Risk factors for adverse drug reactions in older inpatients of geriatric wards at admission: Multicenter study.

AIM: To investigate the characteristics of adverse drug reactions (ADR) and their risk factors among very old patients in five geriatric wards in Japan. METHODS: A retrospective observational multicenter study was carried out to investigate factors related to ADR in older inpatients from geriatric wards of five university hospitals in Japan. Data including drugs profile and short-form comprehensive geriatric assessment were obtained from medical charts. ADR were identified from geriatrician's reports. For each ADR, symptoms and causal drugs were clarified, and factors associated with ADR were analyzed statistically. RESULTS: In 1155 patients (52.5% women, mean age 82.8 ± 7.0 years), the proportion with ADR was 15.4%. There was a great variety of signs and symptoms of ADR, and a great variety of drugs suspected to be the cause of ADR. On multiple logistic regression analysis, ADR was significantly associated with an increase in drugs (odds ratio 1.11, 95% CI 1.07-1.16) and emergency admission (odds ratio 2.76, 95% CI 1.82-4.15). Receiver operating characteristic curve analysis showed that the optimal cut-off number of drugs for predicting ADR was ≥7. CONCLUSIONS: In geriatric inpatients, polypharmacy (especially ≥7 drugs) and emergency admission were associated with ADR. Because there was a great variety of ADR in the study, clinicians must consider reviewing all drugs to prevent adverse drugs reactions during admission in this vulnerable population. Geriatr Gerontol Int 2019; ••: ••-••. Geriatr Gerontol Int 2020; 20: 144-149.

A case of upside-down stomach that was effectively treated by postprandial repositioning.

An 88-year-old woman with a history of stomach perforation and lumbar compression fracture was admitted to our hospital with a chief complaint of continuous vomiting, which she had experienced since the previous day. She showed vomiting, spontaneous pain and tenderness from the epigastric fossa through the left flank. In addition, she had marked kyphosis. On a CT scan, although the fornix was located in the abdominal cavity, the antrum and body had escaped into the thoracic cavity. A large volume of gastric content was observed. The patient was diagnosed with upside-down stomach from gastric volvulus and a hiatal hernia. Although we recommended surgery, the patient and her family did not agree with it. Thus, conservative therapy was selected. The patient's symptoms showed a significant improvement after the placement of a nasogastric tube, fasting and fluid therapy. After stabilization, an endoscopic examination was performed. The release of the gastric volvulus was confirmed and the nasogastric tube was removed. We instructed the patient to perform postprandial repositioning, which was based on the running shape of the digestive tract with the goal of achieving the passage of food and preventing a relapse of vomiting. The patient was instructed to first place herself in the right lateral decubitus position and then the prone position after eating. There was no recurrence of vomiting after the patient resumed eating. She was therefore discharged from our hospital. Upside-down stomach is usually an indication for surgery. However, in elderly patients, the fixation of the stomach to the abdominal wall has been reported to occur after endoscopic reduction, and conservative treatment was thus selected in this case.We herein reported a case in which postprandial repositioning was used to treat upside-down stomach.

[Investigation of the Renal Function Evaluation in the Living Donor Renal Transplantation Candidate at Our Center].

In Japan, the number of living renal transplant donors with medical complications has been increasing in recent years due to the.aging of donors. It is important to assess donor renal function properly before donation to ensure donor safety. This study aimed to assess different renal function measures of donors, includ- ing serum creatinine (Cr), creatinine clearance (Ccr), estimated glomerular filtration rate (eGFR), and inulin clearance (Cin). The mean Cr and eGFR values of 64 donors before surgery and at 1 month, 1 year, and 3 years after surgery were 0.74, 1.15, 1.13, and 1.05 mg/dL, respectively, and 71.7, 42.4, 44.9, and 49.5 mL/min/1.73m2, respectively. Values of eGFR 3 years after surgery in 20 out of 36 donors (55.6%) were less than 50 mL/min/1.73m2, showing that moderately decreased levels of GFR persist for a long time after donation. The preoperative renal function of 20 candidate donors was evaluated based on Cr, Ccr, eGFR, and Cin. The mean preoperative values were Cr 0.74 mg/dL, eGFR 71.9 mL/min/1.73m2, Ccr 137.3 mL/min, and Cin 92.9 mL/min. Ccr overestimated Cin in 18 out of 20 donors (90%) and eGFR underestimated Cin in 16 donors (80%). Cin measurements are complicated, which can lead to human errors in measurement. Conversely, eGFR measurements are simple but are inferior to Cin in terms of accuracy; therefore, the pre- operative renal function of donors should be evaluated by Cin, combined with other tests as much as possible to ensure a safe living renal transplant. [Original].

