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Background Dabigatran is a direct thrombin inhibitor and an anticoagulant that is prescribed to prevent ischemic stroke and systemic embolism in non-valvular atrial fibrillation. Dabigatran (150 mg twice daily) is non-inferior to warfarin for the prevention of stroke and systemic embolism. A dose reduction to 110 mg twice daily should be considered for patients with decreased renal function, elderly patients, and those with a history of gastrointestinal bleeding. A small number of patients are prescribed 75 mg twice daily; however, excessive dose reduction below that indicated on the package insert may decrease the effectiveness of dabigatran. In this study, we investigated the incidence of thromboembolic events and hemorrhagic complications in patients receiving different doses of dabigatran, including patients receiving the very low-dose of 75 mg twice daily. Methods Five hospitals in Meguro and Setagaya areas of Tokyo were included in this study. The subjects were patients receiving dabigatran in the hospitals from March 2011 to February 2014. Thromboembolic events (stroke, systemic embolism, and transient cerebral ischemic attack) and hemorrhagic complications occurring before December 2014 were retrospectively evaluated. Results A total of 701 subjects received dabigatran during the study period: 187 patients (26.7%) received 150 mg twice daily (normal dose), 488 patients (69.6%) received 110 mg twice daily (low-dose), and 26 patients (3.7%) received 75 mg twice daily (very low-dose). Thromboembolism occurred in 4 (2.1%), 11 (2.3%), and 3 patients (11.5%), in the normal dose, low-dose, and very low-dose groups, respectively. The odds ratio of the 75 mg dose to the 150 and 110 mg doses was 5.73 (95% CI, 1.55–21.2; p = 0.009), and the incidence with the 75 mg dose was higher than that with the other doses. Although the number of events was limited, it should be noted that 3 patients in the very low-dose group had thromboembolic events. Conclusions The results suggest that sufficient anticoagulation efficacy may not be maintained when the dabigatran dose is excessively reduced to 75 mg twice daily.

Recent data suggest a decreased prevalence of IFN-γ-producing T lymphocytes (Type 1 T cells) in tumor-bearing hosts. Moreover, it has been reported that Treg have a strong impact on the activation and proliferation of CD4 (+) and CD8 (+) lymphocytes; however, no previous reports have described the relationship between Treg and the progression of tumor, or Type 1 T cell populations in dogs with malignant tumor. In this study, the percentage of Treg, Th1, and Tc1 in the peripheral blood of dogs with oral malignant melanoma and healthy dogs was measured and compared. Although the percentages of Th1 and Tc1 in dogs with oral malignant melanoma were less than those in healthy dogs (Th1: P < 0.01, Tc1: P < 0.05), the percentage of Treg was increased (P < 0.01). A significant inverse correlation between the percentage of Tc1 and the clinical tumor stage (P < 0.01), and a significant correlation between that of Treg and the clinical tumor stage (P < 0.001) was found. Moreover, there was a significant inverse correlation between the percentages of Treg and Th1 (P < 0.05) or Tc1 (P < 0.001). In conclusion, the percentage of Treg increases with the tumor stage in the peripheral blood of dogs with oral malignant melanoma. In dogs, Treg appears to suppress Type 1 immunity, which may be responsible for anti-tumor responses.

Secondary brain damage (SBD) is caused by apoptosis after traumatic brain injury that is classified into concussion and contusion. Brain concussion is temporary unconsciousness or confusion caused by a blow on the head without pathological changes, and contusion is a brain injury with hemorrhage and broad extravasations. In this study, we investigated the time-dependent changes of apoptosis in hippocampus after brain concussion and contusion using rat models. We generated the concussion by dropping a plumb on the dura from a height of 3.5 cm and the contusion by cauterizing the cerebral cortex. SBD was evaluated in the hippocampus by histopathological analyses and measuring caspase-3 activity that induces apoptotic neuronal cell death. The frequency of abnormal neuronal cells with vacuolation or nuclear condensation, or those with DNA fragmentation was remarkably increased at 1 hr after concussion (about 30% for each abnormality) from the pre-injury level (0%) and reached the highest level (about 50% for each) by 48 hrs, whereas the frequency of abnormal neuronal cells was increased at 1 hr after contusion (about 10%) and reached the highest level (about 40%) by 48 hrs. In parallel, caspase-3 activity was increased sevenfold in the hippocampus at 1 hr after concussion and returned to the pre-injury level by 48 hrs, whereas after contusion, caspase-3 activity was continuously increased to the highest level at 48 hrs (fivefold). Thus, anti-apoptotic-cell-death treatment to prevent SBD must be performed by 1 hr after concussion and at latest by 48 hrs after contusion.

