe-Gly), which is assumed to be stable in circulation, and were cleaved by lysosomal enzymes following ADC internalization into tumor tissue. These anti-HER2 ADCs exhibited a high potency, specifically against HER2-positive cancer cell lines in vitro. The ADCs, bearing exatecan derivatives which have more than two methylene chains, exhibited superior cytotoxicity. It was speculated that steric hindrance of the cleavable amide moiety could be involved in the drug release. The adequate alkyl lengths of exatecan derivatives (13, 14, 15) were from two to four in terms of aggregation rate. The ADC having a hydrophilic moiety showed good efficacy in a HER2-positive and Trastuzumab-resistant breast carcinoma cell model in mice.

We report the case of a 42-year-old man with chronic hepatitis B virus infection who developed weakness and paresthesia in the extremities 2 months after administration of pegylated interferon (Peg-IFN)α-2a. Nerve conduction studies conducted 6 months after onset showed abnormal temporal dispersions in both tibial nerves. We diagnosed chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) resulting from treatment with Peg-IFNα-2a. Neurological symptoms were prolonged despite suspension of the treatment. Subsequent treatment with intravenous immunoglobulin improved both clinical symptoms and temporal dispersion. IFNα-induced CIDP is rare, but can reportedly progress even after interruption of IFN-α without immunotherapy. Patients presenting with polyneuropathy after initiation of IFN-α thus require close attention.

A standard regimen for ovarian malignant germ cell tumors is bleomycin, etoposide, cisplatin(BEP)chemotherapy. Adherence to a treatment schedule of every 21 days has been reported to be important. However, the incidence of febrile neutropenia( FN)and the optimaluse of granulocyte-colony stimulating factor(G-CSF)are unclear because of the low incidence of ovarian malignant germ cell tumors. We experienced 2 cases of ovarian malignant germ cell tumors that received BEP therapy after fertility-conserving surgery. In 1 case, we delayed drug administration in the first cycle because of FN. However, in order to maintain dose intensity(DI), we performed chemotherapy every 21 days by shortening the rest period. Myelosuppression may be severe in the first cycle of BEP therapy; however, it may be possible to adhere to the treatment schedule by using primary prophylactic administration of G-CSF.

We herein report two cases of acute ischemic stroke associated with iron deficiency anemia (IDA) due to bleeding from uterine fibroids. Anemia is not generally recognized as a risk factor for stroke. The physiological mechanisms that may factor in the development of ischemic stroke in patients with IDA include thrombocytosis, hypercoagulable state, and anemic hypoxia. In our two cases, IDA was considered to be the cause of ischemic stroke because all other known causes of stroke were ruled out. In patients with ischemic stroke due to anemia, early treatment of the anemia is important to prevent stroke recurrence.

We have discovered and reported potent p53-MDM2 interaction inhibitors possessing dihydroimidazothiazole scaffold. Our lead showed strong activity in vitro, but did not exhibit antitumor efficacy in vivo for the low metabolic stability. In order to obtain orally active compounds, we executed further optimization of our lead by the improvement of physicochemical properties. Thus we furnished optimal compounds by introducing an alkyl group onto the pyrrolidine at the C-2 substituent to prevent the metabolism; and modifying the terminal substituent of the proline motif improved solubility. These optimal compounds exhibited good PK profiles and significant antitumor efficacy with oral administration on a xenograft model using MV4-11 cells having wild type p53.

With the aim of discovering potent inhibitors of the p53-MDM2 interaction and thus obtaining a potent anticancer drug, we have pursued synthesis and optimization of dihydroimidazothiazole derivatives, which have been discovered via scaffold hopping by mimicing the mode of interaction between MDM2 and Nutlins. Upon the discovery we encountered a problem involving the chemical instability of the scaffold, that is, susceptibility to oxidation which led to imidazothiazole. In order to solve this problem and to obtain further potent compounds, we executed medicinal research and thus furnished the optimal compounds by incorporating the methyl group onto the C-6 position to avoid the oxidation, and by modifying the C-2 moiety of the additional proline motif, which furnished high potency. The incorporation of the pyrrolidine moiety at the C-2 position raised another hydrophobic interaction site with MDM2 protein, which was generated by the induced-fitting observed by co-crystal structure analysis. These optimal molecules showed significant improvement in potency when compared with the early lead (+)-1 or Nutlin-3a.