Correlation between the serum eicosapentanoic acid-to-arachidonic acid ratio and the severity of cerebral white matter hyperintensities in older adults with memory disorder.

AIM: The relationships of n-3 polyunsaturated fatty acids, such as docosahexaenoic acid and eicosapentaenoic acid (EPA), to stroke and cardiovascular events have been studied extensively. The present study was undertaken to analyze the relationships of the severity of cerebral white matter hyperintensities (WMH) to the blood polyunsaturated fatty acids level and the ratio of serum EPA level to the serum arachidonic acid (AA) level (EPA/AA ratio) among older adults. METHODS: A total of 150 patients underwent diagnostic magnetic resonance imaging and blood sampling under the fasting state. In regard to WMH, the periventricular hyperintensities and deep white matter hyperintensities were rated according to the Fazekas classification. The serum docosahexaenoic acid, EPA, AA, dihomo-γ-linolenic acid and EPA/AA ratio were compared in relation to the grade of severity of WMH. Furthermore, multiple regression analysis was carried out with age, sex and atherosclerosis risk factors (hypertension, diabetes mellitus, hyperlipidemia, smoking status) as the covariables, serum polyunsaturated fatty acids level as an independent variable and Fazekas grade as the dependent variable. RESULTS: A rise of the periventricular hyperintensities grade was associated with a significant reduction of the mean EPA level (P < 0.05) and EPA/AA ratio (P < 0.05). The multiple regression analysis identified a significant negative correlation between the periventricular hyperintensities grade and the serum EPA/AA ratio (ß = -0.215, P < 0.05). CONCLUSION: These results suggest that the serum EPA/AA ratio have an important role in the formation and progression of WMH.

[A case of isolated pulmonary valve infective endocarditis in a 78-year-old woman].

A 78-year-old woman was admitted to our hospital with lumbago. Her activities of daily living had previously been completely independent. However, she developed temporary chills in January 2009, that improved without treatment, but recurred on February 7, 2009 in association with left lumbago and loss of appetite. She was then referred to our hospital with a disturbance of consciousness and high fever on February 14. A blood test performed on admission revealed an elevated inflammatory response, coagulation disorder and low platelet count, and abdominal computed tomography demonstrated findings suggestive of pyogenic spondylitis. The patient was therefore admitted and treated with antibiotic therapy; however, she died on day 8 due to complications of disseminated intravascular coagulation. An autopsy showed isolated pulmonary valve endocarditis. The patient's history was later found to include regular dental treatment, and the same Streptococcus group G was detected in cultures of the sputum, blood and vegetation. It is important to interview patients regarding their history of dental treatment, particularly elderly individuals with fever of unknown origin.

Relationship between interleukin-6 and cerebral deep white matter and periventricular hyperintensity in elderly women.

AIM: We evaluated the relationships between serum levels of high-sensitivity C-reactive protein (hsCRP) and interleukin (IL)-6 with the severity of leukoaraiosis. METHODS: One hundred and thirty-seven elderly women who attended the Center for Comprehensive Care on Memory Disorders at Kyorin University Hospital were enrolled in this study. Leukoaraiosis was assessed by periventricular hyperintensity (PVH) score and deep white matter hyperintensity (DWMH) score. RESULTS: Serum log IL-6 level correlated with PVH and DWMH scores, but hsCRP did not. By multinomial logistic analysis, IL-6 was significantly related to DWMH score, independent of age and systolic blood pressure. CONCLUSION: IL-6 is presumably an important marker of leukoaraiosis, as is the case with silent cerebral infarction.

Plasma sex hormone levels and mortality in disabled older men and women.