It is well known that lymphocytes from patients with advanced-stage cancer have impaired immune responsiveness and that type1 T lymphocyte subsets in tumor bearing hosts are suppressed. Treg have been reported to comprise a subgroup which inhibits T cell mediated immune responses. In the present study, the percentage of Treg, Th1 and Tc1 in the peripheral blood of tumor bearing dogs with or without metastases was evaluated. The percentages of Th1 and Tc1 in dogs with metastatic tumor were significantly less, and that of Treg was significantly greater, than those of dogs without metastatic tumor. The percentage of Treg showed an inverse correlation with that of Th1 and Tc1 in tumor bearing dogs. It was concluded that an increase in Treg in the peripheral blood of dogs with metastatic tumor may induce suppression of tumor surveillance by the Type1 immune response and lead to metastasis of tumor[0][0].[0].

American Journal of Emergency Medicine xxx (2015) xxx–xxx Contents lists available at ScienceDirect American Journal of Emergency Medicine journal homepage: www.elsevier.com/locate/ajem Controversies Editorial: Ambulance Diversion: the Con Perspective Yuko Nakajima, MD ⁎ , Gary M. Vilke, MD Department of Emergency Medicine, UC San Diego Health System, 200 West Arbor Dr #8676 San Diego, 92103 As the ultimate safety net, emergency departments (EDs) are expected to care for any patient, at any time, under any circumstances. When EDs are overwhelmed in periods of surge, one solution is to redistribute pa- tients. A commonly used method for redistributing patients is ambulance diversion. Ambulance diversion is not a new phenomenon and, over time, has become commonly used by EDs to address the growing problem of ED overcrowding and saturation [1]. As ED visits have increased through the years, ambulance diversion has evolved into standard practice in many health systems. Along with this, ambulance diversion has always involved controversy over whether,overall, it is beneficial or detrimental to the pa- tient, emergency medical services (EMS) systems, and hospitals. In some circumstances, EDs and hospitals may occasionally be overwhelmed and may not be able to provide optimal patient care. Di- version may be viewed as a necessary mechanism to avoid the substan- dard situations in the ED represented by crowding, boarding, and hallway beds. It is used as a way to direct patients away from one’s hos- pital when waiting rooms are crowded and ED beds are full. However, in many circumstances, the patient is being directed to another facility that is just as busy and impacted but now further away, keeping pa- tients in the back of ambulances longer and thus keeping ambulances out of service for longer periods of time. Ambulances being out of ser- vice have been associated with delays in response to the next emergen- cy because there are fewer units in service and the available ambulances have to travel further to reach patients. These delays have also attribut- ed to adverse medical outcomes. Recent data support that ambulance diversion does not work to ease ED overcrowding and may result in the worsening of patient care. Stud- ies have shown that ambulance diversion can lead to delays for patients in obtaining definitive medical care given the increased field time and transport time and distances [2,3] leading to adverse outcomes includ- ing death. Diversion increases traffic accident risks and may malposition EMS resources. In addition, some patients may require specialty re- sources only available at the requested hospital and may not be able to receive them at an alternate destination. There is a possible association between ED diversion and increased mortality in certain populations of patients, such as trauma and acute myocardial infarction patients [4,5]. Studies like these led to American College of Emergency Physicians forming an EMS taskforce to review the topic of ambulance diversion. The taskforce penned a position paper that stated, “Ambulance diversion should occur only after the hospital has exhausted all internal mechanisms to avert a diversion, which includes calling in overtime staff” [6]. The National Association of EMS Physicians also states that “… ambulance diversion has not been shown to improve ED patient throughput” [7]. It has been demonstrated that if one hospital goes into ED diversion status, an oscillatory