About three weeks after successful coil embolization of a basilar apex aneurysm, a 66-year-old woman developed occipital headaches. T2 and FLAIR MRI brain images demonstrated multiple new hyperintense lesions in the posterior circulation territory including cerebellum, right superior cerebellar peduncle, left thalamus and bilateral temporo-occipital lobes and she was subsequently hospitalized. Findings suggestive of other underlying disease were not observed, although an increased protein level was noted in cerebrospinal fluid (69 mg/dl). Headache and clinical findings improved approximately 12 weeks after coil embolization. MRI findings also showed improvement. These clinical and radiological findings made this patient a distinctive case of posterior reversible encephalopathy syndrome (PRES) associated with coil embolization suggesting that clinicians should be aware that PRES can present as comparatively mild symptoms several weeks after coil embolization.

Objective: To clarify therapeutic effects of azithromycin, clarithromycin, minocycline and tosufloxacin against macrolide-resistant Mycoplasma pneumoniae (MRMP) pneumonia and against macrolide-sensitive Mycoplasma pneumoniae (MSMP) pneumonia in pediatric patients. Methods: A prospective, multicenter observational study was conducted from July 2013 to August 2015. The therapeutic effects of azithromycin, clarithromycin, minocycline and tosufloxacin were evaluated in 59 patients with pneumonia caused by MRMP and in 50 patients with pneumonia caused by MSMP. In vitro activities of antimicrobial agents against isolates of Mycoplasma pneumoniae were also measured. Results: Mean durations of fever following commencement of treatment in patients infected with MRMP and MSMP were 5.2 and 1.9 days, respectively (log-rank test, P < 0.0001). Among patients infected with MRMP, mean durations of fever were 4.6, 5.5, 1.0 and 7.5 days for patients treated with azithromycin, clarithromycin, minocycline and tosufloxacin, respectively (log-rank test, P < 0.0001). Among patients infected with MSMP, mean durations of fever were 2.5, 1.7, 0.9 and 4.3 days for patients treated with azithromycin, clarithromycin, minocycline and tosufloxacin, respectively (log-rank test, P = 0.0162). The MIC90s of azithromycin and clarithromycin among the 27 isolates of MRMP were 64 and 256 μg/ml, respectively, and those among the 23 isolates of MSMP were

Case Report A 66-year-old man with acute ischemic stroke in the setting of lung adenocarcinoma developed acute-onset deep vein thrombosis (DVT) of the lower limbs after changing to warfarin from a heparin combination. The diagnosis of warfarin-resistant DVT was established based on the laboratory data and clinical evaluation. Heparin administration resulted in good control of thrombin regulation. Cancer patients are at high risk of venous thromboembolism, and the combination of these 2 conditions is known as Trousseau's syndrome. Conclusion Our report suggests that heparin administration may provide good control of thromboembolic events, although there is no established medical treatment to extend the survival of patients with Trousseau's syndrome.

Starting with Nutlins as an initial lead, we designed and generated bicyclic scaffolds aiming to place cis-bischlorophenyl moiety at the equivalent location where the hydrophobic interaction with MDM2 could be expected. As a result, we discovered novel MDM2 inhibitors possessing a dihydroimidazothiazole scaffold. Further exploration of the side chains on the dihydroimidazothiazole scaffold aided by molecular modeling resulted in compounds exhibiting almost comparable in vitro potency to Nutlin-3a.

To assess the safety and efficacy of infliximab (IFX) for the treatment of patients with Kawasaki disease (KD).This was a nationwide survey of 274 Japanese institutions exploring how IFX was used to treat patients with KD. The patients' sex, age, treatment course, pre- and post-IFX therapy blood test results, coronary artery lesions (CALs), and adverse events (AEs) were evaluated.We analyzed 434 patients with KD who received IFX between March 2005 and November 2014. The median age at onset was 33 months (range 1-138), and 66 patients (15.2%) were under 1 year old. In all cases, IFX was administered as additional treatment. The median days of illness at the initiation of IFX was 9 days. In 275 patients (63.4%), IFX was administered as third-line treatment, and in 106 patients (24.4%), IFX was administered as fourth-line treatment. Single dose IFX 5 mg/kg was administered to 412 patients (94.9%). After IFX, 363 patients (83.6%) became afebrile within 2 days, and the white blood cell count, percentage of neutrophils, and serum C-reactive protein levels significantly decreased (P .001), although 119 patients (27.4%) received additional treatment. Before IFX, 132 patients (30.4%) had already developed CALs. In patients without CALs before IFX, 31 patients (10.3%) newly developed CAL after IFX, whereas 32 patients (24.2%) with CAL before IFX showed increased CAL severity. Eighty AEs were observed in 69 patients (15.9%); however, serious AEs were few and reversible.IFX might be an effective and tolerable treatment for refractory KD.