AIM: To investigate the relationship between circulating sex hormone levels and subsequent mortality in disabled elderly. METHODS: This prospective observational study was comprised of 214 elderly subjects aged 70-96 years (117 men and 97 women; mean ± standard deviation age, 83 ± 7 years), receiving services at long-term care facilities in Nagano, Japan. All-cause mortality by baseline plasma sex hormone levels was measured. RESULTS: After excluding deaths during the first 6 months, 27 deaths in men and 28 deaths in women occurred during a mean follow up of 32 months and 45 months (up to 52 months), respectively. Mortality rates differed significantly between high and low testosterone tertiles in men, but did not differ significantly between middle and low tertiles. Compared with subjects in the middle and high tertiles, men with testosterone levels in the low tertile (<300 ng/dL) were more likely to die, independent of age, nutritional status, functional status and chronic disease (hazard ratio [HR] = 3.27, 95% confidence interval [CI] = 1.24-12.91). In contrast, the low dehydroepiandrosterone sulfate (DHEA-S) tertile was associated with higher mortality risk in women (multivariate adjusted HR = 4.42, 95% CI = 1.51-12.90). Exclusion of deaths during the first year and cancer deaths had minimal effects on these results. DHEA-S level in men and testosterone and estradiol levels in women were not related to mortality. CONCLUSION: Low testosterone in men and low DHEA-S in women receiving care at facilities are associated with increased mortality risk, independent of other risk factors and pre-existing health conditions.

Effects of dehydroepiandrosterone supplementation on cognitive function and activities of daily living in older women with mild to moderate cognitive impairment.

AIM: There is little evidence that dehydroepiandrosterone (DHEA) has beneficial effects on physical and psychological functions in older women. We investigated the effect of DHEA supplementation on cognitive function and ADL in older women with cognitive impairment. METHODS: A total of 27 women aged 65-90 years (mean ± standard deviation, 83 ± 6) with mild to moderate cognitive impairment (Mini-Mental State Examination, MMSE; 10-28/30 points), receiving long-term care at a facility in Japan were enrolled. Twelve women were assigned to receive DHEA 25 mg/day p.o. for 6 months. The control group (n = 15) matched for age and cognitive function was followed without hormone replacement. Cognitive function was assessed by MMSE and Hasegawa Dementia Scale-Revised (HDS-R), and basic activities of daily living (ADL) by Barthel Index at baseline, 3 and 6 months. Plasma hormone levels including testosterone, DHEA, DHEA-sulfate and estradiol were also followed up. RESULTS: After 6 months, DHEA treatment significantly increased plasma testosterone, DHEA and DHEA-sulfate levels by 2-3-fold but not estradiol level compared to baseline. DHEA administration increased cognitive scores and maintained basic ADL score, while cognition and basic ADL deteriorated in the control group (6-month change in DHEA group vs control group; MMSE, +0.6 ± 3.2 vs -2.1 ± 2.2, P < 0.05; HDS-R, +2.8 ± 2.8 vs -0.3 ± 4.1, P < 0.05; Barthel Index, +3.7 ± 7.1 vs -2.7 ± 4.6, P = 0.05). Among the cognitive domains, DHEA treatment improved verbal fluency (P < 0.05). CONCLUSION: DHEA supplementation in older women with cognitive impairment may have beneficial effects on cognitive function and ADL.

Association of plasma sex hormone levels with functional decline in elderly men and women.