phenomenon may occur, where the one hospital going on bypass causes a neighboring hospital to receive a dispropor- tionate share of patients and is then forced to go onto bypass itself. This can create a domino effect impacting other hospitals nearby or, if there are no other hospitals to receive the patients, forcing the original hospital to accept more patients until it again gets impacted and goes back onto bypass. The cycle continues ad infinitum [8]. During this time of diversion, the hospital is receiving its own patients as well as pa- tients who originally had requested another hospital as a destination. These patients will arrive to a hospital that does not have immediate ac- cess to medical records, study results, private physicians, and some- times not even an inpatient bed being held for that patient for admission. Countless times, patients arrive to the “wrong” hospital be- cause of diversion and have to be transferred back to the original re- quested destination for admission. And this transfer occurs after possibly an unnecessary workup and evaluation, as well as taking up valuable ED bed time to complete the evaluation, transfer call process, and wait-time for a transport team to remove the patient from the bed and transfer said patient to the hospital that they should have gone in the first place. Hours of physician, nursing, and administrative time are wasted. This does not even quantify the inconvenience and frustration to the patient and families. In the end, the patients ultimately end up at the originally requested hospital, but not until after time and health care dollars are wasted. While this is happening at the receiving hospital, patients requesting said facility end up at the “wrong” hospital, thus creating the same inefficien- cies there. And so the oscillating cycle continues, even leading to defensive ambulance diversion, where the second hospital, though not at saturation status, would go on diversion when hearing that the first hospital just went on diversion. After observing the oscillatory phenomenon, two hos- pitals that collaborated and committed to staying off ambulance diversion for a week were able to demonstrate that this oscillating effect goes away, patients get to the “right” hospital the first time, and still all of the patients get seen without any detriment to patient care [8]. Follow-up work quantified at a more regional level involving multi- ple hospitals working together to collectively stay off ambulance diver- sion demonstrated that this can be done safely with no reported adverse effects to patient care. All of the patients still get seen in the collective group of EDs, but the patients get to the correct hospital the first time [9]. This eliminates the ineffectiveness as described above for patients not being delivered to their requested medical home. San Diego County took the success of these two regional short-trial successes to the next level in 2002. After ambulance diversion was http://dx.doi.org/10.1016/j.ajem.2015.03.005 0735-6757/© 2015 Elsevier Inc. All rights reserved. Please cite this article as: Nakajima Y, Vilke GM, Editorial: ambulance diversion: the con perspective, Am J Emerg Med (2015), http://dx.doi.org/ 10.1016/j.ajem.2015.03.005

We report an effective method for mouth washing after inhalation of corticosteroids for the prevention of local adverse effects such as hoarseness and oropharyngeal candidiasis. This method involves gargling and rinsing immediately after inhalation, repeated at least twice. We performed a questionnaire survey on mouth washing after inhalation of corticosteroids of 19 inpatients who used inhaled corticosteroids at the University of Tokyo Hospital. The questions concerned: 1) awareness of local adverse effects of inhaled corticosteroids; 2) gargling and rinsing habits; 3) repeating mouth washing at least twice; and 4) mouth washing immediately after inhalation. The percentage of patients correctly performing the individual maneuvers were: 1) 63.2%; 2) 36.8%; 3) 36.8%; and 4) 63.2%. The percentage of patients performing our recommended method of mouth washing (all four elements) was 11%. These results suggest that patients receiving inhaled corticosteroids poorly comprehend mouth washing procedures after inhalation of corticosteroids. It is important that pharmacists advise patients on the correct method of mouth washing.