We have published p53-MDM2 interaction inhibitors possessing a novel dihydroimidazothiazole scaffold. Although our lead compound 1 showed strong antitumor activity with single oral administration on a xenograft model using MV4-11 cells harboring wild-type p53, it needed a higher dose (200mg/kg) for distinct efficacy. We executed further optimization with the aim of improvement of potency and physicochemical properties. Thus optimal compounds were furnished by introducing fluorine moieties onto the phenyl ring at the C-6 position and the pyrrolidine part at the C-2 substituent; and modifying the terminal piperazine to 4,7-diazaspiro[2,5]octane variants. Furthermore, replacing 4-chlorophenyl on the C-5 position with pyridyl variant decreased nonspecific cytotoxicity significantly. Our exploration afforded DS-5272 indicating excellent antitumor efficacy from a dose of 25mg/kg on SJSA-1 xenografted models with high safety and good PK profiles, which has appropriate potency as a clinical candidate.

Salmonella Enteritidis often causes food poisoning. In this study, an extremely rare case of cervical abscess caused by S. Enteritidis is reported. In January 2003, a 44-year-old man visited our hospital with swelling of the left submandibular region. He had been suffering from a severe diabetic condition but had neglected to seek medical attention. An incision was made at the abscess to drain the pus from which only S. Enteritidis was isolated. This finding led to the discovery that he had suffered from an episode of food poisoning 6 months earlier. However, the organism was not isolated from the stool. The patient recovered with the administration of panipenem/betamipron and gatifloxacin. The S. Enteritidis strain isolated from the pus obtained from this case and that detected from the samples originating from the other patients during the episode of food poisoning 6 months earlier were examined by using pulse-field gel electrophoresis (PFGE). The PFGE patterns of the strains were almost identical. The molecular epidemiological analysis by PFGE was useful in estimating the infection route. In an immuno-compromised host such as those suffering from diabetes mellitus, one must be reminded that unusual bacteria (including S. Enteritidis) may cause a cervical abscess.

A series of novel 3-[4-phenyl-1-piperazinyl]-1-[5-methyl-1-(2-pyrimidinyl)-4-pyrazolyl]-1-trans-propenes and related compounds were synthesized and evaluated by their cytotoxic activity against several tumor cell lines in vitro and in vivo antitumor activity against some tumor models when administered both intraperitoneally and orally. Compounds with the 3-chloropyridin-2-yl group (9g) and the 3-fluoro-5-substituted phenylpiperazinyl group (29b, c, and e) showed significantly potent cytotoxicity by in vitro testing. Among them, the 3-cyano-5-fluorophenyl derivative (29b) exhibited potent antitumor activity against several tumor cells including human carcinoma without causing undesirable effects in mice.

Myositis ossificans (MO) is a rare disease in which ossification develops in the muscle or soft tissue. MO is divided broadly into myositis ossificans progressiva (MOP) and myositis ossificans traumatica (MOT). MOP is an autosomal dominant disease in which multiple, heterotopic ossifications develop in the systemic muscle, fascia, tendons, and ligaments, sometimes within families.1,2 In many cases, MOP occurs in childhood, and the range of motion of the joints gradually becomes restricted, leading to ankylosis. The patient may die of pulmonary complications due to difficulty of movement of the respiratory muscles by 35 to 40 years of age. Prognosis is poor.1,2 MOT, also called traumatic myositis ossificans, myositis ossificans circumscripta, localized myositis ossificans, or fibrodysplasia ossificans circumscripta, is a disease in which muscles are ossified after trauma or inflammation. Ossification is likely to occur in the femoral region or brachium but rarely in the head or neck, including the masticatory muscle. Unlike MOP, MOT is often remitted through surgical treatment, including excision of the ossification, but some patients have repeated relapses and are refractory to treatment. We report the case of a patient with MOT in the bilateral masticatory muscles after a blow to the face, and we review the survey of literature since 1980 on 23 cases of MOT in the head and neck. Report of a Case

A series of novel 3-substituted-1-[5-methyl-1-(2-pyrimidinyl)-4-pyrazolyl]-1-trans-propenes in order to improve the in vitro and in vivo activity of our prototype 3-[4-(3-chlorophenyl)-1-piperazinyl]-1-[5-methyl-1-(2-pyrimidinyl)-4-pyrazolyl]-1-trans-propene (2) were synthesized and evaluated by assays of growth inhibition against several tumor cell lines in vitro and antitumor activity against some tumor models when dosed both intraperitoneally and orally in vivo. Compounds 7a and 7e, the 3,5-difluorophenyl and 3,5-dichlorophenyl analogues of 2, respectively, showed significantly more potent cytotoxicity than 2 in vitro and potent antitumor activities without causing decrease of body temperature related to side effects.