AIM: We aimed to determine whether plasma sex hormone levels are associated with activities of daily living (ADL), cognition, depression and vitality in elderly individuals with functional decline. METHODS: Two hundred and eight consecutive persons 70 years or older (108 men and 100 women; mean +/- standard deviation, 81 +/- 7 years) with a chronic stable condition, receiving long-term care at a long-term care facilities located in Nagano Prefecture, Japan, were enrolled. Plasma total testosterone, free testosterone (only in men), dehydroepiandrosterone (DHEA), DHEA sulfate (DHEA-S) and estradiol levels were determined in the morning after an overnight fast. Comprehensive geriatric assessment was performed including basic ADL by Barthel Index, instrumental ADL, cognitive function by Hasegawa Dementia Scale--Revised, mood by Geriatric Depression Scale and ADL-related vitality by Vitality Index. RESULTS: Simple regression analysis showed that, in men, plasma total and free testosterone levels were associated with basic ADL (R = 0.292 and R = 0.282), instrumental ADL (R = 0.261 and R = 0.408), cognitive function (R = 0.393 and R = 0.553) and vitality (R = 0.246 and R = 0.396), while DHEA(-S) was associated with cognitive function, and estradiol with cognitive function as well as vitality. In women, the only significant correlation was between DHEA(-S) and basic ADL. Adjustment for age and nutritional markers did not influence the associations of plasma sex hormone levels with functional scores except for that of free testosterone with Barthel Index. CONCLUSION: These results suggest that sex hormones have sex-specific associations with physical and neuropsychiatric functions in elderly individuals, and that endogenous testosterone is related to global function in elderly men.

Raloxifene analogue LY117018 suppresses oxidative stress-induced endothelial cell apoptosis through activation of ERK1/2 signaling pathway.

A selective estrogen receptor modulator, raloxifene, has been shown to reduce cardiovascular events in relatively high-risk postmenopausal women with osteoporosis. However, the mechanisms by which raloxifene exerts a pharmacological effect on cardiovascular organs have not been fully elucidated. The present study was designed to examine whether the raloxifene analogue, 6-hydroxy-2-(p-hydroxyphenyl)-benzo(b) thien-3-yl-p-(2-(pyrrolidinyl)ethoxy phenyl ketone (LY117018), could inhibit apoptosis and to clarify the signaling pathway in vascular endothelial cells. LY117018 significantly inhibited hydrogen peroxide-induced apoptosis in bovine carotid artery endothelial cells. The anti-apoptotic effect of LY117018 was abolished by an estrogen receptor antagonist, 7alpha,7beta-(9[(4,4,5,5,5-Pentafluoropentyl)sulfinyl]nonyl) estra-1,3,5(10)-triene-3,17-diol (ICI 182,780). Mitogen-activated protein kinases (MAPK), including p38, c-Jun N-terminal kinase (JNK) and extracellular signal-regulated protein kinase1/2 (ERK1/2), and Akt, have been shown to act as apoptotic or anti-apoptotic signals. Phosphorylation of p38, JNK, ERK1/2 and Akt was examined. LY117018 increased ERK1/2 phosphorylation but did not enhance the phosphorylation of p38, JNK, or Akt. The anti-apoptotic effect of LY117018 was prevented by treatment with 2-[2'-amino-3'-methoxyphenyl]-oxanaphthalen-4-one (PD98059), an upstream inhibitor of ERK1/2. LY117018 stimulated an increase in ERK1/2 phosphorylation, which was diminished by ICI 182,780. The activation of ERK/1/2 by LY117018 was not inhibited by the transcription inhibitor, actinomycin D. These results suggest that estrogen receptors and the ERK1/2 signaling pathway are involved in the anti-apoptotic action of LY117018 in vascular endothelial cells.

Adiponectin antagonizes stimulatory effect of tumor necrosis factor-alpha on vascular smooth muscle cell calcification: regulation of growth arrest-specific gene 6-mediated survival pathway by adenosine 5'-monophosphate-activated protein kinase.

Adiponectin exhibits diverse protective effects against atherogenesis and antagonizes many effects of TNFalpha. Here, we investigated the effect of adiponectin and TNFalpha on vascular calcification, a critical event in the development and progression of vascular disease. In human aortic smooth muscle cells (HASMC), TNFalpha augmented inorganic phosphate (Pi)-induced calcification, whereas adiponectin significantly suppressed it and abolished the stimulatory effect of TNFalpha in a concentration-dependent manner. Similarly, adiponectin ameliorated the accelerating effect of TNFalpha on Pi-induced apoptosis, the essential process of HASMC calcification. Furthermore, these effects of TNFalpha and adiponectin were associated with AMP-activated protein kinase (AMPK)-dependent growth arrest-specific gene 6 (Gas6) expression and Akt signaling. The AMPK activator, 5-aminoimidazole-4-carboxamide ribonucleoside (AICAR), induced phosphorylation of AMPK and significantly inhibited Pi-induced calcification in HASMC. Conversely, pharmacological inhibition of AMPK by compound C blocked both AMPK activation and the inhibitory effect of adiponectin on calcification, providing evidence that AMPK plays a regulatory role in vascular calcification. Reporter assay revealed that adiponectin restored Gas6 promoter activity decreased by TNFalpha, and the effect of adiponectin was abrogated by compound C. These results demonstrate that adiponectin antagonizes the stimulatory effect of TNFalpha on vascular calcification by restoration of the AMPK-dependent Gas6-mediated survival pathway.