Gastrectomy or vagotomy may result in reactive hypoglycemia, which, in some cases, can reduce the plasma glucose levels to 30-40 mg/dl due to rapid digestion and absorption of food, especially carbohydrates. It also occurs sometimes in patients on hemodialysis, where it is a potentially lethal complication. Because insulin has a longer half-life due to lack of renal degradation, hypoglycemia can be induced by insulin in patients with renal failure. We treated a patient with frequent episodes of severe hypoglycemia, that were sometimes accompanied by convulsions. He had undergone total gastrectomy 8 years before and had been maintained on hemodialysis for 3 years. Hyperinsulinemia caused by oxyhyperglycemia associated with post-gastrectomy led to severe hypoglycemia in this patient because of the lack of renal insulin degradation. Since nutritional treatment did not successfully manage his reactive hypoglycemia, an alpha-glucosidase inhibitor, acarbose, was administered to treat his oxyhyperglycemia. This therapy was very effective and he has not had any recurrence of reactive hypoglycemia since the initiation of the therapy.

The antitumor effect and tumor levels of 5-fluoro-2'-deoxyuridylate (FdUMP) following oral administration of tetradecyl 2'-deoxy-5-fluoro-5'-uridylate (TT-62) were compared with those attained following intravenous (i.v.) or intraperitoneal (i.p.) administration of 5-fluorouracil (5-FU) or 5-fluoro-2'-deoxyuridine (FUdR) in BDF1 mice bearing murine mammary adenocarcinoma 755 and athymic mice bearing the transplantable human colon adenocarcinoma LS174T. Oral administration of TT-62 showed a stronger antitumor effect against adenocarcinoma 755 than FUdR. The maximum effect of TT-62 was similar to that of 5-FU. However, TT-62 and FUdR treatments were more effective than i.v. administration of 5-FU against LS174T. Thus, oral administration of TT-62 showed marked antitumor activity in both tumor systems. The maximum tolerated dose of FUdR resulted in a much higher level of free FdUMP in the LS174T tumor than that obtained with 5-FU. After oral administration of TT-62 the levels of FdUMP in the tumor were about 10 times those attained with 5-FU, but significantly lower than the levels obtained following i.v. administration of FUdR. With TT-62 the levels of FdUMP in the tumor reached their peak at 60 min following the administration and gradually decreased thereafter. However, FdUMP levels after administration of FUdR decreased rapidly. Three hours after the administration of TT-62 and for up to 24 h the FdUMP levels in the LS174T tumor were almost the same as after administration of FUdR, i.e. effective levels of FdUMP were maintained for a long time with TT-62.

Ten patients with chronic inflammatory arthropathy and the human T lymphotropic virus type I (HTLV-I) are described. These patients showed chronic persistent oligoarthritis, associated with proliferative synovitis, in large joints. The place of birth or residence of these patients was within the area endemic for adult T cell leukemia (ATL) and HTLV-I. The age at onset of articular symptoms tended to be higher in these patients than in typical rheumatoid arthritis patients. Anti-HTLV-I antibodies were detected in both sera and synovial fluids from all patients. Western blot analysis revealed antibodies to viral gag proteins (p19, p24, and p28). Atypical lymphocytes with nuclear indentations, consistent with ATL-like cells, were observed in both synovial fluid and synovial tissue. Furthermore, HTLV-I proviral DNA was integrated into the DNA of synovial fluid cells and synovial tissue cells. These findings suggest that HTLV-I might be involved in the pathogenesis of this unique arthropathy.