Spinocerebellar ataxia type 10 (SCA10) is an autosomal-dominant cerebellar ataxia that is variably accompanied by epilepsy and other neurological disorders. It is caused by an expansion of the ATTCT pentanucleotide repeat in intron 9 of the ATXN10 gene. Until now, SCA10 was almost exclusively found in the American continents, while no cases had been identified in Japan. Here, we report the first case of an SCA10 family from Japan. The clinical manifestations in our cases were cerebellar ataxia accompanied by epilepsy, hyperreflexia and cognitive impairment. Although the primary pathology in SCA10 in humans is reportedly the loss of Purkinje cells, brain MRI revealed frontal lobe atrophy with white matter lesions. This pathology might be associated with cognitive dysfunction, indicating that the pathological process is not limited to the cerebellum. Examination of the SNPs surrounding the SCA10 locus in the proband showed the "C-expansion-G-G-C" haplotype, which is consistent with previously reported SCA10-positive individuals. This result was consistent with the findings that the SCA10 mutation may have occurred before the migration of Amerindians from East Asia to North America and the subsequent spread of their descendants throughout North and South America.

OBJECTIVE: To estimate the probability of and risk factors for the recurrence of invasive cervical carcinoma over 5 years after initial therapy. METHODS: Patients (n = 827) with invasive cervical carcinoma were treated and received follow-up care for up to 29 years. Late recurrence was defined as recurrence more than 5 years after initial therapy. The probability of late recurrence was evaluated in terms of clinical stage, histologic type, and type of initial therapy. RESULTS: Late recurrence was seen in 21 of 569 patients who had survived 5 years (3.7%). Recurrence rates were 1.8% (six of 331) in stage I, 5.2% (eight of 154) in stage II, 8.6% (seven of 81) in stage III, and 0% (none of three) in stage IV. The probability of late recurrence in patients with stage I disease was significantly lower than that in stage II and stage III diseases (stage I compared with stage II, P = .038, stage I compared with stage III, P = .002). Late recurrence occurred in 21 (3.8%) of 547 cases of squamous cell carcinoma, whereas no late recurrences were found in 22 cases of adenocarcinoma. The late recurrence rate in patients who received radiation (7.1%, 17 of 241) was significantly higher than that in patients who received surgery (1.2%, four of 328; P = .001). CONCLUSION: Patients with uterine cervical squamous cell carcinoma, especially those with stage II or stage III diseases who received radiation therapy as initial treatment, warrant annual follow-up care beyond the standard 5 years after initial therapy.

We investigated the in vitro antitumor activities toward mouse and human cell lines of optically active synthetic bistetrahydrofuran (bis-THF) derivatives as analogs of Annonaceous acetogenins, which contain bis-THF, long unbranched alkyl chains, hydroxyl groups, and an alpha, beta-unsaturated gamma-lactone. These bis-THF derivatives were synthesized in a stereocontrolled manner, and have several modified structures at the alkyl side chains. We found that: 1) the unsaturated gamma-lactone contributes to high potency in combination with the other less-functionalized alkyl chain, 2) the same absolute configuration of the bis-THF skeleton as that of the natural products produces more potent activity than the counterpart, 3) the alkyl chains and hydroxyl groups are crucial for exhibiting antitumor activity, 4) hydroxyl groups adjacent to the bis-THF skeleton may be replaced by amino or acylamino groups.

We report a case of a 46-year old man with acute autonomic, sensory and motor neuropathy (AASMN). He developed severe orthostatic hypotension, anuria,anhydrosis, tonic pupil with dysarthria, dysphagia, jaw claudication, and dysesthesia and sharp pain several days after symptom of upper respiratory infection. Neurological examination revealed severely decreased superficial sensation with normal deep sensation. Brain MRI findings showed bilateral trigeminal nerve swelling with gadolinium (Gd) enhancement. His motor and sensory symptoms and MRI abnormality were improved after the administration of intravenous immunoglobulin and intravenous methylprednisolone therapy; however his autonomic symptoms scarcely reacted to these immunotherapies. As long as we investigated in AASMN cases, bilateral trigeminal nerve swelling with Gd enhancement and dissociation between superficial and deep sensation disturbance have not reported, suggesting that the present case mainly disrupted C nerve fibers distributing postganglionic autonomic and temperature-pain sensory nerves.

A series of cis-1,2-diaminocyclohexane derivatives were synthesized with the aim of optimizing previously disclosed factor Xa (fXa) inhibitors. The exploration of 5-6 fused rings as alternative S1 moieties resulted in two compounds which demonstrated improved solubility and reduced food effect compared to the clinical candidate, compound A. Herein, we describe the synthesis and structure-activity relationship (SAR), together with the physicochemical properties and pharmacokinetic (PK) profiles of some prospective compounds.