Gas6/Axl-PI3K/Akt pathway plays a central role in the effect of statins on inorganic phosphate-induced calcification of vascular smooth muscle cells.

Apoptosis is essential for the initiation and progression of vascular calcification. Recently, we showed that 3-hydroxy-3-methylglutaryl (HMG) CoA reductase inhibitors (statins) have a protective effect against vascular smooth muscle cell calcification by inhibiting apoptosis, where growth arrest-specific gene 6 (Gas6) plays a pivotal role. In the present study, we clarified the downstream targets of Gas6-mediated survival signaling in inorganic phosphate (Pi)-induced apoptosis and examined the effect of statins. We found that fluvastatin and pravastatin significantly inhibited Pi-induced apoptosis and calcification in a concentration-dependent manner in human aortic smooth muscle cells (HASMC), as was found with atorvastatin previously. Gas6 and its receptor, Axl, expression were downregulated in the presence of Pi, and recombinant human Gas6 (rhGas6) significantly inhibited apoptosis and calcification in a concentration-dependent manner. During apoptosis, Pi suppressed Akt phosphorylation, which was reversed by rhGas6. Wortmannin, a specific phosphatidylinositol 3-OH kinase (PI3K) inhibitor, abolished the increase in Akt phosphorylation by rhGas6 and eliminated the inhibitory effect of rhGas6 on both Pi-induced apoptosis and calcification, suggesting that PI3K-Akt is a downstream signal of the Gas6-mediated survival pathway. Pi reduced phosphorylation of Bcl2 and Bad, and activated caspase 3, all of which were reversed by rhGas6. The inhibitory effect of statins on Pi-induced apoptosis was accompanied by restoration of the Gas6-mediated survival signal pathway: upregulation of Gas6 and Axl expression, increased phosphorylation of Akt and Bcl2, and inhibition of Bad and caspase 3 activation. These findings indicate that the Gas6-mediated survival pathway is the target of statins' effect to prevent vascular calcification.

The role of apheresis therapy for ABO incompatible living donor liver transplantation: the Kyoto University experience.

Liver transplantation is a radical surgical therapy for end-stage liver disease. Although in Japan organ transplantation from brain-dead donors (BDD) has been allowed since October 1997, to date, only 29 liver grafts from BDD have been obtained. Thus, most of the liver transplantations carried out use living-donor liver transplantation (LDLT), and BDD liver transplantation is only used in rare cases. In order to carry out LDLT more safely, apheresis (plasmapheresis: PE) plays a major role in our country because of the prevalence of LDLT wherein later re-transplantation is difficult. Thus, because of a limited donor supply and because the needs of patients with end-stage liver disease is critical, use of grafts from ABO-incompatible (ABO-I) donors might be the only available option. From June 1990 to November 2005, 1100 patients underwent 1151 LDLT cases at Kyoto University Hospital. Additionally, 159 LDLT cases (13.8%) received ABO-I living-donor liver grafts. The role of apheresis in ABO-I LDLT is the reduction of antibody titers such as anti-A or anti-B antibody. We carry out preoperative PE as a general rule for ABO-I cases, and the recipient's antibody level against the donor's blood type is decreased to one eighth of the baseline value before LDLT. Until now, baseline immunosuppressive agents included steroids, tacrolimus and cyclophosphamide. At first, splenectomy was carried out during surgery to suppress antibody production, and intraportal (PV) infusion therapy was carried out to control local disseminated intravascular coagulation (DIC) occurring in ABO-I grafts. At that time, three drugs-methylprednisolone, prostaglandin E1 (PGE1), and gabexate mesylate (FOY) were infused continuously for 3 weeks after LDLT. At present, instead of PV infusion therapy, hepatic artery infusion therapy without splenectomy is adopted because of portal thrombosis, and two drugs- methylprednisolone and PGE1- are infused continuously for 3 weeks following LDLT. Recently, we introduced anti-CD20 monoclonal antibody (Rituximab) instead of splenectomy for B cell deletion before ABO-I LDLT. In the present article, we describe the role of apheresis around ABO-I LDLT based on our recent experiences.