Effects of potassium thiocyanate (KSCN) on normal and neoplastic mammary development in female mice were studied. Administration of KSCN as drinking water (0.1 or 0.3%) for 12 weeks to 8-week-old SHN female mice resulted in the dose-related inhibition of development of normal mammary lobulo-alveolar system, hyperplastic alveolar nodules and spontaneous mammary tumors associated with marked decrease in plasma levels of triiodothyronine and thyroxine. On the other hand, the treatment affected little estrous cycles, ovarian structures, plasma prolactin levels and weights of body, anterior pituitary and adrenals. The incidence and number of pregnancy-dependent mammary tumors in GR/A female mice were also significantly suppressed by the similar treatment with KSCN with no influence on reproductivity as well as pituitary levels of prolactin and growth hormone. These results suggest that KSCN does not affect the secretion of pituitary and ovarian mammotropic hormones and that thyroid hormones are principally involved in normal and neoplastic development of mammary glands.

Daily subcutaneous injection of 200 microgram 5 alpha-dihydrotestosterone to SHN female mice for the first 5 days of postnatal life resulted in the stimulation of normal and neoplastic mammary development at advanced ages and it also induced the ovarian anovulatory syndrome and stimulated pituitary prolactin secretion. Daily subcutaneous injections of 1 mg 5 alpha-dihydrotestosterone to pregnant mice from day 12 to day 15 of pregnancy (prenatal treatment) had no effects on their offspring. Long-term effects of 5 alpha-DHT on normal and neoplastic mammary development in mice were generally not so marked as those observed previously with 5 beta-dihydrotestosterone which is biologically inactive in the adult.

Simple and partial correlation coefficients between incidence or onset age of spontaneous mammary tumors and several reproductive characteristics were examined during the period between the 2 nd and the 30 th generations of brother × sister mating in SLN female mice as a possible step to evaluate the role of reproductivity in mammary tumorigenesis. Mammary tumor incidence had a simple negative correlation with delivery interval and positive simple correlations with pup's weights at days 12 and 20 or pup's growth rate at day 20 as indices of lactational performance. However, the partial correlation coefficient between mammary tumor incidence and delivery interval was not statistically significant when any index of lactational performance was held constant and vice versa . These results indicate that it is difficult to determine which of these characteristics is more primary for mammary tumor incidence, while both participate in this process. No significant simple correlations were observed between onset age of mammary tumors and any reproductive characteristics, suggesting little dependence of progression of this type of mammary tumors on reproductivity.

痛風,痛風腎を合併したBartter症候群の1例を経験した,症例は17才の女性で,手指関節の変形腫脹にて入院,高尿酸血症・低K性アルカローシス,アンジオテンシン-IIに対する昇圧反応の低下が認められた,腎生検では,傍糸球体装置の過形成および遠位尿細管内尿酸結晶が確認された,本症候群では高尿酸血症,痛風の合併頻度が高いとされているが,本邦での報告例は少なく,また組織学的に痛風腎を証明しえた症例の報告はない.

A hepatoma comprised of carcinomatous and sarcomatous proliferation has been considered as collision or carcinoma with sarcomatous proliferation. In this report, an autopsy case of primary hepatocellular carcinoma showing almost equal amount of carcinomatous and sarcomatous proliferations is presented. Serial sections from the tumor showed the frequent transition of the figure from carcinoma to sarcoma, justifying the diagnosis of hepatocellular carcinoma with sarcomatous proliferation. When compared with the usual hepatocellular carcinoma, metastasis with sarcomatous figure was more extensive and both ventricles and atriums of the heart, skin, and intestinal tract were involved. A sarcomatous proliferation in hepatocellular carcinoma and manner of metastasis are discussed with a review of the pertinent literature. Acta pathol. jpn. 34: 839∼845, 1984.

T helper type 1 cell (Th1)/Th2 imbalance has been observed in a variety of pathological conditions, including malignant diseases. We evaluated the Th1/Th2 in peripheral blood Th cells by means of intracytoplasmic cytokine analysis in 11 dogs with advanced malignant tumor; four of them showed metastatic tumor. The percentage of Th1 was significantly lower and the percentage of Th2 was significantly higher in diseased dogs compared to healthy dogs. The percentage of Th1 in three patients with metastatic tumor was significantly lower than that in the patients with non-metastatic tumor. We conclude that the Th1/Th2 balance was polarized to Th2 in dogs with cancer.