Single center experience of 39 patients with preoperative portal vein thrombosis among 404 adult living donor liver transplantations.

Living donor liver transplantation (LDLT) for patients with portal vein thrombosis (PVT) involves technical difficulty. The aim of this research was to analyze their preoperative diagnosis of PVT, operative procedures, and postoperative courses of patients with preoperative PVT. Thirty-nine patients of 404 adult patients (9.7%) undergoing LDLT in our hospital from 1996 June to 2004 December had PVT at their transplantation. Twenty-nine patients had intractable ascites, 21 had gastrointestinal bleeding, and 18 had encephalopathy. The thrombus was located in the portal trunk in 23, in the portal trunk and superior mesenteric vein (SMV) in 7, and developed into the SMV and the splenic vein in 8. The occlusive grade was partial in 29, and complete in 10 patients. The thrombus was removed by a simple technique, and eversion and/or incision technique, or total removal of the portal vein (PV). The PV was reconstructed with the thrombectomized native PV, with an interposed vein graft, or porto-caval hemitransposition. Advanced PVT had a significant impact on blood loss and hospital mortality. Three out of 10 patients with residual PVT required radiological and/or surgical intervention after transplantation. In conclusion, thorough planning is essential for a successful LDLT outcome for patients with preexisting PVT.

Statins protect human aortic smooth muscle cells from inorganic phosphate-induced calcification by restoring Gas6-Axl survival pathway.

Vascular calcification is clinically important in the development of cardiovascular disease. It is reported that hydroxy-3-methylglutaryl coenzyme A (HMG CoA) reductase inhibitors (statins) inhibited vascular calcification in several clinical trials. However, the mechanism is poorly understood. Recently, it has been suggested that apoptosis is one of the important processes regulating vascular smooth muscle cell (VSMC) calcification. In this study, we investigated the effect of statins on VSMC calcification by testing their effect on apoptosis, focusing in particular on regulation of the survival pathway mediated by growth arrest-specific gene 6 (Gas6), a member of the vitamin K-dependent protein family, and its receptor, Axl. In human aortic smooth muscle cells (HASMC), statins significantly inhibited inorganic phosphate (Pi)-induced calcification in a concentration-dependent manner (reduced by 49% at 0.1 micromol/L atorvastatin). The inhibitory effect of statins was mediated by preventing apoptosis, which was increased by Pi in a concentration-dependent manner, and not by inhibiting sodium-dependent phosphate cotransporter (NPC) activity, another mechanism regulating HASMC calcification. Furthermore, the antiapoptotic effect of statins was dependent on restoration of Gas6, whose expression was downregulated by Pi. Restoration of Gas6 mRNA by statins was mediated by mRNA stabilization, and not by an increase in transcriptional activity. Suppression of Gas6 using small interfering RNA and the Axl-extracellular domain abolished the preventive effect of statins on Pi-induced apoptosis and calcification. These data demonstrate that statins protected HASMC from Pi-induced calcification by inhibiting apoptosis via restoration of the Gas6-Axl pathway.

[The role of statins in vascular and valvular calcification].

Vascular calcification, such as coronary and aortic calcification, is a significant feature of vascular pathology, since this lesion is associated with cardiovascular disease. Statins are potent serum cholesterol-reducing drugs, which decrease the risk of cardiovascular diseases. Besides reducing serum cholesterol levels, statins are shown to decrease the rate of coronary artery calcification by unidentified mechanism. Though previous observational studies have shown that statins decrease the rate of calcific aortic valve stenosis, recent prospective study have revealed that statins are not effective against the progression of calcific aortic stenosis. We need to establish the role of statins in the prevention of aortic valve stenosis with long-term, large-scale, randomized controlled study.

Angiotensin converting enzyme inhibitor attenuates oxidative stress-induced endothelial cell apoptosis via p38 MAP kinase inhibition.

BACKGROUND: The effects of angiotensin converting enzyme (ACE) inhibitors on oxidative stress-induced apoptosis of endothelial cells and the intracellular signaling were investigated. METHODS: Cultured endothelial cells derived from a bovine carotid artery were treated with H2O2 or TNF-alpha to induce apoptosis. Apoptosis was evaluated by DNA fragmentation and cell viability, p38 MAP kinase activity by Western blotting, and oxidative stress by formation of 8-isoprostane. The effects of ACE inhibitors were examined by adding them into the medium throughout the experiments. RESULTS: Apoptosis was attenuated by ACE inhibitors, temocapril and captopril, in a dose-dependent manner (1-100 micromol/l). H2O2 (0.2 mmol/l for 1.5 h) or TNF-alpha (10 ng/ml for 72 h) treatment stimulated the activities of p38 MAP kinase. Temocapril and captopril decreased the activity of p38 MAP kinase as well as 8-isoprostane formation induced by H2O2. A p38 MAP kinase inhibitor, SB203580, partially inhibited the effect of temocapril on apoptosis. CONCLUSIONS: These results suggest that ACE inhibitors protect endothelial cells from oxidative stress-induced apoptosis, and that p38 MAP kinase plays a critical role in the process.

[Malignant lymphoma manifested by fever of unexplained origin and pure red cell aplasia in an elderly patient].

A 76-year-old woman was admitted to the University of Tokyo Hospital in June 2002 because of fever of unexplained origin. She had suffered a high grade fever (above 39 degrees C) for 2 weeks. Initial evaluation revealed elevated CRP and pancytopenia. Bone marrow aspiration (BMA) was performed, and a diagnosis of pure red cell aplasia (PRCA) was made. One month later, she complained right hypochondrial pain, and aspiration from her enlarged gall bladder was performed. Her fever and PRCA ameliorated, and she was discharged in August, 2002. In April 2003, she was readmitted to our hospital because of the recurrence of high grade fever, elevation of CRP, and pancytopenia. BMA was performed and revealed diffuse large B cell lymphoma. In the case of extranodal lymphoma which only presents pyrexia, differentiation with other diseases is very difficult especially in the elderly. It is necessary to bear in mind the possibility that a hematological malignancy, especially malignant lymphoma, can be latent in elderly patient with fever of unknown origin.

The absence of platelet-derived growth factor-B in circulating cells promotes immune and inflammatory responses in atherosclerosis-prone ApoE-/- mice.

Both innate and adaptive immunity contribute to the progression of inflammatory-fibrotic lesions of atherosclerosis. Although platelet-derived growth factor (PDGF)-B has been investigated as a stimulant of smooth muscle cells in vascular diseases, its effects on the immune response during disease have not been evaluated in vivo. We used hematopoietic chimeras generated after lethal irradiation of ApoE-/- recipients to test the role of PDGF in atherosclerosis. Monocyte accumulation in early atherosclerotic lesions increased 1.9-fold in ApoE-/-/PDGF-B-/- chimeras. Lymphocytes from null chimeras showed a 1.6- to 2.0-fold increase in the number of activated CD4(+) T cells and a 2.5-fold elevation of interferon-gamma-secreting CD4(+) T cells on ex vivo challenge with modified low-density lipoprotein. Splenocyte transcript levels were also altered with a twofold decrease in interleukin-10 and 1.7- and 3.0-fold increases in interleukin-18 and CCR 5, respectively. These cellular and molecular changes were consistent with a shift to a proinflammatory phenotype in null chimeras. Our data also demonstrated for the first time the presence of a recently discovered family of negative regulators of innate and adaptive immunity, the suppressors of cytokine signaling (SOCS), in developing atherosclerotic lesions. Thus, our studies identify two independent negative immune regulatory pathways-PDGF-B and SOCS-that may help limit lesion expansion.

Living-donor liver transplantation for situs inversus: 2 case reports.

Two cases of living-donor liver transplantation performed in patients with situs inversus are reported. The authors discuss the operative management for a situs inversus recipient to undergo liver transplantation.